      BETA (Bulletin of Experiment Treatments for AIDS) Online - No. 22
      Published by the San Francisco AIDS Foundation - September 1994
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      Electronically distributed for the Global Electronic Network for
      AIDS (GENA) by AEGIS/San Juan Capistrano  *  714.248.2836  *  8N1
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      Individualized Therapy: An Emerging New Treatment Strategy 
      Ronald Baker, PhD

      Ronald Baker is editor of BETA.

      Recent media reports have painted a relentlessly gloomy picture of the
status of AIDS drug development. Yet much useful information on treatment
emerged at the 10th International Conference on AIDS in Yokohama, Japan
(August 7-12, 1994). Encouraging treatment developments presented in Yokohama
include the following:

      *   Recombinant human growth hormone therapy significantly increases
          weight gain as represented by fat-free lean body mass among people
          with AIDS-related wasting.

      *   AZT treatment dramatically reduces the rate of HIV transmission
          from mother to infant. 

      *   Acyclovir co-treatment with anti-HIV therapy significantly
          increases survival time among people with AIDS.

      *   Oral ganciclovir appears to be an effective primary prophylaxis for
          cytomegalovirus disease.

      *   The protease inhibitor drug saquinavir reduces viral load and
          increases CD4 cell counts significantly more when used in a triple
          combination with AZT and ddC compared to 2 double combinations (AZT
          plus ddC or saquinavir plus AZT).

      *   Quantitative polymerase chain reaction (PCR) and branched chain DNA
          (bDNA) testing for measuring HIV load is expected to become a major
          new tool to help guide individual treatment decisions and to
          evaluate anti-HIV therapies in clinical studies.

      While it is important to recognize these treatment-related
accomplishments, it is equally important to acknowledge the pressing need for
a more effective strategy for the treatment of HIV infection and AIDS. AIDS
researchers, community physicians and activists are working together to
achieve this goal. The end result hoped for is better care and improved
clinical benefits for HIV positive individuals.

      ----------------------
      Individualized Therapy

      Today, a handful of physicians are already offering to their patients
components of a new treatment strategyinitially termed "Individualized
Therapy."  Within 6 months, more community physicians will offer elements of
Individualized Therapy to their HIV positive patients, as access increases to
powerful new diagnostic technologies and to more effective treatment
regimens. By the end of 1995, the majority of patients cared for by
mainstream physicians likely will have access to the primary ingredients of
this new treatment strategy. 

      There are 5 key components of Individualized Therapy: 

      1)  wider access to HIV RNA testing, a new medical technology that
          provides an accurate measure of HIV load in the blood plasma of
          HIV-infected patients;

      2)  tailoring anti-HIV treatment to each individual patient, based
          primarily on periodic measurement of HIV load; 

      3)  accelerated approval of and wider access to protease inhibitors and
          non-nucleoside reverse transcriptase inhibitors (NNRTI), 2 new
          classes of anti-HIV drugs that show promise when used in
          combination with the nucleoside analogues; 

      4)  more widespread use of 3- or 4-drug regimens that combine different
          classes of drugs;

      5)  early initiation of drug treatment, while the immune system is
          still relatively intact and capable of a strong response to HIV
          infection.

      To better elucidate the emerging paradigm of Individualized Therapy, it
will be helpful to describe briefly what is currently known about the
pathogenesis of HIV disease and its implications for treatment approaches. 

      ---------------------------
      Pathogenesis of HIV disease

      Scientists do not yet have a clear understanding of how HIV causes
disease, but there is continuing progress in this area. David Ho, MD, and
Robert Coombs, MD, published articles in 1989 suggesting that HIV actively
replicates during the earliest stages of infection and continues to do so
throughout all stages of the disease. Ho and Coombs and colleagues also found
a direct correlation between increasing viral replication and disease
progression. 

      In 1993, Anthony Fauci, MD, and Giuseppe Pantaleo, MD, of the National
Institute of Allergy and Infectious Diseases (NIAID) further elucidated these
groundbreaking findings. They discovered that HIV was present and actively
replicating in the lymphoid tissues of HIV positive individuals throughout
the course of HIV disease. Following initial infection, the amount of HIV in
the body ("viral burden") rises rapidly. In response, the immune system
mounts a vigorous defense that dramatically and quickly reduces the viral
load, but does not eliminate it. 

      Fauci and Pantaleo demonstrated that, over the long course of HIV
disease, through mechanisms that are incompletely understood, the proper
functioning of the lymph nodes and other lymphoid tissue critical to normal
immunity becomes gradually impaired.

      At the 1994 Yokohama AIDS Conference, Ashley Haase, MD, of the
University of Minnesota presented evidence that corroborates the findings of
Ho, Coombs, Fauci and Pantaleo concerning HIV pathogenesis. In addition,
Haase presented data showing for the first time that HIV infects a huge
reservoir of CD4 T-lymphocytes in the lymphoid tissue. Using in situ
hybridization polymerase chain reaction (PCR) with a double-labeled probe,
Haase found that, following the initial immune response, a large
reservoirabout 25%of CD4 T-lymphocytes within lymphoid tissue are
"latently" infected by HIV in the earliest stage of HIV disease. The
"resting" state of HIV inside these lymphocytes allows it to evade detection
by the hosts immune defenses. 

      Only 1% of HIV-infected lymphocytes in the lymph nodes are actively
replicating at any one time, according to Haase. However, there is low-level,
but continuing HIV gene expression in the large reservoir of latently
infected cells. Over time, these cells become activated, creating a cascade
of new viral replication and an increased viral load that eventually results
in disease progression. There is a slow but relentlessly progressive
depletion of CD4 T-cells, the bodys white blood cells responsible for
initiating the immune systems primary defense against invading
microorganisms. Immune system defenses are gradually weakened by this
process, and in time the immune system collapses entirely, leaving the body
vulnerable to opportunistic infections, malignancies and cancers.

      Haase's observation that in early disease 25% of the CD4 T-cells in the
lymph nodes and other lymphoid tissue are covertly infected with HIV is
extraordinarily significant. This means that about 100 billion latently
infected CD4 cells reside in the lymphoid tissue, undetected by immune system
defenses. One percent of CD4 cells/mm3 actively infected translates into 1
billion productively infected CD4 cells that contribute to the viral load in
the blood stream.

      Perhaps the most important conclusion to draw from Haases findings is
that the total HIV burden, comprised of latently and actively infected cells
in an infected individual, is enormous, and is rapidly established in the
earliest stage of infection (after the initial immune response). "This puts
great emphasis on our ability to institute long-term, effective
antiretroviral treatment in the early stages of HIV infection," Haase told
the Yokohama delegates, "and there is a need for multiple types of [viral]
inhibitors and combination therapy."

      -----------------------------
      HIV RNA Assays and Viral Load

      Both the reliability of HIV RNA testing and its practical applications
have expanded dramatically in recent years. Already HIV RNA testing has
become a significant tool in AIDS research. Within a matter of months these
powerful assays may be a major new tool for guiding the course of treatment
for HIV infection. Because of the ability of this new technology to detect
minute quantities of genetic material, it has many potential applications in
medicine. 

      What is HIV RNA? RNA stands for ribonucleic acid, the genetic
information of HIV present within virus particles. After HIV infects human
cells, its genetic information (RNA) is transcribed into DNA
(deoxyribonucleic acid), the substance in human cells that contains their
genetic information. HIV then "takes over" the machinery of the host cell.
When activated, the virus uses the host cell to replicate, producing virions
(new virus particles). These viral progeny then spread to infect new cells in
the bloodstream or tissue of the human host.

      The new tests measure the RNA of HIV, which reflects how much viral
replication is going on in the individual. This is commonly referred to as
"viral load," "viral burden" or "HIV load," which is determined by measuring
free viral particles. When tested in blood samples, the test findings are
expressed as the number of copies of HIV RNA in each milliliter of blood
plasma. A test value (result) of 50,000 copies means the individual has
50,000 copies of HIV RNA per milliliter of blood plasma at the time the
sample was drawn. 

      A test result of 50,000 copies is regarded anecdotally as "medium"
viral load, not dangerously "high," but also not as "low" as might be wished.
A test result of 100,000 copies is regarded anecdotally as a relatively high
viral load. (These are rough guidelines based on preliminary findings, but
the lower the number of copies per milliliter of blood plasma, the better!)

      Work remains to be done in the development and validation of these
tests to ensure that they give accurate, reliable and repeatable results. At
the present time, the tests are not standardized, and results may be
inconsistent. Scientists have not yet determined precisely how HIV load
values correlate with disease stage (although they have a rough idea), nor
can they rely with complete confidence on the viral load result to predict
clinical outcome. Yet several studies using these tests suggest that HIV load
predicts clinical outcome (e.g., decreases in viral load due to treatment
correlate with a clinical benefit). Further studies will be necessary to
verify these preliminary findings.

      Several companies are working to produce assays that measure viral
load. Hoffmann-La Roche (Roche Molecular Systems) and Chiron Corporation are
the 2 companies farthest along in developing standardized assay kits for
widespread use by researchers and physicians. The Roche product is called
"quantitative polymerase chain reaction" or more commonly "quantitative PCR."
The Chiron product is called "branched chain DNA" or, more commonly, branched
DNA (bDNA). Researchers have found that both tests give comparable results in
measuring HIV RNA.

      There are advantages and disadvantages to each of the 2 tests. For
example, the Chiron bDNA assay cannot measure HIV burden if the value is
below 5,000 copies of HIV RNA per milliliter, whereas the Roche quantitative
PCR can measure HIV load as low as 200 copies of HIV RNA per milliliter. Some
researchers prefer the Chiron bDNA because it is simpler to operate, others
prefer the Roche quantitative PCR because it is more sensitive. At this stage
of their development, the tests appear to offer equally reliable and
consistent results. 

      PCR and bDNA are sensitive and fast techniques that can detect and
amplify minute genetic fragments (RNA and DNA). The genetic fragments of
microorganisms present in infected individuals can be identified quickly and
the quantity of the microorganism in blood plasma or tissue measured. Within
a few hours source DNA can be amplified a billion-fold so that scientists can
recognize it. The ability of these tests to quantify the amount of the
organism inside host cells is important to AIDS researchers and clinicians,
offering an easy method for accurately measuring HIV load in infected
individuals.

      This new tool may change significantly the treatment of HIV disease in
many ways. It has already changed the way that researchers are testing the
effectiveness of AIDS drugs in clinical trials. Instead of relying heavily on
CD4 count changes as a surrogate marker for disease progression or drug
effectiveness, researchers are now employing HIV RNA testing, which tells
them with reasonable accuracy how much HIV is in the circulating blood of
individual patients. Preliminary evidence suggests that HIV load correlates
with clinical benefit (the lower the HIV load, the better the clinical
prognosis). High viral burden appears to presage disease progression and
clinical decline. 

      Within a short time these tests may become an accepted method for
demonstrating how well a particular drug (or drug regimen) is working in
individual patients. Eventually, when these tests are standardized and
approved by FDA, community physicians will be able to order them from local
laboratories. Using quantitative PCR or bDNA tests, physicians almost
everywhere will be able to determine whether viral load in each individual
patient is increasing, decreasing or remaining stable. 

      With this critically important information in hand, drug treatment can
be "individualized" for each patient. As a result, recommendations can be
made about continuing, halting, changing or adding drug treatment early,
before patients experience significant CD4 loss and clinical decline. CD4
loss is thought to be a relatively late result of increased viral
replication. Therefore, it is considered more beneficial to make treatment
decisions based on the patient's viral load. 

      Using HIV RNA testing in clinical trials to assess the HIV load in
patients on various treatment regimens, researchers may be able to predict
which drugs will work best for a particular patient or subset of patients.
Assays of viral burden also may dramatically shorten the amount of time
necessary to test the effectiveness of experimental therapiesantiretroviral
drugs, gene therapies, immunomodulating agents and other treatments. By
significantly decreasing the amount of time required to evaluate these
therapies, millions of dollars in research costs may be saved. 

      These tests also can be employed to evaluate the effect of alternative
therapies on viral burden. Therapies with no effective anti-HIV activity
could be identified quickly and abandoned. 

      -----------------------
      Access to HIV RNA Tests

      Both the Chiron bDNA and the Roche quantitative PCR are available to
researchers and clinicians now, but in order to be accessible to large
numbers of community physicians, these tests must receive FDA approval, and
be manufactured and distributed to local laboratories. To receive approval,
FDA requires that the manufacturers create a standardized kit that must be
evaluated in clinical trials. The standardized kits, once certified by FDA,
will yield consistent results when run by different laboratories.

      It is unknown how long it will take for Roche and Chiron to create kits
that will win FDA approval. No one from the companies involved will predict
a specific timeline, but this should be accomplished within the next 12
months, possibly sooner. In the meantime, physicians can order the tests from
certain laboratories, with the most reliable likely to be those operated or
licensed by Roche and Chiron. To order the quantitative PCR test from a
Roche-licensed laboratory, physicians may call 1-800-533-0567, 8 am - 6 pm
Eastern Time. To order a bDNA test from Chiron, physicians may call the
Nichols Institute at 1-800-553-5445. The cost per test is currently about
$200. When commercially available in standardized kit format, the cost for
the test is expected to drop significantly.

      It is important to understand that, much like CD4 T-lymphocyte testing,
the result of a single HIV RNA test is less valuable than tracking changes
over time. Studies show that monotherapy with AZT is able to produce a
ten-fold (1-log) decrease in viral load in antiretroviral-naive patients. If
therapy is stopped, viral load returns to baseline values. It has been
suggested by some scientists that what is needed for effective viral
suppression is a drug regimen capable of reducing viral load by 100-fold (a
2-log drop) for an extended period of time. No currently available
single-agent drug can produce this desired decrease in viral load. 

      ---------------------------------------------
      The Limitations of Monotherapy in HIV Disease

      If the model of HIV disease pathogenesis discussed earlier is
accurateearly and massive presence of HIV in the lymph nodes and other
lymphoid tissuethen beginning antiretroviral treatment at the earliest
possible time seems the most appropriate treatment strategy. Postponement of
treatment allows the viral burden to increase unchecked, which further
damages immune function and results in the patient's clinical decline. The
critically important question is not whether early antiretroviral treatment
will benefit HIV positive individuals, but rather, can currently available
anti-HIV drugs arrest HIV replication in the lymph nodes and decrease viral
burden in early HIV infection? The answer may be yes,' if these drugs are
used in combination.

      There is growing evidence to suggest that monotherapy with currently
licensed antiretrovirals cannot effectively interfere with viral activity in
the lymphoid tissue during the earliest stages of HIV infection. This notion
is supported by the results of 2 studies presented at the Yokohama AIDS
Conference. 

      Paul Volberding, MD, presented results from the part of the ACTG 019
trial that enrolled over 1,600 patients with CD4 counts greater than 500
cells/mm3. Participants received 1,500 or 500 mg/day AZT monotherapy or
placebo. Unfortunately, over the mean followup period of 2.6 years, no
additional benefit in reducing time of progression to AIDS nor in extending
survival time was seen in those patients receiving AZT monotherapy.

      Oren Cohen, MD, of the NIAID presented in Yokohama results of an 8-week
study that examined the effect of AZT monotherapy on HIV in the lymph nodes
of people with early HIV disease (average CD4 count of 654). Using
quantitative PCR to measure HIV replication and viral load, his research team
concluded that AZT monotherapy had no detectable effect on the amount of HIV
in the lymphoid tissue nor in certain mononuclear white blood cells of these
individuals.

      Researchers believe that use of monotherapy with any available drug in
HIV infection inevitably leads to the development of viral resistance, which
in turn may seriously compromise the effectiveness of the drug. Resistance
may occur within weeks or years, depending on the individual patient's viral
strain, viral load and the particular drug used. Most likely, nearly complete
suppression of HIV replication needs to be achieved to prevent the emergence
of resistant virus.

      --------------------------
      Double Combination Therapy

      In contrast to those in early-stage HIV disease on AZT monotherapy,
patients in the NIAID study with more advanced disease (average CD4 count of
394) who added ddI to their AZT regimen experienced decreased HIV replication
in their lymphoid tissue and a decline in plasma viral load. However, these
reductions were temporary and not statistically significant, according to the
researchers. Yet the study did not address the potential benefit of
combination treatment with ddI plus AZT in individuals with early HIV disease
(nor was this approach tested in ACTG 019). It is possible that initiating
antiretroviral treatment with 2 or more agents in patients with early HIV
infection could produce a significant reduction in viral burden in the
circulating blood as well as reduce HIV replication in the lymphoid tissues.

      The results of several studies suggest a survival benefit for patients
on 2-drug antiretroviral therapy, compared to those on monotherapy. Neil
Graham, MD, presented data from the Multicenter AIDS Cohort Study (MACS)
demonstrating a survival advantage from combining AZT and ddI over switching
from AZT monotherapy to ddI monotherapy. Graham told Yokohama delegates that
combining therapy is far better than alternating therapy.

      Melanie Thompson, MD, of the AIDS Research Consortium of Atlanta
presented data in Yokohama showing that the survival benefit of double
combination antiretroviral therapy is significantly greater than that of
sequential therapy. In addition, starting AZT treatment at higher CD4 counts
is correlated with an increased survival benefit, according to Thompson.
      Several small studies have suggested that AZT in a double combination
with ddI, ddC or 3TC provides an advantage over any of these agents used
alone. This may be due to the ability of these combinations to reduce the
development of resistant strains of HIV. Although the mechanism of action of
all 3 drugs is the same, they have different toxicities and therefore
probably represent a useful clinical combination.

      However, reliance on only 2 agents of the same drug class in the
treatment of HIV infection is unlikely to suppress HIV replication for an
extended period of time, due to the extreme mutability of the virus. In
addition, the viral load in many HIV-infected patients, especially those with
advanced disease, is extremely high, and the 2-drug combination probably
cannot reduce it to a level that will halt or significantly delay disease
progression.

      ------------------------------------------------------------------
      Triple Combination Therapy: Best Hope for Maximal Clinical Benefit

      Three-drug combinations hold the most promise for effective, sustained
control of viral activity. Historically, 3- or 4-drug combinations have been
necessary for the effective treatment of certain chronic infections and other
diseases. For example, state-of-the-art treatment for M. tuberculosis calls
for early, initial treatment with 4 chemotherapeutic agents. In therapy for
various cancers and malignancies, treatment with 3 or more chemotherapeutic
agents is commonly the standard of care.

      In HIV disease, laboratory studies of certain 3-drug combinations have
demonstrated complete control of HIV replication at drug concentrations that
can safely be attained in the blood.

      The in vitro combinations of AZT plus ddI plus 3TC and AZT plus ddC
plus nevirapine produce a synergistic effect that reduces HIV activity to
almost zero, according to David Barry, MD, of Burroughs Wellcome. While in
vitro data may not translate into in vivo benefit, the fact that these triple
antiretroviral combinations can completely suppress viral activity in
laboratory cultures suggests that 3-drug combinations hold promise for
providing patients with a clinical advantage over monotherapy and double
combinations. It is also important to note that the drugs that constitute
these promising combinations are available now, and could be approved by FDA
for marketing within a matter of months through the accelerated approval
program.

      In the near-term, these combinations likely will be comprised of
nucleoside reverse transcriptase inhibitors (e.g., AZT, ddI, ddC, d4T, 3TC),
non-nucleoside reverse transcriptase inhibitors (e.g., nevirapine) and a
protease inhibitor. It is hoped that saquinavir (Inverase), the protease drug
farthest along in development, will receive accelerated approval from FDA
within the next 6-9 months. 

      Three-drug combinations using protease inhibitors plus the reverse
transcriptase inhibitors are currently the best hope for improved, sustained
clinical benefits among HIV-infected individuals. Over time (24-36 months),
patients may have increased access to other types of anti-HIV therapies for
use in combination with the nucleoside analogues  and protease inhibitors.
These include immunomodulating therapies such as the treatment vaccines and
autologous CD8+ cell infusion, passive hyperimmune therapy and interleukin-2,
as well as other novel therapeutic approaches now in the research pipeline. 

      ---------------------------------------------
      3-Drug Combinations with a Protease Inhibitor

      Hoffmann-La Roche released in May 1994 preliminary results of a
government-sponsored clinical study (ACTG 229) showing that the triple
combination of saquinavir (a protease inhibitor), AZT and ddC significantly
reduces HIV load and produces a transient, but significant increase in CD4
counts in patients with 50-300 CD4 cells/mm3. This first-ever study that
combines a protease inhibitor with nucleoside analogues compared the safety
and activity of the 3-drug combination to 2 double combinations: ddC plus AZT
and saquinavir plus AZT. Ann Collier, MD, of the University of Washington,
presented the ACTG 229 study results in Yokohama. The data show that the
triple combination was significantly better than the 2 double combinations in
reducing viral load and in increasing CD4 counts. 

      With 302 participants, ACTG 229 is the largest study of an HIV protease
inhibitor yet completed. Participants had used AZT for at least 4 months
before enrollment. While the study results do not prove a clinical benefit
from use of the 3-drug combination studied, the significant decreases
achieved in viral load (as measured by quantitative PCR) and the significant
increases in CD4 counts suggest that this and other triple combinations may
delay disease progression and improve survival. The benefit may be even
greater if 3-drug combination regimens are initiated in patients at earlier
stages of HIV disease (greater than 500 CD4 cells/mm3).

      ---------------------------------------------------------
      The Inter-Company Collaboration for AIDS Drug Development

      Almost everyone with a stake in AIDS drug developmentcompanies,
researchers, clinicians, regulators, patients and activistsagree that new
approaches are needed for the clinical testing of combination regimens that
show promise in the laboratory. There are now 4 FDA-approved anti-HIV drugs:
AZT, ddI, ddC and d4T plus 3 drugs with anti-HIV activity that are
FDA-approved for other indications: alpha interferon, foscarnet and
ribavirin. In addition, 3TC is available through the parallel track program.
This translates into 56 possible 3-drug combinations that might be tested in
clinical studies. 

      In addition, protease inhibitors, non-nucleoside reverse transcriptase
inhibitors and treatment vaccines are emerging from Phase II studies in the
coming months, raising the number of potential 3-drug combinations to several
thousand. If the potential clinical benefits of 3-drug combinations are to be
made available to patients desperately in need of new therapies, it is
imperative to design and implement a new, streamlined AIDS drug research
program. One such approach is already in place, a collaborative program
between a group of the world's leading pharmaceutical companies.

      The Inter-Company Collaboration for AIDS Drug Development, a consortium
of 15 pharmaceutical companies, will begin a program in the fall of 1994 to
test the efficacy of various triple antiretroviral drug combinations. The
3-drug regimens will be tested among HIV positive, asymptomatic individuals
who have never used anti-HIV medication. The goal of the collaboration is to
accelerate research into antiretroviral drugs by sharing information and
compounds, and by conducting joint research. The major objective of the
program is to identify triple drug combinations that demonstrate strong
activity against HIV. Regimens that show early promise will then be evaluated
in traditional trials.

      The collaborators have designed a "Master Protocol" to quickly evaluate
currently feasible 3-drug combinations and to allow for the addition of new
drugs as they become available. The design of these studies is such that the
information they provide can be quickly put into clinical practice. These
protocols are designed as pilot Phase II studies, but if results show a
clinical benefit, the drugs could be made widely available to patients
through the existing FDA accelerated approval and parallel track systems. If
a study shows negative results, then that combination would be dropped from
the options recommended for patients.

      The first 4 triple combinations to be studied using this protocol have
been selected: (1) AZT plus ddC plus saquinavir; (2) AZT plus ddI plus
nevirapine; (3) AZT plus ddI plus 3TC; and (4) AZT plus ddC plus nevirapine.
These combinations have been selected first because they demonstrate in vitro
evidence of synergistic anti-HIV activity and no evidence of overlapping
toxicities. (For a complete review of the Inter-Company Collaboration and a
detailed introduction to the Master Protocol, see the article by David Barry,
MD, in the June 1994 issue of BETA, pp. 46-48.)

      ---------------------------------------------
      Toward a New Definition of Early Intervention

      As mentioned earlier, laboratory studies of antiretroviral drugs
demonstrate clearly that 2 drugs are better than one (in suppressing viral
activity) and that 3 drugs are better than 2. In addition, anti-HIV therapy
appears to work best when the viral load is low. Can these laboratory
findings guide physicians and patients in choosing the most effective time to
initiate treatment as well as the most effective drug regimen(s)?

      If certain 3-drug combinations offer the most promise for suppressing
viral activity, and if viral burden is lowest during early-stage infection,
then initiating a 3-drug combination as early as possible in infected
individuals may be the most effective treatment strategy available to
patients today. 

      In this case, early intervention would no longer mean initiation of AZT
monotherapy among asymptomatics with 200-500 CD4 cells/mm3, but rather
initiation of a 3-drug treatment regimen at the earliest possible moment
following the initial immune response to acute infection. While it will be
necessary to conduct clinical trials to test for the effectiveness of 3-drug
combinations in early-stage infection, existing laboratory and clinical data
are sufficient to warrant serious consideration of such an approach now.

      --------------------
      Accelerated Approval

      To improve the likelihood for a 3-drug combination to provide a
prolonged clinical benefit, one of the 3 drugs used likely would be a
protease inhibitor. The protease inhibitor farthest in development is
saquinavir (Inverase), manufactured by Hoffmann-La Roche. Saquinavir is just
now entering Phase III trials in the U.S. and Europe. It is important that
the drug be made available through the FDA accelerated approval program as
soon as possible so that it can be used in combination regimens.

      A compelling argument can be made that saquinavir has already fulfilled
the requirements for accelerated approval. It fills an "unmet need" in that
it belongs to a new class of drugs with a distinctly different mechanism of
action against HIV than currently licensed drugs. Its toxicity profile is
favorable. No serious adverse reactions have been reported in Phase I or
Phase II trials of the drug. Equally important, the results of ACTG 229
suggest that, in a triple combination with AZT and ddC, the drug
significantly reduces viral burden and significantly increases CD4 counts in
individuals with advanced disease (50-300 CD4 cells/mm3). 

      Thus, already-completed saquinavir studies meet the FDA accelerated
approval requirement of providing "...evidence of the drug's effect on a
surrogate endpoint [in this case, CD4 counts and viral burden] that
reasonably suggests clinical benefit to patients..., pending completion of
studies to establish and define the degree of clinical benefits to patients."
("Accelerated Approval." Federal Register. December 11, 1992). In addition,
given the desperate need of thousands of AIDS patients who have failed on all
approved anti-HIV therapies, it may be unethical to deny them access to
saquinavir, which has shown no undue toxicities and has demonstrated a
reasonable promise of efficacy for patients in intermediate to advanced
stages of HIV disease. 

      --------------------------------
      The FDA and Accelerated Approval 

      The FDA will play a critical role on several levels in determining how
quickly Individualized Therapy becomes a reality in HIV disease. First, FDA
must collaborate with Roche and Chiron to ensure the timely design and
implementation of studies to test the reliability of the HIV RNA assays and
the potential of these assays to evaluate treatment regimens and shorten the
duration of clinical studies of AIDS therapies.

      Most importantly, FDA must continue its policy of granting accelerated
approval to experimental AIDS therapies that show reasonable safety and
reasonable promise of benefit. Unfortunately, the agency is now considering
proposals to make more stringent requirements for accelerated approval of new
AIDS drugs, specifically the protease inhibitors. In the opinion of many
researchers, clinicians and activists, such action would represent a major
step backwards for people with HIV/AIDS in their continuing struggle to gain
earlier access to promising new therapies. Changing the standard for
accelerated approval also will send a chilling message to drug developers,
large and small. The end result of making it more difficult, time consuming
and expensive to bring products to market could be a retreat by these
companies from the development of new AIDS drugs.

      Until a protease inhibitor receives FDA approval, there is no
possibility of their use in 3-drug combinations outside of clinical trials.
Yet triple combination regimens offer the current best chance for prolonged
viral suppression and improved clinical benefits. Raising the regulatory
hurdle for accelerated approval of the protease inhibitors (and other
experimental AIDS drugs) will make widespread access to Individualized
Therapy an unobtainable goal for the foreseeable future. It is to be hoped
that FDA will not revise the existing standards for accelerated approval for
AIDS drugs, and thus undermine the medical needs of individual patients who
require the earliest possible access to new treatments.
      ----------
      Conclusion

      Individualized Therapy is an emerging new treatment strategy for HIV
infection that differs from the current "cookbook" approach which relies
almost exclusively on CD4 cell counts and clinical symptoms to guide
treatment decisions. The essential elements of Individualized Therapy include
the use of powerful new tests for (1) measuring HIV load to determine disease
stage, (2) evaluating treatment regimens and (3) guiding the timing and
choice of changing therapy. 

      The concept of early antiretroviral treatment in HIV disease, also a
component of Individualized Therapy, is supported by the finding that, after
the initial immune response to acute infection, 25% of CD4 T-lymphocytes in
the lymph nodes are infected with HIV. Furthermore, it is now well
established that HIV is actively replicating in the lymph nodes and other
lymphoid tissue throughout the asymptomatic stage of HIV disease. Since
monotherapy with AZT in early disease appears to have no significant effect
on HIV load in the lymph nodes, early treatment with double and triple
combination regimens using nucleoside reverse transcriptase inhibitors plus
a protease inhibitor offer the possibility of producing prolonged suppression
of viral replication and improved clinical benefits for patients.

      Before Individualized Therapy can be put into widespread practice, the
following ongoing developments require completion: (1) Clinical trials now in
progress must be completed and new ones must be designed and implemented to
show conclusively that viral load measurement using quantitative PCR and
branched chain DNA assays correlates with clinical outcome. (2) Standardized
kits of these 2 assays must be developed and approved by FDA to ensure
consistent results when the tests are run by different laboratories. (3) New
drugs currently in the research pipeline, most notably the protease
inhibitors (e.g., saquinavir) and the non-nucleoside reverse transcriptase
inhibitors (e.g., nevirapine), must become available as soon as possible for
use in 3- or 4-drug combination regimens. (4) FDA must maintain the current
standards for accelerated approval of promising new AIDS drugs, namely that
these drugs demonstrate "reasonable" safety and a "reasonable" promise of
efficacy.   

      Sample HIV-1 RNA Quantitation Cumulative Report

      Social Security   Chiron      Nichols     Date  HIV-1 RNA   CD4   
Time  Drug
Number    Reference #   Reference # Collected   Quantitation      Count 
Point Therapy

549-34-8976   940001    4089878923  3/1/90      110200      177   
Pre-Therapy   None
      940008  4089908767      6/1/90      87720 198   During Therapy    AZT
      940015  4089938611      9/1/90      19880 250   During Therapy    AZT
      940022  4089968455      12/1/90     <10000      223   During TherapyAZT
      940029  4089998299      3/1/91      37800 245   Post-Therapy      None
      940036  4090028143      8/17/92     >1600000    190   Post-TherapyNone

      Source: Chiron Reference Testing Laboratory
      ****************************************************************
      Treatment Updates from the X International Conference on AIDS In
      Yokohama, Japan 
      Harvey S. Bartnof, MD

      Since 1985, Dr. Bartnof has served as course coordinator for "AIDS/HIV
Overview and Update" at the University of California at San Francisco (UCSF)
School of Medicine. He is also a member of the San Francisco AIDS
Foundation's Scientific Advisory Committee. Except for 1991, Dr. Bartnof has
attended and/or presented papers at every International AIDS Conference since
1985.

      Twelve thousand four hundred seventeen (12,417) participants (2,178
media representatives) from 130 countries attended the Yokohama AIDS
Conference (August 7-12, 1994), including 5,737 Japanese citizens. There were
a total of 3,400 abstracts submitted to the Conference, including 600 oral
and 2,800 poster presentations. In the following article, Dr. Bartnof
summarizes the most important Conference presentations on treatment
developments.
      
      
      Treatment Highlights

      ---------------------------------------------------------
      Growth Hormone Increases Lean Body Weight in AIDS-Related
      Wasting

      Morris Schambelan, MD, from UCSF-affiliated San Francisco General
Hospital reported on the results of a Phase III multicenter, double-blind,
placebo-controlled study of 178 patients with AIDS-related wasting syndrome
who were treated daily for 3 months with recombinant human growth hormone.
The treatment group gained a mean of 2.9 kg of lean body (muscle) mass when
compared to the placebo group, which had a 0.1 kg lean weight loss. The
treatment group and placebo groups lost 1.7 kg and 0.2 kg of body fat,
respectively. Total mean weight gain during the 3 months was 1.4 kg for the
treatment group and 0.2 kg for the control group. Both the lean muscle and
total weight gains in the treatment group were statistically significant. The
body compositions were measured by Dual Energy X-Ray Absorptiometry (DEXA).

      Upon entering the study, the patients had a mean HIV-related weight
loss of 11.2 kg and 14% of ideal weight. Average dosage of recombinant human
growth hormone was 6 mg/day, administered subcutaneously, with subsequent
adjustments for toxicity. There were 172 men and 6 women in the study. Mean
age was 39 years. Mean CD4 T-lymphocyte count was 84/mm3 at entry.

      Treadmill work performance was significantly improved in the treatment
group when compared with the control group. Changes in lean body mass were
correlated with changes in treadmill work performance. However, AIDS
progression, based upon clinical events and CD4 and p24 antigen counts, was
similar in the treatment and control groups.

      Serious events, dropouts and deaths were similar between the treatment
and control groups. Side effects potentially due to growth hormone were
usually mild or moderate in severity and responded to dose reduction. Side
effects included musculoskeletal discomfort, edema (fluid retention),
elevated blood glucose or triglycerides, parasthesias (numbness), nausea and
carpel tunnel syndrome in the wrists.

      Even though the cost of the dosage used in the study is prohibitively
expensive, the 13 clinical investigators of the study conclude that
recombinant human growth hormone appears to be safe and effective as a
therapy for AIDS-related wasting syndrome.

      Schambelan M and others. Growth hormone therapy of AIDS wasting. X
      International Conference on AIDS. Yokohama, August 1994. Abstract 423B
      and oral presentation.

      ----------------------------------------------------------------------
      Oral Ganciclovir Beneficial for Primary Prophylaxis of Cytomegaloviral
      (CMV) Disease

      An independent Data Safety Monitoring Board (DSMB) for the Syntex ICM
1654 study evaluating the potential benefit of oral ganciclovir for
prevention of CMV disease has recommended ending the placebo arm due to a
highly statistically significant difference in the incidence of and time of
development to CMV disease in the treatment arm. All patients in the placebo
arm have been offered active drug. Approximately one-half of the enrollees
had completed 10 months of therapy at the interim analysis. The study was
designed as a double-blind, placebo-controlled multicenter Phase III trial
that began enrollment in November 1992. Enrollment of 725 participants was
completed in December 1993. The entry criteria included HIV seropositivity,
CMV seropositivity and a CD4 lymphocyte count less than 50/mm3, or less than
100/mm3 and history of an AIDS-defining opportunistic infection. Two-thirds
of enrollees were randomized to receive active drug while the other third
received placebo. The treatment arm dosage was 1,000 mg 3 times a day of oral
ganciclovir.

      Follow-up has included eye examinations by an ophthalmologist every 2
months along with CMV cultures and other laboratory measurements. The primary
endpoint was diagnosis of CMV disease, while secondary endpoints included
survival and quality of life. The study will continue as an open-label
unblinded one to monitor the patients for further safety and efficacy. 

      While a formal presentation of the data was not given in Yokohama, an
information sheet was made available by Mary Jean Stempien, MD, from Syntex.
Stempien and colleagues anticipate an analysis of the data will be released
at the upcoming International Conference on Anti-Microbial Agents and
Chemotherapies (ICAAC) meetings. The ICM 1654 study is similar though not
identical to the Community Programs for Clinical Research on AIDS (CPCRA) 023
study of oral ganciclovir for primary CMV prophylaxis. That study completed
enrollment of approximately 995 patients in June 1994. The CPCRA study has an
endpoint of symptomatic CMV disease, while the Syntex study included an
endpoint of asymptomatic CMV disease.

      Syntex information sheet. Oral ganciclovir CMV prevention study 1654.
      X International Conference on AIDS. Yokohama, August 1994.

      Stempien MJ, Syntex Corporation. Personal Communication. August 1994.
      -----------------------------------------------
      Oral Ganciclovir for Treatment of CMV Retinitis

      Oral ganciclovir is much more convenient than the intravenous (IV)
route and is a viable alternative to IV ganciclovir for maintenance treatment
of retinitis. Time to progression of CMV retinitis averages 5-12 days faster
on oral compared to IV. The safety profile is better for the oral form: fewer
catheter-related events, less sepsis and less neutropenia. The data were
reviewed by David Hardy, MD, of the UCLA School of Medicine.

      Hardy WD. HIV-associated opportunistic infectionsnew progress in
      treatment and prophylaxis. Presented at Treatment of HIV Disease:
      Advances and Future Challenges, University of California at Los Angeles
      (UCLA) satellite symposium. X International Conference on AIDS.
      Yokohama, August 1994.

      -----------------------------------------------------------
      Atovaquone for Relapse or Resistant Toxoplasma Encephalitis

      In patients with AIDS-related toxoplasmic encephalitis relapse or
intolerance to standard regimen or pyrimethamine and a sulphonamide,
atovaquone therapy for 6 weeks led to a 64% clinical response rate and a 61%
radiologic response rate. The study was presented by Ramon Gabriel Torres,
MD, from New York Medical College.

      Gabriel Torres RA. Atovaquone in toxoplasmosis. Presented at New
      Strategies for Treatment and Prevention of HIV Disease, a Wellcome
      Foundation satellite symposium. X International Conference on AIDS.
      Yokohama, August 1994.

      -------------------------------
      Atovaquone for Microsporidiosis

      Eight homosexual men treated with atovaquone 750 mg tablets thrice
daily for 13 days had a mean weight gain of 9.5 pounds and a 70% decrease in
the number of daily stools from a mean of 10 to 3, according to Ramon Gabriel
Torres, MD, from New York Medical College.

      Gabriel Torres RA. Atovaquone in toxoplasmosis. Presented at New
      Strategies for Treatment and Prevention of HIV Disease, a Wellcome
      Foundation satellite symposium. X International Conference on AIDS.
      Yokohama, August 1994.

      ---------------------
      HIV Drug Interactions

      *   Rifabutin causes a 30% decrease in serum zidovudine [AZT] level.
      *   Rifabutin causes a 50% decrease in serum clarithromycin level.
      *   Rifabutin causes a 30-50% increase in serum fluconazole level.
      *   Oral ganciclovir causes a 15-38% increase in serum zidovudine [AZT]
          level.
      *   Oral ganciclovir causes a 50-80% increase in serum didanosine [ddI]
          level.
      *   Didanosine [ddI] causes a 25% decrease in oral ganciclovir level. 

      Data were presented and reviewed by David Hardy, MD, of the UCLA School
of Medicine.

      Hardy WD. HIV-associated opportunistic infectionsnew progress in
      treatment and prophylaxis. Presented at Treatment of HIV Disease:
      Advances and Future Challenges, University of California at Los Angeles
      (UCLA) satellite symposium. X International Conference on AIDS.
      Yokohama, August 1994.

      Gaines K and others. Pharmacokinetic interactions with oral
      ganciclovir, zidovudine, didanosine, probenecid. X International
      Conference on AIDS. Yokohama, August 1994. Abstract 004B and oral
      presentation.

      --------------------------------------------------
      Treatment for Pneumocystis carinii Pneumonia (PCP) 
      Causes Drop in PCP as AIDS Indicator Disease

      In the U.S. in 1993, PCP was the AIDS indicator disease in 16% of AIDS
patients compared to 43% in 1992, 50% in 1990 and 57% in 1988, according to
data presented by David Hardy, MD, of the UCLA School of Medicine.

      Hardy WD. HIV-associated opportunistic infectionsnew progress in
      treatment and prophylaxis. Presented at Treatment of HIV Disease:
      Advances and Future Challenges, University of California at Los Angeles
      (UCLA) satellite symposium. X International Conference on AIDS.
      Yokohama, August 1994.

      --------------------------------------------------------------
      Mycobacterium avium Complex (MAC) is the Leading Opportunistic
      Infectious Cause of Death

      In ACTG 021 in the U.S., MAC disease accounted for 13% of AIDS deaths
compared to PCP, which only accounted for 3% of AIDS deaths, according to a
review by David Hardy, MD, of the UCLA School of Medicine.

      Hardy WD. HIV-associated opportunistic infectionsnew progress in
      treatment and prophylaxis. Presented at Treatment of HIV Disease:
      Advances and Future Challenges, University of California at Los Angeles
      (UCLA) satellite symposium. X International Conference on AIDS.
      Yokohama, August 1994.

      ---------------------------------------------------------------------
      Oral Prednisolone Stabilizes Immune Deterioration in Asymptomatic HIV
      Disease

      Forty-four (44) asymptomatic HIV-infected patients at Laennec Hospital
in France were treated with oral prednisolone, an immune suppressing
glucocorticoid for 6 months at a dose of 0.5 mg/kg, followed by another 6
months at a dose of 0.3 mg/kg. The mean entry CD4 T-lymphocyte count among
the patients was 421/mm3, with a range of 207-775/mm3. Treatments while on
the study also included 1,200 mg potassium daily to offset steroid side
effects and Bactrim prophylaxis 3 times a week. Some patients were prescribed
fluconazole, and one-fourth of the patients had some AZT therapy. J.M.
Andrieu, MD, and colleagues noted that after 1 year of prednisolone therapy:

      (1) CD4 lymphocytes increased more than 100/mm3 (median);
      (2) CD8 lymphocyte counts decreased somewhat;
      (3) no progression to symptomatic AIDS-defining disease occurred;
      (4) viral load (HIV, DNA and RNA) remained unchanged;
      (5) lymphadenopathy as well as seborrheic dermatitis decreased or
          disappeared;
      (6) markers of immune activation (beta-2 microglobulin, immune
          globulins, CD4+DR+ and CD4+CD25+ cells) decreased, and;
      (7) T-cell apoptosis (premature cell death) decreased significantly.

