        BETA (Bulletin of Experiment Treatments for AIDS) Online - No. 16
        Published by the San Francisco AIDS Foundation - March 1993
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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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        Table of Contents

        Vaccines for HIV      
               Mark Bowers
        Pregnancy and HIV Infection          
               Teryl Nuckols
        Guidelines for Prevention of Pneumocystis carinii Pneumonia (PCP)
               Ronald A. Baker, PhD and Joan Kapusnik-Uner, PharmD
        Guidelines for Treatment of Pneumocystis carinii Pneumonia (PCP)
               Ronald A. Baker, PhD and Joan Kapusnik-Uner, PharmD
        When Should Persons with Asymptomatic HIV Disease Begin Anti-HIV 
        Therapy?
               Thomas Mitchell, MPH
        Guidelines for Treatment of HIV Infection
               Ronald A. Baker, PhD
        The Role of Cytokines in AIDS-related Septicemia and Wasting
        Syndrome
               Dan Medynski, PhD
        SUPLEMENTO EN ESPAOL
        Notas de Investigacin       
               Ronald A. Baker, PhD
        Infeccin del Papilomavirus Humano en las Mujeres con el VIH
               Teryl Nuckols
        Glosario      
        Research Notes        
               Ronald A. Baker, PhD
        Multiple Prophylaxis for Opportunistic Infections
               Bernard Bihari, MD
        OPINION
        Epidemic of Mistrust: Hoffman-La Roche and the Treatment Activist 
        Community
        A Selection of Open Clinical Trials for HIV/AIDS                   
        Drugs in Development for HIV Infection
        Drugs in Development for Herpes Viruses
        Corrections
        Patient Drug Assistance Programs
        Glossary
        
        **********

        VACCINES FOR HIV
        Mark Bowers

        Mark Bowers is a medical writer and AIDS treatment activist living in
        San Francisco.

        Soon after researchers identified HIV as the cause of AIDS, work began
on the development of a vaccine for the virus.  Previous successes with viral
vaccines have come only after many years of research and testing that yielded
detailed knowledge of how these viruses caused infection.  Vaccines have been
developed for viral infections such as polio, smallpox and, more recently,
for hepatitis B.  Researchers are currently grappling with the special
problems that hinder the development of effective vaccines for other viral
diseases, including herpes and HIV.

        Many of the problems hindering development of an effective HIV vaccine
have now been identified, and several candidate (experimental) vaccines are
currently in various stages of animal and human testing.  Animal models for
studying HIV infection are improving, and hope is building that a successful
vaccine for HIV will be available within the foreseeable future.  How
realistic is that hope?  What can be said about the current vaccine
candidates?  What are the differences (or similarities) between preventive
and treatment vaccines? We will look first at some data from a vaccine trial,
then turn to a deeper exploration of the immune responses to vaccines.

        ---------
        Therapeutic vaccines 

        Dr. Jonas Salk began the discussion of immunizing HIV positive persons
to prevent or reverse progression to AIDS in 1987.  The only successful
therapeutic viral vaccine for humans is the rabies vaccine, administered
after human exposure to the rabies virus from a rabid animal bite.  The goal
of therapeutic (treatment) vaccines is to reduce or reverse the spread of HIV
in the individual.  Continuing studies at the University of Southern
California are assessing the effectiveness of a vaccine made from an
inactivated HIV preparation in incomplete Freund's adjuvant.  The likelihood
of therapeutic success depends on the extent of infection and immune
compromise during treatment.  Nevertheless, preliminary results from a study
begun in 1990 and scheduled to end in February 1993 seem to indicate that
this vaccine may increase cell-mediated immunity (T-helper cell activity), as
measured by skin tests for delayed-type hypersensitivity.

        After the antigen (vaccine) is injected subcutaneously, a "delayed"
response develops and persists for days.  An induration (hardening of soft
tissue) filled with macrophages and T-helper cells develops in response to
the skin test.  The size of induration is considered a reflection of the
extent of T-helper cell activity.  Induration occurs for all of the groups of
volunteers tested in the double-blind dose-ranging study.  Volunteers are all
HIV positive and asymptomatic, have no AZT use, and have T-helper cell counts
over 600/mm3.  With a dose of 10 mg of the HIV immunogen, a response was
observed of > or = 2 of 7 antigens on the Mirieux CMI test for control
antigens, and > or = 5 mm induration upon skin test.  It is nearly
unquestionable that there are new immune responses elicited by this vaccine
product.  Once the study is unblinded, what doses produced the new responses
will be better understood.  Before we can understand new immune responses, we
need to examine how vaccines are classified.

        -------
        Vaccine Classification

        All effective vaccines accomplish a common goal: the establishment of
immune responses that confer long-lasting protection to an individual from
disease if exposure to the infectious agent occurs.  Viral vaccines can be
classified into several broad categories, named for the methods used to
create them.

        ------
        Whole-killed Viral Vaccine

        A whole-killed viral vaccine looks just like "live" virus to the
immune system, which musters its defenses against the killed virus just as it
would against a live virus.  The killed virus is recognized by a subset of
B-cells, which clone and produce antibodies ready to fight off the viral
invader.  Helper T-cells recognize patterns on the surface of the virus,
engulf it, and process parts of the disassembled virus to show to killer
T-cells, the soldiers of the immune system.  Armed with a detailed
description of the virus, the killer cells seek out the invading virus and
destroy it.  At the same time, the body releases chemical messengers called
cytokines to induce a proliferation of these killer cells.  The B-cells and
T-cells, along with macrophages, monocytes and natural killer cells (other
important cellular components of the immune system), attack and repel the
invader, leaving behind an army of seasoned veterans (memory B- and T-cells)
on continual alert in case the virus appears again.  These sentries stand
ready to destroy the viral invader before it can cause infection.  In this
way, protection is conferred against that particular virus.

        ------
        Live-attenuated Vaccine

        A live-attenuated vaccine provokes many of the same immune responses
as a whole-killed viral vaccine.  The differences are that the virus used to
make the vaccine is still alive (although artificially altered in ways that
prevent it from causing disease) and that a strong, but different immune
response occurs (immunoglobulin A response that provides protection at the
point of viral entry), which is absent from and unprovoked by killed virus
vaccine.  Live vaccines typically produce longer-lasting immune responses
than killed virus vaccines.  A live vaccine has been successfully used to
immunize individuals against polio.  But there are potential dangers with any
live virus vaccine.  Back-mutation can cause the virus to revert to a
wild-type virus, which can cause infection.  Each year, a handful of children
contract paralytic polio from live-attenuated polio vaccine.  In addition,
the wild-type virus may not look enough like the real thing to enable memory
B- and T-cells to recognize it, if and when it appears.  The live vaccine can
also be excreted intact (in body fluids) by the immunized person to infect
other individuals.  Which body fluid(s) can transmit the virus depends upon
the mode or site of administration--for example, if the vaccine is oral
sabin, then saliva may carry the transmissible virus, as well as urine.

        These are substantial risks when the virus in question is HIV, yet
this avenue of research is being explored.  Dr. Ronald Desrosiers of the New
England Regional Primate Research Center has developed a successful
live-attenuated Simian Immunodeficiency Virus (SIV) vaccine in rhesus
monkeys.  Since HIV-2 and SIV are approximately 70% homologous (the sequences
of nucleic acid building blocks in each are similar), the extent to which the
rhesus monkeys were protected from infection by the vaccine (4 of 4 resisted
infection with live SIV virus) has a direct bearing on the search for a
viable vaccine against HIV-2.  HIV-2 is the variant of retrovirus originating
in West Africa, while strains of HIV-1 are associated with the worldwide AIDS
pandemic.  HIV-1 is pandemic around the world; HIV-2 has been found in many
countries around the world but is not pandemic.

                        Vaccines in Clinical Trials
                        ---------------------------  
  VACCINE       COMPANY            INDICATION       U.S. DEVELOPMENT STATUS
 __________________________________________________________________________

 AIDS vaccine   Immuno AG           AIDS            Phase 1 (WAB)
 (rgp 160)      Vienna, Austria); 
                NIH (Bethesda, MD)

 gp120          Genentech           HIV infection   Phase I as therapeutic
                (S. San Francisco)  and prevention  (WA)

 HIV immuno-    Immunization        asymptomatic    Phase II/III as
 therapeutic    Products Ltd.       HIV infection   therapeutic (WCAB)
 vaccine        (Horsham, PA)
 (RG-83894)

 HIV vaccines    Chiron (Emery-     AIDS             2 in Phase I
 (gp120)         ville, CA); CIBA-
                 GEIGY (Basel,
                 Switzerland)


 Theravir murine IDEC Pharma-       asymptomatic     Phase 1 as
 monoclonal      ceuticals          HIV infection    therapeutic (WA)
 anti-idiotype   (Mountain View,
 vaccine         CA)

 VaxSyn HIV-1    MicroGeneSys       early HIV        Phase II as
 (rgp 160)       (Meriden, CT);     infection, and   therapeutic
                 Wyeth-Ayerst       HIV negative     Phase I/II as
                 (Philadelphia,                      preventive
                 PA)                                 vaccine

 VaxSyn HIV-1    MicroGeneSys       AIDS             Phase I as
 (rp24)          (Meriden, CT)                       therapeutic

 WCAB codes in parentheses to right of development status: 
       W--Women are included in the human clinical trials for this product.
       C--Children are included in the human clinical trials for this product.
       A--This product is being developed with the intent of labeling and
          marketing for use in women.
       B--This product is being developed with the intent of labeling and
          marketing for use in children.

       Source: AIDS Medicines in Development, p. 7.  Published by the
       Pharmaceutical Manufacturers Association.  October 1992.

       -------------
       Recombinant Vaccines

       The use of recombinant (genetically-engineered) technology has led to the
development of an important recombinant vaccine for widespread use: the
hepatitis B vaccine, Engerix B.  Encouraged by the success of this vaccine,
several experimental vaccines for HIV have been designed using genetically
engineered parts of the virus.  Because they are created from pieces of the
virus, rather than whole-killed or live-attenuated virus, recombinant vaccines are
considered safer for human use.  In fact, several of them have been pronounced
"safe" by government researchers.  Unfortunately, HIV-1, the target of most HIV
vaccine research in the U.S., mutates rapidly.  Researchers have concentrated on
creating a recombinant vaccine using parts of the virus that do not change as
the virus mutates.  The hope is that the non-mutating region of the outer
covering of the virus (the envelope) will serve as a universal immunogen that
will confer protection against the 5 major strains of HIV identified thus far.  The
impractical alternative to this approach would be to make a separate vaccine for
every mutant form of HIV.

       Each candidate vaccine raises its own specific safety and effectiveness
concerns.  Among researchers and governmental regulatory bodies, recombinant
vaccine candidates raise questions about the safety standards that apply to
gene-cloning.  Most of the biotechnological companies that design these candidate
vaccines focus on the synthetic reproduction of the envelope regions of HIV
called glycoproteins 120 and 41 (or simply gp120 and gp41).  These are
structures on the surface of HIV.  gp41 is an anchor in the virus envelope
surface from which gp120 projects.  Both parts are forged from gp160, which is
produced by an HIV gene known as env.  Most people infected with HIV make
antibodies to all 3 of the gp molecules. 

       The gp120 molecule is thought to attach itself to T-helper cells during
active  infection of a healthy human cell.  gp 120 is also thought to be the
"glue" that can bind up to 500 healthy T-cells to 1 infected cell, in arrangements
known as syncytia.  One part of gp120, the V3 loop, is referred to as the
principal neutralizing determinant.  The V3 loop is the target most commonly
recognized by killer T-cells.  If gp120 were to be blocked by humoral immune
response (antibodies produced by B-cells), HIV could not infect normal healthy
cells, nor could gp120 provoke immunosuppressive syncytia formation.  If a
cell-mediated immune response (T-cell immunity) were also to be stimulated by
gp120, anti-HIV memory T-cells would be generated, presumably diminishing the
chances for HIV to successfully evade the surveillance of the immune system long
enough to establish infection.

       Recombinant vaccine candidates are produced by gene-cloning, which
involves biochemical manipulation of DNA.  The DNA of HIV is cut to excise the
env gene, to produce large quantities of the envelope glycoproteins (gp120, gp
41 or gp160), or to excise the gag gene in order to produce p24, a major core
protein of HIV.  Cell lines are mixed with the DNA fragments in a way that causes
the DNA to move inside them and take up permanent residence.  The cells then
manufacture the desired proteins in large quantities, which can be harvested and
which will act as the antigenic component of the candidate vaccine.  For example,
the MicroGeneSys Company grows gp160 in a baculovirus inside insect cells. 
Scientists must test for and guard against insect protein allergic reactions that
could arise if traces of insect protein were to find their way into the final
vaccine product.  Vaccine candidates that are grown in invertebrate or mammalian
cells are not entirely free of allergic reactions either.  Quality control is of
paramount importance to eliminate harmful contaminants that may be left over
from the gene-cloning process.  FDA guidelines have been carefully devised to
ensure that each recombinant vaccine candidate meets strict requirements that
ensure its safety as much as possible.  

       Some researchers question whether non-human cell lines will express
(manufacture) the env and gag gene products exactly as human cells do.  If they
do not, will they induce relevant human immune responses when they are
administered in vaccine form?  An example of a relevant human immune response
would be the stimulation and proliferation of neutralizing antibodies that block
the ability of HIV to infect T-cells.  Neutralizing antibodies to the V3 loop are
particularly good at stopping viral infectivity, but the V3 loop is one of the most
variable regions of gp120 (with variation as great as 50% between different
strains of HIV-1).  Moreover, the V3 loop of gp120 is apparently not the binding
site for the T-helper molecule on helper T-cells, since binding can take place
when the loop is itself bound to antibody.  It is thought that gp41 hooks onto
the T-cell membrane and brings it towards the virus in a slow fusion process. 
There are at least some conserved nucleic acid positions in the loop, perturbation
of which can prevent post-binding fusion and infectivity.  The challenge then is
to find the sequences of amino acids that are common to all the V3 loops of all
strains of HIV.  Some conserved sequences and positions have been found in the
245 HIV-1 isolates (individual virions) that have been compared so far.

       ---------------
       Treatment Vaccines

       The design of an effective therapeutic vaccine is more difficult than the
design of a preventive HIV vaccine.  The goal of a therapeutic vaccine is to
produce new or reinforced immune responses in persons already infected with
HIV.  Ideally, these new responses would control or possibly abort the infection. 
One example of a successful therapeutic human vaccine is that for rabies, which
is given after a person is exposed to the rabies virus.

       Suppose a vaccine candidate shows a strong effect on T-cell - mediated
cytotoxicity.  In general, this is a desirable characteristic of an antiviral vaccine. 
But may this effect also lead to increased HIV replication and spread? If the
number of T-helper cells that recognize gp120 increases dramatically, will the
number of T-helper cells that successfully find and bind to gp120 also increase?
Will they become infected, too?  One of the noteworthy properties of HIV is that
it integrates its RNA into the DNA of the host cell, and appears to remain latent
until activated.  Would the presence of excess gp120, whether virulent or not,
trigger viral activation?

       --------------
       Pathogenesis theories affect vaccine choices

       The above questions arise because HIV induces immune dysfunction.  In
contrast to other viral infections, most of which are thought to cause transient,
generally reversible changes within the immune system, HIV infection often causes
progressive, destructive and irreversible autoimmunity.  The destruction is not
limited to T-helper cells, nor can syncytia formation alone account for the
collapse of the immune system.  Other mechanisms describing the course of
disease progression have been postulated that, if accurate, would affect the
design of vaccine candidates in important ways.  

       One proposed mechanism of infection is that HIV contains a superantigen. 
If gp120 acts as a superantigen that activates 1 in every 20 T-cells instead of
one in every 100,000, then huge numbers of T-cells will be activated during
infection.  Researchers think that gp120 binds to an outer region of the T-cell
receptor and cross-links it to a molecule found on all antigen-presenting cells. 
When this happens in excess, the T-cells are programmed to self-destruct. 
So-called "holes in the repertoire" are created, and some categories of immune
response are completely eliminated.  There are genetic measurements that support
the superantigen model.  If this is an accurate model, why would it be helpful
to add yet more superantigen (a gp120 vaccine) to the system? How can we safely
stimulate the immune system without losing enormous numbers of T-cells?

       Another view of pathogenesis is based on antibody regulation.  The concept
of anti-idiotypic networking describes an immune system where antibodies
regulate each other.  The network acts as a feed-back mechanism whereby no
single antibody response becomes so overpowering that it overwhelms all the
others.  Many researchers believe that HIV causes antibody dysregulation.  What
are the consequences of contributing to antibody imbalance by adding vaccines
that induce new and  powerful antibody responses? Will there be a domino effect
that will "burn out" the immune system? Will only T-cell response confer
immunity? These questions are new to the makers of vaccines, and need to be
considered because of the unique pathology of HIV.

       --------
       Animal models

       More than 27 vaccine preparations are in various stages of testing, ranging
from pre-clinical test-tube experiments to animal trials to Phase II safety and
efficacy trials in human volunteers.  Every vaccine candidate must travel the
same road to approval.  A major stumbling block has been the lack of an
appropriate animal model in which to test vaccine candidates.  Laboratory
chimpanzees do not get AIDS from HIV-1 infection.  Investigators can look for
vaccine effects on viral replication, but chimpanzees do not display the full
spectrum of immune dysfunction that characterizes human infection.  There has
been greater success with the study of HIV-2 infection in rhesus macaques,
which produces simian AIDS.  The effects of a vaccine on their immune systems
can be measured, and careful extrapolations to human responses are possible. 
Other animal models include HIV-2 in cynomolgous (a primate species) monkeys,
and SIV in rhesus macaques and African Green monkeys.  Because of the
similarities between SIV and HIV-2 (70% amino acid sequence homology), animal
models of infection with SIV are relevant to the study of human AIDS vaccines,
and may have predictive value.  The best animal model for HIV-1 would not only
show signs of viral infection but would also develop progressive immune system
deterioration in response to the infection, closely approximating the course of
HIV-1 infection in humans.  Another promising animal model is the SCID-hu
(severe combined immune deficiency-human) mouse, a mouse devoid of its own
immune system.  Human immune cells can be transferred to these mice, and the
effects of infection and vaccination can be studied directly.  

       -----------
       The public debate

       Another therapeutic vaccine candidate has made national news because of
an unorthodox end run around traditional peer review at the National Institutes
of Health, the national body that shepherds and regulates vaccine and drug
development and testing.  MicroGeneSys created a major splash in the research
world by successfully lobbying Congress to earmark $20 million of a Department
of Defense appropriation for a large-scale trial of recombinant gp160 therapeutic
vaccine.  Although several companies make a gp160 product, it is generally
understood that the appropriation was intended for the MicroGeneSys candidate,
and that Robert Redfield of the Walter Reed Army Institute of Research would
conduct the research.  The lobbying effort earned nearly unanimous condemnation
from both the AIDS research and activist communities; neither group felt that
Congress was qualified to dictate which vaccine candidate should be tested in a
large simple trial.

       The NIH reacted to the appropriation by convening a blue ribbon panel of
researchers, activists and public officials to investigate the advisability of that
specific earmarking, and the Army followed suit with an investigation of Dr.
Redfield's interpretation of trial data previously submitted to the VIII
International Conference on AIDS in Amsterdam in June 1992.  These ongoing
investigations underscore how little is known about the efficacy of therapeutic
vaccines or how to test them.  Public debate over what constitutes an effective
therapeutic vaccine has raised important issues, and spurred the NIH to promise
a comparative trial of vaccines made by Chiron, Genentech and MicroGeneSys in
early 1993.

