       Bulletin Experimental Treatments for AIDS (BETA) - June 1996


       Table of Contents

	  BETA News Briefs
         HIV Viral Load Supercedes CD4 Count as Best Marker for
            Predicting Risk of AIDS and Death
         Pneumonia
         Non-Nucleoside Reverse Transcriptase Inhibitors
         HIV/AIDS in Children
         Cervical Intraepithelial Neoplasia
         Cervical Cancer Screening Issues for HIV Positive Women
         Research Notes
         Prevention of Opportunistic Infections: USPHS/IDSA Guidelines
         Open Clinical Trials
         Glossary

       About BETA

       Editor-in-Chief: Ronald Baker, PhD  Managing Editor: Mark
       Bowers  Associate Editor: Leslie Hanna  Editorial Assistant and
       Webmaster: Liz Highleyman  Design and Production Manager of
       print edition: Dave Robb  Scientific Advisory Committee:

         Ronald Baker, PhD
         Harvey Bartnof, MD
         Mark Bowers
         Rene Durazzo
         Mary Romeyn, MD

       Contributors to this issue:

		Ronald Baker, PhD
		Lisa Bardaro, MD
		Harvey S. Bartnof, MD
		Mark Bowers
		Leslie Hanna
		Bruce Mirken

       BETA is published quarterly by the San Francisco AIDS
       Foundation. Funding is provided by paid subscriptions and by
       private and corporate donations. Copyright 1996 by the San
       Francisco AIDS Foundation. All rights reserved. No part of BETA
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       any information retrieval system without the permission of the
       editor. Brief passages may be quoted for review. Library of
       Congress ISSN 1058-708X. Editorial office: P.O. Box 426182, San
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       Free subscriptions are available to HIV positive, low-income
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       Home Page Send questions or comments to beta@thecity.sfsu.edu.
       Page developed by Liz Highleyman Last updated: 30 July 1996.

       **********
       New Briefs
       by BETA Editorial Staff

       FDA Approves Roche Viral Load Test

       On June 3, 1996, the Food and Drug Administration (FDA)
approved the viral load test manufactured and distributed by Roche
Diagnostic Systems Inc. (a subsidiary of Roche Molecular Systems
Inc.). The assay, known as the Amplicor HIV-1 Monitor Test, is a
reverse transcriptase polymerase chain re-action (RT-PCR) test that
amplifies and measures the amount of HIV RNA in the blood plasma; the
test can measure viral load levels as low as 400 HIV RNA copies/mL.
The test was approved for HIV disease prognosis, or predicting the
risk of disease progression. Approval was based in part on clinical
studies that demonstrated that persons with higher viral load levels
experienced more rapid disease progression and had a higher risk of
death. In 2 studies of persons with advanced HIV disease, a high
pre-treatment viral load or a five-fold or greater increase in viral
load predicted accelerated disease progression.

       The Roche test is the first viral load assay using this
technology to be FDA-approved; approval came less than 7 months after
Roche submitted their application. The test currently costs $150-200;
the price is expected to decline as the test becomes more widely
available. Roche has announced plans to offer 2 free Amplicor HIV-1
Monitor test kits to all HIV positive persons in the U.S. for a 60-day
period starting June 17, 1996. For information on the free test kits,
call 888-TEST-PCR. For more on viral load, see page 9.

       HIV Home Test Kit Approved

       Confide is the first anonymous HIV home test with counseling
service to be approved by FDA. The new test was developed and will be
marketed by a company called Direct Access Diagnostics, a subsidiary
of Johnson and Johnson.

       The new test has 3 components: an over-the-counter home blood
collection kit, HIV-1 antibody testing at a certified lab and a test
result center that provides the results and counseling. The procedure
allows for complete anonymity.

       The testing process begins by reading a pretest counsel-ing
booklet. Using an enclosed retractable lancet, the test-kit user takes
a blood sample from the finger and places it on a test card imprinted
with a unique identification number. The test card is then mailed in a
prepaid, preaddressed pro-tective envelope to the Confide laboratory.
Results may be obtained 7 days later by calling a toll-free number.
Counseling and referrals are offered at the same time that results are
delivered.

       The test will be available over-the-counter on a limited basis
in Texas and Florida in June 1996. Nationwide distribution will not
begin until early 1997. Confide will retail for about $40, part of
which will be donated to AIDS research; it will cost $50 if ordered by
calling 1-800-THE-TEST.

       An FDA advisory committee recommended approval of the home
testing kit at a June 1994 meeting, after concluding that the
potential benefits outweighed the potential risks. The risks center
mainly around the counseling issue. Critics contend that, without
face-to-face counseling, some test-kit users may commit suicide.

       HIV DYNAMICS

       HIV Variation and Disease Progression

       A team of researchers including Steven Wolinsky, MD, at
Northwestern University Medical School and David Ho, MD, at the Aaron
Diamond AIDS Research Center, has evaluated the number of genetic
variants of HIV found in the blood of HIV-infected individuals and
attempted to correlate that information with rates of disease
progression. Contrary to a widely accepted model of HIV disease which
contends that extremely rapid rates of evolution give HIV an advantage
in overcoming host immune defenses, the team found that those whose
disease progressed fastest were the ones who exhibited the least
genetic diversity in their HIV. Those with many different genetic
varieties of HIV progressed more slowly.

       The study, reported in the April 26, 1996 issue of Science, was
based on blood samples taken every 3-6 months from 6 volunteers, 2 of
whom showed rapid declines in CD4 cell counts, 2 with moderate
declines and 2 with relatively stable CD4 cell counts. The sample size
was small and the study has not yet been replicated to validate the
findings. If the study is confirmed, some basic assumptions about how
HIV causes immune decline will need to be reevaluated.

       Wolinsky SM and others. Adaptive evolution of human
       immunodeficiency virus-type 1 during the natural course of
       infection. Science 272:537-41. April 26, 1996.


       HIV Replication, Infected Cell Life Span

       A team of researchers led by David Ho , MD, of the Aaron
Diamond AIDS Research Center in New York, estimates that 10 to 30
billion new HIV viral particles are produced each day. In a study
reported in Science on March 15, 1996, blood samples were drawn from 5
volunteers who were taking the newly approved protease inhibitor drug
ritonavir (Norvir, produced by Abbott Laboratories) at a dose of 600
mg twice daily. Polymerase chain reaction (PCR) measurements of HIV
RNA in the plasma were taken every 6 hours for the first 2 days, then
once daily for 6 more days.

       The team assumed that ritonavir does not affect the rate at
which infected cells produce new HIV, and that after about 1.25 days
after beginning ritonavir, the HIV produced by infected cells is
noninfectious. Calculations based on these assumptions allowed Ho and
his team to estimate that the average life span of an HIV virion (a
single virus particle) in the blood is 0.2-0.4 days, while the average
life span of an infected cell is 1.4-3 days.

       The report provides further evidence that there is no latency
period in HIV infection, and offers some theoretical principles to
guide treatment strategies. According to the Ho team, "an effective
antiviral agent should detectably lower the viral load in plasma after
only a few days of treatment." Because of the enormous daily turnover
of HIV, mutation rates are even higher than previously thought. Hence,
the development of resistance to the current generation of
antiretroviral drugs when used as monotherapy is inevitable, and
"effective treatment must instead force the virus to mutate
simultaneously at multiple positions in the viral genome by means of a
combination of multiple, potent antiretroviral agents."

       Perelson A and others. HIV-1 dynamics in vivo: virion clearance
       rate, infected cell life-span and viral generation time.
       Science 271:1582-85. March 15, 1996.


       Fusin: HIV Cofactor

       Since 1984, researchers have known that the receptor protein
for HIV is CD4, but CD4 alone is not enough to permit passage of HIV
into immune system cells. In the May 10, 1996 issue of Science, the
long-sought cofactor was identified by a team of researchers at the
National Institutes of Health (NIH). Fusin is a protein that helps
cells fuse with the surface of HIV. Without the presence of both the
CD4 receptor and fusin on the cell surface, HIV cannot infect the
cell.

       The discovery of fusin, coupled with recent research findings
that suggest that certain inflammation-causing cytokines can block
HIV's ability to infect cells, raises some new possibilities. It may
be that these cytokines (which not everyone produces in abundance)
will block fusin, preventing HIV fusion with immune cells. If so, that
could explain why some people are able to resist HIV infection despite
multiple exposures to the virus, and why some people with HIV are
long-term nonprogressors. Furthermore, strategies could be developed
to block fusins and prevent new infections in people who are exposed
but not infected, or the spread of infection in people already
infected with HIV.

       A second important avenue of research will probably open up as
a result of the identification of fusin. It may now be possible to
genetically engineer rabbits or other animals to produce fusins, and
an animal model for AIDS could at last be developed. Current models
based on simian immunodeficiency virus (SIV) infection are inadequate
to answer the questions researchers most want answered about human
AIDS.

       One of the team of researchers, Edward Berg, MD, cautions that
there are very likely different kinds of fusin that play different
roles for different strains of HIV. This is the first, but probably
not the only, fusin or cofactor that will be discovered.

       BLUEPRINTS FOR RESEARCH AND PREVENTION

       Office of AIDS Research Advisory Committee Report

       A report issued on March 13, 1996, by the 118-member AIDS
Research Program Evaluation Working Group criticizes AIDS research at
NIH and recommends that the Office of AIDS Research (OAR) retain
control over research at the 24 institutes and centers that comprise
NIH. Another key recommendation is to strictly define AIDS and
AIDS-related research, in order to redirect funding for research that
is unrelated or indirectly related to AIDS into research which is
clearly related to AIDS and done by non-NIH scientists.

       Other recommendations from the advisory committee include:

        Bolster current vaccine research by creating an NIH vaccine
         research unit within the National Institutes of Allergy and
         Infectious Diseases (NIAID)

        Refocus funding away from areas of drug discovery that are
         likely to be done by pharmaceutical companies

        Provide a blueprint for future HIV prevention efforts

        Integrate all existing adult clinical trials networks into
         one.

       Recommendations for Prophylaxis against HIV-Related Infections

       The United States Public Health Service and the Infectious
Diseases Society of America published extensive consolidated
guidelines for the prevention of opportunistic infections (OI)
associated with HIV disease in July 1995. A condensed version of the
guidelines appeared in the February 1, 1996 issue of Annals of
Internal Medicine. The original report is available from the Centers
for Disease Control and Prevention National AIDS Clearinghouse, P.O.
Box 6003, Rockville, MD 20849-6003; telephone 800-458-5231.

       The current recommendations for preventing OI are ranked in
order of importance. The designation "A" indicates those that are
strongly recommended (both strong evidence and substantial clinical
benefit support prophylaxis), "B" designates those recommended for
consideration (moderate evidence or strong evidence for only limited
benefit) and "C" indicates those that are considered optional (poor
evidence for prophylaxis). These recommendations differ from previous
ones in 3 areas: prophylaxis for Pneumocystis carinii pneumonia (PCP),
Mycobacterium avium complex disease (MAC) and toxoplasmosis.

       For preventing PCP as well as toxoplasmosis, trimethoprim-
sulfamethoxazole (TMP-SMX, brand name Bactrim or Septra) is
recommended, and guidelines for desensiti-zation are included (see
also the update on pneumonia on page 13.) After a reanalysis of the
data from rifabutin studies, the threshold for the initiation of
prophylaxis for MAC disease has been reduced from 100 to 75 cells/mm3
or fewer. See summary of guidelines, this issue.

       Powderly W. Prophylaxis for HIV-related infection: a work in
       progress. Annals of Internal Medicine 124(3): 342-4. February
       1, 1996.

       USPHS/IDSA guidelines for the prevention of opportunistic
       infections in persons with human immunodeficiency virus: a
       summary. Annals of Internal Medicine 124(3): 348-68. February
       1, 1996.

       Research Agenda for HIV-Infected Children

       Over the past few years, some exciting research advances have
offered hope for ways to reduce perinatal HIV transmission, the mode
responsible for nearly all new pediatric HIV infections today. The FDA
has approved a highly publicized AZT regimen, which requires both
mother and newborn to take AZT for a period of weeks, gives
intravenous AZT during childbirth, and was shown in AIDS Clinical
Trials Group (ACTG) 076 to reduce transmission rates by nearly
two-thirds. Another experimental and promising strategy involves the
non-nucleoside reverse transcriptase inhibitor drug nevirapine
(Viramune). Currently under study in clinical trials, this promising
regimen requires mother and newborn to take only a single dose.

       It is widely hoped that these and upcoming strategies will
drastically reduce the numbers of pediatric cases of HIV/AIDS. In
order for this hope to be realized, pregnant HIV positive women must
have the information and resources to act accordingly. The number of
new infections among women, especially minorities, and their children
hints at the staggering socioeconomic and political factors that must
be addressed in order to curtail new pediatric infections. According
to the National Center for Health Statistics, there are approximately
10,000 HIV-infected children in the U.S. In order for these children
to receive the care they require, research into pediatric antiviral
strategies and other strategies related to managing HIV disease must
continue. Particularly conspicuous is the lack of pediatric trials of
the new protease inhibitors, the latest best antiviral hope for
persons with HIV. To date, there are virtually no pediatric data, and
the protease inhibitors that are already FDA-approved cannot be used
by children.

       See also HIV/AIDS in Children, this issue.


       NUCLEOSIDE ANALOGS

       3TC Patient Assistance Program Expanded

In response to requests from community advocates, Glaxo Wellcome has
acted to increase patient access to the nucleoside analog drug 3TC
(Epivir). On May 20, 1996, the Patient Assistance Program was
broadened to include patients who are qualified to receive their
HIV/AIDS drugs from state drug-assistance programs, but who are unable
to access 3TC due to either state funding shortages or the absence of
3TC on the formulary of the state program for which they qualify. In
addition, a 60-day extension of drug availability has been added for
patients receiving 3TC through the expanded access program. For
further information, contact the Patient Assistance Program at
1-800-722-9294.

PMPA Prevents Vaginal SIV Transmission

The nucleotide analog PMPA (Gilead Sciences), in preclinical testing
for possible use in the treatment of HIV infection, was intravaginally
administered in topical gel form to female primates who were then
challenged with simian immunodeficiency virus (SIV), a retrovirus
related to HIV. One hundred percent of the PMPA-treated primates (4 of
4) were protected from SIV infection, while both control animals who
were also challenged with SIV showed signs of SIV transmission and
infection within 2 weeks of exposure. Human studies of PMPA will begin
this year; the topical drug will undoubtedly be evaluated for its
ability to prevent HIV transmission from infected sexual partners.


       PROTEASE INHIBITORS

       Saquinavir Prolongs Survival and Slows Disease Progression

       The final analysis of the Hoffmann-La Roche sponsored study
NV14256, a randomized, double-blind comparison of saquinavir
(Invirase) versus ddC (HIVID) versus the combination in 1,086 HIV
positive volunteers showed that the combination reduced mortality more
than two-thirds and reduced disease progression by about one-half. The
results showed that there were 28 deaths among those who received only
ddC, 34 a-mong those who received only saquinavir and 9 among those on
the combination. There were 85 instances of disease pro-gression on
ddC, 77 on saquinavir and 46 on the combination.

       Study participants had at least 16 weeks of prior AZT therapy
and CD4 cell counts at baseline were between 50 and 300 cells/mm3. All
participants were followed for a median of 73-74 weeks. More
participants in the combination group completed the protocol than in
either monotherapy group; the main reason for discontinuing
participation among the ddC monotherapy group was toxicity, including
peripheral neuropathy.

       A study of the new gel-cap formulation of saquinavir has been
initiated at 40 sites in the U.S. Participants must be at least 13
years old and there are no CD4 cell count restrictions. Most
participants will not have used any protease inhibitor drug
previously, although 100 of the total 400 participants will have
received prior treatment with a protease inhibitor. For further
information, call the AIDS Clinical Trials Information Service at
1-800-TRIALS-A.

       NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS

       Nevirapine Recommended for Approval

       An antiviral drugs advisory committee unanimously recommended
on June 7, 1996 that the Food and Drug Administration grant nevirapine
(Viramune, produced by Boehringer Ingelheim Pharmaceuticals, Inc)
accelerated approval for use in combination with other anti-HIV drugs
for the treatment of HIV infection. The meeting was unusual, in that
the decision was made both quickly and unanimously. Nevirapine is the
first member of the non-nucleoside reverse transcriptase inhibitor
(NNRTI) class of drugs to receive FDA approval.

       Although committee members did not wish to limit the use of
nevirapine in combination with other antiretroviral drugs to a
specific CD4 cell range, it was noted that the best results were seen
when patients started the drug at the same time that they began using
a previously untried nucleoside analog. Triple combination regimens
demonstrated the greatest decreases in viral load and the most
sustained increases in CD4 cell count among study participants. The
committee also wanted assurance from Boehringer Ingelheim that
clinical studies of drug interactions will be performed quickly. A
study of the interactions between saquinavir and nevirapine is
underway, and similar studies are planned for ritonavir and indinavir.

       The side effect profile for nevirapine is favorable, with rash
being the most common event experienced, usually within the first few
weeks of initiating therapy. The incidence of severe rash and
Stevens-Johnson syndrome, a potentially lethal inflammation of the
skin or mucous membranes, was limited to 0.5% of all study
participants. Boehringer Ingelheim has developed a rash management
protocol. See Non-Nucleoside Reverse Transcriptase Inhibitors, this
issue.

       An expanded access program for Viramune was launched in April
to make the drug available to adult and pediatric patients with
progressive, symptomatic disease. To be eligible, participants' CD4
cell counts must be below 200 cells/mm3. Children under 13 years of
age must have a CD4 percentage of less than 14% or they must have had
a less than 50% decrease in CD4 percentage in the previous 6 months.
Pregnant or breastfeeding women are excluded, as is anyone using
certain medications that interact with Viramune. Physicians may call
1-800-595-5494 to enroll their eligible patients.

       Delavirdine Expanded Access Program

       Upjohn Pharmacia, makers of the experimental non-nucleoside
reverse transcriptase inhibitor drug delavirdine (Rescriptor),
instituted an expanded access program for the drug on April 1, 1996.
The program will make delavirdine available to men and women (who are
not pregnant or breast-feeding) over the age of 13 who have CD4 cell
counts from 0-300 cells/mm3, are failing other therapies and are
receiving at least one other antiretroviral drug. Physicians may
register their eligible patients by calling 1-800-779-0070.

       Delavirdine has been studied in more than 2,600 study
participants and has been found to be synergistic with other
antiretroviral drugs such as AZT and ddI. Clinical studies of
combination therapy with delavirdine plus AZT or ddI resulted in an
average 68% decrease in viral load and an average CD4 count increase
of 25 cells/mm3.

       See a review of non-nucleoside reverse transcriptase inhibitor
drugs in development, see Non-Nucleoside Reverse Transcriptase
Inhibitors, this issue.

       HIV VACCINES

       VaxSyn Testing Comes to an End

       Further testing of the MicroGeneSys candidate therapeutic
vaccine VaxSyn, based on the HIV envelope protein gp160, has been
halted because the vaccine did not demonstrate statistically
significant clinical benefit. A pivotal 5-year study at the Walter
Reed Army Institute of Research in Washington, DC, and NIAID gave
VaxSyn or placebo to 608 volunteers. The data suggest that VaxSyn had
no impact on the course of HIV disease. A similar study of VaxSyn
conducted in Canada recruited 278 volunteers who were injected with
gp160 or placebo. According to lead investigator Chris Tsoukas, MD, of
the Canadian HIV Trials Network, "analysis of the data has revealed no
clinical benefit from this product nor any usefulness in maintaining
immune competence."

       VaxSyn has a history of controversy. In 1992, former Senator
Russell Long (Democrat, Louisiana) successfully lobbied Congress for
$20 million in Department of Defense money to fund a large trial of
the candidate vaccine. Bernadine Healy, MD, then director of NIH, took
exception to the allocation and lobbied successfully for the funds to
be transferred to general vaccine research efforts at NIH.

       New Vaccine Strategy

       NIAID is developing guidelines for HIV vaccine development that
will allow vaccine developers to proceed smoothly along the pathway to
licensing if they meet precise criteria at each step of development.
The criteria have not yet been established, but the promise of clear
guidelines should remove some of the obstacles to vaccine development
that have plagued vaccine developers in the past. Potential vaccine
developers in private industry have been hesitant to commit research
funds to HIV vaccine research when NIAID appears to change
requirements and expectations frequently.

       Anthony Fauci, MD, Director of NIAID, also called for a balance
between basic and empirical vaccine research, for better collaboration
with drug industry and academic partners in vaccine development, for
better exploitation of opportunities to hasten vaccine research and
for better links with other organizations that are pursuing
development of vaccines, such as the Joint United Nations Programme on
HIV/AIDS, Great Britain's Medical Research Council and France's Agence
Nationale de Recherches sur le SIDA.

       OPPORTUNISTIC INFECTIONS

       DaunoXome Available for Advanced Kaposi's Sarcoma

       DaunoXome, a chemotherapy agent for advanced Kaposi's sarcoma
(KS) that consists of daunorubicin encased in fat globules called
liposomes, won FDA approval for marketing in April 1996. DaunoXome is
the second liposomal drug product to be developed by Nexstar
Pharmaceuticals, following liposomal amphotericin B (AmBisome). Data
from the randomized, controlled trial that compared DaunoXome with the
standard chemotherapy combination of adriamycin, bleomycin and
vincristine (ABV) showed no statistical differences in survival rates,
time to treatment failure, or time to disease progression between the
2 regimens. However, the participants who received DaunoXome
experienced less neuropathy, hair loss and heart toxicity, and were
able to gain weight while on treatment.

       DaunoXome has been available by prescription since May 1, 1996.
The standard dosage is 40 mg/m2 every 2 weeks. A patient assistance
program has been established to help people applying for federal and
private assistance, to answer questions and to assist with
reimbursement. Call 1-800-226-2056 for more information or to enroll.


       WOMEN AND HIV

       Do Injectable Contraceptives Increase the Risk of HIV
       Infection?

       An animal study at the Aaron Diamond AIDS Research Center in
New York City has raised concern that 2 popular birth control methods
-- the injectable Depo-Provera and Norplant, which is implanted under
the skin -- may elevate the risk of contracting HIV in women who use
them. The study found that female monkeys that were given
progesterone, a natural human hormone, were 7 times more likely than
monkeys receiving placebo to be infected with simian immunodeficiency
virus (SIV) after vaginal exposure.

       Progesterone is associated with thinning of the vaginal mucous
membranes. Although earlier studies had raised the possibility that
use of exogenous (not produced by the body) progesterone might make it
easier for the virus to cross the vaginal membrane and enter and
infect circulating blood cells, the investigators in this study say
they did not expect to actually see such striking results.

       Results of animal studies do not necessarily translate to
humans. Moreover, the monkey study used natural progesterone, whereas
Depo-Provera and Norplant use a synthetic version called progestin.
Nonetheless, the increasing popularity of these methods worldwide and
especially in developing nations with high rates of HIV infection have
triggered swift development of human studies. The same division of NIH
that sponsored the monkey study is funding a New York study involving
15 women, who will receive progestin or placebo. Monthly measurements
will be made of vaginal mucus layer thickness to determine if the
synthetic hormone actually causes thinning of human vaginal linings.

       To date, the concern offers additional support for the
recommendation to use barrier methods such as condoms for protection
against sexually transmitted diseases, which neither Depo-Provera nor
Norplant claims to prevent. Whether or not they actually elevate risk
for HIV infection remains to be seen.



       *************************************************************
       New Public Health Service Recommendations on HIV Postexposure
       Prophylaxis

       by Ronald Baker, PhD

       Individuals exposed to HIV in the workplace should start anti-HIV
treatment with a 3-drug regimen within 1-2 hours after exposure to
HIV, according to new recommendations from the Public Health Service
(PHS). The recommended triple drug therapy consists of AZT (200 mg 3
times daily) plus 3TC (150 mg 2 times daily) plus indinavir (800 mg 3
times daily). If indinavir is not available, saquinavir is recommended
at 600 mg 3 times daily. If the acquired HIV strain is resistant to
AZT, 3TC and indinavir, the group advises seeking expert consultation
on an alternative regimen. Individuals identified for postexposure
prophylaxis (PEP) should receive expert medical care and appropriate
counselling. The provisional PHS recommendations appear in the June 7,
1996 issue of the Morbidity and Mortality Weekly Report, published by
the Centers for Disease Control and Prevention (CDC).

       Can Drug Treatment Eradicate HIV from the Body?

       The objective of PEP with AZT/3TC/indinavir is to eradicate HIV
before the virus establishes infection in the body. The prophylactic
3-drug regimen should be taken for [at least] 4 weeks. Even though
animal studies suggest that PEP is not effective when initiated later
than 24-36 hours after infection with HIV, starting AZT/3TC/indinavir
therapy as late as 2 weeks after initial infection should be
considered for those at highest risk for infection, say the
recommendations. In these cases, even if the 3-drug regimen fails to
eradicate the infection, very early treatment of HIV infection may be
beneficial.

       Studies on Prevention of HIV Infection through Sexual Contact

       The preliminary PHS treatment recommendations are intended only
for use in trying to prevent infection from workplace-associated
exposure to HIV (e.g., a stick with a contaminated needle). Several
U.S. medical centers are studying the same treatment regimen
(AZT/3TC/indinavir) started within the first few days of acute
infection in individuals exposed to HIV through sexual conduct. The
studies will evaluate whether the 3-drug therapy can eradicate HIV in
these individuals.




       *****************************************************
       HIV Viral Load Supercedes CD4 Count as Best Marker for
       Predicting Risk of AIDS and Death

       by Ronald Baker, PhD  Ronald Baker is Editor-in-Chief of BETA
       and Director of Treatment Education and Advocacy at the San
       Francisco AIDS Foundation.

       "The extent of viremia, measured by HIV RNA, is the best
available surrogate marker of HIV disease progression. Use of HIV RNA
as a surrogate marker should help guide future therapeutic research
and individual patient management."

       --John Mellors and others. Prognosis in HIV-1 infection
         predicted by the quantity of virus in plasma. Science 272:
         1167-1170. May 24, 1996.

       Using Chiron Corporation's branched-chain DNA (bDNA) test, John
Mellors and colleagues at the University of Pittsburgh conclude that
viral load predicts the risk of HIV disease progression (time to AIDS
and death) better than CD4 count. The study population consisted of
180 gay and bisexual men enrolled in the Pittsburgh subset of the
Multicenter AIDS Cohort Study (MACS). The Pittsburgh researchers' new
findings have important implications for the management of HIV
disease. Based on these and other study results, viral load testing is
expected to supercede CD4 count as the principal marker for guiding
individual HIV treatment decisions and for evaluating the
effectiveness of anti-HIV drugs in clinical studies.

       Armed with accurate measurements of the amount of HIV in their
blood plasma as measured by HIV viral load testing, physicians and
patients can make more informed decisions about when to start anti-HIV
therapy, when to stop using an ineffective treatment and when to add
or switch to a new treatment. In addition, monitoring viral load over
time allows patients to make treatment decisions much earlier, prior
to a significant loss of CD4 cells and well before clinical decline
occurs. CD4 cell loss is thought to be a relatively late result of
increased HIV replication. Therefore, it appears more beneficial to
make anti-HIV treatment decisions based on HIV viral load rather than
on CD4 cell count alone, particularly when the CD4 count is greater
than 500 cells/mm3 (see Research Notes).

       When to Start Anti-HIV Therapy?

       The article on viral load in Science adds a new dimension to
the ongoing debate about the optimal time to start anti-HIV treatment.
The Pittsburgh cohort data suggest that the appropriate time to
initiate therapy is when HIV viral load exceeds 10,000 copies/mL,
regardless of CD4 cell count. Many individuals in the study with CD4
counts greater than 500 cells/mm3 progressed as rapidly to AIDS and
death as those with much lower counts when their viral load levels
were greater than 10,190 copies/mL. In current clinical practice, a
CD4 cell count of fewer than 500 CD4 cells/mm3 is commonly used as the
trigger to start anti-HIV treatment. This recommendation needs to be
reconsidered, given the researchers' finding that 50% of the men in
the study with greater than 500 CD4 cells/mm3 (median CD4 count 781
cells/mm3) at study entry and a viral load greater than 10,190
copies/mL died within 6 years after entering the study. In comparison,
only 5% of those in the same cohort with similar CD4 counts (median
CD4 count 787 cells/mm3) at study entry and viral loads less than
10,190 copies/mL died within 6 years.

       The implication of these findings is clear: the decision to
begin anti-HIV therapy should not be based solely on CD4 cell counts.
Individuals should consider starting anti-HIV therapy when their viral
load is greater than 10,000 copies/mL, regardless of their CD4 cell
count. These conclusions do not diminish the value of CD4 cell testing
in the management of HIV disease, which continues to serve as a
reliable marker for predicting the risk of opportunistic infections
and for determining the appropriate timing of initiating preventive
treatment for these infections. In addition, many clinicians believe
that a CD4 count less than 350 cells/mm3 represents an indication for
starting anti-HIV therapy, regardless of HIV viral load.

       Viral load level (HIV RNA copies/mL): less than 4,531 Median
       time to AIDS (years):  greater than 10 Median survival time
       (years): greater than 10

       Viral load level (HIV RNA copies/mL): 4,531-13,020 Median time
       to AIDS (years):  7.7 Median survival time (years): 9.5

       Viral load level (HIV RNA copies/mL): 13,020-36,270 Median time
       to AIDS (years):  5.3 Median survival time (years): 7.4

       Viral load level (HIV RNA copies/mL): greater than 36,270
       Median time to AIDS (years):  3.5 Median survival time (years):
       5.1

       Viral Load and Disease Progression

       The University of Pittsburgh investigators followed study
participants for up to 11 years. They determined 4 groups of
increasing viral load levels at study entry, and correlated each one
with progression to AIDS and survival. The following chart outlines
the results of their findings.

       In this cohort of men, baseline HIV viral load levels correlate
directly with time to AIDS diagnosis and with survival time. Simply
stated, the lower the viral load, the longer the time to AIDS
diagnosis and the longer the survival time. Conversely, the higher the
viral load, the shorter the time to AIDS and the shorter the survival
time. The study results indicate that HIV RNA levels can predict
disease progression as far as 10 years into the future.

       The investigators also noted that when study participants are
divided into 2 levels based on their viral load at entry -- greater
than 10,190 or less than 10,190 copies/mL -- a surprising trend
emerges. The 10-year rate of survival was 70% for those with less than
or equal to 10,190 copies/mL compared to a survival rate of only 20%
for those with greater than 10,190 copies/mL, including those in this
group who had greater than 500 CD4 cells/mm3 at entry!

       New Treatment Recommendations

       Researchers at the University of California at San
Francisco-affiliated San Francisco General Hospital (SFGH) have
formulated interim recommendations on how to interpret viral load test
results in conjunction with CD4 cell counts (see Research Notes).  A
group of researchers and clinicians from the International AIDS
Society-USA also has published recommendations on how to interpret
viral load test results (Michael Saag, MD, and others. Nature Medicine
2: 625-629. May 1996).

       In these recommendations, the critically important numbers are
fewer than 5,000 copies/mL and greater than 10,000 copies/mL. An HIV
viral load test result of 5,000 copies/mL or less suggests a low level
of viral replication, and probably no immediate need to start therapy,
unless the CD4 count is less than 350 cells/mm3 (NOTE: some
researchers argue that any level of HIV activity above the level of
detection of the test used ought to prompt treatment!) A test result
of 10,000- 50,000 copies/mL or greater suggests significant viral
replication, and the SFGH recommendation is to consider therapy,
regardless of CD4 cell count. The higher the viral load, the higher
the risk for clinical decline and the more pressing the need to begin
(or change) treatment. A test result of over 100,000 copies/mL may
predict a rapid deterioration in clinical status. At this high level
of HIV RNA concentration, the recommendation is to immediately start
(or change) anti-HIV treatment.