      Lu W and others. Glucocorticoids rescue CD4+ T cells from
      activation-induced apoptosis triggered by HIV-1. X International
      Conference on AIDS. Yokohama, August 1994. Abstract 021A and oral
      presentation.

      ---------------------------------------
      Oral Valaciclovir Passes Phase I Trials

      Seventeen (17) HIV-infected patients with a mean CD4 lymphocyte count
of 44/mm3 completed the Phase I Study of oral valaciclovir, 4 times a day
with 1,000 mg or 2,000 mg for 1 month. Valaciclovir is a prodrug of acyclovir
that significantly increases serum levels of acyclovir. There were few side
effects. With the higher dosage, serum levels of the active metabolite
acyclovir were 5-fold greater than levels achieved with the highest dose of
oral acyclovir (800 mg 5 times a day). Such levels hold promise in the
prevention and treatment of HIV-related CMV, varicella-zoster virus (VZV),
herpes simplex virus (HSV) and possibly human herpesvirus 6 (HHV-6)
infection. The lead author is Mark Jacobson, MD, of UCSF/San Francisco
General Hospital.

      Jacobson MA and others. Phase I trial of valaciclovir, the l-valyl
      ester of acyclovir, patients with advanced human immunodeficiency virus
      disease. Antimicrobial Agents and Chemotherapy 38(7): 1534-1540. July
      1994.

      ------------------------------------------------------
      Benefits for AZT Therapy for Acute Retroviral Syndrome

      Seventy-two (72) patients with various HIV behavioral risk factors were
treated for 6 months with AZT 250 mg twice daily or placebo, during or
shortly after the onset of their acute HIV infection illness, the flu-like
symptoms which occur prior to the immune response and within a few weeks
after HIV infection (in the majority of patients). After a mean follow-up of
15.4 months, a trend was observed toward higher CD4 lymphocyte counts
(553/mm3 versus 460/mm3 in placebo after 12 months), higher CD8 lymphocyte
counts and lower HIV RNA viremia. There were fewer clinical events in the
treatment group, when compared to controls (oral candidiasis, herpes zoster,
hairy leukoplakia), which was statistically significant. The lead author was
Luc Perrin, MD, from the Central Laboratory of Virology in Switzerland.

      Perrin L. Treatment of HIV infection during primary infection.
      Presented at New Strategies for Treatment and Prevention of HIV
      Disease, a Wellcome Foundation satellite symposium. X International
      Conference on AIDS. Yokohama, August 1994. 

      ---------------------------------------------------
      No Clinical Benefit for AZT With CD4 Count Over 500

      In ACTG 019, when AZT was given to asymptomatic patients with a CD4
lymphocyte count of greater than 500/mm3, there was no added clinical benefit
when compared to starting at a CD4 count of less than 500/mm3, according to
Paul Volberding, MD, of UCSF/SF General Hospital. He noted that it would be
difficult to measure a beneficial effect at such high CD4 counts because the
risk of disease at that time is low.

      Volberding PA and others. Zidovudine in early asymptomatic HIV disease:
      a controlled trial in subjects with greater than 500 CD4+
      cells/microliter. X International Conference on AIDS. Yokohama, August
      1994. Abstract 355B and oral presentation.

      Volberding PA. Considerations in the initiation of antiretroviral
      therapy. X International Conference on AIDS. Yokohama, August 1994.
      Abstract PS17 and oral presentation.

      ----------------------------
      Acyclovir Survival Advantage

      Acyclovir at a dose of 400 mg twice a day along with anti-HIV therapy
increases survival in HIV-infected patients with less than 150 CD4
lymphocytes/mm3, according to the European-Australian and Multicenter AIDS
Cohort Study (MACS) studies. However, a Maryland study to be presented at the
upcoming ICAAC meetings may indicate otherwise, according to researchers at
Johns Hopkins School of Medicine.

      Cooper D. Acyclovir cotherapy in advanced HIV disease. Presented at New
      Strategies for Treatment and Prevention of HIV Disease, a Wellcome
      Foundation satellite symposium. X International Conference on AIDS.
      Yokohama, August 1994.

      Stein DS and others. The effect of the interaction of acyclovir with
      zidovudine on progression to AIDS and survival. Annals of Internal
      Medicine 121(2): 100-108. July 15, 1994.

      ----------------------------------------------------------------------
      Triple Therapy Leads to Highest CD4 Counts and Lowest Mononuclear Cell
      HIV Levels

      In ACTG 229, the results of a randomized, 3-arm, double-blind (with
open-label AZT), 24-week trial among 300 patients were reviewed by Ann
Collier, MD, from the University of Washington. Two arms included the
proteinase inhibitor saquinavir (saq), while all 3 arms included the reverse
transcriptase inhibitors AZT with or without ddC. After 24 weeks, the
percentage of baseline CD4 count was lowest in the AZT/ddC group at 90%,
intermediate in the saq/AZT group at 100%, and highest in the triple-therapy
group at 109% of baseline. More impressive were the results of the mean HIV
levels in peripheral mononuclear cells: lowest in the triple-therapy group at
30% of baseline, intermediate in the ddC/AZT group at 62% of baseline, and
highest in the saq/AZT group at 140% of baseline. Moderate-to-severe adverse
experiences were not different statistically when comparing the 3 groups,
ranging from 31-40%.

      Collier AC and others. Comparative study of Ro 31-8959 and zidovudine
      vs ZDV and zalcitabine vs Ro 31-8959, ZDV and ddC. X International
      Conference on AIDS. Yokohama, August 1994. Abstract 058 and oral
      presentation.

      Collier AC. Advances in retroviral therapy. Presented at Treatment of
      HIV Disease: Advances and Future Challenges, University of California
      at Los Angeles (UCLA) satellite symposium. X International Conference
      on AIDS. Yokohama, August 1994.

      --------------------------------------------------
      Survival Advantage in Combination Anti-HIV Therapy

      Neil Graham, MD, from Johns Hopkins University presented an interim
analysis from the MACS involving 853 gay or bisexual men with
intermediate-stage HIV disease who either: continued AZT as monotherapy
(ZMT), switched to ddC or ddI (sequential monotherapy = SMT), or added ddC or
ddI (combination anti-retroviral therapy = CART). Those patients who took
CART had a 34% survival advantage (i.e., 66% risk of death) when compared to
either SMT or ZMT regimens. The results were adjusted for disease stage,
other therapies and time on AZT.

      Graham NMH. Survival in ZDV-experienced patients: combination
      antiretroviral therapy vs ddI/ddC monotherapy vs continued ZDV
      montherapy. Presented at New Strategies for Treatment and Prevention of
      HIV Disease, a Wellcome Foundation satellite symposium. X International
      Conference on AIDS. Yokohama, August 1994.

      -------------------------------------------------------------------
      Survival Advantage in Switch to ddI Associated With Decreased Viral
      Load

      Ann Collier, MD, from the University of Washington reviewed the NWCS
032 analysis of ACTG 116b/117 Trial in which patients were switched to ddI or
maintained on AZT after 4 weeks or more of prior AZT therapy. For those who
switched to ddI, a 32% decrease in the relative risk of disease progression
was associated with a 50% decrease in the HIV viral burden (RNA). 
Furthermore, regardless of the assignment group, there was a 178% increased
risk of disease progression or death and a 278% increase in the risk of death
alone associated with AZT resistance at study entry.

      Collier AC. Advances in retroviral therapy. Presented at Treatment of
      HIV Disease: Advances and Future Challenges, University of California
      at Los Angeles (UCLA) satellite symposium. X International Conference
      on AIDS. Yokohama, August 1994.

      ------------------------------------
      Viral Burden Predicts Outcome on AZT

      William O'Brien, MD, presented findings from the Veterans Affairs
Cooperative Study #298A, which indicate that baseline plasma HIV viral burden
(RNA count) was strongly correlated with clinical response to AZT therapy, in
addition to the CD4 lymphocyte percent and absolute count. He also reported
that the decrease in HIV RNA copy number over 6 months after initiation of
AZT therapy can be used to predict clinical outcome. The log HIV RNA
explained a greater percent of treatment effect than the CD4 lymphocyte count
and beta-2 microglobulin combined.

      O'Brien WA and others. Plasma HIV RNA and beta-2 microglobulin as
      surrogate markers. X International Conference on AIDS. Yokohama, August
      1994. Abstract 254B and oral presentation.

      -----------------------------------------------------
      Viral Burden Associated with Death and AZT Resistance

      Maryanne T. Vahey, MD, and colleagues from the Walter Reed Army
Institute of Research in Maryland presented their findings from the RV43
Study Group, which consisted of 95 HIV-infected patients with a mean entry
CD4 lymphocyte count of 252/mm3 placed on AZT monotherapy for 2 to 3 years.
Their findings indicated that viral burden (HIV RNA/ml plasma) is strongly
associated with death and the development of AZT resistance in patients on
long-term AZT therapy. Risk of adverse events increased directly with
increasing plasma HIV RNA levels. Patients with 107 plasma HIV RNA copies/ml
had a 7-fold increased risk of death when compared to those with less than
103 copies/ml.

      Vahey MT and others. Plasma RNA predicts clinical outcome of AZT
      therapy. X International Conference on AIDS. Yokohama, August 1994.
      Abstract 253B and oral presentation.

      -----------------------------------------------
      Decreased Viral Burden with Combination Therapy

      David Barry, MD, from Burroughs Wellcome Company, presented the results
of a laboratory study comparing the viral burden after initiation of AZT with
or without one other nucleoside analog, either ddC or ddI. After 48 weeks of
drug therapy, AZT treatment led to a median 70% of baseline RNA copies/ml,
whereas therapy with AZT and either ddC or ddI led to a median 30% of
baseline RNA copies/ml.

      Barry D. Triple combinations and future research direction. Presented
      at New Strategies for Treatment and Prevention of HIV Disease, a
      Wellcome Foundation satellite symposium. X International Conference on
      AIDS. Yokohama, August 1994.

      -------------------------------------------------------------
      Viral Burden to Help Determine Initiation of Anti-HIV Therapy

      Clifford Lane, MD, of the NIAID has proposed that it may be useful to
use viral burden measurements, along with CD4 lymphocyte counts, to determine
when to initiate anti-HIV therapy. He noted that in HIV-infected patients
with a viral burden of more than 50,000 RNA copies/ml by the bDNA test, CD4
lymphocyte counts were lower (280 cells/mm3) when compared to those with less
than 10,000 RNA copies/ml (340 cells/mm3). When the 2 groups were followed
over 8 months, the group with the higher viral burden had a steep decline in
the CD4 count to 185/mm3, while those in the low viral burden group decreased
only slightly to 330/mm3. He proposed that the viral burden marker may be
even more important than the CD4 count.

      Lane HC. When to start antiretroviral treatment. X International
      Conference on AIDS. Yokohama, August 1994. Round-table session.

      -------------------------------------------------------------------
      Developing Anti-HIV Drug Strategy Similar to Tuberculosis (Tb) Drug
      Development

      In a plenary session called "Update on Antiretroviral Strategy,"
Stefano Vella, MD, from the Instituto Superiore in Italy declared, "If
anti-Tb drugs had been developed the way we currently develop anti-HIVs, we
would not know now that tuberculosis is a treatable condition." He continued,
"One Concorde Trial' on INH [isoniazid] would have proven the drug to be
fairly useless." Prior to the advent of antibiotics in the 1940s,
tuberculosis was difficult to treat and often fatal. When streptomycin was
first made available for Tb treatment, resistance to the drug developed in
many cases. The current strategy for active Tb treatment includes 4
antibiotics, each of a different type.

      Vella S. Update on antiretroviral therapy. X International Conference
      on AIDS. Yokohama, August 1994. Abstract PS3 and plenary session oral
      presentation.

      -----------------------------------------------------
      AZT Decreases HIV Transmission from Mother to Newborn

      While the results of ACTG 076 had already been released before
Yokohama, the CDC published their recommendations for AZT therapy in
HIV-infected pregnant women and their newborns during the week of the
Yokohama Conference. Hence, several sessions addressed different aspects of
the study and the recommendations. An African study showed that HIV
transmission from mothers to their newborns occurs: 31% intrauterine (during
pregnancy), 58% intrapartum (during delivery), and 11% postpartum (after
delivery). Increasing risk of transmission is associated with maternal viral
burden, higher p24 antigenemia and lower CD4 lymphocyte counts.

      As of December 1993, an interim analysis of ACTG 076, a Phase III,
double-blind, placebo-controlled trial were as follows. Four hundred
seventy-seven (477) women with a median age of 25 years, a median CD4 count
of 550 cells/mm3, and no prior AZT exposure (during the current pregnancy)
were enrolled. The race/ethnic background was 50% African-American,
29% Hispanic and 19% Caucasian/non-Hispanic. Daily oral AZT 500 mg (100 mg 5
times a day) was given to the pregnant women after 14 weeks gestation and
continued until the onset of labor. At the start of labor, an IV loading dose
of 2 mg/kg of AZT was given, followed by a continuous IV infusion at the rate
of 1 mg/kg/hour. The infant was treated with 2 mg/kg orally 4 times a day
until age 6 weeks.

      There were 364 infants born with known HIV status. Of the 180
mother/infant pairs who received AZT, there were 13 HIV-infected infants, an
8.3% transmission rate. Of the 184 mother/infant pairs who received placebo,
there were 40 infected infants, a 25.5% transmission rate. Therefore, there
was a 67.5% reduction in HIV transmission from mother to newborn in the
treatment group. This result was highly statistically significant
(p=0.000056). 

      Dr. Yvonne Bryson from UCLA School of Medicine stated that there was no
significant toxicity in either the mothers or their infants. A slightly
decreased hemoglobin in some infants resolved by age 3 months. There were no
obvious teratogenic effects. 

      Based on these results, the U.S. Public Health Service, via the CDC,
has published the recommended guidelines for AZT treatment of HIV-infected
mothers after the 14th week of gestation, during labor, and to their infants
up to age 6 weeks. The doses are the same as those used during the ACTG 076
Study above. Mothers and fathers need to understand that the long-term
effects to the infant are unknown, including possible future carcinogenic
and/or reproductive effects, as well as physical and mental growth
abnormalities. 

      Several comments were voiced in Yokohama that the expense of AZT
precludes the vast majority of HIV-infected women or their infants in
developing countries from access to the drug.

      Balsey J. Mother-to-child infection. X International Conference on
      AIDS. Special recent report session SR-2. Yokohama, August 1994. Oral
      presentation.

      Blanche S. Materno-fetal HIV transmission. X International Conference
      on AIDS. Yokohama, August 1994. Abstract PS11 and plenary session oral
      presentation.

      Bryson Y. Protective role of zidovudine in reduction of maternal-fetal
      HIV transmission during pregnancy. Presented at New Strategies for
      Treatment and Prevention of HIV Disease, a Wellcome Foundation
      satellite symposium. X International Conference on AIDS. Yokohama,
      August 1994.

      Rogers M. Prevention of maternal-fetal transmission of HIV. Presented
      at Treatment of HIV Disease: Advances and Future Challenges, University
      of California at Los Angeles (UCLA) satellite symposium. X
      International Conference on AIDS. Yokohama, August 1994.

      U.S. Department of Health and Human Services. Recommendations of the
      U.S. Public Health Service Task Force on the use of zidovudine to
      reduce perinatal transmission of human immunodeficiency virus.
      Morbidity and Mortality Weekly Report 43(RR-11). August 5, 1994.

      ----------------------------------------------------
      Pregnancy Hormone for AIDS-Related Kaposi's Sarcoma?

      Robert Gallo, MD, of the National Institute of Health (NIH) has
suggested using beta-human chorionic gonadotropin (b-HCG) to treat
AIDS-related Kaposi's sarcoma (KS). He and his co-workers have observed that
KS cells failed to grow in vitro when b-HCG was added and that in an
immunodeficient-mouse model with KS, treatment with HCG led to KS tumor
regression. Clinicians have also noted that KS tumors among HIV-infected
women resolved when they became pregnant, only to return after their babies
were born.

      Gallo RC. Presented at HIV Ten Years On: Research Findings and Future
      Prospects, tenth anniversary special session. X International
      Conference on AIDS. Yokohama, August 1994. 

      -----------------------------
      Hydoxyurea for HIV Infection?

      Just as he did at the IX International Conference on AIDS in Berlin,
Robert Gallo, MD, has called for trials to evaluate the cancer chemotherapy
agent hydroxyurea as an anti-HIV co-therapy along with a reverse
transcriptase (RT) inhibitor(s). He stated that it would decrease the
nucleoside pool (DNA building blocks) available for incorporation into HIV
DNA, thereby allowing the RT inhibitors to be more effective. Hydroxyurea is
an FDA-approved drug for use in chronic leukemia and other cancers. It is
inexpensive, orally available, crosses the blood-brain barrier, and would
synergize with AZT, ddI and/or ddC.

      Gallo RC. Presented at HIV Ten Years On: Research Findings and Future
      Prospects, tenth anniversary special session. X International
      Conference on AIDS. Yokohama, August 1994. 

      -----------------------
      Oral Ulcers and ddC Use

      Deborah and John Greenspan, MD, from UCSF presented a study on the
incidence of oral ulcerations following zalcitabine (ddC) therapy. They
reported that the increased risk of oral ulcers from ddC peaks between 3 and
6 months after starting therapy. They also found that the risk is higher for
non-smokers compared to smokers. However, considering previous reports of
negative effects of smoking among those infected with HIV, the benefits of
stopping cigarette smoking far outweigh the potential avoidance of oral
ulcers while taking ddC.

      Greenspan D and others. Association between oral ulcers and
      zalcitabine. X International Conference on AIDS. Yokohama, August 1994.
      Abstract 200B and oral presentation.

      ---------------------------------------------------------
      Magnesium Supplement Beneficial for Peripheral Neuropathy

      Sally Stroud, MD, and colleagues at the Houston Immunological Institute
reported on the benefits of giving supplemental magnesium to AIDS patients
with peripheral neuropathy and hypomagnesemia (low serum magnesium).
Sixty-eight (68) HIV-infected patients, including 59 with AIDS, had histories
and physical examinations consistent with sensory dysfunction.
Electromyographic (EMG) nerve studies were performed on 46: 38 had peripheral
neuropathy. Neurotoxic drugs, diabetes and alcohol usage were excluded as
causes. All patients had a decreased serum magnesium level, with normal B-12
and thyroid function tests. Patients received IV magnesium initially, with
subsequent oral magnesium supplements (doses not stated).

      Response was measured by improved vibration sensation and pinprick,
increased ankle reflex, decreased subjective pain and decreased usage of pain
medications. 78% had improvement in symptoms within 24-48 hours; 32% (22
patients) showed no initial improvement. However, 7 of those 22 did show
improvement after a mean of 14 days taking oral magnesium. After 12 months,
81% of the patients continued to demonstrate improvement in symptoms from
baseline, excluding 13 patients lost to follow-up.

      Stroud S. Magnesium and peripheral neuropathy. X International
      Conference on AIDS. Yokohama, August 1994. Abstract PBO235 and poster
      presentation.

      -------------------------------------------------------------
      Long-Term Non-Progressors (LTN) and Long-Term Survivors (LTS)

      Several speakers addressed the topic of long-term non-progressors.

      Susan Buchbinder MD, from the SF City Department of Public Health
presented an update from the San Francisco City Clinic Cohort. She and her
colleagues have determined that the progression to AIDS after HIV
seroconversion is: 1% progression by 2 years; 11% by 5 years; 51% by 10
years; and 79% by 15 years. For 552 patients infected with HIV for 10-16
years, 6.9% still have CD4 counts greater than 500 cells/mm3 and are
classified as "non-progressors." The non-progressors had broadly reactive
cytotoxic T-lymphocyte responses in vitro, and had certain human leukocyte
antigen (HLA) markers in both Class I and Class II more frequently than
progressors. Ongoing studies in the non-progressors include viral burden,
lymph node assays, qualitative CD8 functioning and apoptosis measurements.

      Jay Levy, MD, from UCSF reviewed the findings of his laboratory's
studies of long-term survivors (LTS). He defines such individuals as:
infected with HIV for 10 or more years; clinically healthy; having a stable
CD4 count of greater than 500/mm3; and taking no anti-HIV therapy. He and
others have acknowledged that the CD8 antiviral factor is strong in the LTS.
The CD8 antiviral factor appears to be mediated by a novel factor; is
observed in activated CD8+CD28+ cells; is active against HIV-l, HIV-2 and
SIV; blocks HIV RNA expression, and; does not work by a lytic mechanism
(i.e., does not cause cells to break up and die). He also reviewed selected
cytokine secretion and functioning in relation to an altered THl-TH2 immune
response in LTS when compared to those with HIV disease progression. 

      Levy and co-workers have discovered an exciting breakthrough in an
animal AIDS model. They have determined that HIV-2 causes an AIDS-like
disease in baboons. These baboons demonstrate CD4+ cell 1086; lymphoid
depletion; lymphoid interstitial pneumonitis (similar to pediatric AIDS); and
skin lesions. Having an AIDS-like animal model will help researchers' efforts
to uncover safe and effective HIV therapies and vaccines.

      David Ho, MD, from the Aaron Diamond AIDS Research Center in New York
reviewed his findings among 10 LTS referred to his laboratory. He defines LTS
as: HIV infection for longer than 12 years; no HIV symptoms; and normal and
stable CD4 lymphocyte counts. His 10 patients include: 9 men and 1 woman; 7
homosexual men, 2 IVDU men and 1 heterosexual woman. HIV infection was
documented for over 12 to 15 years. The age range was 38-47 years. Ho has
found that the viral burden, as measured by plasma HIV RNA and HIV DNA in
peripheral blood mononuclear cells, among LTS is low. They have strong
neutralizing antibody responses and strong CD8 antiviral responses,
associated with control of HIV replication. He found evidence for HIV strains
in LTS which are attenuated (weakened), i.e., they do not grow well in the
laboratory even when the CD8 antiviral factor is removed. He also found no
evidence of a host-cell resistance to HIV. 

      Ho believes that LTS "have distinctive virologic and immunologic
features to suggest that they are not merely one extreme of a normal
distribution curve." In his studies of rapid HIV progressors, he found that
they have increased viral load in blood and tissues, and that about half have
syncytium-inducing (SI) viruses.

      Anthony Fauci, MD, and colleagues from the NIH presented their findings
of 7 long-term non-progressors (LTN) followed at the NIH. Their definition
for LTN is the one used in the MACS: HIV seropositivity at study entry; CD4
T-lymphocyte measurements for greater than 7 years, with a CD4 cell slope
greater than or equal to zero (i.e., not declining); and no anti-HIV therapy.
Their 11 patients included 10 men and 1 woman, with an age range of 32 to 46
years. His laboratory performed various measurements on lymph node biopsies
from the LTN. They found that the germinal center area in the lymph nodes of
LTN was the same as for HIV negative controls, but was abnormally elevated in
HIV-infected progressors. When comparing the viral burden (DNA) in
mononuclear cells found in lymph nodes, there was a lower viral burden in the
LTN than in progressors. 

      A similar pattern was observed in the DNA in mononuclear cells in
peripheral blood, though the difference was not as striking. More impressive
were the plasma viral burden (RNA) measurements comparing the 2 groups. LTN
had a mean of 77,061 HIV RNA copies/mm3 of plasma (standard deviation
77,540), whereas 8 HIV progressors had a mean of 1,676,001 HIV RNA copies/mm3
of plasma (standard deviation 2,522,009). Fauci believes that it will be
important to determine what allows for the maintenance of normal germinal
centers in the lymph nodes of LTN. The disruption of normal germinal center
architecture, he believes, is an important early event in HIV disease, long
before the onset of CD4 T-lymphocyte decrease and AIDS disease symptoms.

      Buchbinder S. Healthy long-term HIV positives: viral burden and
      cell-mediated immunity. X International Conference on AIDS. Yokohama,
      August 1994. Abstract 007C and oral presentation.

      Fauci AS. Host factors in immunopathogenesis. X International
      Conference on AIDS. Yokohama, August 1994. Abstract PS2 and plenary
      session oral presentation.

      Ho DD. Long-term non-progressors. X International Conference on AIDS.
      Yokohama, August 1994. Abstract PS10 and plenary session oral
      presentation.

      Ho DD. Presented at Treatment of HIV Disease: Advances and Future
      Challenges, University of California at Los Angeles (UCLA) satellite
      symposium. X International Conference on AIDS. Yokohama, August 1994.

      Levy JA. Presented at HIV Ten Years On: Research Findings and Future
      Prospects, tenth anniversary special session. X International
      Conference on AIDS. Yokohama, August 1994. 


      Developments in Basic Science

      ----------------------------------
      100 Billion CD4 Cells Have HIV DNA

      Ashley Haase, MD, from the University of Minnesota Medical School gave
an impressive plenary session oral presentation. Haase has developed a new in
situ PCR technique to measure viral burden in resting cells in lymphoid
tissue. He has found that "...during the early symptomatic stages. . .
approximately 25% or more of the CD4 positive cells (and macrophages in
lymphoid tissue and spleen) harbour HIV DNA, yet only about 1 in a 100 of
these are actively productive." 

      Haase continued, "If 25% of CD4 cells are infectedthis translates into
approximately 100 billion covertly infected CD4 cells. If only 1% of these
are productively infected, this gives rise to one billion productively
infected cells, which can account for the viral loads in the peripheral blood
at one time." He felt that this indicated a need for "long-term effective
anti-HIV treatment in the early stages of HIV infectionand a need for
multiple types of inhibitors and combination therapy."

      Haase AT. New molecular technology in HIV research. X International
      Conference on AIDS. Yokohama, August 1994. Abstract PS16 and oral
      presentation.

      Miscellaneous Presentations 

      --------------------------------------------------------------------
      Pap Smears for HIV Positive Women as Effective as Colposcopy for CIN

      Carol Brosgart, MD, and colleagues of UCSF and the East Bay AIDS Center
in Berkeley, CA, have determined that an adequately performed Pap smear of
the uterine cervix in women is as effective as colposcopy for the detection
of cervical intraepithelial neoplasia (CIN), a precancerous condition found
more commonly in HIV-infected women. Colposcopy, less widely available than
the Pap smear, traditionally has been thought to be more specific for the
detection of CIN.

      Brosgart C and others. Papanicolaou (Pap) smears versus colposcopy as
      screening tests for cervical intraepithelial neoplasis (CIN) in
      HIV-seropositive women. X International Conference on AIDS. Yokohama,
      August 1994. Abstract 079B and oral presentation.

      -----------------------------------------------------------
      Rectal Pap Smears for Men and Women With Rectal Sex History

      Joel Palefsky, MD, of UCSF reported on the prevalence of human
papillomavirus (HPV) isolated from the rectums of 57 homosexual men with
symptomatic HIV disease. HPV is associated with the development of anal
cancer, which has been increasing in the AIDS epidemic. Early detection of a
precancerous lesion would allow for earlier treatment and prolonged survival.
After 1 year, the prevalence of HPV in the study increased from 67% at
baseline to 84%. Dr. Palefsky said that although he used PCR testing, rectal
Pap smears might also be useful. Rectal Pap smears might also be indicated in
women who had engaged in receptive anal intercourse.

      Palefsky JM and others. Anal infection with multiple HPV types in men
      with symptomatic HIV disease. X International Conference on AIDS.
      Yokohama, August 1994. Abstract 081B and oral presentation.

      -----------------------------------------------------
      Subset of Gay Men Possibly Resistant to HIV Infection

      Roger Detels, MD, and co-workers from the UCLA School of Public Health
have compared 23 gay men with multiple exposures to HIV over 21 years, who
remained persistently HIV antibody-negative, to 137 gay men who seroconverted
to HIV. The men were from the MACS. A subset of the groups were evaluated.
For 90-100% of 10 different clinic visits, the "HIV-resistant" men had higher
numbers of white blood cells including lymphocytes and neutrophils. They also
had higher numbers of leukocytes positive for the CD3, CD4 and CD8 markers,
compared to the men who seroconverted to HIV. In addition, the HIV-resistant
men had an increased frequency in the class-1 human leukocyte antigen markers
A26, B38 and TAP1.4. The HIV-resistant men also had an increased prevalence
of CD25+CD8+ cells. These findings could have applicability to vaccine and/or
therapeutic research.

      Detels R and others. Persistently seronegative men from whom HIV-1 has
      been isolated are genetically and immunologically distinct. X
      International Conference on AIDS. Yokohama, August 1994. Abstract 163A
      and oral presentation.

      ------------------------------------------------------
      Increased Funding for Vaginal HIV Microbicide Research

      Several sessions on issues for women addressed the need for research
into preventive female-controlled microbicides which could be placed into the
vagina prior to intercourse to help prevent HIV transmission. William Paul,
MD, from the Office of AIDS Research at the NIH indicated that his office is
committed to providing research dollars for finding anti-HIV vaginal
microbicides. Paul delivered a plenary presentation entitled, "A Turning
Point in AIDS Research: the Search for New Frontiers."

      Elias C. Presented at Female-controlled Prevention, special session
      SS2. X International Conference on AIDS. Yokohama, August 1994.
      Abstract SS7 and oral presentation.

      Paul WE. A turning point in AIDS research: the search for new
      frontiers. X International Conference on AIDS. Yokohama, August 1994.
      Abstract PS9 and plenary session oral presentation.

      Stein ZA. Women helping themselves. X International Conference on AIDS.
      Yokohama, August 1994. Abstract PS5 and plenary session oral
      presentation.

      Weiss E. Presented at Female-controlled Prevention, special session
      SS2. X International Conference on AIDS. Yokohama, August 1994.
      Abstract SS9 and oral presentation.

      ----------------------------------------------------------
      Cesarean Delivery to Help Prevent HIV Infection in Infants

      Martha Rogers, MD, reviewed a meta-analysis of 11 studies that
evaluated the potential lower risk of HIV transmission from mother to newborn
when delivered by cesarean section. Six studies showed a lower risk of
transmission, while 4 showed a higher risk (and one revealed no difference).
However, when the mother-infant pairs from all 11 studies were tallied for
the meta-analysis however, there was a 20% lower risk of HIV transmission
from cesarean section versus vaginal delivery.

      Rogers M. Prevention of maternal-fetal transmission of HIV. Presented
      at Treatment of HIV Disease: Advances and Future Challenges, University
      of California at Los Angeles (UCLA) satellite symposium. X
      International Conference on AIDS. Yokohama, August 1994.

      ----------------------------------------------
      One-Third of World Population Infected With Tb

      Of the 5.7 billion people on the planet, one-third or 1.9 billion
people are infected with Tb. Those who are co-infected with HIV and Tb number
5.6 million. Yet tuberculosis is considered a low priority in the world,
according to Arata Kochi, MD, the Tb Program Manager for the World Health
Organization.

      Kochi A. Tb, a global emergency: World Health Organization report on
      the Tb epidemic. X International Conference on AIDS. Yokohama, August
      1994. Oral presentation.

      --------------------------------------------------------------
      HIV Infection Worldwide (Cumulative HIV as of January 1, 1994)

                           Adults        Men     Women  Children      Total

 1  North America       1,123,000    963,000   160,000     4,000  1,138,000
 2  Westem Europe         654,000    545,000   109,000     6,000    660,000
 3  Oceania                27,000     24,000     3,000   < 1,000     27,000
 4  Latin America       1,252,000  1,002,000   250,000    61,000  1,313,000
 5  Sub-Saharan Africa 13,463,000  6,411,000 7,052,000 1,996,000 15,459,000
 6  Caribbean             376,000    225,000   150,000    26,000    402,000
 7  Eastern Europe         28,000     25,000     3,000   < 1,000     28,000
 8  SE Mediterranean       57,000     47,000     9,000     2,000     58,000
 9  North East Asia        93,000     77,000    15,000     1,000     94,000
10  Southeast Asia      2,952,000  1,968,000   984,000    68,000  3,020,000
      
    Total World        20,025,000 11,287,000 8,737,000 2,175,000 22,200,000

      Source: Global AIDS Policy Coalition, AIDS in the World, vol. II
      (Oxford University Press, 1995, forthcoming)

      --------------------------------------
      Aggressive Treatment for HIV Infection

      The following is an edited transcript of 3 BETA LIVE! telephone
      teleconferences held July 12, 14 and 19, 1994. Participants included
      Ronald Baker, PhD, Mark Feinberg, MD, PhD, Thomas Merigan, MD, David
      Katzenstein, MD and Mary Romeyn, MD.

      Dr. Mark Feinberg is Director of the Virology Research Laboratory at
San Francisco General Hospital, where he also cares for patients at the
hospital's world-renowned AIDS clinic. 

      Dr. Thomas Merigan is Professor of Medicine at Stanford University,
where he also directs the University's AIDS Clinical Trials Unit (ACTU). The
Stanford program is part of a government-funded coalition of medical centers
across the country that conduct human studies of AIDS treatments.

      Dr. David Katzenstein is Associate Medical Director of the AIDS
Clinical Trials Unit of Stanford University. He is also co-directing a large
government-sponsored trial (ACTG 175), a study among 2,500 people that is
comparing the effectiveness of immediate versus deferred double-combination
treatment for HIV infection.

      Dr. Mary Romeyn is an internist and community physician with an HIV
practice in San Francisco. She has a special interest in nutrition and has
written a book entitled, Nutrition and AIDS: A New Model for Treatment,
scheduled for publication next year.

      Ronald Baker is editor of BETA.

BAKER: Dr. Feinberg, let's start with a question for you. As you know,
      there's considerable controversy among physicians, researchers and even
      patients about the most appropriate time to begin anti-HIV treatment.
      Could you describe for us what is now known about the pathogenesis of
      HIV disease and how our understanding of this process may affect the
      decision of when to start drug treatment?

FEINBERG: The understanding of the pathogenesis of HIV infection, or how the
      virus causes disease, is an incredibly important thing to consider when
      you're trying to figure out how best to treat it. Earlier in the course
      of the epidemic, after HIV had been identified as the cause of AIDS,
      the tools to detect how much viral replication was going on in
      HIV-infected people were really quite insensitive. As a result of that,
      there was a tremendous under-estimation of how much viral replication
      was going on throughout the course of the disease. It was believed that
      there was little viral replication going on during the asymptomatic
      period of HIV infection, and that viral replication would only be seen
      in the later stages of the disease, when people started showing signs
      of immunodeficiency, such as developing opportunistic infections.

      If there's not much viral replication going on, it seemed to make sense
      that you don't really need to treat people during the asymptomatic
      phase of the disease. As a result, a lot of the therapies were reserved
      for people in later stages of disease. 

      We now appreciate that notion was fundamentally wrong. What allows us
      to say this are technological advances that have changed the way we
      think about the disease process. In the future, this new medical
      technology will have direct application to the care of HIV positive
      people, and will probably improve the outcome of that care.

      We now have tools that are very sensitive at detecting HIV replication
      in people. Studies using these tools of how much viral replication is
      going on in different stages of the disease give clear and striking
      answers. It's clear now that there is much more replication of HIV
      going on throughout the disease process from the time that one is first
      infected with the virus, during the asymptomatic period and
      increasingly in the later stages of the disease process. 

      This leads one to an important theoretical conclusion: if the
      replication of the virus is what causes the disease (and we now have
      reason to believe that this is true) then it makes sense to try to
      intervene early, perhaps very early in the disease, when you first
      identify someone as being HIV positive. You want to preserve their
      immune function when it is maximal and the amount of virus replication
      is as low as it is ever going to be found in that individual.

      Unfortunately, as I'm sure everyone listening today knows, the results
      of the recent Concorde study of when to intervene with zidovudine [AZT]
      were not what everyone had hoped. The study conclusions were not a
      ringing endorsement for early intervention. It's important for us to
      think about why that might be the case. Is that because the notion of
      early intervention is wrong, or is it because AZT, when used by itself,
      is not a particularly potent anti-HIV drug?

      We now have ways to document if antiviral therapy is effective and
      beneficial. We also can apply those tools to try to individualize
      therapy: to identify which are the most active drugs for a given
      individual, to decide when those drugs may no longer be benefiting that
      person, and to know specifically when to change to another drug. 

      I hope this will be translated into improved outcomes in the care of
      people, prolonging the quantity and improving the quality of their
      lives. The means to do this are not available today. It's going to take
      a lot of effort to make that happen. I hope it will be happening with
      increased vigor over the course of the next year.

BAKER: Dr. Merigan, first, thank you for taking time from your vacation to
      join us. Mark mentioned the concept of individualized therapy. Could
      you explain what that concept means in the context of HIV disease?

MERIGAN: For many years, even with imperfect tools, physicians have tried to
      monitor the impact of the drugs they're giving, and to avoid toxicity.
      Determining for example, whether a patient might have peripheral
      neuropathy, you could choose to use or not use a given drug. CD4 counts
      [T-cell counts] have been monitored as another way of determining
      whether the immune system was being protected. 

      The problem is that CD4 cell loss is a relatively late result of
      increased changes in viral replication. It's better to look at the
      viral load itself. Our first efforts to look at viral load were by
      culturing the virus from plasma or cells. We found that people in
      advanced disease had higher levels than people with earlier disease,
      and that drug therapy reduced those levels. Now we have RNA detection
      methods for measuring viral load in the serum of patients. I think
      these techniques promise to be able to give day-to-day,
      minute-to-minute information as to whether we're suppressing virus in
      the patient. 

      We actually want to move one more step closer. We want to see whether
      the drug is active or not by looking at the important drug-sensitivity
      loci, to see whether there is the smallest percentage of mutant virus
      arising in the patient. I've noticed that a patient sometimes develops
      a mutant virus at very low viral loads. So if you can identify those
      mutational changes, you can move even closer to the action of the drug.
      What we want to do is to use these drugs as long as they're active in
      a given patient. When we look at mutation rates, we see that some
      patients don't become mutant for 3 or 4 years, while others may do so
      in a few months. 

BAKER: Dr. Feinberg, both you and Dr. Merigan have mentioned "new tools."
      What are these tools, and what can we expect from them?

FEINBERG: The new tools that I think are most promising are ones that measure
      the amount of HIV RNA (the genetic material of the virus that's found
      in the virus particles that are present in the blood) in the plasma of
      people who are HIV positive. There is enough HIV RNA present throughout
      the course of the disease process to be detected by the sensitive
      methods that are now available.     T-cell counts drop after the amount
      of virus replication in an individual has already started to increase.
      Ideally, you would prevent that sort of damage before it happened. What
      these new tools do is permit us to look directly at the amount of virus
      in an individual. The amount of virus in an individual is frequently
      referred to as the viral load. 

      Basically, these methods basically amplify a signal that is there so
      that you can detect minute quantities of HIV RNA. One of the methods to
      detect that signal is the so-called polymerase chain reaction or PCR,
      which is a very sensitive technique that amplifies the numbers of RNA
      copies. With certain modifications you can actually estimate the
      precise number there. So, ideally, if you had someone with 100,000
      copies of HIV RNA in their blood, you would start them on treatment.
      You would want to see that number fall significantly, maybe down to
      10,000 or 1,000. You could monitor the level of the HIV RNA in their
      blood at intermittent periods. If the drugs were losing their
      effectiveness, you would expect to see the copy number of RNA increase,
      which would tell you that it's time to change to another drug. These
      tools allow you to really individualize therapy. 

      There are a number of versions of PCR in development. Hopefully, they
      will soon be available in a format that can be used in clinical labs
      and by physicians. They aren't validated for that use yet, so it's not
      going to be something that someone can go and ask their physician for
      tomorrow, but maybe next year.

      There's another technique that measures the genetic material of the
      virus, or HIV RNA, called a branched DNA assay [bDNA]. It works in a
      different way. It uses very sensitive probes to detect limited
      quantities of HIV RNA in the plasma. The bDNA test is probably closer
      to clinical usefulness. It's not as sensitive as PCR, but it's easier
      to use and slightly further along in its development. Hopefully, again,
      both tests will be available for clinical practice soon. But before
      that, it's going to be important to validate that, yes, this notion of
      individualizing therapy by decreasing viral load actually gives you a
      clinical benefit.

MERIGAN: The tests will probably become available before they're completely
      validated. Probably next year, both the PCR and the bDNA tests will be
      available to more practicing physicians, but we will only have them
      document where we are with a given patient, and that's different than
      knowing that you can use it usefully. We're going to have to set up
      clinical trials with the final forms of the tests, and then show that
      knowing the information [HIV load] allows you to do better than if you
      don't know the information. We're having a lot of trouble designing
      those trials at present, but we are all committed to doing them. 
      Another approach is to actually look at the key mutations of the virus.

      In ACTG 244 we're monitoring for the key mutation in AZT resistance,
      which takes place before the CD4 count drops, and we're seeing if
      switching drugs based on that really has an advantage for the patient.
      We're randomizing patients to continue AZT or combinations to see if
      the rational shifting of the drug based on what we think is the key
      mutation defends the immune system longer against destruction by the
      virus.

BAKER: Thank you, Tom. Let's take a few questions now. San Diego, California?

SAN DIEGO, CA: Good afternoon. Several different labs here in California are
      evaluating whether it's better to look at PCR as a qualitative or a
      quantitative test. Is there anyone out there who has done clinical
      trials to test this PCR, if it's going to be the surrogate marker of
      choice in the future?

MERIGAN: We went back to specimens from ACTG 019 and ACTG 016 and looked at
      viral load. In some of the original AZT trials, we saw that using PCR
      you can measure quantitative viral load, and that when that rises in
      the patient on AZT, CD4 counts fall. We think that viral load is
      closely associated with CD4 changes, but it's a more precise
      measurement. If you look at patients on a day-to-day, week-to-week
      basis, it's much more steady as a signal, and we're talking about
      changes, as Mark said, from 10 to the 6 down to 10 to the 2. With the
      best drug combinations, you can get 2 and 3 changes. And as long as
      those continue, I think you're doing well with the drug, but we have
      to find that out, and that's why this validation phase is necessary.