       There is much more at stake than whether or not Congress should be
setting AIDS research agendas.  Experiences from the polio vaccine trials of the
1950s indicate that the first HIV vaccine to be tested in a Phase III trial will
garner the greatest number of volunteers in the shortest period of time.  While
hundreds of volunteers are sufficient to establish safety in Phase II trials, many
thousands are needed to establish efficacy in Phase III trials.  The shorter the
trial, the more volunteers are needed.  Concerned researchers fear that the pool
of volunteers will dry up if one vaccine candidate is tested alone in a
30,000-person, 2-year trial.  Some positive effect would have people clamoring for
the tested vaccine, while a negative or inconclusive analysis could frighten away
volunteers who might otherwise participate in later trials of other vaccine
candidates.  The reality of today's surrogate markers for disease progression is
also at issue.  A large, simple trial would concentrate on clinical endpoints (the
development of specific opportunistic infections or death), rather than on
surrogate markers such as T-helper cell counts or polymerase chain reaction
(PCR) measures of viral load.  NIH Director Bernadine Healy, FDA Commissioner
David Kessler and the Secretary of Defense have until April to decide how to
design the large simple trial, and which vaccine candidates merit inclusion.

       --------------
       Preventive vaccine trials

       The National Institute of Allergy and Infectious Diseases (NIAID) has
established the AIDS Vaccine Clinical Trials Network to conduct Phase I and Phase
II trials of various vaccine candidates at 5 university-based research centers
called AIDS Vaccine Evaluation Units (AVEUs).  Eleven trials are in operation
using 7 vaccine candidates.  Three trials test a combination of 2 vaccine
candidates.

       Recently published results of current trials indicate that the recombinant
gp120 and gp160 products are safe, with side effects limited to injection site
soreness and influenza-like symptoms in some volunteers.  Trials in France and
Zaire with a vaccinia live-virus vector (the virus used in smallpox vaccine)
report more problematic side-effects, including papular skin reactions and
abscesses, with little in the way of additional cell-mediated immune response to
motivate the added risk of using live viral vectors for vaccine delivery. 
Furthermore, 3 people who received vaccinia vaccine in Zaire died from
disseminated vaccinia infection.  However, NIAID feels that the use of a safe
live-vector vaccine to prime the immune system, followed by booster shots of a
recombinant vaccine, warrants testing.

       The current Phase I trials in the United States are attempting to assess
the safety of vaccine candidates specific to several HIV-1 strains.  So far there
are few answers to the many specific questions that have been asked.  It still
is not known whether a strain-specific vaccine protects only against that
particular strain of HIV-1 or if the strain-specific vaccine confers cross-immunity
to other strains; whether vaccines elicit antibody protection in mucous
membranes, the site of HIV sexual transmission; and whether it makes a difference
if recombinant vaccine products are grown in cells from one species or another. 
At this time, the answers to these questions can only be inferred from carefully
designed animal tests, but the answers should provide enough information for
most people to make intelligent decisions about participation in preventive AIDS
vaccine trials.

       The first Phase II preventive vaccine trial in the U.S. will compare 2
recombinant gp120 vaccine candidates in several groups of volunteers.  One
gp120 candidate is made from HIV-1 strain SF-2; the other is made from strain
MN.  The 330 volunteers will be classified by high- or low-risk sexual and
drug-use behavior patterns, and randomly assigned to 2 treatment arms and 2
control groups.  The multi-center trial will be conducted at the 5 AVEG sites:
Seattle, Baltimore, St. Louis, Nashville and Rochester.  Because high-risk
individuals will be included, some critical questions about immunogenicity should
receive at least partial answers by the end of the 18-month trial.  Researchers
then hope to have a better idea of which vaccine candidate(s) to include in the
World Health Organization's huge, international prevention studies.  More
questions regarding access to vaccines will arise when candidates reach Phase
III efficacy testing.  As the AIDS pandemic continues to rage, persuasive
arguments for elegant experiments and idealized goals are difficult to make, yet
cautious progress in efficacy trials seems a pragmatic approach to the current
phase of vaccine research.

       -----------
       Selected Sources:

       Cohen J.  Did political clout win vaccine trial for MicroGeneSys? Science
258: 211.  1992.

       Cohen J.  Lobbying for an AIDS trial.  Science 258: 536-539.  1992.

       Cohen J.  Army investigates researcher's report of clinical trial data. 
Science 258: 883-884.  1992.

       Cohen J.  MicroGeneSys vaccine trial gets a public peer review.  Science
258: 1079-1080.  1992.

       Desrosiers R.  HIV with multiple gene deletions as a live attenuated vaccine
for AIDS.  AIDS Research and Human Retroviruses 8: 411-421.  1992.

       Edgington S.  Biotech vaccines problematic promise.  Biotechnology 10:
763-7661.  1992.

       Edgington S.  Is an AIDS vaccine possible?  Biotechnology 10: 768-771. 
1992.

       Editor.   AIDS research and the Army calling the shots.  The Economist 28. 
 November 14, 1992.

       Eiben T.  New weapons against AIDS.  Fortune 104-107.  November 30, 1992.

       Graham B.  Clinical trials of AIDS vaccines in seronegative volunteers:
vectors and combinations.  AIDS Research and Human Retroviruses 8: 1327-1328. 
 1992.

       Hilleman M.  The dilemma of AIDS vaccine and therapy: Possible clues from
comparative pathogenesis with measles.  AIDS Research and Human Retroviruses
8: 1743-1747.  1992.

       Ho D.  Discontinuous epitopes on gp120 important in HIV-1 neutralization. 
AIDS Research and Human Retroviruses 8: 1337-1339.  1992.

       Kahn J and others.   A phase I study of HGP-30, a 30 amino acid subunit
of the HIV p17 synthetic peptide analogue sub-unit vaccine in seronegative
subjects.  AIDS Research and Human Retroviruses 8: 1321-1325.  1992.

       Mann D.  HLA phenotype is a factor in determining rate of disease
progression and outcome in HIV-1 infected individuals.  AIDS Research and Human
Retroviruses 8: 1345-1346.   1992.

       Matthews T and others.  AIDS vaccines.  In The Science of AIDS,  W.H.
Freeman and Co.  1988.

       National Institute of Allergy and Infectious Disease.  NIAID vaccine
research: Key to disease prevention.  US Government Printing Office.  August
1991.

       National Institute of Allergy and Infectious Disease.  NIAID AIDS Agenda. 
U.S. Government Printing Office.  Fall 1992.

       Petricciani J and others.   Efficacy trials of HIV/AIDS vaccines.  AIDS
Research and Human Retroviruses 8: 1527-1529.  1992.

       Picard O and others.  A 2-year follow up of an anti-HIV immune reaction
in HIV-1 gp160-immunized healthy seronegative humans: evidence for persistent
cell-mediated immunity.  Journal of Acquired Immune Deficiency Syndrome 5:
539-546.  1992.

       Putney S.  How antibodies block HIV infection: paths to an AIDS vaccine. 
Trends in Biochemical Sciences 17: 191-196.  1992.

       Rowland-Jones S and others.  HIV variants that escape cytotoxic T-cell
recognition.  AIDS Research and Human Retroviruses 8: 1353-1354.  1992.

       Slade H and others.  Immunotherapy of HIV-seropositive patients:
preliminary report on a dose-ranging study.  AIDS Research and Human
Retroviruses 8: 1329-1331.  1992.

       ********

       PREGNANCY AND HIV INFECTION
       Teryl Nuckols

       Teryl Nuckols is a volunteer for the San Francisco AIDS Foundation and
       the Shanti Project.  She is a graduate of Cornell University, and lives and
       works in San Francisco. 

       NOTE: THE PURPOSE OF THIS ARTICLE IS TO PROVIDE BASIC INFORMATION
       REGARDING CERTAIN ASPECTS OF PREGNANCY AND HIV INFECTION.  IT IS
       NOT INTENDED TO BE COMPREHENSIVE, NOR TO ADDRESS ALL ASPECTS OF
       THE TOPIC.  ANY DECISIONS REGARDING TREATMENT DURING PREGNANCY
       MUST BE MADE WITH THE WOMAN'S PRIMARY PHYSICIAN OR OBSTETRICIAN. 
       REFERRAL INTO TREATMENT PROTOCOLS IS STRONGLY ENCOURAGED.

       ------------
       Overview

       Due to the increasing incidence of HIV in women in the United States, and
because many HIV positive women have no known history of classical risk factors
for HIV transmission, some health-care workers recommend routine prenatal
testing for HIV.  Critical to obtaining expedient treatment, early detection of HIV
also grants an expectant mother more time to evaluate whether or not to continue
her pregnancy.   

       HIV infection in pregnant women is accompanied by several important
medical and social issues.  First, there is a significant possibility (about 25%)
that the HIV positive mother will transmit the virus to her child.  Second, if the
woman has symptomatic HIV disease or AIDS, drug treatments that may be
necessary for the protection of her health may harm the fetus.  Third, the
mother's illness will have an impact on both her life and her newborn's life.

       While these issues may be used to argue against continuing a pregnancy,
various circumstances and factors influence each woman's decision.  An
asymptomatic woman may choose to continue her pregnancy because she has up
to a 75% chance of delivering a healthy, HIV negative baby (depending upon the
mother's blood tests and other factors).

       ----------
       Transmission of HIV from Mother to Child

       According to the U.S. Public Health Service, mothers transmit HIV to their
children at an overall rate of 25 percent.  For asymptomatic HIV positive women,
2 major U.S. studies reported a transmission rate of 29-30 percent.  Transmission
can occur at any point during pregnancy or delivery.  Some evidence suggests
that the risk of transmission may be greater during childbirth than during
pregnancy.  Studies also indicate that the first-born of HIV-exposed identical
twins generally has a higher risk of contracting the virus than the sibling.  

       Some researchers have reported that the concentration of the virus in the
mother's body (viral burden) is tied to the likelihood of transmission.  Pregnant
women with high viral burdens may transmit HIV to their children at higher rates
than those with low viral burdens.  Because initial infection with HIV is
associated with a high viral burden, this is particularly relevant for women who
acquire HIV during pregnancy.    

        HIV has also been isolated in breast milk.  While less common than
transmission during pregnancy or delivery, the transmission of HIV from mother
to child through breast-feeding does occur.  In most documented instances of
transmission via breast milk, the mother had contracted HIV from a blood
transfusion or heterosexual transmission after giving birth, and therefore had a
high viral burden associated with primary HIV infection while breast-feeding. 
Breast-feeding carries an 11-14% risk for mother-to-child transmission.

       Because maternal IgG antibodies are transferred to the child during late
pregnancy, almost all infants born to HIV-infected mothers initially test positive
for HIV antibodies.  Some HIV negative babies will have positive antibody tests
up to 15 months after birth.  For this reason, a standard FDA-licensed antibody
test cannot reliably be used to determine the HIV status of these infants until
they are at least 15 months old.  Other tests are helpful in establishing HIV
infection in these infants before they have reached 15 months of age.  They
include IgA HIV antibody determinations and polymerase chain reaction (PCR)
testing, which can detect HIV DNA.

       A government-sponsored study is currently underway to examine the safety
and effectiveness of AZT in preventing mother-to-child transmission of HIV.  HIV
positive women with T-helper cell counts greater than 200 will receive AZT during
the second and third trimesters of their pregnancies, and during delivery.

       ---------
       Pregnancy and Immunosuppression

       While researchers generally believe that pregnancy has little effect on the
progression of HIV disease, the data currently available are scant.  The incidence
of opportunistic infections appears to be the same among pregnant and non-
pregnant women with similar T-helper cell counts.  However, studies have
reported that certain opportunistic infections may be more severe when they
occur during pregnancy.

       A mild state of immunosuppression naturally accompanies pregnancy (even
in HIV negative women), preventing rejection of the fetal genes from the father. 
During pregnancy, herpes and genital warts outbreaks increase in HIV negative
as well as HIV positive women.  Pregnant women also suffer from more severe
bouts of influenza, and are generally more susceptible to viral, bacterial and
fungal infections than non-pregnant women.  A number of studies have reported
a decrease in the ratio of T-helper to T-suppressor cells in HIV negative women
during pregnancy.  HIV infection also changes the T-helper to T-suppressor cell
ratio, probably increasing the immunosuppression that occurs naturally in
pregnancy.

       -------------
       Care During Pregnancy

       During the first examination of an HIV positive pregnant woman, the
clinician has several primary objectives: to determine the stage of HIV disease
and whether the patient has any HIV-related infections, and to examine the
patient's history for factors which may suggest future complications.  

       If HIV infection is diagnosed during pregnancy, the clinician will obtain a
baseline T-helper cell count as soon as possible.  For all HIV positive pregnant
women, the clinician will also likely order blood tests for indications of HIV
disease progression, including T-helper/suppressor ratio and beta-2 microglobulin
or neopterin.

       The physical examination will include a search for evidence of HIV-related
illnesses, including but not limited to oral (thrush) and vaginal candidiasis,
enlarged lymph nodes, genital herpes and other sexually transmitted diseases. 
The clinician will use the patient's history, examination and periodic intradermal
tests (which can be falsely negative due to severe immunosuppression) to screen
for signs of mycobacterial infection.  Baseline and periodic cultures will be taken
for gonorrhea and chlamydia.  The clinician will use antibody tests to obtain a
baseline for opportunistic infections that can have an impact on the fetus, such
as toxoplasmosis and syphilis (see Table 1).  A (surface) test for hepatitis B
should be included; for those with fewer than 300 T-helper cells, a cryptococcal
antigen test may also be desirable.

       The courses of any previous pregnancies should be considered, and any
unusual, attendant conditions noted, such as pneumonia or diarrhea.  The
clinician should consider the health of any previous children.  It is also
important to obtain the patient's sexual history, because many opportunistic
infections are sexually transmitted.

       A pregnant woman with HIV should report any new symptoms to her
clinician as soon as possible.  Particularly important symptoms include weight loss
or inability to gain weight, recurrent vomiting, upper respiratory infection,
excessive fatigue, cough or fever.

       ---------
       Asymptomatic HIV Disease

       Asymptomatic HIV positive pregnant women should receive prenatal
examinations at the same intervals as HIV negative women.  Administration of the
Pneumovax vaccine should be considered during the first visit to induce
antibodies to common pneumococcal lung strains.  Examinations should include
evaluations for opportunistic infections, particularly syphilis and other sexually
transmitted diseases.

       Asymptomatic patients should have T-helper cell counts performed at least
once each trimester.  If the count drops below 350, the test should be repeated
monthly for the remainder of the pregnancy.  Based on the results of these
tests, anti-HIV treatment and/or prophylaxis against Pneumocystis carinii
pneumonia (PCP) may be appropriate, as discussed below.   

       ----------
       Symptomatic HIV Disease and AIDS

       A patient with symptomatic HIV disease or AIDS needs to be aware of the
harmful effects certain medications or treatments could have on the fetus.

       As with asymptomatic women, T-helper cell counts need to be obtained at
least once each trimester, or, if the count is less than 350, each month.  If a
woman's T-helper cell count is under 500, she should consider taking AZT. 
Women with T-helper counts below 300 are candidates for both AZT and
prophylaxis against PCP.             

       A recent study of 43 women who received oral AZT in doses ranging from
300 to 1200 milligrams per day during pregnancy showed encouraging results. 
Generally well-tolerated by the mothers, AZT caused no malformations, premature
deliveries or fetal stress, according to researchers.

       However, potential adverse effects of AZT have been reported by some
researchers.  One study using an animal model linked AZT with genital cancers. 
Anemia, a common side effect of AZT therapy and a condition sometimes associated
with pregnancy, appears to be an important complication.  Fetal anemia (including
hydrops fetalis) and intrauterine growth retardation are also theoretical side
effects from AZT use by pregnant women.

       One clinical group recommends the following baseline tests prior to AZT
treatment in pregnant women:  a complete blood count, including platelets, liver
enzymes and serum creatine level.  If hemoglobin levels are below 11 grams per
deciliter, the possibility of giving the woman a blood transfusion prior to
treatment should be considered.  Periodic follow-up monitoring, through blood
counts and SMA 12 determinations, is likely to be indicated.  Ultrasound scanning
may be used to monitor for hydrops fetalis and to assess fetal growth and
amniotic fluid volume.  In the third trimester, non-stress tests and fetal
biophysical profiles may be appropriate. 

       PCP is the most common opportunistic infection affecting HIV positive
women, with a 5-10% mortality associated with the first episode.  Subsequent
episodes are substantially more life-threatening.  For this reason, PCP
prophylaxis should be considered for those with T-helper cell counts ranging
from 200-300.

       Trimethoprim-sulfamethoxazole (TMP-SMX; Bactrim, Septra) is the preferred
first-line drug for the treatment of PCP.  However, TMP-SMX is not generally
recommended for use by pregnant women, because the prenatal risk from this
drug can be significant.  However, TMP-SMX use is preferred by some clinicians
over intravenous pentamidine when the mother's life is in danger.  The new anti-
PCP drug Mepron (atovaquone) may become the drug of choice to treat PCP in
pregnant women, due to its low toxicity profile.  Dapsone-trimethoprim or
clindamycin-primaquine are other drugs that may be appropriate to treat PCP
during pregnancy.  Decisions about the appropriateness of a specific anti-PCP
therapy should be made on a case-by-case basis. 

       Dapsone or aerosolized pentamidine (AP) may be the preferred prophylaxis
for PCP in pregnant women.  One study concluded that there are benefits to
administering AP 300 mg every 4 weeks with the Respirgard II jet nebulizer for
pregnant women at risk for PCP.  However, the safety of this treatment for the
fetus has not been conclusively determined.   

       Prior to PCP prophylaxis with aerosolized pentamidine, active pulmonary
disease must be ruled out via a normal chest radiograph, a negative Tb test, and
a negative sputum stain for acid-fast bacteria.  Subsequent monitoring should
assess breakthrough PCP, which is likely to occur at the lung apices.

       -----------
       Maternal Death

       If PCP or another condition poses a substantial threat to a woman's life,
the woman, her clinician, her social worker and her family need to work together
to resolve several important issues.  Ideally, these discussions should take place
in advance of an emergency situation.  The use of various medications and
therapies (such as hyperalimentation and ventilator support) should be discussed,
as should the risk of premature delivery, fetal compromise or fetal distress.  The
appropriateness of performing a Cesarean section in a life-threatening situation
should also be determined.

       ----------
       Care During Delivery

       Since HIV has been isolated in blood, vaginal secretions, the placenta,
amniotic fluid and fetal tissue, care should be taken to prevent transmission of
HIV to the infant during delivery.  Tests or procedures which might damage the
integrity of fetal skin have relative contraindication and should be avoided
during delivery, including internal scalp monitoring and fetal scalp pH testing. 
After delivery, the infant should be cleaned thoroughly to remove maternal fluids,
and the infant's skin should be sterilized locally prior to any needle punctures. 
Cesarean sections do not appear to affect the chances of maternal-to-fetal HIV
transmission. 

       ----------
       Care After Delivery

       The woman should be instructed not to breast-feed her infant due to the
possibility of HIV transmission.  In the longer-term care of the mother, the
clinician should monitor for cervical dysplasia, opportunistic infections and
cancers, in addition to assessing any other indications of the progression of HIV
disease.

       -----------
       Recruiting Trials

       Information concerning open and ongoing clinical trials for pregnant HIV
positive women can be obtained by calling 1-800-TRIALS-A (1-800-874-2572),
Monday through Friday, 9 a.m. to 7 p.m. Eastern Time.  

       ----------
       Selected Sources:

       Baker RA and others.  Early Care for HIV Disease, 2nd Ed.  1992.

       Carpenter C and Flanigan T.  HIV infection in women.  AmFAR AIDS/HIV
Treatment Directory 5(4): 5-10.  Spring 1992.

       Denenberg R.  Women, immunity, and sex hormones.  Treatment Issues: The
Gay Men's Health Crisis Newsletter of Experimental AIDS Therapies 6(4). 
Summer/Fall 1992.

       Hayes B.  Women and HIV disease: an interview with Constance Wofsy, M.D. 
Bulletin of Experimental Treatments for AIDS (BETA).  1-6.  November 1991.

       Nanda D.  Human immunodeficiency virus infection in pregnancy. Obstetrics
and Gynecology Clinics of North America 17(3).  September 1990.