       FDA Approves Roche Viral Load Test for Prognosis

       The U.S. Food and Drug Administration (FDA) approved the
Amplicor HIV-1 Monitor Test (the viral load test from Roche Molecular
Systems Inc.) for HIV disease prognosis on June 3, 1996, seven months
after Roche submitted an application for approval. This test is called
the reverse transcriptase polymerase chain reaction (RT-PCR) test or
simply "PCR." FDA is expected to approve Quantiplex (the viral load
test from Chiron Corporation) in the near future. The Chiron test is
commonly called the branched-chain DNA test or simply "bDNA."
Researchers have found that both the Roche PCR and the Chiron bDNA
tests give comparable results in measuring HIV RNA levels in the blood
plasma. Both tests cost $150-$200 per test, a price set by the
laboratories where the tests are processed. The cost is expected to
decline as laboratories face increased competition from each other.
Roche has announced plans to offer 2 free HIV RNA baseline tests to
all HIV positive patients in the U.S. over a 60-day period starting
June 17, 1996. Call 888-TEST-PCR for more information.

       Some researchers prefer the Chiron bDNA test because it is
simpler to conduct and provides a direct quantification of the HIV RNA
in plasma. Others prefer the Roche PCR test because it is more
sensitive and capable of measuring HIV RNA levels as low as 400
copies/mL. Both Roche and Chiron have developed more sensitive second
generation HIV RNA tests, which are not yet available except in
research settings. The second generation bDNA test will measure HIV
RNA levels as low as 300 copies/mL; the new Roche test will measure
HIV RNA levels as low as 20 copies/mL.

       Whichever test is chosen -- the Roche PCR or the Chiron bDNA --
it is important to continue using that same test to determine future
HIV RNA values. At present, it is also advisable to use only the Roche
or the Chiron test kits rather than "generic" viral load test kits
from a laboratory. For now, only the Roche and Chiron tests can be
expected to give consistent, reliable and comparable results. A third
test that is also accurate and reliable -- the nucleic-acid
sequence-based amplification (NASBA) test from Organon Teknika -- is
more commonly used in Europe than in the U.S.

       In using viral load testing to determine the level of HIV
concentration, it is necessary to obtain a baseline value for each
patient against which all future values can be compared. This is
achieved by averaging the results from 2 viral load tests taken 2-4
weeks apart It is also important to base treatment decisions on
sustained changes in viral load, not on a single measurement. Certain
factors, such as vaccination for influenza and herpes simplex
outbreaks transiently increase HIV levels in the bloodstream; other
types of immunizations and other acute illnesses also may transiently
increase HIV replication. Therefore, patients should avoid taking a
viral load test for about 4 weeks following immunizations and after
resolution of acute illnesses. When monitoring viral load results over
time, it is important to note that only increases or decreases in
viral load values of 3-fold or greater are considered significant
enough to warrant a change in treatment regimen. For example, if an
individual not on anti-HIV therapy with a baseline viral load test
result of 4,000 copies/mL takes the test 3 months later and has a test
result of 8,500 copies/mL, the increase is not considered significant
because it is less than 3-fold. However, if the new test result is
12,500 copies/mL or higher, the change is significant (greater than
3-fold), and the physician and patient should discuss starting
treatment.

       Viral Load Results for Evaluating the Success of Therapy

       In the coming months, more and more physicians will use the
Roche and Chiron viral load tests to monitor the effects of anti-HIV
therapy in their patients. Researchers have employed these test for
several years in AIDS drug research to help evaluate the effectiveness
of AIDS drugs. For example, FDA granted accelerated approval to the
protease inhibitor drugs saquinavir, ritonavir and indinavir based in
large measure on their ability to significantly decrease viral load as
measured by HIV RNA in HIV positive individuals. Within a short time,
viral load testing is expected to become an FDA-approved method for
demonstrating how well a particular anti-HIV drug or drug combination
works, without having to wait for clinical outcomes. In the future,
anti-HIV drugs may be routinely evaluated based on whether or not they
produce a sustained, significant decrease in viral load. Use of viral
load testing also may dramatically shorten the time needed to test
drug effectiveness. This could save millions of dollars in research
costs by dramatically reducing the need for long clinical studies.

       The increasing availability of the 3 new protease inhibitor
drugs and of viral load testing has ushered in a new era in the
treatment of HIV disease. With increased access to this powerful new
technology and to a new class of potent anti-HIV drugs, we are closer
to achieving the goal of making HIV disease a chronic manageable
illness.


       *********
       Pneumonia

       by Bruce Mirken  Bruce Mirken is a freelance writer based in
       San Francisco.

       Pneumocystis carinii pneumonia (PCP) was one of the first
identified manifestations of AIDS. Although improved strategies for
prevention and treatment of PCP have greatly reduced the number of
cases and deaths, PCP and other pneumonias remain a major cause of
illness and death among people with AIDS, and account for roughly
one-third of AIDS deaths. Because bacterial pneumonias and other
respiratory problems can sometimes produce similar symptoms, diagnosis
of PCP can be tricky. Today, use of prophylactic treatment to prevent
PCP in persons with fewer than 200 CD4 cells/mm3 is universally
regarded as one of the most effective medical interventions available.

       History and Trends

       Pneumonia -- infection and inflammation of the lungs in which
parts of the lungs may fill with fluid -- can be caused by a wide
variety of organisms, including bacteria, viruses and fungi. Whatever
the cause, pneumonia can be debilitating and often deadly.

Until the 1980s pneumonia caused by Pneumocystis carinii was extremely
rare: only about 50 cases were reported in 1970. Although the
organism--long regarded as a protozoan, but now understood to be more
like a fungus--is quite common, it is harmless in individuals with
healthy immune systems. Before AIDS, the few instances of PCP disease
occurred in people whose immune systems had been seriously weakened.
Cases were reported in malnourished World War II orphans and, more
recently, in organ transplant recipients receiving immunosuppressive
anti-rejection therapy and in people with cancer undergoing
chemotherapy.

When PCP began appearing in 1980 and 1981 in young gay men with none
of the usual risk factors, alarms went off at the Centers for Disease
Control (CDC).

In the early 1980s, doctors had little experience treating PCP; the
death toll was astonishing, and an average patient had only a 50%
chance of surviving an episode of the disease. Among those whose
illness was severe enough to require a breathing tube and ventilatory
support, the incidence of death reached 80%. For many years, PCP
remained the number one killer of people with AIDS. Even those who
recovered from a first episode of PCP generally saw their health
continue to decline. In over 60% of cases, PCP recurred, often with
increasing severity.

Despite recent progress, PCP is still cause for concern. As San
Francisco physician Lisa Capaldini, MD, put it recently, "If someone
gets PCP out of the blue, they're likely to have a progressive decline
in their health, because a rip-roaring pneumonia can really knock your
socks off."

Fortunately, progress on all fronts against PCP has made the outlook
more hopeful since the late 1980s. Improved diagnostic and treatment
methods began to increase survival. Perhaps most importantly,
increasing use of prophylactic medications to prevent PCP began to
reduce the number of cases.

An analysis by CDC researchers of HIV-related causes of death listed
on death certificates from 1987-1992 illustrates the point
dramatically. While the rates of death involving most other
opportunistic infections remained fairly constant, PCP-related
mortality dropped from 32.5% of HIV-related deaths in 1987 to 13.8% by
1992. In that same period, deaths due to bacterial pneumonia increased
from 1.2% to 2.1%. Unspecified pneumonias remained constant at about
18%. Some of these unspecified pneumonias no doubt represent
undiagnosed cases of PCP, while others represent divergent causes. The
researchers believe the decline in PCP canceled out increases in other
types of pneumonia in this "unidentified" group.

A similar trend has been seen in another CDC study, the Adult Spectrum
of Disease Project, which collected data from 100 inpatient and
outpatient medical facilities in 10 U.S. cities from 1990-1995.
Although only some of the data have been released, figures through
1993 show a gradual but steady decline in PCP incidence among gay and
bisexual men. In contrast, PCP rates increased among injection drug
users (IDU), although the increase did not quite achieve statistical
significance. Fewer of the IDU were receiving PCP prophylaxis, and the
researchers theorize that those who were may not have adhered to their
prophylactic regimens as well as the gay and bisexual men. Data on
other causes of pneumonia in this study have not yet been released.

The incidence of PCP in San Francisco has more or less conformed to
the national trend. Annual PCP cases peaked at 1,095 in 1987, leveled
off for a few years, and dropped to 613 by 1994. Data for 1995 are
still incomplete. According to Kevin McKinney of the city's AIDS
Office, reliable figures are not available for other types of
pneumonia.

Still, for a city as renowned for state-of-the-art HIV care as San
Francisco, PCP is far from vanquished. John Stansell, MD, Medical
Director of the AIDS Program at San Francisco General Hospital, notes,
"We still see a very large number of PCP cases here. Per month it's
probably gone from a high of about 30 cases to about 20-25. It's true
that there's been somewhat of a decline, but it's by far still the
most frequent opportunistic infection that we encounter here at San
Francisco General."

About half of those cases, Stansell continues, occur in people who
were not receiving PCP prophylaxis. Most of the others occurred in
persons who did not take their medication as scheduled or who were on
aerosolized pentamidine or dapsone, which are considered weaker PCP
preventatives than trimethoprim-sulfamethoxazole (TMP-SMX, brand names
Bactrim and Septra). Stansell believes that true "breakthrough"
infections while on TMP-SMX are "very rare" (see below for a detailed
discussion of PCP prophylaxis).

Stansell is part of the team conducting the long-term Pulmonary
Complications of HIV Infection study, which recruited patients at 6
sites around the country beginning in 1987 and followed them for 5
years. The study enrolled 1130 HIV positive participants and 167 HIV
negative controls matched for age and gender. Stansell calls it "the
first study that really aimed at enrolling a cohort that looked like
the AIDS epidemic" in terms of demographics. Much of the data are
still awaiting publication, but some appeared last September in the
New England Journal of Medicine (333(13): 845-51. September 28, 1995).

"The incidence of bacterial pneumonia was about 10-fold higher among
HIV-infected people than it was in uninfected individuals," Stansell
says. Although the rates of bacterial pneumonia--caused by various
organisms including Streptococcus pneumoniae and Haemophilus
influenzae--increased as CD4 counts declined, HIV positive persons
with normal CD4 counts still had significantly higher rates than the
uninfected controls. The explanation, Stansell suspects, is that
"there are probably qualitative differences in the ability of the body
to rid itself of pathogens if you're HIV-infected. The immune cells,
even if they're there, probably don't work as well."

Smoking was also associated with higher rates of bacterial pneumonia.
Strikingly, PCP prophylaxis with TMP-SMX was associated with a
two-thirds reduction in bacterial pneumonia, in addition to a decrease
in PCP.

Overall, those who experienced any type of pneumonia had a mortality
rate 4 times higher than those who did not. Equally distressing,
Stansell notes, is that "the people who have bacterial pneumonia
appear to have a greater risk of rapid progression in their HIV
disease. Those data are just being ferreted out now, but it looks like
it's a very bad prognostic indicator."

       Prophylaxis

PCP prevention has been one of the areas of greatest progress in HIV
care over the years. Some precautions can be taken to reduce the risk
of bacterial pneumonias as well.

The first line of defense, and one not to be underestimated, is to see
a physician who is knowledgeable about HIV disease. An assessment of
HIV care provided by primary care doctors published last year in
Archives of Internal Medicine found that large numbers of physicians
did not prescribe or recommend the most basic elements of HIV care.
For example, only half indicated that they would start appropriate PCP
prophylaxis.

If there is anything that AIDS-experienced physicians agree upon, it
is that PCP prophylaxis works. Standard practice is to recommend
prophylaxis for any HIV-infected person with 200 or fewer CD4
cells/mm3 or whose CD4 percentage is less than 14% of total
lymphocytes. PCP prophylaxis is also recommended for anyone,
regardless of CD4 count, who is experiencing a sharp decline in CD4
counts or persistent, unexplained fevers or thrush (shown in some
studies to be independent predictors of high risk for PCP). Anyone who
has already had 1 or more bouts of PCP should also receive
prophylaxis. Study after study has demonstrated that effective
prophylaxis sharply reduces the incidence of PCP in such individuals.

The CDC has developed specific PCP prophylaxis guidelines for infants
and children. The agency recommends prophylaxis for all infants born
to HIV-infected mothers starting at age 4-6 weeks, to be discontinued
if HIV antibody testing after 4 months of age indicates that the child
is HIV-uninfected. For HIV-infected children aged 1-5 years,
prophylaxis is recommended for those with fewer than 500 CD4 cells/mm3
or a CD4 percentage less than 15%. TMP-SMX, an oral antibiotic, is the
preferred drug. (For more on pediatric HIV infection, see HIV/AIDS in
Children, this issue.)

TMP-SMX is the prophylactic drug of choice for adults as well. Other
regimens, notably dapsone, another oral drug, and aerosolized
pentamidine (AP), inhaled in mist form through a device called a
nebulizer, are also used extensively. Besides being extremely
effective at preventing PCP, TMP-SMX has 2 other advantages: it is
inexpensive, and it also helps to prevent other diseases such as
toxoplasmosis (a brain infection) and bacterial infections including
pneumonia. However, TMP-SMX can produce a number of toxic side
effects, including rash, fever, nausea, vomiting and neutropenia (loss
of white blood cells). Life-threatening reactions, including severe
anaphylactic reactions or Stevens-Johnson syndrome (a condition
involving severe blistering and sloughing of skin and mucous
membranes) can occur, but are rare. Aerosolized pentamidine does not
prevent extrapulmonary PCP.

The scales were definitively tipped towards TMP-SMX by a study known
as ACTG 021, in which 1 double-strength tablet of TMP-SMX daily was
compared to 300 mg of AP given once per month to HIV positive persons
who had already had PCP at least once. PCP recurred in the AP group
more than twice as frequently as in the TMP-SMX group. Based on this
study, the U.S. Public Health Service recommended this dose of TMP-SMX
for PCP prophylaxis.

A later study, ACTG 081, published in the March 16, 1995 New England
Journal of Medicine, seemed to muddy the picture a bit. This trial
compared a higher dose of TMP-SMX (1 double-strength tablet twice
daily) to dapsone (50 mg twice daily) to AP (300 mg every 4 weeks) in
people with fewer that 200 CD4 cells/mm3 and no prior history of PCP.
Those who had serious (grade 3) toxic effects had their doses reduced
and/or were switched to a different therapy. Although TMP-SMX was more
active against PCP than the other drugs, toxicity forced 79% of those
receiving it to reduce the dose or switch to another drug.

The "intent-to-treat" analysis--comparing the groups based on the drug
they were originally assigned, regardless of later changes--showed
only statistically insignificant differences in the risk of developing
PCP among the 3 groups. Over 36 months, the risk was 18% in the
dapsone group, 17% in the TMP-SMX group and 21% in the AP group. For
those with fewer than 100 CD4 cells/mm3, though, the difference was
more pronounced: the risks of developing PCP were 22%, 19% and 33%,
respectively.

However, an "as-treated" analysis--looking at the therapy the patient
was actually receiving at the time of the PCP episode--tells a
somewhat different story. Only 4 of 34 treatment failures in the
TMP-SMX group occurred among people still taking the drug at the
original dose, and none occurred in those whose dose was reduced to
once daily. The failures overwhelmingly occurred after patients had
switched drugs. By contrast, 21 of 33 dapsone treatment failures
occurred while on that drug, and the failure rate increased 4-fold at
the first dose reduction. Few AP patients switched drugs, and 37 of 38
failures occurred while on AP.

The researchers concluded that although TMP-SMX is clearly stronger
against Pneumocystis (P.) carinii, use of this drug as the first
prophylactic strategy did not produce significantly better results
than starting with dapsone or AP. The reason, the researchers write,
is that "because of continuing cross-overs and dose reductions as the
trial progressed, more patients were receiving less adequate
treatments even as their vulnerability to P. carinii increased" due to
declining CD4 counts.

The impact of this study is somewhat uncertain. Clearly 2
double-strength TMP-SMX tablets per day showed no advantage over one.
Just as clearly, 100 mg per day of dapsone per day performed better
than 50 mg. Overall the researchers found "similar effectiveness," no
matter which drug patients started with. An accompanying editorial
went further, suggesting that AP, with its low toxicity, might be the
drug of choice for those with CD4 counts over 100 cells/mm3, and
TMP-SMX the preferred prophylaxis for those with fewer than 100
cells/mm3.

That suggestion goes against the generally accepted recommendation to
use TMP-SMX as first-line prophylaxis across the board. There seems
not to have been a general move in favor of AP since the study was
published. A meta-analysis of 35 randomized PCP prophylaxis trials
that appeared in the January 22, 1996 Archives of Internal Medicine
sheds more light on the situation.

The researchers pooled and analyzed the results from all 35 studies,
which looked at a variety of drugs--including TMP-SMX, AP and
dapsone--and dosing regimens. Some of the studies combined dapsone
with pyrimethamine.

Such an analysis has limitations. In comparing results from different
trials, it is impossible to  completely adjust for all of the
differences in trial methodology. Still, the researchers found clear
patterns that allowed them to draw some fairly solid conclusions.

"Regardless of dose," they wrote, "TMP-SMX was almost universally
effective for patients who tolerated it" [emphasis added]. Overall,
the drug was 42% more effective than AP in preventing PCP. The
difference between TMP-SMX and dapsone was not statistically
significant, though the trend favored TMP-SMX. A dose of 100 mg of
dapsone was more effective than 50 mg. Overall, AP had the fewest side
effects while TMP-SMX had the most.

There were few treatment failures on TMP-SMX, most of which occurred
after the drug had been discontinued. Most striking were the
dose-response relationships uncovered. For example, increasing the
daily dose of TMP-SMX seemed to hurt more than it helped; in fact,
there was a trend toward more failures at the highest dose tried (2
double-strength tablets per day, the regimen used in ACTG 081). AP,
meanwhile, did better when given twice monthly instead of the standard
once monthly dose.

Thus, reduced dosing of TMP-SMX--such as 1 double-strength tablet 3
times per week--might minimize the need to discontinue therapy due to
toxicity, with little loss in efficacy. The scientists caution that
relatively little data exists to support using this regimen in people
with lower CD4 counts or those who have already had PCP.

Another approach to dealing with the toxicity of TMP-SMX is known as
desensitization. This involves starting with tiny, diluted doses of
the drug and building up to the regular dose over a period of days, so
that the body gradually learns to tolerate it. Many different
desensitization protocols exist. One version offered by Project Inform
takes 8 days; others take more or less time. Considerable success has
been reported with desensitization, although it is generally
considered too risky to attempt with persons who have had a severe
anaphylactic reaction to sulfa drugs or who have had Stevens-Johnson
syndrome.

What is less clear is which protocol is best. "There's no standard,"
observes San Francisco clinician and AIDS researcher Gifford Leoung,
MD. "It's all arbitrary; there are no published data from
well-organized trials. In fact," he continues, "there's a paper that
came out last year that suggested you don't even need to desensitize
people." Instead, you can "just give them a single dose--directly
challenge them right up-front." Leoung is protocol chair of an
American Foundation for AIDS Research-financed trial that is now
comparing this direct-rechallenge approach with gradual
desensitization.

In any case, Stansell declares, "The most important thing you can do
for yourself is to take PCP prophylaxis." Whatever treatment you're
on, it is critical to do it right. That means taking your pills as
scheduled, and if side effects make that difficult, talking with your
doctor about ways to manage the problem, rather than haphazardly
skipping doses. If you are using AP, follow the instructions you are
given about posture and breathing during the treatment. Slouching and
breathing shallowly will prevent the medication from getting all the
way into the lungs, reducing the benefit.

For protection against bacterial pneumonia, the CDC recommends
vaccination with pneumococcal vaccine as soon as possible after
testing HIV positive, a recommendation the agency calls "especially
pertinent in light of the increasing incidence of invasive infections
with drug-resistant strains of Streptococcus pneumoniae." Vaccination
against Haemophilus influenzae "may be considered, but data are
insufficient to recommend the use of this vaccine in HIV-infected
adults at this time."

As Stansell points out, TMP-SMX seems to offer some protection against
bacterial pneumonias as well as PCP. Although the CDC suggests this be
considered when choosing PCP prophylaxis, it warns that
"indiscriminate use of this drug 'when not indicated for PCP
prophylaxis or other specific reasons' may promote the development of
resistant organisms." In addition, the drug will not protect against
drug-resistant strains.

       Diagnosis

A constellation of symptoms, including fever, cough, fatigue and
shortness of breath, can signal the onset of pneumonia. Some or all of
these symptoms may be present. Of course, many other conditions, such
as bronchitis and the common cold, can produce some of the same
effects. If symptoms continue beyond a few days or worsen, it is
essential to seek medical evaluation. Caught early, most pneumonias
can be successfully treated, often on an outpatient basis, but if
allowed to worsen, they can be life-threatening.

It is important to be able to describe your symptoms in as much detail
as possible, including the length of time they took to appear, because
these details will help your physician to narrow down a diagnosis.
Symptoms can be clues to the cause of the pneumonia. For example,
bacterial pneumonias tend to develop rapidly, often within 24 hours or
less, while other lung infections, including Aspergillus or Mycoplasma
infections, tend to have a slower onset. PCP also tends to come on
slowly. Leoung says symptoms may be barely perceptible at first but
then worsen slowly over a period of weeks.

The cough can also be an important clue. A classic PCP cough is dry,
with little or no sputum; any sputum that is produced is likely to be
clear. Bronchitis, on the other hand, can often produce large amounts
of sputum; and bacterial pneumonias produce greenish, rust-colored,
bloody or yellow-tinged sputum.

Often a doctor will listen to the patient's chest with a stethoscope.
Pneumonias often produce a characteristic breathing sound called
"rales," while bronchitis usually does not; PCP may or may not produce
recognizable chest sounds.

Chest X-rays are often used to make a diagnosis because different
illnesses produce characteristically different patterns. However, a
certain amount of natural variation occurs on X-rays, and PCP may not
always be visible. Further testing is required to confirm a diagnosis
made by X-ray.

Along with identifying the cause of the problem, Leoung notes, it is
important to quickly make other key determinations. "How sick is this
person? Do they need to be in the hospital? That's the real next
question. If they're not getting enough oxygen they can't go home. Is
this illness serious enough to require IV antibiotics, as opposed to
oral antibiotics? If so, the person most likely needs to be
hospitalized."

One important measure of the seriousness of any type of pneumonia is
its effect on the amount of oxygen that gets into the blood. Two
different tests are commonly used for making this determination. The
simplest but crudest is known as pulse oximetry, which involves
placing a device that resembles a clothes pin on a finger to measure
the amount of oxygen under the skin. Although oximetry is simple and
fast, Stansell dismisses it as "very inexact." A far more precise
method is to draw arterial blood and measure the gases it contains.
Unfortunately, arterial blood gas measurement can be painful, because
arteries tend to have more nerve endings than the veins used for most
other blood tests.

Aside from these test results, the decision to hospitalize or not can
involve what Leoung calls a somewhat subjective evaluation of "how
much you think this person can tolerate in terms of getting worse. If
there's a lot of leeway, you can go home because there's time to get
you back in here. But if you're close to the edge, I don't want to
send you home. Sometimes I rely on my gut feelings; the numbers may
look great, but the person just does not look good." As with
prophylaxis, these judgment calls tend to be most reliably made by an
HIV-experienced physician.

If the symptoms, history and X-rays seem to point in one
direction--PCP, for example--the physician will probably recommend
beginning treatment immediately. Even so, standard practice in San
Francisco is to make a confirmatory test for the responsible organism.
Unusual symptomology can occur, and sometimes more than one condition
may be present at once, with one set of symptoms partly masking
another.

The least invasive way to confirm a diagnosis is through a procedure
called sputum induction. The patient breathes a saline mist which
provokes coughing, hopefully bringing up sputum which can be examined
for P. carinii, bacteria, fungi or whatever organisms the symptoms and
X-rays suggest. Patients are advised not to eat for 8 hours before the
procedure, nor to use toothpaste or mouthwash, all of which can
interfere with the results. Stansell calls sputum induction "a
technically difficult procedure," which not everyone manages to do
well. At San Francisco General Hospital, where the procedure is
frequently used, over 70% of PCP diagnoses are made this way, but
facilities that use the technique less are not usually this
successful.

If sputum induction fails to enable a diagnosis, the next, more
invasive step is bronchoscopy. In this procedure, a tube is inserted
through the mouth or nose into the breathing tubes. The patient is
generally sedated and the throat numbed, which makes bronchoscopy "a
very quick, very easy, painless procedure," according to Stansell.
Still, the invasive procedure is not easy to tolerate. One or both
lungs are washed  out (lavaged) to flush out the organisms, and
brushings of the bronchial walls may also be done. The fluid and
brushings are then examined by microscope.

Fortunately, bronchoscopy tends to be extremely accurate at producing
a confirmed diagnosis. A far more invasive approach, a surgical
procedure called an open-lung biopsy, is now only very rarely used to
diagnose HIV-related pneumonia.

Recently, researchers from the National Institutes of Health have
advocated treatment for AIDS-related pneumonia, including PCP, without
necessarily looking for the Pneumocystis organism, if cost-effective
facilities for PCP testing are not available (see Research Notes, this
issue).

       Treatment

General guidelines for treatment of all pneumonias emphasize adequate
hydration to help clear secretions. If a patient is so sick that
adequate intake of fluids by mouth is difficult, intravenous
supplementation may be needed.

The drug therapy used depends on the organism responsible. Pneumonias
caused by fungi such as Cryptococcus or Histoplasma are treated with
the same antifungals, such as amphotericin B, itraconazole and
fluconazole, that are used to treat other ailments caused by these
organisms. Similarly, the relatively rare pneumonia caused by
cytomegalovirus (CMV) is treated with the familiar anti-CMV drugs
ganciclovir and foscarnet.

Treatment of bacterial pneumonias may require any of numerous
antibiotics, including penicillin, amoxicillin, TMP-SMX,
clarithromycin, azithromycin and the cephalosporins, depending on the
specific bacteria involved. A potential source of difficulty is the
increasing occurrence of drug-resistant strains, and the CDC
recommends drug sensitivity testing to ensure that an appropriate
therapy is chosen.

Although PCP treatment has improved steadily over time, the picture
has not changed dramatically since BETA published "Guidelines for
Treatment of Pneumocystis carinii Pneumonia," by editor Ronald Baker,
PhD, in March, 1993. TMP-SMX remains the first-line treatment, whether
administered intravenously for severe cases or orally for milder ones.
The drug's toxicities may be problematic, but can often be controlled
with dose adjustments and/or use of antihistamines and fever-reducing
drugs. Still, in some cases it is necessary to switch to another drug.

In severe cases that require intravenous (IV) therapy, IV pentamidine
remains the second-line drug of choice. Like TMP-SMX, it is extremely
effective against PCP. However, IV pentamidine can produce serious,
sometimes irreversible side effects, such as abnormally low blood
pressure, or blood sugar level abnormalities including diabetes,
pancreatitis (pancreas inflammation), kidney toxicity and loss of
white blood cells. Because of these toxicities, most physicians use IV
pentamidine only in the worst cases, and only after first trying
TMP-SMX.

In recent years, trimetrexate has emerged as a third-line IV therapy
for PCP. The drug must be administered with a second drug, leucovorin,
to counter its toxic side effects. In an ACTG-sponsored study
comparing trimetrexate plus leucovorin to TMP-SMX in patients with
moderate to severe PCP, trimetrexate was better tolerated but less
effective; the trimetrexate group had a significantly higher death
rate. The high cost of trimetrexate-leucovorin is another
disadvantage.

In moderate to severe cases, using a short course of corticosteroids
such as prednisone along with antibiotic therapy has been shown to
reduce the chances of respiratory failure and death. These regimens do
not affect P. carinii directly; rather, they apparently decrease the
body's inflammatory response to the organism, thereby alleviating
breathing difficulties.

Several options are now available for people who cannot tolerate
TMP-SMX but do not need IV therapy. The first fallback option is
usually dapsone-trimethoprim or clindamycin-primaquine.
Dapsone-trimethoprim, Leoung notes, is simple to administer and
generally easier to tolerate than clindamycin, but some physicians
prefer clindamycin-primaquine. In a recent 91-patient Canadian study,
clindamycin-primaquine worked roughly as well as TMP-SMX, with fewer
serious side effects but greater incidence of rash.

A more recent entry among the oral drugs is atovaquone (Mepron).
Manufacturer Burroughs Wellcome (now Glaxo-Wellcome) took offense when
Baker listed atovaquone as the fourth-line therapy 3 years ago (BETA,
pp 18-19, March 1993). Data obtained since then, as well as a new
formulation, have only somewhat boosted the drug's position.
Atovaquone's strongest positive attribute is its low level of side
effects. In studies comparing it to either TMP-SMX or pentamidine,
atovaquone generally was less active against PCP but better
tolerated--enough so that significantly more patients completed
therapy without having to switch drugs.

A new, better-absorbed liquid formulation could improve atovaquone's
efficacy, but the new formulation came with new labeling reducing the
dosing from 3 to 2 times a day--producing approximately the same blood
levels of the drug. To get new labeling, the company will need to do
further research on the new formulation; in the meantime, doctors are
not sure how best to use the drug. Leoung comments that "people have
always had a little concern about using atovaquone alone. Most doctors
who've had experience with atovaquone say, 'Well, I wouldn't give it
to somebody who's really sick.' We don't know yet."

As with all areas of HIV/AIDS care, optimal prevention and treatment
of pneumonia are facilitated when patients take an active role in
their care. Persons who carefully note and report symptoms and side
effects to their health care providers and who ask questions when they
are unsure about tests or treatments improve their chances for
successful care. In the present cost-conscious managed-care
environment, doctors can be under tremendous pressure to do things as
quickly and inexpensively as possible. "Be proactive," Leoung advises,
"Speak up."

       References

       Baker RA and J Kapusik-Uner. Guidelines for treatment of
       Pneumocystis carinii pneumonia (PCP). BETA 18-19. March 1993.

       Bozette S and others. A randomized trial of 3 anti-pneumocystis
       agents in patients with advanced human immunodeficiency virus
       infection. New England Journal of Medicine 332(11): 693-699.
       March 16, 1995.

       Centers for Disease Control and Prevention. 1995 revised
       guidelines for prophylaxis against Pneumocystis carinii
       pneumonia for children infected with or perinatally exposed to
       human immunodeficiency virus.  Morbidity and Mortality Weekly
       Report 44(RR-4). April 28, 1995.

       Centers for Disease Control and Prevention. Bacterial
       respiratory infections, prevention of exposure. Morbidity and
       Mortality Weekly Report 44(RR-8). July 14, 1995.

       Clumeck N. Primary prophylaxis against opportunistic infections
       in patients with AIDS. New England Journal of Medicine 332(11):
       739-740. March 16, 1995.

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

       Hirschtick RE and others. Bacterial pneumonia in persons
       infected with the human immunodeficiency virus. New England
       Journal of Medicine 333(13): 845-51. September 28, 1995.

       Hughes W and others. Comparison of atovaquone (566C80) with
       trimethoprim-sulfamethoxazole to treat Pneumocystis carinii
       pneumonia in patients with AIDS. New England Journal of
       Medicine 328(21): 1521-1527. May 27, 1993.

       Ioannidis J and others. A meta-analysis of the relative
       efficacy and toxicity of Pneumocystis carinii prophylactic
       regimens. Archives of Internal Medicine. 156: l77-188. Jan. 22,
       1996.

       Luce J and MJ Clement. Pulmonary diagnostic evaluation in
       patients suspected of having an HIV-related disease. Seminars
       in Respiratory Infections. 4(2): 93-101. June 1989.