FEINBERG: I think that there is accumulating information about the utility of
      these tests. For instance, Tom referred to looking back at studies that
      had already been completed to see if you could learn more by applying
      these RNA tests, and he found that the answer was yes. There are
      other examples. For instance, studies of the Merck non-nucleoside RT
      [reverse transcriptase] inhibitor, the so called L-drug [L-554], where
      resistance was found to develop quite rapidly. You can see a dramatic
      fall in RNA levels, which then shortly afterward increase again because
      the virus has become resistant to the drug. PCR really does allow you
      to monitor in real terms the amount of replication going on in a patient.

      But the caller raises an important question: a number of these assays
      are being explored now in research laboratories to try to figure out
      what is best. I don't know that those are yet available to the average
      practicing clinician. It's important that these tests be performed by
      people who know what they're doing. Otherwise, the information you get
      can be very misleading, and I think that would be a disservice to the
      patient.

MERIGAN: Two diagnostic companies, Hoffman-La Roche and Chiron, are very
      serious about this. Both are on a development track toward licensing
      their own kind of assay for looking at viral load. ACTG has gone
      through a number of prospective and retrospective studies with them.
      I think that these assays are going to be convincing enough for the
      FDA to license them. More and more drug companies are now using them
      in their trials of new drugs. That these assays are now available only
      in research labs is a necessary but temporary phase. In this disease we
      have to move quickly to make them available to practicing physicians. 

      MIAMI BEACH, FL: Hi. This is for Dr. Merigan. I was one of the original
      participants in the ACTG O19 AZT study in 1985-86.  What is the
      outcome of ACTG 019, and what has it shown, generally, compared to the
      Concorde AZT trial? I believe that the conflicting results of these trials
      are keeping people off of AZT, when they may benefit from treatment
      early on. Thank you.

MERIGAN: Well, I think you're certainly right that the release of the Concorde
      AZT information confused a lot of people. Concorde was basically not so
      much a direct comparison of drug to placebo, but rather a comparison
      of delayed versus immediate treatment. Once the 019 results were
      released, the patients in the Concorde AZT trial could start themselves,
      and their doctors could start them on therapy [AZT], even if they were
      in a placebo limb. The Concorde trial shows a more transient impact
      from AZT therapy on disease than we thought, based on data from the
      019 study. The Concorde study indicated that the main impact of AZT
      was for the first 1-3 years of use, and it was better at higher CD4
      levels than it was at lower CD4 levels. All of us who were in the
      original 019 study knew we wanted to get an active drug out there, and
      we thought we had seen a permanent, durable AZT effect. What has
      been disappointing, really, is that we've been slow to develop the
      followup drugs or the drugs to use in combination. It isn't because
      people weren't working on it, but that there were difficulties. A lot of
      drugs have fizzled out in late-stage testing. 
      We're starting to develop a new class of drugs, the protease inhibitors.

      I think the protease inhibitors will meld in with the nucleoside analogs,
      [AZT, ddI, ddC, 3TC and d4T] and probably will only be used in
      combination. 

      Some people like yourself, perhaps, did well with early initiation of AZT.
      On the other hand, the average patient probably gets a benefit from
      AZT of 1-2 to maybe 3 years. What we need to learn is when to move
      on to other drugs, or how to maximize the durable impact of AZT by
      combining it with other drugs. And I think we're continuing to learn
      more about both of those issues, as well as these diagnostic tests to
      help drive rational therapy. 

      I know that people were looking for something that would completely
      normalize the process, like insulin for diabetics. Instead, it's more likely
      to be a matter of changing drugs periodically. My hope is to normalize
      the lifetime of an HIV-infected person. That's the driving principle in
      the field and what all of us want. I think it can happen, but it's going
      to take more drugs, more testing and new methods to evaluate drug
      activity.

BAKER: Dr. Romeyn, a question for you. If an HIV positive patient who is
      asymptomatic or mildly symptomatic comes to you and says, "I want to
      pursue a very proactive, aggressive treatment strategy," what practical
      advice can you offer him/her in terms of drug therapy and other
      possible interventions? 

ROMEYN: Given what we've learned over the past couple of years about HIV,
      my own bias is more and more in favor of early and aggressive
      antiretroviral therapy. We saw in the European/Australian collaborative
      group study that people with high CD4 counts actually benefitted from
      antiretroviral therapy, and they had 650 CD4 cells on average. That's
      a powerful indication that there's value to early treatment. So given
      that, and given the fact that people with HIV don't have time to wait
      to be sure of what the results are going to be, I think when people ask
      for it, it's appropriate to offer treatment regardless of CD4 count. We
      now know that AZT has a more lasting effect before resistance develops
      in a less advanced population, and I think it seems reasonable for
      people to push that as far as possible while waiting for definitive data.
      We also know we have new drugs coming, something we just talked
      about. So if a patient wants to take an aggressive approach, and if the
      medicines are available, I think it's reasonable to throw everything we
      can at the virus right from the beginning.

      In my practice many patients start with combination antiretroviral
      therapy right from the beginning. We already have some evidence that
      this type of therapy is more successful in people with lower CD4
      counts, and I think we'll look with interest at the results of ACTG 175
      to find out what it does at an earlier stage. But for now, if a patient
      wants to jump right in with both feet, I offer both. We offer AZT in
      combination with ddI or ddC right from the beginning. We usually start
      the AZT at half dose, or about 100 mg 3 times a day, and we check with
      the patient by phone in about 2 weeks. If he or she is comfortable with
      the drug by then, and any side effects have been managed, we push
      the dose up to 500 or 600 a day. When they come back 2 weeks later,
      we start the next drug. That way if we have a problem, we have a
      better sense of which drug caused it, and we don't lose access to the
      other.

      Acyclovir also may have some value. It's been shown to increase
      survival in late-stage patients and I think there's some interest in
      using it in the early phases. Again, this is an aggressive approach, as
      we don't have proof of its impact on progression in early stages. But
      I think it's worthwhile to consider. In later stages we routinely
      recommend acyclovir.

      But what I'd really like to talk about is the whole picture of HIV
      treatment. I think of us as sort of getting ready for a marathon. If you
      go into training, you last longer, and you feel better while you do it.
      So we try to get our patients to prepare, to be stronger for what's
      coming up. Alcohol, for instance, has been shown to increase viral
      replication in vitro, so we discourage it. We recommend not smoking
      cigarettes. We particularly discourage methamphetamine and cocaine.

      We stress safe-sex activities to protect the HIV negative partner and,
      in the HIV positive patient, to avoid infection with other organisms
      which might trigger the acute phase response. As you can tell from the
      title of my book, Nutrition and AIDS: A New Model for Treatment, I have
      a special interest in maintaining nutritional competence. We've seen from
      the early Cotler studies that there's a clear correlation between the
      degree of wasting and the timing of death. This suggests that
      prevention and attenuation of the wasting process may give us a shot
      at longer survival, and I don't think any of us would question that it
      improves quality of life.

      So as soon as a patient walks in the door, we get a nutritional consult.
      We assess their lean body mass, urge them to pay attention to what
      they eat and how much, and to stay alert for abnormalities in their
      absorption. We continue to monitor their nutritional markers all the way
      through their disease course. We also recommend antioxidants, and
      everybody in the practice takes multivitamins and trace elements. For
      those who are asymptomatic or mildly symptomatic, such as you
      suggested, Ron, I prescribe progressive resistance exercises in the hope
      of adding to lean body mass while we can. We don't yet have
      information on the value of exercise in later stages. 

      We also ask patients to watch closely for signs of infection, and to alert
      us quickly so we can get ahead of things. We stress hygiene and ways
      to avoid common infections. We stress sleep and recreation. We ask
      about stress and major areas in people's lives that are the focus for
      pain. I think some of these can be changed easily, and I think others
      should be considered for change over the long term. 

      There are other things, too, you can do to be proactive. There are
      studies in cancer showing that survival can be increased by belonging
      to support groups. I think this should be suggested to patients. There
      have been some writings by Frankel on survivors of German
      concentration camps, who noted that probably a critical element to the
      people who survived was that they were dedicated to something outside
      of themselves. I think there's a real good way to apply that here, and
      to join the fight against HIV on a bigger level. We suggest that people
      participate in trials or studies whenever it could be to their advantage.
      We always urge membership in an observational database. We also
      suggest volunteering or political activity targeted to HIV. That's how we
      get started; then we go on to the drugs.

BALTIMORE, MD: I am at a late stage of HIV disease. I have very low T-cell
      counts, in the single digits, and I have been on AZT for over a year.
      I'm considering changing to another drug. One of the suggestions that
      my physician had was d4T [Zerit], which was recently approved. But I
      have several friends who've had negative experiences with d4T, ddI and
      ddC, so I'm a little hesitant about going on d4T. Could any of the
      panelists talk about this?

MERIGAN: I'll take a quick stab at it. I think d4T is a good drug for patients
      with advanced HIV infection. We don't have, however, a lot of experience
      with it in patients who aren't having problems with AZT or ddI or ddC.
      I think that the safety of d4T is pretty good. d4T is the one of these
      drugs [nucleoside analogs] where we have not yet seen a mutation
      pathway. I think the risk of neuropathy from d4T is less than 5%, and
      if you can catch it early, it's completely reversible. That's the
      downside. The potential rise in CD4 and arrest of virus replication is
      the upside.

FEINBERG: I would agree with what Tom just said. The worst thing probably
      that would happen is you would try the drug for a brief period of time
      and find that it didn't suit you, that you experienced neuropathy. If
      you and your physician are aware of it, the drug could be stopped as
      soon as possible, and the neuropathy should go away. At this point, it
      might be a reasonable treatment to consider trying.

ROMEYN: I'd like to say one thing. I think one consideration would be the
      possibility of continuing the AZT, and adding ddI or ddC. While it's true
      that there are resistant mutants that develop that still need attention,
      we continue to have a suppressed, wild-type virus in people who've
      been on AZT, and I'd rather not let that get away from us. I guess I'm
      more concerned about this in people with low CD4 counts, based on
      some of the suggestions that AZT prevents or at least greatly reduces
      the cytopathic changes in the brain on autopsy in late-stage HIV
      patients. I guess my own interest, if the virus had escaped AZT, might
      be in adding something, rather than changing to something.

BAKER: Dr. Katzenstein, you're directing a large government-sponsored study
      that's comparing the effectiveness of early versus deferred combination
      treatment. If you were HIV positive and you had made the decision to
      start drug treatment, would you start with a combination of anti-HIV
      drugs or would you use only one drug? Please explain the reasons for
      your decision.

KATZENSTEIN: Sure, and I welcome the opportunity to talk about
      decision-making in this, because that's what so many people are
      spending so much time doing. I think there are some fundamental
      principles in the world of infectious disease, which is where I trained,
      that are as applicable to HIV infection as to any other serious bacterial,
      fungal or viral infection. In terms of drug management, it's a very good
      idea for patients and HIV positive people to try to do one thing at a
      time so you can really assess what effect that one thing is having. This
      is a simple principle but one I have to constantly reinforce in the
      course of doing infectious disease consultations and talking to patients.
      It's a very important one with antiretroviral therapies, prophylactic
      therapies and, perhaps as Mary will be talking about later, even
      nutritional or alternative therapies. It's easy to embark on a course of
      treatment where there are multiple drugs or alternative
      immunotherapeutic agents, and then become embroiled in a very difficult
      situation where you're not sure which of the many things you may be
      trying is producing either a good or an ill effect.

      I don't think there's any compelling argument at the moment that shows
      that bringing all the elements and even combination therapy together
      at once in an individual patient achieves anything greater than the sum
      of their sequential addition. My advice to people is to certainly initiate
      at the point where they want to initiate antiretroviral therapy. Most
      experts recommend beginning somewhere below 500 CD4 cells. Most
      people recommend beginning with AZT, and to see how that affects you,
      your CD4 count and any of the different parameters which can either
      be measured at the moment or may be measurable in the future, such
      as viral load.

      In answer to your question, Ron, I would start AZT, wait a period of
      time, and then probably add a second antiretroviral drug, unless I was
      extremely happy with the response that I was getting from AZT alone.
      I think people should assess antiretroviral therapy the way they would
      almost any other therapeutic relationship with a drug. That is, if it
      makes you feel much worse, perhaps it's not the best drug for you,
      even if it's recommended at that phase of the disease. Some of the
      problems we've seen in people initiating AZT, including severe nausea
      or headache, are the kind of thing which I don't think should be
      tolerated for long periods of time.

      There's often a 1 or 2 month period of getting used to the drug, after
      which these side effects go away, so I encourage people to give it some
      time to be sure that they can or can't tolerate AZT. Perhaps to play
      with the dose to reduce it a bit if they're having a great deal of
      difficulty taking it. The second step would be to add a second
      antiretroviral. 

      The jury is certainly still out as to whether it's best to start with
      combination therapy or to take monotherapy with AZT or potentially ddI
      initially, and then to move to a combination. We may have better
      information next spring about initiating single-agent vs combination
      therapy. ACTG 175 is scheduled to close in April 1995 and we'll begin
      analyzing all the data.

BAKER: When is your Data and Safety Monitoring Board (DSMB) taking a look
      at the data? The trial has been going on for about 2 years now, hasn't
      it?

KATZENSTEIN: That's right. And they've been looking essentially twice a year.
      At our upcoming DSMB meeting [August 1994] the blinded data will be
      revealed to the DSMB by the protocol statistician. It's possible, if
      there's a particularly dramatic difference, that the DSMB would tell us
      to stop the study. But it's more likely that we will continue until April
      1995. We've tried to incorporate all the experiences of the last few
      years in terms of looking at endpoints. We began this study convinced
      that we could use the falling CD4 cells as an endpoint. Now, we use it
      as a means of deciding to switch people from monotherapy to
      combination, or if they're on combination, switch them to a different
      combination, based on a 50% fall in their CD4 count.

      In the wake of results from the Concorde AZT trial and concern about
      the importance of clinical as opposed to the surrogate marker endpoints,
      we made our constraints on stopping the study tighter. We said we
      wanted to see some difference in clinical endpoints before stopping the
      study. Now, because we started with a large group of people, but
      nevertheless a largely healthy group of people, we're not likely to see
      big differences in clinical endpoints. So, again, I suspect that we will
      continue until April '95. We should have very interesting comparisons
      in the rate of CD4 cell decline and the frequency with which people on
      monotherapy or combination have a loss of CD4 cells, but I can't tell
      you exactly how it's going to turn out.

FREEHOLD, NJ: I have a question for Dr. Feinberg. Considering vital
      resistance factors, how would you treat patients who are on combination
      ddI and AZT who are failing that treatment?

FEINBERG: I can make certain recommendations but it's currently difficult to
      know exactly what the right choice is. With the availability of d4T and,
      in many places, 3TC, adding to the list of the other approved nucleoside
      analogs such as AZT, ddI and ddC, people do have options. Things to
      consider would be trying to switch to an alternative of nucleoside
      therapy or, if possible, entering into a clinical trial of another agent,
      such as a protease inhibitor.

BAKER: One immediate option that comes to mind is perhaps switching to Zerit
      (d4T), which will be available by prescription in mid-August. You might
      also want to consider combination therapy with ddI and d4T. There's a
      pilot study of ddI plus d4T that's recruiting now.

FEINBERG: But it is important to see that study through, because both drugs
      can cause neuropathy.

BAKER: Absolutely. Your physician would want to monitor you carefully for
      peripheral neuropathy, on that combination. A call from Detroit,
      Michigan.

DETROIT, MI: The first question I'd like to ask is for Dr. Romeyn. If you
      found a patient who has been prescribed Bactrim to be allergic to it,
      would you consider desensitizing that patient as opposed to switching
      to dapsone, which may have a higher breakthrough rate than Bactrim?

ROMEYN: Initially I probably would have already done a G6PD test, and I'd go
      ahead and try the dapsone, but frequently somebody who has a problem
      with Bactrim is also going to have a problem with dapsone. I am
      interested in Bactrim desensitization, and we've had a lot of luck with
      it, though I don't know that we call it desensitization any more. 

      Initially we thought this [side effect from Bactrim] was an allergy, but
      now what we're finding is that it has to do with the body's
      inappropriate capacity to break down the drug. There are some
      metabolites that can make trouble if it's present in high doses. We have
      certainly had good luck working with the Bactrim suspensions, starting
      in low doses and eventually getting people up to the equivalent of one
      double-strength tablet, 3 times a week without much problem.

      Some new information has come out suggesting that the problem with
      the metabolism of Bactrim is part of the whole glutathione reductase
      process. Part of why we're doing so well with Bactrim may be because
      we're swarming our patients with antioxidants. 

BAKER: Any comments from the other panelists on desensitization for
      Bactrim/Septra?

KATZENSTEIN: At Stanford we're using Dr. Marcus Conant's protocol, which
      was worked out with some of the pharmacologists at UCSF. I favor
      trying this desensitization regimen over switching because I think
      there's value to Bactrim prophylaxis that extends outside of PCP, in the
      world of other bacterial infections. Bactrim is a useful antibacterial
      agent against a number of common problems that might be listed among
      those that cause a lot difficulties for people with HIV, such as sinusitis
      and pneumococcus.

BAKER: A recent study at UCSF showed that Bactrim not only was the best
      prophylaxis for PCP, but also for toxoplasmosis. That certainly would be
      an added advantage of using the drug, if people can tolerate it. 

WASHINGTON, DC: I have 2 questions. The first question is for Dr. Romeyn on
      her comment about acyclovir. I wanted her to clarify whether or not
      she suggests acyclovir should be used in all patients and if so, just as
      a suppressive regimen, or just in people with positive histories of
      shingles or genital herpes.

ROMEYN: There have been studies that show that the daily use of acyclovir
      significantly increases the lifespan of people with HIV and AIDS who are
      also on AZT. In the atmosphere of managed care in San Francisco, I
      certainly would be happy to find a diagnosis that gave me an excuse
      to prescribe acyclovir. My interest would be in using acyclovir at any
      rate. There are many herpesviruses present in the body, possibly even
      some that we don't yet know about, but we do have evidence that some
      herpesviruses do act as cofactors in disease progression, others even
      than HSV-1 and HSV-2 or Epstein-Barr virus. 

      I tend to test routinely when people come in for the presence of
      herpes-1 and-2 antibodies. It's very, very rare that I don't find them.
      Another indication for acyclovir that one can use to get the medicine
      for a patient is hairy leukoplakia.

KATZENSTEIN: I think it may be important to note that the studies
      demonstrating the utility of acyclovir were in patients with low CD4 cell
      counts, and I think the caller's question, if I heard it correctly, was
      whether the use of acyclovir would be recommended at all CD4 levels or
      stages of HIV infection.

WASHINGTON, DC: Yes, that's correct, Dr. Katzenstein.

KATZENSTEIN: Although it's hard to come up with an argument against
      instituting it early, other than the $2,000 or $3,000 a year that it costs,
      I'm not sure that we have any real indications that for someone without
      recurrent herpes who's asymptomatic otherwise, and who has high CD4
      cell counts, that we get any extra boost or bang out of adding chronic
      acyclovir to their regimen. Dr. Romeyn's quite right that the Australian
      study implied that people with CD4 cell counts of, I believe it was less
      than 100 and/or an AIDS diagnosis, seemed to benefit from being on
      chronic acyclovir. There isn't any evidence of efficacy of a combined
      regimen in asymptomatics, and certainly as part of early intervention
      it could be proposed, but there's little data to base it on. Is that a fair
      summary, Dr. Romeyn?

ROMEYN: I would agree with that. I do think, though, that people who have
      HIV now sometimes are willing to base their behavior and their choices
      on theoretical or potential advantage, and I guess in this office we tend
      to operate from the "couldn't hurt" mentality once in a while. There's
      another study that showed a remarkably high amount and frequency of
      viral shedding from the oropharynx of persons with HIV who had
      positive antibody tests for herpes, but who had no idea that they had
      it. My real interest is in dampening the fires of the cytokine response,
      which essentially causes the conversion of monocytes to macrophages
      and the release of HIV which into the body, which increases viral
      replication. I would imagine we probably are on the aggressive side in
      this area.

FEINBERG: I would also like to respond to that question. We need to
      understand exactly what the role for acyclovir in the treatment of HIV
      positive people is both mechanistically and practically. Dr. Romeyn's
      concerns about activating HIV replication by having these sort of
      ongoing chronic immune stimuli is a very important subject. If true, it
      has implications for all kinds of other infections that would be going on
      [in HIV positive people.] I would prefer to try to sort that out rather
      than just assume that it's true. Otherwise everyone who's HIV positive
      is going to end up taking multiple drugs, some of which they may not
      need. I think we need more information to really understand, if
      acyclovir does have a survival benefit, how it is mediated.

GAINESVILLE, FL: Yes, I was wondering about protease inhibitors and also
      about peripheral neuropathy.

KATZENSTEIN: Well, we now have a little experience with them in combination.
      There was an AIDS Clinical Trials Group study [ACTG 229], which you
      summarized in the most recent BETA very nicely, Ron, where there were
      clearly some short-term benefits, in terms of surrogate markers, to
      using protease inhibitors in combination with AZT and ddC. I think the
      protease inhibitors are going to be very useful for people who have
      experienced peripheral neuropathy on ddC, ddI or d4T, because they
      represent an alternative.

SAN FRANCISCO, CA: In 1985 I only had 40 T-cells, and today I only have 10.
      I'm still alive. My question is, why hasn't there been an effort to
      develop a recombinant human T-cell growth factor? I know it's been
      used in laboratory experiments in virology to keep human T-cells
      growing in the test tube. Without the substance it's very difficult to
      culture CD4 cells outside of the body. But when you have this
      ingredient, the rate of success is much higher. So my question is, why
      hasn't somebody tried to develop a product like Neupogen, which is a
      recombinant granulocyte cell-colony stimulating factor? I think Neupogen
      infusions could be clinically useful.

MERIGAN: Well, this is a 2-sided coin you're talking about. That is, activating
      the cells can also make them more able to replicate virus. Mark, I'm
      sure you could say something interesting about that.

FEINBERG: There actually is a recombinant human T-cell growth factor. It's
      known as interleukin-2 (IL-2). Interleukin-2 has been evaluated in HIV
      positive people for [its possible] benefit. Some of those studies were
      conducted by Tom Merigan's group at Stanford, and he may want to
      talk about that. There are more recent trials that have some intriguing
      preliminary evidence about infusions of IL-2 being able to increase
      T-cell counts in people in the range of 200 or so, or higher than the
      caller's. But, as Tom said, it's a 2-sided sword. We don't really know
      whether those increases are beneficial, but we do know that HIV
      replication is activated by things that activate T-cells, IL-2 being one
      of them.

      It looks like there are short bursts of increased viral replication after
      you give someone IL-2. Whether that causes them any harm or not, we
      don't know, but it will have to be answered in clinical trials. It's
      important that trials with IL-2 move ahead. The problem with IL-2 being
      given to people with advanced HIV disease is not analogous to giving
      Neupogen to someone with advanced HIV disease. Not only does HIV
      damage T-cells, but it also damages the architecture of the lymph
      nodes, the thymus and other important lymphoid organs that are
      necessary for the maturation and development of T-cells. I don't think
      it's going to be so simple as just giving back the growth factor. We're
      going to have to figure out ways to fix or reverse the damage that HIV
      causes to the structures of the immune system as well.

MERIGAN: And what we do may be very disease stage-specific. In our studies
      of IL-2, people also took AZT. One of the reasons we were one of the
      first groups to measure RNA viral load was that we had to do it
      because of the interleukin-2 studies. We were afraid that something that
      increased virus replication in vitro would do it in vivo. As Mark said,
      there's a small burst with each infusion, but we don't know whether
      that's bad or good. It does mean we have to go a little slower. 

      Once patients have less than 100 CD4 cells, we haven't seen a big
      increase in their CD4 cell numbers with interleukin-2. It's really only
      from 100 to 200 that we might get a 25% increase, whereas some
      phenomenal increases of 200% and 400% have been seen in patients who
      had over 200, or over 300 CD4 cells. But we don't know whether those
      lymphocytes are educated and knowledgeable, whether they'll do
      anything to microorganisms, or anything useful for the patient. You
      have to know, are those dumb or smart lymphocytes, can they do the
      job lymphocytes have to do? Rebuilding the immune system is a new
      game, and we have to go at it thoughtfully.

KATZENSTEIN: Interleukin-2 is a cytokine that is probably very important in
      the stimulation of T-cell replication, T-cell signalling and communication
      between macrophages and T-cells within the immune system. It's kind
      of a growth factor for CD4 cells, thought to promote their division and
      certainly their movement into the peripheral blood. Some promising
      results came from our laboratory as long as 2 or 3 years ago, as well
      as from the NIH and Dr. Cohen in New York, and one of his associates,
      Heady Kepler. All have published on CD4 increases in people receiving
      interleukin-2. That's the good news. 

      The bad news is this is a difficult drug to take because it causes a
      myriad of systemic changes. It changes the vascular permeability of the
      lungs, causing the "6-hour flu-from-hell" syndrome in which people
      have a lot of watering of their eyes, stuffiness in their sinuses.

      A lot of interleukin-2 is presumably produced in the course of viral
      infection, so you get a kind of viral syndrome associated with high
      doses of it. Another thing that hasn't been sorted out yet is the
      duration of the effect on CD4 cells that has been documented in some
      patients receiving IL-2. Although people's CD4 counts go bouncing up,
      is IL-2 perhaps just causing a shift in the location of CD4 cells in the
      body? Is it causing a lot of CD4 cells to move out of the lymph nodes
      and the spleen, and into the peripheral blood, where they can be
      counted; do they then sort of disappear back from whence they came?
      Or are we really increasing the number of immunologically active CD4
      cells [with IL-2 treatment]? 

      There's a lot of encouraging work saying that people have somewhat
      better immune responses in vitro after receiving IL-2, but again, these
      effects tend to be fairly short-lived. The drug is fairly hard to
      tolerate, but it seems that it's not dangerous. By that I mean that
      people were also very worried about IL-2 being a sort of
      "pouring-gasoline-on-a-fire" kind of drug. We use it in the laboratory
      all the time to keep CD4 cells activated and replicating so they can
      grow virus [for us to use in experiments]. 

      We've done PCR measurements of viral load in people receiving
      interleukin-2, and so far we're comfortable with its safety. We've always
      done this in people who are simultaneously receiving antiretrovirals. We
      require all of the patients to whom we give IL-2 to at least also take
      AZT, and often another antiretroviral as well, because of the concern
      that unopposed CD4 activation could cause a lot of virus replication,
      and make things worse. Also, IL-2 is expensive. So I guess that's the
      good news/bad news. It would be an experimental therapy that you'd
      have to do with a physician; there's no guaranteed information about
      whether it's going to help or not, but it's something which can be done.
      You can follow your own CD4 cell counts after receiving IL-2 and see
      how it makes you feel, and look at the range of side effects that are
      occurring and ask yourself, is it tolerable? Those are all possibilities
      as long as you're on an antiretroviral. From the work that's been done
      in several laboratories that have tried to look at changes in viral load,
      I don't think IL-2 poses the danger that was initially one of the
      concerns about it.

ROMEYN: One of the concerns that I have about interleukin-2 is that we also
      know it as one of the metabolic or immunoregulatory triggers for the
      anorexia and the metabolic disregulation that contribute to the wasting
      response. I may be particularly attuned to that because we work so
      hard to maintain lean body mass here. Since we are working with weak
      cytokine blockers now to block or attenuate IL-2 and other cytokines,
      I have a concern about giving IL-2 to the same organism that on the
      other end of the spectrum we're trying to protect from IL-2.

SHELBYVILLE, IN: I'd like to know about the benefits versus the detriments
      of using AZT and ddI together in people with CD4 counts over 500.

ROMEYN: We offer it. If a patient is anxious to take their one shot in the
      absence of confirmed information as to what that one shot should be,
      and if we're willing to monitor them carefully, and be sure that what
      we're doing isn't going to harm them, then I'm comfortable with that.
      We actually have a couple of people in our practice on AZT and ddI who
      have CD4 counts over 800.

BAKER: Any other comments on using double-combination treatment in early
      disease?

FEINBERG: Right now it's impossible to give someone an honest answer to the
      question about whether it's beneficial or not. Right now I would agree
      with Dr. Romeyn that it's really a personal decision, and that if someone
      wants to go ahead with it, it wouldn't be unreasonable. But, quite
      honestly, it would be a decision for which the available clinical data has
      no real guidance.

BROOKLYN, NY: Hello. I'm wondering why the Centers for Disease Control
      added cancer as a criteria for AIDS. Is there a higher incidence of it
      in HIV-infected women?

KATZENSTEIN: I can talk about what we're starting to do at Stanford. It's a
      difficult area because the risk factors associated with cervical cancer
      or genital neoplasia in general are often the same risk factors
      associated with the acquisition of HIV: having early sexual activity,
      having many sexual partners. Herpes simplex used to be associated with
      cervical cancer; now the papillomavirus is much more closely linked to
      cervical neoplasia. And all of those things are increasingly common in
      the general population, and probably somewhat increased among women
      who are HIV positive, often because of other things that have taken
      place in their life that may or may not have much to do with the HIV.

      There is an increased frequency of abnormal Pap smears in HIV positive
      women, so we recommend Pap smears every 3 or at least 6 months, with
      prompt referral to a gynecologist who can look carefully at the cervix
      when there are abnormal results. We're working right now to better
      understand how changes in the cervix and/or the presence of other
      papillomaviruses impact HIV replication and, potentially, relate to
      maternal fetal transmission of HIV. These and many other phenomena in
      HIV in women are not well understood, because we haven't studied a
      large number of HIV positive women in this country. 

ROMEYN: I would agree with that. I would also like to note that not only is
      there an increasing frequency of abnormal Pap smears, but there is a
      truly alarming increase in the rate of change of an abnormal Pap smear.
      We may already be seeing progression in the patient who doesn't keep
      her appointment for colposcopy and who gets a repeat Pap smear in 4
      to 6 weeks. When it does occur, it looks as though the progression from
      initial dysplasia to cervical carcinoma is very rapid.

      If you are a woman with HIV it's important to maintain good vaginal and
      genital hygiene to try to prevent infections and bacterial imbalances,
      which can promote a low-grade chronic activation of immune response.

NEW YORK, NY: I'm HIV positive and currently asymptomatic. I wanted to ask
      the panelists what they see as being the next generation in HIV
      management. I'm looking at antiviral therapy and combination therapy,
      and I'm curious to know what might be in the research pipeline.

MERIGAN: Two things that are really starting to take off now are cell and
      gene therapy. An article in today's New York Times that discusses a
      chimpanzee transplant is an example of how imaginatively we're willing
      to think. In that spirit, new kinds of immunotherapy and gene therapy
      to block deterioration of the immune system, match donors or even
      animal transplants are being considered. 

      We're beginning to get a good strategy for early intervention, but
      patients present at a variety of stages of infection. And, patients who
      have been treated for a long time can get to very low immune cell
      numbers, and we've got to have a strategy to try and reverse that.
      This is a new but important undertaking, and we're going to push very
      hard. Perhaps some of you've heard of Project Restore Immune
      Function, sponsored by Project Inform. I think it's made a lot of
      investigators realize that we need to work on the lower end of the CD4
      spectrum, to come up with new ideas. It's a complex undertaking
      because we really don't know enough about the immune system. We're
      like the transplanters 30 years ago. I was an internist then, and I
      remember thinking how radical those surgeons were, and now that's all
      become standard, accepted practice.

IRVINE, CA: I don't think I have wasting syndrome, but what signs should I
      look out for? I've lost a lot of weight, and I have a low CD4 count. No
      OI [opportunistic infections] ever, just shingles. What do I look for?

ROMEYN: Well, I think the first thing I would do if I were you is get a
      nutritional consult. What you look for is, number one, how much and
      what kinds of food you are taking in. People who are HIV positive tend
      to eat less than people who are negative, and people who have
      secondary infections or OI as well tend to eat even less. Secondly, you
      may want to rely less on dairy products for your nutritional needs, as
      lactase deficiency and therefore lactose intolerance is an early factor
      in HIV. I would also try to determine what your absorption is like. If
      you are not absorbing well, that can be addressed. In addition, I would
      pay attention to your triglyceride counts. If they're going up, it's time
      to begin to look aggressively for occult opportunistic infections which
      can activate your immune system in such a way that they cause your
      body to inappropriately use those nutrients that you take in, using
      them to make fat and spending your protein.

      I would suggest to you that weight loss is not only enough to raise a
      concern about wasting, but is one of the later manifestations of wasting.
      It would be worthwhile to get an idea of what your lean body mass is.
      If you're healthy and essentially asymptomatic, progressive resistance
      exercise may be a helpful way for you to put on weight. Otherwise,
      there are supplements that can be taken. There are several standard
      nutritional interventions to the wasting syndrome, but you have to start
      by knowing you have it before you can treat it.

BALTIMORE, MD: This is for Dr. Romeyn, about nutrition. You said, in an
      aggressive diet, cut out all processed foods, go to freshly cooked food,
      etc.do you have any other comments on that?

ROMEYN: To eat things that taste good certainly does a lot for quality of life.
      What I'm really concerned more about, in terms of aggressive
      supplementation of diet, is if you can take in calories properly and if
      you can absorb properly.

RANCHO MIRAGE, CA: Is there a place for alpha interferon or even a
      combination of alpha interferon and 3TC in treating a patient who has
      pretty much run the gamut of the neucleosides, including Zerit?

FEINBERG: I don't know if Tom Merigan wants to address that; I can comment
      on it. There's really no clear indication that that specific combination
      would be beneficial or that alpha interferon administered in the long
      term would be beneficial. It does seem to have an antiviral effect, but
      unfortunately we don't know as much about that as I think would be
      good to know. Certainly alpha interferon can have side effects that
      make it less than optimal to take on an ongoing basis.

BAKER: Another problem is that 3TC is available only through expanded
      access. 

HONOLULU, HI: I have a question for Dr. Romeyn. I'm a nutritionist that works
      with small children. How do your treatment recommendations, as far as
      nutrition, exercise and the use of antioxidants differ for small children,
      as compared to adults?

ROMEYN: That's a good question. I actually researched it extensively in the
      process of hoping to write a book on pediatric nutrition in kids and in
      women, but I found there has not been a lot of work done on that. 

      I will say that the antioxidant studies which have been done in vitro
      are interesting in their ability to slow the replication of the virus. We
      know this isn't going to hurt adults. We know it isn't going to hurt
      kids. It's inexpensive and appears to me to be a wise approach. I don't
      treat children so I don't know about doses, but certainly if I had a
      child who was HIV positive, I would be aggressive with antioxidant
      therapy and with vitamin therapy, as well.

SAN FRANCISCO, CA: Hello. My question also has to do with antioxidants. A lot
      of people seem to be recommending beta carotene, but there's a lot of
      variance in the recommended dosage. Do any of you, perhaps Dr.
      Romeyn in particular, have any suggestions about adult dosage of beta
      carotene or any other antioxidants?

ROMEYN: I have some suggestions, but the fact is we don't have any answers.
      Some studies have been done at a level of 60 mg a day, but very little
      work has been done. Certainly 60 mg a day is not likely to hurt you.
      I do monitor my patients to make sure they don't turn orange. We
      recommend 30 to 60 mg/day. My guess is it may be possible to go
      higher. But we're guessing at this time in terms of making practical
      applications of antioxidant therapy. We do have our cookbook recipe
      that we recommend to people, but I'm not sure that any validity has
      been assigned to those numbers at this time.

SAN FRANCISCO, CA: I also wanted to know how milligrams [mg] translate into
      international units [IU], which is how they seem to measure it when you
      buy it at the market.

ROMEYN: I think 15 mg of betacarotene is 25,000 units of vitamin A. I'm hope
      I'm right.

BAKER: I would refer the caller to the March '94 issue of BETA. There's an
      extensive article there on the use of nutrients, including antioxidants,
      in HIV infection, along with a comprehensive chart of suggested dosing.
      
AUSTIN, TX: This is for any of the panelists. What would you recommend for
      people who declined to take antiretroviral medication?

FEINBERG: I feel that it's most important to honor people's feelings about how
      they want to approach therapy. I would want to make sure that they
      had all the information that was available or, if something new became
      available, that they were informed of it so that they could reevaluate
      their decision, but I do think that it's a decision that a patient can
      make. If my patients choose to make that decision, I respect their
      ability.

ROMEYN: I'd like to add something to that. My own bias is in favor of
      aggressive treatment, but it's true that it's important not to impose
      your bias on patients. My sense of the people who refuse antiretrovirals
      is that they fall into 2 categories. One is a group of people who don't
      trust the establishment or don't trust doctors, and the other is a group
      of people whose personal life philosophy involves leading a life of great
      delicacy and health orientation.

      If it's a matter of not trusting doctors, you can spend time with these
      people, and do a lot of listening as well as talking. I make my pitch
      once with everybody.

      If they feel that it is criminal to assault their body with antiretrovirals,
      then we're in a position to urge them to be extraordinarily responsible
      about other aspects of their health care, which include exercise, stress
      education, antioxidants, getting the calories in, whatever it takes that
      are basic health practices. If that's all we have to work with, I try to
      work with them very hard.

MERIGAN: I'd like to add to that. Another point that is important is
      appropriate prophylaxis. When the patient drops to low CD4 levels, we
      know we can get benefit and predictable impact. You really can cut the
      risk for opportunistic infections with appropriate prophylaxis for people
      with low CD4 cell counts.

AKRON, OH: This question is for Dr. Romeyn. Have you had any experience
      with testosterone or the transcrotal patches they're using for wasting
      syndrome? 

ROMEYN: Well, we do have a lot of interest in testosterone supplementation. We
      do testosterone supplementation in this office but only when we have
      a testosterone level that documents hypogonadism. In late-stage HIV this
      is common. I do not have experience with the new scrotal patch. I have
      one patient who swears that he will be our test case. My own
      experience here is that people would rather come in for a shot every
      3 weeks than place a patch on their scrotum. So far we haven't had a
      whole lot of takers. I'd be interested in the experience of others with
      it.

BAKER: What about the potential benefit of using testosterone to treat wasting
      syndrome?

ROMEYN: Morris Schambelan and Marc Hellerstein, who did the growth hormone
      study at San Francisco General, did trial runs with testosterone and
      with growth hormone when they were deciding what to study. They
      decided that growth hormone was the one to go with. There is a lot of
      interest in testosterone, though, and there is actually a study, I
      believe, in formation at San Francisco General Hospital. We don't have
      any results yet beyond theory to tell us that there is definitely going
      to be a benefit to lean body mass from testosterone supplementation.

      There seems to be an increased sense of well-being from the
      testosterone injections, but I haven't been doing them long enough yet
      to know if that's a placebo effect. I think we will have to look to the
      clinical studies to tell us exactly what the benefits are. Theoretically,
      testosterone could produce an increased sense of well-being and an
      opportunity to maintain lean body mass.

MONTEREY, CA: This is a question for Dr. Romeyn. It's on the same level as
      the last question. Can you talk about using growth hormone for wasting
      syndrome?

ROMEYN: A few small studies have been published. Growth hormone has been
      used previously in non-HIV people who showed a deficit of lean body
      mass, and was helpful in laying down lean body mass. With the
      exception of the studies on progressive resistance exercise in early
      asymptomatic people, we really haven't come up with anything yet that
      helps build lean body mass as opposed to holding on to it. These
      growth hormone studies seem to show that it may do that. The effect,
      which appears to be significant, seems to be more profound during the
      early part of treatment. However, the product [human growth hormone]
      is extremely expensive and moderately inconvenient, and there have
      been 1 or 2 cases of side effects. In fact, one person developed
      diabetes, although I believe that was resolved with cessation of
      treatment.

      Ongoing treatment with growth hormone right now would be enormously
      costly. I'm not sure that we see that the benefits are maintained if the
      injections are not maintained, nor have we yet seen if continuing
      treatment involves continuing, increasing benefit. However, growth
      hormone is incredibly exciting. I think that Kathy Mulligan and the
      other people who have been working on this feel that if enough benefit
      is shown, if there's an indication for it, and if enough people want it,
      we could get the cost down.

      It's still only available in research settings. I was actually fortunate to
      be around when a pilot study was beginning in 1988. It's only
      anecdotal, and there's not enough research yet, but I can't tell you
      what it looks like to watch people put on 2.2 kg in the space of a week.
      It just knocks your socks off. If I had HIV and were wasting, I'd be
      in a hurry to get my hands on some of that stuff.

PHOENIX, AZ: This question could be for any of the panelists. Just to give us
      all some hope with this disease, what do you see as the most promising
      treatment in the future and do you anticipate a cure or a vaccine?

FEINBERG: There are a number of advances that I'm optimistic about. The
      availability of the protease inhibitors is an important step in the right
      direction. Not that these drugs will necessarily be panaceas but, as Tom
      Merigan suggested, protease is another target in the virus that we can
      attack, which gives us more choices.

      The way the protease inhibitors are being developed now is an
      interesting process, i.e., going about it by understanding what the
      target is and trying to specifically focus a therapy on that target. We
      are better able to do that with the protease drugs than we've been able
      to do with the reverse transcriptase drugs like AZT, ddI, d4T, ddC and
      3TC. Even if these drugs [protease inhibitors] don't work the first time
      around, it will be possible to improve their design. 

      Having more targets and having more drugs is beneficial but, in and of
      itself, it isn't enough. What you need is a way of knowing whether
      these drugs are working. You need to be able to identify the best time
      to intervene, and the best combinations of drugs for a given individual,
      and know when to switch the therapies. That is something that will be
      standard of practice in the next year or so. For me, these are really
      hopeful signs.

      I don't know that there's going to be a cure for this disease, although
      I certainly hope there will be. Perhaps a more feasible goal to pursue
      now would be if we could simply turn this into a disease that was
      really a bit more like diabetes, where people can lead normal lives for
      long periods of time.

      Do I think there's going to be a vaccine? That's a hard question to
      answer, because to make a vaccine for HIV you would have to be able
      to do things that no other vaccine has been able to do for other
      diseases. For all the diseases for which there are successful vaccines,
      there is what's called natural immunity. If someone gets exposed, their
      body can fight it off, eliminate that agent, never to be infected with it
      again. The fact that HIV causes a chronic infection that the immune
      system can't get rid of is a major challenge that we don't know enough
      about yet.