       Table 1. CARE FOR ASYMPTOMATIC HIV POSITIVE PREGNANT WOMEN
       (with T-helper cell counts >500)

       ---------
       Prenatal               

       First visit: antibodies to toxoplasma, cytomegalovirus and syphilis (VDRL);
skin test for tuberculosis; Pneumovax vaccine; hepatitis B (surface) and
cyptococcal antigens

       Follow-up visits: cultures for gonorrhea and chlamydia; beta-2
microglobulin; SMA 12

       T-helper cell counts once each trimester

       ---------
       Delivery

       Urine for cytomegalovirus testing

       Repeat toxoplasma and cytomegalovirus titers for seronegative patients


       ---------
       Prenatal and Postpartum Therapy

       If T-helper < 500, discuss AZT therapy

       If T-helper < 200, discuss PCP prophylaxis 

       [Note: > = greater than; < = less than]

       Source:

       Nanda D. Human immunodeficiency virus in pregnancy.  Obstetrics and
Gynecology Clinics of North America 17(3).  September 1990.

       **********

       Guidelines for Treatment of HIV Infection in Adults
       Ronald A. Baker, PhD

       <This is a Table.  It has been deleted from the Online Version>

       **********

       GUIDELINES FOR PREVENTION OF PNEUMOCYSTIS CARINII PNEUMONIA (PCP)
       Ronald A. Baker, PhD and Joan Kapusnik-Uner, PharmD

       Ronald Baker is editor of BETA.  Joan Kapusnik-Uner is Associate Clinical 
       Professor, School of Pharmacy, University of California, San Francisco. She
       is a Pharmacist at the UCSF AIDS Clinic and on the Infectious Disease
       Inpatient Service at San Francisco General Hospital.  

       When should primary prophylaxis against PCP begin?  The standard
recommendation calls for initiating prophylaxis among HIV positive adults with
fewer than 200 T-helper cells or less than 14% T-helper cells.  Because the
absolute number of T-helper cells may vary considerably in individual patients,
it may be prudent to start prophylaxis at a higher T-helper count, e.g. 250-300,
especially if recent counts show a pattern of decline.  In infants and children
under 5, prophylaxis should begin at a higher T-helper cell count, approximately
400-500.

       Individuals with symptoms such as thrush (oral candidiasis) or unexplained
fever above 100 F for more than 2 weeks should begin PCP prophylaxis,
regardless of their T-helper cell count.  Once started, PCP prophylaxis should
continue for the individual's lifetime.  Secondary PCP prophylaxis (for people who
have recovered from an episode of PCP) should also continue for life.

       ---------
       Prophylaxis for PCP

        Trimethoprim-sulfamethoxazole (TMP-SMX = Bactrim, Septra and generics)
is the preferred (first-line) drug for the prevention of PCP in adults and
children.  The most commonly-used doses are 1 single or 1 double strength tablet
a day.  Some physicians recommend other dosing regimens, including 1 double
strength tablet 3 times a day, every other day or only on weekends (Saturday,
Sunday).  The major limitation of TMP-SMX is its tendency to cause a high
incidence of allergic reactions in people with HIV infection.

       The weight of current evidence suggests that dapsone may be more
effective than aerosolized pentamidine (AP) in preventing PCP. Dapsone is also
less expensive and more convenient to use than AP.  For these reasons, dapsone
appears in the PCP prophylaxis summary chart on page__ as second-line PCP
prophylaxis, for TMP-SMX intolerance.  The most commonly prescribed dose of
dapsone for prophylaxis is 100 mg/day. 

               Aerosolized pentamidine (AP) may be best utilized as the third-line
PCP prophylaxis, for TMP-SMX and dapsone intolerance.  Three hundred mg per
month delivered by the Respirgard II nebulizer is the FDA-approved dose and
schedule.  The Fisoneb nebulizer (60 mg every 2 weeks) has the advantages of
being hand-held, portable and uses less pentamidine, but is more expensive and
not widely available.  Regardless of the nebulizer used, coughing spasms and
wheezing may be reduced by pretreatment with a bronchodilator.

       The FDA has approved the new anti-Pneumocystis drug Mepron
(atovaquone) for treatment of acute PCP, but the drug's effectiveness as
prophylaxis is not yet known.  If used as preventive treatment, the dose should
be the same as for acute therapy (2,250 mg/day).  The biodisposition of this drug
is not yet clear.  Less frequent dosing may eventually prove effective.  

       Once monthly IV pentamidine (4mg/kg) has also been studied for PCP
prophylaxis, but the drug's potential toxicities and high cost may outweigh its
usefulness as a prophylactic treatment.

       **********

       GUIDELINES FOR TREATMENT OF Pneumocystis carinii pneumonia (PCP)
       Ronald A. Baker, PhD and Joan Kapusnik-Uner, PharmD

       Despite early diagnosis and treatment, Pneumocystis carinii pneumonia (PCP)
remains the leading cause of death among people with AIDS, regardless of their
race or gender.  PCP is also frequently the first serious HIV-related illness
experienced by people living with HIV disease.  

       Numerous treatment options exist for individuals who develop PCP.  To
choose the most effective therapy, physician and patient must consider a variety
of factors, including the severity of the disease and the individual's ability to
tolerate a variety of therapies with a wide range of adverse side effects.

       The first-line treatment for acute PCP is trimethoprim-sulfamethoxazole
(TMP-SMX = Bactrim, Septra and generics).  The oral form of the drug is used
to treat mild to moderate PCP, while the IV formulation is preferred for
individuals with severe disease.  For people with mild to moderate PCP who fail
on TMP-SMX or cannot tolerate it, dapsone-trimethoprim is the second-line
treatment.  Dapsone-trimethoprim causes far fewer adverse side effects than TMP-
SMX, is equally inexpensive, but has been less extensively studied.

       Clindamycin-primaquine is the third-line treatment for PCP.  These 2 drugs
are used most often in an oral formulation for individuals with mild to moderate
PCP who fail or cannot tolerate either TMP-SMX or dapsone-trimethoprim.  The
IV formulation of clindamycin is available for treatment of severe PCP, if the
patient fails or cannot tolerate IV TMP-SMX or IV pentamidine.  Clindamycin-
primaquine has the advantage of not suppressing the bone marrow, but
clindamycin may cause diarrhea or rash.  

       The U.S. Food and Drug Administration (FDA) recently approved Burroughs
Wellcome's new oral antibiotic atovaquone (Mepron) for use in individuals with
mild to moderate PCP who cannot tolerate or fail TMP-SMX.  Until there is more
experience with this drug, however, clinicians are likely to use Mepron as the
fourth-line treatment, after TMP-SMX, dapsone-trimethoprim and clindamycin-
primaquine.  The drug has low bioavailability, and should not be used by
individuals with persistent diarrhea.  A major advantage of Mepron is its low
incidence of adverse side effects and its category C toxocologic rating.  These
features may make it an attractive option in the treatment of mild to moderate
PCP in pregnant women.

       Intravenous pentamidine is highly effective against severe PCP, and does
not suppress the bone marrow.  However, it may cause other serious, irreversible
side effects (e.g. pancreatitis), and therefore should be reserved for severe cases
following TMP-SMX intolerance or failure.  When their condition becomes stable,
most individuals receiving IV pentamidine may be switched to an oral regimen
using TMP-SMX, dapsone-trimethoprim or clindamycin-primaquine.  IV clindamycin-
primaquine offers a good option for people who experience serious adverse side
effects from IV pentamidine.

       The experimental agent trimetrexate is sometimes used with leucovorin as
"salvage therapy" for PCP in individuals who fail all the treatments discussed
above.  Trimetrexate, although effective, often causes severe bone marrow
toxicity, a major limitation. 

       Concomitant use of steroids with any of the antibiotic regimens described
here may improve survival in people with moderate to severe PCP, if administered
within 72 hours after starting anti-PCP therapy.

       Finally, it should be noted that the standard of care for the treatment of
PCP exists in a state of continual flux, as results of ongoing studies yield more
information about both standard and experimental treatments for the disease. 
The information provided here and in the accompanying charts should not be
considered the "last word" on regimens for PCP, but rather as guidelines that
reflect a "snapshot" of the best therapeutic options available to clinicians and
patients as of February 1993. 

       *********

       WHEN SHOULD PERSONS WITH ASYMPTOMATIC HIV DISEASE BEGIN ANTI-HIV
       THERAPY? A LARGE, SIMPLE TRIAL COULD PROVIDE THE ANSWER
       Thomas Mitchell, MPH

       Thomas Mitchell is the Program Director of the Community Consortium, an
association of more than 250 health care providers who care for the majority of
people with HIV disease in the San Francisco Bay Area.

       Anti-HIV drugs such as AZT, ddI and ddC have been studied in numerous
clinical trials and are currently used by thousands of people with HIV disease. 
The body of research on these drugs suggests that they may slow disease
progression, at least temporarily, but may also cause seious side effects, or lose
their effectiveness against HIV with long-term use.

       What we don't know is at what stage of HIV disease patients should begin
taking anti-HIV drugs in order to have the best chance of long-term survival --
at first diagnosis of HIV infection? at 500 T-helper cells? at the time of onset of
symptoms?  For the estimated one million people in the U.S. who are HIV positive
but asymptomatic, even a moderate survival advantage conferred by one strategy
over another could affect the treatment of hundreds of thousands of people with
HIV disease.

       While many people would argue that it is the quality, not the length, of life
that matters most, critics of the AIDS research effort of the National Institutes
of Health have charged rightly that "after ten years of AIDS and five years of
AZT, we still don't know for sure whether it, or its cousins ddI and ddC, actually
extend survival."

       The answer to the survival question remains uncertain because death is a
relatively rare event in studies with patients who have high T-helper cell counts
or who are asymptomatic.  Unless there are many deaths, it is usually impossible
to tell whether a difference in survival among patients in a clinical trial is due
to differences in treatment or to chance.  Only large studies --with tens of
thousands of patients-- are able to detect small, but important reductions in
mortality. 

       In an effort to answer the survival question, AIDS researchers have been
debating the advantages of a novel, though controversial, form of clinical
experimentation called "large, simple trials."  These trials do not conform to the
conventions observed in traditional clinical trials, but they are particularly well-
suited to discovering --with great certainty--  whether a treatment strategy,
such as the early use of anti-HIV therapy, has any effect on survival. 

       A difference in survival (if there is one) between patients who begin anti-
HIV therapy while they are still asymptomatic and patients who wait until they
develop symptoms is probably not large, or it would have been detected already. 
Nevertheless, the survival question is fundamental, affecting many thousands of
people with HIV disease, and no clinical trials of the early use of anti-HIV
therapy are designed to answered it.

       This month, the Community Consortium in San Francisco, in collaboration
with Professor Richard Peto at the University of Oxford, will begin the pilot
phase of a "large, simple trial" to help answer that question.

       The Community Consortium is an association of over 250 health care
providers who care for the majority of people with HIV disease in the San
Francisco Bay Area.  The Community Consortium pioneered the development of
"community-based" research and is currently conducting studies at more than 25
doctors' offices and clinics throughout the Bay Area.  Professor Peto developed
the methodology for large, simple trials, and has used it with remarkable success
in trials that have enrolled as many as 50,000 patients.  

       Funded by the American Foundation for AIDS Research and entitled
"ComPACT 1," this study is the inaugural project of a new entity within the
Community Consortium's clinical trials program.  The Community Partnership in
AIDS/HIV Clinical Trials (ComPACT) was established to develop innovative
strategies to answer questions that directly affect the health of large numbers
of people with HIV disease.  The ComPACT series of studies continues the
Consortium's tradition of innovative approaches to clinical trials for HIV disease,
an approach dating back to its first study of aerosolized pentamidine as
prophylaxis against Pneumocystis carinii pneumonia -- the first community-based
study to lead to the licensing of a new HIV therapy by the U.S. Food and Drug
Administration.

       The goal of the pilot phase of ComPACT 1 is to enroll 200 patients locally -
- enough to determine if a larger study, which will require as many as 10,000
patients, is feasible.  If the results of the pilot phase are promising, ComPACT
1 will be expanded to other cities across the U.S. later this year.

       To insure that the study reflects the variety of patients actually seen in
clinical practice, the eligibility criteria are broad.  The study is open to
asymptomatic patients at any T-helper cell level who are substantially uncertain
whether they should start anti-HIV therapy immediately, or whether there should
be a substantial delay (which might last some years) before such treatment is
needed.

       Patients will be randomly chosen to receive either immediate anti-HIV
therapy, or to follow a policy of deferred anti-HIV therapy.  Because the
fundamental question addressed by this study is when to begin therapy, rather
than which therapy to use, the choice of anti-HIV therapy is left entirely to the
patient and his or her provider.  Those patients randomized to immediate therapy
may start any anti-HIV therapy (monotherapy or combination therapy) they and
their providers prefer.  Because patients' health status and treatment options
change over time, those randomized to deferred anti-HIV therapy may begin anti-
HIV therapy when they or their providers become reasonably certain that it is
time to do so.  However, it is hoped that the period of deferral of therapy would
be at least a year, and preferably several years, so there will be on average a
large difference in the time of intervention between the two groups.

       To determine when anti-HIV therapy should begin, the study needs to
assess separately the effects on those patients with relatively low, moderate or
high T-helper cell counts at the time of randomization.  In each of these 3 cases
the eventual results may be different from early results, because an early
advantage for immediate therapy need not imply a long-term benefit.  Indeed, if
the risk of causing viral resistance implies that it is better to defer therapy for
several years, then there might be no difference, or even a slight (but perhaps
statistically significant) survival advantage for immediate therapy in the first few
years, followed eventually by a significant survival advantage for deferred
therapy.

       Such possible complexities mean that many thousands of low T-helper cell
patients, many thousands of mid-T-helper cell patients, and many thousands of
high T-helper cell patients need to be randomized, so that in each separate case
the survival difference between immediate treatment and deferred treatment is
known accurately when a moderate proportion have died.  This requires at least
a few thousand, and preferably several thousand, in each initial T-helper cell
category.

       In order to enroll as many as 10,000 patients, ComPACT 1 requires almost
no extra effort from busy primary care providers or people with HIV disease. 
For example, rather than requiring providers to fill out additional forms in order
to enroll a patient, providers simply make a brief toll-free telephone call to
Oxford, England.  No extra paperwork or record-keeping is necessary.  

       Unlike most clinical trials that require providers to keep detailed records
of changes in patients' health status, current medications and clinical laboratory
data, only three pieces of information are collected each year in ComPACT 1 -- 
the most recent T-helper cell count, anti-HIV therapy (if any), and death.  

       By simplifying the study design and limiting the amount of information
collected, it should be possible to enroll as many as 10,000 people -- enough to
insure that there will be a sufficient number of people to settle the survival
issue -- without bankrupting the system.  To succeed, ComPACT 1 will rely
heavily on the volunteered time of providers, none of whom has to interrupt the
workday very much to participate.  Patients make no more clinic visits than they
would normally.  

       Pharmaceutical companies have agreed to supply drug to patients in the
pilot study who do not fit the label indications for their drug (such as patients
with more than 500 T-helper cells who want to take AZT).  Insured patients with
medication coverage who meet the labeling indications are expected to bill their
insurance companies.  Patients without medication coverage, or without insurance,
are assisted in obtaining drug free-of-charge from federal, state and
pharmaceutically-sponsored AIDS drug programs.

       Once new anti-HIV drugs are licensed by the U.S. Food and Drug
Administration and are widely available, we must be able to determine which
dosages, schedules or combinations are best, and when in the course of the
disease to initiate therapy for maximimal benefit.  To ensure that we are able to
evaluate as many promising therapies as quickly as they are developed, we must
limit the overall costs of such studies, yet continue to enroll large numbers of
people.  We can achieve the lowest cost per patient by having broad eligibility
criteria, simplifying enrollment procedures, collecting minimal data and defining
our outcomes as major clinical endpoints, such as mortality.  In chronic diseases
such as HIV, a balanced strategy of clinical research should involve both small,
carefully controlled trials and some large, simple trials.

       For more information about ComPACT 1, please all 415/476-7126.

       Selected Sources

       Brown D.  Large, simple trials for big medical answers.  Washington Post,
August 10, 1992.

       Byar D.  Design considerations for AIDS trials. New England Journal of
Medicine 323: 1343-1348.  1990.

       Ellenberg S.  Do large, simple trials have a place in the evaluation of AIDS
therapies?  Oncology 6(4): 55-63.  April 1992.

       Gonsalves G and others.  AIDS research at the NIH: a critical review. 
Treatment Action Group (TAG), New York, NY.  July 1992.

       Green S.  Issues in the design of drug trials for AIDS.  Controlled Clinical
Trials 11: 80-87.  1990.

       ***********

       The Role of Cytokines in AIDS-Related Septicemia and Wasting Syndrome
       Dan Medynski, PhD

       Dan Medynski is a medical writer and biomedical researcher who lives in
       San Francisco.

       ----------
       Introduction

       Cytokines are proteins, secreted by macrophages and other immune system
cells, that act as biological messengers and play essential roles in coordinating
the body's immune response against bacterial infection.  They stimulate the
migration of white blood cells to sites of inflammation and infection, and initiate
tissue repair.  In response to invading microorganisms, however, immune cells
sometimes secrete excessive amounts of cytokines.  The ensuing immunological
hyper-responses to infection and inflammation can cause serious cellular and
tissue damage.  Fever, chills, increased cardiac and respiratory rates
(collectively: septicemia), decreased blood pressure (collectively: shock), decreased
appetite, loss of weight due to non-nutritive metabolic changes and even death
are among the negative consequences of excessive quantities of cytokines.

        Tumor necrosis factor (TNF) and interleukin 1 (IL1) are cytokines that
play important roles in AIDS-related septicemia and wasting syndrome.  Drug
treatments to avert septicemia, shock and wasting syndrome in people with AIDS
will be featured.

       ----------
       AIDS, Cytokines, and Septicemia

       The presence of bacteria in the blood, or bacteremia, can progress to
septicemia, a more serious condition that involves increased cardiac and
respiratory rates, and fluctuations in body temperature.  If unchecked, septicemia
can progress to septic shock, an even more life-threatening condition that adds
a dangerous drop in blood pressure to all of the symptoms of septicemia.  Septic
shock is frequently irreversible and potentially lethal.  

       What causes these exaggerated immunological responses to bacterial
infection?  Lipopolysaccharide (LPS), or endotoxin, is a cell wall component
unique to certain bacteria called gram-negative, and is the most potent stimulus
known to induce immune cells, particularly macrophages, to release TNF and IL1. 
Blood-borne infections by gram-negative bacteria almost inevitably lead to greatly
elevated levels of IL1 and TNF.  Opportunistic infections caused by gram-negative
bacteria such as  E. coli, Salmonella pneumoniae, Klebsiella and Pseudomonas in
people with AIDS always involve the risk of developing into septicemia and septic
shock.  Gram-positive bacteria, which lack LPS as a cell wall component, do not
trigger the release of significant amounts of  TNF and IL1.  Thus, although the
gram-positive bacteria Mycobacterium avium intracellulare (MAC), M. kansasii and
M. tuberculosis cause life-threatening infections in HIV positive individuals, the
complications of septicemia and septic shock are typically absent. 

        Among the general population of the United States, 70,000-80,000
hospitalized patients die of bacteremia and septicemia every year, rather than of
complications due to the condition that led to hospitalization.  In 1 study, 11% (38
of 336) of people with AIDS suffered 49 episodes of septicemia, 19 cases of which
were caused by gram-negative bacteria.  Four of 6 patients in another study
died of pneumonia and bacteremia.  In the same study, 6 episodes of gram-
negative bacteremia resulted in shock.  

       Advanced HIV infection appears to exacerbate cytokine release.  In 1 study,
TNF levels in blood serum were elevated in 9 people with AIDS, with secondary
infection and weight loss occurring in 5 individuals; TNF was not elevated in HIV
positive asymptomatic individuals. 

       TNF is named for its ability to destroy tumors by inducing hemorrhagic
necrosis (cell death).  However, in laboratory experiments, mice injected with high
concentrations of TNF developed lethal septic shock.  The adverse side effects
of high concentrations of TNF may outweigh its potential benefits as an anti-
cancer drug.