       Moe AA and WD Hardy. Pneumocystis carinii infection in the
       HIV-positive patient. Journal of the Physicians Association for
       AIDS Care 20-35. June 1994.

       Rubin RH. Infection in the immunosuppressed host. Scientific
       American Medicine 7:X:1-23. July, 1994.

       Rubin RH and R Greene. Clinical approach to the compromised
       host with fever and pulmonary infiltrates. Clinical Approach to
       Infection in the Compromised Host. Plenum Medical Book Company,
       New York, NY, 1994.

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

       Schwab D. Sulfa desensitization. Project Inform Fact Sheet
       Supplement. May 23, 1993.

       Selik RM and others. Trends in infectious diseases and cancers
       among persons dying from HIV infection, USA, 1987-1992. 35th
       Interscience Conference on Antimicrobial Agents and
       Chemotherapy. September 17-20, 1995. Abstract #I-22.

       Toma E and others. Clindamycin/primaquine (C/P) vs.
       trimethoprim-sulfamethoxazole (T/S) for PCP in AIDS. 35th
       Interscience Conference on Antimicrobial Agents and
       Chemotherapy. September 17-20, 1995. Abstract #LM96.   Back to
       the BETA Page Back to the Treatment Education and Advocacy Page
       Back to the San Francisco AIDS Foundation Home Page


       ***********************************************
       Non-Nucleoside Reverse Transcriptase Inhibitors

       by Mark Bowers

       Mark Bowers is Managing Editor of Treatment Publications at the
       San Francisco AIDS Foundation.

       The drugs that can be used to treat HIV infection may be
divided into several classes, according to the stage of viral
replication that they target. An understanding of the benefits and
limitations of the drugs by class, by themselves and in combination
with other antiretroviral drugs, can help physicians and patients make
rational decisions and establish long-range strategies for the
management of HIV disease.

       The Food and Drug Administration (FDA) has approved
antiretroviral drugs for treating HIV disease from 3 different
classes. The first class is nucleoside analog reverse transcriptase
inhibitor drugs, often called simply nucleosides, e.g., AZT
(Retrovir), ddC (Hivid), ddI (Videx), d4T (Zerit) and 3TC (Epivir).
The second class is protease inhibitor drugs, including saquinavir
(Invirase), indinavir (Crixivan) and ritonavir (Norvir).

       Non-nucleoside reverse transcriptase inhibitor (NNRTI) drugs
are a third class of antiviral drugs. On June 7, 1996, an antiviral
drugs advisory committee recommended accelerated approval for
nevirapine, the first NNRTI to receive such approval. These drugs
target the same enzyme as the familiar nucleoside analog drugs, but
interfere with the enzyme in a different way. It is not clear exactly
how NNRTI drugs work, but it is known that they target the structure
of reverse transcriptase to inhibit enzyme activity. Nucleoside analog
drugs do not target reverse transcriptase structure; instead they
cause premature termination of the viral DNA chain.

       Although many different NNRTI drugs have progressed to clinical
study, only nevirapine (Viramune, from Boehringer Ingelheim), a-APA
(Loviride, from Janssen) and delavirdine (Rescriptor, from Upjohn
Pharmacia) have been investigated in Phase III trials. All 3 drug
developers are expected to submit data to FDA for marketing approval
during 1996. A new drug application (NDA) for nevirapine was filed on
February 23, 1996 and the supporting data was evaluated in June; the
makers of delavirdine are preparing an NDA; and loviride will be
evaluated at the end of the year. Nevirapine and delavirdine have been
extensively tested in the U.S., while loviride has been clinically
tested only in Europe.

       The major issues that face the future development of NNRTI
drugs are the rapid emergence of resistance when they are used as
monotherapy, cross-resistance with certain other antiviral drugs, and
the potential for use in combination with antiviral drugs of other
classes.

       Resistance and Cross-Resistance

       Resistance is the ability of HIV (or any pathogen) to change
its chemical structure in order to withstand the effects of drugs used
to treat it. Any antiretroviral drug used as monotherapy may breed
some level of resistance. Initial studies of NNRTI drugs indicated
that viral resistance quickly emerged in monotherapy-treated study
participants. Resistance developed more quickly than with nucleoside
analog drugs, and dampened early enthusiasm for the whole class of
drugs, probably inappropriately.

       HIV can become resistant to 2 or more drugs at the same time,
resulting in cross- resistance. The cross-resistance patterns of the
many antiretroviral drugs from various classes, including nucleoside
analogs, NNRTI, protease inhibitors and integrase inhibitors are being
continuously evaluated. The National Cancer Institute screens 10,000
synthetic compounds each year for anti-HIV activity. More than 2,500
NNRTI drugs have been screened, and their in vitro resistance patterns
mapped against anti-HIV drugs from other classes. Resistance to 1
NNRTI drug usually results in cross-resistance to the entire class.
However, clinical benefit may continue even when resistance is
detected, through mechanisms that are not currently understood.

       The relationship between resistance and how best to treat HIV
disease is not yet clear. However, the use of NNRTI drugs in
combination with other anti-HIV drugs may be the best strategy to
avoid or delay resistance. The cornerstone of most clinical experience
with NNRTI drugs is their lack of cross-resistance with AZT. Other
possible combinations are also being explored by the drug
manufacturers, including combining NNRTI drugs with other approved
nucleoside analogs and with protease inhibitors.

       The Rationale for Combination Therapy

       Combinations of drugs are more effective than monotherapy at
reducing viral replication and viral burden. Some combinations
demonstrate cumulative or synergistic antiviral effects, such as the
combination of 3TC and AZT, or nevirapine and AZT. Furthermore,
considerable benefit can be gained from pairing drugs that have
opposing resistance patterns: when one drug induces viral resistance,
the mutant HIV that is created becomes susceptible to the other drug.
A possible role for NNRTI drugs in combination antiviral strategies
was framed in 1991 by Douglas Richman, MD, and colleagues, who
demonstrated that nevirapine is active against AZT-resistant HIV and
synergistic with AZT. Optimal clinical benefit may depend on the
selection of antiretroviral drugs that are not cross-resistant. At the
Sardinia AIDS Conference in July 1995, S.K. Sharma, PhD, of Upjohn
Laboratories, reported that a specific genetic mutation of reverse
transcriptase that appears in response to treatment with the NNRTI
drug U-104489 produces a virus that is less able to replicate.

       Useful combinations of anti-HIV drugs must not include drugs
that induce cross-resistance, create synergistic toxicities (augmented
adverse side effects) or work against one another because of
interactions. Despite the fact that known toxicities of some drugs
make them appear to be poor choices for combination, some studies
indicate that overlapping toxicities may be managed by reducing the
dosages of the drugs. In some cases, expected additive or synergistic
toxicities simply have not emerged clinically in the people who are
taking the drugs. The combination of d4T and ddI or ddC was predicted
to result in more incidences of drug-related peripheral neuropathy
because of overlapping toxicities, but increased peripheral neuropathy
has not often been seen clinically.

       Some of the FDA-approved antiretroviral drugs also have
significant interactions with other drugs that are commonly used to
treat people with HIV. For instance, AZT interacts with ganciclovir (a
drug for treating cytomegalovirus infection) to cause hematologic
toxicities, and AZT interacts with fluconazole (a drug used to treat
fungal infections) such that blood levels of AZT are significantly
increased. These problems can be managed by substituting different
drugs that have similar therapeutic effects but do not have
interactions with the selected antiretroviral drug, or by altering
dosages.

       Richard D'Aquila, MD, at Harvard Medical School, cites data
that show that viruses with some AZT resistance mutations replicate
better than wild-type virus (HIV that has not been exposed to pressure
to mutate, e.g., by the use of antiretroviral drugs). The creation of
a specific mutation in HIV through the addition of 3TC results in
increased sensitivity to AZT, which makes this combination attractive
to many people. Additionally, synergism between AZT and nevirapine or
delavirdine and many other NNRTI has been demonstrated. What remains
to be seen is how durable the effect of combinations of NNRTI drugs
with other drugs will be, and the impact on survival and disease
progression.

       Clinical Data

       Nevirapine

       Boehringer Ingelheim was recommended for accelerated approval
to market nevirapine for the treatment of HIV disease in combination
with 1 or more nucleoside analogs on June 7, 1996. Accelerated
approval is a drug evaluation mechanism created and regulated by FDA
that brings promising drugs for life-threatening illnesses to the
market more quickly than the standard drug approval process.
Boehringer proposed an indication that would limit the use of
nevirapine to HIV positive people who have been previously treated
with nucleoside analog drugs and for whom current therapies are deemed
inadequate, but the advisory committee recommended wider approval.

       To support the request for accelerated approval, Boehringer
Ingelheim submitted to FDA clinical 2 surrogate marker studies, data
from 2 confirmatory endpoint trials that demonstrate a measurable
antiviral effect, and an expanded access protocol initiated in April
1996.

       Evaluation of the 2 confirmatory endpoint studies was crucial when FDA
decided on the appropriate indication for nevirapine. The indication
defines the appropriate patient population and approved reasons to use
a drug clinically. Physicians refer to the drug's indication when
deciding who is an appropriate candidate for therapy, and insurers
often look closely at the indication when they decide whether to
reimburse for a prescription. State-run drug reimbursement programs
such as the California AIDS Drug Assistance Program (ADAP) also look
at the indication when deciding whether a drug should be covered.
Physicians are not limited when they write prescriptions for any
approved drug as long as the use of the drug is, in their opinion,
clinically legitimate.

       AIDS Clinical Trials Group (ACTG) 193a, a double-blind,
placebo-controlled study, evaluated the differences in survival and
clinical AIDS progression in 1,307 volunteers with fewer than 50 CD4
cells/mm3. One of 4 drug regimens was assigned to each volunteer: AZT
plus ddI, AZT alternating with ddI, AZT plus ddC, and AZT plus ddI
plus nevirapine. The direction of this study was in-fluenced by data
that emerged from studies of protease inhibitors and by competition
for volunteers when ACTG 320, a study that includes a protease
inhibitor (indinavir) or placebo plus open-label AZT and 3TC was
opened. The results of study 193a are being analyzed to see what
statistically significant differences in survival and in clinical AIDS
progression were revealed. Analysis is expected to be completed in
June 1996.

       Boehringer Ingelheim is now sponsoring study 1100.1090, a large
(2,000 persons with CD4 counts below 200 cells/mm3) double-blind,
placebo-controlled study in the U.S., Canada, Australia, Europe and
South Africa to evaluate survival and AIDS progression. Two
triple-drug regimens are offered: AZT or ddC or ddI plus 3TC plus
nevirapine, or AZT or ddC or ddI plus 3TC plus placebo.

       The use of protease inhibitors in combination with nevirapine
will not be permitted until drug interaction studies have shown that
the combination is safe. A pharmacologic interaction study of
saquinavir plus nevirapine is underway. The primary concern is to
determine if nevirapine will significantly reduce plasma levels of
saquinavir, or vice versa. Because of the way in which these 2 drugs
are metabolized, saquinavir would theoretically be most likely to be
affected by the co-administration of nevirapine. Other protease
inhibitors are expected to be less affected by the induction brought
about by nevirapine. Preliminary data from the interaction study was
available for presentation at the June FDA advisory committee hearing.
Although not conclusive, the interaction between saquinavir and
nevirapine seems mild so far.

       Of particular interest to the antiviral advisory committee were
preliminary data from a study of the administration of a single dose
of nevirapine to HIV infected pregnant women when they begin labor,
followed by a single dose later given to the newborn. Because the
serum concentrations of nevirapine are so reliable, because the drug
crosses the placenta easily and is found in therapeutic concentration
in the umbilical cord, and because the half life of the drug is
comparatively long, nevirapine may provide protection against
mother-to-infant transmission comparable to that seen with the
perinatal administration of AZT. Preliminary data indicate that
therapeutic levels of nevirapine are maintained in the mother's
colostrum (first breast milk) after only 1 dose of nevirapine.

       In order to persuade FDA to grant marketing approval for
nevirapine, Boehringer Ingelheim needed to demonstrate that:

        A serious medical need not met by currently available
         therapies can be filled by nevirapine

        The use of nevirapine provides meaningful benefit beyond what
         is available with existing treatments

        Nevirapine has a favorable impact on survival or disease
         progression in some identifiable group of patients.

       Maureen Myers, MD, the person in charge of nevirapine
development at Boehringer Ingelheim, says, "the way to use nevirapine
to maximum effect is to avoid the emergence of resistance, and in so
doing, minimize viral replication."

       An expanded access protocol for nevirapine has been established
for those who are ineligible or unable to participate in the current
active clinical studies. Contact the Viramune Expanded Access Program
at 1-800-595-5494.

       Delavirdine

       Few published clinical data support an application for
accelerated approval for delavirdine. However, the analysis of the
data collected so far from Upjohn protocols 0017 and 0021 illustrate
the potential benefits of delavirdine in combination with nucleoside
analog drugs.

       Upjohn protocol 0021 was a randomized, double-blind 2-year
dose-response study in volunteers with CD4 counts between 200 and 500
cells/mm3. The study compared 200 mg, 300 mg and 400 mg of delavirdine
3 times a day in combination with AZT. The study also included an
AZT-only group. Because data from ACTG 175 and the European Delta
Study showed that AZT monotherapy was less effective than AZT plus
ddI, AZT plus ddC, or ddI monotherapy, participants in the AZT-only
group and those in the 200 mg delavirdine group are being
re-randomized to receive the triple combination of AZT plus 3TC plus
either placebo or delavirdine at 400 mg 3 times a day. The difference
in effect of the triple combination of AZT plus 3TC plus delavirdine
compared to AZT plus 3TC will be measured by CD4 cell counts, ICD p24
antigen levels, and HIV RNA and DNA levels measured by polymerase
chain reaction (PCR).

       A preliminary look at the data from 800 participants enrolled
in protocol 0021 showed an average 20 cell/mm3 increase from baseline
CD4 cell count sustained for more than 1 year and a long-term decrease
in viral burden (more than 1 year) as measured by HIV RNA levels of
greater than or equal to 0.5 log. Viral burden decreases were noted
for up to 60 weeks. The group receiving 400 mg of delavirdine 3 times
a day showed the greatest reductions in viral burden. Interestingly,
the participants who saw a 0.5 log reduction in viral burden by the
eighth week of treatment were about 2.5 times less likely to progress
to AIDS or death after 60 weeks. The response to treatment also
appears to depend on the magnitude of viral burden at entry into the
study; for participants with a viral burden greater than 5 logs at
entry, a treatment-associated decrease in viral burden of 0.5 log for
as little as 8 weeks reduced the incidence of disease progression by
50% or more.

       Upjohn protocol 0017, begun in April 1994, is a double-blind,
randomized, comparative study of delavirdine in combination with ddI
versus ddI monotherapy. The same surrogate markers are being used to
evaluate this study as are used in protocol 0021. Study participants
have lower CD4 counts (between 0 and 300 cells/mm3), and may have had
unlimited exposure to AZT and less than 4 months of prior ddI use.
About 400 participants are now registered in each of 2 study arms. One
arm offers 400 mg of delavirdine 3 times daily plus ddI at 200 mg
twice daily to participants who weigh more than 60 kg, or 125 mg twice
daily to those who weigh less than 60 kg; the second arm offers
placebo plus ddI by weight, as above.

       ACTG 261, begun in September 1994, is a Phase II, randomized,
double-blind trial of delavirdine in combination with AZT and/or ddI
versus AZT monotherapy versus ddI monotherapy for participants with
CD4 counts from 100-500 cells/mm3 and less than 6 months prior AZT or
ddI use. The study of 549 volunteers will continue for 48 weeks;
analysis of data is not expected until early 1997.

       Important drug interactions with delavirdine include rifampin
and rifabutin, and the antihistamines terfenadine (Seldane),
astemizole (Hismanal) and loratidine (Claritin). Clarithromycin can be
used instead of rifabutin to prevent Mycobacterium avium complex
(MAC). The use of ddI decreases the absorption of delavirdine. To
manage this interaction, delavirdine should be taken 1 hour before
taking either ddI or antacids. Delavirdine is now available through an
expanded access program for HIV positive people over 13 years old who
have CD4 cell counts ranging from 0-300 cells/mm3, are failing to
respond to other therapy and are receiving at least 1 other
antiretroviral drug. Physicians may contact the Delavirdine Expanded
Access program at 1-800-779-0070.

       Loviride

       The European clinical experience with Janssen Pharmaceuticals'
non-nucleoside reverse transcriptase inhibitor has been more extensive
than American clinical experience. In one study, loviride monotherapy
was compared to AZT monotherapy, loviride plus AZT, and 3 months of
placebo followed by 3 months of loviride monotherapy in a 6-month
double-blind study of 56 volunteers with CD4 cell counts between 200
and 500 cells/mm3 and some prior AZT experience. Quantitative PCR
measures of HIV RNA in peripheral blood revealed that the combination
arm of the study had an average 1 log drop in viral load from baseline
to week 8.

       A second 6-month double-blind, placebo-controlled study of 114
participants with no prior antiretroviral drug experience and CD4 cell
counts less than 400 cells/mm3 compared the effects of R18893 (another
NNRTI drug) at 200 mg 3 times a day to loviride at 100 mg 3 times a
day or to placebo. CD4 cell counts rose 15% over baseline measurements
after 8 weeks on loviride and were sustained for at least 6 months.

       A current Phase III study of loviride compares AZT monotherapy,
AZT plus 3TC and AZT plus 3TC plus loveride. Janssen is expected to
submit collected results of clinical studies to FDA for an NDA in late
1996 or early 1997.

       Drug Approval Considerations

       Since both nevirapine and delavirdine have time-limited
anti-HIV activity, it will be important for the drug manufacturers to
show where NNRTI drug use is of greatest utility. One consideration is
the relatively few side effects and drug interactions that accompany
the use of NNRTI drugs when compared to the more powerful protease
inhibitor drugs. A key issue for FDA to consider when deciding whether
to give other NNRTI drugs accelerated approval is that they
demonstrate considerable clinical benefit by reducing viral load at
nearly any point in HIV infection.

       The most complex issue involving the potential use of NNRTI
drugs is to settle on a group or groups of patients who will likely
benefit from a combination therapy that includes an NNRTI.
Theoretically, a combination of drugs that work at different stages of
the viral life-cycle may more effectively delay the emergence of
resistance and prolong inhibitory activity, producing clinical
benefit.

       What benefit can NNRTI drugs really offer? Clinical experience
so far is somewhat puzzling; although resistance to NNRTI drugs can
emerge as quickly as days to weeks after starting them, reductions in
viral load continue after resistance has been documented. Do the drugs
in this class exert selective pressure on HIV to hold down the rate of
replication even as resistance increases? The answers to these
questions probably depend on individual responses to antiretroviral
combinations, and the use of NNRTI drugs should be evaluated on a
case-by-case basis.

       Other NNRTI Drugs

       Several other NNRTI drugs are in earlier stages of development
and evaluation. HBY097 (Hoechst Roussel and Bayer) is in Phase I/II
testing at Stanford University; this is a novel NNRTI that produces a
specific genetic mutation in HIV in the test tube that may correlate
with the emergence of a less virulent virus. Thomas Merigan, MD,
principle investigator for the study, is looking for the mutation and
the durability of the drug's antiviral effect. If the mutation
consistently appears, it will be necessary to demonstrate that the
resulting virus is less able to cause HIV disease progression or leads
to increased survival, questions which are open at this time.

       Conclusions

       The number of approved antiretroviral drugs has increased
significantly in the last few years. As the number increases, the
number of possible combinations increases as well. Experience has
taught clinicians that the best strategy for managing HIV disease is
individualized therapy. Individualized therapeutic strategies can be
evaluated for their continuing effectiveness by periodic reference to
the results of viral load tests, such as branched-chain DNA and PCR
assays. For some people, NNRTI drugs will significantly reduce viral
load, and it will remain low for long periods. These are the best
candidates for NNRTI drug use. It remains for clinical studies to
pinpoint who will benefit most, and for FDA to provide guidelines
through the wording of the individual drug indications.

       References

       Cheeseman S and others. Phase I/II evaluation of nevirapine
       alone and in combination with zidovudine for infection with
       human immunodeficiency virus. Journal of Acquired Immune
       Deficiency Syndromes and Human Retrovirology 8: 141-151. 1995.

       Dueweke T and others. U-90152, a potent inhibitor of human
       immunodeficiency virus type 1 replication. Antimicrobial Agents
       and Chemotherapy 37(5): 1127-1131. May 1993.

       Freimuth W. Delavirdine mesylate, a potent non-nucleoside HIV-1
       reverse transcriptase inhibitor. Antiviral Chemotherapy 4:
       279-289. 1996.

       Hammer S and others. Issues in combination antiretroviral
       therapy: a review. Journal of Acquired Immune Deficiency
       Syndromes and Human Retrovirology 7(Suppl.): S24-S37. 1994.

       Havlir D and others. A pilot study to evaluate the development
       of resistance to nevirapine in asymptomatic human
       immunodeficiency virus-infected patients with CD4 cell counts
       of > 500 cells/mm3 : AIDS Clinical Trials Group protocol 208.
       Journal of Infectious Diseases 172: 1379-83. 1995.

       Havlir D and others. High-dose nevirapine: safety,
       pharmacokinetics, and antiviral effect in patients with human
       immunodeficiency virus infection. Journal of Infectious
       Diseases 171: 537-545. 1995.

       Larder B. Viral resistance and the selection of antiretroviral
       combinations. Journal of Acquired Immune Deficiency Syndromes
       and Human Retrovirology 10(Suppl. 1): S28-S33. 1995.

       Mellors J and others. Mutations in HIV-1 reverse transcriptase
       and protease associated with drug resistance. Journal of the
       International Association of Physicians in AIDS Care 1(7):
       28-32. 1995.

       Merrill M and others. Lamivudine or stavudine in two- and
       three-drug combinations against human immunodeficiency virus
       type 1 replication in vitro. Journal of Infectious Diseases
       173: 355-64. 1995.

       Richman D and others. BI-RG-587 is active against
       zidovudine-resistant human immunodeficiency virus type 1.
       Antimicrobial Agents and Chemotherapy 37: 144-147. 1993.

       St. Clair M and others. In vitro comparison of selected
       triple-drug combinations for suppression of HIV-1 replication:
       the inter-company collaboration protocol. Journal of Acquired
       Immune Deficiency Syndromes and Human Retrovirology 10(Suppl
       2): S83-S91. 1995.

       Wainberg M and others. Enhanced fidelity of 3TC-selected mutant
       HIV-1 reverse transcriptase. Science 271: 1282-1285. March
       1996.

       Yang S and others. Characteristics of a group of nonnucleoside
       reverse transcriptase inhibitors with structural diversity and
       potent anti-human immunodeficiency virus activity. Leukemia
       Suppl. 1: S75-S85. 1995.


       *********************************************************
       HIV/AIDS in Children: Overview and Guidelines for Disease
       Management

       by Leslie Hanna

       Leslie Hanna is Associate Editor of BETA.

       By the end of 1995, the World Health Organization Global
Programme on AIDS had received reports of nearly 1,300,000 cumulative
cases of AIDS in 193 countries. The estimated number of actual cases
is closer to 6 million. Nearly 40% of reported worldwide cases occur
in the U.S., and, while the majority occur among gay and bisexual men,
women and children are increasingly affected. By 1995, the U.S.
Centers for Disease Control and Prevention (CDC) had received reports
of 58,000 AIDS cases in women and over 5,500 AIDS cases in children.
The National Center for Health Statistics (NCHS) estimates that there
are approximately 10,000 HIV-infected children living in the U.S.

       The first U.S. case of pediatric AIDS was reported in 1982.
Early reports attributed HIV/AIDS in children to perinatal (vertical)
transmission, transfusion and the use of contaminated blood products.
Since the implementation of screening protocols for blood products and
donor self-deferral, the proportion of children infected postnatally
through transfusions and use of blood products has decreased
substantially. Today, nearly 90% of cumulative pediatric AIDS cases
and nearly 100% of new HIV infections in children result from
perinatal transmission. Each year, an estimated 1,750 children in the
U.S. are infected with HIV. AIDS is now the fifth leading cause of
death for all children under 15 years old, and the leading cause of
death for children 1-4 years of age, according to the NCHS.

       Increasingly, perinatal infections are traced to women who
report acquisition of the virus through heterosexual contact with a
partner whose HIV status and risk factors were unknown. Heterosexual
contact is the mode of HIV transmission increasingly responsible for
new infections in women. In the U.S. Northeast and South, women of
color are predominantly affected by rising rates of infection; thus,
children of color likely will be disproportionately affected in years
to come. In 1994, the annual rate of adult female AIDS cases per
100,000 population was: Caucasian, 3.8; African American, 62.7;
Latina, 26.0; all women, 12.8. The rate among African American women
was 15 times that for Caucasian women, and 3 times higher than among
Latinas. The median age at AIDS diagnosis for women was 35. Urban
areas with high seroprevalence rates among women may in turn be
predicted to have high seroprevalence rates among children. In New
York City and in Oakland, CA, in 1990-1991, seroprevalence of HIV
among women of childbearing age was 40/1,000.

       Defining children as persons less than 13 years of age is
important for medical research and practice. The official CDC
definition of pediatric AIDS for the purposes of case diagnosis and
reporting pertains to children under 13. Clinical trial data specifies
age group or developmental stage, and drug approvals and package
insert labeling agrees with data gathered in rigorously conducted
studies. Adults are persons 18 years of age and over, and adolescents
are those from 13-17. (Some adult studies include adolescents 13-17.)

       Statistics gathered on Americans under age 20 indicate that the
rate of HIV infection in this group is increasing. In addition to
children with perinatally transmitted HIV infection, this group
includes adolescents at risk. A related topic that will not be a focus
of this article is often termed "youth and HIV/AIDS," which tends to
refer to HIV/AIDS in older children or adolescents. According to the
March 1996 "Youth & HIV/AIDS: A Report to the President," increased
access to HIV counseling and testing for adolescents will be key
elements in improving prevention and treatment efforts for this group.
In this article, pediatric infection refers to HIV in children less
than 13 years of age.

       Identification of HIV Positive or At-Risk Children

       Since mother-to-child infection is by far the most common route
of transmission for children, intense research is underway to develop
methods for reducing the risk of perinatal transmission. AZT
(Retrovir) is now approved for use during pregnancy as a risk
reduction strategy, according to the regimen used in AIDS Clinical
Trials Group (ACTG) 076. (See BETA, June 1995, for a review of ACTG
076, the study that showed that use of AZT by mother and child could
substantially reduce the risk of mother-to-child transmission.) An
ACTG study currently underway is evaluating the utility of HIV immune
globulin (HIVIG) and pooled intravenous immune globulin (IVIG)
regimens for reducing transmission rates. Other antiretroviral agents,
such as nevirapine (Viramune), are candidates for this use as well. A
study of nevirapine has begun in which mothers and infants receive a
single dose; another perinatal transmission reduction study evaluting
ddI for this purpose is now beginning to enroll. Much has been written
and publicized elsewhere about public health and policy issues
associated with maternal HIV treatment.

       Perinatal exposure to HIV is the backdrop, but infected
children and their treatment are the focus of this article. In order
to initiate prompt, optimal healthcare for perinatally exposed
children, the CDC adjures healthcare providers to promptly identify
infants born to HIV positive women in order to begin monitoring,
diagnostic procedures and Pneumocystis carinii pneumonia (PCP)
prophylaxis (recommendations appear later in this article).
Approximately 1 in 4 children born in the U.S. to HIV positive mothers
who use no perinatal transmission reduction strategy (AZT) will have
confirmed HIV infection; since children routinely carry their
mothers's antibodies for up to 18 months, various strategies have been
implemented for HIV testing and care before that time.

       The best way to identify at-risk children is to diagnose women
with HIV before pregnancy, which is also critical for initiating care
for the women themselves. To this end, the CDC has recommended that
HIV counseling and voluntary testing be routinely offered to all
pregnant women. If the mother's HIV status is not determined before
delivery, pediatric healthcare providers should attempt to identify
infants born to HIV positive women as soon as possible after birth.
Symptoms of illness in all infants should be taken very seriously,
since they may be signs of serious, life-threatening conditions (e.g.,
PCP) and HIV infection.

       Diagnosis of  Pediatric Infection

       All infants born to HIV positive women should be monitored for
HIV status as close to birth as possible. If test results at birth are
negative by polymerase chain reaction (PCR), HIV culture and p24
antigen, testing should be repeated either at 1, 3 and 6 months of age
(Dorenbaum), or before 1 month and again before 4 months (CDC). PCR
and HIV culture are the preferred methods for HIV detection. If
results are negative for HIV on at least 2 occasions, ELISA testing
(HIV antibody test) should be performed at 12, 15 and 18 months of
age. HIV ELISA and Western blot antibody tests are used as screening
tools; confirmatory tests include HIV culture, PCR, immune-complex
dissociated (ICD) p24 antigen and IgA assay. A positive HIV test
result in an infant should be confirmed by repeat testing.

       For at-risk infants who are being monitored for HIV status and
for infants who have tested positive, CD4 cell counts should be
obtained as an adjunct diagnostic tool. Although PCP prophylaxis is
not initiated on the basis of CD4 count, the count is still clinically
useful. For example, the CD4 count may help determine prognosis or
risk for disease progression and guide decisions about whether or not
to continue PCP prophylaxis after 1 year of age. The CDC recommends
obtaining CD4 counts and percentages for HIV-exposed infants at 1 and
3 months of age, and for infants and children who are HIV
indeterminate or HIV positive at ages 6, 9 and 12 months.

       Recently, a University of South Florida study showed that a
commercial PCR test was quicker and less expensive than HIV culture
for detecting HIV in newborns. PCR results are available in 3-10 days
compared with 3-4 weeks for HIV culture results; PCR costs about $175,
compared to $300-600 for HIV cultures. This study is considered one of
the first to establish the accuracy of PCR as a tool for diagnosing
pediatric HIV infection. The investigators suggest that PCR be
regarded as a standard, rather than investigational, clinical test for
pediatric infection. In this study, PCR was performed in a commercial
laboratory on blood samples from 286 newborns older than 1 week and
children at risk for HIV infection. Samples were collected and mailed
for testing. Among infants between the ages of 1 week and 1 month, PCR
accurately detected HIV infection 95% of the time and correctly ruled
it out 100% of the time. Standard HIV IgG antibody tests can diagnose
HIV in children older than 18 months.

       Pediatric HIV Classification

       The CDC case definition for pediatric AIDS pertains to children
through 12 years of age. Initially created in 1983, the definition was
last revised in 1987 (unlike the adult AIDS case definition, which was
revised most recently in 1993). The pediatric HIV/AIDS definition is
similar to the adult definition in terms of HIV disease staging, but
also contains conditions specific to children such as lymphoid
interstitial pneumonitis (LIP) and recurrent serious bacterial
infections. In the U.S. and Europe, an AIDS diagnosis requires a
positive diagnostic test result for HIV infection. In developing
nations or places where diagnostic tests for HIV are not readily
available, pediatric AIDS diagnoses are based on clinical criteria
published by the World Health Organization.

       The CDC has established an HIV classification system to define
the spectrum of pediatric HIV disease. HIV-infected children are first
grouped into 3 immunologic categories: no evidence of
immunosuppression, moderate immunosuppression or severe
immunosuppression. There are also 4 clinical categories: N, A, B and
C.

       Children in category N have no signs or symptoms. Those in
clinical category A may have lymphadenopathy, splenomegaly (enlarged
spleen), hepatomegaly (enlarged liver), parotitis (inflamed salivary
glands), dermatitis (skin condition), recurrent upper airway
infections, bilateral otitis media (BOM, an ear infection) or
sinusitis (sinus infection).