MERIGAN: I agree with Mark's outline and his sense of where we're beginning
      to succeed. I'd add one more component: in addition to chemotherapy,
      we should be able to set up specific and nonspecific immunotherapy
      that will be effective against the virus. In years to come, it will be, as
      Mark said, a matter of chronic suppressive therapy. We have no means
      at the present time of getting rid of the virus for now so we just have
      to suppress it, and know where we are in that process all the time.

BAKER: Thank you all for your excellent questions. I want to report briefly
      now on recent AIDS drug developments, and to mention important open
      studies that are actively recruiting for volunteers.

      One recent and welcome development mentioned earlier in the program
      is that the U.S. Food and Drug Administration has granted accelerated
      approval to the experimental drug called d4T. Its tradename or
      brandname is Zerit. It appears to be about as effective against HIV
      infection as AZT, and has a different toxicity profile. FDA approval of
      Zerit is a welcome development, because it offers people with AIDS a
      new anti-HIV treatment option. 

      In approving Zerit, the FDA has suggested that the drug be used only
      by people who have failed all other approved drugs, i.e., who have
      failed or are intolerant to AZT, ddI and ddC. But now that Zerit is
      FDA-approved, physicians can prescribe it for any HIV positive patient.
      You may want to speak with your doctor about whether Zerit can
      benefit you. The drug's manufacturer, Bristol-Myers Squibb, has said
      that Zerit will be available in pharmacies by August 15th. The wholesale
      cost of Zerit will be about $6 a day for a daily dose of 40 mg taken
      twice daily. The cost to consumers (patients) will be higher, and will
      vary depending on where you buy it. 

      --------------------------------------
      Accelerated Approval for Protease Drug

      As many of you have read in BETA and elsewhere, probably the most
promising anti-HIV drugs that are likely to be approved in the near future
are the protease inhibitors, a new class of anti-HIV drugs. About a dozen
pharmaceutical companies are now developing protease drugs. The protease
drug that is farthest along in development is called Inverase. The results of
a government-sponsored study of this drug were released earlier this summer
[June 1994]. 

      The most promising results of this study were among people who took
Inverase in a triple combination of Inverase plus AZT plus ddC. Individuals
using these 3 drugs together had greater increases in their CD4 T-cell counts
and greater decreases in the amount of HIV in their bodies, compared to other
people in the study who took the double combinations of AZT plus ddC or
Inverase plus AZT. 

      Simply stated, it looks like taking these 3 drugs together may produce
more benefit than taking only 2 of them together or one of them alone. Based
on these and other study results, it's likely that the FDA will be asked to
grant accelerated approval to Inverase. This would mean that doctors could
write prescriptions for Inverase for their HIV positive patients. The drug
would be widely accessible. Without accelerated approval from the FDA,
Inverase probably will not be available by prescription for several years.

      If you support accelerated approval for this promising new protease
drug, it's important that the FDA hear from you. I urge you to write or fax
the Commissioner of the FDA. His name is Dr. David Kessler; his office address
is 5600 Fishers Lane, Rockville, Maryland, 20857. Or you may want to fax Dr.
Kessler. His office fax number is 301-443-3100. Your letter or fax could be
short and simple. Simply let Dr. Kessler know that you support accelerated
approval for Inverase because people with AIDS need access to promising new
drugs as soon as possible.

      ------------
      Open Studies

      I want to mention some studies that are now open to enrollment. First,
the largest enrollment openings currently are for Phase III trials of Inverase.
They are open to enrollment for up to 1,800 volunteers at 40 sites in the
United States and Puerto Rico. In Europe, about 1,200 people will be enrolled
in Inverase Phase III trials. For the location of individual study sites, and for
information about entry criteria for this study, call Hoffmann-La Roche at the
following toll-free number: 1-800-526-6367.

      In addition to the Inverase trials, human studies of 6 other protease
drugs are also ongoing. There are 2 protease drugs from Abbott Laboratories,
2 from Merck, and 2 from Searle. But right now, only the Hoffmann-La Roche
and Abbott protease drug studies are open and actively recruiting. [Since the
teleconference, enrollment into Abbott protease studies has ended.]

      ------------------------
      Aspirin, Tagamet, Zantac

      One interesting experiment managed by the Community Research
Initiative in New York City, is an 8-week study of aspirin using 1,000 mg a
day of aspirin among 50 asymptomatic individuals with 50 to 350 CD4 cells.
Researchers are also recruiting for a 12-week and a 16-week study of Tagamet
and Zantac, both commonly used drugs for stomach ulcers, that may have some
benefit for HIV positive individuals. These studies will enroll 400 asymptomatic
or symptomatic volunteers with 200 to 700 CD4 cells. There are a number of
sites for this study, including New York City, Boston, Milwaukee, Houston and
others.

      Curcumin is also being studied. This is an orange-yellow substance
found in the spice turmeric. This new study will enroll 40 volunteers in the
greater Boston area.

      A one-year pilot study of Zerit plus ddI is now open; the study is
designed to test the Zerit/ddI combination among 75 people who have had no
previous use of AZT or ddI, and no history of pancreatitis or peripheral
neuropathy. The study sites are New York City, Los Angeles and San
Francisco.

      Earlier in the program, Dr Feinberg discussed recombinant human
growth hormone. There is an open study comparing human growth hormone to
insulin-like growth factor. These are both genetically engineered products.
The study will enroll 30 HIV positive children aged 6 months to 18 years who
exhibit failure to grow.

      The antioxidant NAC (N-acetylcysteine) is being studied in the San
Francisco Bay area. Participants in this 8-week, Stanford University-sponsored
study, may have between 0 and 500 CD4 cells, and be taking AZT, ddI, ddC
or d4T for at least 4 months. [Since the teleconference, enrollment has closed.]

      There are several large, open studies of nevirapine in double and triple
combinations with AZT, ddI and ddC. About 1,600 people are being recruited
for these 3-year Phase II/II studies at 52 medical centers. [Accrual into
nevirapine trials has been suspended, pending results of an FDA review. For
more information, see the report in this edition of Research Notes.]

      Passive hyperimmune therapy. This treatment involves taking plasma
from healthy HIV positive donors who have high levels of HIV-neutralizing
antibodies. The plasma has been processed to inactivate HIV, and it is then
infused into patients with AIDS. This is a 2-year Phase III trial that's
recruiting 600 volunteers with 50-400 CD4 cells.

      Finally, thymopentin, also known as TP5. This is a one-year study at 22
sites with 2,100 asymptomatic individuals who are also using some other
anti-HIV drug. TP5 is self-administered by subcutaneous injection.

      The telephone number to call for more information on all open AIDS
clinical studies in the United States is toll-free, 1-800-874-2572.

      Dr. Merigan, Dr. Feinberg, Dr. Katzenstein and Dr. Romeyn, thank you
for participating in today's teleconference. Many thanks as well to
Hoffmann-La Roche for providing the educational grant that supports these
free BETA LIVE! teleconferences.

      **********************
      Accelerated Approval for New AIDS Drugs Faces Uncertain Future
      Ronald Baker, PhD

      Ronald Baker is editor of BETA.

      The New York-based treatment activist organization Treatment Action
Group (TAG) has generated considerable controversy in the AIDS community
by asking FDA to slow the approval process for new AIDS drugs. In addition,
TAG has lobbied FDA to deny early approval to saquinavir, the promising
protease inhibitor drug from Hoffmann-La Roche (Roche). 

      In discussions with FDA and others, TAG has argued that saquinavir is
not a suitable candidate for accelerated approval because the drug has been
studied in too few patients for too short a time. For this reason, its safety
for humans is uncertain, according to TAG. In addition, TAG argues, the use
of surrogate markers (e.g., CD4 count and viral load) to evaluate the
effectiveness of the protease inhibitors is untested and therefore suspect. 

      Current FDA policy allows drug sponsors to use surrogate marker
endpoints (such as increases in CD4 counts) as data to support a drug's
candidacy for early approval. Roche had been expected to apply before the
end of 1994 for accelerated approval of saquinavir in combination with AZT
and ddC, based primarily on promising surrogate marker results from ACTG
229. This Phase II study among 302 participants compared saquinavir in a
triple combination with AZT and ddC to 2 double combinations: ddC plus AZT
and saquinavir plus AZT. Results show that the 3-drug combination is
significantly better than the 2-drug combinations in reducing viral load and
in increasing CD4 counts. 

      Although neither FDA nor Roche will comment on their discussions
concerning saquinavir, reliable sources say that FDA has asked Roche not to
apply for accelerated approval of the drug at this time. Many community
activists believe that TAG opposition to early approval of saquinavir
influenced FDA's decision.

      "Placebo-controlled trials of drugs for life-threatening illnesses are
considered unethical by many community members and physicians."

      -----------------
      The TAG Proposals

      In a letter to FDA Commissioner David Kessler in June, and in a closed
meeting with top agency officials in July, TAG has argued against considering
saquinavir for accelerated approval: "Saquinavir is not yet an appropriate
candidate for an accelerated NDA [New Drug Application]....We feel that such
an approval would penalize people with AIDS/HIV by setting an inappropriately
low standard of evidential requirements that would govern the regulation of
this entire class of therapies. We urge you not to invite Hoffmann-La Roche
to apply for accelerated approval of saquinavir until we can complete further
discussion between FDA, its advisory committee, the company and people with
AIDS/HIV." (TAG letter to FDA Commissioner David Kessler. June 20, 1994.)

      The TAG letter argues further that in order to receive accelerated
approval, the protease inhibitors first must demonstrate clinical benefits (e.g.,
significantly delayed disease progression or significantly increased survival
time). To evaluate the clinical benefits of the protease inhibitors, TAG has
proposed implementing a large simple trial (LST) that would attempt to enroll
within one year 18,000 participants taking a protease inhibitor or placebo,
with 3-4 years of follow-up. The primary endpoint of the trial would be an
AIDS-defining event or death.

      -------------------------------------------------
      Concerns About Large Simple Trials for AIDS Drugs

      There are several reasons for widespread community concerns about the
TAG proposals: (1) There is no evidence that a LST will provide more or
better data on AIDS drugs. (2) Placebo-controlled trials of drugs for
life-threatening illnesses are considered unethical by many community members
and physicians, especially in studies that have AIDS-defining conditions or
death as clinical endpoints. (3) An LST of protease inhibitors with one-third
of participants expected to take placebo likely would never enroll enough
participants to yield meaningful data. (4) The manufacturers of protease
inhibitors would be unwilling to provide free drug to thousands of
participants in a lengthy study. (5) Several community groups oppose LST
because of the difficulties related to recruiting people of color into trials
scheduled to run for several years.

      LST cannot gather meaningful data reasonably quickly and economically.
The most cost- and time-effective way to evaluate AIDS drugs is in smaller
studies that enroll fewer people for less time. Moreover, future studies of
AIDS drugs likely will rely heavily on the use of powerful new diagnostic
technologyquantitative PCR and branched chain DNA (bDNA) assays.
Widespread use of these new tests may change dramatically the design of
clinical studies of AIDS drugs. When used to best advantage, these tests
promote an efficient use of financial and human resources in clinical trials
while still yielding important information in a relatively short period of time.
Many researchers believe that this fast, sensitive technology will promote a
better assessment of drug effectivenss in individual patients and to a more
reliable and faster evaluation of anti-HIV AIDS therapies in clinical trials. 

      ------------------------
      AIDS Community Reactions

      Many AIDS advocates, including this writer, regard the TAG proposals
as well-intentioned, but unfortunately, also outdated, unworkable and too
costly. Most importantly, implementation of these proposals would be
devastating to people with AIDS whose pressing medical needs require that
they have the earliest possible access to new therapies. Early access to
promising new drugs such as saquinavir is a fundamental right for people
who no longer benefit from available treatments. As Martin Delaney of Project
Inform wrote in a consensus statement addressed to FDA:

      "People with HIV and AIDS in recent years fought aggressively for the
      right to earlier and broader access to new therapies than was afforded
      by clinical trials. This hard-won right must not be threatened or
      rescinded by efforts to solve other possible problems in the drug
      development process."

      Many AIDS researchers, clinicians and activists believe that 3- and
possibly 4-drug combinations that include at least 1 protease inhibitor
currently offer the best hope for effective, sustained control of HIV activity.
Without early approval of a protease inhibitor, patients remain restricted to
monotherapy or combination regimens comprised of nucleoside analogues, a
class of drugs that offers limited clinical benefits for a limited time. 

      "Early access to promising new drugs such as saquinavir is a
fundamental right for people who no longer benefit from available treatments."

      In August, Merck and Company announced that it will not seek
accelerated approval for its lead protease drug, L-524. In addition, Merck said
it may take up to 3 years to bring L-524 to market, due to a limited drug
supply and other difficulties. Within 3 years, thousands of people with AIDS
may die awaiting access to a protease inhibitor that might help to improve the
quality of their lives and extend their survival. 

      With increasing frequency, patients are calling physicians and AIDS
hotlines to ask how and when they can get a protease inhibitor. Because
saquinavir is the protease inhibitor farthest along in development, the demand
for access to this particular drug will increase dramatically in the coming
weeks and months. There are 3 mechanisms through which patients might gain
access to saquinavir: clinical trials, parallel track and accelerated approval. 

      (1) Clinical trials: Many if not most HIV positive individuals do not
          qualify for enrollment in clinical trials of the protease inhibitors
          because of their prior use of other anti-HIV drugs. 

      (2) Parallel track: The high costs of producing the protease inhibitors
          makes it extremely unlikely that these drugs will become available
          though parallel track, an FDA program through which drug
          companies provide experimental drugs free to patients who have
          failed on all approved therapies. (ddI and d4T first became widely
          available through the parallel track.) 

      (3) Accelerated approval: For the vast majority of people with AIDS,
          the accelerated approval program is the only hope for access to
          saquinavir and other promising new drugs. Established by FDA 5
          years ago, this program provides promising AIDS drugs to patients
          through the simple mechanism of a prescription written by a
          physician.

      FDA could make saquinavir available by prescription within the next 6
months if the agency would evaluate the drug using existing criteria for
accelerated approval. Because early studies show that saquinavir demonstrates
"reasonable" safety and a "reasonable" promise of clinical benefit, it appears
to meet current FDA standards for early approval. Under prevailing FDA
rules, drugs for life-threatening illnesses need not demonstrate clear clinical
benefits in order to win early approval. Rather, the clinical efficacy of these
drugs are determined in post-marketing studies that follow accelerated
approval. The FDA can revoke approval and remove the drug from the market
if it fails these evaluations.

      ------------------------
      Drug Company Perspective

      A recent front-page article in the financial magazine Barron's entitled
"Do We Have Too Many Drugs for AIDS?" carries the subtitle, "In a turnabout,
some AIDS activists are now asking the government to slow down its drug
approval process." The article suggests that FDA intends to revise its
accelerated approval policies, making it more difficult for new AIDS drugs to
get to market. 

      Raising the hurdle for accelerated approval of promising new AIDS
drugs will send a chilling message to AIDS drug developers large and small.
The content of that message reads something like this: "Spend millions on
developing experimental AIDS drugs that may or may not be approved for
marketing after up to 5 years of clinical testing. And remember, no early
marketing of compounds unless they show clear clinical benefits!" 

      This misguided policy may provoke a discontinuation of AIDS drug
research and development by both large pharmaceutical firms and the smaller
biotechnology companies that now are risking huge financial investments on
AIDS research. If these companies cannot bring promising therapies to market
early through the mechanism of accelerated approval, there will be little
incentive for them to develop new AIDS drugs. 

      --------------------
      FDA Responsibilities

      When FDA grants accelerated approval to drugs based on surrogate
marker endpoints, the drug's sponsor is required by FDA to conduct
"post-approval" clinical studies to verify the drug's clinical benefit. If these
studies are not carried out, or if the studies fail to show a clinical benefit for
the therapy in question, FDA may withdraw approval and remove the drug
from the market. It is the responsibility of FDA to ensure that these
post-marketing studies are adequately designed and implemented.

      FDA itself has determined the rules governing accelerated approval, and
also decides which drugs are appropriate candidates for early approval.
However, individuals and communities most affected by the AIDS epidemic, in
particular people living with HIV infection and AIDS, should have significant
input regarding these issues. FDA has the responsibility to weigh carefully
the views and suggestions of diverse community organizations and individuals
before altering existing guidelines on accelerated approval for new AIDS
therapies. 

      When the FDA Antiviral Advisory Committee meets on September 12 and
13, 1994, the topic for consideration will be "Early Access to Drugs for
Life-threatening Illness: Improving the Process." The purpose of the meeting
is to hear comments from people living with HIV infection and AIDS, the
pharmaceutical industry and the advisory committee on all aspects of the
current mechanisms for early access. 

      -----------------------------
      Community Consensus Statement

      A coalition of community groups is gathering signatures on a consensus
statement that calls on FDA to retain existing standards for accelerated
approval of the protease inhibitors and other promising AIDS drugs. The
coalition is comprised of the following community organizations and
publications: Project Inform, San Francisco AIDS Foundation's BETA, ACT-Up
Golden Gate, AIDS Treatment News, ACT-UP New York, ACT-UP NYTreatment
and Data, Positive Awareness Coalition (PAC), Community Consortium, Direct
Action for Treatment Access, Mobilization Against AIDS, National Association of
People with AIDS, ACT-UP San Francisco, ACT-UP East Bay, Search Alliance
Los Angeles, AIDS Foundation of San Diego, Physicians Association of AIDS
Care (PAAC), PWA Coalition of Dallas, The Committee of Ten Thousand, Atlanta
Buyers Club, AIDS Survival Project, Atlanta, Los Angeles City AIDS
Commission, Robert Smith Medical Group, Housing Works. 

      Other community groups are expected to sign the document as they
become aware of the important issues involved. 

      -----------------------
      A Role for BETA Readers

      It is important for BETA readers who support existing FDA guidelines
for accelerated approval to send a signal of support for this policy to FDA.
Consider making a personal contribution to the community effort to preserve
early access by signing and mailing the "Dear Dr. Kessler" card inserted in
the September issue of BETA. Also consider asking your friends, healthcare
providers or other concerned individuals to fax or write a brief note to Dr.
Kessler in support of accelerated approval for saquinavir and other promising
AIDS drugs. Write or fax: David Kessler, MD, FDA Commissioner, 5600 Fishers
Lane, Rockville, Maryland 20857. FDA FAX: 1-301-443-1863.

      The Implications of AIDS for the Development of Therapies and Vaccines:
      A Pharmaceutical Industry Perspective
      R. Gordon Douglas, Jr., MD

      R. Gordon Douglas is President of the Merck Vaccine Division of Merck
      & Co., Inc.

      This article is based on a presentation made at the AIDS History Group
Conference on "AIDS and the Public Debate," held at the National Institutes
of Health in Bethesda, Maryland, on October 28, 1993. A fully documented
version will appear in the conference proceedings: Caroline Hannaway, Victoria
Harden, and John Parascandola, eds., AIDS and the Public Debate: Historical
and Contemporary Perspectives (Amsterdam, The Netherlands: IOS Press, 1994).

      Finding effective treatments for those infected with HIV is clearly one
of the top priorities for biomedical research today. This worldwide effort
involves thousands of researchers in the basic and clinical sciences at
academic, government and industrial laboratories, including Merck. Indeed, a
1993 survey by Pharmaceutical Research and Manufacturers of America
(PhRMA) reports that 103 medicines and vaccines are in development by 74
different companies. This essay discusses Merck's efforts to develop new
therapies and vaccines for AIDS and places those efforts in the context of the
pharmaceutical industry's overall approach to the problem. I'll discuss the
critical success factors involved in the assault on AIDS, some of the
difficulties we face in clinical research and regulatory review, and the
challenges of distributing new therapies to the patients who need them around
the world. I'll conclude with a brief overview of the Inter-Company
Collaboration for AIDS Drug Development, an unprecedented consortium of 15
leading pharmaceutical companies designed to help hasten the process of
finding effective treatments. 

      First, let me note that Merck's objectives are to develop the most
effective therapies and vaccines for AIDS in the most efficient manner
possible, and get them licensed and delivered as quickly as we can to patients
whose lives depend on them. In the best of times, drug or vaccine discovery
and development is a risky business. But because HIV is such an intricate
virus and AIDS is such a complicated and deadly condition, they present
extraordinary challenges to the global medical community. Nonetheless, I'm
confident that we will succeed in finding treatments and preventives for AIDS,
but it will take cooperation between the private and public sectors, and it will
not be easy. 

      Despite the strength of our commitment, resources are finite, and there
are limitations on what industry can realistically do, or be expected to do.
Government's roleand responsibilityin this search is to fund some of the
basic scientific research that provides a foundation for the development of
new antivirals, immunostimulants and vaccines. Government should also work
with industry to overcome the hurdles inherent in bringing these products
to the marketplace. The pharmaceutical industry's role is to discover, develop,
manufacture and market new vaccines and therapies. Working together,
government and industry need to overcome a number of major hurdles.

      -----------------------------------------------
      Critical Success Factors in the Assault on AIDS

      There are 4 basic critical factors to consider in developing effective
treatments and preventives for AIDS: technical feasibility, sustaining
incentives for innovative research and development (R&D), overcoming
difficulties in clinical research and regulatory review, and how to distribute
the new therapies to people in need. 

      ---------------------
      Technical Feasibility

      Available therapies so far have been hampered by toxicity and limited
effectiveness. For example, patients on AZT face the threat of anemia; ddI
patients can develop pancreatitis; and ddC patients sometimes experience
peripheral neuropathy. An allied problem with current therapies as well as
many of those in early clinical trials is the rapid onset of resistance. This has
led to a strategy of trying to develop combination therapies (discussed in
more detail below). But HIV has proven to be remarkably adaptable, making
it impervious to many of the weapons now available to fight it.

      There are 2 key aspects to this adaptability. First, the virus mutates
rapidly in the face of challenges from different antiviral agents. That
property alone would not necessarily be a problem, if the mutant strains were
not robust enough to survive and if they did not remain virulent. However,
HIV's turnover time is so fast, its mutation rate so high, and the number of
progeny of each generation significant enough that selection pressures
quickly lead to the dominance of resistant strains of the virus. Add to that
the relatively high virus titers in infected individuals, and we find that HIV
can respond to a therapeutic challenge with new strains resistant to the agent
within a matter of weeks. 

      Just as important is the antigenic variation of HIV, which has major
implications for vaccine research. Unlike other viruses, such as measles,
mumps and rubella (which don't mutate) or influenza viruses (which, while
known for variable antigenicity, change slowly enough that an annual change
in the vaccine is sufficient), HIV varies so extensively and unpredictably, both
among a population and within an infected individual, that we have been
unable to find a vaccine that can combat it effectively. Finding an effective
vaccine assumes we could define what constitutes effective immunity, which
we have not been able to do yet, either. Furthermore, successful therapeutic
agents against AIDS will need to deal with these unpredictable properties of
HIV without the drawbacks of toxicity. That has proven to be a tall order,
despite dozens of research projects with various approaches to developing
vaccines and inhibitors of reverse transcriptase, HIV-1 protease or the
regulatory protein, Tat. 

      ---------------------------------------
      Sustained Incentives for Innovative R&D

      The United States leads the world in drug discovery because our
research system is an effective partnership between government, academe and
private industry, and because our free market economy has provided an
environment that supports sustained innovation. Government excels at basic
research, both in its own laboratories and through funding of academic
science. Industry, which also does basic research, excels at developmental
research and manufacturing, the most costly and time-consuming phases of the
process. Government scientists facilitate clinical studies, but they do not
generally conduct or pay for the clinical research, process R&D, quality
control, regulatory development work and manufacturing investment required
to bring new therapies to patients who need them. Vaccine development
provides a good example of the complexity of the process and the institutional,
economic and social pressures involved. 

      "Merck's objectives are to develop the most effective therapies and
vaccines for AIDS in the most efficient manner possible, and get them licensed
and delivered as quickly as we can to patients whose lives
depend on them."

      In 1983, there were 11 companies involved in the discovery, development
and manufacture of vaccines in the United States: now there are only 4.
Merck is one of only 2 U.S.-based firms still in the business, and only one
other company manufactures vaccines in the U.S. If claims that vaccine profit
margins are excessive were true, one would expect to see a reverse trend.
Instead, company after company decided to leave the industry. In the 1970s
and early 1980s, the key reasons were low profitability and increased liability.
The National Vaccine Injury Compensation Program, created by Congress in
1986 and implemented in 1988, provided a measure of stability on the liability
front. A few more pharmaceutical and biotechnology companies have entered
the field since then, largely through mergers and strategic alliances designed
to develop new pediatric combination vaccines. 

      But the added stability on the liability issue has been offset by the
troublesome threat of decreased revenues for vaccine developers from the
Clinton Administration's original Vaccines for Children program. While we share
the goal of assuring the availability of vaccines to children whose families
cannot afford them, the Administration's policy supporting universal purchase
of vaccines at discounted rates for distribution by government agencies is
problematic on several counts. For instance, the U.S. General Accounting Office
has stated that vaccine costs are not an obstacle to childhood immunization,
and that the costly Vaccines for Children program will not result in more kids
getting their shots. Indeed, it is clear that this initiative will not improve
immunization rateswhich depend crucially on the infrastructure for delivery
and on effective communication with parents, not on the price of the
vaccinesbut it will have an impact on the profitability of vaccine
manufacturers by eroding the returns on sales revenues, which balance the
discounted prices for public-sector purchases and the prices available to
children of insured and affluent families. (This erosion would result from
shifting the 50-50 public/private market balance to a private market of less
than 20%.) This situation, in turn, will force developers to reconsider their
long-term commitment to investment in the discovery and development of new
vaccines (including AIDS vaccines), if adequate returns are neither predictable
nor certain. This includes continued industry research on new and improved
vaccines, including combination vaccines and heat-stable, oral delivery and
timed release forms, which public health officials agree is one certain way to
address barriers to immunization. More than anything else, government should
provide the stability to ensure a steady flow of research funding for the
development of promising new vaccines. 

      Recent claims that the U.S. federal government itself funds and
conducts the majority of basic research leading to the development of new
vaccines are simply incorrect, in part because they grossly underestimate the
R&D spending of the vaccine industry. In fact, industry is the leading source
of new funds for vaccine research and development of new vaccines. Most of
the vaccines currently in use have come from the private sector; examples
include vaccines to prevent measles, mumps, rubella, polio, pneumococcal
pneumonia, hepatitis B, hepatitis A and Haemophilus influenzae type-b
meningitis. Worldwide research spending for major vaccine companies is some
$400 million, and Merck alone invested more than $100 million in vaccine
research and development in 1992. Vaccine research and production are
delicate, time-consuming and resource-intensive. The ability to maintain a flow
of new capital and profits for re-investment in basic research and capital
investment for manufacturing is critical to the development of new vaccines
and other therapies. The threat of decreased revenues for vaccine products
(a real possibility with the constraints of the Omnibus Budget Reconciliation
Act of 1993 and the Administration's policy of encouraging universal purchase)
will inevitably mean a decline in private-sector R&D investments in coming
years and a slowdown in the discovery, development and introduction of new
life-saving vaccines. 

      ------------------------------------------------------------------
      Overcoming Difficulties in Clinical Research and Regulatory Review

      It is becoming increasingly clear that the road to a safe, effective and
successful AIDS vaccine is longer and more tortuous than we originally
expected. Initially the scientific community had high expectations because we
thought that basic virology and immunology would lead quickly to finding a
simple component of HIV that would produce a vaccine. But this view has
proven naive, and a moment's reflection from the viewpoint of vaccinology
explains why: all effective vaccines involve the duplication of a naturally
occurring protective immune response to the infective organism. But with HIV,
we've found no evidence of this protective response among infected
individuals, a factor that wasn't sufficiently appreciated earlier. Secondly,
early efforts were focused on relatively simple proteins or glycoproteins of
HIV, e.g., gp160 and gp120. Most effective vaccines involve whole viruses or
whole bacteria, except where pathogenesis is known to involve only a single
virulence factor, e.g., tetanus, diphtheria or Haemophilus influenzae type-b.
Moreover, HIV has a unique capability of adapting to immune system
responses. This aspect of AIDS is what makes our basic biological and clinical
research so challenging. 

      But once a viable vaccine candidate does emerge, a productive
partnership between the public and private sectors will be absolutely
essential. Early safety, tolerability and efficacy studies of an HIV vaccine will
take place primarily in the United States and Europe, but large-scale efficacy
trials will depend on populations in developing nations. Mastering the logistics
alone (not to mention the intricacies of study design and analysis) will require
close industry and government cooperation. Merck has the expertise to design
efficient, scientifically rigorous and medically sound programs to achieve
licensure. But we will need to work closely with the National Institutes of
Health (NIH), the World Health Organization (WHO) and other government
laboratories on studies to evaluate vaccines in special populations, to test
alternate dosing regimens or formulations and to assess the impact of
pre-existing disease conditions in patients receiving an HIV vaccine.
Particularly important is the need to develop an international consensus on
standards for demonstrating the safety, immunogenicity and protective efficacy
of new vaccines. Such standards will provide advance guidelines to developers
on criteria for eventual approval and adoption of vaccines in development, and
will thus encourage the risk-taking and investment needed to complete the
costly clinical development phase for new vaccines. 

      ------------------------------
      Distribution to People in Need

      Obviously, it's not enough to have an effective therapy; we must find
ways to deliver it to patients in need. Gross inefficiencies exist in healthcare
delivery systems for under-served populations, both in the United States and
in the developing world. Without an infrastructure on which to build a
distribution network, no amount of innovative resources, economic incentives
or technology transfer will overcome these barriers and ensure access to
populations at risk of HIV infection. Equally important will be a mechanism to
pay for the vaccines and other new therapies, particularly in countries in the
developing world. 

      Policy-makers cannot rely solely on industry to solve these problems.
Let's take an example to show the magnitude of the task. Since 1987, Merck
has donated supplies of MECTIZAN (a human formulation of the antiparasitic
ivermectin) to agencies and governments around the world to treat people
infected with onchocerciasis, or "river blindness," a painful and disfiguring
illness endemic to certain equatorial regions. This donation program has been
enormously successful, having treated more than 6 million affected individuals.
But even after working with the WHO's Onchocerciasis Control Programme and
a variety of voluntary agencies, MECTIZAN has yet to reach all who need it,
despite the geographical concentration of the disease in equatorial regions of
Africa and Latin America. With an AIDS vaccine, even this solution is not
possible because the populations at risk are too large to support a similar
program. The only existing mechanism industry generally has to subsidize the
cost of vaccine sales and distribution in the developing world would be the
price differential between sales in the developed world and sales elsewhere.
Political as well as financial considerations limit how large that differential can
be. Thus the solution to finding efficient ways to ensure the availability of
new vaccines to all those who need them around the world will necessarily
involve complex considerations of technical feasibility, economic resources,
public policy and political will. 

      One novel response to this challenge is Merck's recent project to
transfer the technology for manufacturing recombinant hepatitis B vaccine to
China, where hepatitis B is a major public health problem affecting both
children and adults. The magnitude of the challenge is daunting. There are
360 million children in China who are at risk. Some 150 million Chinese are
carriers of hepatitis B and thus at increased risk to develop primary liver
cancer. Of the 20 million children born in China each year, 1 in 10 acquires
chronic hepatitis B from its mother. To combat the spread of hepatitis B, the
Chinese government turned to Merck.

      Under a 1989 agreement, Merck sold to the Chinese the know-how to
produce the vaccine and worked with Chinese engineers, quality control and
production people, first in the United States, then at China's National Vaccine
and Serum Institute, to design and then construct a plant in Beijing to
manufacture 20 million pediatric doses of hepatitis B vaccine annually. The
Beijing plant opened in October 1993; a second manufacturing plant, opened
at Shenzhen in June 1994, has a similar capacity. China thus has found a
mechanism to tackle a severe health crisis and to protect the lives of its 360
million children by developing indigenous expertise and manufacturing
capabilities. This case illustrates dramatically the need for public and private
sector cooperation to meet these challenges around the world and to move
forward quickly to provide society with important new drugs and vaccines to
conquer not just AIDS, but also the many other devastating diseases of our
time. 

      -------------------------------
      What is Merck Doing About AIDS?

      Having reviewed the critical factors that will govern our success in
developing new drug therapies and vaccines for AIDS, let me turn to what we
have been doing at Merck. We have made a major commitment to AIDS research
for nearly a decade: in fact, it is one of the largest research programs in our
company's history. We are investigating the development of active preventive
vaccines, antiretroviral drugs, passive immunoprophylaxis and agents to
prevent and treat opportunistic infections. Several drug candidates have
entered clinical trials to date. But the route to a successful therapy has not
been easy. For a sense of just how complex and risky drug development is,
let me describe in some detail our decision last year to terminate development
of the pyridinone non-nucleoside reverse transcriptase inhibitor, L-697,661. 

      Merck researchers had high hopes for this promising class of
compounds when clinical development began in the fall of 1990. We conducted
preliminary clinical trials of 4 reverse transcriptase inhibitors and, based on
clinical and preclinical data, chose L-661 for further development. Monotherapy
trials began in December 1990. In anticipation of the development of
resistance, the Company began combination trials in the summer of 1991 in
Germany. Clinical proof of the development of resistance to the monotherapy
came in less than 12 months, but combination trials continued for a full year
and a half, into 1993. We had hoped that by increasing the dosage and by
combining L-661 with AZT (which inhibits reverse transcriptase through a
different mechanism), we could slow down or prevent the resistance that we
saw with L-661 alone. While it was safe and well-tolerated at the higher
dosageand did show significant dose-related activity against HIV-1resistance
still broke out rapidly and could not be suppressed. Moreover, this resistance
problem made it likely that L-661 would not enhance AZT therapy; that is, the
combination was no better at sustained viral suppression than AZT alone. 

      On the basis of these disappointing results, Merck decided that we
should not hold out false hope to patients about L-661. Accordingly, in early
September 1993 we decided to stop development of this compound. As HIV
mutated rapidly against the drug challenge, the early promise of L-661 as a
possible combination therapy with AZT was dashed. As is so often the case in
pharmaceutical R&D, the basic and clinical research failed to lead us to the
discovery of a life-saving compound. Simultaneously, Merck had invested
millions of dollars on a risk basis for parallel development of chemical
processes to manufacture enough drug in the event of expanded trials. In the
process, Merck researchers did gain valuable knowledge about the molecular
biology of HIV (how specific strains of the virus developed resistance), and
about the bioavailability and pharmacokinetics of L-661 (and, by extension,
this class of compounds). But after years of research effort and millions of
dollars invested, in a certain sense we were "back to square one." 

      We are continuing our efforts to discover and develop inhibitors that
act against other enzymes of HIV. One of those targets is the enzyme HIV
protease. Merck research on this enzyme began in 1985. Early structure
determinations were used to develop models for protease inhibitors that would
work effectively in vitro and, hopefully, in vivo. Five years of dedicated,
difficult research led to a product candidate, but it failed in animal safety
assessment early in 1990. It took 3 more years before another suitable product
candidate was found, and clinical trials of the HIV-1 protease inhibitor,
L-735,524 began in February 1993. The goal was to assess safety and
tolerability and to make a preliminary assessment of L-524's antiviral activity.
The early results provided evidence that L-524 was generally safe and
well-tolerated (although there was some concern about elevated liver enzymes
in some of the patients in the earliest trials). A pilot antiviral activity study
that began in June 1993 at the University of Alabama in Birmingham and at
Thomas Jefferson Hospital in Philadelphia, Pennsylvania, showed sufficient
evidence of antiviral effect to proceed with the clinical development program. 

      Accordingly, a phase II clinical study was begun in October 1993 to test
the antiviral effects of L-524 monotherapy (at 200 mg every 6 hours [q6h] and
400 mg q6h) in 60 HIVseropositive, p24-antigenemic patients with CD4 counts
below 500 cells/mm3. Another small study was initiated to investigate the
safety, tolerability and biological activity of L-524 at 600 mg q8h. These
studies showed encouraging signs that L-524 has a significant antiviral effect,
measured by decreases in p-24 antigen and plasma viral RNA. Patients on
L-524 also exhibited improvements in CD4 counts, weight and hematological
parameters. But after a number of weeks of treatment with L-524, the level
of viral RNA in some patients began to rebound, and eventually returned to
near-baseline levels. At the same time, the associated rise in CD4 counts also
leveled and returned, in some cases, to near-baseline levels. This pattern
could indicate the emergence of viral resistance. 

      Our immediate response was to halt plans to expand the clinical program
rapidly and to explore the causes of the viral rebound more fully. Merck's
clinical scientists increased the dose of L-524 to 600 mg q6h for all patients
in the trial that began in October, since in their judgment (and in
consultation with outside investigators), this increased dose would be
generally well-tolerated by most patients and might increase the antiviral
effect. We also began small clinical studies to test the safety, tolerability and
antiviral activity of L-524 in combination with AZT in AZT-naive patients with
CD4 counts less than 500 (now underway), and L-524 together with AZT and
ddI (set to begin in late August or September 1994), also in AZT-naive and
ddI-naive patients with CD4 counts below 500. An additional 60-patient study
(involving individuals with CD4 counts between 150 and 500 cells/mm3) will
also be conducted this fall to optimize the dose of L-524. 

      We will not know until early in 1995 whether the higher dose of L-524
or of L-524 combined with AZT and ddI is successful in overcoming viral
resistance. As yet, the number of patients studied remains small and we are
gaining clinical data daily. We are keenly aware that HIV is a wily opponent,
and it's still early in the game. While the world anxiously awaits, progress has
been slower than we hoped, and we have looked for other ways to speed up
the development process. 

      ---------------------------------------------------------
      The Inter-Company Collaboration for AIDS Drug Development

      The innovative solution to this concern was the Inter-Company
Collaboration for AIDS Drug Development, a virtually unprecedented consortium
of 15 leading pharmaceutical companies that have made a commitment to pool
their efforts in order to identify the most effective AIDS therapies in the
shortest possible time, and to deliver them to the patients whose lives depend
on the success of our efforts. The AIDS Collaboration was announced in April
1993, with the specific goal of working together to facilitate early human
effectiveness trials of combination drug therapies to fight AIDS and HIV
infection. The objective is to expedite comparative studies of different
investigational compounds by sharing scientific information and drug supplies,
and by collaborating on certain aspects of drug development such as assay
standardization. 

      The movement to create the AIDS Collaboration was led by Merck
Chairman Dr. P. Roy Vagelos and by Dr. Edward M. Scolnick, President of the
Merck Research Laboratories. Dr. Vagelos and Dr. Scolnick along with other
research leaders and scientists realized that, because of its unique
adaptability, HIV was likely to develop resistance to every antiviral compound
tested against it. At the same time, more and more compounds were becoming
available for possible use in combination therapies that might mitigate the
resistance problem. Discussions among leading companies took place for more
than a year before the formation of the AIDS Collaboration to design a
structure that would maintain competitivenessto foster continued
innovationwhile catalyzing the sharing of data and compounds at an early
stage in clinical development, where it might make a difference in the
daunting odds against success. The Collaboration is not a "Manhattan Project"
for AIDS: it is not a public-sector initiative, nor are the scientific processes
of HIV infection as well understood as nuclear fission was when J. Robert
Oppenheimer and General Leslie Groves began their work during World War II.
But the Collaboration's ambitious focus is appropriate for the current state of
knowledge, and together, perhaps we can speed the development of effective
AIDS therapies.

      To date, the Collaboration's participants include: AB Astra, Aji Pharma,
Boehringer Ingelheim, Bristol-Myers Squibb, Burroughs Wellcome, DuPont
Merck, Glaxo, Hoechst AG, Hoffmann-La Roche, Merck, Pfizer, Miles (on behalf
of its German parent company, Bayer), Sigma-Tau, SmithKline Beecham and
Syntex. All pharmaceutical companies actively involved in HIV antiviral
development are eligible to join the Collaboration, and researchers from
universities and government, as well as representatives from the HIV
community, are consulted and kept informed on a regular basis. In addition,
Dr. Scolnick and Dr. Stephen Carter (Bristol-Myers Squibb) from the
Inter-Company Collaboration have been appointed to the National Task Force
on AIDS Drug Development (chaired by Dr. Philip R. Lee, Assistant Secretary
for Health of the U.S. Department of Health and Human Services). 

      The Collaboration meets periodically, and the exchange of basic scientific
data on prospective antiviral agents is well under way, along with discussions
on such issues as standardizing assay methodology and creating databases for
antiviral resistance and historical controls. One of the most exciting results
of the Collaboration's first year of activity, a consensus protocol for the rapid
evaluation of triple-drug combinations for the treatment of AIDS, was
announced at the inaugural meeting of the National Task Force on AIDS Drug
Development in April 1994, by Dr. Juergen Drews of Hoffmann-La Roche, the
Chair of the Collaboration's Scientific Panel. 

      The consensus protocol, developed by the Collaboration's Clinical Trial
Subcommittee (led by Dr. David Barry of Burroughs Wellcome), uses a
continuous cohort variable regimen modeled after a strategy that has led
successfully in the past to treatments for leprosy, tuberculosis and certain
cancers. The selection of the triple combinations to be evaluated under the
master protocol will be based on available clinical data generated by
Collaboration members and scientific evidence of additive or synergistic effects
of the combinations in cell culture, as determined by a standard laboratory
protocol also developed by the Collaboration. 

      The overall objective of the protocol is to identify those triple
combinations of HIV antivirals that can produce significant decreases in plasma
viral RNA and sustained increases in CD4 counts. Studies conducted under the
master protocol are only pilot studies to identify truly effective triple
combinations of HIV antiviral compounds. Additional studies will then be done
to evaluate further the long-term safety and clinical benefit of triple
combinations that look promising. The first combinations planned by the
Collaboration will test various combinations of AZT, ddI, ddC, 3TC, saquinavir
and nevirapine. The master protocol has been reviewed by the FDA, and the
Collaboration's Clinical Trial Subcommittee is now revising the protocol and
preparing to implement the trials this fall. 