       ---------
       Treatment of Bacteremia and Septicemia

       Physicians often begin treatment of suspected cases of septicemia before
results of a patient's blood cultures return from the laboratory.  This type of
active though partially "blind" intervention, referred to as empiric treatment,
reduces the probability of infectious progression to septic shock.  The standard
antimicrobial chemotherapy against gram-negative bacterial infection, a
combination of a type of penicillin and gentamicin or other cephalosporins, is
usually effective.  However, the undesired side effects of certain drugs can
actually promote the onset of septic shock.  The anti-HIV drugs AZT and
gancyclovir reduce the production of blood cells, platelets and granulocytes, and
may increase the risk of severe bacterial infection.  (Note: granulocyte numbers
are always monitored by the complete blood count (CBC) when patients take AZT
or gancyclovir.  When absolute neutrophil counts falls below 500, AZT and/or
gancyclovir is discontinued or decreased in dosage, thereby avoiding the risk of
bacterial infection.)  Recent advances in understanding the biological basis of
septicemia have provided clinical insights into more effective treatment for this
condition.  Two newly discovered human proteins, IL1 receptor antagonist (IL1ra)
and bacterial permeability increasing protein (BPI), are thought to be part of a
natural feedback loop that mitigates uncontrolled immunological responses to
gram-negative bacterial infection and TNF.  Clinical trials are exploring the use
of these proteins for the prevention and reversal of septicemia and septic shock. 
Nontoxic, synthetic derivatives of a natural polypeptide antibiotic, polymyxin B,
have been shown to block LPS from its cellular binding sites, prolonging survival
of laboratory mice suffering from septic shock.  Human clinical trials of these
synthetic peptides may begin soon.

       Pentoxifylline (Trental):  Recent laboratory experiments have demonstrated
that this blood viscosity drug blocks LPS-induced TNF biosynthesis, and also
reduces induction of HIV replication caused by TNF.

       IL1 receptor antagonist:  Presently in Phase II clinical trials (Synergen,
Inc.), IL1 has been demonstrated to stabilize blood pressure in animal models of
septic shock. 

       Bacterial Permeability Increasing Protein (BPI):  Bacterial Permeability
Increasing Protein (BPI) is released from white blood cells (neutrophils) in
response to gram-negative bacterial infection and binds specifically to LPS.  In
this way, LPS is prevented from interacting with macrophages, and macrophages
are prevented from releasing TNF and IL1.  BPI will be entering clinical trials
soon (Incyte Corp. and Xoma Corp.).

       Monoclonal antibody therapy:  Antibody therapy may be useful for the
treatment of gram-positive as well as gram-negative septicemia.  Monoclonal
antibody therapy (Chiron/Bayer and Centocor) directed against TNF is in clinical
trials.  Recent tests of monoclonal antibody therapies directed against LPS were
not clinically effective  in humans, which may be due to the complexity of the
physiological response to bacteremia.  New tests are being conducted; if effective,
monoclonal antibody therapies are expected to be expensive.

       <Tables omitted from Online version>

       -------
       Cytokines in AIDS-Related Wasting Syndrome

       AIDS-related wasting syndrome is a complex disorder.  Decreased appetite
(anorexia), lack of nutrition in chronic disease (cachexia), gastrointestinal
malabsorption and diarrhea all contribute to wasting syndrome.  However, a
significant number of cases of progressive tissue wasting occur among individuals
with only modest gastrointestinal damage and without diarrhea.  These cases are
almost certainly caused by a combination of anorexia and cachexia.  

       IL1 and TNF cause significant reorganization of metabolic functions, which
are some of the most significant causes of progressive tissue wasting due to
cachexia and anorexia.  Both IL1 and TNF act directly on the hypothalamus in the
brain stem to cause anorexia.  Experimental animal studies provide dramatic
experimental evidence for the role of cytokines in cachexia and anorexia.  When
the human TNF gene is inserted into cancerous cells implanted into
immunodeficient mice, the implanted cells continuously secrete high levels of
human TNF.  Eighty-seven percent of the mice developing nonmetastatic tumors
suffered from wasting syndrome--primarily due to anorexia--and ultimately died
from progressive weight loss and cachexia.

       Most of the physiological effects of cytokines in reorganizing metabolism
are more subtle.  Cytokine-induced fever accelerates the body's metabolism by
14% for every 1 degree F increase in temperature.  TNF causes inefficient
utilization of lipids by reducing levels of enzymes needed for fat metabolism.  In
addition, people with AIDS usually experience elevated levels of protein
metabolism relative to fat metabolism, in order to provide sufficient levels of
glucose to meet the body's energy needs.  Carbohydrate stores are usually
limited.  And, since IL1 triggers the release of amino acids from muscle tissue,
significant decreases in lean body mass occur due to muscle and protein
breakdown.

       Levels of TNF are significantly higher in people with AIDS than in HIV
negative individuals, but the extent to which the HIV virus alone influences the
elevation of circulating levels of cytokines is unclear.  Researchers do not fully
understand how chronic elevated circulating levels of cytokines vs rapid
transient rises of these proteins (accompanying sepsis or opportunistic infections)
influence metabolic activity.  Physiological aberrations attributed to chronically
elevated levels of cytokines in people with AIDS, such as hypertriglyceridemia,
can occur for many months without significant tissue wasting or diminished lean
body mass.  Transient rises in IL1, TNF and other cell mediators above
chronically elevated levels, caused by sudden outbreaks of infection and sepsis,
probably trigger muscle wasting.  Moreover, laboratory experiments have
indicated that TNF stimulates HIV replication.

       Treatments for Anorexia and Cachexia:  Severe malnourishment can weaken
the entire immune system.  Symptoms include decreased T-helper and suppressor
cell numbers, killer T-cell activity and impaired function of white blood cells. 
The Taskforce on Nutritional Supports in AIDS has published dietary guidelines
for individuals to insure proper nourishment.

       Megestrol acetate (Megace):  Megestrol acetate is a synthetic, orally
administered progesterone used to treat breast cancer that has a side effect of
potential benefit: the promotion of significant weight gain.  Progesterone also
inhibits biosynthesis of the cytokine IL1, one of the mediators of anorexia.  In
a published study, 14 people with AIDS gained an average of 14 pounds over a
10-week period.  In more extensive Phase III placebo-controlled trials, 64% of the
people with AIDS taking 800 mg of megestrol acetate gained at least 5 pounds,
compared to 21% of placebo patients.  Nearly 23% of patients taking megestrol
gained 15 pounds, while none of the patients in the placebo group did.  Clinical
trials for megestrol acetate are ongoing in San Francisco.  The drug is available
by prescription.

       Dronabinol (Marinol):  An active component in marijuana used to reduce
nausea and vomiting caused by cancer chemotherapy, Dronabinol has received
FDA approval as an appetite stimulant.  Preliminary results indicate that low
doses of this drug (2.5 mg orally, twice a day) caused a median weight gain of
4.8 pounds in 6 of 8 patients after 4 weeks.

       Other less conventional clinical trials to test the effect of growth factors
to increase lean body mass are also in progress:

       Growth Hormone (GH):  GH promotes increased rates of protein synthesis
and muscle growth, increased use of fats as an energy source, and even
stimulates certain components of the immune system (increased T-cell cytolytic
and natural killer cell activity, and increased differentiation of white blood cells). 
GH is in Phase I clinical trials to prevent weight loss and tissue wasting.

       Human Insulin-like Growth Factor (IGF-1):  IGF-1 is being tested for its
value as a prophylaxis for AIDS- related cachexia.  IGF-1, whose cellular
synthesis and release is mediated by growth hormone, has many of the same
physiological effects as growth hormone.

       Treatments for chronic diarrhea and malabsorption are discussed in the
AmFAR AIDS/HIV Treatment Directory.

       ----------
       Selected Sources:

       Abrams D and others.  Wasting syndrome.  AmFAR AIDS/HIV Treatment
Directory  6(1): 85-86, 142-143.  September 30, 1992.

       Fazely F. Pentoxifylline (Trental) decreases the replication of the human
immunodeficiency virus type 1 in human peripheral blood mononuclear cells in
cultured T cells.  Blood 77(8): 1653-1656.  1991.

       Johnston J.  Molecular science sets its sights on septic shock.  Journal of
NIH Research 3: 61-65.  October 1991.

       Keutsch GT and others.  Nutritional aspects of AIDS.  Annual Review of
Nutrition 10: 475-501.  1990.

       Rustici A and others. Molecular mapping and detoxification of the lipid A
[LPS] binding site by synthetic peptides.  Science 259: 361-365.  1993.

       Tracey K and others.  The role of cachectin/tumor necrosis factor in AIDS. 
Cancer Cells 1: 62-63.  1989.

       Wenzel R.  Anti-endotoxin monoclonal antibodies--a second look. New
England Journal of Medicine  326: 1151-1152.  1992.

       Winick M.  Guidelines for nutrition support in AIDS.  Nutrition 5: 396-446. 
1989.

       Witt DJ and others.  Bacterial infections in adult patients with the acquired
immune deficiency syndrome (AIDS) and AIDS-related complex.  American Journal
of Medicine 82: 900-906.  1987.

       *********

       RESEARCH NOTES
       Ronald A. Baker, PhD

       Ronald Baker is editor of BETA and coauthor of Early Care for HIV Disease,
       a book for people living with HIV infection.

       ----------
       ddI vs AZT In Advanced HIV Disease

       The National Institute of Allergies and Infectious Diseases (NIAID)
announced on December 30, 1992 the long-awaited results of its trial (ACTG 116A)
comparing the effectiveness and toxicity of ddI at 2 different doses (500 and 750
mg/day) to standard treatment with AZT (600 mg/day).  The trial enrolled people
with AIDS, AIDS-related Complex (ARC) and asymptomatic HIV infection who had
no prior AZT use, or who had taken AZT for 16 weeks or less at the time of
study entry.

       The primary objective of the trial was to show whether ddI had similar
clinical effectiveness to AZT in people with little or no prior AZT use.  The
results show that ddI and AZT do not have similar efficacy.  The most important
finding of ACTG 116A is that the efficacy of ddI as compared to AZT is
significantly affected by the duration of prior AZT therapy, according to the
NIAID.  

       AZT appears to be the more effective drug among individuals with advanced
HIV disease who have never taken AZT, while ddI appears to be the more
effective drug among those who have used AZT for at least 8 weeks.  "Physicians
who care for HIV-infected patients with advanced disease should discuss these
new data with their patients to plan the best treatment for their individual
needs.  Further discussions in the scientific community will help us to
understand the implications of these results and their impact on patient care" 
(Anthony S. Fauci, MD, NIAID Director).

       The study was carried out at 33 sites of the AIDS Clinical Trials Group
(ACTG), 4 sites supported by Bristol-Myers Squibb Company and 1 regional center
funded by the National Hemophilia Foundation.  The ACTG is a nationwide network
of AIDS clinical research centers funded by the NIAID.  Burroughs Wellcome
Company provided AZT for the study, and Bristol-Myers Squibb Company
provided ddI.  Investigators enrolled people with AIDS or advanced ARC with
fewer than 300 T-helper cells and asymptomatic individuals with 200 or fewer T-
helper cells.  

       Participants were randomly assigned to take daily either 600 mg AZT, 500
mg ddI or 750 mg ddI.  Neither the investigators nor the study participants
knew which treatment an individual received.  The sachet (powdered buffer)
formulation was used for ddI.  (A 500 mg ddI dose in the sachet form is
equivalent to a 400 mg dose of ddI in tablet form.)  Study participants were
followed for a median of 85 weeks.

       Among 380 individuals in the study with no prior AZT use, 18% of those
taking AZT developed a new AIDS-defining condition or died within 1 year.  In
comparison, 31% of those on the 750 mg ddI dose and 29% of those on the 500 mg
ddI dose who had never taken AZT developed new AIDS-defining conditions or
died within one year.  Clearly, AZT was the more effective treatment for this
group.

       Among the 118 individuals with 8 to 16 weeks of prior AZT therapy, 33% of
those taking 600 mg/day AZT developed a new AIDS-defining condition or died
within 1 year, compared to only 11% of those taking 500 mg/day ddI and 17% of
those taking 750 mg/day ddI.  Clearly, ddI was the more effective treatment for
these individuals.

       The treatment comparisons between AZT and ddI were inconclusive among
the 119 patients with 8 or fewer weeks of previous AZT therapy.  No significant
differences between the effectiveness of the 2 doses of ddI were noted, but
people taking 750 mg/day ddI were more likely to develop pancreatitis within 1
year than those on the 500 mg/day ddI dose or those on AZT.  The rate of
development of peripheral neuropathy was not significantly different among those
taking either drug. 

       Study participants taking AZT were more likely than those taking ddI to
have lowered white blood cell counts (granulocytopenia).  Both those on AZT and
ddI had a low risk of developing severe anemia (a marked decrease in red blood
cells).

       DO THE STUDY RESULTS SHOW THAT ddI AND AZT HAVE SIMILAR
       EFFECTIVENESS?

       No.  The most important finding is that the effectiveness of ddI as
compared to AZT depends on the duration of previous AZT treatment.  AZT is
more effective than ddI among people who have not taken AZT previously.  In
contrast, ddI is more effective than AZT among those with more than 8 weeks of
AZT treatment.  It should be noted that people in this study may not have been
representative of all individuals with advanced HIV disease who have had no or
less than 16 weeks of AZT therapy.

       WHICH DRUG PROVIDED A GREATER SURVIVAL BENEFIT? 

       Among people with no prior AZT use, those taking AZT tended to survive
longer than those taking ddI.  Among individuals who had taken AZT for between
8-16 weeks before entering the trial, those taking ddI tended to survive longer
than those who continued taking AZT.

       WHAT HAPPENED TO THE T-HELPER CELL COUNTS OF PEOPLE IN THE
       TRIAL?

       Individuals taking AZT for the first time had significantly greater increases
in T-helper cells by week 8 when compared to those taking ddI.  By week 48,
however, the AZT group experienced the greatest decline in T-helper cells. 
(Because of the significant drop-out rate by week 48, these long-term trends
should be cautiously interpreted.)  Among people with prior AZT treatment,
researchers noted no significant differences in T-helper cell count increases or
declines between the 2 treatment groups.

       HOW DO THESE STUDY RESULTS AFFECT THE USE OF ddI AND AZT AS
       MONOTHERAPY BY PEOPLE WITH FEWER THAN 300 T-HELPER CELLS?

       These individuals should discuss the study results with their physician
before altering their current drug regimens.  After approximately a year each of
ddI and AZT monotherapy, combination therapy (taking both drugs concurrently)
may be the appropriate action.  Ongoing clinical trials are evaluating the
effectiveness of double and triple combination anti-HIV therapy.  Small studies
of ddI plus AZT and ddC plus AZT suggest a benefit from combination treatment.

       "The results of this trial are interesting but also potentially confusing. 
AZT was the more active drug only in those study participants who had never
taken it before.  After only 2 months of prior AZT treatment, ddI became more
effective in slowing disease progression.  What is not clear is how to use these
results in practice.  Should everyone be switched to ddI after a few months on
AZT, even if they appear to be tolerating AZT and benefitting from it?  We really
don't know."

       "What most will take away from these results is a sense that both drugs
work and a reassurance that 'secondary' treatment with ddI can add further
benefit in addition to that from AZT.  How this will change long-term treatment
strategies, and how it might compare to combination treatment remain unknown.

       Paul Volberding, MD,  Chief of the AIDS Program and Clinical Oncology
Division of San Francisco General Hospital.

       Reference

       Folkers G. Relative benefit of ddI and AZT depends on duration
       of patients' previous AZT use.  News from NIAID.  December 13,
       1992.

       ---------
       ddI vs ddC Following AZT Failure

       ddI and ddC monotherapy appear equally safe and effective
among individuals who fail or cannot tolerate AZT, according to
results of a community-based trial at 78 sites enrolling 467
participants.  ddC is currently FDA-approved only for use in
combination with AZT, while ddI is the only drug approved for
monotherapy in individuals who cannot take or do not respond to
treatment with AZT.  "These new findings suggest that single-drug
therapy with ddC has a role in the treatment of people with HIV
disease who are unable to tolerate AZT or in those whose disease
worsens while taking AZT." (Anthony Fauci, MD, Director of NIAID).

       Over two-thirds (156 of 230) of the individuals in the trial
taking ddI died or became sick.  Approximately the same percentage
in the ddC group (150 of 237) died or experienced a worsening of
their HIV disease.  "The trend in survival rate for patients taking
ddC was slightly better, but not statistically significant. 
Patients taking ddI had a small, transient rise in their CD4 [T-
helper count] early in the study, but this increase lasted only a
short time."  (Donald Abrams, MD, Chair of the Community Consortium
of San Francisco.)

       The pattern of side effects differed for each drug.  People
taking ddI reported more stomach pains, diarrhea and symptoms of
pancreatitis compared to the ddC group.  People taking ddC reported
painful mouth ulcers and more symptoms of peripheral neuropathy
(numbness, pain or burning in the feet or hands).

       Physicians and health care providers may call 1-800-TRIALS-A
for more information on study results and the trial results'
implications for clinical care.

       FDA APPROVES NEW DRUGS FOR PCP AND MAC

       Following the recommendation of its Antiviral Advisory
Committee, the FDA has approved both Mepron (atovaquone) and
Mycobutin (rifabutin) for marketing.  Mepron is now available by
prescription for the treatment of mild to moderate Pneumocystis
carinii pneumonia (PCP) in individuals who cannot tolerate the side
effects of the first-line treatment for the disease, trimethoprim
plus sulfamethoxazole (TMP-SMX = Bactrim, Septra).  Mepron has also
shown early promise as a treatment for toxoplasmosis.

       FDA approval of Mepron does not necessarily mean that the drug
should be used by all individuals who are intolerant to Bactrim. 
Many clinicians consider dapsone plus trimethoprim the preferred
second-line treatment for TMP-SMX intolerance.  The oral form of
clindamycin plus primaquine might also be preferred over Mepron in
treating people who fail or cannot tolerate TMP-SMX.

       ---------
       Mycobutin

       Mycobutin (rifabutin) is the first drug approved by FDA for
the prevention of Mycobacterium avium Complex (MAC), a life-
threatening infection developed by about 25-50% of all people with
advanced HIV disease.  Recent studies suggest that Mycobutin at 300
mg/day approximately halves the rate at which people with AIDS
develop MAC.  The drug also significantly delays the development of
MAC symptoms, even among people who become infected with the
organisms.  Unfortunately, Mycobutin does not appear to prolong
survival among people taking the drug.

       Although individuals with T-helper counts above 60 rarely
develop MAC, a T-helper count of approximately 100 may be a better
cut-off point for starting Mycobutin as preventive treatment for
the disease.  Some clinicians recommend prophylaxis with Mycobutin
for individuals with fewer than 200 T-helper cells who have had a
previous AIDS-defining illness (the risk for developing MAC in this
population is about 20% within 1 year).  Other clinicians do not
recommend initiating Mycobutin preventive treatment until an
individual has 50 or fewer T-helper cells; still other clinicians
do not use prophylaxis for MAC out of concern about the development
of drug resistance and drug interactions.  Given the relative
variance of T-helper cell counts, people with advanced HIV disease
should discuss with their physician the advantages and
disadvantages of beginning MAC prophylaxis when their T-helper
count is below 100.

       Some physicians recommend against MAC prophylaxis, regardless
of T-helper count.  Fifty to seventy-five percent of people with
AIDS never develop MAC, they argue, and the drug may produce
adverse side effects.  Early preventive treatment with Mycobutin
may also lead to the development of drug-resistant strains of the
MAC organisms, which may in turn make the disease more difficult to
manage.  The recent trials of Mycobutin that led to its approval
did not document any resistance, but physicians and patients should
consider this possibility before starting preventive treatment.

       There is a theoretical concern that Mycobutin may trigger
adverse interactions when used with drugs such as ketoconazole
(Nizoral), Methadone or AZT, but no data are available on this
subject.

       Wynne B and others.  The development of Mycobacterium avium
       complex bacteremia in AIDS patients in the placebo-controlled
       MAC prophylaxis studies (087023 and 087027).  1992
       Interscience Conference on Antimicrobial Agents and
       Chemotherapy.  Abstract #890.