       Those in category B may have recurrent herpes simplex virus
(HSV), herpes zoster/varicella (VZV, chickenpox, shingles), bacterial
infections, chronic fever, cardiomyopathy (heart muscle disease),
cytomegalovirus (CMV), chronic diarrhea, hepatitis (liver infection),
anemia (low red cell count), leiomyosarcoma (muscle tumor), neuropathy
or LIP. Finally, those in category C may have classic AIDS-related
opportunistic infections (OI) such as PCP, Mycobacterium avium complex
(MAC), cryptosporidial diarrhea, severe failure to thrive,
toxoplasmosis, lymphoma, encephalopathy (brain disease), severe
recurrent bacterial infections or cryptococcal meningitis.

       Pathogenesis of Pediatric HIV Infection

       Because HIV-related immunosuppression is imposed upon
still-developing immune, nervous and other systems, HIV disease tends
to be more aggressive in children than in adults, and leads to a range
of unique problems.

       Among children as a group, 2 patterns of HIV disease
progression have been observed. The first is characterized by rapid
progression, with 10-25% developing AIDS by 2 years of age. Mortality
in rapid progressors approaches 100% by 4 years of age.

       The second pattern is characterized by slower progression.
Earlier studies that evaluated the mode of HIV acquisition found that
children who were perinatally HIV-infected progressed more rapidly
than children who were infected after birth, e.g., by transfusion. As
perinatal transmission increasingly becomes the predominant route of
pediatric infection, children in the latter group will account for
progressively fewer infections.

       In the case of the perinatally infected child, the timing of
transmission also impacts the child's health. Perinatal transmission
may occur in utero (during pregnancy), intrapartum (during delivery)
or postpartum (after birth), primarly through breast-feeding. Studies
suggest better clinical prognoses for children infected relatively
late, e.g., during childbirth or through breast-feeding. Children
infected during pregnancy, particularly earlier during pregnancy, tend
to progress much more rapidly. Infants infected in utero who are
positive by HIV culture or by PCR at birth often develop symptoms by
4-8 months; PCP is frequent in these babies and LIP is rare. They
often develop AIDS by 1 year of age and their prognosis is poor.
Infants infected during delivery usually are negative by PCR or HIV
culture at birth; in these babies, LIP is frequent and PCP less
common. They are more likely than those infected in utero to have
lymphoid hyperplasia (increased amounts of lymphoid cells and tissue)
and to survive longer.

       Neurological Concerns

       Neurodevelopmental delays and neurological complications often
occur in children with HIV, especially after an AIDS diagnosis. HIV
infection itself may cause developmental delays in the areas of speech
and fine and gross motor skills. Progressive cognitive impairment may
be due to central nervous system (CNS) effects of HIV. Children may
even lose pediatric milestones already passed. They may experience
short-term memory loss or have attention deficit disorder. Acquired
microcephaly (abnormally small brain) is another neurological
condition found in children with HIV/AIDS. Computerized tomography
(CT) scans reveal cerebral atrophy (brain tissue wasting),
calcifications (calcium deposits) in basal ganglia (nerve structures
deep inside the brain) and white matter changes.

       Psychosocial Considerations for Children

       In addition to their medical problems, children also are likely
to have enormous social and emotional problems. Many have parents who
are ill or dead; many are in foster care and thus are involved in the
social service or juvenile justice systems. Many HIV-infected children
are economically disadvantaged and likely to have poor access to
health care.

       HIV-related neurodevelopmental impairment may impact daily
functioning. Children may have extra difficulty expressing themselves;
they may perform poorly on intelligence tests taken, e.g., at school.
All of these factors are likely to affect an HIV positive child's
overall socialization and growth.

       Older HIV-infected children are also at risk for depression,
which may manifest as apathy, withdrawal and loss of appetite.
Moreover, children often lack the coping skills or defense mechanisms
more mature people have developed. HIV-related dementia may also occur
in children or adolescents, with symptoms similar to those in adults
with AIDS-related dementia or encephalopathy. Although the psychology
of children with HIV/AIDS has not been well studied, psychotherapy and
psychopharmacology (use of drugs) may be helpful.

       Complications of HIV Disease in Children

       While the clinical categories that define stages of pediatric and
adult HIV infection are similar, the clinical manifestations of HIV
disease in children can differ greatly from those in adults. Children
develop OI at much higher CD4 counts than do adults. They also have a
somewhat different pattern of clinical manifestations, e.g., children
have a much higher rate of recurrent and serious bacterial infections.
Certain developmental problems are also uniquely pediatric; e.g.,
failure to grow and to thrive at an early age is common in
HIV-infected children, albeit somewhat parallel to the adult problem
of HIV-related wasting. However, while wasting occurs late in HIV
disease for adults, failure to grow and thrive may occur early for
children.

       Children are more likely than adults to have enlarged livers,
spleens and lymph nodes. LIP, common in children, is uncommon in
adults. Malignancies are uncommon in children but more common in
adults. CNS abnormalities may occur early in the course of HIV disease
in children, whereas AIDS dementia complex (ADC), a specific
HIV-related CNS condition, occurs late in HIV disease for adults.
Parotitis is another primarily pediatric concern. At one time,
HIV-infected children were considered at risk for a disability called
HIV-related dysmorphic syndrome. Researchers have since attributed
this condition to alcohol use by the mother, and now generally relate
the condition to fetal alcohol syndrome rather than to HIV.

       Pediatric infections common among all children are exacerbated
in children with HIV, including chronic ear infections and respiratory
tract infections. Chronic infection of both middle ears, known as
bilateral otitis media (BOM), is common in HIV-infected children
without AIDS, as is thrush (oral candidiasis). In children with an
AIDS diagnosis, thrush has been estimated to occur in more than 80%.
Thrush is frequently the initial clinical sign of HIV disease. It is
rarely disseminated but frequently involves the esophagus.

       The top 4 AIDS-defining conditions in children are, in order of
decreasing frequency: PCP, other OI, LIP and recurrent bacterial
infections. PCP is often diagnosed in the first few months of life,
and actually may occur at CD4 cell counts considered normal for the
child's age. Often, PCP occurs before a child's HIV infection has been
identified.

       Gastrointestinal pathogens commonly found in children with AIDS
include protozoa (Cryptosporidium, Isospora, Giardia), viruses (CMV,
HSV, Epstein-Barr virus [EBV], adenovirus, hepatitis viruses),
bacteria (Salmonella, Shigella, Mycobacterium tuberculosis,
Mycobacterium avium, Clostridium difficile) and fungi (Candida
albicans, Histoplasma gondii, Coccidioides immitis, Cryptococcus
neoformans).

       HIV Disease Management Guidelines for Children

       Optimal management of HIV disease in children often requires a
team approach which involves physicians, nutritionists, social workers
and psychotherapists.

       Diligent primary care is essential. According to Ho and Wei
(1995), several features of pediatric HIV disease make a compelling
case for aggressive HIV treatment. Newly infected infants usually have
a very homogenous population or type of HIV-1 virus, which means that
the virus is very sensitive and thus relatively more responsive to
antiretroviral treatment. Today, scientists know that HIV replication
in the body is a continuous, dynamic and rapid process. Tests now
available to measure viral RNA (viral load) in plasma can be used
after primary infection, when the viral RNA concentration reaches a
plateau, to try to predict longer-term clinical progress or outcomes.
Finally, there are powerful anti-HIV inhibitors now available, such as
the protease inhibitors and combinations of other antiretroviral
agents, that have been shown in studies of adults to reduce the
concentration of virus in blood serum by as much as 2-3 logs, or 100-
to 1,000-fold. Although protease inhibitor data in children are
sparse, it is hoped that these powerful compounds will be as important
for pediatric as for adult treatment.

       The goals for antiretroviral treatment are to slow or eradicate
viral replication, which is likely to mean life-long therapy for
children. Prophylaxis and treatment, when necessary, for OI are also
essential. Acute medical care may be necessary at times. Pain
management as well as nutritional and psychosocial support are
extremely important aspects of HIV disease management in children.

       Antiretroviral Treatment

       Antiretroviral therapy is warranted in children who have
developed an AIDS-defining condition such as PCP, failure to thrive,
HIV-related progressive encephalopathy, recurrent serious bacterial
infections, thrombocytopenia (low platelet count),
hypogammaglobulinemia (low antibody levels) or low CD4 cell count,
even without symptoms. Antiretroviral drug choices for children are
nearly the same as for adults, with a few important qualifications and
exceptions. In some cases antiretroviral drugs involve different side
effect profiles for children, or there are insufficient pediatric data
to substantiate their use.

       An important pediatric antiretroviral treatment update came on
February 28, 1996, with the official release of final data from ACTG
152. The large nationwide trial enrolled nearly 900 children with
AIDS, aged 3 months to 18 years, who had little or no prior
antiretroviral treatment. The study's goal was to compare the efficacy
of 3 different antiretroviral treatment regimens for delaying disease
progression when used as initial or first-line antiretroviral
strategies. Originally, participants were randomized to receive one of
3 treatments: AZT monotherapy, ddI monotherapy or combination AZT/ddI.
However, an interim analysis about a year ago indicated that children
receiving AZT monotherapy were faring much worse than children in
either of the other 2 arms. Children receiving AZT alone had "more
rapid rates of disease progression as measured by growth failure, new
opportunistic infections, neurologic and neurodevelopmental
deterioration or death." A Public Health Service press release dated
February 13, 1995, states that interim results show that "zidovudine
(AZT) alone was the least effective as an initial therapy to prevent
HIV disease progression." In February 1995, the AZT monotherapy arm
was discontinued, and the study continued with the 2 remaining arms.

       Therefore, final results compare ddI monotherapy to combination
ddI/AZT treatment. At this time, the data suggest that there are no
significant differences in disease progression or survival between the
2 treatment strategies. Even though AZT is believed to penetrate the
CNS better than ddI, children taking ddI alone did not fare worse than
those taking combination ddI/AZT in terms of neuropsychological
dysfunction or deterioration (experienced by about 19% of all
participants). Although some physicians feel that clinically stable
children may fare well on AZT monotherapy, others feel that the
results of ACTG 152 argue strongly against the use of AZT monotherapy
in any HIV-infected child. Thus, the emerging trend for antiretroviral
treatment in children is similar to that for adults, with providers
and advocates on the "cutting edge" proposing that first-line
treatment for children, like adults, should consist of combination
antiretroviral therapy.

       AZT, the first antiretroviral approved for children, is
available in tablet, intravenous (IV) and raspberry-flavored syrup
formulations. The dose recommendations are 2-3 mg/kg (180 mg/m2) every
6 hours for children older than 3 months. Children absorb oral AZT
well (about 65% absorption). AZT, which penetrates the blood-brain
barrier to the CNS, is found in cerebrospinal fluid at amounts equal
to about 25% of serum concentration. Another advantage of AZT is its
ability to readily cross the placenta. HIV resistance to AZT develops
as a function of length of time used, not dose; in children,
resistance correlates with disease progression.

       ddI is also approved for pediatric use. At 40%, its oral
bioavailability is lower than that of AZT or ddC (87%). ddI must be
taken on an empty stomach, during fasting, which may be difficult for
children. It is available in chewable tablet, powder and pediatric
oral solution forms. The dose is 200 mg/m2 twice daily. ddI fails to
penetrate the CNS well. Pancreatitis, peripheral neuropathy, retinal
damage and diarrhea may result from its use.

       ddC is 10 times as potent against HIV as AZT in vitro. It is
available on the market in tablet form, and in clinical trials only in
syrup form. The suggested dose is 0.005-0.01 mg/kg orally, every 8
hours. ddC has poor CNS penetration. Side effects include neuropathy,
stomatitis (mouth sores), esophageal ulcers and rash.

       d4T is considered to have good bioavailability and CNS
penetration. There are limited Phase I data in children; a Phase
II/III trial is in progress.

       Other drugs being studied in children include the new class of
protease inhibitor drugs. Nevirapine and delavirdine, also under
study, belong to a class of drugs that seems to be powerful in vitro
and minimally toxic, although HIV mutates extremely quickly to become
highly resistant to them.

       Other agents used in pediatric antiretroviral therapy include
those that diminish HIV stimulation, those that decrease antigen
stimulation and those that block mediators that stimulate HIV
infection. Agents used to stimulate the immune system include certain
hormones and growth factors, certain cytokines, immunizations, bone
marrow transplants and gene therapy.

       Prophylaxis and Treatment of OI and Childhood Conditions

       Since PCP is the most common serious OI in children with AIDS,
prevention is of paramount concern. While recommendations for
beginning prophylaxis in adults are based on a CD4 cell count of fewer
than 200 CD4 cells/mm3, the CD4 count is an inadequate marker for
infants and children. CD4 counts vary more from child to child than
among adults, and thus are not particularly helpful indicators of when
to begin PCP prophylaxis. Because PCP kills many infants younger than
1 year, recommendations are to begin prophylaxis at 4-6 weeks of age
in all infants, regardless of CD4 count, born to HIV positive mothers.
(Prophylaxis is delayed until 4 weeks of age because it takes about
that long for an infant to develop the necessary ability to metabolize
bilirubin.) Infants who are identified as HIV positive after 6 weeks
of age should immediately begin PCP prophylaxis.

       Currently, the National Pediatric and Family HIV Resource
Center and the CDC recommend PCP prophylaxis for all "at-risk" infants
1-4 months of age, until HIV status can be firmly determined, and for
all HIV-infected infants 4-12 months of age. After 12 months of age,
recommendations for PCP prophylaxis for infected children are based on
CD4 cell counts and history of PCP. Because CD4 percentages vary less
than CD4 counts, some physicians prefer to use them as a marker.
Generally, PCP prophylaxis is recommended for children 1-2 years of
age with fewer than 750 CD4 cells/mm3 or 15%; children 2-5 years of
age with fewer than 500 CD4 cells/mm3 or 15%; and children 6-12 years
of age with fewer than 200 CD4 cells/mm3 or 15%.

       The first-line choice for PCP prophylaxis is
trimethoprim/sulfamethoxazole (TMP/SMX, Bactrim or Septra) at an oral
combined dose of 150 mg/m2 TMP and 750 mg/m2 SMX 3 times a week. For
children who cannot tolerate TMP/SMX, alternative regimens are oral
dapsone, 1-2 mg/kg once daily; aerosolized pentamidine, 300 mg monthly
(only for children over 5 years of age); and parenteral (by injection,
bypassing the gastrointestinal tract) pentamidine, 4 mg/kg every 2-4
weeks. Breakthrough PCP has been documented in infants on dapsone and
pentamidine. Also, the CDC currently recommends that infants who
received AZT for the prevention of vertical transmission not begin
prophylaxis with TMP/SMX until AZT  has been discontinued at 6 weeks,
per the ACTG 076 regimen, because of potential liver toxicity. (Some
physicians feel that the high risk of PCP before 1 year of age
warrants beginning PCP prophylaxis with TMP/SMX at 4 weeks, even while
infants finish the AZT regimen.)

       Prophylactic use of TMP/SMX also protects against bacterial
infections. IVIG has also been used to prevent bacterial infections
and related hospitalizations. IVIG has been used at a dose of 400mg/kg
every 28 days in HIV-infected children, especially those with
hypogammaglobulinemia, thrombocytopenia or recurrent infections not
ameliorated by routine use of antimicrobial agents. Prophylaxis for
other OI depends on the child's age, degree of immunosuppression and
other individual factors, such as physician and parent preferences. In
general, different dose levels of the same drugs that are used to
prevent OI in HIV-infected adults are used for children.

       In the February 1996 issue of Pediatrics, the American Academy
of Pediatrics (AAP) published an updated policy on tuberculosis (TB)
skin testing for children. The AAP now recommends that children's risk
level for TB be assessed, and that testing schedules complement risk
level determination. For example, children who have recently come into
contact with a TB-infected person should be tested immediately.
Children with HIV should be tested annually.

       HIV-infected children are at elevated risk for more severe
versions of common childhood illnesses like measles and chickenpox,
which may be fatal. Common, minor symptoms like cough and fever must
be taken very seriously in HIV-infected children, for they may herald
potentially life-threatening infections.

       Certain immunizations routinely given to HIV negative children
are also recommended for HIV positive children; others are not (see
chart). The main caveat about routine vaccinations is the possibility
that consequent immune system stimulation may activate CD4 cell
activity and, in turn, enhance HIV replication. For example, the
wisdom of vaccinating HIV-infected adults and children against
influenza has been widely debated. Some researchers have argued that
HIV positive children tend to be at even greater risk for the flu than
adults, e.g., through contact with large numbers of other children in
daycare or at school. In a recent study at the University of Texas
Medical Center in Dallas, Octavio Ramilo and others used viral load
tests to investigate the effects of flu vaccines on HIV activity in
infected children. Investigators found that 5 of 16 children
experienced significant post-vaccination viral load increases.
However, viral load changes were transient, with levels returning
within 2 months to baseline in 4 of the 5 children. Investigators
concluded that children, relative to adults, were less likely to
experience increases in HIV burden (but demurred, recommending further
studies in children with different disease stages taking different
treatment regimens). The debate is likely to continue.

       RECOMMENDATIONS FOR IMMUNIZATIONS IN THE CHILD WITH HIV/AIDS
       FROM THE AMERICAN ACADEMY OF PEDIATRICS

       Vaccine: DPT (diptheria, tetanus, pertussis) Known
       Asymptomatic: Yes Known Symptomatic: Yes**

       Vaccine: OPV (Sabin, oral polio vaccine)  Known Asymptomatic:
       No Known Symptomatic: No  Vaccine: IPV (Salk, inactivated polio
       vaccine) Known Asymptomatic: Yes Known Symptomatic: Yes**

       Vaccine: BCG (Bacille Calmette-Guerin, for tuberculosis)  Known
       Asymptomatic: No Known Symptomatic: No

       Vaccine: MMR (measles, mumps, rubella -- live-attenuated)
       Known Asymptomatic: Yes Known Symptomatic: Yes

       Vaccine: Hibc (Haemophilus influenza type b/c)  Known
       Asymptomatic: Yes Known Symptomatic: Yes**

       Vaccine: Pneumococ cal* Known Asymptomatic: Yes Known
       Symptomatic: Yes**  Vaccine: Influenza* Known Asymptomatic: Yes
       Known Symptomatic: Yes**

       NOTES:

        * Pneumococcal vaccines should begin when a child reaches 2
          years of age. Flu vaccines should be given annually starting
          at 6 months of age.

       ** Inactivated vaccines are recommended, although patient
          responses may not be optimal. Definitely, HIV positive
          children and even HIV negative children residing in the same
          household should receive the killed polio Salk vaccine and
          not the live attenuated Sabin product.

       Nutritional Considerations and Therapy

       Competing theories on the role of nutrition in HIV disease
abound. Important research continues to delineate the roles played by
nutrients and micronutrients, and will permit the formulation of
recommendations for diet and nutritional supplementation. Associations
between nutritional deficiencies and disease stage in adults have been
fairly well established; as disease advances, so does the extent of
nutritional depletion. While malnutrition enhances disease-related
immunosuppression in persons of all ages, the nutritional requirements
of any child differ significantly from those of any adult. So far,
little data exist to establish the impact of HIV infection on
nutritional status in children. The known catabolic and metabolic
problems experienced by HIV positive children, as well as endocrine
problems and failure to grow and thrive, underscore the importance of
optimal nutrition. Adequate dietary intake of nutrients is the most
important, first-line approach to nutritional management; children
must receive adequate calories and protein. However, supplementation
should be considered for children who fail to grow despite adequate
oral intake.

       In France, a recent study evaluated nutritional abnormalities
in 21 generally healthy children with HIV. The prospective study
involved a group of HIV positive children and a matched control group
of HIV negative children. Investigators assessed health history (e.g.,
fever, diarrhea), height, weight, dietary intake and nutritional
status, including total calories, protein, fiber, fat, cholesterol,
vitamins, calcium, iron, zinc, copper and fatty acids. All children
were relatively well-nourished. Measures of nutritional status
appeared unaffected by origin of maternal infection (injection drug
use versus heterosexual contact), ethnic background, or socioeconomic
or educational status. Within the HIV positive group of children,
about half were symptomatic but "non-AIDS." The remainder had AIDS
diagnoses, and a lower average CD4 cell count that was associated with
lower vitamin A levels. There was no correlation between CD4 cell
count and vitamin E, beta carotene, zinc, copper or selenium. CD8
levels were significantly correlated with zinc levels.

       HIV positive children did not differ from HIV negative children
in dietary intake, nor was their ability to absorb nutrients impaired.
Generally, study data suggest that, as HIV disease progresses, so does
the extent of vitamin level depletion (with the exception of beta
carotene, levels of which did not appear to change after receiving an
AIDS diagnosis). This finding was particularly true for the
micronutrients known to influence immune status--vitamins A and E and
the carotenoids, zinc, copper and selenium--and mirrors the same
phenomenon known to occur in HIV-infected adults.

       Although more significant as HIV progressed, micronutrient
deficiencies were noted even in children with early-stage HIV disease.
However, remedial supplementation is not automatically recommended;
for example, iron supplementation to address the low iron levels often
seen in people with infections often exacerbates infectious
complications by providing fuel for the pathogens. Essential findings
indicated that, despite adequate diets, notable micronutrient
alterations were common in these children, even though none of them
manifested signs of malnutrition. Research into the utility of
nutritional interventions early in the course of pediatric HIV disease
remains to be done.

       Various studies have demonstrated that vitamin A
supplementation benefits immune status in HIV-infected children. In a
study from South Africa, researchers studied the effects of vitamin A
supplementation on morbidity (sickness) in 118 children born to HIV
positive mothers. Vitamin A plays various roles in optimizing immune
function and maintaining the health and integrity of epithelial
tissues, which include the mucosal tissues of the gastrointestinal
tract and the eye. These characteristics led to dubbing vitamin A the
"anti-infective" vitamin. (Durban, the study locale, is not considered
a vitamin A deficient area.) The study was randomized, double-blind
and placebo-controlled. At 1 and 3 months of age, children received
50,000 International Units (IU); at 6 and 9 months, 100,000 IU; and at
12 and 15 months, 200,000 IU of vitamin A. HIV status was determined
at 15 months, and data on health status were collected up to 18 months
of age. HIV negative children had roughly the same number of illnesses
and hospitalizations, whether or not they received supplemental
vitamin A. However, HIV positive children who received supplemental
vitamin A had less diarrhea, fewer hospitalizations for diarrhea and
less severe illnesses overall (e.g., respiratory infections, rashes)
than those who received placebo. The researchers hope that vitamin A
supplementation in HIV positive children, especially economically
disadvantaged children, may be an effective and inexpensive means for
reducing illness. (See the report "Mother-to-Child HIV Transmission,"
by Leslie Hanna, on vitamin A levels and vertical HIV transmission in
the September 1994 BETA.)

       A Clinical Research Agenda for Children

       According to pediatrician Paula Botstein, MD, Deputy Director
of FDA's Office of Drug Evaluation, FDA is encouraging clinical trials
in children. She explains that the majority of approved drugs have
been studied in and labeled for adults, and that package inserts
commonly rely on disclaimers that explain that safety and efficacy
have not been established for children. Historical reasons for lack of
pediatric research include little financial incentive on the part of
pharmaceutical companies and the difficulties inherent in pediatric
research. Parents and guardians as well as children must understand
what involvement in a trial means and must provide informed consent.
The collection of data on a drug's safety and efficacy is important
because children may metabolize drugs differently than adults; adult
doses cannot simply be reduced for use in children. Botstein says FDA
is trying actively to encourage drug companies to test drugs in
children during the drug development process, and that FDA reviews of
new drug applications (NDA) include consideration and evaluation of
pediatric data. FDA is also creating ways to evaluate a drug's
post-marketing use in children.

       Recently, however, the Office of AIDS Research called for
dramatic cuts to the pediatric research budget through the nation's
largest research mechanism, the ACTG. There are 2 rumored reasons for
the proposed cuts: 1) the pediatric ACTG has in the past been too
generously supported, relative to adult studies, and 2) now that AZT
has been officially approved for use in pregnant women, fewer children
will be HIV-infected so less research will need to be done.

       Conclusion

       Early identification of children at risk for HIV infection and
especially HIV positive children is essential for optimal treatment,
defined as early, aggressive treatment. Quality counseling about HIV
disease and testing should be routinely offered to all pregnant women.
Counseling ensures that women have adequate information to make
informed choices.

       Infants of women considered "at risk" should be monitored so
that infants and children who develop lymphadenopathy (lymph node
swelling) or frequent bacterial infections, or who have low platelet
counts or other unusual clinical findings may be promptly attended.
Mothers of such children must be integrally involved in their
children's medical care, one reason being that HIV testing of such
children guarantees revelation of the mother's serostatus.

       The epidemic in children less than 13 years of age reflects the
epidemic in women. According to the CDC, the proportion of cases among
women has increased steadily over the past decade. The official hope
of government and medical researchers is that Public Health Service
recommendations for routine counseling and voluntary prenatal HIV
testing for women, and the use of AZT and forthcoming antiretroviral
strategies (e.g., protease inhibitors) for interrupting perinatal
transmission will minimize the pediatric epidemic. Nevertheless, new
pediatric infections are likely at least in the near future. It is
important for research to go foward to better understand HIV disease
in children and to learn how best to treat it.

       Sources

       Genetic test improves ability to diagnose HIV in newborns. AIDS
       Weekly Plus: 23-24. February 26, 1996.

       Dorenbaum A. HIV and AIDS in children. The Fourth Annual Women
       and HIV Conference. San Francisco, CA. October 20, 1995.

       Grossman M. Pediatric AIDS. Chapter 27 of The Medical
       Management of AIDS, 3rd edition. Sande and  Volberding,
       editors. W.B. Saunders Company. Philadelphia. 1992.

       Interim results lead to discontinuation of AZT-only study arm.
       Public Health Service/National Institutes of Health press
       release. February 13, 1995.

       Martorell R and Ramakrishnan U. Vitamin A supplementation in
       children born to HIV-infected women. The American Journal of
       Public Health 85(8): 1,049-1,051. August 1995.

       1995 revised guidelines for prophylaxis against Pneumocystis
       carinii pneumonia for children infected with or perinatally
       exposed to human immunodeficiency virus. Morbidity and
       Mortality Weekly Report 44(RR-4). April 28, 1995.

       Peckham C and Gibb D. Mother-to-child transmission of the human
       immunodeficiency virus. The New England Journal of Medicine
       333(5): 298-302. August 3, 1995.

       Periquet BA and others. Micronutrient levels in HIV-1-infected
       children. AIDS 9(8): 887-893. August 1995.

       Ramilo O and others. Pediatric Infectious Disease Journal 15:
       197-203. 1996.

       Stephenson KS. Pediatric HIV infection. Chapter 15 of HIV
       Manual for Health Care Professionals. Appleton and Lange. 1994.

       Vitamin A supplementation in children born to HIV-infected
       women. Medical Alert: 4. November/December 1995.

       U.S. Public Health Service Recommendations for Human
       Immunodeficiency Virus Counseling and Voluntary Testing for
       Pregnant Women. Morbidity and Mortality Weekly Report 44(RR-7).
       July 7, 1995.

       Why FDA is encouraging drug testing in children. FDA Consumer
       Special Report: From Test Tube to Patient, 2nd edition. January
       1995.

       Protease Inhibitor News for Children

       Important recent news in antiretroviral treatment for persons
with HIV concerns protease inhibitors and combination antiretroviral
therapy, often including a protease inhibitor. Most new drug approvals
have been granted for adult HIV infection; unfortunately, there is
relatively little news about protease inhibitors for children.

       Abbott Laboratories' protease drug, ritonavir (Norvir),
FDA-approved on March 1, 1996, was widely hailed because data showed a
survival benefit in people with advanced HIV disease. The clinical
studies that led to ritonavir's approval have also been denounced for
failing to gather safety and efficacy data in children. In late
February, when FDA advisory committee meetings which led to FDA
approval were held, no pediatric data were reported. Part of the
approval agreement between FDA and Abbott was a plan that requires
Abbott to conduct trials to provide additional data, including a
pediatric trial of ritonavir to provide safety and efficacy data for
children. A small pediatric study is currently underway at the
National Cancer Institute (NCI), and other protocols are being
developed.

       Hoffmann-La Roche's (Roche) protease inhibitor saquinavir
(Invirase), which received FDA marketing approval in December 1995, is
indicated for use in adults and children over 16. Currently, Roche
will only say that it is committed to developing a sprinkle
formulation for use by children, and that the process is underway.

       Merck's protease inhibitor indinavir (Crixivan) was
FDA-approved on March 14, 1996, on the basis of studies in over 2,000
volunteers with AIDS. Study participants showed improvements in
markers of HIV disease such as CD4 count increases and viral load
decreases, especially when indinavir was used in combination with AZT.
The indicated use is for adults older than 18 years of age only. There
are no current indications for pediatric use; the adult dose cannot be
adjusted or altered. "With Crixivan, it is very, very important, in
order to keep viral load down and to erect and maintain a wall against
resistance, to start with and maintain the optimal, approved dose: 800
mg 3 times daily. You cannot titrate up or down, you cannot try drug
holidays. Timing and conditions around taking doses are important,
too; Crixivan must be taken every 8 hours, in a fasting state or with
a very light meal, in order for maximum absorption," says Kyra
Lindemann of Merck Corporate Public Affairs. Therefore, until studies
establish the optimal dose(s) for children, there will be no
indication for pediatric use. A pediatric dose-ranging study using a
capsule form of indinavir is currently underway at NCI, where safety
and efficacy data for the different doses are being gathered.
Meanwhile, Merck is working to develop an oral suspension formulation
for pediatric use.





       WOMEN AND AIDS

       Cervical Intraepithelial Neoplasia

       by Leslie Hanna

       Leslie Hanna is Associate Editor of BETA.

       Terminology

Dysplasia and cervical intraepithelial neoplasia (CIN) are different
terms or names for the same condition. Dysplasia simply means abnormal
tissue development; while dysplasia is still sometimes used to mean
CIN, the term is not used as frequently as in the past. Squamous
intraepithelial lesions (SIL) is another term that is used with regard
to CIN, and describes the type of cervical cells that undergo changes
in 80% of cervical neoplasia.

Both terms--dysplasia and CIN--remain in use today. Despite the fact
that the interchangable use of these terms can be confusing, the
important thing is to understand what this type of abnormal tissue
development means (it is a precursor to cervical cancer) and that the
severity of the condition when detected has prognostic or predictive
value (regardless of the system used to describe it).  --L. Hanna

Cervical intraepithelial neoplasia (CIN) is now used to describe what
was once called dysplasia:


  CIN I = minimal dysplasia

  CIN II = moderate dysplasia

  CIN III = severe dysplasia or carcinoma in situ

*  CIN III, severe dysplasia and carcinoma in situ are all different
   names for the same thing--early cervical cancer. While
   approximately one-third of all cases of CIN I will resolve in time,
   the rest will progress. All degrees of CIN, however, require
   immediate colposcopy. -- L. Bardaro

       Introduction

Cervical intraepithelial neoplasia (CIN) is a condition characterized
by new growth (neoplasia) in the normal tissue (epithelium) of the
cervix, the lowest portion of the uterus leading into the vagina (see
diagram on page 33). A diagnosis of CIN means that abnormal tissue has
been detected in a woman's cervix. In addition to CIN, other types of
lower genital tract neoplasias reported in women with HIV include
vulvar intraepithelial neoplasia (VIN) and perianal intraepithelial
neoplasia (PIN or AIN, anal intraepithelial neoplasia).