      Collaboration might seem antithetical in such a competitive environment
as the pharmaceutical industry. But, as George W. Merck observed in 1950,
"Medicine is for the people. It is not for the profits...." The critical need for
effective AIDS therapies means we must make our best collective effort to
surmount the problems faced. By pooling our knowledge about available drug
candidates and cooperative clinical trials of these agents in combination, we
are confident that we can develop new AIDS therapies more rapidly, thus
benefiting the patients who need them and strengthening our own research
efforts for new generations of therapy. 

      ----------
      Conclusion

      The Inter-Company Collaboration for AIDS Drug Development is the most
recent innovation on the AIDS research front. It offers our best hope to
optimize the chance of discovery and development of medicines that work
against this elusive enemy and to expand and expedite access to new AIDS
drugs. But I don't want to minimize the inherent risks or the uncertainty of
our efforts. For the Collaboration to succeed with an effective AIDS drug,
establishing technical feasibility is not enough. In addition, we will need
public and private sector cooperation to assure that the regulatory review
process is quick and that delivery mechanisms don't impede our ability to
reach patients in need. Most importantly, we must preserve a climate that
encourages investment in innovation. That investment is our strongest
guarantee that we will ultimately be able to stop the AIDS epidemic. 

      **********************************************
      Update on the Merck Protease Inhibitor (L-524)
      Ronald Baker, PhD

      Background

      In early studies, the Merck protease inhibitor L-524 showed promising
results, reducing substantially the amount of HIV in the blood plasma of study
volunteers. However, HIV load in these individuals returned to near baseline
levels within a few weeks, probably due to the ability of the virus to develop
resistance to L-524. Ongoing Phase II studies are evaluating the safety and
effectiveness of L-524 at varying doses as monotherapy, in a double
combination with AZT and in a triple combination with AZT and ddI. Phase III
trials, tentatively planned to start in the spring of 1995, may enroll up to
1,800 volunteers. In a meeting with treatment activists on August 22, Merck
made a commitment to circulate for community input a draft concept sheet on
the design of the Phase III trials.

      -----------------------------
      L-524 Approval Timeline: 1997

      According to Merck, FDA has informed the company that the agency will
not consider surrogate marker data alone as sufficent evidence for accelerated
approval of the protease inhibitor drugs. 

      Merck says it intends to develop L-524 as fast as possible in Phase II
and Phase III studies that will evaluate the drug using clinical endpoints
(e.g., AIDS-defining illnesses).

      Merck does not plan to apply for accelerated approval of L-524, nor will
the company seek "expanded access" status for the drug. Expanded access is
an FDA program that provides promising experimental drugs free to people
who have failed on all approved anti-HIV therapies. "At this time we do not
have enough data on the safety and efficacy of L-524 at its projected dose
to begin large trials or to consider expanded access," said John Ryan, MD,
Executive Director, Infectious Diseases, Merck Clinical Research. The decision
not to establish an expanded access program for L-524, says Merck, also is
due to the company's current inability to manufacture an adequate drug
supply for a program that might enroll up to 10,000 people. 

      "L-524 is the most complex molecule Merck scientists have ever
discovered," according to Paul Reider, PhD, Executive Director, Merck Process
Research. In addition, Merck says, the high dose of L-524potentially as high
as 3 grams dailypresents an unprecedented manufacturing challenge.

      It will take about 3 years for L-524 to win FDA approval, assuming no
major obstacles arise in the course of the Phase II and III studies.

      *****************************************
      HIV Disease: New Tools, New Understanding
      Mark B. Feinberg, MD, PhD

      Mark B. Feinberg is Director of the Virology Research Laboratory at San
      Francisco General Hospital and Associate Director of the Center for AIDS
      Research at the University of California at San Francisco.

      It has been approximately 10 years since the discovery of HIV and its
identification as the cause of AIDS. Since then, tremendous progress has been
made in understanding fundamental aspects of the biology of HIV. It is
probably fair to say that we now know more about HIV than any other virus
or infectious agent that causes disease in humans. Yet, all too obviously, we
still do not have very effective antiviral treatments that limit the damage that
HIV inflicts on the immune system and that clearly prolong the lives of
infected people. Certainly, there have been obstacles to progress along the
way including bureaucratic inefficiencies, adherence to procedures of bygone
days, discrimination, alienation and unfortunate examples of corporate and
personal self-interest. With hard work, advocacy and creativity, some of these
obstacles have been overcome, while others need continuing attention.
However, the biggest obstacle to progress in developing effective treatments
for HIV infection has been the amazing and frustrating complexity of HIV
itself. Nevertheless, research conducted over the past 10 years has provided
a substantial foundation of basic knowledge about HIV, which now must be
reinforced and expanded. This is a critical time in AIDS research and
tremendous opportunities exist to now learn a great deal more about HIV. We
must consider all we know about HIV, and carefully identify the most
important and potentially fruitful new directions for future research efforts.
If this is done aggressively and creatively, the results emerging from basic
research hopefully will soon be increasingly translated into more effective
therapies for HIV disease. 

      Prior to the advent of HIV, the popular notion was that medical science
had largely prevailed over infectious diseases. The expectation arose that,
given an important problem, modern science could find a solution. This
popular view was encouraged in part by scientists who were themselves
impressed by the explosion of information and technology that has been taking
place in the life sciences since the 1950s. But the HIV epidemic has taught all
of us that this view is naive, and that we cannot simply solve a problem just
because we want to do so. 

      HIV has also taught us a number of other important lessons that, if
heeded, may expedite its conquest. It is now clear that scientists, healthcare
providers and advocates for HIV-infected people must continue listening to
and learning from each other, in order to best identify effective treatments
for HIV disease. It is also clear that we must confront the hard questions
concerning the intricacies of HIV infection. Likewise, we must not expect that
a cure be here next week or even next year. As has been demonstrated far
too many times, raising false hopes diminishes everyone's motivation for
continued effort, as the promise of the latest "breakthrough" fades. Progress
will be made, but it will likely be incremental. 

      It was tremendously disappointing to realize only recently, 6 years after
the FDA approved zidovudine (AZT), that the drug does not work as well as
was hoped. However, this realization does not return us back to where we
started or anywhere near it. Although much of the recent pessimism about
available HIV treatments is understandable, there is significant cause for
optimism, as well. New information about HIV biology is accumulating at an
impressive rate, and new research techniques that promise to teach us a great
deal more have been developed recently. We now have the tools to determine
why AZT and the other available antiviral drugs are incompletely active, to
define how long they might be of benefit to individuals and to identify
whether they are of benefit for some people but not others. With these tools,
we hopefully will soon be able to use the drugs presently available in the
most effective ways possible. Testing new drugs to treat HIV infection also
now can be pursued more rigorously, definitively and quickly than ever
before. In many ways, we are no longer in the dark about how HIV behaves
in infected people. 

      Calls for a renewed emphasis on so-called basic research have come in
the wake of recent disappointments about the benefit of antiviral drugs such
as AZT. Basic research can be defined as investigation into the fundamental
aspects of the structure of HIV constituents, their mechanisms of action in
promoting virus reproduction, and analyses of the sequential stages of HIV
infection within individual cells and within the human host. In many ongoing
discussions, it is often implied that progress in basic research has been
neglected because of an early emphasis on clinical investigation, defined as
the testing of drugs in HIV-infected people in the hopes of identifying useful
therapies. There now seems to be general agreement that, in the absence of
a better appreciation of why the currently available drugs do not work as
well as had been hoped, conducting additional large-scale clinical trials of
similar drugs is not likely to be very useful. 

      One important basic research topic that has been identified as essential
for more intensive study is that of HIV pathogenesis: how HIV is transmitted
from one person to another, how it causes a chronic infection that cannot be
cleared by the immune system, and how it irreversibly damages the immune
system resulting in the development of AIDS. The importance of answering
these fundamental questions, which have received far too little attention to
date, cannot be over-emphasized. It is wrong to view the choice between
clinical and basic research as a dichotomy, however. Certainly, in a world of
limited resources, talent and energy, priorities must be established. Yet
progress may be most effectively realized by an approach to AIDS research
that emphasizes synthesis of the disciplines of basic and clinical investigation.

      Insights and questions emerging from basic research studies can and
should greatly influence the design of more meaningful clinical trials.
Likewise, basic scientists will need to better understand the clinical
presentation of HIV disease in order to identify the most important questions
for their studies. Neither clinical nor basic research should take place in a
vacuum. In either realm, a good question for study and clear-cut methods and
criteria for answering it are critical. The better we understand how HIV
behaves in infected persons, the more effectively we will be able to intervene
with antiviral drugs to protect their health. Similarly, if we pay careful
attention to how anti-HIV drugs affect the replication of the virus in infected
people, we may derive new insights into the basic mechanisms of HIV disease
that might not have emerged from simple observational studies.

      In many ways the study of HIV infection represents the frontier of
medical investigation, a hybrid of clinical and basic research. With the tools
recently provided by basic HIV research efforts, we now have the opportunity
to define new approaches to study a disease process as it is progressing in
vivo (within an affected, living person). This new approach necessarily
consists of a collaboration of clinicians, basic scientists and HIV-infected
people. If we work together with imagination and commitment, it promises to
be an extremely productive process.

      The perceptions of medical researchers about a disease process are
greatly influenced by the nature of the tools with which they study it. The
prevailing view about the pathogenesis of HIV disease evolved in this fashion,
which also serves to highlight how basic insights can inspire better HIV
treatments. Until relatively recently, the tools used to measure both the
amount of HIV present in an infected person and how actively the virus was
reproducing (collectively referred to as the "viral load" or "viral burden")
were rather insensitive. As a result, scientists believed that very little viral
replication was taking place during the asymptomatic phase of HIV infection.
This perception made it difficult to understand how HIV infection resulted in
the progressive depletion of CD4+ T cells (also known as T4 cells). Numerous
hypotheses were proposed to explain how the virus, if it were not present at
high levels, might damage the immune system. However, the recent
development of sensitive methods to detect the relative amount of HIV present
in an infected person, and to determine how actively the virus is replicating,
have drastically changed this view. 

      These new methods measure the amount of HIV RNA (the genetic material
of HIV that is contained within viral particles) either in the blood or in the
tissues of infected people. A variety of techniques based on either the
polymerase chain reaction (PCR) method or so-called signal amplification
strategies (known as branched DNA or bDNA) are now available to measure HIV
RNA levels in the blood. These techniques currently seem to be the best way
to monitor HIV activity (viral load) in infected people. With these techniques,
it is now clear that significantly more HIV replication is taking place
throughout the course of the disease process than was ever previously
imagined. This new appreciation is incredibly important in terms of our basic
understanding of HIV biology, as well as our clinical approach to treating HIV
infection. From a basic science perspective, the fact that active viral
replication takes place during the asymptomatic phase of the disease suggests
that HIV is directly damaging the immune system. From a clinical perspective,
this same information argues that, if effective drugs can be identified, they
will probably be most effective if used early in the course of the disease, to
preserve immune function when it is still largely intact. From both
perspectives, we now have tools to study the disease process and to
accurately monitor the impact of specific interventions on HIV replication in
infected individuals.

      What can we now try to learn about the pathogenesis of HIV infection
that might have important impact on designing better approaches to treat HIV
infection? Previously we had the tools to measure the ability of a given
antiviral drug (such as AZT) to inhibit HIV replication in vivo. However, we
could not know whether the drugs were not doing what we thought they
would (namely, decrease HIV replication in treated individuals) or were simply
not doing it effectively. Recent studies indicate that drugs like AZT decrease
HIV RNA levels in the blood, but by only about 1/3rd to 1/10th of their
original levels. In some people (presumably those with drug-resistant viruses),
the levels do not change at all with therapy. For the first time, we can see
that these drugs do have some impact, but that they are not particularly
potent inhibitors of HIV replication in vivo. The question that we must now
answer is why this is the case. Are the drugs simply poor HIV inhibitors or
is there something about the way that HIV behaves in people that limits the
drug's effectiveness? This latter topic is a critical issue, but one that we
presently know little about. It is essential that we determine the fundamental
aspects of HIV replication in infected people if we are to design and use
antiviral drugs most effectively. Where in the body, for instance, is the
residual viral replication (seen after starting AZT) taking place? What allows
this "reservoir" of HIV to escape the inhibitory effects of the drug? How long
do HIV-infected cells live and how long can they continue to produce virus?
As discussed below, the answers to these questions can now be productively
pursued.

      The newly available methods to measure the levels of HIV replication
taking place in infected individuals should also now facilitate the testing of
new drugs in a much more rapid and definitive manner than previously
possible. If an antiviral drug is to be useful in treating HIV infection, it is
reasonable to expect that it will inhibit replication of the virus. Earlier clinical
trials of anti-HIV drugs could not evaluate this important criterion directly,
because they lacked sensitive measures. Instead, inferences were based on
so-called surrogate markers or the occurrence of clinical endpoints (such as
the development of an opportunistic infection) that might only occur after a
long delay. Unfortunately, such trials necessarily involved large numbers of
patients and could not readily identify subgroups of patients who might be
benefitting from the treatment. Furthermore, they took a long time to produce
answers. And all too often, when the results arrived, their meaning was
unclear. These earlier trials were, I believe, pursued in good faith, but with
more than a little wishful thinking. With the availability of more clear-cut
measures to monitor the activity of antiviral drugs, a new paradigm for
testing of antiviral drugs is emerging. Most new antiviral drugs will likely be
tested first in small-scale intensive studies in a limited number of patients.
Should a new drug effectively inhibit HIV replication in these study
participants, it might then be evaluated in larger-scale studies for its ability
to delay disease progression and prolong survival. In this way the community
of HIV-infected individuals might be spared the expenses, toxicities and
disappointments of relatively inactive drugs. 

      Does this new approach actually work better? Results from some recent
drug trials suggest that it does. The so-called non-nucleoside reverse
transcriptase inhibitors (NNRTI) like L-697,661 and nevirapine work very well
at inhibiting the growth of HIV in a tissue-culture flask in the laboratory,
and seem to be fairly nontoxic in people. Unfortunately, variants of HIV
emerge shortly after initiation of treatment in infected people that are
resistant to the antiviral action of the NNRTI. Using the older methods of
clinical trials, it might have taken a fairly long time to realize that this class
of drugs is unlikely to be useful when used alone for treating HIV infection.
However, the newer approaches for monitoring the activity of antiviral drugs
in people readily detected the appearance of drug-resistant virus variants
and the loss of drug efficacy.

      In addition to helping validate the usefulness of the new generation of
viral markers, the NNRTI saga is also an example of how "mistakes" or
unanticipated results can present opportunities for greater learning. The
rapidity with which viruses resistant to the NNRTI emerge after initiation of
treatment demonstrated, for the first time, that there is a rapid turnover in
the pool of HIV that is being expressed at any one time. This insight doesn't
sound all that exciting, but it is. With this information, basic researchers
should now be able to identify the reservoirs of HIV infection and measure
the rates at which HIV replication is occurring. By defining these issues, we
may be able to formulate entirely new treatment strategies to most effectively
decrease HIV replication, and measure and augment the effectiveness of a
person's immune response to help further decrease the resident viral burden.

      What needs to be done before we can apply these tools to improve the
care of HIV-infected people? First of all, it is essential that studies be
undertaken as soon as possible to prove that treating HIV-infected individuals
based on the results of HIV RNA determinations actually does lead to better
clinical success. Does making treatment decisions based on these tests help
keep people healthier longer? As soon as possible, we also need to validate
the utility of these tests in a clinical setting and answer important questions,
including the following:

      *   Which of the alternative approaches to measure HIV RNA levels are
          most accurate, most reliable and least expensive? How often should
          they be measured? 

      *   What is a significant enough increase in HIV RNA levels to warrant
          adding a new antiviral drug or switching to another drug? 

      *   What combinations of drugs work best in a given individual? 

      *   How much do we have to decrease viral burden in order to realize
          a meaningful clinical benefit? 

      The challenge for scientists, healthcare providers and HIV-infected
people is to work together to answer these questions as quickly and clearly
as possible.

      *******************************************************
      Food-Based Nutrients as Therapeutic Options in HIV Care 
      Cade Fields-Gardner, MS, RD

      Cade Fields-Gardner is the Director of Services for The Cutting Edge.

      Nutritional recommendations for HIV-infected people abound. There seem
to be as many strong opinions as there are healthcare professionals, product
purveyors and patients. In spite of some uncertainties regarding what
constitutes optimal nutritional therapy, nutrition clearly plays an important
role in healthcare plans for all persons with HIV infection. Nutritional care can
help prevent the general decline and progressive immune dysfunction seen in
malnourished patients. In addition, because nutrients act as cofactors in
chemical reactions that occur in the body, using nutrient supplements to
emphasize certain physiological pathways may help prevent or reverse certain
detrimental metabolic changes.

      How to accomplish nutritional goals simultaneously and safely can be
challenging. Individuals should evaluate their particular circumstances in
consultation with their healthcare teams to determine the most effective
strategies. For some, the best approach will be a supplementation program.
For others, it will mean modifying their dietsa challenge to their shopping
and cooking talents. A combination of both strategies usually works best for
most HIV positive people: a supplementation program that targets specific
problem areas plus thoughtful food choices. In the process, it is important to
be realistic and aware that "natural" [i.e., some nutritional] therapies can be
as dangerous or, in some cases, even more of a gamble than the current
standardized medical therapies.

      The purpose of this article is to explore a few ways in which an HIV
positive person can meet many of the current therapeutic recommendations
easily, safely and effectively.

      --------------------------------
      Maintaining Nutritional Adequacy

      The fundamental goals of maintaining nutritional adequacy are the
adequate intake of fluids, calories, protein and micronutrients. Accomplishing
this creates a good foundation for all other therapies. In other words, without
attention to these nutritional priorities, drugs, supplements, psychosocial and
physical therapy will be ineffective. Though specific measurements should be
made to determine individual needs, general guidelines recommend the daily
intake of about 1 cup of fluid for each 15 pounds of body weight, and at
least 16 calories and 1/2 gram of protein for each pound of normal body
weight (baseline weight prior to infection or wasting).

      Although micronutrient requirements for persons with HIV are
controversial and tentative, a number of different recommendations have been
made. In general, the recommendation is to take 1-2 balanced
multivitamin/mineral supplements daily, in addition to a sound diet based on
the above recommendations for maintaining adequacy. Any other
supplementation may interact with other therapies and normal body processes,
and therefore should be plannned carefully with and monitored by the
healthcare team.

      ---------------
      Beyond Adequacy

      Many nutrition-related therapies are based on the potential that some
single and/or multiple nutrients have to act as pharmaceuticals. Although the
lack of research in this area prohibits firm, conclusive recommendations,
anecdotal accounts have formed the basis for a number of published
recommendations. Again, individual treatment plans should be based on the
results of individual evaluations by the healthcare team.

      For example, antioxidant therapies are gaining attention as a potential
treatment for people with HIV. The premise is that one of the body's cellular
activities is the production of "pro-oxidant" molecules, such as oxygen
radicals (superoxide anion and hydroxyl, alkyoxyl, and peroxyl radicals);
reactive nonradical oxygen molecules (hydrogen peroxide and singlet oxygen)
and; radicals of carbon, nitrogen and sulfur. A growing body of evidence
shows that pro-oxidant production may be stimulated by a range of events,
from immune dysfunction to oxidative challenges from environmental factors,
and may contribute to disease progression. Normally the body would "detoxify"
the destructive radical species of molecules formed during the pro-oxidant
phases with its own supply of regenerating antioxidants. When the production
of reactive radicals exceeds the body's supply or action of cellular
antioxidants, an imbalance known as "oxidative stress" results. This state is
characterized by cellular damage that interferes with normal body processes
and, in severe cases, cellular death. 

      Current investigations are exploring whether or not taking additional
dietary antioxidants has a protective effect. In theory, antioxidant
supplementation would bolster the body's ability to "detoxify" these
destructive radical species of molecules and keep the overproduction of
pro-oxidants in check. Moving from the cellular level into the real world of
a patient, additional questions arise. Will dietary antioxidant supplementation
significantly reduce the potential for damage from oxidative stress seen in HIV
disease? Will dietary antioxidant supplementation bind or neutralize traditional
HIV-related therapies including antibiotics? What antioxidants and what forms
can be used? Where can antioxidants be obtained? How much is more beneficial
than harmful?

      -------------------------------
      Dietary Sources of Antioxidants

      The combined recommendations of the panelists of the April 1994 BETA
LIVE! teleconference will serve as the guidelines for this discussion. The use
of antioxidants was specifically addressed by panelist Howard Greenspan, MD,
a researcher who was asked, "If you were HIV positive, what antioxidant
regimen would you personally follow?" His answer was a daily range of
specific antioxidant nutrients that included 50,000 IU beta carotene, 500 mg
vitamin C, 1200 IU vitamin E, 1500 mg broad-based flavonoids, 3-6 mg
quinones, 1-2 grams cysteine and 3-6 grams carnitine.

      Food should be regarded not only as a source of nutrients needed for
normal body functioning but also as an important source of antioxidant-acting
substances, which may be present in substantial amounts in selected foods.
One example is beta carotene, a form of vitamin A with strong antioxidant
properties. One-half (1/2) cup of cooked carrots (an obvious choice) has 11
milligrams of beta carotene, more than 1800 retinol equivalents (RE) or more
than 18,000 IUs of beta carotene. [Note: Vitamin A activity in foods is
expressed in "retinol equivalents," a representational standard unit. 1 RE =
1 mcg of all-trans-retinol or 6 mcg of all-trans-beta carotene or 12 mcg of
other provitamin A carotenoids.] Carrots contain other antioxidant substances
as well. Canthaxanthin is one such substance in the carrot. A pigment with as
much antioxidant activity as beta carotene, canthaxanthin also may work
synergistically with beta carotene to improve its overall effectiveness. Another
good source of beta carotene is the sweet potato. Each 1/2 cup serving of
sweet potatoes contains 32 mg beta carotene or more than 5000 RE, and more
than 50,000 IU vitamin A activity from beta carotene.

      ------------------
      Nutrient-Rich Menu

      Combining food-based antioxidant recommendations with other nutritional
recommendations often given to HIV patients, a 3-day menu that met several
criteria was developed. First, the menu incorporates as many of the
antioxidant recommendations made during the BETA LIVE! teleconference as
possible. Second, the menu is realistic and easy to prepare. Third, it includes
various food groups important for maintaining good nutritional status in
persons with HIV. The menu meets the tough recommendations made for a
well-balanced, high-calorie, high-protein diet to replete and maintain
nutritional stores. Additional emphasis was placed on such nutrients as
bioflavonoids as additional antioxidant sources, fiber for bowel function and
omega-3 fatty acids, which act as anti-inflammatory and anticytokine agents.
(Certain cytokines including some of the interferons and interleukins have
been implicated in a cascade of physiological events that lead to catabolism
and wasting.)

      The best food sources of the antioxidant nutrients beta carotene,
vitamin C and vitamin E are shown in Table 1. A computerized analysis of
foods provided the best combination of nutrient antioxidants. Figure 1
presents an overview of each day of the menu. The actual guidelines used (a
combination of Dr. Greenspan's recommendations and some general patient
recommendations made in educational bookssee references) and how the menu
met specific goals are shown in Table 2.

      Top sources for calories in the menu are the meat, dairy and grain
groups. High-protein guidelines are met by the meat and dairy groups. The
best sources of beta carotene and vitamin C are the fruit and vegetable
groups. Vitamin E is mostly contributed by the fat and vegetable groups.

      Finally, the menu went through a "reality check," guided by the
question, "Could you eat like this?" The overarching goal was maximum
contribution to clinical well-being as well as a positive effect on quality of
life.

      -------
      Summary

      Nutrition and nutrient-related therapies are unfolding as a new
cornerstone of HIV therapies. Successful nutritional management contributes
to success in other realms of health management. Since improving
quality-of-life and maintaining nutritional adequacy are primary goals,
nutritional regimens probably work best when they are relatively simple and
practical. Effective guidelines to meet a patient's nutritional goals always need
to be realistic.

      Most importantly, HIV positive persons and their healthcare teams need
to keep the "big picture" clearly in sight. Therapeutic regimens should not
heavily compromise overall physical and mental well-being, which are always
fundamental goals. While it is up the the patient to make any ultimate
decisions, it is up to the healthcare professional to explore, weigh and present
options in the context of a complete and objectively evaluated picture, on
which the patient can base his or her decisions.

      ----------
      References

Salomon SB and others. Living well with HIV and AIDS: a guide to healthy
      eating. The American Dietetic Association. Chicago, IL. 1993.

Wong G. HIV disease nutrition guidelines. Practical Steps for a Healthier Life.
      Stadtlanders Pharmacy. Pittsburgh, PA. 1993.

Table 1.  
FOOD SOURCES OF ANTIOXIDANT
NUTRIENTS 

                     BETA CAROTENE     VITAMIN C    VITAMIN E
 carrots            melons             seeds, nuts
 carrot juice       citrus fruits      mayonnaise, salad dressings
 sweet potatoes     red and green peppers     wheat germ
 yams               leafy green vegetables    fish
 pumpkins           other fruits: papaya, kiwi      avocados
 leafy green vegetables                  mango, berries   mangoes
 winter squashes    cruciferous vegetables:   whole grains
 apricots, mangoes    broccoli, cauliflower   fortified cereals
 broccoli             brussel sprouts
                    fortified cereals
                    tomatoes
      sweet potatoes


Figure 1.
THREE-DAY MENU
(*see recipe on page 47)
Day 1                Day 2              Day 3
BREAKFAST
1 cup vegetable omelette*               3 pancakes  1 cup corn flakes
1 rye toast (1 tsp. margarine)          4 ounces vanilla yogurt 1 banana
3/4 cup apple sauce  4 ounces berries   1 cup 1% fat milk
1 cup 1% milk        tea                1 can apricot nectar
tea

LUNCH
1 bean and cheese burrito*              tuna fish sandwich on   
chicken/swiss cheese                    
1/4 cup avocado         whole wheat bread*     sandwich on pumpernickel*  
1/2 cup tomato       spinach, pepper and      1 can (12-oz) vegetable juice
2 ounces onions         mushroom side dish*   1 cup carrot sticks
1/2 cup Spanish rice                    1 cup 1% fat milk
1/2 cup cooked carrots
tea

DINNER
1 cup vegetable-beef stir-fry*          4-ounce pork chop       4 ounces
rosemary salmon*
1 cup rice           1 artichoke with dressing      1/2 cup asparagus tips
tea                  1/2 cup sweet potato     1/2 cup mashed potatoes
                     1/2 cup carrot-raisin salad    1/2 cup applesauce
                     tea                1 cup 1% fat milk

SNACKS
6 ounces flavored yogurt                1 cup honeydew melon    bagel and
cream cheese
1/2 cup orange/grapefruit juice         orange sections (1 orange)    1 cup
cantaloupe
1/2 banana           1 (12-ounce) can of      1 slice angel-food cake with 
1 slice pumpkin pie      tomato juice      berries
1 cup 1% fat milk    rice cake with peanut butter
                     frozen yogurt      4 square saltines
                     wheat germ
      nectarine

Table 2.
Guidelines and Menu Comparison
Guideline                   Menu Comparision

Basic Composition:
     50-55% carbohydrates   50% carbohydrates
     15-20% protein         20% protein
     <30% fat               30% fat

Servings by food group:
     Protein: 2-3 servings  2.5 servings
     Dairy: 2-3 servings    3+ servings
     Starch: 7-12 servings  7 servings
     Fruits/Vegetables: 6+ servings      9 servings
     Fats: in moderation    30% of calories as fat

Antioxidant nutrients:
     Vitamin C              390mg
     Vitamin E              31 mg
     beta carotene          approximately 15,000 RE or 150,000 IU beta
carotene
     flavonoids             high in flavonoid sources: fruits/vegetables and
teas

Other elements:
     omega-3 fatty acids    approximately 8 grams
     fiber                  40 g dietary fiber (emphasis on whole grains
and
                             fruit/vegetable groups)

Recipes
Vegetable Omelette
1/4 cup mushrooms
1/4 cup diced tomatoes
1/4 cup cooked spinach
2 eggs
2 ounces low-fat cheddar cheese
     Saute vegetables in non-stick pan until heated. Add beaten eggs and
cover over low heat until firm. Top with cheese.

Bean and Cheese Burrito
1 large flour tortilla
1/2 cup low-fat refried beans
1/4 cup low-fat cheese
     Spoon beans on top of tortilla and sprinkle with cheese. Roll tortilla
burrito-style and place in microwave oven for 1 minute and 30 seconds at
80% power or wrap in foil and heat in oven for approximately 20 minutes,
or until thoroughly heated.

Vegetable-Beef Stir-Fry
1/4 cup tofu
1/4 cup diced bell peppers
1/3 cup chopped broccoli
1/4 cup snow peas
2 teaspoons sesame oil
2 teaspoons light soy sauce
3 ounces thinly sliced beef
     Stir-fry beef in non-stick pan. Add vegetables and stir-fry until
thoroughly heated. Serve over rice.
Tuna Fish Sandwich
1/2 cup tuna mix:
     1 6-ounce can of tuna
     2 tablespoons non-fat salad dressing or mayonnaise
     1 teaspoon mustard
2 slices whole wheat bread
     Spread tuna mix onto bread.

Chicken and Swiss Cheese Sandwich
4-5 ounces chicken breast
2 slices tomato or 1/4 cup drained canned diced tomatoes
2 ounces Swiss cheese
2 teaspoons fat-free salad dressing or mayonnaise
2 slices pumpernickel bread

     Spread dressing or mayonnaise on bread. Top with chicken breast,
tomatoes and Swiss cheese. Serve as hot or cold open-faced sandwiches.

Spinach, Pepper and Mushroom Side Dish
1/2 cup spinach
1/4 cup diced sweet red or green peppers
1/2 cup sliced mushrooms or canned mushrooms
garlic powder or minced fresh garlic (to taste)
     Stir-fry in non-stick pan over medium heat or place in covered glass
dish and microwave for 4 minutes on the high setting.

Rosemary Salmon
5-ounce salmon filet or salmon steak
1 teaspoon rosemary (dried)
1 teaspoon canola oil
lemon juice (to taste)

     Mix oil, lemon juice and rosemary together, and let stand. Dip salmon
     steak or filet in mixture and place on foil to broil in oven. Bake or
     broil until fish is thoroughly heated and flaky.

     *********************
     Research Notes
     Leslie Hanna

     Leslie Hanna is associate editor of BETA.

     This edition of Research Notes is organized under 7 categories: (1)
Basic Science, (2) Treatment for HIV Infection, (3) Treatment for
Opportunistic Infections, (4) Immunotherapy, (5) Nutrition and Weight
Management, (6) Tuberculosis and (7) Miscellaneous.

     Basic Science

     -------------------------------------------------
     Viruses Evolve Ways to Outwit Immune System Cells

     HIV

     Immune system white blood cells called cytotoxic T-lymphocytes (CTL)
normally respond to the presence of foreign proteins (antigens) by
targeting, binding to and destroying them. CTL play a critical role in the
immune system counterattack on HIV. However, variations of HIV proteins
are capable of eliciting altered, ineffectual responses from CTL. The
variant HIV proteins trigger an incomplete response from CTL, which
recognize and target the proteins but fail, ultimately, to destroy them. Why
this happens is unclear, but probably has to do with failure of the
mechanisms that normally cause the foreign protein and immune system cell
to bind together. Researchers who have seen this disruption in in vitro
laboratory studies describe this inhibition of CTL-driven cell destruction
as "antagonism" of CTL activity.

     The variant HIV proteins studied by the researchers are naturally
occurring. The aberrant responses were observed in studies that used
viruses and CTL isolated from the same people. If the same disruption
occurs in vivo, these individuals' immune system cells' antigen-fighting
capability may be effectively shut down. In vivo CTL antagonism, if it
actually occurs, is a unique method devised by the virus to evade the
immune system.

     -----------------
     Hepatitis B Virus

     Another study examined the ability of the hepatitis B virus (HBV) to
evade immune responses. In a manner similar to HIV, HBV may do so by
altering or mutating proteins that are required for binding to CTL.
Examination of the virus types and immune responses in 2 people
chronically infected with HBV indicated that the viral protein variants were
natural antagonists that inhibited the CTL antiviral response to the
wild-type viral proteins. The cells that are infected by the variant virus
survive and multiply. 

     The researchers conclude that mutations of this type may be one
cause of persistent HBV infection, and that other viruses known to be
highly mutable, such as HIV and hepatitis C, may become persistent in the
same manner. Additional studies of individuals who have recovered from
hepatitis B may provide insights into the abnormal CTL responses in those
chronically infected with hepatitis B and/or HIV.

     Klenerman P and others. Cytotoxic T-cell activity antagonized by
     naturally occurring HIV-1 gag variants. Nature 369: 403-407. June 2,
     1994.

     Bertoletti A and others. Natural variants of cytotoxic epitopes are
     T-cell receptor antagonists for antiviral cytotoxic T cells. Nature 369:
     407-410. June 2, 1994.

     Allen PM and Zinkernagel RM. Promethean viruses? Nature 369: 411.
     June 2, 1994.

     -------------------------------------------------
     Studies Fail to Find Evidence for a TH1/TH2 Shift

     Cytokine dysregulation is common in people with HIV infection.
Increased production of certain cytokines such as tumor necrosis factor
may actually enhance disease progression. Recent research efforts inspired
a pathogenic theory that describes discernible patterns of cytokine release
that correspond to the earlier and the more advanced stages of HIV
infection. According to the theory, there is a shift in 2 distinct patterns
of cytokine release, TH1 and TH2, that indicates advancing disease and the
immune system's ultimate failure to resist infection. Although the TH1 and
TH2 patterns have opposing, cross-regulatory actions, the TH1 pattern
tends to predominate earlier in HIV infection and the TH2, later.

     Early in HIV infection, a subset of CD4 of T-helper cells called TH1
cells, which release the cytokines IL-2 and interferon gamma, have the
upper hand. TH1 cytokines, which dominate as long as the body resists
infection, are associated with cell-mediated immune responses. During this
phase, cytotoxic lymphocytes (CTL) and natural killer (NK) cells abound,
destroying infected cells, and the individual is relatively healthy and
asymptomatic. At some point (for reasons not fully elucidated by this
theory), a shift occurs and a TH2 type of response begins to prevail. At
this time, as levels of the cytokines IL-4, IL-5 and IL-10 increase and
stimulate antibody production, an (ineffectual) humoral response begins to
edge out the cell-mediated response.

     This theory derived in part from study of long-term nonprogressors,
people infected with HIV who maintain "normal" CD4 cell levels (for at least
7 years) even without receiving antiviral treatment. Researchers found that
these individuals tend to have strong cell-mediated responses as well as
relatively high levels of the so-called TH1 cytokines.

     Now, results of 2 studies, both of which appear in the July 8, 1994
issue of Science, challenge the TH1/TH2-shift theory. The basic finding in
common was that there was no evidence for a shift in dominant T-helper
cell type nor in the cytokines associated with them. 

     NIAID researchers analyzed the types of cytokines found in peripheral
blood and lymph node cells taken from people with HIV, at various stages
of infection. In brief, they detected little IL-2 and IL-4 expression from
individuals at various stages of disease. They found that interferon gamma
and IL-10 were expressed by CD8 cells, rather than by any type of CD4
(T-helper) cell, and that levels of these cytokines were basically the same,
regardless of disease stage. They conclude that "these results indicate
that a switch from the TH1 to the TH2 phenotype does not occur during
the progression of HIV disease."

     The other study, conducted by an Italian team of researchers, found
that levels of interferon gamma and of IL-4 were reduced in people with
HIV. Studies with laboratory cell lines indicated that less IL-4 and IL-5 is
produced in advanced HIV infection. Moreover, it looks as though, if any
clear shift occurs, it may be from a TH1-type response to a TH0 response!
TH0 cells produce both sorts of cytokines, i.e., those produced by both
TH1 and TH2 cells. They also found that HIV replication is stronger in CD4
cells that produce TH2-associated cytokines (i.e., TH2 and TH0 cells).

     The full reports are cited below.

     Graziosi C and others. Lack of evidence for the dichotomy of TH1 and
     TH2 predominance in HIV-infected individuals. Science 265(5169):
     248-252. July 8, 1994.

     Maggi E and others. Ability of HIV to promote a TH1 to TH0 shift and
     to replicate preferentially in TH2 and TH0 cells. Science 265(5169):
     244-248. July 8, 1994.

     Mosmann TR. Cytokine patterns during the progression to AIDS.
     Science 265(5169): 193-194. July 8, 1994.

     ---------------------------------------
     HIV Replication in Non-Lymphoid Tissues

     A post-mortem examination of tissue samples from 8 HIV-infected
persons found that the amount of HIV in non-lymphoid tissues differed
greatly depending on disease stage (at time of death). 

     The people whose tissues were studied were categorized as either
pre-AIDS (Centers for Disease Control and Prevention [CDC] class II) or
AIDS (CDC class IV). Three had presymptomatic HIV infection and died
without HIV-related disease (e.g., drug overdose). Five died with CDC
AIDS-defining illnesses (e.g., cerebral lymphoma). The researchers obtained
blood, lymphoid (lymph node, spleen) and non-lymphoid (brain, spinal cord,
lung, colon, kidney, liver) tissue samples. Using a quantitative polymerase
chain reaction (PCR) technique, they determined viral load in all the tissue
samples, and compared the incidence of significant versus non-significant
infection between the 2 groups.

     Among immune system tissues, lymphoid tissues (lymph nodes and
spleen) from all 8 individuals were significantly infected. An unexpected
finding was that the HIV load in all white blood cells was lower in those
with AIDS than in presymptomatic individuals. This finding may be due in
part to the much lower CD4 cell counts in the group with AIDS. However,
the viral load in CD4 cells, the main cellular target of HIV, was similar in
both groups. 

     No significant infection was found in organs outside the lymphoid
system in tissues from presymptomatic individuals. On the other hand,
significant infection was found in the brain, colon and lung tissues of
several of the persons with AIDS, the lung being significantly infected in
all 5. The abnormalities seen in non-lymphoid organs from the people with
AIDS were associated with high levels of HIV. Researchers postulate that
"although the immune system seems to be very effective in controlling the
spread of HIV infection outside lymphoid tissue, it has no effect on the
frequency of infection of lymphocytes and possibly other cell types in
lymph nodes and spleen."

     The presence of lymphocytes in certain areas of the brain in
presymptomatic individuals was unrelated to the presence of HIV. In AIDS
patients, however, large amounts of provirus were associated with brain
lesions and changes. Although previous studies have suggested that HIV
infects the brain relatively early, these researchers found no evidence for
an early spread of HIV into the brain or other areas of the CNS, such as
the brain stem and spinal cord. They offer 2 explanations for the absence
of significant HIV infection of the brain in the presymptomatic individuals:
(1) their immune systems may have successfully prevented the spread of
replicating HIV into the brain, and/or (2) cytotoxic lymphocytes (CTL)
within the brain may suppress HIV replication by continually destroying
HIV-infected cells.

     The investigators also suggest that the presence of HIV in the brain
does not mean that fatal HIV-related CNS problems will automatically follow.
Other factors may contribute to such complications.

     Researchers note that the highest HIV load was found in the tissues of
the person with AIDS who, unlike the others in that group, had never
taken either AZT or ddI.

     Donaldson YK and others. Redistribution of HIV outside the lymphoid
     system with onset of AIDS. The Lancet 343: 382-85. February 12, 1994.

     ----------------------------------------------
     New Directions for U.S. AIDS Research Programs

     Dr. William Paul, coordinator of the Office of AIDS Research, stated at
a news conference at the X International Conference on AIDS in Yokohama
that federal monies allocated for AIDS research will be redirected from
clinical trials of new drugs and toward basic research. Dr. Paul said that
improving the efficiency of clinical trials of drugs would also save some
money.

     Dissatisfaction with the mediocrity of the HIV/AIDS drugs and vaccines
currently approved and/or in testing has reinforced the impetus to study
the virus itself and the pathogenesis of HIV disease, or the way it causes
disease in humans. The continuing release of information from studies of
long-term survivors of HIV brings into view one potentially navigable
bridge from basic science to treatment. That is, if researchers can
understand better the nature of well-adapted immune responses to HIV
infection, such as those observed in long-term survivors, they may be able
to produce treatments designed to regulate the immune system that any
infected individual could use as well as in conjunction with antiviral
treatments. 

     Pollack A. U.S. official to shift funds toward basic AIDS research. The
     New York Times. A6. August 10, 1994. 

     ---------------------------------------------------------
     Natural Human Cell Receptor Assists in Syncytia Formation

     In vitro studies show that the natural human protein and cell receptor
CD7 participates in the enhancement of HIV infection. CD7 promotes both
cell infection by free-floating HIV virions and syncytia formation.
Membrane fusion via the cell receptor is an integral step in both
processes. 

     CD7 is found on various human cells including T-cells, natural killer
cells and certain B-cells. It appears to be one of several necessary
elements for membrane fusion to occur. In laboratory studies, blocking the
CD7 receptor (by introducing antibodies to it) prevented cells from being
infected by free virions and inhibited HIV-infected cells from fusing into
syncytia. Syncytia are clumps of HIV-infected and healthy immune cells
that the immune system targets for elimination from the bloodstream.
Syncytia formation is associated with disease progression.

     Sato AI and others. Identification of CD7 glycoprotein as an accessory
     molecule in HIV-1-mediated syncytium formation and cellfree infection.
     Journal of Immunology 152(10): 5142-5152. May 15, 1994.

     --------------------------------------------------
     Standard Antibody Tests Fail to Detect HIV Subtype

     Two separate reports appearing recently in Science and The Lancet
discuss the failure of standard screening tests to detect a rare strain of
HIV known as HIV-1 subtype O. To date there are no known cases in the
U.S. and very few outside of the West African nations of Cameroon and
Gabon. The reports are based on 11 cases of HIV-1 subtype O infection in
France, which HIV tests there failed to detect but which subsequently
came to the attention of public health authorities.