       Chaisson R and others.  Managing Mycobacterium avium complex
       infection.  AIDS Clinical Care 5(1): 1-8.  January 1993.

       Kovacs JA and others.  Efficacy of atovaquone in the treatment
       of toxoplasmosis in patients with AIDS.  The Lancet 340(8820):
       637-638.  September 12, 1992.

       ----------
       Dapsone vs Aerosolized Pentamidine for PCP Prophylaxis

       A study of 96 individuals showed no difference in
effectiveness or toxicity between dapsone and aerosolized
pentamidine (AP) in preventing first-episode PCP.  Study
participants used either dapsone 100 mg 2 times a week or AP 300 mg
once a month.  The researchers recommend dapsone in preference to
AP as preventive treatment for PCP, because dapsone is
significantly cheaper and easier to take than AP.  Neither drug is
as effective as trimethoprim-sulfamethoxazole (TMP-SMX) for PCP
prophylaxis.  

       Slavin and others.  Oral dapsone versus nebulized pentamidine
for Pneumocystis carinii pneumonia prophylaxis: an open randomized
prospective trial to assess efficacy and hematological toxicity. 
AIDS 6(10): 1169-1174.  October 1992.


       WARNING ON PYRIMETHAMINE FOR TOXOPLASMOSIS PRIMARY PROPHYLAXIS

       Although pyrimethamine is FDA-approved for the treatment of
toxoplasmosis and, in combination with sulfadiazine, for secondary
prophylaxis (following treatment for acute disease), the drug has
not been approved as preventive treatment for first-episode
toxoplasmosis.  Nonetheless, many physicians use pyrimethamine for
primary prophylaxis, based on the drug's effectiveness as therapy
for acute disease.

       A recent clinical trial (stopped in March) showed a large
number of deaths among individuals taking pyrimethamine for primary
prophylaxis compared to those taking placebo.  After about 36 weeks
of follow-up, the death rate for pyrimethamine-treated individuals
was almost twice that of those taking placebo.  

       A French trial of 540 individuals and an AmFAR-sponsored
community-based trial are both evaluating 50 mg pyrimethamine
either 3 times weekly (the French trial) or once or 3 times weekly
(the AmFAR trial) as primary prophylaxis for toxoplasmosis.

       Pyrimethamine manufacturer Burroughs Wellcome advises against
using the drug for primary prophylaxis against toxoplasmosis until
ongoing clinical trials yield more information about the drug's
safety and effectiveness.  For more information, call 800-443-6763. 

       Toxoplasmosis Primary Prophylaxis Warning.  AIDS Clinical Care
       4(12): 104.  December 1992.

       FLUCONAZOLE (DIFLUCAN) SUPERIOR TO KETCONAZOLE (NIZORAL) FOR
       CANDIDA ESOPHAGITIS

       Candida esophagitis, an infection of the esophagus with the
yeast-like fungus candida albicans, occurs commonly in individuals
with advanced HIV disease, and is considered an AIDS-defining
illness.  Several drugs have been used in the treatment of this
disease.  A recent double-blinded trial comparing Diflucan (100
mg/day) and Nizoral (200 mg/day) shows that Diflucan is the
significantly superior agent for treatment of candida esophagitis.

       Endoscopic cure occurred in 91% of patients using Diflucan and
in 52% of those using Nizoral, a difference of 39%.  Esophageal
symptoms resolved in 85% of Diflucan-treated patients compared to
65% of Nizoral-treated individuals.  Adverse side effects--nausea,
diarrhea, rash--were minimal in both treatment groups.  The
researchers suggest that the superior effectiveness of Diflucan may
be due to its superior absorption by the gastric juices.

       Laine L and others.  Fluconazole compared with ketoconazole
       for the treatment of esophagitis in AIDS.  Annals of Internal
       Medicine 117(8): 655-660.  October 15, 1992. 

       ----------
       Roche Tat Inhibitor (Ro 24-7429)

       Tat is a gene of HIV with a protein whose production is
necessary for HIV to replicate.  In laboratory studies, the Tat
inhibitor created by scientists at Hoffmann-La Roche inhibits HIV
replication in both uninfected and HIV-infected cells. AIDS
treatment specialists and the treatment activist community are
closely following development of the Tat inhibitor because the drug
is widely regarded as a potential "breakthrough" treatment.

       A Phase I/II 12 week study of the drug's safety and activity
(ACTG 213) as monotherapy (varying doses) and in combination with
AZT has begun at 4 U.S. medical sites.  Researchers have enrolled
76 individuals with T-helper counts between 50-500 who have taken
no anti-HIV therapy for 28 days prior to study entry.

       The safety profile of the Tag drug remains unclear.  In early
human tests, adverse side effects were reportedly mild to moderate,
and included GI upset, headache and somnolence (drowsiness). 
However, Roche researchers recently reported that monkeys on high
doses of the drug have become anorexic.  They are also concerned
about data that shows the drug may accumulate to high levels in the
body when used for an extended period.  

       Two other studies conducted by Roche will evaluate Tat drug
activity and safety in people with advanced HIV disease (fewer than
200 T-helper cells) and in individuals with AIDS-related Kaposi's
Sarcoma.  These 2 studies are planned to begin in 1993, but no firm
dates for open enrollment are available.

       PASSIVE IMMUNOTHERAPY IN AIDS

       In a recent French trial of passive immunotherapy  in people
with AIDS, an adverse rebound effect occurred when the treatment
stopped: p24 antigen levels of the trial participants increased to
levels higher than before treatment, and the individuals
experienced a rapid clinical decline.

       In passive immunotherapy, blood plasma from healthy,
asymptomatic HIV-positive individuals with high titers of HIV-
neutralizing antibodies is transfused into people with AIDS.  Early
studies have shown promising results, with participants developing
fewer opportunistic infections and lower p24 antigen levels.  

       The French researchers conclude that although passive
immunotherapy is a promising treatment for AIDS, withdrawal of
therapy may be disastrous: "Virologic relapse may be extensive and
poorly tolerated."

       Vittecoq D and others. Passive immunotherapy in AIDS--a
       randomized trial of serial human immunodeficiency virus
       positive transfusions of plasma rich in p24 antibodies versus
       transfusions of seronegative plasma.  Journal of Infectious
       Diseases 165(2): 364-368.  February 1992.

       
       REVISION OF PASSIVE HYPERIMMUNE THERAPY (PHT) PHASE I/II DATA

       The HemaCare Corporation has reported an updated and revised
analysis of its Phase I/II clinical trial of Passive Hyperimmune
Therapy (PHT) for the treatment of AIDS.  The revisions resulted
from a retrieval of data missing from the original report on the
trial, according to a company news release.  "The revised data
verify the promising nature of the preliminary data, namely, that
PHT enhances inmunity through significant increases in T-helper
cell levels, and shows a strong trend toward increasing survival in
patients starting treatment with T-helper cell counts between 50-
200".  (Joshua Levy, MD, HemaCare Medical Director and principal
investigator of the PHT project).


       12-Month Clinical Trial Results for Patients Beginning
       Treatment with T-helper Cell Counts Between 50-200


               Full-strength                 Half-strength
               Hyperimmune                   Hyperimmune
               Plasma                        Plasma                Placebo                

 Mortality     5 percent                     14 percent            20 percent
               (one death)                   (3 deaths)            (6 deaths)
               n = 21                        n = 21                n = 30

 Changes in
 T4 cell
 levels        +33 percent                   -2 percent            -4 percent             
               n = 20                        n = 20                n = 28                 


       An abstract of the results outlined in the chart above has
been submitted to the IXth International Conference on AIDS in
Berlin (June 1993), and a complete analysis of the data from the
trial will be submitted to a scientific journal for peer review and
publication, according to the HemaCare news release.  HemaCare has
asked the California State Department of Public Health (Food and
Drug Branch) to approve the start of a Phase II trial of up to
1,000 individuals with HIV infection to evaluate dosing and long-
term effectiveness of PHT.

       FDA APPROVES WIDER ACCESS TO MARINOL

       The FDA has approved a supplemental new drug application   
(SNDA) for the drug Marinol (dronabinol) to treat AIDS-related
cachexia (wasting syndrome).  The FDA first approved the drug in
1985 for nausea and vomiting associated with cancer therapies. 
People with AIDS (PWA) who experience appetite and weight loss may
develop wasting syndrome that can cause severe disability and even
death.  Marinol is the only drug FDA-approved to treat cachexia in
PWA.

       Marinol is a synthetic form of tetrahydrocannabinol (THC), the
mayor active ingredient of marijuana.  Like codeine, use of this
drug is regulated under schedule II of the Controlled Substances
Act.

       Marinol will be available by prescription for PWA in 2.5 mg
capsule form.  The recommended daily dose is 2 capsules, one taken
before lunch and one before dinner.  The dose may be increased or
decreased, depending on individual tolerance.  If well-tolerated,
the dose may be gradually increased up to 10 mg twice daily.  Side
effects may include abnormal thinking, euphoria, dizziness, anxiety
and transient coordination difficulties.  Individuals using Marinol
should not drive, operate complex machinery or engage in activity
"requiring sound judgment and unimpaired coordination", according
to a spokesperson for Roxane Laboratories, distributor of Marinol.

       The clinical indications for Marinol therapy are not yet
firmly established.  Participants in the Marinol trials had both
weight and appetite losses, and low T-helper cell counts (averaging
in the 30s).  Many physicians are interested in initiating Marinol
therapy earlier, after a loss of appetite, but before any loss of
weight.  Earlier initiation of therapy would probably be more
effective for maintaining or improving quality of life.  However,
secondary causes of weight and appetite loss, such as the use of
certain medications, should be eliminated to ensure the
appropriateness of Marinol.

       A DATRI study currently underway is exploring the combination
of Marinol and Megace (megestrol acetate) for the treatment of
wasting syndrome.  Megace, a synthetic progesterone, promotes
weight gain.  Each drug affects a different mechanism, and their
actions are synergistic.  Thus far, the combination appears well-
tolerated.  Results of this study may be available by early summer.

       The wholesale price for a 30-day supply of Marinol (60
capsules) is $120.  The cost at pharmacies will likely be $150-
$180.  The company says it expects Marinol costs to be reimbursed
by third-party insurers and government programs, because the drug
is already reimbursed by Medicare, Medicaid and private insurers as
an anti-nausea medication for people receiving cancer treatment. 
In addition, Roxane Laboratories has established a patient
assistance program for indigent PWA who do not qualify for other
reimbursement programs.  To enroll patients, physicians or
pharmacists may call 800-274-8651.  For more clinical and medical
information about Marinol, call 800-327-4865.

       A NEW CLASS OF ANTI-HIV DRUGS?

       In laboratory testing, low concentrations of new compounds
called NABA and NABP destroy certain chemical components ("zinc
fingers") of HIV, preventing the virus from replicating and
entering new, uninfected cells, according to Dr. Ernest Kun, a San
Francisco State University researcher.  The new compounds appear to
be non-toxic to healthy, uninfected cells.

       Although some researchers urged caution in evaluating the
therapeutic potential of the new compounds in humans, other
scientists expressed an uncharacteristic optimism: "...These
results are pointing in new directions for antiviral therapy," said
UCSF AIDS researcher Dr. Jay Levy in an interview with the San
Francisco Chronicle.  Results of the laboratory research on NABA
and NABP appeared in the February 4 issue of the British medical
journal Nature.

       ********

       MULTIPLE PROPHYLAXIS FOR OPPORTUNISTIC INFECTIONS: A
       LONGITUDINAL OBSERVATIONAL STUDY
       Bernard Bihari, MD
       Aaron Bihari

       Bernard Bihari is a physician in New York City with a large
       HIV practice.  Dr. Bihari has served as the principal
       investigator of several clinical trials of HIV/AIDS therapies. 
       He is currently conducting a trial of hypericin as an anti-HIV
       agent.  The following article is drawn from a poster
       presentation by Dr. Bihari at the Harvard-Amsterdam AIDS
       Conference in July 1992 (PoB 3144).

       Many clinicians and investigators have noted that prophylaxis
against Pneumocystis carinii pneumonia (PCP) significantly
increases the average survival time after an AIDS diagnosis.  As a
result of the widespread practice of PCP prophylaxis, the incidence
of and death rate from other opportunistic infections (OI) has
increased.  Mycobacterium avium complex (MAC) and invasive
cytomegalovirus infections (CMV retinitis, gastritis and colitis)
are most prominent.  Although clinicians do not typically recommend
prophylaxis against OI other than PCP, there are scientific and/or
clinical grounds for considering the use of currently available,
licensed drugs for prophylaxis against the 4 other most common OI:
MAC, invasive CMV, toxoplasmosis and major fungal OI (cryptococcal
meningitis, esophogeal candidiasis). 

       MAC:

       Clinical trials of rifabutin (Mycobutin) for MAC prophylaxis
demonstrated that the drug had a significant protective effect
against the development of positive MAC blood cultures (Wynne, B. 
Personal communication).  Despite reservations about the clinical
efficacy of Rifabutin, the FDA recently approved the drug for
preventive treatment for MAC in individuals with advanced HIV
disease (fewer than 50 T-helper cells).  In a 1991 study at Johns
Hopkins Hospital, clarithromycin was the first single agent to show
significant efficacy in the treatment of disseminated MAC in
patients with AIDS (Chaisson, R.  Personal communication). 
Clarithromycin's efficacy as a treatment for disseminated MAC
suggests that it also might be effective as prophylaxis, although
single agent therapy for MAC may lead to the development of
resistant strains.  No clinical trials of clarithromycin as
prophylaxis for MAC have yet been carried out, but the rifabutin
trials suggest that prophylaxis is possible.    

       CMV:

       Invasive CMV is the most difficult OI to treat.  Both approved
agents, ganciclovir (Cytovene) and foscarnet (Foscavir), require
intravenous infusions 5 to 7 days a week and indwelling intravenous
catheters.  Partly because of the toxicities of the 2 drugs and the
infectious complications of the indwelling catheters, mean survival
is only 10 months after the initiation of ganciclovir treatment and
12 months with foscarnet.  Neither drug is yet widely available in
a less toxic oral form, but a Phase I-II trial of oral ganciclovir
for treatment of CMV retinitis in progress has promising
preliminary results.  Evidence from a placebo-controlled clinical
trial indicates that high-dose oral acyclovir (Zovirax) has some
efficacy in preventing CMV disease in renal transplant patients. 
In addition, an observational, non-randomized study, based on a
large, private practice of people with AIDS with less than 150 T-
helper cells, reported that only 5 of 220 patients taking 4,000
mg/day acyclovir developed CMV disease, while 9 of 14 who refused
treatment and 3 of 5 whose acyclovir doses were lowered to 2,000
mg/day developed invasive CMV disease.  A large study of CMV
prophylaxis comparing 3,200 mg/day acyclovir to placebo was
reported at the VIII International Conference on AIDS in Amsterdam,
in July 1992.  While no decrease in the incidence of invasive CMV
disease in those who took acyclovir was observed, a survival
benefit was.  A recent review of acyclovir research by Whitely and
Gann found that "acyclovir is not effective for the treatment of
CMV,"  although it "decreases the frequency of symptomatic [CMV]
disease after transplantation."  This finding may have some
applicability to people with HIV, since organ transplant patients
are immunocompromised due to the drugs given them to reduce
rejection of the new organ.  In the (Bihari) study reported herein,
patients took at least 4,000 mg/day acyclovir.

       Toxoplasmosis:

       Pyrimethamine 25 to 50 mg/day is the standard treatment
recommended for secondary prophylaxis for toxoplasmosis in people
with AIDS.   Similarly, long-term maintenance therapy with
fluconazole (Diflucan) after successful treatment of cryptococcal
meningitis is recommended for secondary prophylaxis.  However, a
recent, randomized, placebo-controlled trial of Pyrimethamine for
primary prophylaxis of toxoplasmosis showed an increased mortality
among those receiving the drug.  (The study was terminated.)

       One of the major clinical arguments against simultaneous
multiple OI prophylaxis rises from concern about the development of
drug resistance.  Drug resistance is common in bacteria, including
mycobacteria.  In the John Hopkins clarithromycin trials, a
significant number of patients developed relapsing signs, symptoms
and positive MAC blood cultures from 8-12 weeks after initiation of
treatment with clarithromycin as a single agent (Chaisson, R. 
Personal communication).  Although the development of drug
resistance is less likely in the absence of an active infection,
the biological behavior of MAC supports the wisdom of using a
second agent with significant anti-mycobacterial activity for
primary prophylaxis.  In a recent literature search by the author,
no reports were found of drug resistance to Toxoplasma gondii or
Pneumocystis carinii pneumonia.

       Fungal OI:

       The other common OI are caused by organisms that rarely, if
ever, develop drug resistance.  Three or 4 cases of acyclovir-
resistent herpes simplex 1 or 2 have been reported, all of which
responded to treatment with foscarnet.  The 5 documented cases of
candida resistance to fluconazole all responded to ketoconazole
and/or amphotericin B.  There have been no reports of ganciclovir-
resistant CMV in patients who have previously taken acyclovir.   

       Study Premises:

1.     In patients with low T-helper counts, simultaneous prophylaxis
       for 3 or more OI results in significantly fewer OI than in the
       absence of such prophylaxis.

2.     There are significantly fewer deaths among patients treated
       with multiple OI prophylaxis than among patients who do not
       not receive multiple prophylaxis.

3.     There are few adverse drug interactions among the multiple
       agents involved.

       Methods:

       Over the past 20 months, in a clinical practice that
concentrates on the management of HIV infection, 105 patients were
offered prophylaxis for 3 or more of the OI to which they were
susceptible (see Table I for criteria and agents used). 
Approximately 1/3 of the patients were seen only in consultation,
with primary care provided elsewhere; the other 2/3 received
primary care in the senior author's practice.  OI were identified
as early as possible.  Patients were identified as compliant if
they took the prophylactic agents exactly as prescribed.  Primary
care patients' compliance with the recommended regimen was
evaluated during regular medical visits.  Follow-up data on the
patients seen in consultation were collected by telephone.  

       Results:

       The charts of all patients seen in the practice during the
preceding 24 months were reviewed, and all patients for whom 3 or
more prophylactic agents were recommended were included in the
study.

       One hundred seven patients fit these criteria.  The mean time
patients were followed on these agents was 10.3 months, and the
mean baseline T-helper count was 79.  The age range was 12 to 63. 
Eleven were female.  Seventy-three of the 107 patients were
compliant, 32 were noncompliant with regard to 1 or more of the
prescribed drugs, and 2 were unavailable for follow-up information. 
Of the 73 compliant patients, 4 developed mild, subacute PCP,
treated on an office basis.  None required hospitalization for
treatment of PCP.  Fifteen of the 32 noncompliant patients
developed 17 opportunistic infections: 9 with invasive CMV, three
with MAC, 2 with PCP, 2 with cryptococcal meningitis and 1 with
toxoplasmosis.  This group had a total of 19 hospitalizations. 
Five of the 32 noncompliant patients died of OI.  The only death
among the 73 compliant patients was that of a patient who died of
an aggressive lymphoma.

       In addition, 7 patients developed OI for which they were not
being prophylaxed.  Two patients developed Tb for which they had
not been prophylaxed, 1 in each group.  Five cases of MAC occurred
in patients whose T-helper counts dropped from 75 to below 50
between visits.  Three such cases were in the compliant group and
2 in the noncompliant group.  The 3 cases in the compliant group
were not counted in the analysis, but the 2 cases in the
noncompliant group were.  The difference lies in the patients'
entrance T-helper counts and in the standard of care.  Because MAC
is not recommended until T-helper counts fall below 75, and because
the 3 patients in the compliant group had starting T-helper counts
> 75, they were not prescribed drugs for MAC prophylaxis.  They
were prescribed medication for prophylaxis of diseases other than
MAC, which they took.  Their subsequent development of MAC occurred
when their T-helper counts dropped rapidly below 75.  However, the
2 patients in the noncompliant group had starting T-helper counts
< 75, and had been prescribed drugs for MAC prophylaxis that they
did not take.  