CIN is much more common than the other types of genital neoplasia in
women with HIV. The tissue changes that signify CIN are premalignant,
or precancerous; CIN is essentially a precursor to invasive cervical
cancer. Since the most recent revision of the official Centers for
Disease Control and Prevention (CDC) case definition of AIDS in 1993,
invasive cervical cancer is an AIDS-defining illness in women with HIV
infection.

In the U.S. alone, nearly 16,000 new cases of cervical cancer and
nearly 5,000 deaths from cervical cancer occur each year, and 600,000
more women are diagnosed with CIN. The incidence rates of both CIN and
cervical cancer are elevated in women with HIV. Since the primary
medical goal for women with HIV is to reduce sickness and death,
prevention of cervical cancer necessitates routine screening for CIN
and early, aggressive intervention.

       What is CIN?

CIN may be mild, moderate or severe. Several terms may be used to
describe this condition, including dysplasia, CIN and squamous
intraepithelial lesions (SIL). The term CIN is used in this article
because it is arguably the most popular term in use today.

The abnormal tissue of CIN is collectively composed of cells that have
undergone abnormal, individual changes, and which have formed lesions
in the cervix. Cervical lesions can regress (grow smaller and
disappear), persist or progress to early cervical cancer, more
formally called cervical carcinoma in situ, and finally invasive
cervical cancer. Moderate or severe CIN (high-grade SIL, CIN II-III)
is more likely to persist or progress. Mild CIN (low-grade SIL, CIN I)
often regresses without any treatment, overcome by a successful immune
system defense.

       What Causes CIN?

The single most frequent cause of CIN is infection with human
papillomavirus (HPV), the virus that causes genital warts and common
skin warts. There are many types of HPV; some types are relatively
harmless, but others can cause aggressive disease.

HPV is one of the most common sexually transmitted diseases in the
U.S. About one-third of the more than 60 identified types can be
sexually transmitted. Several types cause visible genital warts, or
condyloma acuminata; certain other sexually transmitted types lead to
cervical, vulvar and anal cancers. The types that are oncogens, or
cancer-causing agents, are not associated with genital warts and are
usually detectable only by Pap smear screening. Tests for HPV type
exist but are expensive and largely unavailable.

Women with genital warts should be treated for warts and also examined
for cervical HPV infection by Pap smear (cervicovaginal cells are
smeared on a slide and examined under a microscope) and colposcopy (a
technique that allows visual examination of the living tissue of the
vagina and cervix using an instrument that is essentially a
high-powered microscope). Although the HPV types that cause genital
warts are not the same ones that are associated with cervical cancer,
the sexual exposure that resulted in genital warts might also have
resulted in infection with more virulent HPV types. Depending on the
size and location of the genital wart, treatment options are:
trichloracetic acid application, 20% podophyllin solution application,
5% 5-fluorouracil cream, electrocautery (with an instrument that
allows the passage of electrical current through selected tissue, in
order to remove or destroy it) or laser treatment. Cryotherapy, or
freezing of the warts, is currently falling out of favor; alpha
interferon has been used on persistent warts, and surgery may remove
large warts that do not respond to other treatments.

Because HPV is known to be the central cause of cervical cancer around
the world, the National Cancer Institute's plans for cervical cancer
prevention strategies include the development of a vaccine targeted at
genital HPV.

       Cofactors that Facilitate CIN

A successful immune response can attack clones of abnormal cells,
repair abnormal DNA and prevent CIN without any medical intervention
or treatment. In the presence of other damaging factors (cofactors),
CIN and ultimately invasive cancer may develop. If the oncogen is a
particularly virulent strain of HPV, little else in the way of
cofactors may be required. Cofactors include immunosuppression,
cigarette smoking and poor nutrition. Having other sexually
transmitted diseases (STD), particularly herpes simplex virus type 2
(HSV-2), also may increase the risk for CIN.

HPV-related CIN has been noted in women who receive transplants and
are taking immunosuppressive drugs, as well as in women with
HIV-related immunosuppression. Studies of HPV-related CIN in women
with HIV all conclude that HIV influences the development of CIN. A
review of 5 studies  reported that HIV positive women are
approximately 5 times as likely as HIV negative women to develop CIN
(Mandelblatt, 1992). Among HIV-infected women, as immunosuppression
increases, so does the risk of developing CIN. Women with AIDS have an
approximately 2-fold greater risk than asymptomatic HIV positive women
for developing CIN. Moreover, the more severe a woman's
immunosuppression, the more severe her CIN is likely to be. CIN
progresses more rapidly to cancer, and treatment failures are more
common in HIV positive women.

Some studies have shown that HIV-infected women who are injection drug
users (IDU) had higher rates of CIN than their non-drug-using HIV
positive counterparts; one theory is that IDU suffer additional
immunosuppression related to ongoing exposure to toxins and other
pathogens through drug use (Carpenter and others, 1991; Bradbeer,
1987; Crocchiolo and others, 1988).

Cigarette smoking is known to increase the risk for squamous cell
cancer, which includes cervical cancer. (Eighty percent of cervical
cancers are squamous cell cancers.) Risk is believed to increase with
the duration and amount of smoking. Some studies have shown increased
risk for current smokers but not for former smokers (Brock, 1989). In
addition, poor nutritional status is another known risk for CIN. Beta
carotene seems to be an especially important micronutrient; studies
have shown that women with adequate levels and intake are at reduced
risk for CIN. Folate may be another important micronutrient for
reducing risk. There have also been suggestions that vitamin A may act
to reduce HPV proliferation.

Still other risk factors are actually surrogate markers for exposure
to HPV, including having multiple sex partners, other STD or early
onset of sexual activity (at or earlier than 16 years of age).

Finally, studies that suggest that older women and ethnic minorities
are at increased risk for cervical cancer really have shown that a
very real risk for cervical cancer is lack of medical care, from
screening to treatment. These risks are often based on socioeconomic
factors. (The explanation for increased risk in older women is simply
that women aged 60 and older are less likely to seek regular care.)
Since primary care practitioners may be providing care for many women
who do not have obstetrician/gynecologists, one efficient approach to
reducing sickness and mortality would be for more primary care
practitioners to perform routine Pap smears.

       How does CIN Develop?

Most CIN as well as cervical cancer develops in the so-called
transformation zone. The transformation zone refers to an area of the
cervix where 2 types of cells and tissues meet. Squamous epithelial
cells line most of the vagina, while the cervix and uterus are
composed of columnar epithelial cells and tissue. The transformation
zone is where the 2 cell types meet and overlap, at the transition
from vaginal mucosa to uterine mucosa. This is the region most
vulnerable to attack by HPV.

The transformation zone usually lies inside the endocervical canal,
which is why Pap smears must include samples of endocervical cells
(see below, on the Bethesda System). The placement of the
transformation zone can shift through aging, extended use of oral
contraceptives or hormones, multiple pregnancies and births, and
surgery, including cryotherapy, which was once extensively used for
treating cervical lesions and abnormalities related to HPV. In women
who have had cryotherapy, especially multiple treatments, the
transformation zone may heal, scar over and move up inside the cervix,
where it cannot be reached for Pap smear sampling or seen on
colposcopic examination. If this is the case, a procedure called
endocervical curettage (ECC) may be required (see Cervical Cancer
Screening Issues for HIV Positive Women this issue).

At a conference on women and HIV in San Francisco in the fall of 1995,
Michael Policar, MD, offered a "weed" analogy to help explain the
pathogenesis of CIN (how the disease develops). The soil is the
cervical tissue. The seed is the cancer-causing agent, HPV. Fertilizer
that helps the seedling grow into a weed (cancerous growth) are
cofactors like smoking. The best weed killer is the immune system.

When some types of HPV encounter the vulnerable tissue of the
transformation zone, the virus may incorporate abnormal viral DNA into
the normal genetic material of the cells. In a person with a strong
immune system, repair often takes place without any intervention;
healthy squamous epithelial tissue will develop and the oncogen is
effectively eradicated. The other possibility is that the abnormal DNA
prevails, abnormal cells multiply to become lesions, and CIN develops.
If abnormal DNA dominates, as may occur if a woman does not know she
has cervical HPV infection or CIN, cancer may develop.

       Treatment for CIN

Ideally, the natural immune response would be powerful enough to
eradicate any low-grade CIN or tissue abnormalities. Observation and
repeat Pap smears and biopsies can confirm such spontaneous
self-correction. Currently, there is no treatment per se for CIN I,
which either resolves or progresses to CIN II, which is treated. If
CIN does not resolve but instead progresses, or is detected at CIN
stage II or III, treatment is needed to prevent the development of
invasive disease. CIN lesions may be treated on an outpatient or
inpatient basis. Outpatient techniques include laser vaporization or
excision and loop electrosurgical excision procedure (LEEP); inpatient
techniques include cone biopsy or cervical (cold knife) conization,
which involves removing a cone-shaped portion of the cervical tissue,
and simple hysterectomy. Some strategies, like LEEP or cone biopsy,
combine diagnosis and treatment by removing all abnormal tissue. CIN
II-III often can be treated with outpatient techniques; higher-grade
CIN likely requires inpatient treatment.

One study showed that HIV-infected women with fewer than 500 CD4
cells/mm3 were more than twice as likely to have recurrent or
persistent CIN after LEEP (Wright and others, 1993). The key to
survival for women with HIV who have been treated for CIN is careful,
regular life-long follow-up. Abner Korn, MD, researcher and clinician
at San Francisco General Hospital (SFGH), says that "HIV positive
women with dysplasia [CIN] need careful follow-up after treatment and
often need second or third therapeutic procedures. Vigilant
surveillance and retreatment alone may be sufficient care for these
women." One important surveillance tool is the same tool used for
primary screening and prevention: the Pap smear.

       Prevention and Screening

The elevated risk for cervical cancer in women with HIV, especially
those with a history of HPV or CIN, makes prevention of cancer and
early intervention for precursor conditions extremely important.
Screening procedures are of paramount importance for achieving the
goal of preventing sickness and death.

The most appropriate screening procedure for CIN is a topic of debate.
The debate centers on which technique(s) should be used for screening
and how often to screen. An early study compared the 2 most widely
available screening technologies, the Pap smear and colposcopy.
Results showed a high rate of false-negative results for Pap smears
compared to colposcopy in HIV positive women. Colposcopy appeared much
more reliable than Pap smears for detecting cervical abnormalities.
This finding triggered a shift towards utilization of the more
invasive, expensive and labor-intensive colposcopic method. Several
studies later, current opinion holds that the Pap smear is as
effective in HIV positive as in HIV negative women at diagnosing CIN.
How often women with HIV should have Pap smears and colposcopic
examinations remains hotly contested (see Cervical Cancer Screening
Issues).

The 1993 CDC STD Treatment Guidelines provide current recommendations
for screening for HIV positive women. The CDC recommends an initial
Pap smear when HIV infection is diagnosed; if the results of that test
are normal, the woman should have at least one Pap smear during the
next 6 months. If the second Pap smear is also normal, the CDC
recommends annual Pap smears for screening from then on. If any Pap
smear result in an HIV positive woman indicates inflammation or
"reactive atypia," CDC recommends that she return in 3 months for
another Pap smear. If any Pap smear test indicates SIL or atypical
squamous cells of undetermined significance (ASCUS), CDC recommends
colposcopic evaluation. CDC does not recommend routine colposcopy
screening for HIV positive women.

The SFGH guidelines for HIV positive women differ from the CDC's. In
particular, the SFGH team recommends baseline colposcopy (their
treatment recommendations are included in the following list):

		1) perform baseline colposcopy at HIV diagnosis

		2) evaluate the entire lower genital tract for
                 multifocal disease (vulvar intraepithelial neoplasia
                 [VIN] and perianal intraepithelial neoplasia [PIN],
                 in addition to CIN or SIL)

		3) treat genital warts per routine

		4) if normal, repeat inspection and Pap each 6-12 months
                 (6 months for HIV symptomatic women, 12 months for
                 HIV asymptomatic women)

		5) colposcopically evaluate women with ASCUS, atypical
                 glandular cells of undetermined significance (AGCUS),
                 low-grade and high-grade SIL on Pap smear

		6) observation of biopsy-proven low-grade lesions (CIN
                 I)

		7) since women with HIV and cervical cancer are more
                 likely to die of cancer, do not withhold treatment
                 solely because of HIV disease

		8) cease or decrease cigarette smoking.

The main drawback of Pap smears for screening HIV positive women is
that cervical Pap smears cannot detect vulvar lesions that women with
HIV may have. However, VIN or PIN can be detected by colposcopy (Korn,
1994).

       Other Types of Genital Neoplasia and Related Concerns

Guidelines for cervical Pap smears and cervical screening in women
with HIV are limited by the nature of what is being tested; a cervical
Pap smear gives information about the cervix alone. While the cervical
Pap test is an important, sensitive and accurate tool for that
purpose, significant neoplasias develop in extracervical genital
regions as well. A study at SFGH that involved both HIV positive and
negative women found that 15% of the HIV positive women had "only
vulvar, vaginal or perianal lesions that would not usually be detected
with Pap smears" (Korn, 1994). Although vulvar and anal cancer has
been reported in HIV positive women, it is rare. However, this rarity
does not obviate the importance of screening for precursor conditions
to such cancers. Thus, anal Pap smears are increasingly regarded as an
important screening tool for women and men at risk.

Colposcopy is a valuable tool for detecting noncervical lesions. It
also permits more efficient diagnosis and therapy of cervical lesions.
Still, colposcopy is expensive and must be performed by a trained
clinician--classic reasons for reluctance to routinely recommend
colposcopy as a screening measure, even for HIV positive women. All
things considered, Korn's suggestion that "a single colposcopic exam
on diagnosis of HIV or AIDS may be a cost-effective compromise" seems
eminently reasonable.

       References

Brinton LA. Epidemiology of cervical cancer--overview. IARC Scientific
Publication 119: 3-23. 1992.

Bosch FX and others. Prevalence of human papillomavirus in cervical
cancer: a worldwide perspective.  Journal of the National Cancer
Institute 87: 796-802. 1995.

Bradbeer C. Is infection with HIV a risk factor for cer-vical
intraepithelial neoplasia? Lancet 2: 1,277-1,278. 1987.

Brock KE and others. Smoking and infectious agents and risk of in situ
cervical cancer in Sidney, Australia. Cancer Research 49(17):
4925-4928. 1989.

Cannistra SA and Niloff JM. Cancer of the uterine cervix. The New
England Journal of Medicine 334(16): 1030-1038. April 18, 1996.

Carpenter CJ and others. Human immunodeficiency virus infection in
North American women: experience with 200 cases and a review of the
literature. Medicine 70: 307-325. 1991.

Crocchiolo P and others. Cervical dysplasia and HIV infection. Lancet
7: 238-239. 1988.

Hirschowitz L and others. Long term followup of women with borderline
cervical smear test results: effects of age and viral infection on
progression to high-gread dyskaryosis. British Medical Journal
304(6836): 1209-1212. 1992.

Korn AP and Landers DV. Gynecologic disease in women infected with
human immunodeficiency virus type 1. Journal of Acquired Immune
Deficiency Syndromes and Human Retrovirology 9: 361-370. 1995.

The 1991 Bethesda Workshop. The revised Bethesda system for reporting
cervical/vaginal cytologic  diagnoses: report of the 1991 Bethesda
workshop. Journal of Reproductive Medicine 37(5): 383-386. 1992.

Wright TC and others. Treatment of cervical intraepithelial neoplasia
in HIV-infected women with loop electrosurgical excision. First
National Conference on Human Retroviruses and Related Infections.
Washington, DC. December 1993. Abstract 32.


       THE BETHESDA SYSTEM FOR INTERPRETING PAP SMEAR RESULTS

The Pap smear is considered an effective screening tool for CIN in HIV
positive women. The system for reporting Pap smear results is the
Bethesda System II. This system came into use in 1991, and is used
today according to the recommendations for managing abnormal Pap smear
results known as the Bethesda Interim Guidelines, published in the
Journal of the American Medical Association in 1992 (271: 1866).

The Bethesda System first reports on the adequacy of the sample (e.g.,
if endocervical cells are present) and uses descriptive terms for
abnormal results. This system may describe any infection detected on
Pap smear, such as fungal (e.g., candidiasis), bacterial, protozoal
(e.g., Trichomonas) or viral (e.g., cyto-megalovirus, herpes simplex
virus) infection. The results report if the Pap smear detected
inflammation, squamous cell abnormalities or glandular cell
abnormalities.

Cervical cancer is primarily a squamous cell cancer. A Pap smear
result of atypical squamous cells of undetermined significance (ASCUS)
indicates abnor-malities that do not fit the criteria for SIL, but
which are significant. An estimated 20% of women with ASCUS results
will go on to develop SIL or invasive cancer (Hirschowitz and other).
For the details and guidelines for clinical management of results, see
the 1994 Bethesda Interim Guidelines.

The Official Bethesda System for Reporting Cervical/Vaginal Cytologic
Diagnoses

FORMAT OF THE REPORT: a. A statement on Adequacy of the Specimen for
Evaluation b. A General Categorization which may be used to assist
with clerical triage (optional) c. The Descriptive Diagnosis

ADEQUACY OF THE SPECIMEN

Satisfactory for evaluation Satisfactory for evaluation but limited
by...(specify reason) Unsatisfactory for evaluation...(specify reason)

GENERAL CATEGORIZATION (OPTIONAL)

Within normal limits Benign cellular changes: see descriptive
diagnoses Epithelial cell abnormality: see descriptive diagnoses

DESCRIPTIVE DIAGNOSES  Benign cellular changes

		Infection

              Trichomonas vaginalis

    	 	Fungal organisms morphologically consistent with Candida
              species

    	 	Predominance of coccobacilli consistent with shift in
              vaginal flora

    	 	Bacteria morphologically consistent with Actinomyces
              subspecies

    	 	Cellular changes associated with herpes simplex virus

    	 	Other

       Reactive changes

		Reactive cellular changes associated with:

    	 	Inflammation (includes typical repair)

    	 	Atrophy with inflammation ("atrophic vaginitis")

    	 	Radiation

    	 	Intrauterine contraceptive device (IUD)

		Other

       Epithelial Cell Abnormalities

		Squamous Cell

    	 	Atypical squamous cells of undetermined significance:
              Qualify1

    	 	Low-grade squamous intraepithelial lesion encompassing:

         		HPV2

         		Mild dysplasia/CIN I

    	 	High-grade squamous intraepithelial lesion encompassing:

         		Moderate and severe dysplasia

         		Carcinoma in situ/CIN 2 and CIN 3

    	 	Squamous cell carcinoma

		Glandular Cell

    	 	Endometrial cells, cytologically benign, in a
              postmenopausal woman

    	 	Atypical glandular cells of undetermined significance:
              Qualify*

    	 	Endocervical adenocarcinoma

    	 	Endometrial adenocarcinoma

    	 	Extrauterine adenocarcinoma

    	 	Adenocarcinoma, not otherwise specified (NOS)

Other malignant neoplasms: specify  Hormonal evaluation (applied to
vaginal smears only)

		Hormonal pattern compatible with age and history

		Hormonal pattern incompatible with age and history:
              specify

		Hormonal evaluation not possible due to: specify

1. Atypical squamous or glandular cells of undetermined significance
should be further qualified as to whether a reactive or a
premalignant/malignant process is favored.

2. Cellular changes of human papillomavirus (HPV)--previously termed
koilocytosis atypia, or condylomatous atypia--are included in the
category of low-grade squamous intraepithelial lesion.  Back to the
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 WOMEN AND AIDS

       Cervical Cancer Screening Issues for HIV Positive Women: A
       Physician's Perspective

       by Lisa Bardaro, MD

       There is a general lack of consensus regarding how best to
       screen for, diagnose and manage cervical neoplasia (abnormal,
       precancerous cells) and cervical cancer for the general
       population. Since the scientific evidence confirms that women
       with HIV infection have higher rates of cervical neoplasia and
       more aggressive cervical cancers, these issues have particular
       importance for women with HIV. Many clinicians agree that women
       with HIV should probably have frequent Pap smears, but we
       cannot yet agree on a definitive answer to the crucial
       question: how often?

       Terminology

       Cervical intraepithelial neoplasia (CIN) is now used to describe what was once called dysplasia:

		CIN I = minimal dysplasia

		CIN II = moderate dysplasia

		CIN III = severe dysplasia or carcinoma in situ

CIN III, severe dysplasia and carcinoma in situ are all different
names for the same thing--early cervical cancer. While approximately
one-third of all cases of CIN I will resolve in time, the rest will
progress. All degrees of CIN, however, require immediate colposcopy.

       Medical Historical Background

The Pap smear came into widespread use in the 1960s, although the test
was available to women in major urban centers in the 1950s. The advent
of the Pap smear revolutionized one aspect of women's healthcare.
Widespread availability of this simple, low-cost, easily performed
test has saved countless lives. Before the Pap smear came into use,
cervical cancer was virtually never diagnosed before a woman had
entered the terminal stages, when cancerous growths had become
sufficiently large to cause obvious symptoms. A symptom such as
bleeding after intercourse might bring a woman in to see her doctor;
examination might reveal a large tumor and necrosing (dying) tissue,
and ultimately result in a diagnosis of stage IV cancer. (Cervical
cancer is classified into 4 stages--see chart of FIGO staging.)

In 1988, a coalition of organizations (the American College of
Obstetrics and Gynecology, the American Academy of Family Practice,
the American Cancer Society, the National Cancer Institute, the
American Medical Association, the American Nursing Association and the
American Medical Women's Association) developed a consensus statement
regarding cervical Pap smears. The statement recommended annual Pap
smears for all women who were or had been sexually active, or were at
least 18 years of age. However, just 1 year later, the United States
Preventive Services Task Force issued a very different statement,
recommending Pap smears every 1-3 years, depending on risk factors. In
addition to HIV infection, other established risk factors for cervical
cancer are infection with human papillomavirus (HPV), especially types
16 and 18, immunosuppression due to any cause and cigarette smoking.
Current evidence suggests that low dietary levels of folate, vitamin C
and beta carotene may also predispose women to cervical neoplasia.

Another crucial question then arises: what is the cost of a Pap smear
versus the cost of treating invasive cervical cancer?

Pap Smear and Colposcopy

The Pap smear and colposcopy are the 2 basic tools used for screening
and follow-up for CIN. A Pap smear is a simple test performed as part
of a regular, simple pelvic examination. Cells are removed from the
cervix and vagina with a small flat stick and a cervical brush, and
smeared on a glass slide. The slide is sent to a laboratory for
analysis. A Pap smear allows a technician to look at cells but not to
make a diagnosis, since it only includes cells but not the entire
tissue. To make a definitive diagnosis, it is extremely important to
be able to view the entire tissue, which is what colposcopy and biopsy
allow. Only then can an appropriate treatment plan be devised.

Colposcopy is a diagnostic procedure that entails magnified
examination of the vulva, vagina and cervix, with what is essentially
a very high-powered microscope. A somewhat involved although not
painful procedure, colposcopy must be performed by a trained
healthcare provider. Any suspicious areas seen under the lens are
biopsied (sampled). A complete colposcopy also entails biopsy of the
cervical canal, a procedure known as endocervical curettage (ECC).
This step is especially important because many cancers arise from the
cervical canal. ECC is contraindicated only during pregnancy.

False-Negative Smears

A very significant issue is the high rate of false-negative Pap
smears. A false-negative Pap smear is one that fails to detect
existing neoplasia. False-negative Pap smears generally result from
either incorrect performance of the Pap smear test (i.e., abnormal
cells actually present in the cervix were not gathered, due to poor
technique on the part of the health professional) or incorrect reading
of the test slide by the laboratory technicians, who view the smear
under a microscope. Adequately performed and adequately read smears
have a false-negative rate of up to 25%. Clearly, under less than
optimal conditions, this rate is even higher.

The inherently high rate of false-negative smears must be offset; one
of the best ways is to have Pap smears on a regular basis.

Slow and Rapid Disease

Cervical cancer generally takes either a slowly progressive or a
rapidly progressive course. The former refers to cases that progress
from a normal Pap smear to invasive cervical cancer over a period of
about 20 years. The latter describes cases that traverse that journey
in 1-3 years, with 10% developing invasive cervical cancer in the
first year. While it is generally believed that rapidly progressive
disease occurs primarily in high-risk groups, there is no practical
way to determine before the development of neoplasia into which group
a woman will fall. The strain or type of HPV may be most predictive of
the group in which a woman will be classified, but this is of limited
utility because 1) tests of HPV type are not routinely performed,
except in research settings and 2) typing is not conducted until after
the development of neoplasia.

Besides HPV, immunosuppression is also associated with more rapidly
progressive disease. Therefore, it is particularly important for women
with HIV to have regular Pap smears to diagnose neoplasia early enough
for potential cure. Cure rates are high for cervical cancer detected
early (stage I and most stage II), but the chance for cure decreases
with increasing stage at time of diagnosis.

What Next?

If biopsy reveals CIN I, women should get a repeat Pap smear and
colposcopy in 3-6 months. An upcoming trial, AIDS Clinical Trials
Group (ACTG) 293, will evaluate a possible treatment regimen for women
with HIV and CIN I. Participants will be randomized to receive either
oral isotretinoin (Accutane) or observation (no treatment) for 6
months, with an additional follow-up period of 1 year.

If biopsy reports confirm CIN II or CIN III, the next step is a biopsy
of the cervix called conization or a cone biopsy, so named because it
describes the shape of tissue removed. This can be done by scalpel
(cold-knife cone), by laser or, most commonly, by loop electrosurgical
excision procedure (LEEP). Essentially, LEEP uses an electric scalpel.
The cone biopsy allows a pathologist to stage disease by determining
the depth of invasion of cancerous cells. It also can be curative, if
all margins of the removed tissue are free of cancer.

Regardless of biopsy results, most authorities recommend cone biopsy
or LEEP if:

		1) the ECC reveals CIN,

		2) any biopsy reveals glandular CIN, or

		3) the transformation zone has retracted within the
                 cervical canal and cannot be fully visualized.

Squamous cell cancers account for about 80% of all cases, with the
remainder being adenocarcinoma, adenosquamous or undifferentiated
cancer.

Staging and Treatment of Cervical Cancer

Treatment of cervical cancer or CIN III depends on the International
Federation of Gynecology and Obstetrics (FIGO) stage at the time of
diagnosis. This system is used by physicians worldwide to devise
treatment plans and to provide consistency in reporting diagnoses to
public health authorities.

Four possible FIGO stages are determined by 2 factors: the depth of
invasion on the biopsy report and careful pelvic examination. In
developed nations, frequently intravenous pyelograms (IVP),
computerized axial tomography (CAT) scans and magnetic resonance
imaging (MRI) can help to define the stage of disease. In general,
FIGO stages I and II are treated with radical hysterectomy (removal of
the cervix, upper vagina, fallopian tubes, ovaries, pelvic lymph nodes
and supporting ligaments). In younger women, the ovaries may be left
intact.

After stage II, the cancer cannot be entirely removed by surgery
alone. The surrounding abdominal region is now involved, including the
lymph nodes and muscles. More advanced stages--stages III-IV, although
some physicians recommend the following for stage IIB as well--are
treated with radiation therapy using both external beam (a machine is
used to radiate the external pelvic region and any other areas where
the cancer might be present) and intracavitary radiation (radium
pellets are surgically implanted into the tissue of the vagina and
cervix).

Chemotherapy with anticancer drugs is no longer used to treat cervical
cancer.

Cryotherapy and its Legacy

Cryotherapy involves the use of liquid nitrogen to freeze and thereby
destroy abnormal tissue. For many years and until recently,
cryotherapy was regularly used to treat CIN. Its benefits were ease of
use, low cost and the fact that it was a non-surgical approach. Now
the bad news: cryotherapy can cause scarring and narrowing of the
cervical canal (cervical stenosis). It can also cause the
transformation zone (where squamous and columnar tissues meet) to
retract upward as it heals, which makes future visualization and
biopsy of this area impossible.

However, the worst legacy of this procedure is still more ominous.
Cryotherapy can cause normal tissue to heal over a deeper area of
neoplasia, causing future Pap smears to appear normal while abnormal
tissue continues to grow undetected underneath. For these reasons,
gynecological oncologists (specialists in the treatment of
reproductive cancers) now recommend against cryotherapy. Women who
have been treated with cryotherapy in the past should be examined
regularly and carefully.

Previous Hysterectomy

There is no general consensus about the frequency of Pap smears for
women who have had hysterectomies for benign conditions. However,
women with a history of cervical cancer have a higher rate of
subsequent vaginal neoplasia and should have yearly vaginal Pap
smears.

Conclusion

When cervical cancer is undiagnosed, untreated or fails to respond to
treatment, 95% of women will die within 2 years. Given these facts,
and the high rates of cervical neoplasia in women with HIV infection,
increasing survival should be the top priority. This author strongly
recommends that all women with HIV infection have Pap smears every 6
months.

INTERNATIONAL FEDERATION OF GYNECOLOGY AND OBSTETRICS (FIGO) STAGING
OF CERVICAL CANCER

		Stage I -- The cancer is confined to the cervix

    	 	Stage IA -- Microinvasive disease

         		Stage IA1 -- Stromal (connective tissue) invasion
                     less than 3 mm

         		Stage IA2 -- Stromal invasion 3-5 mm, not in
                     excess of 7 mm in horizontal spread

    	 	Stage IB -- Lesions greater than 7 mm in horizontal spread

  		Stage II -- Involvement extends beyond the cervix,
              including the vagina except for the lowest third, or
              infiltration of the parametrium (connective tissue near
              the uterus) but not out to the pelvic sidewall.

    	 	Stage IIA -- Involvement of the upper two-thirds of the
              vagina, without lateral extension  into the parametrium

    	 	Stage IIB -- Lateral extension into the parametrial
              tissue but not out to the pelvic sidewall

  	  	Stage III -- Involvement of the lowest third of the
              vagina or the pelvic sidewall or causes hydronephrosis
              (nonfunctioning kidney)

    	 	Stage IIIA -- Involvement of the lowest third of the
              vagina

    	 	Stage IIIB -- Involvement of the pelvic sidewall or
              hydronephrosis

		Stage IV -- Cancer extends beyond the reproductive tract

    	 	Stage IVA -- Involvement of the bladder or rectal mucosa

    	 	Stage IVB -- Distant metastasis (cancer that spreads to
              other parts of the body away from the original, primary
              site) or disease outside the true pelvis.

       References

American College of Obstetricians and Gynecologists (ACOG). Cervical
cytology: evaluation and management of abnormalities. ACOG Technical
Bulletin 183: 1-8. Washington, DC. 1993.

Benedet JL and others. Results of conservative management of cervical
intraepithelial neoplasia. Obstetrics and Gynecology 79: 105. 1992.

Cuthill S and others. Complications after treatment of CIN in women
infected with HIV. Journal of Reproductive Medicine. 1994.

El-Sadr W and others. Managing Early HIV Infection: Quick Reference
Guide for Clinicians. Agency for Health Care Policy and Research
(AHCPR) 94-0573. AHCPR, Rockville MD:, Public Health Service, U.S.
Department of Health and Human Services. 1994.

Koss LG. The Papanicolaou test for cervical cancer detection: a
triumph and a tragedy. Journal of the American Medical Association
261: 737-743. 1989.

Kurman RJ and others. Interim guidelines for management of abnormal
cervical cytology. Journal of the American Medical Association 271:
1866-1869. 1994

Lungo O and others. Relationship of human papillomavirus type to grade
of cervical intraepithelial neoplasia. Journal of the American Medical
Association 267: 2493-2496. 1992.

Maiman M and others. Colposcopic evaluation of HIV sero-positive
women. Obstetrics and Gynecology 78: 84-88. 1991.

Maiman M and others. Human immunodeficiency virus infection and
cervical neoplasma. Gynecological Oncology 38: 377-382. 1990.

Maiman M and others. Recurrent CIN in HIV seropositive women.
Obstetrics and Gynecology 82:2 170-174. 1993.