     The cases reported in France were primarily among immigrants from
West Africa. In the immediate future, there is little likelihood that this
subtype will threaten public health outside of that region, where, despite
already being well established, it accounts for fewer than 10% of HIV
infections. The World Health Organization (WHO) met to discuss subtype O
and decided that testing procedures should be evaluated for
appropriateness only in those regions where the subtype is found, rather
than globally.

     One screening test has been pulled from the market in France for
failing to detect the virus in multiple samples. A spokesperson for the U.S.
Food and Drug Administration (FDA) stated that currently used tests could
be modified to detect the new strain. However, the stories illustrate the
limitations of tests that are highly specific. Although sensitive, the tests
detect only what they are designed to detect, and therefore have the
potential to fail to identify a viral variant. 

     This scenario is similar to one in the past, when the FDA-licensed HIV
ELISA antibody tests did not recognize the HIV-2 variant. The test kit
manufacturers subsequently modified the test kits to the current form,
which detects both HIV-1 and HIV-2.

     Russell S. Rare HIV strain eludes screening tests. San Francisco
     Chronicle. A2. June 8, 1994.

     French blood test misses some HIV. AIDSWeekly. 2. April 11, 1994.

     ---------------------------
     Treatment for HIV Infection 

     FDA Approves Zerit 

     On June 27, 1994, Bristol-Myers Squibb received marketing clearance
from the FDA for the antiretroviral Zerit (d4T). Reviewed and authorized
under the accelerated approval mechanisms, Zerit was shown in clinical
trials to affect surrogate endpoints (CD4 counts) and to satisfy an "unmet
need." Zerit is the fourth anti-HIV compound to be approved by the FDA
and the first to be brought to market since ddC in 1992. Like AZT, ddI
and ddC, d4T is a nucleoside analog that inhibits the ability of HIV to
replicate and to infect healthy cells.

     Zerit is indicated for adults with advanced HIV disease who are
intolerant to or failing to benefit from other approved antiretroviral
agents. Approval was largely based on data submitted from a study
referred to as 019 and the parallel track study. Study 019 compared d4T
to continued use of AZT in people with 50-500 CD4 cells who had used AZT
in the past. The eligibility criterion specified at least 6 months on AZT
but, in fact, the average length of prior AZT use was 18 months. In 019,
those who were assigned to the Zerit arm took 40 mg twice daily if they
weighed over 60 kg, or 30 mg if they weighed less than 60 kg. At 12
weeks, CD4 levels had risen by 22 in the Zerit group and had decreased
by the same amount in the AZT group. p24 antigen levels also decreased in
those taking Zerit, while they increased in those taking AZT. 

     The parallel track study, which began in October 1992, involved 13,000
people. Data gathered from 10,000 people and presented at the FDA
advisory committee meeting showed no difference in survival at 40 weeks
between the 2 study groups (20 vs 40 mg twice daily). The principal side
effect, peripheral neuropathy, is dose-related, and was considered by
researchers to be the only dose-limiting adverse reaction. Across all trials,
15-21% of the participants experienced peripheral neuropathy. Stopping the
drug usually resolves the symptoms.

     The accelerated approval mechanism requires applicants to continue to
evaluate the drug even after approval. At this point, Bristol-Myers Squibb
plans both to continue ongoing confirmatory studies and to begin new
ones. Study 019, comparing Zerit and AZT, is ongoing but should be
completed in December 1994. A European parallel track study that is
looking at the dose effect of Zerit in "less advanced patients" has a May
1995 expected completion date. The company has additional plans for Phase
IV studies to evaluate various drug interactions; pediatric use of Zerit;
safety and prevention of perinatal transmission; and pharmacokinetic safety
in women and minorities.

     On August 15, 1994, Bristol-Myers Squibb sent the final shipments of
Zerit under the parallel track program, which was concluded the same day.
Bristol-Myers Squibb has set up a phone line to answer any questions
about the parallel track discontinuation; call 1-800-842-8036. 

     For help finding sources of third-party reimbursement for patients
who wish to continue taking Zerit, doctors may call the HIV Products
Reimbursement HelpLine and Temporary Assistance Program at
1-800-788-0123. Patients who do not qualify for third-party reimbursement
but are in need of financial assistance may be eligible for free drug
through the Temporary Assistance Program. Zerit will be available in 40,
30, 20 and 15 mg capsules. 

     Hellman N. Director, Antiviral Clinical Research, Bristol-Myers Squibb.
     Personal Communication. June 27, 1994.

     HHS [U.S. Department of Health and Human Services] News. June 27,
     1994.

     Yarin S. Public Affairs Manager, Bristol-Myers Squibb. Personal
     Communication. June 27, 1994.

     ----------------------------
     ddC Approved for Monotherapy

     On August 8, 1994, the Food and Drug Administration (FDA) approved
ddC (zalcitabine, HIVID) as a monotherapeutic (single-agent) treatment "for
HIV infection in adults with advanced HIV disease who either have
experienced disease progression while receiving zidovudine [AZT], or who
are intolerant to zidovudine." Approval was based on a multicenter,
open-label trial among 467 people with advanced HIV who were failing on
AZT. Participants were randomized to either take ddI or ddC. The study
concluded that ddC was "at least as efficacious" as ddI in treating HIV
and in delaying death. For a review of this study, see the June 1994 issue
of BETA, page 50.

     ddC will continue to be available in combination with AZT for people
with fewer than 300 CD4 cells, under the FDA accelerated approval
mechanism.

     The recommended dose for monotherapeutic ddC is one 0.750 mg tablet
every 8 hours. For combination therapy with AZT, 200 mg of AZT every 8
hours are added to the ddC regimen just described. ddC is available in
0.375 mg and 0.750 mg tablets, in 100-tablet bottles. For information on
ddC reimbursement, call ASSIST at 1-800-285-4484, Monday-Friday, 9 am to
5 pm, Eastern Standard Time. 

     HIVID (zalcitabine) available as monotherapy for HIV infection. Roche
     News. August 8, 1994.

     -----------------------------
     Thymomodulin for Treating HIV

     An article in the July 8, 1994 issue of AIDS Treatment News explores
the idea of using thymomodulin, a thymus gland extract, as an anti-HIV
treatment. Based on an extensive medical literature search as well as
anecdotal reports, the report presents a compelling case for scientific
study of thymomodulin. The premise is that this agent, which showed early
promise in a small, European study in people with HIV, has been
wrongfully neglected.

     Thymomodulin is made from animal (calf) thymus glands and is taken
orally. Used in Europe as an immune treatment, it is an approved drug in
Italy. Studies have shown it to be of benefit in treating a range of
conditions related to immune dysfunction in humans, including hepatitis B,
post-operative infections and allergies. Laboratory and animal studies have
indicated that the agent has mechanisms of action that may improve certain
aspects of immunity.

     One of the most important published studies of thymomodulin in people
with HIV took place in 1987, in Italy. In that study, 15 people with HIV
received 60 mg/day of a syrup formulation of the drug for approximately 2
months. Two participants with advanced AIDS apparently experienced no
benefit. However, symptoms such as fever were alleviated in 12 of the 15
(80%); chronic lymphadenopathy (lymph node inflammation) resolved in 6;
thrush (oral candidiasis) resolved in 6; and CD4 cell counts increased.
Other white blood cell measurements had mixed results. There were no
adverse reactions. An Argentinean study in 11 people with HIV reported
that the use of thymomodulin in combination with AZT produced laboratory
marker and clinical benefits in 9.

     The article also provides profiles of 3 people (noted as being well
known by the authors) who have been using thymomodulin for
approximately 2.5 years, and mentions other anecdotal accounts as well. A
recurring theme is improvement in blood markers, particularly elevations in
CD8 cells counts. A tentative proposal, prompted largely by anecdotal
testimony, is to combine thymomodulin with an antiviral, to reduce the
chances of CD4 cell (hyper-) activation.

     Nowhere in the literature was thymomodulation associated with any
toxicity. Anecdotally, side effects were reported of "an aggravated,
unpleasantly stimulated feelingredness of the skin, and sometimes
headache." Some people reported feeling "warmth in the chest, where the
thymus is located, shortly after it is taken." The article closes by
emphasizing the need for research to begin at once and proposing specific
questions for study. The authors also provide an exhaustive "thymomodulin
bibliography," consisting of all medical-journal articles they were able to
find.

     Thymomodulin is available in the U.S. only for personal use and by
prescription through some buyers' clubs.

     A follow-up note in the July 22 issue of AIDS Treatment News reports
that the German Ministry of Health recently issued a warning against the
use of "calf thymus or other organ extracts (widely used in Europe in
cancer treatment) because of a theoretical risk of contamination with BSE
(bovine spongiform encephalopathy)." BSE, also known as "mad cow
disease," has caused the deaths of over 100,000 cattle in England. Although
there are no reported cases of human infection with BSE, laboratory
animals have been infected. Some suspect that BSE may be related to a
rare but fatal human disease called Creutzfeldt-Jakob disease.

     Apparently, concern about BSE is nothing new in Europe.
Manufacturers of calf thymus extracts have instituted previous precautions
such as procuring animals from areas in which BSE is unknown.
Nevertheless, people considering using thymomodulin or any thymus extract
may want to consider the warning, which applies to natural thymic extracts
only, not to synthetic forms. Natural thymic extracts include thymomodulin
and thymostimulin. Synthetic compounds, exempt from the warning, include
thymopentin (TP-5, Timunox), thymic humoral factor (THF) and
thymosin-alpha-1.

     James JS and Getty J. Thymomodulin. AIDS Treatment News 202: 1-7.
     July 8, 1994.

     James JS. Thymomodulin warning. AIDS Treatment News 203: 4. July 22,
     1994.

     ---------------------------------------
     Acyclovir plus AZT: the Official Report

     Several studies have associated a survival benefit with acyclovir use
in people with HIV. The June issue of BETA contains a report on the
preliminary results of an analysis of data from the observational
Multicenter AIDS Cohort Study (MACS). The full report on the survival
benefit detected in MACS from combined use of AZT and acyclovir appears
in the July 15, 1994 issue of Annals of Internal Medicine. In this latest
published study of the effects of acyclovir on HIV disease, researchers
sought to determine the effect of acyclovir on HIV disease progression and
survival in people taking AZT. 

     Researchers conducted an in-depth statistical analysis of data collected
in the MACS, an ongoing prospective study of over 2,000 gay and bisexual
men with HIV. There was complete data for 786 MACS participants who
started taking AZT before receiving AIDS diagnoses, which were based on
the 1987 CDC definition, which did not include having fewer than 200 CD4
cells as AIDS-defining. Among these 786, 515 also took acyclovir. Four
hundred and eighty-eight (488) people took acyclovir as an antiherpes
treatment and/or as an anti-HIV treatment. Two hundred and forty-two
(242) reported using acyclovir solely for its anti-HIV potential. The
available data indicated that the median dosage used for anti-HIV purposes
was between 600-800 mg daily. 

     Compared to people who took AZT alone, people who took both AZT and
acyclovir were found to have a "clinically significant prolonged survival"
period of about 1 year. In fact, using acyclovir for any reason and using
acyclovir specifically for HIV "were each associated with a 44% decreased
probability of death if the drug was used after AIDS developed...but not
before." Taking the combination (AZT and acyclovir) was not associated
with any change in time to AIDS diagnosis. 

     Again, the 1987 CDC definition of AIDS was used in formulating study
conclusions. Based on this study, the overwhelming evidence suggests that
it is only after an AIDS diagnosis (or, perhaps, after CD4 cell levels fall
below 150 or 200, based on an AIDS diagnosis) that any survival benefit is
detected. The study could not measure any increase in lifespan that may
take place before an AIDS diagnosis. The way the evidence was analyzed
suggests only that it did not permit the detection of an effect in people
who are HIV positive but pre-AIDS.

     Taking acyclovir consistently was more positively associated with
prolonged survival. Increasing length of continuous use of acyclovir at
doses required to suppress herpes was also associated with increased
survival (i.e., 600-800 mg/day).

     The dose level appeared to have no influence on survival. There was
no survival difference between people using high- vs low-dose acyclovir. 

     Analysts focussed on acyclovir. Although everyone initially used AZT,
some people switched from AZT to other antivirals such as ddI or ddC, or
simply stopped taking any anti-HIV drug altogether.

     Stein DS and others. The effect of the interaction of acyclovir with
     zidovudine on progression to AIDS and survival. Annals of Internal
     Medicine 121(2): 100-108. July 15, 1994.

     ---------------------------------------
     ACTG Suspends Nevirapine Trials Accrual

     Concerned about the potential for nevirapine to cause liver toxicity,
the ACTG, at the behest of the FDA, has temporarily ceased further
enrollment of participants into ACTG trials involving nevirapine. Trials that
are already closed to enrollment (i.e., fully enrolled) will continue
unchanged. People already enrolled into affected trials, i.e., those not yet
fully accrued, will continue on the existing protocol. In the meantime, the
FDA is reviewing all nevirapine protocols to determine to what extent, if
any, nevirapine may adversely affect the liver. 

     The decision followed the release of information gathered in a trial
conducted by Boehringer-Ingelheim, manufacturer of nevirapine. In this
pharmacokinetic study, 3 HIV negative women developed reversible but
significant liver toxicities. 

     Apparently, no signs of unusual liver toxicity have emerged from ACTG
nevirapine trials thus far, although scrutiny and careful analysis of data
will continue. At this time, it is unclear what the next step will be. If the
review proves satisfactory, it is possible that enrollment will soon resume
and the trials will proceed unaltered.

     Haas G. ACTG studies involving nevirapine temporarily closed. Critical
     Path AIDS Project 29: 41-42. Summer 1994.

--------------------------------------
Treatment for Opportunistic Infections

TMP-SMX desensitization protocol

     Laboratory and clinical evidence indicate that TMP-SMX (Bactrim,
Septra and generics) is an effective agent for preventing PCP as well as
toxoplasmosis. However, an estimated 50% of individuals who attempt taking
TMP-SMX are intolerant of it. Common adverse reactions include high
fevers, rash, itchiness, and muscle aches and pains. Recent studies
suggest that these are not allergic reactions, but occur because the drug
is metabolized differently by people with HIV. 

     Individuals intolerant of TMP-SMX may switch to another prophylactic
agent such as dapsone or aerosolized pentamidine. Increasingly, however,
people are considering another option: TMP-SMX desensitization. This allows
an individual to begin taking the drug at very low doses, which are
tolerable, and to gradually and steadily increase the tolerated amount until
an effective dose level is reached (usually 1 double-strength tablet daily
or 3 times a week).

     Several groups have developed or are developing TMP-SMX
desensitization protocols. In San Francisco, California, the Conant Medical
Group has developed one desensitization protocol that purportedly
succeeds in 84% of people who complete it. Christopher King, former
Associate Director of Research Activities for the Conant Medical Group, told
BETA, "it is our intention to aggressively advocate that the standard of
care be to offer to any individual with a history of hypersensitivity to
TMP-SMX (or who develops hypersensitivity to the drug during
prophylaxis or therapy) an effective standard desensitization before
moving to a less effective agent." 

     The protocol begins with a dose of pediatric-strength TMP-SMX oral
suspension that has been heavily diluted (1,000,000 times) with sterile
distilled water and administered 4 times over a 24-hour period. An outline
of this protocol, presented at the X International Conference on AIDS in
Yokohama and currently in use by the Conant Medical Group, follows:

       Day 1    Day 2    Day 3    Day 4    Day 5       Day 6       Day 7 
Day 8 
Dose 1     1 cc      1 cc     1 cc     1 cc      1 cc  1 cc  1 cc  5 cc
Dose 2     2 cc      2 cc     2 cc     2 cc      2 cc  2 cc  2 cc  10 cc
Dose 3     4 cc      4 cc     4 cc     4 cc      4 cc  4 cc  4 cc  20 cc
Dose 4     8 cc      8 cc     8 cc     8 cc      8 cc  8 cc  8 cc  DS
tablet*
*DS = double strength

       For more information on the desensitization protocol, call M.J. Norman
       at 415-923-0222.

       King C and others. Survival, death, and desensitization to
       trimethoprim/sulfamethoxazole (TMP/SMX). X International Conference
       on AIDS. Yokohama, August 1994. 388B.

       King C. Associate Director of Research Activities, Conant Medical
       Group. Personal Communication. June 14, 1994.

       Conant M. Medical Director, Conant Medical Group. Personal
       Communication. August 3, 1994.

       -----------------------------------------------
       Mepron for Pneumocystis carinii Pneumonia (PCP)

       A study of people with HIV and mild-to-moderate PCP concluded that
Mepron is as effective as intravenous (IV) pentamidine for treating the
disease, and involves far less toxicity and fewer adverse reactions.
Manufactured by Burroughs Wellcome, Mepron is the brand name for an
oral formulation of atovaquone. Burroughs Wellcome is currently developing
a suspension formulation of Mepron that is expected to produce higher,
more therapeutically effective blood levels of the drug than do the tablets
that were used in this study.

       The drug of choice for treating PCP is trimethoprim-sulfamethoxazole
(TMP-SMX: Bactrim, Septra and generics). However, many people who begin
taking the drug are forced to discontinue it because of the serious side
effects it frequently causes. This study compared the efficacy and side
effects of Mepron and IV pentamidine, alternatives to TMP-SMX, in people
with AIDS and PCP. 

       The multicenter trial randomized 56 people to take Mepron and 53 to
take pentamidine for a 21-day period. All had histologically confirmed PCP.
Laboratory and clinical tests were used to monitor participants for
treatment success and adverse reactions, both during treatment and for 8
weeks afterward.
       Of participants whose treatment was considered successful, 57%
received Mepron and 40%, pentamidine. More response failures occurred
among people taking Mepron (29%) than pentamidine (17%). However, the
incidence of "treatment-limiting" side effects that forced the
discontinuation of therapy was much lower in the Mepron group (4%) than
in the pentamidine group (36%).

       Significant adverse side effects in the pentamidine group were
hypoglycemia, vomiting, nausea, elevated creatinine (a liver enzyme) and
rash. The only significant adverse side effect for those in the Mepron
group was rash.

       Dohn MN and others. Oral atovaquone compared with intravenous
       pentamidine for Pneumocystis carinii pneumonia in patients with
       AIDS. Annals of Internal Medicine 121(3): 174-180. August 1, 1994.

       --------------------------------------------------
       ACTG Study Results Support Use of Trimetrexate for
       Moderate-to-Severe PCP

       Results of ACTG 029/031 confirm that trimetrexate with concurrent
leucovorin administration (brand name Neutrexin) can be used as an
effective alternative treatment for moderate-to-severe PCP in people who
are intolerant of or refractory to trimethoprim-sulfamethoxazole (TMP-SMX).
This is the indication approved by the FDA in December 1993.

       Two hundred fifteen (215) people with HIV who were hospitalized for
moderately severe PCP were randomly assigned to intravenously receive
either trimetrexate or TMP-SMX. None had yet received any treatment for
the current episode, and none had a history of hypersensitivity to TMP.
The groups were similar in terms of disease severity, as determined by
various laboratory and clinical markers. AZT was discontinued for the
study period. Trimextrexate was taken at a dose level of 45 mg/m2 daily,
with IV leucovorin at 5 mg/m2 every 6 hours (20 mg/kg/day). The
TMP-SMX dose used was 20 mg/m2 every 6 hours. After 10 days, if the
patient had improved, the study drug was unblinded and the patient was
discharged, thereafter receiving medication once daily on an ambulatory
outpatient basis. Patients too ill to leave the hospital continued to receive
their treatment intravenously.

       Survival at day 21 was the primary endpoint. Secondary endpoints
were therapeutic response at days 10 and 21, and side effects. 

       Overall, the study indicated that TMP-SMX had superior efficacy. At
day 10, 16% of those taking TMP-SMX had died or failed to respond,
compared to 27% of those taking trimetrexate. By day 21, the cumulative
number of failures were 20% in the TMP-SMX group and 38% in the
trimetrexate group. At follow-up at day 49, a distinct survival advantage
for those taking TMP-SMX was noted as well.

       Serious side effects were more frequent in the TMP-SMX group:
fever, nausea, vomiting, abnormal liver and blood tests.

       Therapeutic success rates, roughly equal for both treatment groups,
were 51% in the TMP-SMX group and 52% in the trimetrexate group. The
trends were that people discontinued TMP-SMX because of intolerance
(adverse reactions) and discontinued trimetrexate because of inefficacy.
This observation in part allows researchers to conclude that "trimetrexate
is an effective therapy for moderate-to-severe PCP, although inferior to
TMP-SMX."

       Since approval of this study protocol, evidence has emerged that
indicates that concomitant use of corticosteroids may improve survival in
people being treated for moderately severe PCP. Another change in the
standard of care is that the dosage of TMP-SMX that is now commonly
recommended is 15 mg/kg/day, rather than 20, as was used in the study.

       Sattler FR and others. Trimetrexate with leucovorin versus
       trimethoprim-sulfamethoxazole for moderate-to-severe episodes of
       Pneumocystis carinii pneumonia in patients with AIDS: a prospective,
       controlled multicenter investigation of the AIDS Clinical Trials Group
       protocol 029/031. The Journal of Infectious Diseases 170: 165-172.
       July 1994.

       ----------------------------------------------------------------
       HPMPC for Treatment of Acyclovir- and Foscarnet-Resistant Herpes
       Simplex Virus

       Persistent and recurring mucocutaneous herpes simplex virus (HSV)
types 1 and 2 are common in immunosuppressed people. Acyclovir is the
drug of choice for anti-HSV therapy in people with HIV, but the same
people not infrequently develop viral strains resistant to such treatment.
Foscarnet is sometimes used for treating people with acyclovir-resistant
herpes, yet the risk of toxic reactions (especially renal failure) is
considerable. Many studies have shown the antiherpetic potential of HPMPC,
a nucleoside analog under investigation for treating cytomegalovirus
infection (CMV). Now, a report details the successful use of HPMPC in the
topical treatment of herpes lesions in 2 immunosuppressed people infected
with herpesviruses (simplex 1 and 2) who failed on either acyclovir and/or
foscarnet.

       One HIV-infected patient had genital herpes that failed to respond to
oral acyclovir; laboratory tests showed that his HSV-2 strain was
acyclovir-resistant. Renal (kidney) insufficiency forced him to stop
foscarnet, and ganciclovir produced unsatisfactorily transient relief.
Following topical application of HPMPC, the lesions regressed. One week
after ending HPMPC treatment, no virus was isolated. Virus isolated from
subsequent recurrences had become sensitive to acyclovir, and the patient
was successfully treated with it.

       The other patient studied was a bone marrow transplant recipient.
After surgery, he developed neutropenia, fever and oral mucosal
inflammation and lesions. Cultures of specimens from his mouth were
positive for HSV-1, but subsequent tests (after failing treatment with
acyclovir and foscarnet) revealed that he was infected with a strain of
herpes simplex virus-1 that was resistant to acyclovir, foscarnet and
ganciclovir. The oral lesions disappeared after topical treatment with
HPMPC. However, after discontinuation, the patient developed lesions in
different orofacial sites (chin, forehead and new places inside his mouth).
Tests revealed that these most recent lesions were all HSV-1 positive, and
that the HSV-1 was sensitive to acyclovir. Topical application of HPMPC
caused resolution of the lesions on his chin and forehead but not in his
mouth. Since tests had indicated that the strain was sensitive to acyclovir,
acyclovir therapy was restarted. The oral lesions were completely resolved.
The patient tapered off of acyclovir over a 1-month period, and thereafter
remained lesion-free.

       Researchers conclude that topical HPMPC is a successful treatment
for mucocutaneous herpes lesions that are resistant to acyclovir. Moreover,
in this study, herpetic relapses following treatment with HPMPC had
regained susceptibility to acyclovir. Alternating acyclovir and HPMPC may
be an effective approach to treating herpes strains (especially those that
are intermittently acyclovir-sensitive) in immunocompromised people,
especially when foscarnet is of limited use. 

       Snoeck R and others. Successful treatment of progressive
       mucocutaneous infection due to acyclovir- and foscarnet-resistant
       herpes simplex virus with (s)-1-(3-hydroxy-2-
       phosphonylmethoxypropyl)cytosine (HPMPC). Clinical Infectious
       Diseases 18(4): 570-578. April 1994.

       ---------------------------------------
       Clinical Trial: HPMPC for CMV Retinitis

       Ganciclovir (Cytovene) and foscarnet (Foscavir) are the 2 standard
agents used to treat CMV retinitis, a condition that affects up to 25% of
people with AIDS. CMV retinitis causes retinal lesions and, without
treatment, can cause permanent vision damage. Individuals with strains of
cytomegalovirus that are resistant to the standard drugs, however, face
additional complications.

       On July 12, 1994, Gilead Sciences announced the beginning of an
open-label study of their product HPMPC, or GS 504, for the treatment of
refractory CMV retinitis in people with AIDS. About 100 people will be
enrolled at 6 centers in the U.S. and 1 in the U.K. The study will be open
to people with AIDS with ophthalmologist-diagnosed CMV retinitis who have
unsuccessfully used the standard approved treatments, ganciclovir and/or
foscarnet, for at least 4 weeks. Participants will be randomized to receive
one of 2 dose levels of intravenous (IV) GS 504. For the 2-week induction
phase, everyone will receive 5 mg/kg once per week. Then, once every
other week, participants will receive either 5 mg/kg or 3 mg/kg.
Participants may remain on the regimen until they experience
treatment-limiting toxicity or sight-threatening retinitis. The clinical
endpoint is "time to progression of retinal lesions measured by retinal
photographs."

       Two other studies of GS 504 in previously untreated people with CMV
retinitis are ongoing. In a small study, high-dose IV HPMPC (5 mg/kg
weekly) caused CMV urine cultures to revert to negative in 4/6 people.
Researchers are also studying the use of IV GS 504 to prevent CMV-related
lung infection in immunosuppressed bone marrow-transplant patients.

       AmFAR AIDS/HIV Treatment Directory 7(3): 76-79. June 10, 1994.

       Gilead sciences commences open-label clinical trial of GS 504 for AIDS
       patients with relapsing CMV retinitis. Gilead Sciences press release.
       July 12, 1994.

       -----------------------------------------------
       New Drug Application Filed for Oral Ganciclovir

       Syntex Corporation, manufacturers of ganciclovir, submitted a new
drug application (NDA) to the FDA on June 30, 1994. Syntex is seeking FDA
approval to market oral ganciclovir for maintenance treatment of
cytomegalovirus (CMV) retinitis in immunocompromised people, including
people with AIDS.

       Intravenous (IV) ganciclovir (Cytovene) for CMV retinitis has been
on the market since 1989 in the U.S. Compared with people who are
untreated, people who receive maintenance treatment with IV ganciclovir
have significantly prolonged periods of disease remission. Oral ganciclovir,
studies have shown, can suppress viral replication. Encouraging results
from 3 clinical trials of the efficacy of oral ganciclovir for maintenance
treatment of CMV retinitis formed the basis of the Syntex NDA. (See
Research Notes, BETA, 41, March 1994, which reported on data available at
that time from 2 U.S. trials.) All 3 trials had similar, comparative designs. 

       In the most recently completed, European trial, 159 participants with
CMV retinitis first went through a 2-3 week induction phase that involved
treatment with IV ganciclovir. Once the disease stabilized, participants
were randomized in a 2:1 ratio to either take 3,000 mg/day of oral
ganciclovir or to continue taking 5 mg/kg IV ganciclovir once daily.
Researchers then looked at the different mean times to disease recurrence
or progression, as revealed by retinal photos and fundoscopic evaluation
(taken every 2 weeks during the study), as well as safety and tolerance of
the oral regimen. Based on fundoscopic evaluation, the mean time to
disease progression was 109 days for people taking IV ganciclovir and 86
days for those taking oral ganciclovir. (At press time, results of the
retinal photographs had not yet been released.) People taking oral
ganciclovir experienced more gastrointestinal upset; people taking the IV
formulation experienced more neutropenia and leukopenia.

       Syntex press information. Syntex submits oral ganciclovir NDA. June
       30, 1994.

       Volker K and others. A randomized comparison of the efficacy and
       safety of maintenance treatment with oral and IV ganciclovir (GCV) in
       the prevention of recurrence of cytomegalovirus retinitis in AIDS
       patients. Fourth European Conference on Clinical Aspects and
       Treatment of HIV Infection. Milan. March 1994. Abstract #021.

       ----------------------------------------------
       New Drug Approved for Herpes Zoster (Shingles)

       On June 30, 1994, SmithKline Beecham received marketing approval
from the FDA for its new drug famciclovir (Famvir). Famciclovir is
indicated for the treatment of acute herpes zoster, or shingles. It is the
first antiherpes drug to reach the market since 1982, when acyclovir was
first introduced in ointment and intravenous formulations. (Zovirax brand
acyclovir capsules were introduced in 1985 for the treatment and
suppression of primary genital herpes and then, in 1990, approved for
treating shingles.)
       Taken orally in 500 mg doses 3 times daily for 7 days, famciclovir is
being marketed as an equally effective alternative to acyclovir, which
needs to be taken at higher doses, more often (800 mg, 5 times daily).
Once ingested, famciclovir is converted inside the body to penciclovir, the
active ingredient that prevents herpesvirus replication. Penciclovir does
this by selecting infected cells and inhibiting viral DNA replication.
Famciclovir has 77% bioavailability. Oral administration of 800 mg of
acyclovir, the only other drug currently available for treating shingles,
results in 10% penciclovir bioavailability, according to SmithKline Beecham.
In a study, the side effects of famciclovir, considered well tolerated, were
similar to placebo (diarrhea, nausea and headache). 

       Shingles is a viral disease caused by reactivation of the
varicella-zoster virus, which also causes chickenpox. Shingles manifests as
an outbreak of itchy, blister-like sores that are typically extremely painful
and sensitive to most stimuli. About 600,000 people in the U.S. develop
shingles each year; the elderly and other immunocompromised people are at
increased risk. Famciclovir reduces the period known as postherpetic
neuralgia, pain that persists after the blisters have healed, as well as the
healing time of the blisters.

       Sharyn Arnold of SmithKline Beecham said that the wholesale cost for
a course of therapy (500 mg 3 times daily for 7 days) is approximately
$103, compared to $147 for a course of acyclovir therapy (800 mg 5 times
daily). On July 26, the company announced that shipments were being made
and that supplies should be available at once in local drugstores.

       Famvir, SmithKline Beecham's new treatment for shingles, cleared for
       marketing by FDA. News release. June 30, 1994.

       ---------------------------------------------------
       Official Approval Sought for Valtrex (Valacyclovir)

       Wellcome plc filed an application for approval of its oral "next
generation antiherpes" drug Valtrex (valacyclovir) with the FDA in the
U.S., and with regulatory bodies in 18 other countries worldwide. Clinical
studies of Valtrex have shown that it has greater bioavailability than
acyclovir, which confers better clinical results. In other waysmode of
action, safety profileValtrex differs little from acyclovir.

       The application currently seeks approval of Valtrex as a treatment
for herpes zoster, or shingles. Other studies are ongoing to determine its
efficacy for treating genital herpes and cytomegalovirus (CMV).

       Wellcome plc news release. Wellcome files for approval for new herpes
       product. July 8, 1994.

       -------------
       Immunotherapy

       NIAID Recommends No Expansion of gp120 Vaccine Trials

       In an atmosphere of general ambivalence about the HIV preventive
vaccines now in development, the National Institute of Allergy and
Infectious Diseases (NIAID) has made a procedural decision about its trial
of the 2 gp120 HIV vaccines farthest along in development. After a full day
of meetings on June 17, 1994, several key NIAID AIDS advisory committees
submitted a unanimous recommendation to NIAID director Anthony Fauci,
MD, who agreed to it. NIAID will proceed with the current clinical
evaluation, but will not expand the trial(s) until new and compelling data
from other studies arrives or until a new type of vaccine emerges.

       The 2 gp120 vaccines in the NIAID trial are made by Biocine
Company in Emeryville, California, and by Genentech, Inc., in South San
Francisco, California. Both are currently in a Phase II clinical trial which
began in December 1992, among 300 individuals. 

       NIAID plans to continue to evaluate data from various HIV vaccine
studies in the hopes of identifying suitable candidate preventive vaccines
for expanded trials. A large-scale HIV vaccine trial probably is still 1-3
years away.

       Other unsettling news about these 2 candidate vaccines was widely
reported recently as well: 5 volunteers in the NIAID vaccine gp120 study
became infected with HIV after receiving the vaccine. Two of the people
who seroconverted were considered low-risk and 3, high-risk. One of the
high-risk seroconverters has reportedly lost CD4 cells at a particularly
high rate. Researchers note that the initial humoral immune responses of
the individuals were normal post-vaccinationall developed expected levels
of HIV antibodies.

       An article in the June 17, 1994 issue of Science reports that, among
various combined HIV vaccine trials, a total of 10 people have become
HIV-infected. Six of those had not yet received the total of 3 shots
typically given to be considered fully vaccinated.

       The gp120 study, in which the 5 widely discussed seroconversions
occurred, is designed to look at the safety of the vaccine and the
immunologic responses of the participants. Therefore, in terms of the gp120
candidates' efficacy, it is not yet known what the seroconversions really
mean. 

       NIAID News Release. June 17, 1994.

       Cohen J. Will media reports KO upcoming real-life trials? Science
       264(5166): 1660. June 17, 1994.

       Crewdson J. AIDS vaccine future in doubt. The San Francisco
       Examiner. A7. May 29, 1994.

       ------------------------------------------------------
       Flu Vaccines for HIV Positive Children and Adolescents

       Each year, influenza is a major cause of illness among all children.
Studies have estimated that up to 30% of children develop symptoms that
result in missed school and, for some, even hospitalization.
Immunocompromised children have increased risk factors for developing
serious influenza-related conditions such as anorexia, weight loss and
malnutrition. Clearly, a successful prophylactic strategy would be valuable.
Unfortunately, HIV-related impairment of the humoral immune response, the
branch of the immune system that produces antibodies, causes diminished
antibody response in infected children to various types of vaccines:
tetanus, diphtheria, pneumococcal and others. Recently, however, a study
of HIV positive children and adolescents concluded that HIV-infected
children do have the ability to respond to influenza vaccinations,
especially if they have not progressed to AIDS.

       Forty-six (46) HIV-infected children and 61 age-matched HIV negative
controls between the ages of 6 months and 21 years completed the study.
They were vaccinated before the beginning of the influenza season,
according to the instructions on the package insert, against 3 strains
(Taiwan, Shanghai and Yamagata). Blood samples were measured for levels
of antibodies to influenza before and 1 month after each vaccination. CD4
cells were measured during the 3 months prior to vaccination.

       HIV positive children who received 2 injections had the greatest
increases in antibody levels. Investigators suggest routinely using a
2-injection strategy for immunizing HIV positive children, and are
currently conducting further studies to test that hypothesis.

       Another finding was that CD4 cell counts were not associated with
responsiveness to the vaccine (serologic response to influenza A antigens),
which is different from the pattern in adults. The child's clinical status,
based on the CDC's case definition of AIDS, however, was correlated with
immune response; children with CDC-defined clinical AIDS had much lower
postimmunization influenza antibody levels than did children with
earlier-stage HIV disease.

       Chadwick EG and others. Serologic response to standard inactivated
       influenza vaccine in human immunodeficiency virus-infected children.
       Pediatric Infectious Disease Journal 13(3): 206-211. March 1994.

       ----------------------------------------------------
       Promising Vaccine Being Developed for Genital Herpes

       Once infected with herpes simplex 2 (HSV-2), a person may
experience either rare, isolated or frequent outbreaks of genital herpes.
However, as with HIV, an infected individual carries the virus for life. One
approach to treating such a chronic viral infection is through the use of
an immunotherapeutic vaccine, although a successful one for any chronic
viral infection has yet to be developed. Results of a study of an
experimental treatment vaccine for genital herpes, published in the June
11, 1994 British medical journal The Lancet, constitute the first substantial
evidence that "a vaccine can modify the course of a chronic viral infection
in human beings."

       The randomized, double-blind study enrolled 86 healthy men and
women with confirmed HSV-2 infection. Participants received an injection
on the first day and then another, 2 months later, of either vaccine
(recombinant glycoprotein D, or gD2) or placebo (alum). Thereafter,
participants received periodic examinations and follow-up bloodwork for 1
year. Suspected recurrences were evaluated by standard cultures as well
as clinical examinations. Episodic acyclovir use was permitted for confirmed
recurrences, but long-term acyclovir use was disallowed during the study.

       The time to first recurrence was not statistically different for the
vaccine vs the placebo group, but the frequency of outbreaks was less
among the vaccine recipients. For the year overall as well as per month,
the vaccine recipients had fewer post-vaccination outbreaks than did the
placebo recipients. This trend or difference was most pronounced during
the first 4 months following the vaccination: 34% less frequency for the
first 4 months and 24% for the year overall.

       Side effects were common among both study groups but generally
mild (headache, chills, transient pain at the injection site).

       After 2 injections, the vaccine recipients had substantial rises in
levels of antibodies directed at the antigen (a protein fragment of HSV-2)
and also in levels of neutralizing antibodies. Antibody levels were highest
at day 84, but remained above baseline throughout the study year. The
levels of antibodies in the placebo recipients did not change, despite
recurrences. Outbreaks were not correlated with (high) antibody levels in
either group.

       The reduced number of recurrences and the greater number of
isolated prodromal symptom reports (tingling, etc. that failed to result in a
blister or outbreak) among the vaccine recipients lead researchers to
conclude that the vaccine successfully altered the recipients' immune
responses. They note that daily use of acyclovir to suppress herpes
resulted in fewer recurrences per month than did the vaccine, although
episodic use of acyclovir did not change the frequency of outbreaks. 

       Investigators are trying to identify additional HSV-2 proteins to use
in the vaccine, to further boost the immunological response. Nonetheless,
the results from this study alone indicate that vaccines can be effective
treatments for chronic viral diseases.

       Straus SE and others. Placebo-controlled trial of vaccination with
       recombinant glycoprotein D of herpes simplex virus type 2 for
       immunotherapy of genital herpes. The Lancet 343: 1460-1463. June 11,
       1994.

       -------------------------------------------------
       Vaccines for Sexually Transmitted Diseases (STD)?

       In the U.S., rates of the sexually transmitted diseases syphilis,
chlamydia and chancroid continue to climb. The bacteria that cause these
diseases infect the genital tract and may provoke repeated infections. The
infections, or STD, cause numerous adverse effects ranging from infertility
to death. More recently, the role of STD in facilitating the sexual
transmission of HIV has heightened interest in developing effective
vaccines against them. An article in the March 1994 Proceedings of the
National Academy of Sciences USA reviews the status of experimental
vaccines for several common bacterial STD. 

       The article, which evaluates research to date into vaccines for
chancroid (genital ulcer syndrome, a significant cofactor in HIV
transmission), syphilis, gonorrhea and chlamydia, finds that the greatest
progress has been made toward vaccines for gonorrhea and chlamydia.
Currently, researchers are trying to find which bacterial proteins trigger
the most effective immunological responses, and thus would be the best
targets for vaccines.

       Sparling PF and others. Vaccines for bacterial sexually transmitted
       infections: a realistic goal? Proceedings of the National Academy of
       Sciences USA 91: 2456-2463. March 1994.

       -------------------------------
       Nutrition and Weight Management

       Polyp Prevention Study Finds No Protective Effect from Antioxidants 

       A large clinical trial that investigated the potential of the
antioxidants beta carotene and vitamins C and E to prevent precolonic
cancerous development concluded that the agents had no impact on the
rate of polyp development among people who had already had 1 polyp
removed.

       Previous studies have shown associations between diet and cancer.
For example, diets high in vegetables and fruits are associated with
reduced rates of colorectal cancer. Other studies have suggested that the
antioxidant vitamins (A, C and E) may protect against cancer. With these
precedents in mind, a team of researchers from several prominent clinics
studied the efficacy of beta carotene and vitamins C and E to prevent the
recurrence of colorectal polyps, precursors of colorectal cancer. While none
of the 864 participants had a history of invasive colorectal cancer, all had
at least one polyp removed from the bowel within 3 months prior to
entering the study. At entry, all were judged to be free of polyps.
Participants' diets were analyzed at study entry and exit (and deemed to
have no significant changes).

       Essentially, researchers wanted to evaluate the separate effect of 2
treatments: beta carotene and a combination of vitamins C and E. The
study endpoint was the development of new polyps. Participants were
randomly assigned to receive 1 of 4 daily regimens: (1) placebo, (2) 25 mg
of beta carotene, (3) 1 g of vitamin C plus 400 mg of vitamin E (d-alpha
tocopherol, a form of vitamin E) or (4) beta carotene plus vitamins C and
E. Two follow-up colonoscopic examinations were conducted at the end of
the first and fourth years. During the examinations, the entire mucosa was
viewed and any polyps or lesions detected were noted, measured and
removed. 

       Blood levels of beta carotene and vitamin E were measured at study
entry and at the time of colonic examination. (Since blood levels of vitamin
C do not reflect intake, they were not measured.) After the first year,
serum beta carotene levels had doubled in the 2 groups receiving the
agent. Blood levels of vitamin E increased by 40% among people receiving
the agent.

       Based on data from 751 participants available for analysis at the end
of the 4 years, the overwhelming finding was that "treatment for 4 years
with either beta carotene or vitamins C and E did not affect the rate of
occurrence of new adenomas in patients who had an adenoma removed
before entering the study." The size of the detectable adenomas or polyps
appeared equally unaffected by treatment modality. Equal proportions of
people in the beta carotene and vitamin C/E groups developed new polyps
(about 37%). Adjusting for variables like age, sex, number of prior polyps,
study center, and so forth, did not affect the finding.

       People who took the vitamin C/E combination had a slightly higher
incidence of right colonic polyps, a finding that was "unexpected and
plausibly due to chance." 