       Patients who complied with the multiple prophylaxis regimen
had significantly fewer OI than patients who did not comply (see
Table 2).

       The mean baseline T-helper counts showed that those who were
compliant had higher initial counts than those in the non-compliant
group, but the difference was not statistically significant.  Six
of the 32 noncompliant patients were on AZT for more than 1 month,
as were 21 of the 73 compliant patients (statistically
insignificant).  Although the 2 groups did not differ with regard
to baseline T-helper counts or AZT treatment, 2 differences were
noted.  More of the noncompliant than of the compliant patients
expressed a strong orientation towards alternative medical
approaches to HIV management, and a reluctance to take "Western" or
"allopathic" drugs.  Acyclovir posed a problem for many in this
group, particularly before the 800 mg tablets became available in
the fall of 1991.  At that time the 4,000/mg daily dosage required
the ingestion of five 200/mg capsules 4 times a day.  In addition,
24 of the 32 noncompliant patients were seen in consultation,
receiving primary care elsewhere.  On follow-up visits, several of
these indicated considerable resistance to the regimen recommended
by their primary physicians.

       Single agent prophylaxis was identified as the cause of all
adverse drug reactions; drug interactions appeared to involve no
adversity.  There were 38 adverse reactions, mostly drug rashes
and/or drug fevers caused by Bactrim or Dapsone.  Several patients
experienced mild nausea from taking clarithromycin on an empty
stomach, which was relieved by taking it with food.  A number of
patients appeared to develop leukopenia secondary to Bactrim. 
Pyrimethamine, ciproflaxacin and ethambutol each produced a rash in
1 patient.  Eight patients complained of fatigue and/or neck
stiffness secondary to acyclovir while taking twenty 200 mg
capsules per day, which was resolved for all but 1 of these by
switching to five 800 mg tablets per day.

       Study Limitations:

       Several important limitations of this study should be noted. 
Patients were not randomly assigned to treatment versus a placebo. 
Randomization is important because research consistently finds that
studies which retrospectively follow patients obtain more positive
results than studies in which patients are randomly assigned to
treatment or placebo (Hassard, 1991 cites numerous examples).  For
this reason, retrospective observational studies, such as the
present one, cannot usually definitively prove whether a treatment
is effective.  In retrospective observational studies, one cannot
control for a variety of factors which may affect the results. 
Studies have also shown that compliant patients do better than non-
compliant patients, whether taking active drug or placebo.

       The results of the large European-Australian study (MoB 0056)
of acyclovir for CMV retinitis prophylaxis, which did not find a
prophylactic benefit of acyclovir, suggests either that our results
may be an artifact of our design, or that the former study
administered too low a dose of acyclovir to be effective, or that
its results are falsely negative.  It is also possible that the
compliant patients were more likely to seek out other types of
antiviral therapy and to seek early attention for symptoms of OI
than were the noncompliant patients.

       Conclusions:

       Multiple OI prophylaxis with currently available drugs is
feasible.  Within  the limitations of this observational study,
multiple OI prophylaxis appears to provide potential protection
against OI and death, with no serious drug interactions.

       Large, simple, controlled clinical trials to evaluate these
findings are essential in view of the apparently significant
decrease in incidence of OI and in mortality, and the increased
survival suggested by the results of this study.

       Greg Dubs, Ph.D., a statistical consultant, performed the
       statistical analysis of this study.

       Aaron Bihari, Dr. Bihari's son, served as a research
       assistant, extracting and coding data from patient files. 


       Selected Sources:

       Balfour H and others.  A randomized placebo-controlled trial
of oral acyclovir for the prevention of cytomegalovirus disease in
recipients of renal allografts.  New England Journal of Medicine
320: 1381.  1989.

       Fox R.  Fluconazole-resistent candida in AIDS.  Journal of
Infection 22: 201-204.  1991.

       Horowitz RI and others.  Treatment adherence and risk of death
after a myocardial infarction.  The Lancet 336: 542-545.  September
1, 1990.

       Kitcheu JS.  Candida albicans resistance in AIDS.  Journal of
Infection 22: 204-205. 1991.

       Metroka C and others.  Possible usefulness of high dose
acyclovir as prophylaxis for CMV.  V International Conference on
AIDS.  Stockholm, June 1989.  Abstract MDP126.

       Powderly W and others.  Fluconazole versus amphotericin B
(AMB) as maintenance therapy for prevention of relapse of AIDS-
associated cryptococcal meningitis.  Thirtieth Interscience
Conference on Antimicrobial Agents and Chemotherapy.  Atlanta,
1990.  Abstract 1162.  

       Remington JS and others.  "Toxoplasmosis" in Infectious
Diseases.  Gorbach SL and others.  WB Saunders, ed. Philadelphia. 
1328-1343.  1992.

       Whitely R and others.  Acyclovir: a decade later.  New England
Journal of Medicine 327(11): 782-789.  1992.

       Youle M. Dose acyclovir for the prevention of cytomegalovirus
(CMV) disease in late stage HIV disease.  VIII International
Conference on AIDS.  Amsterdam, July 1992.  MoB0056.

       ***********

       Epidemic of Mistrust: Hoffmann-La Roche and the Treatment
       Activist Community

       Ronald A. Baker, PhD

       Ronald Baker is editor of BETA.  He served for a year on the
       Hoffmann-La Roche Community Advisory Board.

       Members of the Treatment Action Group (TAG), ACT-UP and other
treatment activists staged protest demonstrations last month in New
York, San Francisco, Atlanta and other cities against the giant
Swiss pharmaceutical corporation Hoffmann-La Roche (Roche). 
Treatment activists accuse Roche of grossly mismanaging its AIDS
drugs program, and have called on the federal government to take
away from the company patent rights for the Tat inhibitor, a new
anti-HIV drug now in early human testing under Roche sponsorship. 
The activists have also threatened to organize a national boycott
of Roche products and services unless the company meets certain
demands, which include a call for the company to provide $100
million in seed money for an AIDS research consortium.  

       Hoffman-La Roche is a large, multi-national corporation that
produces vitamin supplements and markets pharmaceuticals such as
Bactrim (for PCP prophylaxis and treatment), Roferon-A (for AIDS-
associated KS) and Valium, Dalmane and Librium (anti-anxiety
agents).  Roche also owns rights to expensive medical diagnostic
equipment such as the new Polymerase Chain Reactions (PCR) test, a
breakthrough technology that can quickly and accurately detect
infectious diseases such as tuberculosis, hepatitis, HIV disease
and toxoplasmosis.  Roche also operates laboratories for blood
testing and other diagnostic procedures, and provides home health
care services.

       Roche is currently developing 3 experimental anti-HIV drugs:
(1) ddC (Hivid), approved by the FDA in combination with AZT for
people with advanced HIV disease who have failed AZT monotherapy; 
(2) the Tat inhibitor, now in Phase I/II testing at 4 U.S. medical
centers (ACTG 213);  and (3) the proteinase inhibitor, now in Phase
II study at 10 U.S. sites (ACTG 229), following a year of
pharmacokinetic and Phase I studies in England and Europe.

       Many treatment activists and others involved in AIDS treatment
research believe that the Roche Tat and proteinase drugs are
potential "breakthrough" treatments that could bring significant
clinical benefits to people living with HIV infection and AIDS. 
The HIV/AIDS community understandably wants these 2 drugs tested as
rapidly as possible.  If found reasonably safe and even moderately
effective, these agents should be made available quickly through
FDA "accelerated approval" programs.

       Roche argues that it is testing these experimental compounds
as quickly as possible, and that the delays in Tat development have
resulted from the complex composition of the compound and its
unique pharmacologic properties.  Before asking the FDA to rush the
Tat and proteinase compounds into expanded access programs, Roche
scientists say they must first discover whether these drugs are at
least reasonably safe for human use.  For the Tat inhibitor in
particular, toxicity may yet emerge as a major limitation of the
drug.  Roche announced in December 1992 that monkeys receiving high
doses of the Tat drug have developed symptoms of anorexia that may
be drug-related.  Roche scientists also cite data showing that the
Tat drug may accumulate to high and potentially harmful levels in
the body when used for extended periods.

       The current treatment activist campaign against Roche pits
dying AIDS patients against a large, wealthy and powerful
pharmaceutical company that continues to delay testing and the
release of data on its promising AIDS treatments, and that may be
price-gouging on the sale of PCR equipment for which it owns
exclusive rights.  A brief summary of treatment activist demands of
Roche includes the following: 

ON THE TAT DRUG: submit a plan within 30 days to fully evaluate the
drug's safety and effectiveness; provide the drug immediately to
government researchers.

ON THE PROTEINASE DRUG: release the data from completed proteinase
inhibitor studies in England and Europe.

ON DDC: make good on its promise to conduct post-marketing studies
of the drug.  (The FDA approved marketing of ddC in 1992 on the
condition that Roche continue to test the drug's effectiveness.)
ON THE PCR TEST: cut the price of the PCR test by 50%.  This new
technology is revolutionary, and will become increasingly important
in detecting infections and in guiding the course of treatment for
many diseases.

ON WOMEN AND PEOPLE OF COLOR IN ROCHE CLINICAL STUDIES: finance
programs that recruit women and people of color into Roche studies.

ON COMMUNITY SUPPORT: contribute $1 million dollars a year to
support community-based AIDS treatment education.  As a company
that profits from the sale of drugs and services to the AIDS
community, Roche financial support for educating people in that
community about treatment options seems appropriate.

ON FUNDING AIDS RESEARCH: contribute $25 million to complete an
ongoing government study of ddC (ACTG 155).  This trial is
comparing ddC alone to AZT alone to AZT/ddC combination therapy;
provide $100 million to an AIDS research consortium of
pharmaceutical companies that would finance basic research on AIDS
and encourage cooperative ventures between companies.

       To allow both sides in the Roche/activist conflict to speak
for themselves, BETA reprints here 2 letters.  The first is from
TAG/ACT-UP New York to Roche executives, and outlines their major
concerns about Roche.  The second letter is from Roche to the
members of its Community Advisory Board (CAB), which met 3 times
with Roche representatives over a 12-month period in 1992 to
provide community input into Roche development, testing and
marketing of its AIDS drugs.  The Roche letter addresses issues
under dispute between the company and the Community Advisory Board,
and provides the Roche perspective on past and future protest
demonstrations.

       --------
January 26, 1993

To:    Patrick J. Zenner, Harold F. Boardman, Fritz Garbjr of
       Hoffmann-La Roche

From:  Treatment Action Group and ACT-UP New York

       At the time that your Company was seeking FDA approval to
market ddC in the United States, you began to meet with the HIV-
infected community to gain community support for the ddC
application.  At the time, your company made many public promises,
basically to correct the abhorrent way in which you developed ddC. 
In addition, a Community Advisory Board (CAB) was established, with
much fanfare, to maintain community input.

       Since ddC's approval, Hoffmann-La Roche has gone back on each
and every one of its commitments.  The CAB has been nothing but a
cruel hoax.  After repeated efforts to maintain communication, on
Saturday, January 16, 1993 in New York City, the entire Community
Advisory Board suspended relations.  A copy of their statement is
enclosed.

       There can be no more polite dialogue with your company.  While
you profit and intend to continue to profit from AIDS by selling
drugs and providing laboratory work and home health care services
to the HIV-infected community, you show no responsibility to that
community.  This can no longer be allowed to continue.  The
community has begun to express its outrage--after the resignation
of the CAB, members of the community directly confronted your
scientists and public relations people in New York.

       Among the most glaring and reprehensible acts of Hoffmann-La
Roche is the cruelly inept development of your TAT antagonist
compound.  You are the only company that has a TAT antagonist,
which is a unique compound that, in vitro, stops viral replication
in chronically infected cells.  You identified this compound years
ago.  You told us this compound is easy to manufacture and produce. 
Approximately $2.8 million in U.S. taxpayer monies has been spent
on developing this compound.  Drs. Fauci and Lane of the National
Institutes of Health and others for years have begged you to
provide them with the compound so that they, at the National
Institutes of Health and at no expense to you, could rapidly test
this drug.  Despite all this, and after so many years, this drug
has barely been tested and no answers are available.

       Scientists involved in the testing of your TAT drug at Johns
Hopkins have publicly stated:  There is no scientific reason that
Hoffmann-La Roche's TAT compound has not been more rapidly tested.

       We believe that your behavior in regard to the development of
ddC (for which you still have not yet announced the required post-
marketing efficacy trials that were promised as part of your FDA
approval) and the ongoing development of AIDS drugs like TAT and
protease compounds is criminal.  The development of AIDS drugs like
TAT is a major international health issue, and we intend to make it
a major priority of the [new] administration [in Washington, DC]. 
When a drug company has identified a compound that may be crucial
to a life-threatening illness and that company refuses repeatedly
to act responsibly in the development of the compound, the
government has a right to take over the development of that drug. 
As you know, we have been influential in obtaining many of the
recent health care reforms in the United States.  By this letter,
we also intend to begin urging officials of the United States
Government to commence whatever actions are necessary to assure
immediate and responsible development of your TAT compound.

       Because of all that Hoffmann-La Roche has not done for people
living with HIV, if these demands are not met we intend to ask all
those with HIV, and all doctors treating people with HIV, to stop
using Roche laboratories for blood and other tests and to stop
using Roche home care services.

       -----------

To:    Community Advisory Board
From:  Gail Levinson, Manager, Public Policy and Communications,
       Hoffman-La Roche

       Let me begin by indicating that we support and had hoped to
implement the majority of the points of concern to you.  The
particular items listed are, for the most part, appropriate and
necessary if the board is to function as a meaningful advisory
body.  I will review our position on each of these issues, but will
caution you that we are unwilling to continue the Community
Advisory Board (CAB) if aggressive and hostile actions against
Roche cannot be prevented.

       As you know, the 1/16/93 meeting of the CAB was fiercely
interrupted by a group of members from ACT-UP and TAG (whose
membership is represented on the CAB).  These individuals proceeded
to pour red paint, shout obscenities, turn over tables, chairs and
generally trash the room.  Quite frankly, the action had a chilling
effect upon all Roche employees present and places us in a
difficult position of having to attend all future CAB meetings with
security present.  If we as a group are unable to meet together
without the threat of violence, then there is little opportunity to
develop the kind of trusting relationship we both so strongly
desire.  The pending demonstration against Roche, which we also
anticipate, will serve only to further distance us and increase
everyone's frustration level.  Although you have asked us to do so,
we cannot separate these hostile actions from the activities of the
CAB.

       The decision to suspend activities with Roche until all issues
are resolved is unproductive and unreasonable.  While our goals are
the same, it is inevitable that we will have points of departure
requiring continued discussion and negotiation.  Yes, we want your
input and guidance on issues of drug development and planning.  How
can our meetings continue productively, however, under the
continued threat of walk-out by community members if and when Roche
makes decisions that you do not approve of?  How can we trust each
other when the public media is brought in to scrutinize our
differences of opinion?

       I review all this with dismay, for we had hoped that the board
would be in another, more positive, place at this juncture.  The
reason for our disappointment is that, as stated below, we support
the majority of your requests, and believe that, in time, the
remaining issues may be resolved:

       1.  We agree with and would seek to implement the measures
proposed in your 12/21/92 letter including a roster of all HIV-
related studies mailed out on a monthly basis accompanied by copies
of any new or updated concept sheets and protocols, including                                    
interim analyses for both U.S. and international studies.  We
expect this information to remain confidential and not be released
or discussed outside the CAB.

       2.  We would provide a projection of planned studies; however,
time extensions will vary depending upon the compound and the
comprehensiveness of the plans.

       3.  CAB participation in access-to-treatment issues, including
expanded access programs, requires further explanation on your
part.  What type of participation would the CAB wish                              to have on
issues of expanded access?  Roche continues to support the concept
of expanded access and welcomes the CAB's recommendations in this
area.

       4.  The portion of your letter which addresses community
representation is an area we support.  A reorganization of the
board to reflect the demographics of the disease as well as a cross
section of the AIDS community across geographical areas is most
appropriate.  The assistance of Iris Long, Sandra Palleja and
Vctor Rivera would be most helpful.  The inclusion of a pediatric
and an adolescent advocate as well as a HIV-positive woman and IVDU
is acceptable, as long as these individuals are knowledgeable about
the issues and are preferably connected to a wider local
constituency.  We also support a goal of 50% people of color on the
board as long as the size of the CAB membership remains workable.

       5.  Identifying one person per protocol team is something we
offered to implement.  Who these CAB individuals would be, the
details of the involvement, etc. would have to be worked out.

       6.  Participation in FDA meetings is perhaps the most
sensitive issue for us.  At present, we cannot agree to this
request given proprietary and confidential issues that are
discussed at such meetings.  Continued discussion and negotiation
on this topic would be necessary.  Our belief is that if the CAB
can begin to progress more smoothly, with volunteers on protocol
teams, etc., such participation may evolve on a case-by-case basis.

       We support the issues raised in your letter, but cannot at
this time agree to the continuation of the CAB.  We need assurance,
as do you, that we can engage in  mutual dialogue without the
threat of violence.  We all need to evaluate whether the current
CAB is the most appropriate vehicle for communication at this time. 
Given the fragile nature of our relationship at present, we do not
want to resurrect a forum that will not prove worthwhile or safe. 
I sincerely hope that you will consider our concerns and contact us
after you have had your conference call with the remaining members.

       ********

       OPEN CLINICAL TRIALS FOR HIV/AIDS TREATMENTS
       
       For location of the clinical trials described here, and for
       inclusion and exclusion criteria, call the AIDS Clinical
       Trials Information Service at 1-800-874-2572.

       AZT Use in Early Primary HIV Infection

       The goal of this study (DATRI 002) is to determine if AZT can
delay progression to AIDS if taken within the first 2-12 weeks of
infection with HIV.  Eighty participants will be enrolled.

       Therapy with "Killer T-cells"

       This study (DATRI 006) will evaluate the safety and
feasibility of infusing HIV-positive individuals with "killer T-
cells" (cytotoxic T-cells) drawn from their own blood, selected for
their ability to kill HIV-infected cells, and cultured in the
laboratory.  Only 24 individuals will be enrolled  in the study,
which is expected to take 2 years to complete.

       Roche Proteinase Inhibitor (Ro 31-8959)

       This Phase I/II study (ACTG 229) will determine the safety and
effectiveness of the anti-HIV drug Ro 31-8959, a proteinase
inhibitor manufactured by Hofmann-La Roche.  One primary objective
of this 24-week study is to determine the reduction in HIV "viral
load" as measured by quantitative blood cultures and by PCR
testing.  This new drug has shown early promise in laboratory tests
and early human testing in Europe, and is widely regarded as one of
the few anti-HIV drugs currently under study with the potential to
become a "breakthrough" AIDS therapy.  

       ACTG 229 will enroll 300 individuals at 10 sites in 3 study
groups with 100 participants each to evaluate the following
regimens: (1) Ro 31-8959 plus AZT vs (2) AZT plus ddC vs (3) Ro 31-
8959 plus ddC plus AZT.              

       gp160 Treatment Vaccine

       gp160 is a "therapeutic" HIV vaccine that consists of
genetically-engineered (recombinant) glycoprotein (gp) 160, a
protein component on the envelope of HIV.  It is hoped that
injection of this vaccine into HIV-positive individuals will
enhance the host individual's immune response and possibly slow HIV
disease progression.  

       gp120 Treatment Vaccine

       gp120 is also a "therapeutic" HIV vaccine, produced from
glycoprotein(gp) 120, another protein component of the HIV
envelope.  Researchers hope that administration of the vaccine will
slow disease progression in people who are HIV-positive.  

       Large Simple Trial of Anti-HIV Therapy 

       This unique trial (COMPACT 1) will evaluate at what stage of
infection HIV-positive individuals should begin taking anti-HIV
drugs to produce the greatest survival benefit: as early as
possible following initial infection with HIV? At 500 T-helper
cells?  At the onset of symptoms?  For more information on this
unique trial, see the article by Tom Mitchell in this issue of
BETA.