Palan PR and others. Plasma levels of anti-oxidant beta-carotene and
alpha-tocopherol in uterine cervical dysplasias and cancer. Nutrition
and Cancer 15: 13-20. 1991.

Peterson F. Annual report on the results of treatment in
gyncecological cancer 21. International Federation of Gynecology and
Obstetrics. 1991.

Romney SL and others. Retinoids and the prevention of cervical
dysplasias. American Journal of Obstetric Gynecologic 141: 890-894.
1981.

Schiffman MH. Recent progress in defining the epidemiology of human
papillomavirus infection and cervical neoplasia. The National Cancer
Institute 84: 392-398. 1982.

Sedlacek T. Clinical options in dealing with minor cytologic
abnormalities. Colposcopist 24(4): 1-2. 1992. U.S. Preventive Services
Task Force. Screening for cervical cancer. Guide to Clinical
Preventive Services: an Assessment of the Effectiveness of 169
Interventions. Baltimore, Williams and Wilkins. 1989

Van der Graaf Y and others. Screening errors in cervical cytology
screening. ACTA Cytologica 31: 434-438. 1987.

Winkelstein W. Smoking and cervical cancer current status: a review.
American Journal of Epidemiology 131: 945-957. 1990.< \font>  Back to
the BETA Page Back to the Treatment Education and Advocacy Page Back
to the San Francisco AIDS Foundation Home Page


       Research Notes

       by Harvey S. Bartnof, MD

       Dr. Harvey S. Bartnof has been a member of the Scientific
       Advisory Committee at the San Francisco AIDS Foundation since
       1987.

       HIV RESEARCH HIGHLIGHTS

       New HIV Treatment Recommendations

HIV treatment is indicated if CD4 count is over 500 cells/mm3 and
viral load is high; alternative may be observation.

Paul Volberding, MD, Steven Deeks, MD, and colleagues from the
University of California at San Francisco-San Francisco General
Hospital (SFGH) have proposed a set of guidelines outlining which type
of anti-HIV therapies should be used at various CD4 cell counts and
viral load measurements. Clinicians at SFGH and the San Francisco
Department of Public Health (SFDPH) are already using the guidelines.
The proposal incorporates the recent findings that HIV RNA viral load
is a better predictor of HIV progression than CD4 cell counts,
especially when the CD4 count is greater than 500 cells/mm3 (see Viral
Load is a Better Predictor of Disease Progression). They also
incorporate the findings that 2-drug therapy is generally better than
monotherapy in delaying AIDS and prolonging survival. The
recommendations are shown in the chart below.

Ultimately, treatment decisions should be based on mutual agreement
between patient and physician. An alternate, more aggressive strategy
that is part of the recommendations includes treating all HIV positive
patients until the HIV RNA level is less than 10,000 copies/mL.

John G. Bartlett, MD, Chief of Infectious Diseases at Johns Hopkins
University School of Medicine, has recently published the HIV
treatment guidelines used by the Johns Hopkins AIDS Care Program.
Physicians there advocate anti-HIV therapy for those with a CD4 cell
count greater than 500 cells/mm3 when the HIV RNA viral burden is
greater than 106 (one million). That level of viral load is higher
than the SFGH recommendations. However, the fact that both UCSF-SFGH
and Johns Hopkins University use HIV viral load and CD4 cell count
measurements in determining the starting point of HIV treatments
represents a major shift in the standard of HIV care. Both
institutions would advocate anti-HIV therapy at a CD4 cell count
greater than 500 cells/mm3 if the HIV viral load is high. The 2
institutions differ as to what level of HIV viral load is high. The
Johns Hopkins AIDS Care Program also monitors viral loads and uses a
high or increasing viral burden to determine that a change in HIV
therapy is indicated. Dr. Bartlett's recommendations are published in
the May 1996 issue of Infectious Diseases in Clinical Practice.

PROPOSED NEW HIV TREATMENT RECOMMENDATIONS FROM SFGH/SFDPH**

CD4 cell count (cells/mm3): fewer than 350; Viral load (RNA
copies/mL): any level; Recommendation:2 nucleoside analogs plus a
protease inhibitor   CD4 cell count (cells/mm3): 350-500; Viral load
(RNA copies/mL): more than 5,000-10,000; Recommendation:2 nucleoside
analogs plus a protease inhibitor if needed to reduce viral load to
less than 10,000 copies/mL  CD4 cell count (cells/mm3): 350-500; Viral
load (RNA copies/mL): less than 5,000-10,000; Recommendation:ddI or
d4T** monotherapy or 2 nucleoside analogs or observation  CD4 cell
count (cells/mm3): greater than 500; Viral load (RNA copies/mL): more
than 5,000-10,000; Recommendation:ddI or d4T** monotherapy or 2
nucleoside analogs or observation or participation in clinical trials
CD4 cell count (cells/mm3): greater than 500; Viral load (RNA
copies/mL): less than 5,000-10,000; Recommendation:observation or
participation in clinical trials   Notes to the table:

Another option in the SFGH recommendations is to treat all patients
until thay have a viral load less than 10,000 copies/mL.

To obtain a baseline viral load, the initial test should be repeated
2-4 weeks later.

Nucleoside analogs include AZT (Retrovir), ddI (Videx), ddC (Hivid),
d4T (Zerit) and 3TC (Epivir).

Recommendations for 2 nucleoside analogs would include one of the
following 2 choices:

		AZT plus either ddI or ddC or 3TC

		d4T plus either ddI or 3TC.

Approved protease inhibitors include saquinavir (Invirase), ritonavir
(Norvir) and indinavir (Crixivan). Protease inhibitors in development
include nelfinavir (Agouron Pharmaceuticals) and VX-478
(Glaxo-Wellcome/Vertex).

*    d4T monotherapy would be an option only after a prior regimen
that included AZT.

**  San Francisco General Hospital/San Francisco Department of Public
Health.

Source: S. Deeks, MD, P. Volberding, MD (SFGH) and M. Katz, MD
(SFDPH); adapted for BETA by H. Bartnof, MD.

Bartlett JG. Antiretroviral therapy in patients with HIV infection.
Infectious Diseases in Clinical Practice 5(3): 172-179. May 1996.

Deeks, S. Personal communication. June 5, 1996.

Volberding PA. Considerations in the initial therapy of HIV
infections. Advances in the Management of HIV Infection. San
Francisco, CA. May 11, 1996.


Guidelines for Using HIV Viral Load Tests

Interim recommendations published by leading AIDS researchers

Additional studies show HIV RNA viral load is better than CD4 count in
predicting disease progression and survival

A group of prominent AIDS clinical researchers and investigators has
published an interim set of guidelines on practical utilization of HIV
viral load tests. Their report appears in the June 1996 issue of
Nature Medicine. The group represented an ad hoc panel of the
International AIDS Society-USA.

On June 3, 1996, FDA approved the Amplicor HIV-1 Monitor Test, the
polymerase chain reaction (PCR) test from Roche Molecular Systems Inc.
Chiron's branched-chain DNA (bDNA) test is expected to be approved
soon (see "HIV Viral Load Supercedes CD4 Count").

The paper states that "the goals of antiretroviral therapy are to
limit or delay disease progression and increase survival. Decreases in
CD4 cell counts occur as a result of viral replication and, in that
sense, represent a clinical endpoint rather that a 'surrogate marker'
of disease activity. It is this very process -- HIV-mediated
lymphocyte destruction -- that physicians attempt to prevent rather
than observe. [Therefore], ideally, the goals of [antiretroviral]
therapy are to reduce the plasma HIV RNA level as much as possible and
for as long as possible."

The authors state that, "Monitoring plasma HIV RNA levels adds
important information for patient management, including:

(1) information on risk of disease progression;

(2) when to initiate therapy;

(3) the degree of initial antiretroviral effect achieved; and

(4) when a drug regimen is failing.

The CD4 lymphocyte count remains an essential index for making
decisions regarding prophylaxis for opportunistic infections and for
evaluating the immunologic effects of antiretroviral therapy."

The authors include Paul Volberding, MD, and Margaret Poscher, MD,
both from UCSF-SFGH; Michael Saag, MD, and George Shaw, MD, both from
University of Alabama; Douglas Richman, MD, from University of
California at San Diego; William O'Brien, MD, from University of
California at Los Angeles; Mark Holodniy, MD, from Stanford
University; D. Kuritzkes, MD, from University of Colorado; Robert
Coombs, MD, from University of Washington; and Donna Jacobsen from the
International AIDS Society-USA.

In a commentary in Lancet Paul Volberding, MD, states, "when the HIV
RNA (level) approaches or exceeds baseline after a period of
suppression, alternative drugs, or combinations should be considered,
again using HIV RNA [levels] as an estimate of efficacy. [HIV RNA
viral load] concentrations above 100,000 copies per milliliter may
predict rapid deterioration, while those below 10,000 copies per
milliliter may be associated with a more favorable course."

The Nature paper also makes some specific recommendations regarding
appropriate processing of blood samples for plasma RNA viral load
testing. Inadequate processing can lead to falsely low levels.
Specifically, the same type (color) of collection tube and
anticoagulant should be used each time for appropriate comparison. All
plasma specimens should be separated from the cellular fraction and
frozen within 6 hours of collection. A second choice would be
refrigerating the plasma after separation. The last choice would be
refrigerating the whole blood, but not for more than 24 hours before
plasma separation and freezing. The blood sample should be drawn into
a purple top tube with EDTA (ethylenediaminetetraacetic acid)
anticoagulant OR a yellow top tube with ADC (acid citrate dextran)
anticoagulant. A green top (heparin) tube is an alternative only for
the NASBA viral load test. A green top tube isolates blood serum,
which is plasma with certain proteins removed. According to Michael
Saag, MD, during comments made at a recent AIDS conference, a viral
load test cost of more than $100-150 represents an excessive profit by
the laboratory or processor.

SUMMARY OF INTERIM RECOMMENDATIONS

Question: At what level of HIV RNA viral load should HIV treatment be
started?

Recommendation: If HIV RNA viral load is greater than 30,000-50,000
copies/mL, anti-HIV treatment should be started; if viral load is more
than 5,000-10,000 copies/mL and the clinical status or CD4 count
suggests progression of disease, anti-HIV treatment should be started.

Question: What is the ideal target level of viral load after starting
anti-HIV treatment?

Recommendation: An HIV RNA viral load that is undetectable; less than
5,000 copies/mL is an acceptable target.

Question: After anti-HIV treatment has been started, what is the
minimal decrease of viral load indicative of anti-HIV activity?

Recommendation: Greater than 3-fold (0.5 log) decrease in HIV RNA
viral load.

Question: After treatment has been started or continued, what is the
change in RNA viral load that suggests drug treatment failure?
Recommendation: Either a return to pretreatment level; or a return to
within 2-3 fold (0.3-0.5 log) of HIV pretreatment level suggests
treatment failure.   Question: When and how often should an HIVRNA
viral load test be prformed?  Recommendation: At baseline:  2
measurements, 2-4 weeks apart; every 3-4 months or in conjunction with
CD4/CD8 count testing; shorter intervals as critical decision points
are neared; 3-4 weeks after starting or changing anti-HIV therapy; the
same manufacturer's viral load assay should be used each time for
comparison.   Question: When should HIV RNA viral load not be
measured?  Recommendation: Within a month of acute illnesses; within a
month after vaccinations, including influenza, pneumococcus, hepatitis
and others.

THE 3 TYPES OF HIV RNA VIRAL LOAD TESTS ARE:

(1) second generation branched-chain DNA (bDNA) test from Chiron;

(2) reverse transcriptase-polymerase chain reaction (RT-PCR) test from
Roche Molecular Systems; and

(3) nucleic-acid sequence-based amplification(NASBA) test from Organon
Teknika.

All of the tests measure RNA, an indication of HIV genetic
replication. Another viral load test is the quantitative
competitive-polymerase chain reaction (QC-PCR) test.

Viral Load is a Better Predictor of Disease Progression

In what appears to be a major turning point in the conceptual
understanding of HIV/AIDS disease progression, John Mellors, MD, and
colleagues have published a paper describing the superior ability of
an HIV viral load test to predict disease progression and death, when
compared with CD4 cell counts. The report was published in the May 24,
1996 issue of Science. The researchers evaluated 184 HIV positive
persons from the University of Pittsburgh arm of the Multicenter AIDS
Cohort Study (MACS).

Participants were followed for up to 11 years. RNA viral loads and CD4
cell counts were measured, starting in 1984-85. During the 11-year
period, 64% were diagnosed with AIDS, while 36% remained AIDS-free.
Those with AIDS progressed to their diagnosis in a mean of 5.1 years;
those who were without AIDS remained so for a mean of 10.6 years.
"Rapid progressors" were defined as the 19% who progressed to AIDS
within 5 years, while "slow progressors" were defined as the 12%
estimated to remain AIDS-free for 20 years.

Entry viral load levels enabled the participants to be classified into
4 different groups of increasing viral load levels: (1) the lowest
level (less than 4,531 RNA copies/mL); (2) the second lowest level
(4,531-13,020 RNA copies/mL); (3) the second highest level
(13,021-36,270 RNA copes/mL); and (4) the highest level (greater than
36,270 RNA copies/mL). When the 4 categories of increasing viral loads
were matched with progression to AIDS, a highly statistically
significant trend was observed: (1) lowest level viral load, greater
than a mean 10 years until AIDS; (2) second lowest level, a mean of
7.7 years until AIDS; (3) second highest level, a mean of 5.3 years
until AIDS; and (4) highest level, a mean of 3.5 years until AIDS. A
similar highly statistically significant trend was observed when
comparing the 4 different viral load groups with survival, with an
approximate addition of 2 years to the AIDS progression time: (1)
lowest level viral load, greater than 10 years survival; (2) second
lowest level, 9.5 years mean survival; (3) second highest level, 7.4
years mean survival; and (4) highest level, 5.1 years mean survival.

A clear inverse correlation exists between starting viral load levels
and both the number of years until AIDS and survival. That is, the
higher the viral load, the shorter the time to AIDS and the shorter
the survival; conversely, the lower the viral load, the longer the
time to AIDS and the longer the survival.

Entry level viral loads were even better at predicting progression and
survival than baseline CD4 cell counts. If all the participants who
had entry level CD4 cell counts of greater than 500 cells/mm3 were
subdivided into 2 viral load levels (greater or less than 10,190 RNA
copies/mL), a surprising trend was found. For the lower viral load
level (less than or equal to 10,190 RNA copies/mL), the 10-year
survival rate was 70%. Whereas, for the higher viral load level
(greater than 10,190 RNA copies/mL), the 10-year survival rate was
only 20% (even with a CD4 cell count greater than 500 cells/mm3).

Dr. Mellors also reviewed several other studies that support the
concept that viral load measurements are better than CD4 cell counts
in determining prognosis and response to therapy. One study that is
particularly noteworthy was published in the February 15, 1996 New
England Journal of Medicine. It was first reported at the 1994 X
International Conference on AIDS (see BETA, September 1994, page 13).
That study, Veterans Affairs 298, found that treatment-induced
decreases in plasma viral load were better than CD4 cell count
increases in predicting a slower progression to AIDS. However, the
treatment-induced increase in CD4 cell count was able to predict some
of the decrease in AIDS progression. The treatment was AZT (Retrovir).
The study found that a 3-fold (0.5 log) reduction in viral load is the
minimum to establish a therapeutic benefit. The emerging standard from
the report and repeated by many AIDS researchers is: "the goal of
antiretroviral therapy should be to reduce the levels of circulating
[HIV] virus as much as possible, for as long as possible."

David Ho, MD, from the Aaron Diamond AIDS Research Center in New York,
commented on the Mellors et al article in the same issue of Science.
The title of his commentary is "Viral Counts Count in HIV Infection."
Dr. Ho declares, "the prognostic utility of measuring plasma viral
load in HIV-1 infection is now unequivocal." He states that measuring
viral load provides a view of HIV viral production, "which in turn
drives a fixed rate of CD4 lymphocyte destruction." He continues, "it
should not be surprising that viral load is a good surrogate marker
for clinical outcome in HIV-1 infection. It is, indeed, a disease
marker." He adds, "there is little doubt that viral load
determinations will become useful tools, along with CD4 lymphocyte
counts, in the clinical management of HIV-1-infected patients."

Dr. Ho notes, "many of the patients on potent combination therapies
now have viral loads below those of long-term nonprogressors." Those
patients on combination therapy "will present a unique opportunity to
define the viral threshold below which disease progression does not
occur."

Other studies have documented the correlation between viral load and
HIV disease progression, including the AIDS Clinical Trials Group, the
European Delta Trial, the Pharmacia and Upjohn studies of delavirdine
(Rescriptor), and the Air Force Tri-Service Natural History Program.
Not all have yet been published by peer-reviewed medical journals.

Clearly viral load tests are rapidly becoming more important than, but
not displacing, CD4 cell counts, in determining progression and
response to anti-HIV therapies.

BETA has published several articles on the significance and utility of
viral load testing. (See this issue: Research Notes, "AZT Decreases
Maternal Viral Load," below; March 1996, pages 13 and 50; December
1995, pages 15-16; June 1995, pages 46-47; March 1995, pages 40-42;
September 1994, pages 13 and 42.)

BETA (Bulletin of Experimental Treatments for AIDS). March 1996, pages
13 and 50; December 1995, pages 15-16; June 1995, pages 46-47; March
1995, pages 40-42; September 1994, pages 13 and 42.

Coombs RW and others. Association of plasma human immunodeficiency
virus type-1 RNA level with risk of clinical progression in patients
with advanced infection.  Journal of Infectious Diseases. 1996 (in
press).

Ho DD. Viral counts count in HIV infection. Science 272: 1124-1125.
May 24, 1996.

Mellors JW and others. Prognosis in HIV-1 predicted by the quantity of
virus in plasma. Science 272: 1167-1170. May 24, 1996.

Mellors JW. and others. Quantification of HIV-1 RNA in plasma predicts
outcome after seroconversion. Annals of Internal Medicine 122:
573-579, 1995.

O'Brien WA and others. Changes in plasma HIV-1 RNA and CD4 lymphocyte
counts and the risk of progression to AIDS. New England Journal of
Medicine 334(7): 426-431. February 15, 1996.

Saag MS and others. HIV viral load markers in clinical practice.
Nature Medicine 2(6): 625-629. June 1996.

Saag MS. Use of Virologic Markers in Clinical Practice. Conference
Improving the Management of HIV Disease, sponsored by the
International AIDS Society-USA, San Francisco. April 20, 1996.

Saksela K and others. HIV-1 messenger RNA in peripheral blood
mononuclear cells as an early marker for risk for progression to AIDS.
Annals of Internal Medicine 123(9): 641-648. November 1, 1995.

Volberding PA, HIV quantitation: clinical applications. Lancet.
January 13, 1996.

Volker R. New studies say viral burden tops CD4 (cells) as a marker of
HIV disease progression. Journal of American Medical Association
275(6): 421-422. February 14, 1996.

Welles SL and others. Prognostic value of plasma HIV-1 RNA levels in
patients with advanced HIV-1 disease and with little or no zidovudine
therapy. The Journal of Infectious Diseases. 1996 (in press).

Wong MT and others. Patterns of virus burden and T cell phenotype are
established early and are correlated with the rate of disease
progression in human immunodeficiency virus type-1 infected persons.
The Journal of Infectious Diseases 173: 877-887. April 1996.

Resistance to HIV is Genetically Mediated

Researchers have described genetic markers on immune cells that may be
associated with resistance to HIV infection. Thirteen gay/bisexual men
from the Los Angeles subset of the Multicenter AIDS Cohort Study
(MACS) were evaluated. These men were selected because they were part
of a unique group of 25 men with multiple HIV exposures who had HIV
transiently isolated from their blood during 1985-1986. However,
through 1992 this group has had no further evidence of HIV infection
by culture or PCR, and they have remained persistently negative for
HIV on antibody testing. In addition, they have remained healthy and
well.

Different subtypes of the genes that regulate the transportation of
antigens to CD8 cytotoxic T-lymphocytes were measured. Variations in
these TAP (transporter associated with antigen processing) genes were
found when comparing the study group to controls who did seroconvert
to HIV positive. There was a statistically significant higher
proportion of the TAP 1.4 and/or 2.3 variants among the transiently
HIV-isolated group compared to control HIV seropositives. Moreover,
the study group had a statistically significant higher percentage of
activated CD8 lymphocytes carrying the CD25 marker compared to HIV
negative controls.

The authors correlate their findings to suggest that certain
individuals have specific genetic TAP markers that may cause a more
efficient presentation of HIV antigens to CD8 cells. This may lead to
an increase in the proportion of CD8 cells that can "clear
HIV-infected cells." Apparently, this can occur even without
generating a detectable antibody response. It is likely that these
findings will have implications for new HIV treatments and a potential
HIV vaccine.

Detels R and others. Resistance to HIV infection may be genetically
mediated. AIDS 10(1): 102-104. January 1996.

HIV Life Cycle More Precisely Described in HIV Positive People

CD4 cell lifespan only 2.2 days

HIV virion lifespan only 7.2 hours

Over 10 billion HIV particles produced daily

In January 1995, 2 different research groups published information
indicating that the HIV life cycle is extremely short. Both groups
found a very rapid turnover of HIV virus particles and CD4 lymphocytes
(see BETA, March 1995, pages 3 and 68-69). Using more sophisticated
techniques and analysis, one of those research groups has since
characterized the HIV life cycle more precisely. David Ho, MD, and
colleagues from the Aaron Diamond Research Center in New York,
published their findings in the March 15, 1996 issue of Science.

The new estimations were made after treating 5 HIV positive patients
with the newly FDA-approved protease inhibitor ritonavir (Norvir). The
dose was 600 mg twice a day. The mean baseline CD4 cell count was 170
cells/mm3, while the mean baseline viral load was 216,000 virions/mL.

Instead of HIV positive individuals producing 100 million to 1 billion
new HIV particles daily, Dr. Ho has estimated that an average of 10.3
billion particles are produced daily. This is approximately 15 times
the previous estimate. Ho found that the average lifespan of an HIV
virus particle was only 7 hours and 12 minutes. Therefore, a given
group of HIV particles in plasma (the liquid portion of blood) has a
half-life of 0.24 days, or 5 hours and 45 minutes (half-life is the
time required for half of an initial number to remain). He also
estimated that the time to generate a new HIV particle is only 2.6
days in vivo. This translates into an annual production of 140
separate HIV viral replication cycles.

Dr. Ho's group also measured the life cycle of activated CD4 cells to
be 2 days and 5 hours. The average half-life of the cells was
approximately 1 day and 14 hours. The life spans of the cells were
very similar among all 5 patients.

Considering the mutation rate of HIV and the calculated duration of
its life cycle, Ho states that "every mutation at every [nucleoside]
position in the genome would occur numerous times daily." Dr. Ho's
article continues, "The failure of anti-[HIV] agents, when used as
monotherapy, is the inevitable consequence of the dynamics of HIV-1
replication. Effective treatment must, instead, force the virus to
mutate simultaneously at multiple positions in one viral genome by
means of a combination of multiple, potent antiretroviral agents.
Moreover, because the process of producing mutant viruses is repeated
for 140 generations each year, early and aggressive therapeutic
intervention is necessary if a marked clinical impact is to be
achieved."

Protease inhibitors cause newly produced HIV particles to be
non-infectious. However, they do not block the production of HIV
particles from cells that are already infected. Also, they do not
prevent the infection of new cells by HIV particles that have already
been produced.

Ho D and others. HIV-1 dynamics in vivo: virion clearance rate,
infected cell life-span and viral generation time. Science 271:
1582-1585. March 15, 1996.

SURVIVAL AND PROGRESSION

AIDS Survival Correlates with Physician AIDS Experience

A few studies in the past have documented a relationship between lower
hospital mortality for AIDS patients and higher numbers of AIDS
patient admissions. Now, researchers from the University of Washington
have found a direct correlation between survival of AIDS patients and
the treating physicians' AIDS experience. They conclude that "practice
makes perfect."

The researchers examined 125 primary care physicians from Group Health
Cooperative of Puget Sound a staff-model health maintenance
organization (HMO) in Washington state. From 1984-1994, 403 adult men
with AIDS were evaluated for their total survival. Physicians were
classified according to their previous experience with AIDS patients,
either the least, moderate or most experience. Physician categories
were as follows: (1) "least experience" meant that the patient was the
physician's first AIDS patient; (2) "moderate experience" meant the
patient was the physician's second through fifth AIDS patient; and (3)
"most experience" meant the patient was the physician's sixth or more
AIDS patient. The categories were modified somewhat by the density of
AIDS cases in the city of the physician's residency training. Family
medicine or general practice was the specialty for 85% of the
physicians, while internal medicine encompassed 15%. By 1994, 39% of
the physicians remained in the "least experience" category, i.e., they
had never treated more than 1 AIDS patient in 10 years.

Primary care physicians provided both outpatient (clinic) and
inpatient (hospital) care. They had no financial incentive not to
refer to specialists. The median survival for AIDS patients treated by
physicians with the least experience was 14 months, whereas, median
survival under treatment by physicians with the most experience was 26
months. The results were statistically significant, including a trend
for increasing experience with increasing survival. AIDS patients
treated by physicians with the most experience had a 31% lower risk of
death than those treated by physicians with the least experience, even
after statistically controlling for severity of illness and year of
AIDS diagnosis. Physicians in the "most experience" category were more
likely to use appropriate antiretroviral and anti-pneumocystis
therapies and to measure CD4 cell counts regularly.

In an accompanying editorial, Paul Volberding, MD, from UCSF-SFGH
commented that the complexities of AIDS care along with the rapidity
of new developments and treatments create a challenge for the AIDS
specialist and an even greater challenge for the primary care
practitioner. The increasing number of preventive antibiotics and
anti-HIV therapies that are state-of-the-art makes keeping current
very challenging. Many AIDS patients are taking 10 or more different
medications each day to treat HIV, suppress opportunistic infections
and control symptoms. Yet, patients have the right to the most recent
advances in medical care.

Maintaining current HIV/AIDS care means more tests and therapies,
which translates into improved survival for patients at greater
expense. All patients with HIV should always ask their new physician,
"How many patients with AIDS have you personally treated?" If the
answer is less than 6 (and certainly if it is less than 2), one's
length of survival may depend upon changing to a physician with more
AIDS experience, if that option is available.

Kitahata MM and others. Physicians' experience with the acquired
immunodeficiency syndrome as a factor in patients' survival. New
England Journal of Medicine 334(11): 701-706. March 14, 1996.

Volberding PA. Improving the outcomes of care for patients with human
immunodeficiency virus infection. New England Journal of Medicine
334(11): 729-731. March 14, 1996.

HIV THERAPIES: NUCLEOSIDE ANALOG DRUGS

Long-Acting AZT Leads to Less Resistance

New formulation requires only twice a day dosing

Fewer side effects noted

A new sustained release, experimental formulation of AZT (Retrovir)
leads to less viral resistance and fewer side effects than the
currently marketed AZT formulation. The newer type needs to be taken
only twice daily, compared with 3 times daily for the current
formulation. It is not certain when the new formulation will be
marketed.

A total of 159 HIV positive patients were randomized to receive
standard AZT, 200 mg every 8 hours or AZT 300 mg (the experimental
formulation) every 12 hours. More than half of the participants had
prior AZT therapy. All had 200-500 CD4 cells/mm3 and no AIDS-defining
illnesses. Researchers measured the development of resistance to AZT
at codon 215 of the HIV reverse transcriptase gene during the 4 months
of the study. The lead researcher was Alan S. Hol-lister, MD from the
University of Colorado Health Sciences Center.

In the standard AZT group, 3 of 79 had AZT resistance at baseline. By
comparison, while 10 more developed resistance after 4 months. In the
twice daily group, 8 of 80 had re-sistance at baseline, and only 1
more developed resistance after 4 months of therapy. The difference
between the 2 groups in the rates of developing resistant virus was
statistically significant when AZT-experienced and AZT-inexperienced
groups were analyzed separately. AZT side effects of fatigue,
headache, nausea and vomiting were all less common in the experimental
therapy group than in the standard therapy group. Changes in CD4 cell
counts and viral load were similar in both groups.

Dr. Hollister interpreted the findings to mean that a twice daily
dosing of a 50% higher dose "maintains therapeutic plasma and
intracellular drug concentrations throughout the dosing interval."
Dosing with the standard formulation can lead to low levels of drug
just before the next dose is due.

It is likely that AZT will continue to be a part of the multi-drug
strategy against HIV, since the newly-approved protease inhibitors do
not penetrate the brain very well. In contrast, AZT penetrates the
blood-brain barrier quite well. Also, 3TC (Epivir) causes HIV to
reverse its resistance to AZT, making an AZT/3TC combination very
attractive. Glaxo-Wellcome is currently developing a combination pill
with both AZT and 3TC using the longer acting 300 mg AZT formulation.
The combination pill would only need to be taken twice daily.

Baker B. Sustained-release AZT spurs less viral resistance. Internal
Medicine News 29(6): 1-2. March 15, 1996.

HIV THERAPIES: PROTEASE INHIBITORS

Ritonavir Increases Naive Lymphocyte Subsets and CD8 Lymphocyte Subset

Australian researchers from St. Vincent's Hospital in Sydney have
measured several immune benefits from the recently approved protease
inhibitor, ritonavir (Norvir). A report in the March 1996 issue of
BETA (pages 7-9) described the impressive viral load reductions and
CD4 cell increases due to ritonavir. This new report describes some of
the more specific immune changes resulting from use of the drug. Among
the improved immune responses are increases in naive subsets of CD4
and CD8 lymphocytes and increases in the total CD8 subset of
lymphocytes.

One of the more significant HIV/AIDS research findings in 1995 was the
recognition that the "resting" or naive subsets of both CD4 and CD8
cells are lost with worsening immune dysfunction in HIV/AIDS (see
BETA, June 1995, pages 44-45). The naive subsets respond to new
antigens, while memory lymphocyte subsets "remember" a previous
antigen and will respond when the antigen again presents itself. CD8
cell functioning is critical to suppressing HIV growth. Normal CD8
cell function correlates with long-term HIV survival (see BETA, June
1995, pages 29-32).

The 21 patients in the study were part of a dose-ranging study of
ritonavir. The mean baseline CD4 cell count was 153 cells/mm3, while
the mean baseline RNA viral load was 368,000 copies/mL. When compared
with placebo patients, those taking ritonavir had a significant
increase in their CD4 cell count to 404 cells/mm3. Within the first
week, most of the CD4 cell increase was CD4 memory cells. However,
starting at the 4th week of therapy, naive CD4 cells began increasing.
The increase in naive cells became statistically significant at 6-8
weeks into ritonavir therapy. There was a less marked increase in the
naive subset of CD8 cells at week 3-4. However, there was a marked
increase in the total CD8 suppressor lymphocytes in the first week.
The CD8 cell increase statistically correlated with the magnitude of
the total CD4 cell increase.

The authors also documented significant improvements in immune cell
responses to antigens in vitro when ritonavir-treated patients' white
cells were tested. The improved immune cell responses statistically
correlated with the duration of HIV viral load reduction. Some of the
immune improvements included enhanced responses to HIV antigens in
vitro.

The researchers state that the increase in total CD8 cells "...has not
been reported with any other HIV antiviral therapy." They continue
that "treatment with ritonavir tended to give patients with late-stage
disease a numerical and functional T-lymphocyte profile more akin to
subjects in the asymptomatic phase of HIV infection." Ritonavir is a
very potent anti-HIV drug which leads to a wide spectrum of immune
improvements.

Kelleher AD and others. Alterations in the immune response of human
immunodeficiency virus (HIV)-infected subjects treated with an
HIV-specific protease inhibitor, ritonavir. The Journal of Infectious
Diseases 173: 321-329. February 1996.