       The researchers posit 2 possible explanations for the failure of the
study to demonstrate any benefit. First is that it may be that other
substances, such as fiber and folate, in fruits and vegetables are what
confer a protective benefit, rather than antioxidant vitamins. Second, the
study may simply have been too short: it may be necessary to consume
high levels of antioxidants for many years before gaining anticancer
benefits. 

       Greenberg ER and others. A clinical trial of antioxidant vitamins to
       prevent colorectal adenoma. The New England Journal of Medicine
       331(3): 141-147. July 21, 1994.

       ----------------------------------
       Endocrine Function and HIV-Related Wasting

       HIV-related wasting and weight loss probably has multiple causes.
Possible causes include metabolic disturbances caused by cytokine
dysregulation or by infections, which increase the body's metabolic
requirements; reduced food intake; malabsorption; and endocrine
dysfunction. 

       The endocrine system is collectively composed of various glands,
distributed throughout the body, that produce hormones that regulate
different body activities. Previous studies have indicated a possible link
between endocrine dysfunction and HIV-related weight loss. Other studies
have shown that levels of testosterone, a hormone produced by endocrine
glands (gonads/testes), are reduced in advanced HIV disease. At Oregon
Health Sciences University, researchers studied endocrine function in
various people with HIV to determine if there were any associations with
wasting. 

       Sixty-six HIV positive people with a range of CD4 cell counts (both
above and below 200) were followed for 2 years. None took any steroid or
hormone medications. Fourteen people met the CDC criteria for wasting,
which is greater than 10% loss of body weight without a clear cause other
than HIV infection, such as an opportunistic illness. Levels of various
hormones were measured and compared between the groups with and
without wasting. 

       People with wasting syndrome were found to have lower serum total
and free testosterone levels than nonwasting people. Levels of the hormone
prolactin were higher in wasting participants (compared to nonwasting
participants with similar CD4 counts), and levels of the hormone cortisol
were higher in wasting participants and in people with Mycobacterium
avium complex (MAC). Thyroid function was essentially the same across all
groups studied, and was normal even in those with significant wasting.

       Decreased testosterone was associated with wasting, although
whether it was a cause or an effect (of wasting) remains unclear. These
results suggest that testosterone replacement therapy in HIV positive
people with abnormally low testosterone levels should be actively explored.

       This study concentrated on the role of endocrine function in
wasting. Lean body mass, caloric intake and malabsorption were not
examined. Other studies are needed to continue to define the causes of
wasting.

       Coodley GO and others. Endocrine function in the HIV wasting
       syndrome. Journal of Acquired Immune Deficiency Syndromes 7(1):
       46-51. 1994.

       Thalidomide Promotes Weight Gain

       French researchers reported the results of a small study of
thalidomide at the Fourth European Conference on Clinical Aspects and
Treatment of HIV Infection in Milan, Italy. Three people with advanced HIV
disease (fewer than 50 CD4 cells), severe HIV-associated wasting, fever and
myalgia took 100 mg of thalidomide daily. They also took AZT and PCP
prophylaxis. 

       After treatment, serum levels of tumor necrosis factor (TNF), a
cytokine associated with wasting that previous studies had suggested
might be suppressed by thalidomide, were unchanged. CD4 counts also
remained unchanged. Other tests failed to detect any inhibition of HIV
replication. However, after 2 weeks, the participants no longer experienced
fever or myalgia and, after 3 weeks, all 3 gained weight. The median
weight gain was 5 kg. 

       While larger-scale testing will be necessary to substantiate the
benefits reportedly observed in this study (and perhaps to give further
information about the weight gains, such as whether there were increases
in lean body mass or not), the authors imply that the benefits noted would
be unlikely to occur in control patients. These study results do not
address the type of weight gain; some researchers and clinicians consider
lean body mass increases to be the most relevant concern for people with
wasting.

       Couderc L and others. Thalidomide in wasting syndrome of AIDS.
       Fourth European Conference on Clinical Aspects and Treatment of
       HIV Infection. Milan. March 1994.

       ------------
       Tuberculosis

       New Combination Drug for Tuberculosis

       A new drug has been approved by the Food and Drug Administration
(FDA) for tuberculosis. Rifater, made by Marion Merrell Dow, Inc., combines
3 approved drugs commonly used to treat tuberculosis: rifampin, isoniazid
and pyrazinamide. This new 3-in-1 product should increase compliance and
decrease the chances for either under- or overdosing any of the 3
components, all of which reduce the likelihood of drug resistance. 

       In the wake of increasingly common drug resistant strains of
tuberculosis, the CDC has recommended the use of combination drugs. Poor
patient compliance has been one factor contributing to the rise of
multidrug resistant strains of tuberculosis. With assistance from the FDA,
Marion Merrell Dow has worked for 2 years to bring this product to
market. The specific indication for Rifater is "in the initial phase of the
short-term treatment of pulmonary tuberculosis." Other drugs may be
added when indicated. 

       The initial phase of treatment is designed to last 2 months, after
which the individual should take rifampin and isoniazid for a minimum of 4
months.

       Nightingale SL. From the Food and Drug Administration. Journal of
       the American Medical Association 272(5): 344. August 3, 1994.

       -----------------------------
       Tuberculosis in San Francisco

       San Francisco researchers used a DNA fingerprinting technique to
study patterns of Mycobacterium tuberculosis (M. Tb) among cases
reported in San Francisco from January 1991 through December 1992.
Scientific and epidemiologic analysis of the results indicated that many
more cases than expected resulted from new infection, rather than
reactivation of the causative bacteria.

       Conventional methods of tracing contacts of people with Tb to try to
uncover patterns identified clusters involving a total of 10% of the
patients. Using the more innovative DNA fingerprinting method, 191 of 473
patients or 40% were found to be epidemiologically linked. Approximately
one-third of the new cases seen in the 2-year study period resulted from
recent infection. However, the actual incidence of tuberculosis due to
recent infection is probably higher because only people with active
disease, rather than latent infection, were considered by the study. 

       Similar disease patterns or clusters indicated risk factors (combined
epidemiologic and biologic risk factors). In people under 60, independent
risk factors were associated with an AIDS diagnosis, and Hispanic and
African-American ethnicity. Since HIV infection was not a risk factor, but
AIDS was, the degree of immunosuppression appears related to the risk of
developing active Tb.

       Birth in the U.S. was found to be a risk factor, even though many
cases of Tb in San Francisco classically have been among immigrants. The
explanation is that, at least among younger people, birth outside the U.S.
and previous exposure probably protects against newly acquired Tb
infection. Reactivation of latent infection is a likely cause of disease among
the immigrant population.

       The CDC reports that 95% of patients treated in San Francisco
during the study period completed their anti-Tb drug regimens. Yet the
risk posed by noncompliant patients is best depicted by the finding that 1
unsuccessfully treated patient accounted for 6% or 29 of the 473 cases
studied here. 

       The study has "3 major implications for urban tuberculosis control."
One is learning more about places where Tb is commonly transmitted, and
taking active steps to improve conditions there, to decrease the risks. Two
is emphasizing effective and timely treatment of people with Tb ("because
a single infectious patient may have devastating effects on tuberculosis
control.") And finally, researchers recommend increased use of newer
methods such as those employed in the study for tracing contacts of
people with Tb.

       Small PM and others. The epidemiology of tuberculosis in San
       Francisco. The New England Journal of Medicine 330(24): 1703-1709.
       June 16, 1994.

       ---------------------------------------------------
       National Tuberculosis Center Opens in San Francisco

       On June 29, the National Tuberculosis Center opened in San
Francisco's South of Market district. The center is charged with
disseminating information about the most up-to-date as well as
cost-effective methods for preventing Tb transmission, and with training
healthcare workers to use the most current techniques for identifying and
treating Tb patients. 

       Today's anti-tuberculosis strategies emphasize using improved
research and technological methods (DNA fingerprinting, directly observed
therapy) over isolation and quarantine in sanatariums.

       New York City and Newark, New Jersey have the other 2 national
tuberculosis centers funded by the CDC.

       Coile Z. City organizes command post for the battle against Tb. San
       Francisco Examiner. A4. June 20, 1994.

       -------------
       Miscellaneous

       Inadequate Treatment of Pain in People with HIV

       Results of a self-administered survey given to patients at the
infectious disease clinic at St. Paul's Hospital in Vancouver, British
Columbia indicate that vast improvements are needed in the treatment of
HIV disease-related pain.
       Faculty of Pharmaceutical Science at the University of British
Columbia/Clinical Pharmacology modified the Wisconsin Brief Pain
Questionnaire so as to evaluate the prevalence and effects of pain on
patients' lives, treatments employed and the effectiveness of those
treatments. One hundred forty-eight (148) ambulatory patients with HIV
disease who visited the clinic between November 1991 and April 1992
voluntarily completed a survey on pain and pain management.

       The average age of the patients was 40.4 years, and the median CD4
cell count, 173. Ninety-one patients (61%) reported HIV disease-related pain
at some point. Eighty-two (55%) had experienced such pain within the
month prior to answering the survey; this is the group the researchers
focused on.

       Those experiencing pain within the month prior reported, in order of
decreasing frequency, pain in their legs, back, head, arms/hands, pelvic
area and abdomen. Sixty (73%) reported pain in at least 2 locations. About
half reported that pain was always present, and about 40% said they did
not know the cause of their pain.

       Sixty percent (60%) said that pain interfered "moderately to
extremely with their enjoyment of life," affecting their ability to work,
mood, relationships, sleep and movement. Yet only 40% overall said they did
not use any treatment for their pain. Many reported not doing so at some
point out of concern that taking pain medication might worsen their
medical condition. And, of those whose pain was treated, the average rate
of relief was only 65%.

       The most common pain treatments used were acetaminophen, plain or
with codeine, aspirin, morphine and other narcotics. 

       Researchers concluded that pain is prevalent and has a significant
impact on people with HIV, particularly on quality of life, and is currently
inadequately managed. Clinicians "should realize that pain can be present
regardless of the duration of the disease and its severity. Patients need to
be educated about the proper use of pain medications and helped to
understand that pain medications will not worsen their disease'."

       McCormack JP and others. Inadequate treatment of pain in
       ambulatory HIV patients. The Clinical Journal of Pain 9(4): 279-283.
       1993.

       --------------------------
       Seminar on Pain Management

       San Francisco Bay Area physicians, nurses and other AIDS patient
care providers are invited to attend a dinner, followed by a seminar on
pain management in HIV/AIDS. Sponsored by BETA, Roxanne Laboratories
and Stadtlanders Pharmacy, the seminar will be held at the Hotel Nikko,
222 Mason Street, San Francisco, California on October 8, 1994. Guest
presenters are Drs. Paul Volberding, William Breitbart and Matthew
Lefkowitz. Please RSVP to Ellena Friedman at 1-202-333-7400. Participation
will be limited to the first 150 people who register.

       *********************************************
       Results from the 1994 BETA Readership Survey
       Prepared by Communication Technologies

       Background and Methodology

       Since 1988, the San Francisco AIDS Foundation has published and
distributed BETA (Bulletin of Experimental Treatments for AIDS), a
quarterly magazine that focuses on experimental and approved treatments
for HIV infection and AIDS-related illnesses.  The average length of each
issue of BETA is 72 pages.

-----------
BETA Online

       Over twenty million users worldwide can access BETA electronically
and download its contents.  INTERNET users can retrieve BETA through
the HIVNET system in Amsterdam, Holland.  BETA is also distributed in
computer format through the OUTline San Francisco BBS and the AEGIS
Network.  AEGIS distributes BETA directly to numerous computer Bulletin
Board Systems in the U.S., Canada, Europe and Australia. (For information
about accessing AEGIS, call 714-248-5843.)

       The FidoNet FILEBONE hub in Virginia links BETA to approximately
20,000 active electronic bulletin boards.  Once the file has been received
by a local system, it can be displayed and downloaded by any user
logging on to that system.  PLANET CONNECT uplinks BETA to the Galaxy
II satellite.  Anyone with a C- or KU-band satellite disk and Planet
Connect decoder can retrieve these files.  HIVNET in Amsterdam, Holland,
distributes BETA to all of its downlinks in Europe.  In addition, it
forwards BETA to APC/GreenNet, which distributes BETA to its downlinks
in sub-Saharan Africa, India, Thailand and the Philippines.  

       
BETA in Print Format

BETA is distributed quarterly in print format to over 19,000 readers,
including to approximately 1,500 paid subscribers.  Over 10,000 low-income,
HIV positive individuals receive BETA free of charge through the BETA
National Scholarship Program. Approximately 5,000 free copies of BETA are
distributed quarterly to AIDS clinics and AIDS service organizations in San
Francisco through the BETA San Francisco Bay Area Scholarship Program. 
In addition, each quarter over 4,000 copies of the Spanish edition of BETA
(Bolet_n de Tratamientos Experimentales Para el SIDA) are distributed
nationwide free to AIDS agencies that serve Spanish-speaking clients. 
About 1,000 copies of BETA are also distributed free quarterly to media,
policymakers, researchers, community physicians, and other healthcare
providers involved in AIDS work. Finally, over 600 copies of BETA are
provided free to libraries and resource centers in correctional institutions
nationwide, and AIDS service organizations in over 40 countries worldwide.
       The following report, prepared by the San Francisco marketing
research firm Communication Technologies, summarizes the findings of a
national survey of the BETA print readership, which includes the combined
readership of the BETA National Scholarship Program, the Paid
Subscription Program, and the BETA San Francisco Bay Area Scholarship
Program.

       In order to evaluate the effectiveness of BETA as an educational
resource for HIV/AIDS treatment information, and to learn the demographic
profile of its readership, a four-page survey questionnaire was included in
4,897 randomly chosen copies of the March 1994 issue.  Readers were asked
to return their completed surveys by April 15, 1994, for analysis by
Communication Technologies.  Eleven hundred and sixty-eight
questionnaires were returned by April 15th.  These questionnaires were
key-entered, and the results of this survey are discussed below.  Since
the cut-off date, just under 200 additional questionnaires have been
received.  These questionnaires have not been key-entered and are not
included in the analysis.  Counting the late questionnaires, this survey
achieved a return rate of 28%an unusually high rate of response.

       With a 1994 sample size of 1,168 respondents, the results reported
here are accurate with 3.0% at the 95% level of confidence.  This means
that we can have 95% confidence that our results vary no more than
plus/minus 3.0% from the results we would obtain if we interviewed every
individual who receives BETA.

       In 1989, Communication Technologies conducted a similar study of the
BETA readership, when the publication's total quarterly circulation was
5,000 and its average length was 20 pages.  In the following report,
comparisons are made between the results of the 1989 and the 1994
readership studies.

Executive Summary

HIV Profile of BETA Readership

       Three-quarters (75%) of BETA readers are HIV positive.  One-fifth
(21%) are HIV negative.  Among those readers who are HIV positive, 32%
have received a diagnosis of AIDS and 25% are HIV positive with no
symptoms.  

       Thirty-one percent (31%) of HIV positive readers are not pursuing
any drug therapies for HIV.  Sixty-nine percent (69%) of HIV positive
readers are pursuing drug therapies for HIV.  Thirty-six percent (36%) of
readers are taking AZT.  One-fifth (19%) are taking ddI, 16% are taking
ddC, and 11% are taking d4T. (Responses add to more than 69% because
some readers are taking more than one medication.)

       One-fifth (19%) of HIV positive readers do not have medical
insurance.


Demographic Profile of BETA Readership

       *   One-fifth (19%) of readers are female, compared to the 1989
           study in which 11% of readers were female.

       *   One-fifth (19%) of 1994 BETA readers represent ethnicities other
           than Caucasian.  In 1989, 11% of readers were not Caucasian.

       *   One-fifth (20%) of readers identify themselves as heterosexual,
           compared to 1989 study results in which 14% identified
           themselves as heterosexual.

       *   Four in ten (39%) readers are not employed or retired.  In
           1989, 23% were not employed or retired.

       *   Four in ten (39%) readers report an annual income of $25,000 or
           less.  These results are similar to those seen in 1989.

       *   Two-thirds (67%) of readers have a college degree or higher. 
           These results are similar to those seen in 1989.

       Mother-to-Child HIV Transmission 
       Leslie Hanna

       Leslie Hanna is associate editor of BETA.

       According to the Global AIDS Policy Coalition, there are approximately
2,175,000 children worldwide who are living with HIV infection today. The
majority became infected through vertical transmission, i.e., they acquired
the virus from their HIV positive mothers. During this calendar year alone,
the World Health Organization (WHO) estimates that 200,000 HIV-infected
babies will be born.

       There are 3 main ways that mother-to-child infection occurs: an HIV
positive woman may infect her child while carrying it (intrauterine), while
giving birth (intrapartum) or after birth, primarily by breast-feeding
(postpartum). As the fetus grows in utero, cells of the placenta, a
combination of fetal and maternal tissues that act as the organ of exchange
during pregnancy for mother and fetus, may become infected. Free virus
or HIV-infected cells from the mother may enter the fetal circulation
system. Although there are no documented cases of intrapartum infection,
passage through the birth canal at the time of birth involves risk of
infection to the infant through exposure to a large amount of infectious
maternal blood and fluids.

       Like other retroviruses, HIV has been isolated in breast milk. Some
pediatric AIDS cases have been reported in children whose mothers were
infected by postpartum transfusions of HIV-infected blood, and who likely
infected their infants by breast-feeding during primary (maternal)
infection, when viral load is extremely high. A 1992 European Collaborative
Study found that rates of vertical transmission among 721 children and 701
mothers were twice as high for mothers who breast-fed their children,
compared to mothers who never breast-fed (median duration of
breast-feeding was 4 weeks). There are no direct studies of breast-feeding
and perinatal transmission, nor have prospective studies been well able to
identify many exclusively breast- or bottle-fed infants from whom to
gather data. Yet, the weight of evidence suggests that HIV is transmissible
through breast milk, and thus is a mode of transmission of relevant
concern even to women infected before pregnancy (in contrast to women
infected after giving birth but while breast-feeding).

       Cumulative research suggests that pregnant women with HIV have a
10-40% risk of transmitting the infection to their infants. Vertical
transmission rates appear to be highernearly twice as highin developing
countries than in developed countries. Reasons include possible differences
in regional definitions of pediatric infection; design differences in studies
of vertical transmission; and differences in the methods used to determine
transmission.

       Research into the primary modes of transmission is ongoing. Risk
factors associated with modes of transmission include maternal viral load,
vaginal delivery and breast-feeding. However, other contributory risk
factors as well as relative risk remain to be elucidated. Results of a
groundbreaking study published in the June 25, 1994 issue of The Lancet
offer important information about one possible factor in mother-to-infant
HIV transmission, and suggest questions for further investigation. Another
study recently published, in which researchers measured maternal viral
load during pregnancy, at birth and afterward, presents the first
conclusive data on the impact of viral load on mother-to-child transmission
(Proceedings of the National Academy of Science USA, August 1994).
Finally, based on the results of ACTG 076, FDA has approved the use of
AZT during pregnancy as a strategy to prevent vertical transmission. The
U.S. Public Health Service has published guidelines for that usage.

       Maternal Nutritional Deficiencies May Facilitate Perinatal HIV
       Transmission

       For this study, researchers wove together a few known facts about
immunity and nutrition with speculation about perinatal transmission risks
to arrive at a hypothetical question for scientific investigation: could poor
maternal nutritional status increase the likelihood of vertical transmission?
Specifically, could a maternal deficiency of vitamin A, known for playing a
role in stimulating the immune response and protecting mucosal tissues,
make it more likely that a baby will acquire HIV from its mother?

       Study Participants and Methods

       A team of U.S. and African researchers conducted the study in
Malawi, in southeast Africa. The participants were HIV positive pregnant
women who were patients at Queen Elizabeth Central Hospital in Blantyre,
Malawi. Consenting women who visited the hospital's prenatal clinic between
November 1989 and August 1991 were tested for HIV infection. Positive
ELISA results were confirmed by Western blot.

       Three hundred and thirty-eight (338) HIV positive pregnant women
from whom the researchers were able to gather complete data formed the
core study group. During their first prenatal visit, healthcare workers
recorded each woman's age, weight, height, length of pregnancy thus far,
body mass index (equal to weight divided by height squared). Samples of
blood serum were collected and stored at -70 C. Levels of vitamin A in
serum were determined using a liquid chromatography technique, with
standardized quality control monitoring (National Institute of Standards
and Technology, USA). For a subset of women, flow cytometry was used to
determine CD4 and CD8 counts at the first visit. (CD4 and CD8 counts were
obtained from the other women after delivery.)

       Infants' weights were recorded at birth. Regular follow-up visits
with both mothers and infants occurred every 3 months after birth for one
year. During the follow-up visits, mothers reported if they were
breast-feeding or not. [Note: a potential criticism of this study is that
breast-feeding may have been a confounding factor. However, (1) over 99%
of the 338 women for whom full data was collected and analyzed all
breast-fed their children for at least 12 months, as is customary in Malawi,
and (2) the study results do not purport to quantify vertical transmission
rates due to vitamin A deficiency; rather, the study results show that,
comparably, all other factors aside, vertical transmission rates were
significantly higher among mothers who were vitamin A-deficient. In other
words, study mothers who breast-fed their infants but had what
nutritionists consider sufficient levels of vitamin A were less likely to
transmit HIV to their infants than mothers who also breast-fed but were
vitamin A-deficient.] 

       When the babies were 1 year old, they were tested for HIV using
ELISA with confirmatory Western blot. Follow-up tests at 18 months of age
confirmed that all the babies had indeed lost maternal antibodies by 1 year
of age. (Babies routinely acquire antibodies from their mothers, which are
detectable by blood tests. This direct transfer of antibodies from mother to
fetus across the placenta, or from mother to child through breast milk, is
an important protective mechanism for the infant. However, children
usually lose maternal antibodies by 1 year of age, when the (child's)
immune system has become capable of actively producing its own
antibodies. In fact, previous studies performed in Africa have shown that
most infants lost maternal antibodies to HIV by 1 year of age.)

       Calculations and statistical analyses compared mothers of HIV positive
babies to mothers of HIV negative babies, with emphasis on the vitamin A
status of the mother. Because serum concentrations less than 1.05
micromoles/liter are associated with biological dysfunction, serum vitamin A
sufficiency was defined as greater than 1.05 micromoles/liter.

       Results

       From November 1989 to August 1991, there were 567 births to HIV
positive women. Of these, 146 mothers had infants who died before their
first birthdays. Another 40 infants did not take further part in the study,
because their mothers disagreed to testing them for HIV or for another
reason.

       Three hundred eighty-one (381) infants were tested for HIV-1
infection when they reached 12 months of age. Fourteen (14) had
indeterminate test results; 84 were HIV positive; 283 were HIV negative.
Regardless of HIV status at 1 year, mean birthweight, proportions of low
birthweight infants and mean gestational age were similar among all
infants. The rate of perinatal HIV transmission among mothers whose
infants survived to 1 year was 21.9% (84/381).

       Of the children whose HIV status was determined, data on the serum
level of vitamin A was available for 338 mothers. Of these 338, mothers who
transmitted HIV to their children and mothers who did not were similar in
terms of the interval between prenatal screening and birth (105 vs 106
days), age and body-mass index. The mean serum vitamin A concentration
for these 338 women was 1.02 micromoles/liter. However, the mean level for
mothers of HIV-infected infants was 0.83 micromoles/liter compared to 1.07
for mothers of HIV negative infants.

       Overall, total lymphocyte count, maternal CD4 count, CD4% and
CD4/CD8 ratios were lower "in mothers who transmitted HIV to their infants
than in mothers who did not." The mean difference in CD4 percentage
between transmitting and nontransmitting mothers was greater and more
significant than CD4 cell count. 

       Researchers examined history of sexually transmitted diseases and
patterns of breast-feeding among the women as possible alternative
explanations for the transmission rates seen in the study. However, neither
sexually transmitted diseases nor length of breast-feeding were found to
have had any impact on the rate of HIV transmission to infants. Again,
lengthy breast-feeding is common in Malawi; more than 99% of all
participants were still breast-feeding at 1 year.

       In summary, "maternal vitamin A and maternal CD4% were
independently predictive of vertical transmission of HIV...and total
lymphocytes, CD4 count and CD4/CD8 ratio were each highly correlated
with CD4%." The latter 3 measures were not, compared to the CD4%,
themselves significantly associated with vertical transmission.

       Vitamin A

       One hundred ninety-six (196) of the 338 mothers whose infants' HIV
serostatus was known were found to be vitamin A-deficient (serum vitamin
A levels below 1.05 micromoles/liter). The mean serum vitamin A level for
all 338 women was 1.02 micromoles/liter. Mothers were grouped into 4
categories, based on their level of serum vitamin A: (1) 0.70
micromoles/liter or less, (2) 0.70-1.05 micromoles/liter, (3) 1.05-1.40
micromoles/liter and (4) greater than or equal to 1.40 micromoles/liter.

       The relative risk of transmitting HIV to their infant "increased with
decreasing serum vitamin A" (see Figure 1). The transmission rates for
groups 1-4, respectively, were 32%, 26%, 16% and 7%.

       Researchers also had data on serum vitamin A from 136 mothers
whose infants died before 12 months. The mean serum vitamin A level for
these women was 0.78 micromoles/liter, a figure that was not (statistically)
significantly different from the mean for mothers of HIV-infected babies,
which was 0.86 micromoles/liter. Again, however, both figures are
significantly lower than the mean serum vitamin A level for mothers of HIV
negative babies (1.07 micromoles/liter).

       Conclusion

       Overall, vitamin A deficiencies were "associated with a three-fold to
four-fold increased risk of mother-to-child transmission of HIV." This
observation clearly suggests a relationship between nutritional status and
vertical transmission of HIV.

       Vitamin A is known to play important immunological roles, disruption
of which may increase the risk of vertical transmission. Vitamin A deficits
are associated with impaired lymphocyte functioning, which may cause a
higher viral burden in pregnant women. Similarly, impaired lymphocyte
functioning could play a role in preventing protective maternal antibodies
from crossing the placenta. Vitamin A deficiencies are also associated with
mucosal impairment, involving the loss or destruction of mucus and certain
cell types, which may damage the placenta. Mucosal surface damage could
also mean that the birth canal is more susceptible to trauma, which could
increase the amount of maternal blood the infant is exposed to during
birth, in turn increasing the risk of HIV transmission. And, although this
study did not show an association between vitamin A deficiency,
breast-feeding and mother-to-infant HIV transmission, researchers suggest
that vitamin A deficiency may permit the accumulation of higher levels of
virus in breast milk, which may influence HIV transmission.

       Researchers note that "although our study showed that vitamin A
deficiency was associated with increased mother-to-child transmission of
HIV, we cannot attribute these findings to lack of vitamin A alone, since
other micronutrient abnormalities may act as cofactors." HIV infection is
associated with altered levels of other nutrients, such as vitamins E and B,
copper and zinc. However, only vitamin A deficiencies "have been shown
[elsewhere] to be risk factors [in HIV-infected individuals] for progression
to AIDS, mortality, and increased perinatal and infant mortality."

       Sixty-five percent (65%) of the women in this study were found to
be vitamin A-deficient. Vitamin A deficiencies are common in HIV-infected
pregnant women in Africa and are probably attributable to a number of
causes, including pregnancy itself. Other factors contributing to vitamin A
deficiency include not taking in and/or absorbing enough foods containing
vitamin A and opportunistic infection-related vitamin A depletion.

       Mothers whose children died before their first birthdays had the
lowest average serum levels of vitamin A of any study subgroup. An
earlier Rwandan study found an association between vitamin A deficiency
and increased perinatal and infant morality.

       The mean CD4 cell count of the women in this study was 570 and the
mean CD4 percentage, 29%, indicating that most were in the early stages of
HIV infection. Because advancing HIV infection is associated with declines
in serum vitamin A, researchers postulate that additional pregnancies in
these women may be accompanied by greater deficits of vitamin A, and
higher rates of vertical transmission and infant mortality.

       Finally, researchers emphasize that their study involved women in
their second and third trimesters. Given the relationship between vitamin A
deficiency and increased risk of transmission, they propose investigating
repletion of vitamin A during pregnancy as a relatively inexpensive and
simple strategy for reducing HIV-related infant risks.

       Regardless of its ultimate applicability, this study warrants further
investigation of its central findings and implications.

       Global AIDS Policy Coalition. AIDS In the World, Vol. II. Oxford
       University Press, forthcoming.

       Mok JY. Vertical transmission. In HIV Infection in Women. 191-211.
       Johnson MA and Johnson FD, editors. Edinburgh. Churchill
       Livingstone. 1993.

       Semba RD and others. Maternal vitamin A deficiency and
       mother-to-child transmission of HIV-1. The Lancet 343: 1593-1597.
       June 25, 1994.

       Maternal Viral Load and Vertical Transmission

       Various groups are working to develop strategies to interrupt
vertical transmission; the new U.S. Public Health Service guidelines, based
on ACTG 076, represent the latest advancement in this area. One of the
questions that guides current research efforts is, when is such
transmission most likely to occur: in utero? during childbirth? A closely
related question is, what are the determinants of vertical transmission? In
other words, since in the U.S. the overall rate of perinatal transmission is
about 25%, 3 of 4 pregnant women with HIV will not transmit the virus,
while 1 will. What determines whether a mother will transmit infection to
her child, or not? A precept of a study recently conducted by researchers
in New York was that more definition is needed of the factors that
determine whether vertical transmission will or will not occur, before
developing strategies aimed at interrupting vertical transmission. Thus,
investigators chose to quantify the impact of maternal viral burden on
vertical transmission rates. They also evaluated how pregnancy itself
affected viral burden.

       Nineteen mother/child pairs participated. The clinical and immunologic
status of the mothers varied widely, but 12 had greater than 200 CD4 cells
and were asymptomatic, and 7 had less than 200 CD4 cells. Of those 7, 3
had experienced serious opportunistic infections in the past. Nine took AZT
(1 received AZT in ACTG 076). None of the mothers breast-fed their
infants.

       Maternal viral load was determined at various points during
pregnancy and after childbirth by endpoint dilution culture. Viral titers
greater than 125 HIV-1 infectious units per 10 to the 6th peripheral blood
mononuclear cells (IU/10 to the 6th PBMC) were considered high. CD4 and
CD8 cell counts were also measured.

       Infants were followed prospectively after birth to determine their
HIV status (for at least 6 months after their birthdays). Both viral culture
and PCR were used to determine HIV status. Viral cultures using a special
technique were performed in infants; HIV was detected in older children
by using the same method as in mothers. Nested PCR was used to detect
HIV in PBMC in infants and children.

       The overall rate of perinatal transmission in this study was 26%,
consistent with the rate generally reported in the U.S. Of the 5 women
who transmitted HIV to their infants, 4 had high viral loads (>125 HIV-1
IU/10 to the 6th PBMC). In the study overall, 6 women were deemed to
have high viral loads; 4 of these 6 or 67% transmitted the infection to
their infants. The other woman whose infant was infected did not have,
within the study parameters, high viral load; she was the only 1 of 13
with lower viral loads to have an HIV-infected child. Therefore, 7.6% of
study women with low viral burdens transmitted the infection. The
relationship between maternal viral load and perinatal transmission was
statistically significant.

       Maternal CD4 cell counts and viral burden were inversely correlated,
as is frequently the case. Thus, a correlation was found between low CD4
cell count and vertical transmission in the study cohort. However, low CD4
cell count was not as strongly associated with transmission as was viral
burden. Neither of 2 women in the study with fewer than 200 CD4 cells but
relatively low viral titers (5 and 15 IU/10 to the 6th PBMC) transmitted the
infection to her child. 

       Since both viral load and CD4 counts were predictive of
transmission, analysts stratified participants according to these 2
measures, in an attempt to identify women at greatest risk of transmitting
HIV. Four of the 5 or 80% of the women with high viral load (>125) and low
CD4 cell counts (<200) transmitted the virus to their children, compared to
only 1 of the remaining 14 (7%). Researchers considered "this stratification
highly effective in identifying HIV-1-infected women who are at very high
risk for mother-to-child transmission."

       Another study finding was that viral load remained stable during
pregnancy and after delivery. A subset of 12 women had from 3-8 viral
load measurements determined "over periods ranging from 18-65 weeks.
Viral titers varied greatly between the 12 women, but the viral load in
each woman did not vary significantly over time."

       Thus, researchers conclude that "this systematic study identified
maternal HIV-1 titer as a major determinant of mother-to-child
transmission. These data help to elucidate the pathogenesis of HIV-1
mother-to-child transmission and are directly relevant to its prevention."
This finding provides "the scientific rationale for implementing strategies
to interrupt transmission by reducing viral titer." Larger studies will be
needed to quantify the specific risk value associated with particular
(ranges of) viral loads.

       Weiser B and others. Quantitation of human immunodeficiency virus
       type 1 during pregnancy: relationship of viral titer to
       mother-to-child transmission and stability of viral load. Proceedings
       of the National Academy of Sciences USA 91: 8037-8041. August 1994.

       FDA Approves AZT for Pregnant Women and Infants

       Encouraging news about reducing the incidence of pediatric AIDS
stems from a new strategy to prevent vertical transmission of HIV. On
August 9, 1994, the Food and Drug Administration (FDA) approved
marketing AZT as a treatment to prevent pregnant women with HIV from
transmitting the virus to their babies. The FDA Antiviral Drugs Advisory
Committee on July 28 had unanimously recommended approving the new
indication for AZT, on the basis of the application submitted by Burroughs
Wellcome, manufacturer of AZT.

       The application was based on data from ACTG 076, the study that
demonstrated that HIV positive women could significantly reduce the risk
of transmitting HIV to their infants by taking AZT during pregnancy. In
fact, the study was stopped early based on "overwhelmingly positive
findings:" women who took AZT during pregnancy and childbirth, and
whose infants received AZT immediately after birth, reduced by two-thirds
the likelihood of transmitting HIV. Overall, the risk of HIV transmission
between women and infants who received AZT was 8.3%, compared to 25.5%
for those who were not treated with AZT.

       Investigators were excited by the results of this study, stating that
it is the rare single trial that so clearly demonstrates a positive effect. 

       In ACTG 076, women were randomized to receive 500 mg/day of AZT
during pregnancy (after completing the first trimester), and IV AZT during
childbirth. Most began taking AZT between 14 and 34 weeks of gestation;
most had never taken AZT before. Their infants also took AZT, beginning
within 24 hours after birth, for 6 weeks. The only apparent side effect
was transient anemia in some of the infants. No birth defects were
attributed to AZT. While the safety data thus far is promising, the numbers
of mother/infant pairs who have followed this regimen are small, so further
information will need to be gathered. To this end, healthcare providers are
encouraged to call the Antiretroviral Pregnancy Registry at 1-800-722-9292
extension 8465, or 919-315-8465 if outside the U.S. The Registry,
administered by Burroughs Wellcome together with Hoffman-La Roche Inc.
and the Centers for Disease Prevention and Control (CDC), collects
observational data on use of AZT (Retrovir) and ddC (HIVID) during
pregnancy. 

       A Burroughs Wellcome news release states that "the cost for the
doses of Retrovir capsules, IV formulation and suspension called for in the
new indication will vary depending on a number of factors such as the
number of weeks a pregnant woman received Retrovir prior to the onset of
labor." 

       FDA advisory committee recommends approval of Retrovir (AZT) for
       HIV-positive pregnant women and infants. Burroughs Wellcome News
       Release. July 28, 1994.

       Retrovir indicated to prevent transmission of HIV from pregnant
       women to their babies. Burroughs Wellcome News Release. August 9,
       1994.

       U.S. Public Health Service Task Force Recommendations for AZT Use
       in Pregnancy

       The results of ACTG 076, the government study that demonstrated
that use of AZT by certain HIV positive women and their infants could
reduce by 2/3 the risk for perinatal HIV transmission, quickly captured
the attention of government officials and policymakers. Even before the
August 9 FDA approval of AZT for use in treating HIV positive pregnant
women, the U.S. Public Health Service held meetings to discuss the study.
From June 6-7, the U.S. Public Health Service convened people from
various communities (medical, scientific, legal, advocacy, etc.) who were
interested in and affected by ACTG 076 results. The purpose of the
workshop was to review study data, to formulate guidelines for the use of
AZT by pregnant, HIV positive women, and to discuss the clinical
implications for HIV testing and counseling. 

       The official report was published in Morbidity and Mortality Weekly
Report (MMWR) on August 5, 1994. It summarizes study results, discusses
limitations of the applicability of the data and issues recommendations for
treatment with AZT during pregnancy and monitoring. Immediate and
ongoing concerns are noted, such as the unknown long-term risks of fetal
and neonatal AZT use as well as the potential risk posed to the woman who
uses AZT intermittently during pregnancies. A recurrent theme of the
report is that interpretation and extrapolation of ACTG 076 results must be
careful and individualized, since "the clinical status of many HIV-infected
women may differ from that of women in this trial."

       ACTG 076: Summary of Study Participants, Regimen and Results 

       The workshop panelists considered the ACTG 076 participant profile
and exact drug regimen followed by mother/infant pairs to have great
bearing on any possible extrapolation of results. Since these factors
served as the framework for workshop discussions, a brief summary
follows:

       Participants: ACTG 076 enrolled HIV pregnant women between 14 and
       34 weeks of gestation who had greater than 200 CD4 cells, who had
       received no antiretroviral treatment during that (current)
       pregnancy, and who had no clinical indications for antiretroviral
       treatment. Participants who met these criteria were enrolled and
       randomized to receive either placebo or AZT.

       AZT regimen: (treatment arm) oral AZT beginning at 14-34 weeks of
       gestation and lasting for the length of the pregnancy; IV AZT during
       labor; oral AZT for the infant beginning within 24 hours after birth
       and lasting for 6 weeks. The placebo regimen was administered in
       exactly the same way(s).

       Results: Among 184 children in the placebo group, the estimated
       transmission rate was 25.5%. Among 180 in the AZT group, the
       transmission rate was 8.3%. Side effects were minimal among the
       women, and the only apparent side effect of AZT among infants was
       mild, reversible anemia.

       There were no differences observed in the pregnancies of women
receiving AZT and placebo, as measured by sonography at 4-week intervals
from study entry until delivery. Measurements of infants taken at
birthweight, gestational age, length, etc.were similar for both groups, as
were congenital abnormalities. 

       The National Institute of Allergy and Infectious Diseases (NIAID)
ended the study early, based on the promising results of a preliminary
data analysis, and women in the placebo group were offered AZT.

       Limitations

       There are several important limitations to consider when interpreting
ACTG 076 results.

       *   Taking the AZT regimen did not prevent perinatal HIV
           transmission 100% of the time.

       *   It is unclear how effective the regimen may be in groups other
           than the study group(s), such as in women with advanced HIV
           disease, or who have used antiretroviral therapies in the past,
           or who have strains of HIV that show resistance to AZT.

       *   The lack of AZT-related "serious short-term adverse side
           effects" observed in this study may or may not continue, or
           become a trend, as use for this new and related indications
           becomes more widespread and the number of users increases.

       *   Long-term risks for children exposed in utero and neonatally
           have yet to be determined.

       *   It is not yet known whether or not taking AZT during
           pregnancy will diminish the efficacy of the drug for the mother
           if and when she elects to take it later, when indicated for her
           health.

       Other potential problems for clinician and patient include lack of
early prenatal care (e.g., women who do not receive medical attention until
very late in pregnancy or even until delivery) and lack of awareness of
HIV serostatus on the part of pregnant women, both of which obviously
preclude use of the regimen as proscribed by ACTG 076.

       Summary of Workshop Recommendations

       The report outlines various clinical situations and corresponding
recommendations about using AZT to reduce vertical transmission. Table 1
represents a summary of this part of the report, and is reprinted from
MMWR.

       Authors note that the recommendations are designed to provide a
basis for discussion between a woman and her healthcare provider(s) about
the use of AZT during pregnancy. Providers should inform women about
the benefits seen in ACTG 076 but should caution them that the long-term
risks of treatment with AZT to both women and infants are unknown. After
full discussion, whether or not to take AZT as a means for reducing the
likelihood of vertical transmission is ultimately and finally the woman's
choice. 

       Future Investigations

       Several ACTG 076 results or occurrences warrant further
investigation. For example, AZT reduced the incidence of mother-to-child
HIV transmission, but did not completely prevent it. The reasons why some
children become infected with HIV despite AZT treatment need to be
elucidated.

       Children exposed in utero and neonatally need to be followed
carefully in order to determine whether or not there are long-term
adverse effects from such use of AZT. Laboratory and animal studies of
AZT have led to theoretical concern about potential long-term effects of
AZT. One concern is toxic effects on liver and heart tissues, although one
prospective study of HIV positive children detected no effect from AZT on
heart function. There also is concern over the carcinogenic
(cancer-causing), mutagenic (birth-defect-causing) and teratogenic (causing
malformations to occur in offspring) potential of AZT.

       Further data are needed to assess the efficacy of AZT use for
preventing perinatal transmission in women whose clinical situations differ
from those of the women who qualified for participation in ACTG 076,
namely: women who are at >34 weeks pregnant (i.e., initiating AZT late in
pregnancy); women with less than 200 CD4 cells; women who have used AZT
in the past for more than 6 months; and antiretroviral-naive women in
labor. Studies are also needed to determine whether or not giving AZT to
newborns (beginning within 24 hours of life) who did not receive it
antenatally can prevent HIV infection.

       Finally, the women who participated in ACTG 076 and others in
similar situations will need to be followed carefully to determine the effects
of using AZT intermittently during pregnancies.

       The authors note in the conclusion that these recommendations are
designed for use in the U.S. and that other strategies may be more
appropriate in other areas of the world. Relevant factors include access to
AZT and treatment facilities (e.g., for administering IV AZT during
delivery), and policies and interventions in local use.

       Single copies of the MMWR report can be obtained by calling the CDC
National AIDS Hotline at 800-342-2437.   

       U.S. Department of Health and Human Services. Recommendations of
       the U.S. Public Health Service Task Force on the use of zidovudine
       to reduce perinatal transmission of human immunodeficiency virus.
       Morbidity and Mortality Weekly Report 43(RR-11). August 5, 1994.