       SP-303

       This Phase I/II trial at San Francisco General Hospital will
evaluate SP-303, a topical ointment for the treatment of acyclovir-
resistant herpes simplex infection.  SP-303 is a natural plant
product synthesized by Shaman Pharmaceuticals.  Call Julie Cala, RN
at 415-476-9296.

       BW-256U87 for Cytomegalovirus (CMV) Disease

       The experimental oral medication BW-256U87 converts in the
body to higher levels of the drug acyclovir than is possible with
oral acyclovir (Zovirax) itself.  A clinical trial (ACTG 204) with
a target enrollment of 700 will evaluate whether oral BW-256U87 can
prevent cytomegalovirus (CMV) disease in people with AIDS.

       Clarithromycin versus Placebo

       Clarithromycin has shown promising results as a treatment for
Mycobacterium avium complex (MAC).  This new study at San Francisco
General Hospital will enroll individuals with fewer than 100 T-
helper cells and a negative blood culture for MAC.  Call Drew
Catapano at 415-353-6215.

       Pentoxifylline (Trental) To Reduce Tumor Necrosis Factor (TNF)

       High levels of TNF in HIV positive individuals may increase
HIV replication and cause weight loss, fevers and anemia.  Early
human studies show that Trental reduces TNF levels, increases
appetite and promotes weight gain.  Trental is FDA-approved for
other uses, and is therefore readily available by prescription. 
Many HIV-positive individuals are now using 1,200 mg/day Trental in
addition to taking other anti-HIV drugs.

       The Community Research Initiative on AIDS (CRIA), New York
City's community physician research group, wants to determine in a
16-week pilot study if Trental is safe and effective for use as a
treatment for HIV infection.  Study participants will be randomized
to receive either Trental (600 mg twice a day) or placebo.  To
enroll, call the New York CRIA at 212-924-3934.

       Cimetidine (Tagamet)

       This study will evaluate whether Tagamet (600 mg twice daily
for 12 weeks) can significantly increase T-helper cell counts in
HIV-positive individuals with baseline T-helper counts between 200-
400.  Call the New York CRIA at 212-924-3934.

       *********

       GLOSSARY

       ACYCLOVIR: (trade name: ZOVIRAX) an antiviral drug used in the
treatment of herpes simplex virus 1 (HSV-1, fever blisters, cold
sores), herpes simplex virus 2 (HSV-2, genital herpes) and herpes
zoster (shingles).


       ADJUVANT: a drug or substance that enhances the effectiveness
of another drug or substance.
       
       AEROSOLIZED PENTAMIDINE: a drug often used as a preventive
treatment for Pneumocystis carinii pneumonia.  It is administered
as a fine spray and inhaled.
       
       ALLOPATHIC: refers to a therapeutic system in which an illness
is treated by producing a second condition antagonistic to or
incompatible with the first.
       
       ALUM: abbreviation for aluminum, used as a component in
vaccinations and other practices in dermatology.  Odorless,
colorless substance, soluble in water; used as a topical anti-
infective applied to the skin at the infection site.
       
       AMINO ACID: one of the 20 basic structural units of proteins,
the unique sequences of which are specified by genes.
       
       AMNIOTIC FLUID: fluid contained within the amnion, or
innermost membrane of the uterus, that envelopes the fetus during
pregnancy.
       
       AMPHOTERICIN B: an antifungal drug approved for treatment of
progressive, disseminated fungal infections.  Toxicities include
fever, chills, nausea, kidney toxicity and neutropenia.
       
       AMYLASE: a human enzyme (protein); an abnormal increase in
amylase levels may indicate inflammation of the pancreas
(pancreatitis), a potentially life-threatening condition, or
inflammation of the salivary glands.
       
       ANEMIA: a condition marked by an abnormally low number of red
blood cells. 
       
       ANERGY: an abnormal lack of response in the skin to the
injection of a certain foreign substance.  This may indicate the
inability of the immune system to mount a normal allergic response.
       
       ANIMAL MODEL:  new drugs are always tested in animals before
being tested in humans.  Results of animal testing are often
reported as the findings in an "animal model."
       
       ANOREXIA: the lack or loss of appetite for food.
       
       ANTAGONIST: a drug that prevents or reverses the action of
another drug.
       
       ANTI-IDIOTYPIC NETWORK: Jerne's theory of immunoregulation by
antibodies to other antibodies (idiotype-anti-idioptype reactions
involving T-cell receptors and antibodies).
       
       ANTIBODY: a protein substance, developed in response to an
antigen, that destroys or neutralizes bacteria, viruses, fungi,
parasites or other harmful toxins.  This antigen/antibody reaction
forms the basis of immunity.
       
       ANTIGEN: a substance that stimulates an immune response. The
immune system recognizes these substances as foreign, and produces
antibodies to "fight" them.  This antigen/antibody response is an
important part of immunity.
       
       ANTIMICROBIAL: agent that destroys or prevents the growth of
microorganisms such as bacteria, fungi or parasites.
       
       APICES: singular, apex.  Here, the rounded, upper extremity of
the lung; in general, the extremity of any conical or pyramidal
structure, e.g. the apex of the heart.
       
       ASPERGILLOSIS: a fungal infection of the lung which can spread
through the blood to other organs.  Symptoms include fever, chills,
difficulty breathing, and coughing up blood.  If the infection
reaches the brain, it may cause cognitive (dementia) or other
neurologic problems.
       
       ATTENUATED: reduced severity, weakened.  An attenuated virus
is a weakened virus whose ability to infect or produce disease is
potentially reduced.
       
       AUTOIMMUNITY: when one's own immune system fails to recognize
its own biochemical signifiers and characteristics, and approaches
and attacks them as foreign matter.
       
       AZT (RETROVIR): azidothymidine; also called zidovudine.  A
thymidine (genetic building block) or nucleoside analog that
suppresses replication of HIV.  It is the only drug FDA-approved
for the initial treatment of HIV infection.  Adverse side effects
may include anemia, leukopenia, muscle fatigue, muscle wasting,
nausea and headaches.
       
       B-CELL: an immune system cell type; B-cells fight infection
primarily by making antibodies.
       
       BACK-MUTATION: restoration of a mutant gene to the wild-type
condition; reversion.
       
       BACTERIAL PERMEABILITY INCREASING PROTEIN (BPI): a neutrophil-
derived protein that binds to liposaccharide.  Its name refers to
BPI's ability in vitro to make bacterial cell walls more permeable.
       
       BACTEREMIA: the abnormal presence of bacteria in the blood.
       
       BACTRIM: one of the brand names for trimethoprim-
sulfamethoxazole (TMP-SMX), a drug used in the treatment of PCP and
other infections.  Septra and cotrimazole are other brand names for
this drug.
       
       BACULOVIRUS: belonging to a family of viruses that multiply
only in invertebrates.
       
       BETA-2 MICROGLOBULIN: a protein found in the blood.  Higher
than normal amounts of this protein in the blood indicate
replication of HIV and progression of HIV disease.
       
       BOOSTER SHOT: a dose given some time after the initial
administration of a drug or agent, to enhance the antigenic effect.
       
       CACHEXIA: general ill-health and malnutrition.
       
       CANDIDA: refers to candida albicans, a yeast-like fungus. 
       
       CANDIDIASIS: a fungal infection of the skin, nails, or mucous
membranes throughout the body, including the throat, vagina,
intestines and lungs.  Candidiasis is caused by a yeast-like
fungus, Candida albicans.  Oral candidiasis (thrush) is often the
first sign of an impaired immune system.
       
       CATHETER: a tubular instrument that allows fluid to pass from
or into a body cavity, e.g. one designed to pass through the
urethra into the bladder to drain it of retained urine; also, a
semi-permanently installed venous line used to inject fluids into
the body.
       
       CBC (Complete Blood Count):  a screening of the most important
components in the blood.  These include the total white blood
count, the breakdown and counting of white blood cells, the red 
blood count, platelet count and hemoglobin levels.
       
       CD4 CELLS: a subset of white blood cells (see: T-helper or T4
cell) that helps the body fight off certain infections.  HIV
invades these cells and weakens or destroys them.
       
       CD8 CELLS: see suppressor cell.
       
       CELL-MEDIATED IMMUNE RESPONSE: a defensive response produced
by the T-cells, monocytes and macrophages (white blood cells) of
the immune system.
       
       CESAREAN SECTION: procedure wherein incisions are made through
the abdominal and uterine walls, and the fetus extracted from the
uterus.
       
       CHEMOTHERAPY: the use of chemical agents in the treatment of
a disease.
       
       CIPROFLAXACIN (Cipro): an oral antibiotic approved for the
treatment of common bacterial infections.  Under study for the
treatment of MAC in combination with other drugs.  Side effects may
include GI distress, seizures and rash.
       
       CLARITHROMYCIN (BIAXIN): a macrolide family antibiotic
approved in oral form for the treatment of common bacterial
infections in non-immunocompromised patients.  Under study for the
treatment of MAC, alone and in combination with other drugs; also
under study for the treatment of toxoplasmosis.  High doses may
cause abdominal pain.
       
       CLINDAMYCIN: an antibiotic sometimes used in the treatment of
toxoplasmosis and PCP, often in combination with primaquine.
       
       COLITIS: inflammation of the colon. 
       
       COMBINATION THERAPY: the use of 2 or more therapies
administered alternately or simultaneously, in order to achieve
maximum results.
       
       CONJUGATE: joined or paired; in the construction of vaccines,
denotes a carrier molecule attached to an immunogen. 
       
       CONSERVED: not variable over time, or from organism to
organism.
       
       CONTROL GROUP: a group within a scientific experiment, such as
a clinical trial, used to verify the experiment by the omission or
change of a crucial variable, providing a basis for comparing it
with other groups.
       
       CROSS-IMMUNITY: when immunity to one organism serves to
protect the body against a different but related organism; e.g.
immunity to cow pox provides partial immunity against small pox.
       
       CULTURE: the growth of microorganisms or living tissue in the
laboratory, in solutions that promote their growth.
       
       CRYPTOCOCCAL MENINGITIS (CM): a fungal infection of the layers
(membranes) surrounding the brain and spinal cord.  Symptoms may
include headache, confusion, blurred vision, fever and speech
difficulties.  Left untreated, CM can lead to coma and death.
       
       CYTOKINES: proteins produced by white blood cells that act as
chemical messengers between cells.
       
       CYTOLYTIC: having a destructive effect on cells, causing them
to erupt or break open.
       
       CYTOMEGALOVIRUS (CMV): a virus in the herpes family.  CMV
infection can occur without causing symptoms.  In people with
advanced HIV disease, CMV may reactivate to cause blindness,
pneumonia, colitis, nerve inflammation and/or death.
       
       CYTOTOXICITY: the quality of being capable of producing a
specific toxic action against cells.
       
       DAPSONE: the brand name for an antibiotic (4-4'
diaminodiphenylsulfone) drug used in the treatment and prophylaxis
of PCP and other diseases.
       
       DATRI: acronym for Division of AIDS Treatment Research
Initiative of the NIAID.
       
       ddC (dideoxycytodine, trade name HIVID): a nucleoside analog
drug that inhibits replication of HIV.  Adverse side effects may
include peripheral neuropathy, pancreatitis (rare) and oral ulcers. 
FDA-approved for the treatment of HIV, when used in combination
with AZT.
       
       ddI (dideoxyinosine, trade name VIDEX): a nucleoside analog
drug which inhibits replication of HIV.  Side effects may include
pancreatitis and peripheral neuropathy.  FDA-approved for
individuals intolerant to or failing on AZT, and for people who
have taken AZT for 16 weeks or more.
       
       DELAYED-TYPE HYPERSENSITIVITY: cell-mediated immune response
that produces a cellular infiltrate and edema (swelling), redness
and induration (hardness) between 48 and 72 hours after exposure to
an antigen.
       
       DEPOT FORM (OF DRUG ADMINISTRATION): injecting a drug into the
body in a way that causes the drug to be slowly absorbed into the
bloodstream, e.g., into the muscle, or into the shallow layers of
the skin, to create a sustained action.
       
       DETERMINANT: chemical structure on an antigen that determines
antigenic specificity.
       
       DNA: deoxyribonucleic acid.  A complex chemical chain, DNA is
the genetic material of all living organisms, found in the cell's
nucleus. 
       
       DOUBLE-BLINDED STUDY: a method of medical investigation in
which neither the subject nor the investigator knows what
treatment, if any, the subject is receiving.  At the end of the
experiment, the "code" is broken and data are analyzed with respect
to the various treatments used.  This method attempts to eliminate
observer and subject bias.
       
       DRONABINOL: active ingredient in marijuana used to reduce
nausea and vomiting caused by chemotherapy in cancer patients and
for use as an appetite stimulant in people with HIV-related wasting
syndrome.
       
       DYSPLASIA: abnormal development or growth of tissue.
       
       ENDOGENOUS: originating within the organism, or body.
       
       ENDOTOXIN: a toxin that is present within certain bacterial
cells.
       
       ENV GENE: a retrovirus gene encoding envelope spike proteins
and glycoprotein.
       
       ENVELOPE: a covering.  The HIV envelope consists of 2 units
called gp120 and gp41; gp120 is the part of HIV that attaches
itself to the surface protein (CD4) of T-helper cells.
       
       EPIDEMIOLOGY: study of the frequency, distribution and
behavior of a disease in a defined population.
       
       EPSTEIN-BARR VIRUS (EBV): a herpes-type virus that causes
infectious mononucleosis and hairy leukoplakia.  EBV has also been
associated with Burkitt's lymphoma, a cancer of the lymph nodes.
       
       ESOPHAGEAL: relating to the esophagus (swallowing tube), the
portion of the digestive canal between the throat (pharynx) and the
stomach.
       
       ESTROGEN: "female sex hormone;" any natural or synthetic
substance that exerts biological effects characteristic of hormones
such as estradiol, a hormone formed by the ovaries, placenta and
testes.  Stimulates secondary sexual characteristics.
       
       ETHAMBUTOL (MYAMBUTOL): an oral drug used in combination with
other agents to treat tuberculosis; under study, in combination
with other drugs, as a  treatment for MAC; side effects may include
decreased or distorted vision.
       
       FDA ANTIVIRAL ADVISORY COMMITTEE: a group of medical experts
who make recommendations to the FDA regarding the approval (or
rejection) of antiviral drugs for marketing.
       
       FIRST-LINE TREATMENT: the preferred therapy for a particular
condition (e.g. trimethoprim-sulfamethoxazole is the first-line
treatment for PCP).
       
       FLUCONAZOLE (DIFLUCAN): an oral antifungal drug approved for
treatment of cryptococcal meningitis and esophageal candidiasis. 
Side effects may include nausea, rash, abdominal pain and headache.
       
       FOSCARNET (FOSCAVIR): an antiviral drug FDA-approved for the
treatment of acyclovir-resistant herpes virus infections and CMV
disease, usually with co-existent HIV infection; adverse side
effects may include kidney toxicity, muscle twitching, nausea and
genital ulcers.
       
       FUNGAL: refers to a class of microbes that includes yeast,
molds and mushrooms.
       
       G6PD: Glucose-6-phosphate dehydrogenase, a human, red blood
cell enzyme that, if deficient, may cause severe anemia; use of
certain antibiotics may promote this.  The enzyme deficiency tends
to be most common in men of Mediterranean, African or Asian
ancestry.
       
       GAG GENE: a retrovirus gene encoding core and capsid proteins.
       
       GANCICLOVIR (CYTOVENE): an antiviral drug FDA-approved to
treat CMV retinitis, CMV colitis, CMV esophagitis, AIDS-related
meningoencephalitis and AIDS-related polyradiculopathy.
       
       GASTRITIS: inflammation of the mucosal lining of the stomach.
       
       GENTAMYCIN: aminoglycoside under investigation in "TLC G-65"
formulation for the combination treatment of MAC.
       
       GLUCOSE: one form of sugar found in the body that can be
converted into energy or stored; abnormally low or high levels in
the blood often indicate metabolic disturbances.
       
       GLYCOPROTEIN: refers to a small unit made of a sugar and
protein molecule, often part of the cell's membrane.  GP-120 is a
protein on the outer shell, or envelope, of the HIV virus.  GP-120
is the portion of HIV that binds to a helper T-cell's surface
protein, CD4.  
       
       GP-160: glycoprotein molecular weight 160, a protein cleaved
into the gp120 and gp41 portions of the HIV envelope.
       
       GONAD: organ that produces sex cells; testis or ovary.
       
       GRAM-NEGATIVE: refers to bacteria that have a double cell wall
that contains lipopolysaccharide, or endotoxin; these bacteria lose
the crystal violet stain used in Gram's method of staining.
       
       GRAM-POSITIVE: refers to bacteria that have a single cell wall
that does not contain lipopolysaccharide; these bacteria retain the
crystal violet stain used in Gram's method of staining.
       
       GRANULOCYTE: a type of white blood cell that fights bacterial
infections.
       
       GRANULOCYTOPENIA: abnormally low levels of granulocytes in the
blood; may increase risk of severe bacterial infection.
       
       GROWTH HORMONE (GH): hormone that promotes protein synthesis,
muscle growth and fat metabolism, and stimulates the immune system.
       
       HELPER T-CELLS or T-HELPER CELLS: a critically important type
of white blood cell (also known as CD4 or T4 cells) which help the
body fight off infections.  HIV invades these cells and weakens or
destroys them.  Physicians regularly monitor T-helper cell counts
in HIV-infected individuals as an indicator of the progression of
HIV disease; severe immune suppression is correlated with T-helper
counts below 200.
       
       HEMOGLOBINEMIA: the presence of free hemoglobin in blood
plasma.
       
       HEMOGLOBIN: the protein in red blood cells that carries oxygen
to the cells.  Normal hemoglobin values for women are 12-15 grams
per liter and 14-16 grams per liter for men.  These values may vary
according to where the test is performed.
       
       HEPATITIS B: a viral liver infection that can be acute or
chronic and even life-threatening, particularly in people with poor
immune resistance.  Like HIV, the hepatitis B virus can be
transmitted by sexual contact, contaminated needles or contaminated
blood or blood products.  Unlike HIV, it is also transmissible
through close casual contact.
       
       HERPES VIRUS: a group of viruses that includes herpes simplex
type 1, herpes simplex type 2, cytomegalovirus (CMV), Epstein-Barr
virus (EBV), human herpes virus type 6 (HHV6) and varicella-
"chicken pox"-zoster (the "shingles" virus).  Herpes simplex virus
1 (HSV-1) can cause painful "cold sores" or "fever blisters" on the
lips, in the mouth or around the eyes; herpes simplex virus 2 (HSV-
2) is usually transmitted sexually and generally causes lesions in
the anal-genital area.
       
       HERPES ZOSTER (SHINGLES): a condition characterized by a group
or stripe of painful blisters which generally dry and scab,
sometimes leaving minor scarring.  Also known as "shingles," it is
caused by reactivation of a previous infection with varicella-
zoster virus, the agent that causes chickenpox.
       
       HIV-1: human immunodeficiency virus type 1.  The retrovirus
recognized as the causative agent of AIDS.
       
       HIV-2: human immunodeficiency virus type 2.  A virus similar
to HIV-1 that originated in West Africa.
       
       HOMOLOGOUS: corresponding or similar in position; refers to
regions of DNA or sequences of amino acids that are similar because
of common ancestry, e.g. SIV and HIV-2.
       
       HUMAN INSULIN-LIKE GROWTH FACTOR (IGF-1): a substance
naturally produced by the body that has many of the same effects as
growth hormone (GH).  IGF-1 is being tested as a prophylactic agent
for AIDS-related cachexia.
       
       HUMORAL: pertaining to body fluids, primarily serum and lymph.
       
       HUMORAL IMMUNITY: immunity that can be transferred to a non-
immune individual by administering antibodies taken from an immune
individual. 
       
       HYDROPS FETALIS: abnormal accumulation of fluid in fetal
tissue.
       
       HYPERALIMENTATION: consuming or administering nutrients in
excess of minimum normal requirements in an attempt to ameliorate
nutritional deficiencies.
       