CANCER AND ABNORMAL GROWTHS

Hyperthermia Helpful in Kaposi's Sarcoma

FDA approves more clinical testing

A small study using hyperthermia to treat 6 people with AIDS and
Kaposi's sarcoma (KS) has been reported by researchers from St.
Elizabeth Hospital in West Lafayette, Indiana. Six gay men with
AIDS-KS were randomized to have their blood heated to either 40oC
(104oF) or 42oC (107.6oF) for 1 hour outside their bodies. The blood
was then reinfused into the patients.

Heat treatment for HIV-AIDS and KS is attractive since HIV is
heat-sensitive and HIV-infected lymphocytes are known to be more
heat-sensitive than uninfected cells. The researchers used the 104oF
group (104G) as a control, since that temperature level was not
expected to have much of an effect, compared with the 107oF group
(107G).

The lower temperature group (104G) had a mean baseline CD4 cell count
of 51 cells/mm3, compared to 30 cells/mm3 for the higher temperature
group (107G). Baseline RNA viral loads were 203,000 copies/mL for the
104G and 186,000 copies/mL for the 107G.

All 6 subjects had some improvement in their KS during the week
following hyperthermia treatment. The improvements were a lightening
of color and a decrease in size of their KS lesions. One patient each
with KS in the stomach and on the roof of the mouth noted decreased
symptoms in those locations during the week after treatment. However,
in 5 of 6 patients, the improvements regressed to baseline appearance
2 weeks after treatment. The sixth subject in 107G continued to have
improvements during follow-up. Two patients, 1 from each group, later
had KS progression requiring chemotherapy 6 weeks after the heat
treatment. The 3 patients in 104G did not feel any different after the
treatment nor did they have any weight change after treatment.
However, 2 of 3 subjects in 107G felt better after the treatment and
gained weight (amount not stated).

Two weeks after treatment, the mean CD4 counts decreased somewhat in
104G, to 31 cells/mm3, while they increased somewhat in 107G to 55
cells/mm3. Mean RNA viral load measurements 1 week after treatment
remained the same in 104G (210,000 copies/mL), but decreased somewhat
in 107G to 151,000 copies/mL. The small number of people, however,
gives less weight to these numbers. Even though 104G did not have any
blood chemistry changes, 107G did have temporary increases in muscle
and liver enzymes. Most of these abnormalities were resolved 2 weeks
after treatment. The increase in muscle enzymes was associated with
minor muscle soreness.

The authors conclude that "whole body hyperthermia is safe in subjects
with advanced HIV disease and it may have a role in treating HIV
infection." Considering the results, FDA has granted permission for a
second trial of hyperthermia. A total of 30 patients will be divided
into 2 treatment and 1 control groups. Hyperthermia therapy will be
administered twice, with a 5 day rest period in between. Participants
will have less immune dysfunction than in the feasibility trial
discussed here (see also BETA March 1996, page 52).

Steinhart CR and others. Effect of whole-body hyperthermia on AIDS
patients with Kaposi's sarcoma: a pilot study. Journal of Acquired
Immune Deficiency Syndromes and Human Retrovirology 11(3): 271-281.
March 1996.

CYTOMEGALOVIRUS

Oral Ganciclovir Prevention Should Not Be Routine, According to CMV
Researcher

Positive CMV antigen or PCR tests will be helpful in deciding who will
benefit from oral ganciclovir prophylaxis.

W. Lawrence Drew, MD, PhD, a leading CMV researcher at the University
of California at San Francisco Mount Zion Hospital, has stated that
oral ganciclovir (Cytovene) should not be used routinely as a primary
prophylaxis for CMV retinitis among those at high risk. FDA has
recently approved oral ganciclovir for primary prophylaxis against CMV
retinitis for HIV positive individuals with fewer than 100 CD4
cells/mm3. Approval was granted on the basis of a 50% reduction in the
onset of CMV retinitis, as shown in the Syntex 1654 study (see BETA,
December 1995, pages 8 and 28-29; September 1995, pages 37-38).

Dr. Drew is quoted in the March 1, 1996 issue of Internal Medicine
News as saying that any HIV positive patient without live CMV in the
urine should be ineligible for oral ganciclovir, even if the blood is
CMV antibody positive. Live CMV in the urine could be measured by a
CMV antigen test or a labor-intensive culture. Both of these tests are
research tests. He continued that optimal candidates for prophylaxis
have not yet been identified. He also stated that new CMV polymerase
chain reaction (PCR) tests may help to identify those with active CMV
replication who would be good prophylaxis candidates. Dr. Drew added
that he found it disturbing that 20% of patients on primary
prophylaxis still developed CMV retinitis. He felt that those 20% may
have included participants who skipped doses due to side effects. He
was also concerned about the high cost, approximately $1,000/month.

In a related article appearing in the April 1996, issue of Journal of
Acquired Immune Deficiency Syndromes and Human Retrovirology,
researchers from Ko"ln University in Germany have described the
benefits of using a blood CMV antigen test to help predict the onset
of CMV disease in people with AIDS. The test measured CMV antigen in
blood neutrophils (white cells).

In a group of 144 AIDS patients with a median of 20 CD4 cells/mm3, the
CMV antigen test was 90% sensitive and 93% specific for CMV disease.
Sensitivity is the ability of a positive test to predict the presence
of a condition, while specificity is the ability of a negative test to
predict the absence of a condi-tion. A "perfect" test would be both
100% sensitive and 100% specific. The patients were followed for a
median of 14 months.

Larger studies that analyze the utility of CMV PCR or antigen tests to
predict CMV disease are likely to occur. Internal Medicine News: March
1, 1996.

Salzberger B and others. CMV-antigenemia in peripheral blood for the
diagnosis of CMV disease in HIV-infected ptients. Journal of Acquired
Immune Deficiency Syndromes and Human Retrovirology 11(4): 365-369.
April, 1996.

MYCOBACTERIUM AVIUM COMPLEX

Rifabutin Levels Increased with Fluconazole

Given the large number of medications that HIV-AIDS patients are
taking, it is important to know the effects of combinations of drugs.
Two commonly prescribed medications include rifabutin (Mycobutin) and
fluconazole (Diflucan). Rifabutin is used as prevention and with other
medications for the treatment of MAC disease. Fluconazole is used to
treat fungal infections including candida of the mouth (thrush),
esophagus and vagina, as well as certain cases of cryptococcosis.

Researchers from Georgetown University Medical Center have reported
that fluconazole leads to increased blood levels of rifabutin.
Rifabutin levels increased 82%, while its active breakdown product,
LM565, increased 216% compared to rifabutin without fluconazole. The
patients in the study were also taking AZT. The azole antifungal
drugs, including fluconazole and ketoconazole, inhibit certain liver
enzymes responsible for metabolizing other drugs, including rifabutin.

The authors believe that their findings may in part explain the
enhanced efficacy of rifabutin in preventing MAC observed in some
patients. However, they also believe their findings may explain the
increased complication of rifabutin-associated uveitis (painful eye
inflammation) that occurs in some patients on both rifabutin and
fluconazole, often with other medications (see BETA, June 1994, page
41).

The authors conclude that modifications of fluconazole dosages are not
needed when rifabutin is added as a treatment. However, they caution
that patients should be "followed closely" when patients receiving
rifabutin are also given other drugs that inhibit its metabolism. Such
drugs include the new anti-HIV protease inhibitors.

Braun-Trapnell C and others. Increased plasma rifabutin levels with
concomitant fluconazole in HIV-infected patients. Annals of Internal
Medicine 124(6): 573-576. March 15, 1996.

MYCOBACTERIUM TUBERCULOSIS

Multi-Drug-Resistant TB Transmitted aboard a Commercial U.S. Airlines
Flight

Multi-drug-resistant tuberculosis (MDR-TB) can be rapidly fatal for
those with HIV/AIDS. In 1994, a 32-year-old Korean woman transmitted
MDR-TB infection to 6 passengers aboard a commercial jet flight from
Chicago to Honolulu. The woman (index case) was coughing
intermittently during the nearly 9 hour flight. Four of the 6 people
had documented skin test conversions to TB. The other 2 had no known
reasons for positive TB skin tests.

A total of 925 passengers and crew members were notified of the
potential exposure. Of those, 86% had TB skin tests performed, with
results sent to the Centers for Disease Control and Prevention (CDC).
All 6 TB skin test converters sat in the same section of the Boeing
747-100 jet as the index TB case. Passengers who sat within 2 rows of
the infected woman were over 8-fold more likely to become infected by
her compared with passengers seated elsewhere in the section. As of
February 1996, all skin test converters had no signs or symptoms of
active TB.

The infected woman was hospitalized in Honolulu 8 days after flying
there from Chicago. Her TB strain was resistant to 5 antibiotics,
including isoniazid, rifampin, pyrazinamide, streptomycin and
kanamycin. She died on her fifth hospital day. Her HIV status was not
reported.

The report was published in the New England Journal of Medicine by the
CDC. The outbreak prompted the CDC to issue guidelines in 1995
regarding the notification of passengers and flight crews after
exposure to TB aboard commercial aircraft.

The CDC estimates that in the 6 month period from July to December of
1994, approximately 10,000 passengers were exposed to an active TB
patient aboard commercial aircraft. The overall risk for 1 passenger
is still small, approximately 1 in 26,000. However, MDR-TB strains can
be devastating for HIV positive people.

Kenyon TA and others. Transmission of multidrug-resistant
Mycobacterium tuberculosis during a long airplane flight. New England
Journal of Medicine 334(15): 933-938. April 11, 1996.

PNEUMOCYSTIS CARINII PNEUMONIA

Treat for PCP without Testing for the Organism?

Should people be treated for Pneumocystis carinii pneumonia (PCP)
without testing for the organism? National Institutes of Health (NIH)
researchers say "yes," if convenient, cost-effective facilities for
PCP tests are not available.

In an editorial written by researchers at the NIH, a case is made for
instituting treatment for PCP or other pneumonias in specific AIDS
patients even if the organism has not been detected. In the past,
finding the cause of pneumonia was considered standard in HIV/AIDS.
This is due to several reasons: (1) the wide variety of possible
organisms causing pneumonia; (2) the need to treat with many
antibiotics to cover the wide variety of potential organisms; and (3)
the fact that immunocompromised patients can become severely ill very
quickly if the correct antibiotic is not used. A specific or
presumptive diagnosis had to be made.

Routine tests for pneumonia include a chest x-ray, blood count and
oxygen testing. These tests are generally easy to obtain. Specifically
detecting PCP organisms is accomplished by either: (1) sputum
induction (breathing a salt mist to generate coughing); (2)
bronchoscopy (inserting a lighted tube into the breathing tubes); or
(3) rarely by open-lung biopsy. The availability of these latter
procedures may vary outside urban or suburban areas. In recognizing
these limitations, Henry Masur, MD, and James Shelhamer, MD, state
that, "In 1996, empiric therapy for AIDS-related pneumonia seems
appropriate in well-defined subpopulations of patients if convenient,
cost-effective diagnostic facilities are not readily available." Their
guidelines include:

1. The patient should have only mild lung disease:

		No shortness of breath on exertion;

		No onset of symptoms that is very rapid;

		Blood oxygen greater than 70-80 mm mercury (normal is
       99-100 mm) or an oxygen saturation greater than 95% on room air
       (normal is 99-100%);

		Chest x-ray should not have unusual findings;

2. The sputum should be Gram-stained to focus on bacterial causes, not
Pneumocystis.

3. No preventive antibiotics other than trimethoprim-sulfamethoxazole
(TMP-SMX, Bactrim or Septra) should have been used immediately prior
to the time of presentation.

4. The patient should be reliable, compliant and able to tolerate oral
medications.

5. The patient must be willing to contact his/her health provider
promptly if he/she cannot tolerate the treatment regimen or becomes
worse.

6. Empiric therapy should include anti-PCP therapy plus a macrolide
(-mycin) antibiotic.

7. If the patient improves on therapy, a full 14-21 days of therapy
should be completed.

8. If the patient deteriorates on empiric therapy or does not improve
after 4-5 days, then specific tests for diagnosing PCP should be
undertaken, usually with hospitalization.

9. If tuberculosis or fungal infections (coccidioidomycosis or
histoplasmosis) are common, establishing a specific diagnosis is
likely to override an empiric treatment protocol.

There was no question that an era of cost containment in health care
would lead to the publication of an editorial like this one. The
authors ask, "are financial pressures pushing health providers into
imprudent and unsafe practices?" If so, it is the patient who will
ultimately suffer the consequences.

Masur H and others. Empiric outpatient management of HIV-related
pneumonia: economical or otherwise? Annals of Internal Medicine
124(4): 451-453. February 15, 1996.

Diagnosing PCP Using a Blood PCR Test

Using a new research blood test, investigators from National Defense
Medical College in Taiwan and Indiana University School of Medicine in
Indianapolis have reported a potential improvement in diagnosing PCP.
The main benefit of an accurate blood test to diagnose PCP would be
dispensing with the expensive, time-consuming and sometimes
uncomfortably invasive tests that find the organism in lung fluids or
tissues.

The new test uses PCR technology to amplify specific RNA sequences of
the Pneumocystis organism. The test accurately predicted the presence
of Pneumocystis carinii in the blood serum of 27 of 27 PCP patients
for whom the organism was detected in lung fluids using the same test.
Among AIDS patients without PCP, the test was negative in all.

Past reports of using PCR tests of blood serum to diagnose PCP have
had mixed results. If the results of the new test are as accurate with
larger numbers of patients, this could be a breakthrough in the
ability to diagnose PCP.

Atzori C and others. Diagnosis of Pneumocystis carinii pneumonia in
AIDS patients by using polymerase chain reactions on serum specimens.
The Journal of Infectious Diseases 172: 1623-1626. December 1995.

WASTING SYNDROME

Thalidomide Reverses Weight Loss Due to Wasting in Pilot Study

Even greater weight gain observed for those with both HIV and
tuberculosis.

In a pilot study of 39 patients, 3 weeks of 300 mg nightly thalidomide
(Synovir) led to statistically significant weight gain among those
with AIDS wasting. The initial report did not measure whether the
weight gain was lean muscle or fat. However, the researchers are
determining the body composition of the thalidomide-induced weight
gain in ongoing studies.

The study was double-blind and placebo-controlled. All participants
were HIV positive men from Thailand with a reported weight loss of 10%
or more in the prior 6 months. Half had AIDS-tuberculosis (TB), while
the other half had AIDS wasting. The mean entry body weight of those
with AIDS-related wasting who received thalidomide was 49.2 kg (1 kg
equals 2.2 pounds). After 3 weeks of therapy, the mean weight
increased to 51.7 kg. The increase of 2.5 kg was statistically
significant. This compared with the control group that entered with a
mean weight of 50.0 kg and ended the 3 week period with a mild weight
gain and a mean of 50.8 kg. Those who were co-infected with HIV and TB
had even greater weight gains than those with AIDS wasting. A mean
entry weight of 47.9 kg significantly increased to a mean weight of
51.6 kg after 3 weeks of nightly thalidomide plus 4 drugs for
tuberculosis. That represents a significant increase of 3.7 kg.

The researchers determined that the thalidomide and TB therapy for
those with AIDS-TB did decrease HIV viral load levels and tumor
necrosis factor-a (TNF-a). However, thalidomide did not decrease HIV
viral load or TNF-a among those with AIDS wasting. Six of 20 who
received thalidomide developed a skin rash that resolved after
stopping the drug. Studies are continuing.

It is likely that thalidomide will be proven to reverse weight loss in
larger studies of those with AIDS wasting. A similar study showing a
benefit of thalidomide in reversing weight loss in AIDS-TB has already
been reported (see BETA, June 1995, pages 57-58).

Several institutions were involved in this new study, in-cluding New
York University Medical Center, Chang Mai University in Thailand, the
National Institutes of Allergy and Infectious Diseases and Rockefeller
University in New York City.

The manufacturer of thalidomide has made the drug available by
compassionate use (open label) for AIDS wasting. For further
information, call Celgene at 800-253-1596, extension 4123 (see BETA,
September 1995, page 7).

Klausner JD and other. The effect of thalidomide on the pathogenesis
of human immunodeficiency virus type 1 and M. tuberculosis infection.
Journal of Acquired Immune Deficiency Syndromes and Human
Retrovirology 11(3): 247-257. March 1996.

Oxandrolone Reverses Weight Loss

In a double-blind study of 67 patients with AIDS-related wasting, a
16-week course of oxandrolone therapy led to a significant weight gain
when compared with controls. Oxandrolone is an anabolic steroid. The
report was authored by J.R. Berger, MD, from the University of
Kentucky at Lexington. The information was presented at the 7th
Neuroscience Conference on HIV Infection in Paris on March 14, 1996.
Specifics regarding the amount of weight gain were not immediately
available. However, it is likely that much, if not all of the weight
gain, was lean muscle mass.

Berger JR. 7th Neuroscience Conference on HIV Infection. Paris,
France. March, 1996.

WOMEN AND CHILDREN

AZT Decreases Maternal HIV Viral Load and Prevents Transmission to
Infants

Maternal Viral Load Levels Predict HIV Transmission to Infants

New research has shown that specific HIV viral load levels in pregnant
women may help predict HIV transmission to their infants. Moreover,
AZT-induced decreases in maternal HIV viral load helps prevent
transmission to their infants. The research paper was published in the
Journal of the American Medical Association by investigators from the
University of California-Los Angeles.

Past reports have indicated that high maternal viral loads increase
HIV transmission to infants and that AZT has been documented to
decrease the HIV transmission rate from mothers to infants by
two-thirds (see BETA, December 1995, pages 43-44 and 47; June 1995,
pages 41-43; March 1995, page 48; September 1994, pages 13-14 and
70-74). However, the correlation between the levels of maternal viral
load and transmission risk had not been specifically defined. Also,
the correlation between the AZT-induced reduction of viral load and
decreased transmission risk had not been reported.

The study enrolled 92 HIV positive pregnant women who gave birth to 97
infants between 1989-1994. AZT was taken by 42 of the pregnant women
and 11 of their infants after birth. Twenty of the 97 infants (21%)
were infected with HIV at birth. If the maternal HIV RNA viral load
was greater than 50,000 copies/mL, transmission was much more likely
to occur (15 of 20 [75%] of transmitting mothers compared to 4 of 75
[5%] of non-transmitting mothers). These results were statistically
significant. Moreover, none of the 63 mothers with HIV RNA viral loads
less than 20,000 copies/mL transmitted HIV to their infants. Among the
22 pregnant women who took AZT, there was an 8-fold median reduction
in viral load from 43,043 copies/mL before AZT to 4,238 copies/mL at
delivery. None of them transmitted HIV. Four mothers with high viral
loads transmitted HIV to their infants even though they took AZT, and
AZT resistance was not present in their own or their infants' HIV
strains. Some pregnant women had low HIV viral loads early in
pregnancy and high viral loads at delivery, indicating that 1
measurement alone may not be sufficient.

The authors conclude that maternal HIV plasma levels are highly
predictive of transmission to their infants. AZT-induced reductions in
viral load can markedly decrease the risk of transmission. They also
suggest that in order to "to prevent perinatal transmission in women
with high levels of HIV and/or low CD4 cell counts...it may be
necessary to use a combination of antiretroviral and/or
immunomodulatory agents beginning early in [pregnancy]."

Dickover RE and others. Identification of levels of maternal HIV-1 RNA
associated with risk of perinatal transmission: effect of maternal
zidovudine treatment on viral load. Journal of the American Medical
Association 275: 599-605. February 28, 1995.

Landesman SH and others. Quantifying HIV. Journal of the American
Medical Association 275: 640-641. February 28, 1995.

CIN Commonly Recurs in HIV Positive Women

Researchers have documented in a large prospective study that cervical
intraepithelial neoplasia (CIN) very commonly recurs in HIV positive
women, despite multiple treatments. CIN is a precancerous lesion at
the bottom of the uterus or womb.

There were 127 HIV positive women with CIN in the study who were
followed for up to 73 months. After treatment, CIN recurred among 62%
after 36 months, compared with 18% of 193 HIV negative women with CIN.
Moreover, for the 41 HIV positive women with CD4 cell counts less than
200 cells/mm3, the CIN recurrence rate was 87%. Progression to a
worsened pre-cancerous state under the microscope occurred in 25% of
HIV positive women, compared with only 2% of HIV negative women. Even
after a second treatment, second CIN recurrences occurred in 42% of
the HIV positive women. Moreover, after a third treatment, third
recurrences occurred in 50%. The authors indicate that close follow-up
of HIV positive women with CIN is important. The authors also state
that novel approaches to treating CIN must be developed and evaluated
in clinical trials.

The research was conducted at the State University of New York in
Brooklyn. The paper appeared in the March 1996 Obstetrics and
Gynecology. Routine therapies included surgical excision of CIN
lesions or ablation by laser or cryotherapy (freezing). For more
information see Cervical Intraepithelial Neoplasia, this issue.

Fruchter RG and others. Multiple recurrences of cervical
intraepithelial neoplasia in women with the human immunodeficiency
virus. Obstetrics and Gynecology 87(3): 338-344. March 1996.   Back to
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 Prevention of Opportunistic Infections

Excerpted from the United States Public Health Service/Infectious
Diseases Society of America  (USPHS/IDSA) guidelines

Recommendations are rated according to the strength of the
recommendation for or against use (letters A-E) and the quality of the
evidence supporting the recommendation (Roman numerals I-III). When
applying the letter ratings A-E to recommendations involving
chemoprophylaxis, the strength of evidence and magnitude of clinical
benefit were balanced against the toxicity, drug interactions and cost
of the chemoprophylactic regimen and the feasibility of alternative
approaches such as early diagnosis and treatment of the opportunistic
infection. Recommendations designated "A" are supported by evidence
that is both statistically and clinically persuasive, are strongly
recommended, should always be offered and are considered standard
care. Those designated "B" are recommended for consideration; such
measures should generally be offered but should involve some
discussion of the pros and cons between the provider and the patient.
Measures designated "C" are considered optional, either because
evidence of benefit is insufficient or because any proven benefit is
minimal from a clinical standpoint and may not outweigh either the
toxicity, drug interactions or cost of the chemoprophylaxis or the
feasibility of alternative approaches. Measures designated "D" should
generally not be offered; those designated "E" are contraindicated.
The Roman numeral ratings I-III refer to the quality of evidence that
forms the basis for the recommendations regarding the use of a product
or measure for preventing opportunistic infections in HIV-infected
persons.

The prevention recommendations presented here differ from those
previously published because they include strategies for preventing
many opportunistic infections not previously discussed, particularly
those associated with prevention of exposure. They also modify earlier
recommendations. For example, for Pneumocystis carinii pneumonia (PCP)
prophylaxis for sulfa-intolerant patients, either dapsone or dapsone
plus pyrimethamine are now rec-ommended in preference to aerosolized
pentamidine. For prophylaxis against initial episodes of disseminated
Mycobacterium avium complex (MAC) disease, the threshold of treatment
has been lowered from 100 to 75 CD4 cells/mm3. Chemoprophylaxis
against toxoplasmic encephalitis is now recommended.

PNEUMOCYSTIS CARINII PNEUMONIA

Prevention of Exposure

(1) Although some authorities recommend that HIV-infected persons at
risk for PCP not share a hospital room with a patient with PCP, data
are insufficient to support this recommendation as standard practice
(CIII).

Prevention of Disease

(2) Adults and adolescents with HIV infection (including those who are
pregnant) should receive chemoprophylaxis against PCP if they have a
CD4 count of less than 200 cells/mm3 (AI), unexplained fever (greater
than 100 degrees F) for 2 weeks or more (AII) or a history of
oropharyngeal candidiasis (AII).

Trimethoprim-sulfamethoxazole (TMP-SMX) is the preferred prophylactic
agent (AI). TMP-SMX may confer cross-protection against toxoplasmosis
(AII) and many bacterial infections (AII). For patients with an
adverse reaction that is not life-threatening, treatment with TMP-SMX
should be continued if clinically feasible; for those who have
discontinued such therapy, its reinstitution should be strongly
considered (AII). Whether it is best to reintroduce the drug at the
original dose or at a lower and gradually increasing dose or to try a
desensitization regimen is unknown.

If TMP-SMX cannot be tolerated, alternative prophylactic regimens
include dapsone (AI), dapsone plus pyrimethamine plus leucovorin (AI)
and aerosolized pentamidine administered by the Respiragard II
nebulizer (Marquest, Englewood, CO) (AI). Regimens including dapsone
plus pyrimethamine are also protective against toxoplasmosis (AI) but
not against most bacterial infections. Because data on their efficacy
for PCP prophylaxis are insufficient, the following regimens generally
cannot be recommended for this purpose: aerosolized pentamidine
administered by other nebulization devices currently available in the
U. S., intermittently administered parenteral pentamidine, oral
pyrimethamine/sulfadoxine, oral clindamycin plus primaquine, oral
atovaquone and intravenous trimetrexate. However, the use of these
agents may be considered in unusual situations in which the
recommended agents cannot be administered (CIII).

Prevention of Recurrence

(3) Adults and adolescents with a history of PCP should receive
chemoprophylaxis with the regimens indicated above to prevent
recurrence (AI).

TOXOPLASMIC ENCEPHALITIS

Prevention of Exposure

(1) HIV-infected persons should be tested for IgG antibody to
Toxoplasma soon after the diagnosis of HIV infection to detect latent
infection with Toxoplasma gondii (BIII).

(2) All HIV-infected persons, but particularly those who lack IgG
antibody to Toxoplasma, should be counseled about the various sources
of toxoplasmic infection. They should be advised not to eat raw or
undercooked meat, particularly undercooked pork, lamb, or venison
(BIII). Specifically, meat should be cooked to an internal temperature
of 150 degrees F; meat cooked until no longer pink inside generally
has an internal temperature of 165 degrees F and therefore satisfies
this requirement. HIV-infected persons should wash their hands after
contact with raw meat and after gardening or other contact with soil;
in addition, they should wash fruits and vegetables well before eating
them raw (III). If the patient owns a cat, the litter box should be
changed daily, preferably by an HIV negative, nonpregnant person;
alternatively, the patient should wash the hands thoroughly after
changing the litter box (BIII). Patients should be encouraged to keep
their cats inside and not to adopt or handle stray cats (BIII). Cats
should be fed only canned or dried commercial food or well-cooked
table food, not raw or undercooked meats (BIII). Patients need not be
advised to part with their cats or to have their cats tested for
toxoplasmosis (EII).

Prevention of Disease

(3) Toxoplasma-seropositive patients with a CD4 count of less than 100
cells/mm3  should receive prophylaxis against toxoplasmic encephalitis
(TE) (AII). The doses of TMP-SMX recommended for PCP prophylaxis
appear to be effective against TE as well (AII). If patients cannot
tolerate TMP-SMX, the regimens including dapsone plus pyrimethamine
that are recommended for PCP prophylaxis provide protection against TE
(AI). Prophylactic monotherapy with dapsone, pyrimethamine,
azithromycin, clarithromycin or atovaquone cannot be recommended on
the basis of current data (DII). Aerosolized pentamidine does not
afford protection against TE (EI).

(4) Toxoplasma-seronegative persons who are not taking a PCP
prophylactic regimen known to be active against TE should be retested
for IgG antibody to Toxoplasma when their CD4 count falls below 100
cells/mm3 to determine whether they have seroconverted and are
therefore at risk for TE (CIII). Patients who have seroconverted
should receive prophylaxis for TE as described above (AII).

Prevention of Recurrence

(5) Patients who have had TE should receive lifelong suppressive
therapy with drugs active against Toxoplasma to prevent relapse (AI).
The combination of pyrimethamine plus sulfadiazine and leucovorin is
highly effective for this purpose (AII). A commonly used regimen for
patients who cannot tolerate sulfa drugs is pyrimethamine plus
clindamycin (AII); however, only the combination of pyrimethamine plus
sulfadiazine appears to provide protection against PCP as well (AII).

DISSEMINATED INFECTION WITH MYCOBACTERIUM AVIUM COMPLEX

Prevention of Exposure

(1) Organisms of the M. avium complex (MAC) are common in
environmental sources such as food and water. Current information does
not support specific recommendations regarding avoidance of exposure.

Prevention of Disease

(2) Prophylaxis with rifabutin should be considered for HIV-infected
adults and adolescents who have a CD4 count of less than 75 cells/mm3,
although some experts would wait until the count is less than 50
cells/mm3 (BII). Disseminated MAC disease should be ruled out (by a
negative blood culture) before prophylaxis is initiated. Because
treatment with rifabutin may result in the development of resistance
to rifampin in individuals with active tuberculosis, the latter
condition should be excluded before rifabutin prophylaxis is begun.
Drug interactions, partial efficacy and cost are among the other
issues that should be considered in decisions about whether to
institute prophylaxis of MAC disease. Data on the safety and efficacy
of clarithromycin have not yet been reviewed sufficiently to warrant
recommendations concerning these regimens.

(3) Although the detection of MAC organisms in the respiratory or
gastrointestinal tract may be predictive of the development of
disseminated MAC infection, no data are available on the efficacy of
prophylaxis with rifabutin or other drugs in patients with MAC
organisms at these sites and a negative blood culture. Therefore,
routine screening of respiratory or gastrointestinal specimens for MAC
cannot be recommended at this time (DIII).

Prevention of Recurrence

(4) Patients who are treated for disseminated MAC infection should
continue to receive full therapeutic doses for life (BIII). The use of
a macrolide, usually clarithromycin, is generally recommended in
conjunction with at least 1 other drug, such as ethambutol,
clofazimine, ciprofloxacin or rifabutin.  Back to the BETA Page Back
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Open Clinical Trials for HIV/AIDS Treatments

Compiled by Leslie Hanna

This issue of BETA presents new or changed trial information; for
information about ongoing trials, see the March 1996 issue.

For further information about individual listings, call the number
provided or call the AIDS Clinical Trials Information Service (ACTIS),
toll-free, at 800-874-2572 (800-TRIALS-A).

TREATMENT FOR HIV INFECTION

Acyclovir (Zovirax)

In Los Angeles (LA), this study will determine the effect of acyclovir
on HIV viral load in persons with HIV and herpes simplex virus (HSV).
One of the 2 study arms is for people with acute herpes outbreaks, the
other is an acyclovir prophylaxis arm for people who have had an
outbreak within the past year. There are 12 weekly visits. Call Sandra
at Harbor-UCLA at 310-222-5291.

Alpha interferon

The National Institute of Allergy and Infectious Diseases (NIAID) is
sponsoring this multicenter study of 3 different preparations of
low-dose alpha interferon (Alferon LDO, Veldona and Ferimmune).
Approximately 560 people with 50-350 CD4 cells/mm3 will be randomized
to 1 of 4 treatment arms: 3 arms give 1 of the compounds plus placebo
and the fourth arm gives placebo only. Participants may continue
antiretroviral use and prophylaxis against opportunistic infections
(OI). Treatment is given for 6 months of the 18-month study.

Atevirdine and AZT

This study compares the antiviral effects of 2 different doses of
atevirdine, a non-nucleoside reverse transcriptase inhibitors (NNRTI),
combined with AZT in people with 50-350 CD4 cells/mm3 and at least 3
months of prior AZT use. In LA, call Frances Canchola at Los Angeles
County-University of Southern California (LAC-USC) at 213-343-8281.