Table 1.
Summary of Clinical Situations and
Recommendations for Use of Zidovudine* [AZT] to
Reduce Perinatal HIV Transmission

*These recommendations do not represent approval by the Food and Drug
Administration (FDA) or approved labeling for the particular product or
indications in question.


I.Pregnant HIV-infected women with CD4+ T-lymphocyte counts > or = to 200 who
     are at 14-34 weeks of gestation and who have no clinical indications for
     ZDV and no history of extensive (> 6 months) prior antiretroviral therapy.
Recommendation:  The healthcare provider should recommend the full ACTG
Protocol 076 regimen to all HIV-infected pregnant women in this category
[women who meet the eligibility criteria for ACTG 076]. This recommendation
should be presented to the pregnant woman in the context of a risk-benefit
discussion: a reduced risk of transmission can be expected, but the long-term
adverse consequences of the regimen are not known. The decision about this
regimen should be made by the woman after discussion with her healthcare
provider.

[The following clinical situations II-VI concern women who do not meet the
eligibility criteria for ACTG 076. The recommendations result from "consensus
interpretation of available scientific data."]


II.Pregnant HIV-infected women who are at >34 weeks of gestation, who have no
     history of extensive (>6 months) prior antiretroviral therapy, and who do
     not require ZDV for their own health.
Recommendation:  The healthcare provider should recommend the full ACTG
Protocol 076 regimen in the context of a risk-benefit discussion with the
pregnant woman.  The woman should be informed that ZDV therapy may be less
effective than that observed in ACTG Protocol 076, because the regimen is
being initiated in the third trimester.


III.Pregnant HIV-infected women with CD4+ T-lymphocyte counts <200 who are
     at 14-34 weeks of gestation, who have no other clinical indications for ZDV,
     and who have no history of extensive (>6 months) prior antiretroviral
     therapy.
Recommendation: The healthcare provider should recommend initiation of
antenatal ZDV therapy to the woman for her own health benefit.  The
intrapartum and neonatal components of the ACTG Protocol 076 regimen should
be recommended until further information becomes available.  This
recommendation should be presented in the context of a risk-benefit discussion
with the pregnant woman.


IV.Pregnant HIV-infected women who have a history of extensive (>6 months)
     ZDV therapy and/or other antiretroviral therapy before pregnancy.
Recommendation: Because data are insufficient to extrapolate the potential
efficacy of the ACTG Protocol 076 regimen for this population of women, the
healthcare provider should consider recommending the ACTG Protocol 076
regimen on a case-by-case basis after a discussion of the risks and benefits
with the pregnant woman.  Issues to be discussed include her clinical and
immunologic stability on ZDV therapy, the likelihood she is infected with a
ZDV-resistant HIV strain and, if relevant, the reasons for her current use of
an alternative antiretroviral agent (e.g., lack of response to or intolerance of
ZDV therapy).  Consultation with experts in HIV infection may be warranted. 
The healthcare provider should make the ACTG Protocol 076 regimen available
to the woman, although its effectiveness may vary depending on her clinical
status.


V.Pregnant HIV-infected women who have not received antepartum antiretroviral
     therapy and who are in labor.
Recommendation:  For women with HIV infection who are in labor and who have
not received the antepartum component of the ACTG Protocol 076 regimen
(either because of lack of prenatal care or because they did not wish to
receive antepartum therapy), the healthcare provider should discuss the
benefits and potential risks of the intrapartum and neonatal components of the
ACTG Protocol 076 regimen and offer ZDV therapy when the clinical situation
permits.


VI.Infants who are born to HIV-infected women who have received no
     intrapartum ZDV therapy.
Recommendation:  If the clinical situation permits and if ZDV therapy can be
initiated within 24 hours of birth, the healthcare provider should offer the
ACTG Protocol 076 postpartum component of 6 weeks of neonatal ZDV therapy
for the infant in the context of a risk-benefit discussion with the mother. 
Data from animal prophylaxis studies indicate that, if ZDV is administered,
therapy should be initiated as soon as possible (within hours) after delivery.
If therapy cannot begin until the infant is >24 hours of age and the mother
did not receive therapy during labor, no data support offering therapy to the
infant.


      Notes on Care for HIV Positive Women 
      Leslie Hanna

      Are Pap Smears Sensitive in Women with HIV?

      Cervical dysplasia, which may develop as a result of infection with the
human papillomavirus (HPV), is a frequent gynecological complication in women
with HIV. Moderate or severe cervical dysplasia is a category B HIV-related
condition, according to the Centers for Disease Control and Prevention (CDC),
and invasive cervical cancer is an AIDS-defining condition. There have been
reports that the technique most commonly used for routine screening, the Pap
smear, is less sensitive in women with HIV. An ongoing challenge for
caretakers is to determine the best way(s) for monitoring and detecting
cervical abnormalities in their HIV-infected female patients. In San Francisco, a
team of researchers decided to examine the sensitivity of the Pap smear in
their HIV positive patients. HIV negative women referred to the colposcopy
clinic for follow-up of abnormal Pap smears served as controls.

      The study involved 52 HIV positive women and 85 HIV negative women.
All women had Pap smears and colposcopic examinations. Biopsies were
performed where indicated. The pathologists who reviewed the specimens were
unaware of serostatus and/or the study itself.

      The study and control groups were demographically compared, and the
laboratory and clinical examination results were compared and statistically
analyzed.

      Fifty percent (50%) of the HIV positive women had cervical dysplasia.
Cervical dysplasia was detected by Pap smear/cytologic evaluation in 36%, and
by colposcopic/biopsy/histological evaluation in 50%. This gave the Pap smear
a sensitivity rating of 63% in HIV positive women, compared to 64% in the HIV
negative control women. Pap smear specificity was 84% and 74% for HIV
positive and negative women, respectively. 

      Twenty-two of 28 HIV positive women with dysplasia on cytology had
dysplasia on histology, for a positive predictive value of 79%. Of 45 HIV
positive women with no dysplasia on cytology, 32 had none on histology,
either, for a negative predictive value of 71%. In the control group, the
corresponding values were 89% and 36%.

      Researchers gathered data from the control group in order to learn
more about the sensitivity of routine Pap screening in the hospital clinic.
They note that HIV seronegativity was self-reported, but feel that a higher
seroprevalence would not affect their conclusions about sensitivity.
Re-evaluating the cytologic slides from the controls (which they did not do),
on the other hand, may have produced a higher sensitivity rating for this
group. 

      The investigators say that these results can be viewed 2 ways: the Pap
smear sensitivity rating and negative predictive value can be used to "argue
for cytologic screening alone for HIV-seropositive women" especially if they
are able to have regular, repeated smears performed. However, higher
prevalence rates of dysplasia are correlated with lower negative predictive
values (of Pap smears). Since dysplasia was proved in 50% of the HIV positive
women, and since that compares closely to that of all women for whom
colposcopy is normally indicated (as standard procedure), HIV serostatus aside,
one could also argue for routine colposcopic evaluation of HIV positive women.

      Colposcopy is also useful for detection of genital lesions (vulvar,
vaginal, perianal), whereas Pap smears are not. Yet, colposcopic procedures
are fairly involved and expensive. Thus, researchers offer a "reasonable
alternative...colposcopic examination on diagnosis of HIV infection, with
frequent cytologic follow-up if colposcopy is negative." They also state that
further studies are needed to establish the best method for screening for
dysplasia in HIV positive women.

      Korn AP and others. Sensitivity of the Papanicolaou smear in human
      immunodeficiency virus-infected women. Obstetrics & Gynecology 83(3):
      401-404. March 1994.

      Menstrual Symptoms in HIV-Infected Women

      There have been various anecdotal reports of HIV-related menstrual
disturbances. In order to scientifically evaluate the impact of HIV infection on
menstrual symptoms, British researchers conducted gynecological assessments
of 55 HIV positive women and a matched control group of HIV negative women.
This is the first controlled study of HIV-related effects on menstrual symptoms
"in the absence of confounding variables such as substance misuse and
methadone maintenance therapy." Previous studies that dealt with menstrual
disturbances have found them in relation to substance abuse, which is known
to affect the hypothalamus, a gland that controls the release of major
hormones. 

      Researchers postulated that any menstrual disturbances experienced may
be caused by HIV-related endocrine dysfunction. Since gonadal failure has
been reported in men with HIV, and although similar information for women
does not exist, researchers considered that gonadal failure in women may
present as menstrual disturbances. The hypothesis tested by the study was
that HIV infection independently increases menstrual abnormalities such as
dysmenorrhea (painful menstruation), and that this and other symptoms are
related to the degree of immunosuppression.

      Subjects were recruited from medical clinics. Eligible HIV positive women
were menstruating, non-pregnant, non-substance abusing, not receiving
treatment for substance use, and not taking oral contraceptives. CDC-defined
disease stage and most recent CD4 count were noted. A control group of HIV
negative women were matched for age, parity and smoking. All were
interviewed in great detail about gynecologic history and symptoms.

      The finding was that the symptoms of HIV positive women did not differ
from those of HIV negative women. Women in both groups were roughly
equivalent in terms of regularity and duration of cycles. Oligomenorrhea
(scanty menstruation) occurred in 5.5% and 3.6% of study and control group
women, respectively. Dysmenorrhea was reported by 58.2% of the subjects and
by 61.9% of the controls. [Ed. note: the high numbers of both study and
control women who reported dysmenorrhea may be an artifact of the study,
particularly as self-reported pain is quantified with some difficulty.]

      Next, the researchers compared symptoms in asymptomatic to symptoms
in symptomatic HIV positive women. No significant differences between the 2
groups were found here, either.

      Shah PN and others. Menstrual symptoms in women infected by the
      human immunodeficiency virus. Obstetrics & Gynecology 83(3): 397-400.
      March 1994.

      Colposcopy and Treatment for Abnormal Paps
      Joanne Genet, PA

      Reprinted with permission from WORLD, P.O. Box 115335, Oakland, CA,
94611. 510-658-6930.

      Colposcopies should be an important part of routine care for HIV
positive women, especially women with histories of abnormal Pap smears.

      A Pap smear is a sample of cells that have been taken from a woman's
cervix and spread onto a slide. This sample is evaluated by looking at the
slide under a microscope. A colposcopy is a procedure in which the
practitioner actually views the pattern of cells on the cervix rather than the
random sample on the slide. To do this, she uses a colposcopea kind of
microscope with a strong light that magnifies the cells on the cervix.

      A colposcopy can be done in a medical office just like a Pap smear. A
speculum is used to open the vagina, bringing the cervix into view. The
practitioner can view the cervix from outside the vagina through the
colposcope. During this exam, the cervix is washed with vinegar. This cleans
the cervix and helps make some abnormalities more visible. The vinegar can
sometimes cause slight burning, especially if you have been experiencing any
signs of a vaginal infection. If this happens, ask your practitioner to wash
your vagina with some water after the exam. This can be done using a giant
Q-tip, called a scoppette, that has been dipped in water.

      The kinds of cervical changes that your practitioner is looking for are:

      1.    Lesions with increased or unusual patterns of blood vessels. These
            are called "punctation" or "mosaicism."

      2.    A change in color in any part of the cervix to a whitish color
            which may indicate the presence of human papillomavirus (HPV,
            which causes genital "warts") or some other abnormality.

      3.    Ulceration or other problems.

      If anything unusual is seen during this exam, a biopsy will be made.
Tiny tissue samples are removed from the unusual area and other areas of the
cervix, and then sent to a pathologist for evaluation. The biopsy procedure
can cause some cramping similar to menstrual cramps.

      If, through the colposcope, abnormal areas are clearly present on your
cervix, you and your practitioner may decide to treat them during the exam
rather than wait several days for the results of the biopsy.

      The most common treatment, depending on the severity of the problem,
is cryosurgery. During cryosurgery, the top layer of skin on the cervix is
frozen, usually with liquid nitrogen. This may also cause cramping. The
freezing kills the top layers of skin and causes it to slough off. New,
hopefully healthy, skin then grows back. And, hopefully, this procedure also
removes the HPV or whatever was causing the problem. 

      Sometimes the problem is more extensive or persistent. If so, there are a
variety of treatments including laser surgery, treatment-cautery (burning the
skin), radiation, surgery (from removal of the cervix to removal of the uterus
and ovaries) and chemotherapy. All of these treatments attempt to remove the
area that is either pre-cancerous or cancerous. The type of treatment depends
on the severity of the problem.

      As yet, the most effective treatment for HIV positive women with cervical
abnormalities is unknown. If you have had an abnormal Pap smear and have
been treated, then you should be followed closely afterwards to check for
recurrence of the problem. This may mean more frequent Pap smears and
colposcopies.

Places to go for Pap smears and colposcopy (All practitioners seeing HIV
positive women should be doing Pap smears routinely.) 

1.    San Francisco General Hospital,
      Gynecology/Dysplasia Clinic, 415-206-8833.
2.    Lyon-Martin Women's Health Services, 415-565-7667.
      Pleasant, affirmative clinic that receives funding to see
      HIV positive women.
3.    UCSF AIDS Clinic, Women's Clinic, 415-476-3226.
      Open Wednesdays from 9-12. Provides childcare.
4.    Women's Needs Clinic, 415-487-5607.
      A supportive clinic; involved in Pap smear/colposcopy
      study of HIV positive women.


      Drug-Nutrient Interactions
      Edward Lor, PharmD

      Dr. Lor is an Assistant Clinical Professor of Clinical Pharmacy at San
      Francisco General Hospital/UC San Francisco.
      
      Reprinted with permission from AIDS File. 

      The pharmacokinetic and pharmacodynamic efficacy of many commonly
used medications in the treatment of HIV disease can be affected by diet.
Conversely, nutritional status can be altered by various medications. The
majority of AIDS patients take a number of medications, underscoring the need
for awareness of drug-nutrient interactions.

      These interactions become clinically significant when they alter the
intended response to a drug or impair the patient's nutritional status. The
medications may exert a specific appetite-depressant effect, or they may cause
side effects such as nausea, vomiting, diarrhea, alteration in taste, and
anorexia, which in turn decrease appetite and nutrient intake. Some
medications may have decreased or enhanced absorption with food. Although
there are no data, patients with chronic diarrhea may have altered intestinal
absorptive capacities, especially for those medications which need food for
enhanced absorption. The increased transit time in patients with diarrhea may
not allow sufficient time for the absorption of medication.

      Two drugs may increase appetite significantly enough to lead to weight
gain:

      Megestrol acetate
      
      Megestrol acetate is a synthetic, orally active derivative of the naturally
occurring steroid hormone progesterone. Investigators have reported that
megestrol acetate enhances appetite and increases body weight in patients
with AIDS and various advanced malignant diseases. The precise mechanism by
which megestrol acetate stimulates appetite and weight gain in AIDS patients is
unknown. 

      Dronabinol

      The appetite-stimulating effects of marijuana have been well documented.
There are anecdotal reports of marijuana-smoking cancer and AIDS patients
who claim increased appetite and weight gain or stabilization. Dronabinol
(Marinol, Delta-9) has been used as an antiemetic in cancer patients for many
years. Studies of dronabinol in AIDS and cancer patients have shown not only
antiemetic activity but also improved appetite, sense of well being (without
euphoria), and weight gain. The weight gain was shown to have no clinical
evidence of fluid retention contributing to water weight.

      Selected Open Clinical Trials for HIV/AIDS Treatments

      For further information, call the number provided with the individual
listing or call the AIDS Clinical Trials Information Service (ACTIS), toll-free, at
1-800-874-2572 (1-800-TRIALS-A). This government-sponsored service can
provide information about most of the following trials, but can only provide
information about privately sponsored trials when the sponsor has elected to
give that information to ACTIS. 

      ***************************
      Treatment for HIV Infection

      L-735,524 (Merck protease inhibitor), AZT and ddI

      This Phase II clinical trial will look at the safety and tolerability of a
higher dose of the Merck protease inhibitor than previously studied, alone and
in combination with other anti-HIV agents. Participants will be randomized to 1
of 3 treatment arms: (1) 600 mg L-524 plus AZT plus ddI, (2) 600 mg L-524 or
(3) AZT plus ddI. The study lasts for 6 months. Entrance requirements include
fewer than 500 CD4 (T-helper) cells and no less than 2 weeks of previous AZT
and/or ddI use. ddC must be discontinued 2 weeks prior to study treatment,
and d4T, 3TC or any other experimental agent, 30 days prior to treatment.
There are multiple sites.

      saquinavir (Roche protease inhibitor) high-dose study

      This study will randomize 40 people to 2 treatment arms, and will take
place at Stanford University in Palo Alto, CA. Participants in arm 1 will take
600 mg of Hoffman-La Roche (Roche) protease inhibitor, saquinavir, 6 times
daily; those in arm 2 will take 1,200 mg 6 times daily. Entrance requirements
include 200-500 CD4 cells, less than 3 months prior use of AZT and less than 2
weeks prior use of ddC or ddI. Participants may be p24 antigen positive or
-negative. Call Jane Norris, PA, at 415-723-2805.

      saquinavir and ddC

      This 40-center Phase III study will involve 1,200 participants. The trial
is open to people with HIV with 50-300 CD4 cells who have failed on AZT. Prior
use of ddC, ddI or d4T must not be greater than 2 weeks. There are 4
treatment arms: saquinavir monotherapy, ddC monotherapy, ddC plus low-dose
saquinavir and ddC plus high-dose saquinavir. For more information about the
international and North American trials of saquinavir, call 1-800-526-6367.

      saquinavir and AZT

      This study compares saquinavir to AZT. Participants will be randomized
to take protease alone, AZT alone or protease inhibitor in one of 2 doses with
AZT. Some sites are still open. Call 1-800-526-6367.

      d4T (Zerit) plus ddI

      This double-blind, dose-ranging pilot study will evaluate the safety,
efficacy and pharmacokinetics of combination therapy with d4T and ddI.
Seventy-five (75) participants will be assigned to 1 of 5 combination-treatment
arms; doses are based on body weight. The study is open to people who have
never used AZT or ddI and who have no history of pancreatitis or peripheral
neuropathy. Treatment lasts for 1 year. Study sites are New York, Los Angeles
and San Francisco.

      sustained-release AZT

      Aztec is a sustained-release formulation of AZT, developed by Verex
Laboratories. The study will evaluate the safety and effectiveness of the
sustained-release product compared to the standard formulation of AZT. The
18-week, double-blinded study is open to people with HIV and 200-500 CD4
cells. Participants who complete the study will be eligible to enroll in a 3-year
open-label study of Aztec. In the San Francisco Bay Area, call Brian Camp at
the AIDS Community Research Consortium (ACRC) at 415-364-6563.

      OPC-8212

      OPC-8212 is an oral medication used in Japan to treat congestive heart
problems. This Phase I study evaluates the safety, tolerance and antiviral
potential of 3 different doses of OPC. The study lasts for 12 weeks and is
open to people with asymptomatic HIV infection. Call UCLA's Center for AIDS
Research and Education (CARE) at 310-206-1960.

      In Atlanta, a similar Phase I study but with 4 different doses of OPC is
enrolling people with 50-300 CD4 cells. Call the AIDS Research Consortium of
Atlanta at 404-876-2317.

      SC-49483 vs AZT for inhibition of syncytia formation 

      ACTG 259 is a Phase II multicenter study of SC-49483, a new drug that
may help prevent the formation of syncytia, which are clumps of infected and
healthy immune cells that the immune system targets for elimination from the
bloodstream. Syncytia formation is associated with disease progression.
Participants will be randomized to receive either (1) low-dose SC-49483 plus
AZT, (2) high-dose SC-49483 plus AZT or (3) AZT plus placebo. Entrance
requirements include 50-350 CD4 cells and less than 6 months prior use of
monotherapeutic AZT. Treatment lasts 16-24 weeks.

      935U83

      This Phase I study of 935U83 (a nucleoside analog) will evaluate the
safety, tolerance and pharmacokinetics of various oral doses of the drug. The
study is open to people with 200-500 CD4 cells, not more than 1 month's prior
use of nucleoside analogs (AZT, ddI, ddC, d4T) and no prior use of
non-nucleoside reverse transcriptase inhibitors.

      delavirdine (DLV) and AZT 

      A Phase II/III randomized, double-blind study of the BHAP compound
delavirdine (DLV), a non-nucleoside reverse transcriptase inhibitor, will look at
3 fixed doses of DLV plus AZT vs AZT alone to examine safety, tolerance and
preliminary efficacy of the combination. This 6-month study will enroll
asymptomatic, HIV positive individuals with 200-500 CD4 cells. Exclusion criteria
include prior use of AZT for longer than 4 months, AZT intolerance and prior
use of ddI, ddC, d4T or 3TC. For information and study sites, call the Upjohn
AIDS Hotline at 1-800-432-4702.

      delavirdine (DLV) and ddI 

      This Phase II/III randomized, comparative trial will evaluate the safety,
tolerance and efficacy of DLV in combination with ddI vs ddI alone.
Participants have 300 or fewer CD4 cells and less than 4 months prior ddI
experience (unlimited AZT experience is permitted). One arm will receive ddI
and 400 mg DLV; the other arm will receive ddI and placebo. For study sites
and more information, call 1-800-432-4702. Note: participants in both DLV
studies described here who do not respond to the study treatment will be
eligible for open-label, triple-drug therapy containing DLV. The Upjohn AIDS
Hotline is 1-800-432-4702.

      atevirdine 

      atevirdine, another BHAP compound manufactured by Upjohn, is
synergistic with AZT. This one-year, multicenter Phase II trial randomizes
participants to one of 3 arms: atevirdine 600 mg/day + AZT vs atevirdine 200
mg/day + AZT vs placebo + AZT. Participants will have 50-350 CD4 cells, have
had 1 or more opportunistic infection(s), and have been taking AZT for at
least 3 months. For information about trial locations, call the Upjohn AIDS
Hotline at 1-800-432-4702.

      GS-840

      A Phase I study of an oral drug known as GS-840 (also called BIS-PON
PMEA) is underway. Manufactured by Gilead Sciences, GS-840 is a prodrug of
another Gilead Sciences product, GS-393, or PMEA, which is in ongoing Phase
I/II clinical trials. GS-840 is designed to be efficiently converted in the body
into GS 393 and to achieve the highest possible bioavailability. Ongoing trials
of GS 393 or PMEA have shown that taking the drug is associated with
decreased levels of p24 and increases in CD4 cell counts. Call Dr. Paul Leitman
at Johns Hopkins University at 410-955-9707.

      PMEA plus AZT

      The National Cancer Institute (NCI) is conducting a Phase I/II
dose-ranging study of the safety and efficacy of the combination of AZT and
PMEA, a nucleoside analog like AZT, known to be active against herpesviruses
and HIV. PMEA is given in IV form 3 times a week. Participants have less than
500 CD4 cells. Call Sergio Bauzo of NCI at 301-496-8959.

      PMEA for advanced HIV disease

      This Phase I/II study looks at the safety, tolerance, pharmacokinetics
and anti-HIV effect of PMEA in people with advanced HIV disease. PMEA is
administered daily by intravenous (IV) and/or subcutaneous (SC) injection.
Twenty participants will receive a single IV or SC dose once a day for 4
weeks. Entry requirements include less than or equal to 100 CD4 cells and p24
antigen levels greater than 40. This study will take place at the University of
Washington School of Medicine (in Seattle). Call Dr. John Nienow at
206-223-3184.

      oral hypericin (VIMRxyn)

      The NIH is sponsoring an open-label trial of oral hypericin, an antiviral
compound made by VIMrx. The Phase I/II trial will evaluate the efficacy of a
daily oral regimen. Eligibility requirements include being p24-positive and
having less than 350 CD4 cells. Efficacy will be evaluated by measuring p24
antigen levels and viremia using cultures and PCR. Study sites still enrolling
are New York University Medical Center/Bellevue Hospital and Johns Hopkins
University in Baltimore, MD.

      short-term AZT for primary infection

      This NIAID trial, DATRI 002, will evaluate the effect of short-term daily
doses of AZT in people recently infected by HIV. The p24 antigen test will be
used to determine eligibility. Participants will be randomized to receive either
1,000 mg/day AZT or placebo for 24 weeks. CD4 cell counts will be measured
during and after the 24-week period to determine whether or not taking AZT
produced an increase in CD4 cells. 

      BuCast in San Francisco

      BuCast is a compound closely related to a chemical (castanospermine)
that is naturally found in a particular variety of chestnut trees. Laboratory
studies have shown that castanospermine prevents HIV replication, and
prevents HIV from binding to host cells. HIVCare is conducting a Phase I
study to establish a maximum tolerated single dose and to evaluate safety and
pharmacokinetics involved in using the agent over a period of 2 weeks.
Participants have at least 500 CD4 cells. For more information call Mark Bowers
at 415-353-6215. 

      curcumin

      This Phase I/II study evaluates the safety, pharmocokinetics and
antiviral effect of curcumin. A compound found in the cooking spice turmeric,
curcumin has a long history of use in traditional Asian medicine. Forty (40)
people with HIV but without active opportunistic illness(es) will be randomized
to receive either 900 mg 3 times daily, or 1,200 mg 4 times daily. Call Mary
Dugan, CRI of New England in Brookline, MA, at 617-566-4004.

      Children

      AZT vs d4T

      ACTG 240 is a Phase III double-blind study that randomizes children to
take either AZT or d4T. Children are 3 months to 18 years old and taking no
antivirals immediately prior to study entry. Both drugs are taken orally. There
are multiple sites nationwide.

      protease inhibitor

      The National Cancer Institute (NCI) is conducting a Phase I study of the
safety, toxicity and antiviral potential of a new protease inhibitor, KNI-272, in
HIV positive children aged 3 months to 18 years. Children with no prior
antiretroviral treatment will comprise arm A, and children refractory or
intolerant to antiretroviral therapy, arm B. The study will use 5 dose levels to
establish maximal tolerated and minimally effective doses. Initial and final
doses will be single IV or oral, with 12 weeks of oral administration falling in
between. Call 310-402-1391 or 301-402-1387.

      recombinant human growth factor vs growth hormone

      This Phase I/II NCI study compares the safety and tolerance of
recombinant human insulin-like growth factor (rhIGF-1) to recombinant human
growth hormone (rhGH, Nutropin), in combination with antiretroviral therapy,
in children with HIV and failure to thrive or grow. Investigators will also
collect preliminary data on the effects of the growth factor and growth
hormone on growth, immune function and viral burden. Eligible children are 6
months to 18 years old, have used antiretroviral therapy in the past, and
have experienced growth failure. Exclusion criteria include diabetes and
malnutrition. Initially, all children will receive AZT and ddI for 12 weeks. Then
they will be randomized to receive either rhIGF-1 or rhGH for 12 weeks.
Children who benefit from the regimen may continue for another 12 weeks (36
total). Call the NCI at 301-402-1391 or 301-402-1387.

      atovaquone for PCP prophylaxis

  ACTG 227 is a Phase I, open-label study of the safety, tolerance and
pharmacokinetics of atovaquone (Mepron) for preventing pediatric PCP. Eligible
children will be stratified according to age (open to children aged 1 month to
12 years). Within age groups, children will be randomized to receive low- or
high-dose atovaqone for a period of 12 days. 

  non-Hodgkin's lymphoma

  The NCI is conducting a pilot study of 2 drugs, systemic cyclophosphamide
and methotrexate, for the treatment of HIV-related non-Hodgkin's lymphoma in
children. The drugs under study are considered the 2 most effective drugs
for treating childhood lymphomas. During the study, participants will continue
to use antitretroviral therapy as well as IV gamma globulin, acyclovir and PCP
prophylaxis to minimize the risk of complicating infection. The treatment period
is 2 1/2 months. The age range is 3 months to 18 years. For more information,
call the NCI at 301-496-2321.

  Immune Enhancement

  recombinant human interleukin-12 (rh-IL12)

  This Phase I study will evaluate the safety of single doses of rhIL-12, a
natural protein involved in regulating the cell-mediated immune response.
Participants have 100-500 CD4 cells, are currently taking an antiretroviral (for
at least 6 weeks), and are asymptomatic or slightly symptomatic. In the San
Francisco Bay Area, call UCSF at 415-476-9296, extension 84598. In southern
California, call the UCLA CARE Center at 310-206-6414.

  thymopentin (TP5)

  Thymopentin, or TP5, is derived from a natural hormone and stimulates the
immune system. This Phase III double-blind, placebo-controlled trial will
evaluate the safety and efficacy of thymopentin (Timunox) in HIV positive
individuals taking an anti-HIV drug(s). Specifically, participants are
randomized to receive thymopentin with AZT or ddI, or AZT combined with ddI,
or AZT combined with ddC. A previous study indicated that the combination of
thymopentin and AZT was more effective than AZT alone in slowing HIV disease
progression.

  A related Phase II placebo-controlled trial will look at the impact of various
doses of thymopentin on viral load; the study is open to people with less than
400 CD4 cells.

  HIVIG plus AZT vs IVIG plus AZT for pregnant women

  HIVIG, a solution of concentrated antibodies, is a type of passive
immunotherapy. ACTG 185 is a Phase III trial that compares HIVIG to IVIG for
efficacy in preventing transmission of HIV from mother to infant. Participants
are randomized to take either HIVIG or IVIG; all participants take AZT. Mothers
are given AZT intravenously during labor. Infants receive the same treatment
as mothers. Newborns also receive either IV HIVIG or IVIG, within 12 hours of
birth, and a syrup formulation of AZT for 6 weeks. There are numerous sites
nationwide.

  vaccine for CMV

  A Phase I clinical trial has begun of a candidate vaccine against CMV.
Sponsored by Biocine Company in a joint venture with Ciba-Geigy Ltd., the
vaccine will be tested in seronegative healthy adults. The trial will evaluate
safety, tolerability and impact on the immune system of the vaccine. Volunteers
will be monitored through clinical evaluations and laboratory tests that will
measure levels of CMV antibodies as well as CD4 cells and others. 

  Treatment for Opportunistic Infections 

  oral ganciclovir for maintenance treatment of CMV retinitis

  Syntex Research is sponsoring an open-label safety study of oral
ganciclovir for maintenance treatment for CMV retinitis. Enrollment may be
made through any licensed physician in the U.S. and Canada. Participants
have stable CMV retinitis; treatment with IV gancicvlovir or foscarnet during
at least 18 of the last 21 days prior to study enrollment; known difficulty
tolerating the IV catheter; no known sensitivity to acyclovir or ganciclovir.

  HPMPC for refractory CMV retinitis

  Enrollment has begun for an open-label study of HPMPC or GS 504. The
study is being conducted by the manufacturer, Gilead Sciences. Approximately
100 people will be enrolled at 6 sites in the U.S. and 1 in Great Britain.
Entrance requirements include ophthalmologically proven CMV retinitis and
unsuccessful ganciclovir and/or foscarnet treatment (for at least 4 weeks).
During a 2-week induction phase, everyone will receive 5 mg/kg once weekly.
After that, participants will take either 5 or 3 mg/kg once every other week.
Retinal photographs will be used to evaluate efficacy.

  atovaquone (Mepron) vs aerosolized pentamidine for preventing PCP

  In an ongoing research effort to identify effective prophylactic strategies
against PCP for people intolerant of TMP-SMX, Burroughs Wellcome is
sponsoring a study of atovaquone (Mepron) vs aerosolized pentamidine (AP).
The 18-month study will compare the efficacy of high- vs low-dose Mepron to
AP. The study is open to 2 different groups of people with HIV: (1) people
who have had 1 or more previous episodes of PCP and (2) people with HIV and
less than 200 CD4 cells or thrush, or unexplained fever for more than 2
weeks. Other requirements include intolerance of TMP-SMX or some other
trimethoprim or sulfa-containing compound. At study entry, chest x-rays must
be normal or at least not indicative of active PCP. Exclusion criteria include
active PCP, prior history of intolerance to either study agent and current use
of rifampin and/or any other anti-PCP agent. In San Francisco, call Mark
Bowers at HIVCare at 415-353-6215.

  azithromycin (Zithromax) for the prevention of MAC disease 

  This study evaluates the safety and effectiveness of weekly azithromycin
for the prevention of MAC disease in people with fewer than 100 CD4 cells.
Participants take azithromycin or placebo. Criteria include not having had a
positive MAC culture within 1 month of beginning the study, and no treatment
with any anti-MAC drugs within the last 4 weeks.

  azithromycin (Zithromax),

  clarithromycin (Biaxin) plus ethambutol (Myambutol) for treating MAC

  This double-blind study compares 2 combinations of anti-MAC agents for the
treatment of disseminated MAC. Participants will be randomized to take 250 or
650 mg azithromycin plus 800-1200 mg ethambutol daily (based on body weight)
or clarithromycin 500 mg twice daily and 800-1200 mg ethambutol once a day.
At the end of the regular 24-week study, participants may be evaluated for
entry into an open-label maintenance protocol, with monitoring at trimonthly
intervals. The study is open to people with HIV and a positive MAC blood
culture performed within 2 months prior to study entry. Exclusion criteria
include therapy for MAC after the positive culture that qualified for study
entry, and known sensitivity to any of the macrolide antibiotics including
erythromycin, azithromycin, clarithromycin or ethambutol, or concommitant
therapy with another investigational drug starting within 1 week of study
entry. A total of 300 people will be enrolled at 25-30 sites nationwide. In the
San Francisco Bay Area, call the AIDS Community Research Consortium (ACRC)
at 415-364-6563.

  thalidomide (Synovir) for mycobacterial infections

  FDA 133A is a Phase I/II trial of the safety and efficacy of thalidomide in
people with HIV and/or mycobacterial infections, including Mycobacterium
avium complex and tuberculosis. Clinical examinations and laboratory tests will
be used to evaluate the impact of thalidomide on reducing symptoms and
improving immune responses in participants. The trial is open to people with
proven mycobacterial infection (culture or smear), with or without documented
HIV infection. HIV positive participants must have fewer than 500 CD4 cells
and be taking an antiretroviral(s). Recent fever, weight loss and night sweats
are also required. Participants will be randomized to receive oral thalidomide
or placebo the night before beginning anti-tuberculosis treatment, to continue
for 7 nights. Follow-up continues for a total of 28 days. 

  thalidomide (Synovir) for aphthous ulcers

  ACTG 251 is a multicenter study of the safety and efficacy of thalidomide
for the treatment of oral and esophageal aphthous ulcers and HIV viremia.
Investigators will look at viral load and tumor necrosis factor (TNF) levels. To
participate, people with HIV need to have had a biopsy within 8 weeks prior
to study entry that documents the presence of aphthous ulcers lasting at
least 2 weeks, as well as a negative culture for herpes (within the same
period). Participants will be randomized to receive 4 weeks of either 200 mg
oral thalidomide or placebo, once daily.

  foscarnet cream for herpes simplex 

  This New York City pilot study will evaluate the efficacy of foscarnet in a
cream form for herpes simplex lesions. HIV positive participants have
virologically confirmed herpes simplex lesions of the skin or mucous
membranes, within the past 60 days, and have unsuccessfully tried acyclovir
treatment. Unacceptable benefit is defined as <25% decrease in herpes lesion
size. All participants will receive topical treatment of lesions with a 1%
foscarnet cream that is applied 5 times a day for "up to 6 weeks." Patients
who show no improvement after 3 weeks will have the option of trying
intravenous foscarnet. All patients will be followed until complete healing. For
more information, call Arlene Hurley at New York University at 212-263-6411.

  amphotericin B, fluconazole and itraconazole to treat cryptococcal meningitis

  ACTG 159 is a multicenter, Phase I/II comparative trial. For the first 2
weeks of the study, participants will receive either amphotericin B alone or in
combination with flucytosine. Then, for 8 weeks afterward, half will take
fluconazole and half will take itraconazole.

  acitretin for severe psoriasis

  In New York, there is an open-label, dose-escalating trial of the efficacy of
oral acitretin for the treatment of psoriasis in people with HIV. Acitretin is
known to clear psoriasis and is considered an effective treatment in HIV
negative people; this will be the first thorough study of its use in people with
HIV. Eligible participants are 18-55 years of age with psoriasis that affects at
least 10% of their bodies (as measured by the Psoriasis Area and Severity
Index, or PASI). Initially, everyone will begin with a minimum dose of 25
mg/day. Every 4 weeks from then on, depending on PASI score, the dose will
be increased up to a maximum of 100 mg/day. Various assessments will be
performed at regular intervals during the 20-week study, including x-ray,
skin biopsy, blood tests, PASI evaluations and photographic studies. For more
information, contact Dr. Bradford Katchen at the Department of Dermatology,
Beth Israel Medical Center, at 212-420-2184.

  Treatment for Malignancies and Cancers

  topical gel for Kaposi's sarcoma (KS)

  This Phase I/II study is looking at the efficacy of a topical medicine called
LGD1057. People with KS can apply the medicine, which comes in gel form, to
their lesions themselves. A natural retinoic hormone (9-cis-retinoic acid),
LGD1057 is related to vitamin A, which plays various roles in immune system
responses and in protecting body tissues. The study will last for 4 weeks. If
appropriate, participants may be eligible to continue using the agent after the
end of the study. Call the UCLA CARE Center at 310-206-6414.

  OPC-8212 for KS

  OPC-8212 is an oral medication being studied elsewhere for its antiviral
properties. This study will evaluate the ability of 2 different doses of the
agent to cause regression of KS tumors, and is open to people with HIV and
KS, without other current opportunistic infection(s). Use of antivirals is
disallowed during the study. Call the UCLA CARE Center at 310-206-1960.

  interleukin 4 (IL-4) for Kaposi's sarcoma (KS)

  ACTG 224 is a Phase I/II open-label, dose-ranging study of IL-4 for
treating KS. In Boston call Dr. Scadden at 617-632-8528 and in Los Angeles
call Dr. Miles at 310-206-6414. For more information about a Phase II
open-label trial of IL-4 for KS, call Dr. Gill in Los Angeles at 213-343-8275.

  photodynamic therapy for KS: tin ethyl etopurpin and lasers

  This Phase II trial looks at the safety and effectiveness of photodynamic
therapy for cutaneous KS. The drug tin ethyl etopurpin is injected directly
into lesions, followed by irradiation of the lesions with a laser. All participants
receive treatment for a period of only a few days. Participants must have at
least 3 measurable KS lesions that have been not been treated within the last
30 days. Contact Jorge Toro at the UCSF/SFGH Dermatology Department at
415-206-6099 or 415-206-8680.

  5-FU for cervical dysplasia

  5-FU is a cream that is applied intravaginally to prevent and treat cervical
cancer. ACTG 200, a Phase II/III trial of safety and efficacy, compares the use
of intravaginal 5-FU to observation for maintenance treatment of cervical
dysplasia. After standard treatment for high-grade cervical dysplasia, women
participants are randomized to receive treatment (topical vaginal administration
of 5-FU) or to be observed. There are numerous sites nationwide.

  Treatment for Wasting Syndrome and Myopathy

  thalidomide (Synovir) for wasting syndrome

  FDA 230A is a Phase II placebo-controlled study of the safety and efficacy
of thalidomide for treating HIV-related wasting syndrome. In particular,
investigators will be examining the effect of thalidomide on "reducing weight
loss," and on antiviral and anti-tumor necrosis factor-alpha potential. The
study is open to people with HIV and wasting, or greater than 10% loss of
normal/prewasting body weight in the absence of another infection that might
account for such weight loss. Therefore, participants must be negative for
acid-fast bacteria and active opportunistic illness(es) requiring systemic
therapy. Participants will be randomized to receive low- or high-dose
thalidomide (100 or 200 mg/day) or placebo for 8 weeks, and may continue for
an additional 4.

  L-carnitine for myopathy (muscle weakness/degeneration)

  L-carnitine is a natural biochemical that stimulates the oxidation and
synthesis of fatty acids. The NIH is conducting a Phase II placebo-controlled
trial to evaluate L-carnitine as a treatment for myopathy, which at times is a
side effect associated with use of AZT. Call Dr. Cupler at the National Institute
of Neurological Disorders and Stroke (NIND), a division of NIH, at 301-402-4479.

  Miscellaneous

  acupuncture for chronic hepatitis

  This study examines the effectiveness of traditional Chinese acupuncture
compared to traditional Korean acupuncture for treating chronic viral
hepatitis. Participants with HIV and chronic viral hepatitis will be randomized
to receive either Chinese or Korean acupuncture, or to a control group.
Acupuncture is given twice a week for 4 months. For their participation,
members of the control group will receive blood tests and also 2 free
acupuncture visits and a bottle of Chinese herbs at the end of the study. The
study will take place in San Francisco; call the Quan Yin Healing Arts Center
at 415-861-4964.

  Clinical Trials Information by Region

SAN FRANCISCO BAY AREA
415-476-9554

SOUTHERN CALIFORNIA
HIV TREATMENT DIRECTORY
213-469-5888

AIDS/HIV TREATMENT DIRECTORY
FOR NEW ENGLAND
617-424-1524

NEW YORK,
CONNECTICUT,
NEW JERSEY AND PHILADELPHIA
212-268-4196

AIDS Institute
Experimental Treatment Infoline
in New York state: 800-MEDS-4-HIV
outside New York: 212-239-5523

DIRECTORY OF WISCONSIN
HIV/AIDS CLINICAL TRIALS
in Wisconsin: 800-359-9272
outside Wisconsin: 414-291-2799

NORTHERN GEORGIA & ALABAMA
404-874-7926

GULF COAST REGION
504-584-3605

HOUSTON CLINICAL TRIAL NETWORK
713-520-2083

CANADIAN HIV TRIAL NETWORK
604-631-5327

ACTIVELY RECRUITING U.S. TRIALS
AmFAR Treatment Directory
212-682-7440

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  Copyright (c) 1994 - Bulletin of Experimental Treatments for AIDS (BETA), a 
  quarterly publication of the San Francisco AIDS Foundation (SFAF). 
  Reproduced with permission.  Reproduction of this article (other than one
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  beta@sfsuvax1.sfsu.edu.