       HYPERICIN: a chemical substance that in laboratory studies
inhibits HIV replication and spread from cell to cell, and protects
mice from the lethal effects of HIV-like mouse viruses; found in
low concentration in the St. John's Wort plant.  Clinical trials of
hypericin for treatment of HIV infection are about to begin with
both a synthetic version and with a highly concentrated St. John's
Wort extract.
       
       HYPERTRIGLYCERIDEMIA: elevated levels of triglycerides in the
blood.
       
       HYPOGLYCEMIA: insufficient levels of glucose in the blood.
       
       HYPOTENSION: subnormal arterial blood pressure.
       
       HYPOTHALAMUS: a part of the brain, below the cerebrum, that
controls and integrates the autonomic nervous system, and many
other vital functions.
       
       IL1 RECEPTOR ANTAGONIST (IL1RA): cytokine and natural
antagonist to IL1 that acts by blocking IL1's target cell surface
receptors.
       
       IMMUNIZE: vaccinate; confer resistance to an infectious
disease.
       
       IMMUNOGENICITY: having the properties of an antigen, a
substance that produces a state of sensitivity and/or resistance to
infection.
       
       IMMUNOGLOBULIN: proteins that can act as antibodies to help
the body fight off disease.  Recombinant and pooled immunoglobulins
from blood donations have been used successfully to help HIV-
infected children and some adults resist bacterial infections.
       
       IMMUNOSUPPRESSION: reduced function of one or more components
of the body's immune system.  HIV infection causes
immunosuppression and other immune dysfunctions.
       
       INTERLEUKIN: chemical hormone messenger secreted by and
affecting many different cells in the immune system. 
       
       INTERLEUKIN 1 (IL1): a cytokine released by monocytes,
macrophages, T-cells and other immune cells that mitigates
infection.
       
       INTOLERANCE: inability of the body to appropriately metabolize
an agent or drug.
       
       INTRADERMAL: within the cells collectively composing the skin.
       
       ISOLATES: different strains of a virus.
       
       KETOCONAZOLE: oral or topical medication used to treat fungal
or yeast infections.
       
       KILLER CELLS: a class of immune system cells whose function is
to kill cancer and virus-infected cells; also called "Natural
Killer" cells.
       
       KILLER T-CELLS: a type of white blood cell (lymphocyte) that
can kill foreign cells when programmed to do so by the immune
system; also called cytotoxic T-lymphocytes.
       
       LETHARGY: abnormal drowsiness and aversion to activity as the
result of illness.
       
       LEUKOPENIA: an abnormally low number of white blood cells in
the circulating blood.
       
       LIPOPOLYSACHHARIDE (LPS; ENDOTOXIN): a molecule composed of
fat and sugar, LPS is a toxin within the bacterial cell that causes
the immune system to release cytokines.
       
       LYMPH NODES: small, bean-shaped organs made up mostly of
lymphocytes (white blood cells) and connective tissue.  Lymph
glands are widely distributed in the body and are essential to the
functioning of the immune system.
       
       LYMPHOCYTE: a type of white blood cell.  T-helper cells are
lymphocytes.
       
       LYSIS: the fracture, destruction and break-up of a cell. 
       
       MAC (MYCOBACTERIUM AVIUM COMPLEX): an infection caused by 2
bacteria found in water, soil and food.  In PWA, it can spread
through the bloodstream to infect lymph nodes, bone marrow, liver,
spleen, spinal fluid, lungs and intestinal tract.  Symptoms of MAC
include prolonged wasting, fever, fatigue and enlarged spleen.  
       
       MACROPHAGE: a large scavenger cell which ingests degenerated
cells, blood tissue and foreign particles.  Macrophages exist in
large numbers throughout the body, and are key to the development
of immunity to a variety of organisms.  They are a major reservoir
of HIV infection, along with their precursor blood cell, the
monocyte.
       
       MANTOUX TEST: refers to the M. tuberculosis skin test invented
by French physician Charles Mantoux; a.k.a. the PPD test.
       
       MEGESTROL ACETATE (MEGACE): a synthetic, orally administered
progesterone used to treat breast cancer.  Because of its tendency
to promote weight gain, studies are being conducted on the use of
Megace in people with advanced HIV disease.
       
       MEPRON (atovaquone, 566, 566C, 566C80): an antimicrobial drug
used as fourth-line treatment for PCP for individuals who cannot
tolerate or fail on TMP-SMX (Bactrim, Septra).  Mepron has also
shown strong activity against Toxoplasma gondii, the organism that
causes toxoplasmosis.
       
       MHC-II: major histocompatibility complex (MHC), a group of
genes that encode cell-surface molecules that in turn determine
whether a graft will be accepted or rejected; also required for
antigen presentation; class II molecules are present on CD4 T-
helper cells and B-cells.
       
       MIRIEUX CMI TEST: a commercially-prepared plastic device that
administers 8 types of antigens as separate skin tests in order to
measure delayed type hypersensitivity.  Results are read from the
skin test reactions 48-72 hours after placements;  CMI = cell-
mediated immunity.
       
       MITOGEN: a substance that induces the division of cells and
can induce cancer-like effects.
       
       MONOCLONAL ANTIBODY: antibody derived from a single cell
having a single antigen specificity.
       
       MONOCYTE: a type of white blood cell which is one of the
reservoirs for HIV.
       
       MONOTHERAPY: use of a single drug for treatment.
       
       MUCOUS MEMBRANE: a moist layer of tissue that lines body
cavities or passages that have an opening to the external world,
e.g., the lining of the mouth, nose, rectum or vagina.
       
       MYCOBACTERIUM: a group of organisms similar to bacteria that
may cause disease, especially in people with poor immunity, e.g. M.
tuberculosis and leprosy.
       
       MYELOSUPPRESSION: inhibition of bone marrow activity such as
production of blood cells.
       
       MYOPATHY: abnormality or disease of the muscles, or muscle
tissue.
       
       NECROSIS: cell or tissue death. 
       
       NEOPTERIN: neopterin is produced from macrophages and enters
the blood as part of the body's immune response to a foreign agent. 
Neopterin levels have been used to predict HIV disease progression
much in the same way as the beta-2 microglobulin test.  In
uninfected people, the neopterin level is approximately 5.4
nanomoles per liter of blood (nmol/l).  Levels between 20 and 50
nmol/l have been reported in people with AIDS.
       
       NEUROPATHY: any disease of the peripheral nervous system,
nerve tissue found anywhere between its exit from the spinal cord,
and out to the skin.
       
       NEUTRALIZING ANTIBODY: antibody that neutralizes the
infectivity of microorganisms, particularly viruses.
       
       NEUTROPENIA: an abnormally low number of nuetrophils, a type
of white blood cell that helps to defend the body against bacterial
infection.
       
       NEUTROPHIL: the most common type of white blood cell.  They
are the immune system's primary defense against bacterial
infections.  The normal range for neutrophils is from 3000 to 7000.
       
       NIH (National Institutes of Health): part of the Public Health
Service of the federal government.
       
       NONMETASTATIC: refers to a disease that does not transfer or
proceed from one part of the body to others.
       
       OPPORTUNISTIC INFECTION (OI): an illness caused by a
microorganism that usually does not cause disease in people with a
normal immune system.  If the immune system becomes weak, such a
microorganism may cause serious or even life-threatening illness.
       
       ORAL CANDIDIASIS (THRUSH): an infection caused by a yeastlike
fungus called candida albicans.  In the mouth, it is known as
thrush, and often is one of the first symptoms of a weakened immune
system.
       
       PANCREATITIS: inflammation of the pancreas; symptoms may
include intense abdominal pain, nausea, vomiting, constipation and
possibly jaundice; pancreatitis can be life-threatening; the anti-
HIV drugs ddI and ddC may cause pancreatitis in some individuals.
       
       PAP SMEAR (PAPANICOLAOU SMEAR): a specimen of uterine or
cervical cells examined for abnormal development.
       
       PARALLEL TRACK: an FDA program that expands access to a
promising drug to people who cannot participate in clinical trials
of that drug.
       
       PATHOGENESIS: the development of a disease, in particular,
cellular events, reactions and mechanisms.
       
       PATHOLOGY: the medical study of disease, especially with
regard to causes and development of disease progress and the
changes accompanying it, as observed in body tissues.
       
       PCR (POLYMERASE CHAIN REACTION): applies to the PCR test, a
highly sensitive test that can detect DNA fragments of viruses or
other organisms in blood or tissue.
       
       PHARMACOLOGIC: related to pharmacology, the study of the
activity of drugs in the body.
       
       PHASE I STUDY: the first step in human testing of a drug. 
Designed to evaluate toxicity at different dose levels.  Phase I
studies involve only a small number of participants.
       
       PHASE II TRIAL: the second step in the evaluation of a drug in
humans.  Phase II trials are designed to evaluate drug
effectiveness, and involve more study participants than Phase I
studies.  Phase II trials proceed only if 1 or more Phase I trials
have shown the drug's toxicity to be acceptable within a given dose
range.
       
       PHASE III TRIAL: expansion of Phase II trial up to 3,000
volunteers; designed to support information gathered in Phase I and
II; Phase III trials also compare the drug to other agents or to
placebo, either alone or in combination.
       
       PHENOTYPE: the visible characteristics of an organism,
produced by one's genotype (genetic blueprint) and interaction with
one's environment.
       
       PLACEBO: an inert, inactive substance.  In placebo-controlled
studies, a placebo is given to one group of individuals, while the
drug being tested is given to another group.  The results obtained
in the 2 groups are then compared.
       
       PLACEBO-CONTROLLED STUDY: a method of investigation of drugs
in which an inactive substance (the placebo) is given to one group
of patients, while the drug being tested is given to another group. 
The results obtained in the two groups are then compared.
       
       PLACENTA: the vascular organ uniting fetus and (maternal)
uterus, through which metabolic exchange occurs between fetus and
mother.
       
       PLATELET: a type of blood cell that facilitates normal blood
clotting.
       
       PNEUMOCYSTIS CARINII PNEUMONIA (PCP): a life-threatening form
of pneumonia that occurs in people with suppressed immune systems. 
It is the most common opportunistic infection in AIDS.  Its onset
can be prevented or delayed by treatment with drugs such as
dapsone, TMP-SMX (Bactrim, Septra and generics) and aerosolized
pentamidine (Nebupent).
       
       PNEUMOVAX VACCINE: a vaccine developed to prevent a common
type of pneumonia.  
       
       POLYMERASE CHAIN REACTION (PCR): a highly sensitive test that
can detect minute amounts of DNA fragments of viruses or other
organisms in blood or tissue.
       
       POLYSACCHARIDE: a carbohydrate compound made of two or more
sugar molecules.
       
       PPD: abbreviation for purified protein derivative of
tuberculin.  PPD refers to a simple skin test used to detect
tuberculosis.
       
       PRIMARY INFECTION: the initial introduction of an infection,
such as HIV or CMV, into a person.  Primary HIV infection (also
called acute HIV infection) is manifested by a flu-like illness
with fever, malaise, enlarged lymph glands, and sometimes with a
sore throat or rash.
       
       PRIMARY: relating to the first.
       
       PRINCIPAL NEUTRALIZING DETERMINANT: the chemical structure on
an antigen that, if complexed with an antibody, best reduces
infectivity.
       
       PROGESTERONE: a natural or synthetic antiestrogenic steroid.
       
       PROPHYLAXIS: treatment that helps to prevent a disease or
condition before it occurs or recurs.
       
       PROTECTION: reinfection immunity to a microorganism.
       
       PYRIMETHAMINE: a drug used in combination with sulfadiazine to
treat toxoplasmosis.  Side effects include bone marrow suppression
and allergic skin reactions.
       
       RECOMBINANT: produced by genetic engineering in the
laboratory. 
       
       RENAL: relating to the kidneys.
       
       RESISTANT: relating to lost sensitivity to a drug.  For
example, after long-term use of AZT, HIV can develop strains of
virus in the body that are no longer suppressed by this particular
drug, and therefore are said to be resistant to AZT.
       
       RETINITIS: inflammation of the retina (back of the eyeball);
sometimes causes blindness.
       
       RETROVIRUS: a class of viruses that use the genetic material
of RNA to manufacture DNA; enveloped virus family comprising
oncoviruses (HTLV-1, HTLV-2, HTLV-5) and lentiviruses (HIV-1, HIV-
2).  Able to integrate into host chromosome and remain latent.
       
       RIFABUTIN (MYCOBUTIN): an oral drug FDA-approved as a
preventive treatment for Mycobacterium avium complex (MAC).  Side
effects may include rash, fever, gastrointestinal distress and
leukopenia.
       
       RNA: ribonucleic acid.  A nucleic acid that controls the
synthesis of protein in all living cells, and takes the place of
DNA in some viruses, including HIV.
       
       SCID-hu MOUSE: a strain of mice with severe combined
immunodeficiency, leaving them without an immune system; human
immune system components can be transplanted, and the murine immune
system becomes highly analogous to human immune system.
       
       SECOND-LINE TREATMENT: the second preferred therapy for a
particular condition; used when the patient fails or cannot
tolerate the side effects of the first-line treatment.
       
       SEPSIS: the presence of pathogenic organisms or their toxins
in the blood or tissues; septicemia is one form of sepsis.
       
       SEPTICEMIA: physiological response to bacteremia; symptoms
include increased cardiac and respiratory rates and fluctuations in
body temperature.
       
       SEPTIC SHOCK: a condition that adds decreased blood pressure
(systolic blood pressure < 90mm mercury) to the symptoms comprising
septicemia.
       
       SERUM: the clear, non-cellular portion of the blood.
       
       SIMIAN IMMUNODEFCIENCY VIRUS (SIV): endemic to African Green
monkeys and homologous to HIV-2.
       
       SINGLE AGENT THERAPY:  use of a single agent or drug for
treatment.
       
       SMA 12 (Sequential Multiple Analysis): a blood chemistry
screening test (a standardized panel of twelve grouped blood tests
total) for predetermined blood elements, using an autoanalyzer (an
automated machine) and a single sample of 2.5 ml of serum.
       
       SPUTUM STAIN: diagnostic test using mucus or other matter
ejected from the throat by coughing or spitting.
       
       SUPERANTIGEN: an antigen that triggers immune response from a
very large number of antibodies.
       
       SUPPRESSOR CELL: a type of white blood cell that helps
regulate the body's response to an infection; also called CD8 or T8
cell.
       
       SYNCYTIA: a mass of cells which fuse together to form one
"giant cell."  In HIV infection this condition leads to direct
cell-to-cell infection and continued HIV production.
       
       SYNERGISTIC: the action of 2 or more drugs that, when taken
together, have an effect greater than the total effect of the
individual drugs.
       
       T-HELPER CELLS: a critically important type of white blood
cell (also known as CD4 or T4 cells) which help the body fight off
infections.  HIV invades these cells and weakens or destroys them. 
Physicians regularly monitor T-helper cell counts in HIV-infected
individuals as an indicator of the progression of HIV disease;
severe immune suppression is correlated with T-helper counts below
200.
       
       TAMOXIFEN: an anti-estrogen used to treat certain breast
cancers in post-menopausal women.
       
       THERAPEUTIC VACCINE: a vaccine used as treatment to produce
new immune responses and arrest or reverse disease progression.
       
       THIRD-LINE TREATMENT: the third preferred therapy for a
particular condition; used when the patient fails or cannot
tolerate the side effects of the first- and second-line treatments.
       
       THROMBOCYTOPENIA: an abnormally low number of platelets, blood
cells that facilitate blood clotting.
       
       THRUSH: the oral form of candidiasis characterized by white
spots or patches in the mouth or back of the throat.
       
       TOXIN: a harmful or poisonous agent. 
       
       TOXOPLASMOSIS: an opportunistic infection caused by a
microscopic parasite (Toxoplasma gondii) found in uncooked meat and
cat feces.  Symptoms may be so mild as to be barely noticeable or
may be more severe with lymphadenopathy, malaise, muscle pain and
fever.  In more severe forms, there may be pneumonitis, hepatitis,
encephalitis, destructive lesions of the central nervous system,
jaundice, anemia and generalized lymphadenopathy.  Diagnosis is
made by identification of a biopsy of the organism and by serologic
test.  Toxoplasmosis may lead to brain inflammation, coma and death
in people with suppressed immune systems.
       
       TREATMENT ARM: a group of participants in a research study who
all receive the same treatment (or placebo).
       
       TRIMESTER: a 3-month period.
       
       TRIMETHOPRIM-SULFAMETHOXAZOLE (TMP-SMX): the preferred drug
for prophylaxis and treatment of PCP.
       
       TUMOR NECROSIS FACTOR (TNF): also called cachectin; a cytokine
produced by activated macrophages that may destroy tumor cells. 
When chronically elevated in excessive amounts, TNF blocks
production of an enzyme important for the breakdown of fats,
leading to weight loss associated with protein (muscle) breakdown. 
In laboratory tests, TNF stimulates HIV replication.  TNF is often
elevated in people with low T-helper cell counts.
       
       V-3 LOOP: principal neutralizing determinant on HIV-1; the
target of recombinant vaccine candidates.
       
       VECTOR: an agent that transfers a pathogen from one organism
to another, e.g. an insect.
       
       VIRAL BURDEN: refers to the concentration of the virus in the
body.
       
       VIRION: a viral particle existing outside of the host cell.
       
       WASTING SYNDROME: a condition among HIV-infected individuals
characterized by involuntary weight loss of more than 10% of
baseline body weight.  Other symptoms may include chronic diarrhea
or chronic weakness and fever for more than 30 days.  A CDC AIDS-
defining condition.
       
       WILD-TYPE VIRUS: the customary phenotype of a virus before
genetic manipulation or mutation.

       CORRECTIONS

       It is a policy of BETA to correct factual errors.  We regret
these errors, and any misunderstanding they may have caused.

       In the November 1992 issue (page 30) Intron A, a product of
Schering-Plough Corporation, was listed as the trade name for
Interferon alfa-2a-recombinant, and Roferon-A, a product of
Hoffman-La Roche, was listed as the trade name for Interferon alfa
2b, recombinant.  In fact, the opposite is true:  Intron A is the
trade name for interferon alfa-2b, and Roferon-A is the trade name
for interferon alfa-2a.

       BETA is amending its glossary definition of Kaposi's Sarcoma
(KS).  The revised definition incorporates information submitted to
BETA by physicans and people with KS to reflect that KS lesions on
the skin, while usually painless, may cause significant discomfort,
depending on the size and location of the lesions.

       KAPOSI'S SARCOMA (KS):  an abnormal growth in the walls of
blood vessels visible through the skin.  KS typically appears as
pink to purple, usually painless spots on the surface of the skin,
but it can also occur internally.  KS occurs more commonly among
gay and bisexual men with HIV disease than among HIV-infected
heterosexual men and women.  The cause of KS is unknown.

       ***********

       BETA

       Editor
       Ronald A. Baker, PhD

       Assistant Editors
       Leslie Hanna
       Carlos Petroni


       Contributors to This Issue
       Ronald A. Baker, PhD
       Bernard Bihari, MD
       Mark Bowers
       Angel Garca
       Joan Kapusnik-Uner, PharmD
       Robert Neger, MD
       Teryl Nuckols
       Dan Medynski, PhD
       Carlos Petroni
       
       Scientific Advisors
       Harvey S. Bartnof, MD
       Toby Dyner, MD
       Tomas Fabregas
       Mitchell Katz, MD
       Merritt Smith, MD
       Joan Kapusnik-Uner, PharmD
       
       Editorial Production
       Angel Garca
       Mark Gilmore
       Leslie Hanna
       
       Production
       David Hecht

       Design
       Larry Stinson

       For subscription information, call 510-549-4300.  FAX 510-549-4342. 
Editorial correspondence: P.O. Box 426182, San Francisco, CA  94142.  FAX 415-
552-1583.  Tel. 415-863-2437 (San Francisco AIDS Hotline).

       DISTRIBUTED FOR GENA by AEGIS/San Juan Capistrano - 714.248.2836:
       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
       copy for personal reference) requires written consent from the SFAF.  For
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       1.800.959.1059 or 1.510.549.4300, or via the internet at
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