Delavirdine (Rescriptor) expanded access

Upjohn Pharmacia has launched a new expanded access program. The
program is open to HIV-infected persons over the age of 13 with fewer
than 300 CD4 cells/mm3, who have failed or are intolerant to current
approved HIV treatments and who are already taking at least 1 other
antiretroviral drug. Still investigational, delavirdine belongs to the
class of anti-HIV drugs called NNRTI. Physicians may call the
Delavirdine Expanded Access Program at 800-779-0070.

d4T, AZT and 3TC

A 48-week Phase II study, ACTG 298 will compare the efficacy of d4T
monotherapy to combination d4T/AZT to combination AZT/3TC in people
with 300-600 CD4 cells/mm3 and no previous antiviral use (AZT, ddC,
ddI, d4T or 3TC).

DuPont Merck NNRTI and indinavir (Crixivan)

This Phase II multicenter study will evaluate the safety,
tolerability, efficacy and pharmacokinetics of DMP 266, a new NNRTI,
alone and in combination with open-label indinavir, Merck's protease
inhibitor. Approximately 360 participants will be enrolled and
randomized to 1 of 4 regimens. Three groups receive initial
monotherapy for 2 weeks and then combination therapy for 12 weeks.
Initial monotherapy may be either 200 mg DMP 266 or placebo, or 800 mg
indinavir; combination therapy will involve 2 different indinavir dose
additions, or DMP 266 or placebo. The fourth arm begins with
combination therapy. Plasma RNA will be monitored by PCR. The study is
open to persons with HIV and 100-500 CD4 cells/mm3 and plasma viral
RNA levels greater than or equal to 20,000 copies/mL. Exclusion
criteria include prior antiretroviral treatment within 14 days of
study entry and prior use of any other NNRTI or protease inhibitor.
For specific information about sites, call DuPont Merck at
302-992-5000 or 800-TRIALS-A.

FP-21399

This multicenter Phase II study will evaluate the safety and efficacy
of FP-21399, a new antiretroviral that targets lymph nodes and is
given by 1-hour intravenous (IV) infusion. Two-thirds of the
participants will be randomized to receive infusions once a month, and
one-third will receive infusions every 2 weeks. Those receiving
monthly infusions will receive 1 of 2 doses, and all receive drug on
an open-label basis, i.e., all participants receive actual treatment
with a known dose. Eligible participants have between 200-500 CD4
cells/mm3 and must be on a stable antiretroviral regimen. The
treatment part of the study lasts 6 months, with 3 additional months
of follow-up care. In the San Francisco (SF) Bay Area, call Sher
Vieira at HIVCare at 415-353-6215.

HBY 097 and AZT

FDA 252A is a Phase IIA study of the safety and efficacy of HBY 097, a
new second-generation NNRTI manufactured by Hoescht Pharmaceutical.
The study was recently amended to eliminate an AZT monotherapy arm.
Now, participants are randomized to receive 1 of 3 doses of HBY 097
with or without AZT. Eligible participants have 200-500 CD4 cells/mm3
and have never before used any NNRTI.

Hydroxyurea and ddI

ACTG 307 will determine the safety and tolerability of hydroxyurea
alone or combined with ddI, versus ddI alone. Eligible participants
have 200-500 CD4 cells/mm3 and have less than 2 weeks prior ddI use.
After 12 weeks of treatment, all participants will receive combination
hydroxyurea and ddI. Study visits occur every 2-4 weeks. In LA, call
Sally Kruger at Harbor-UCLA at 310-222-3848.

Interleukin 2 (IL-2) and d4T

This Phase II randomized pilot study compares high and low-dose IL-2
in people with 300-700 CD4 cells/mm3. Participants must be able to
tolerate d4T before beginning IL-2 treatment, which is given by
subcutaneous injection (participants will be taught how to
self-inject). Exclusion criteria include having a seizure disorder or
history of psoriasis, Crohn's disease or other autoimmune disease. The
study lasts 8 months. In the SF Bay Area, call Jose Pacheco at the
University of California, San Francisco (UCSF) AIDS Program at
415-476-9296, ext. 84101.

Methotrexate

This Phase I  20-week study will evaluate the antiviral potential of
oral methotrexate, an anti-inflammatory and immunomodulating agent, in
people with greater than 350 CD4 cells/mm3. Participants will be
randomized to receive 1 of 3 doses, and must not have used any
antiretroviral drug(s) in the past 6 months. In LA, call Jacqui Pitt
at Cedars Sinai at 310-855-3755.

Nevirapine, AZT, ddI and 3TC

This Phase II, double-blind, placebo-controlled, open-label trial
gives antiretroviral-naive persons with HIV and 200-500 CD4 cells/mm3
either AZT plus ddI plus nevirapine or placebo, or AZT plus ddI plus
3TC or placebo. Approximately 225 people will be enrolled at 22 sites
nationwide.

1592U89 and AZT

This Phase I/II study will evaluate the safety, pharmacokinetics and
preliminary antiretroviral efficacy of  1592U89. Participants will
receive one of several doses of 1592U89 alone for the first 4 weeks;
for 8 weeks after that, they will receive additional AZT or placebo.
The 12-week study may be extended for another 12. Participants have
200-500 CD4 cells/mm3, have no current or past OI, have not previously
used AZT for more than 12 weeks total, and have used no other
antiretroviral. Foscarnet use is also prohibited. In the SF Bay Area,
call Hunter Morey at 415-353-5623.

Peptide T

In LA, a Phase II/III trial of safety and efficacy will give IV
Peptide T as either continuous infusion or in divided doses, or
placebo. The study will enroll 210 persons with 100-400 CD4 cells/mm3;
treatment lasts 6 months. Persons allergic to protease inhibitors will
be excluded, as will those receiving ongoing treatment for cancer or
active OI. Call Dr. Galpin at the Shared Medical Research Foundation
in Tarzana, CA at 818-345-2172.

PMEA (Adeforvir dipivoxil)

This study evaluates the utility of supplementing a participant's
current, stable antiretroviral regimen with PMEA or placebo. After 24
weeks, all participants receive open-label PMEA for an additional 24
weeks. Eligible participants have 200-500 CD4 cells/mm3, viral load
greater than 5,000 copies/mL and have been on a stable antiviral
regimen for at least 8 weeks prior to study entry. Study visit occur
each 4-8 weeks. In LA, call Dena at Harbor-UCLA at 310-222-3848.

Saquinavir (Invirase) plus ritonavir (Norvir)

This open-label dose-finding study will examine the safety and
efficacy of ritonavir in combination with saquinavir in 120 people
with HIV. Ritonavir increases saquinavir absorption, and the 2
protease inhibitors have different resistance patterns; the
combination appears promising in pre-clinical trials. Eligibility
requirements include having 100-500 CD4 cells/mm3, being at least 12
years old, no prior use of protease inhibitors and no acute OI.
Antiretroviral use (AZT, ddC, ddI, 3TC and d4T) must stop 2 weeks
prior to study entry. There are study sites in 7 cities: Boston, New
York City, Pittsburgh, Ottawa (Canada), Fairfax (VA), Los Angeles and
San Francisco. The drugs' manufacturers, Hoffmann-La Roche and Abbott,
both urge that individuals do not try this combination on their own
until the clinical trial has established safety and optimal dosing.
Prescribing information is available for saquinavir at 800-526-6367
and for ritonavir at 800-441-4987.

Sho-Saiko-To (TJ-9) and AZT

This double-blind trial gives an agent called TJ-9 or placebo plus AZT
to persons with 150-400 CD4 cells/mm3 and greater than 20,000 viral
copies. TJ-9 is a Chinese herbal formula that, in combination with AZT
in in vitro studies, showed a 99% reduction in viral load. Two packets
of TJ-9 powder are taken twice daily. Both treatment and trial last 7
months. Call Dr. Lange (primary investigator) or Dr. Spencer (trial
coordinator) at St. Luke's/Roosevelt Hospital, New York, NY, at
212-523-7238.

Vitamin C

This dose-escalation study evaluates the effect of high doses of oral
vitamin C on CD4 cell count and viral load, and tolerability. Eligible
participants have 50-500 CD4 cells/mm3 and must be on a stable
antiretroviral regimen, if any. All participants will increase from a
low dose to their own maximally tolerated dose, up to 40 g daily. The
study lasts 20 weeks. In LA, call Jacqui Pitt at Cedars Sinai at
310-855-3755.

TREATMENT FOR OPPORTUNISTIC INFECTIONS

Cytomegalovirus (CMV) gastritis: foscarnet (Foscavir)

This is a Phase III, multicenter open-label trial of the safety and
efficacy of induction versus induction plus maintenance foscarnet for
preventing the recurrence of gastrointestinal CMV disease. Induction
therapy involves short-term, high-dose foscarnet, and is given in the
hospital, intravenously, 1-2 times daily for at least 4 days.
Maintenance treatment is ongoing, and requires once daily high-dose
foscarnet. Participants have any CD4 cell count and AIDS; the
individual must be unable to take ganciclovir or this must be their
first episode of CMV gastritis. Previous treatment with foscavir is
not allowed, nor is CMV disease elsewhere in the body that requires
continued treatment. In LA, call Analyn Rollan at LAC-USC Medical
Center at 213-343-8277.

CMV retinitis: cidofovir

ACTG 281 will evaluate the safety and efficacy of cidofovir (formerly,
HPMPC) for treating retinitis that is not immediately
sight-threatening. The 8-month study has 2 stages, essentially an
induction and a maintenance stage. Participants may be randomized to
treatment or delayed treatment at either stage, although if disease
begins to progress, they will receive treatment. Cidofovir is infused
intravenously once a week or once every 2 weeks. There are no
restrictions on CD4 cell count, but CMV disease must be confined to
the eye, and previous or current therapy with ganciclovir or foscarnet
are not allowed.

CMV retinitis: ISIS 2922 and ganciclovir

FDA 251B is a 20-week study that will compare the safety and efficacy
of combination ISIS 2922/ganciclovir to ganciclovir alone for the
treatment of CMV retinitis. Participants are randomized to receive one
of those regimens. ISIS 2922 is administered intravitreally (into the
eye) once a week for the first 3 weeks and then once every other week
after that. Ganciclovir is injected into a vein every 12 hours for 14
days, then taken orally until the end of the study. Each visit
includes an eye exam. Participants may have any CD4 cell count, but
must have CMV that has not improved with other treatments. Prior
treatment with ganciclovir that exceeds 4 months is excluded. In the
SF Bay Area, call Brenda Cayme at the AIDS Community Research
Consortium (ACRC) at 415-364-6563. In LA, call Brian Terry at the
Community Eye Medical Group at 818-287-2000.

CMV retinitis: ISIS 2922

FDA 251A will evaluate the safety and efficacy of immediate versus
delayed treatment with intravitreal ISIS 2922 alone. The purpose is to
establish a safe and effective dose of the agent and to compare
immediate versus deferred treatment approaches in persons with
previously untreated, peripheral CMV retinitis. This study also has 2
stages, induction and maintenance.

FDA 251C is another ISIS 2922 study; it is an open-label study in
persons with CMV who have rolled over from another controlled ISIS
2922 trial. This study will evaluate the safety and efficacy of the
agent in persons intolerant to ganciclovir and foscarnet or who failed
on ISIS 2922 in another trial. Different doses will be tried.

Fungal infections: itraconazole (Sporanox) desensitization

This open-label study will evaluate the efficacy of an itraconazole
desensitization protocol. Persons begin with tolerably low doses of
the drug and gradually increase the dose to the full treatment level.
Participants have 100-1,500 CD4 cells/mm3 and documented
hypersensitivity to itraconazole. In the SF Bay Area, call Greg
Doherty at the Conant Medical Group at 415-661-2613.

Histoplasmosis: itraconazole versus amphotericin B

FDA 254A is a Phase III trial that will compare the safety and
efficacy of IV itraconazole and amphotericin B for treating
histoplasmosis or blastomycosis. Participants will be randomized to
receive IV itraconazole for 2 days, then, for approximately 1 week,
either daily itraconazole or daily amphotericin B. After the IV
treatment phase, oral itraconazole will be taken for up to a year. Any
CD4 cell count is acceptable, but there is a considerable list of
drugs which may not be used concurrently.

Mycobacterium avium complex (MAC) and anemia: erythropoietin (EPO)

This open-label trial randomizes people with anemia and MAC to receive
1 of 2 EPO schedules. The first treatment group receives injections of
EPO for 16 weeks, followed by no injections for 8 weeks; the second
group receives the reverse (no injections for 8 weeks, then EPO for
16). EPO is given subcutaneously or intravenously 3 times a week.
Those who benefit from EPO may continue after the study ends. There
are no restrictions on CD4 cell count, although participants must have
MAC. AZT must be discontinued 3 weeks before the study and throughout,
and low blood iron levels (i.e., other causes of anemia) are not
allowed. In the SF Bay Area, call JB Molaghan at San Francisco General
Hospital (SFGH)/Ward 86 at 415-476-4082, ext. 84240 or Cecily Cosby at
the UCSF AIDS Clinic at 415-476-3226.

TREATMENT FOR MALIGNANCIES AND CANCERS

Anal cancer prevention: isotretinoin and alpha interferon

This dose-escalating study will try to establish the largest tolerable
dose of isotretinoin for use in combination with interferon alfa-2a,
and will also evaluate the efficacy of the combination for treatment
of anal intraepithelial neoplasia (AIN). The study is open to people
with any CD4 cell count, biopsy-proven current grade I AIN or treated
grade II or III AIN. Active OI and other cancers not allowed, except
KS. Isotretinoin is taken in oral pill form. Interferon alfa-2a is
taken by subcutaneous injection. Treatment lasts 12 weeks; follow-up
is 36 weeks. In the SF Bay Area, call Barbara Klencke at UCSF/Mt. Zion
at 415-885-7252.

Kaposi's sarcoma (KS): ALRT1057 topical gel

This Phase III trial will evaluate the safety, tolerability and
efficacy of the topical gel for treating cutaneous KS. The gel or
placebo gel is applied to KS lesions 3 times a day for 12 weeks; after
that, all participants receive open-label treatment gel for KS. As
long as the study is open, patients who benefit may continue
open-label therapy. The study is open to people with 6 or more KS
lesions of the skin; there are no restrictions on CD4 cell count. No
systemic therapy or topical treatment is allowed within 30 days of
beginning this study. There are sites in Berkeley, SF (3), Irvine, LA,
Palm Springs and San Diego. In SF, call Hunter at ViRx at 415-353-5623
or Sher at HIVCare at 353-6215; in LA, call Suzanne at LAC-USC at
213-343-8270.

KS and other advanced malignancies: A-007

FDA 247A is a Phase I study of a topical gel form of an agent called
A-007 for the treatment of advanced malignancies including KS.
Participants must have 100 or greater CD4 cells/mm3, biopsy-proven
cancer and measurable skin or cutaneous lesions for which they have
tried other treatment. Ongoing chemotherapy or immunotherapy is not
allowed.

TREATMENTS FOR WASTING SYNDROME AND MYOPATHY

Wasting Syndrome: OPTIM

This pilot study will evaluate the benefits of OPTIM, a nutritional
supplement in powder form, on body weight and lean body mass. OPTIM
can be taken by mixing it with cold beverages or sprinkling it over
cold foods. Forty participants will receive either 20 g or 60 g daily
for 6-12 weeks; those who benefit may receive OPTIM indefinitely. The
study is open to people with fewer than 500 CD4 cells/mm3 and weight
loss of at least 10% of ideal body weight. Milk allergy and active
conditions of the mouth, throat or esophagus that interfere with
swallowing are excluded. In the SF Bay Area, call Sher Vieira at
HIVCare at 415-353-6215.

       IMMUNE ENHANCEMENT

       Allogeneic lymphocyte transfer

This pilot study will evaluate the safety and efficacy of transferring
lymphocytes from an HIV negative to an HIV positive sibling. Three
transfers occur during the 6-month study. Eligibility requirements
include having a genetically compatible sibling, 200 or fewer CD4
cells/mm3 and being on a stable antiviral regimen. In the SF Bay Area,
call Sher Vieira at HIVCare at 415-353-6215.

       HIV lipopeptide: P3C541B

FDA 090 is a Phase I trial of the safety and immunogenic effects of 2
doses of a new immunotherapeutic agent, P3C541B, in HIV positive
persons. The agent or placebo is administered subcutaneously at either
dose level. Participants have 500 or greater CD4 cells/mm3, no OI, no
oral candidiasis and no chronic herpes infection.

       Remune (the "Salk Vaccine")

This Phase III study will evaluate the ability of Remune, a
therapeutic vaccine, to boost the immune response against HIV,
measured by time to development of AIDS-defining conditions. The
treatment uses a deactivated version of HIV. Participants will be
randomized to receive Remune or placebo by intramuscular injection
every 12 weeks for 3 years. Participants have 300-549 CD4 cells/mm3,
no history of or current AIDS-defining conditions except KS, and have
not been treated with an investigational vaccine or immunotherapy in
the past 3 months; must be stable on current antiviral regimen for at
least 3 months. Approximately 2,500 people will be enrolled at 50
sites. In the SF Bay Area, call Hunter at ViRx at 415-353-5623.

       Therapeutic vaccine: APL 400-003

FDA 089 is a Phase I trial of a new therapeutic vaccine, APL 400-003,
for asymptomatic HIV positive persons. Safety and immune response will
be evaluated for 3 different doses. Participants will receive a total
of 3 administrations in the form of intramuscular injections (on the
first day of the study, at 10 weeks and at 20 weeks). Eligibility
requirements include having greater than 500 CD4 cells/mm3.

       TN antigen

This Phase I/II study will evaluate the safety and potential
immune-boosting activity of TN antigen in people with HIV and at least
200 CD4 cells/mm3. TN is a carbohydrate found in red blood cells that
is thought to have an anti-HIV effect. Participants will be randomized
to receive TN removed from red blood cells or synthetic TN, which will
be given by subcutaneous injection 4 times during a 13-week interval.
In the SF Bay Area, call Dr. Lalezari at Mt. Zion at 415-476-6353.

       CHILDREN AND ADOLESCENTS

       Accessing experimental therapies not in pediatric trials

Although most adult studies are only open to persons over the age of
18 years, several adult studies now also include adolescents 13-17.
Representatives at 800-TRIALS-A can identify which adult studies
permit adolescents.

       HIV infection: AZT, ddI and nevirapine (Viramune)

ACTG 245 compares the efficacy of different combination therapies in
children and adolescents with advanced HIV disease. Participants are
randomized to receive AZT plus ddI, ddI plus nevirapine or AZT or ddI
plus nevirapine. All agents are taken orally. The study, which lasts
about 1 year, is open to HIV positive individuals aged 6 months to 20
years, who have tried anti-HIV treatments (e.g., AZT, ddI, ddC) for at
least 24 weeks total in the past, and who have symptoms of HIV disease
progression such as growth failure, AIDS-defining infections or CD4
percentage below 15%. Those with peripheral neuropathy or pancreatitis
are excluded.

       WOMEN

       Pregnant women: ddI

ACTG 249 is a Phase I study of the safety and pharmacokinetics of ddI
in pregnant women and their newborns. Women in their third trimester
of pregnancy receive a 1-hour infusion of ddI, then take oral ddI
twice a day until labor begins. During labor, mothers receive ddI
infusion until delivery. Eligible women are in their third trimesters
of pregnancy, have 50-350 CD4 cells/mm3 and are unable to take AZT
(side effects, lack of efficacy). The study lasts 3-5 months. In LA,
call Nancy Creighton at the LAC-USC Medical Center at 213-226-5068.
For other information and locations, call 800-TRIALS-A.

       MISCELLANEOUS

       bDNA testing for new users of 3TC

This observational study examines the effect on viral load of adding
3TC to an existing antiretroviral regimen, which may be any
combination except AZT alone or one including protease inhibitors. Ten
bDNA tests will be performed over the course of the 1-year study. In
the SF Bay Area, call Sher Vieira at HIVCare at 415-353-6215.

       Condyloma acuminata: cidofovir topical gel

This Phase I/II study examines the safety and efficacy of a topical
gel formulation of cidofovir, formerly called HPMPC, for treating
condyloma acuminata or anogenital warts, in people with HIV.
Participants apply gel once daily, 5 days a week, for 1-2 weeks.
Entrance requirements include having at least 100 CD4 cells/mm3,
external anal or genital warts that failed at least 1 previous
treatment, and a skin biopsy for diagnosing the warts. The study lasts
4-8 weeks. In the SF Bay Area, call Erika Klemperer at 206-8680.

       Diarrhea: Chinese herbs

This study randomizes people with HIV and cryptosporidiosis-negative
chronic diarrhea to receive Chinese herbs or placebo, to see if taking
Chinese herbs can safely reduce the number of stools per day. Chronic
diarrhea is defined as 3 or more loose stools per day for at least 14
days. Before study entry, stool samples must be negative for treatable
parasites including Cryptosporidium. Exclusion criteria include fever
greater than 101 degrees F and history of cryptosporidiosis. In the SF
Bay Area, call the Community Consortium at 415-476-9554.

       Herbal study: Una de gato ("cat's claw") and aloe vera

This 12-week herbal study will evaluate the antiretroviral activity of
u a de gato, with or without aloe vera, as well as the combination's
ability to relieve gastrointestinal symptoms related to HIV. U a de
gato is an extract of a vine that grows in the Amazon Basin, and has
been used by Native Amercians for years to treat various
gastrointestinal disorders. U a de gato is available commercially in a
low-dose formulation; for this study, a higher-dose tincture (liquid)
and tablet will be used. Participants take oral tablet and liquid
formulations of U a de gato; some take aloe vera. Viral load will be
measured by PCR. The study is open to those with fewer than 350 CD4
cells/mm3. In LA, call Dr. Green at the Institute for Holistic
Treatment and Research at 714-251-8700.

       CLINICAL TRIALS INFORMATION BY REGION

Trials Search Guide to HIV Clinical Trials in California (Northern and
Southern California editions available) 800-492-5777; in Northern
California: 415-476-5777 http://galen.library.ucsf.edu/aids/trial.html
New York, Connecticut, New Jersey and Philadelphia 800-734-7104  AIDS
Institute Experimental Treatment Infoline in New York state:
800-MEDS-4-HIV; outside New York: 212-239-5523  Houston Clinical Trial
Network 713-520-2083  AIDS Survival Project, Georgia and Alabama
404-874-7926  Community Research Initiative of South Florida, Inc.
305-667-9296  Gulf Coast Region 504-584-3605  AIDS/HIV Treatment
Directory for New England 617-566-4004  Wisconsin AIDS Research
Consortium in Wisconsin: 800-359-9272; outside Wisconsin: 414-225-1600
Canadian HIV Trials Network 604-631-5327  Actively Recruiting U.S.
Trials AmFAR Treatment Directory: 212-682-7440


       Glossary

       Compiled by Liz Highleyman

ABSCESS: an isolated accumulation of pus associated with a localized
infection.

ACCELERATED APPROVAL: FDA regulations governing early marketing
approval of promising drugs for life-threatening illnesses.

ACUTE: rapid in onset, aggressive.

ADENOVIRUS: a family of double-stranded DNA viruses that are the cause
of the common cold.

AGCUS: atypical glandular cells of undetermined significance.

AIDS CLINICAL TRIALS GROUP (ACTG): a NIAID-sponsored group of medical
centers, known as AIDS Clinical Trials Units (ACTU), that evaluate
treatments for HIV disease and associated illnesses.

AIDS-RELATED COMPLEX (ARC): symptomatic HIV infection. An older term
used to describe a condition in which a person is HIV positive and has
a variety of symptoms that are related to HIV disease (e.g., swollen
lymph nodes, night sweats, fever, diarrhea, weight loss) but that do
not qualify as AIDS-defining illnesses.

ANAPHYLACTIC SHOCK (ANAPHYLAXIS): a life-threatening allergic reaction
to a foreign antigen mediated by IgE antibodies. Symptoms include
swelling, shortness of breath and a decrease in blood pressure due to
capillary dilation.

ANDROGEN: a hormone (e.g., testosterone, androsterone) that has
masculinizing effects, including stimulation of the male reproductive
organs and development of secondary sex characteristics.

ANEMIA: an abnormally low number of red blood cells or a decreased
concentration of hemoglobin, resulting in a reduction of the supply of
oxygen to cells and tissues.

ANERGY (adjective ANERGIC): the lack of an immune response to a
foreign antigen.

ANOREXIA: the lack or loss of appetite for food.

ANTIBIOTIC: an agent that inhibits the growth of or destroys
microorganisms.

ANTIBODY (AB): an immunoglobulin protein secreted by activated plasma
cells, which evolve from B-cells, in response to stimulation by an
antigen. The antigen/antibody reaction forms the basis of humoral
(TH2) immunity. There are 5 types: IgA, IgD, IgE, IgG and IgM.

ANTICOAGULANT: an agent that reduces or delays blood coagulation or
clotting.

ANTIGEN: any agent or substance that stimulates an immune response,
e.g., microorganisms or the substances they produce.

ANTIGENEMIA: the presence of an antigen in the blood.

ANTIHISTAMINE: an agent (e.g., Benadryl) that counteracts the effects
of histamine. Antihistamines are used to treat allergic reactions and
to block stomach acid production.

ANTIOXIDANT: a substance that inhibits the oxidation reaction by
binding with and neutralizing free radicals and other highly reactive
molecules, thus reducing cellular damage. Some antioxidants are
produced by the body, others are available in foods and supplements
(e.g., beta carotene, vitamin E, selenium).

ANTIRETROVIRAL: an agent used to suppress the activity or replication
of retroviruses such as HIV.

ANTISENSE: a complementary piece of genetic material (DNA or RNA) that
binds to another piece of DNA or RNA and prevents that DNA/RNA from
being used to synthesize new proteins.

ANTIVIRAL: an agent that interferes with the life cycle of a virus and
suppresses its replication.

APOPTOSIS: premature programmed cell death.

ARM: a group of participants in a research trial who all receive the
same treatment (treatment arm) or placebo (control arm).

ASCUS: atypical squamous cells of undetermined significance.

ASSAY: a test used to detect the presence and/or concentration of a
drug, substance or microorganism in the blood and other body fluids or
tissues.

ASPERGILLOSIS: an uncommon, life-threatening infection caused by the
fungus Aspergillus, which typically infects the lungs and sinuses, but
can spread through the blood to other organs including the brain,
heart or spleen.

ASYMPTOMATIC: not feeling or showing outward signs of illness.

ATROPHY (adjective ATROPHIC): progressive degeneration, wasting or
decrease in size, especially the loss of muscle tissue.

ATTENUATE: to weaken or reduce the level of virulence. An attenuated
virus has a diminished ability to cause disease.

ATYPIA: a condition of being abnormal or not typical.

AUTOIMMUNE RESPONSE (AUTOIMMUNITY): a condition in which an
individual's immune system fails to recognize its own biochemical
markers as being "self" and attacks body tissues as if they were
foreign matter.

B-CELL (B-LYMPHOCYTE): an immune system cell that carries out the
humoral (TH2) immune response. B-cells are produced in the bone marrow
and spleen, and mature into plasma cells that produce antibodies.

BACTEREMIA: the presence of bacteria in the blood.

BASELINE: a known value to which later measurements can be compared,
e.g., baseline CD4 cell count.

BIAS: a false association that results from the failure to account for
some skewing or influencing factor.

BILIRUBIN: a yellowish pigment released by red blood cells when they
are removed from circulation and broken down. An excess level of serum
bilirubin (hyperbilirubinemia) is characterized by jaundice and may
indicate stress on the liver.

BIOAVAILABILITY: the extent to which a substance (e.g., a drug) is
absorbed and circulated in the body.

BIOPSY: surgical removal of a small piece of tissue for microscopic
examination and/or culture.

BLINDING: the process of preventing patients and/or their doctors from
knowing whether the patient is taking active drug or placebo; done to
reduce bias in drug trials.

BLOOD GAS: a gas (e.g., oxygen, carbon dioxide, nitrogen) dissolved in
the plasma, or liquid part of the blood.

BRANCHED-CHAIN DNA ASSAY (bDNA): an assay for measuring the amount of
virus (viral load) in plasma or tissue.

BREAKTHROUGH: refers to a condition that has developed despite
measures to prevent it, e.g., PCP that occurs while taking a
prophlactic drug.

BRONCHITIS: an inflammation of the mucous membranes of the bronchial
tubes of the lungs.

BRONCHOSCOPY: a procedure for inspecting the trachea, bronchial tubes
and lungs using a flexible fiber-optic instrument that conducts light.

CACHEXIA: a condition of body wasting and general ill-health.

CANDIDIASIS: a disease caused by a species of the yeast-like fungus
Candida, usually C. albicans. Candidiasis can affect the skin, nails
and mucous membranes throughout the body including the mouth,
esophagus, vagina, intestines and lungs.

CARCINOMA: a malignant tumor of the epithelial cells that line bodily
surfaces and cavities. Carcinoma in situ refers to an early stage of
cancer that has not invaded surrounding tissues.

CARDIOMYOPATHY (MYOCARDIOPATHY): a disease of the myocardium or heart
muscle.

CD4 CELL (CD4 LYMPHOCYTE, T-HELPER CELL, T4 CELL): a type of white
blood cell that carries the CD4 surface marker and helps the body
fight infection. CD4 cells engulf and process invaders (e.g., viruses)
and release cytokines that coordinate a broad range of immune
activity, including killer cell activation and antibody production.

CD4 CELL COUNT (T-HELPER CELL COUNT): the number of CD4 lymphocytes
present in a cubic millimeter (mm3) of blood. The CD4 count is one
indicator of the severity or progression of HIV disease and is
sometimes used as a surrogate marker.

CD8 CELL (CD8 LYMPHOCYTE, T8 CELL): a type of white blood cell that
helps regulate and/or carry out the body's immune response. Two major
subsets of T-cells express the CD8 surface marker: T-suppressor cells
and cytotoxic T-lymphocytes (CTL).

CELL ANTIVIRAL FACTOR (CAF): a factor produced by CD8 cells that has
been suggested to block viral infection. The identity of this factor
is not known; possibilities include IL-16 and 3 recently identified
chemokine proteins, RANTES, MIP-1-alpha and MIP-1-beta.

CELL-MEDIATED IMMUNITY (CELLULAR IMMUNITY, TH1 RESPONSE): the immune
response mediated by the TH1 subset of CD4 cells. Cell-mediated
immunity is stimulated by the cytokines IL-2, IL-12 and gamma
interferon and carried out by CD8 cytotoxic T-cells (CTL) and
macrophages.

CENTERS FOR DISEASE CONTROL AND PREVENTION (CDC): the U.S. federal
agency within the Department of Health and Human Services that
monitors disease occurrence and develops policies for preventing
diseases and maintaining the health of the population.

CENTRAL NERVOUS SYSTEM (CNS): the brain and spinal cord.

CERVICAL INTRAEPITHELIAL NEOPLASIA (CIN, SQUAMOUS INTRAEPITHELIAL
LESION, SIL): abnormal growth of cells of the uterine cervix,
suggesting an early stage of cervical cancer. Human papillomavirus
(HPV) infection and HIV infection are associated with an increased
risk of CIN/SIL.

CERVIX (adjective CERVICAL): the cylindrical, lower part of the uterus
leading into the vagina.

CHRONIC: less intense, slow, persisting over a long period.

CLINICAL TRIAL (CLINICAL STUDY): an organized procedure for
determining the effectiveness of new drugs or therapies by
administering the agent to participants under strictly controlled
conditions.

CLONE: a group of genetically identical cells or organisms derived
from a single common ancestor.

CODON: a sequence of 3 nucleotides or bases that encode the
information for a particular amino acid (the building blocks that make
up proteins). Changes in specific codons can confer resistance to
certain drugs.

COFACTOR: a substance, microorganism or environmental factor that
activates or enhances the action of a disease-causing agent.

COHORT: a group of individuals in a study who share a statistical
factor.

COLONY STIMULATING FACTOR (CSF): a cytokine responsible for
controlling the production of white blood cells. Types include
granulocyte colony stimulating factor (G-CSF) and granulocyte
macrophage colony stimulating factor (GM-CSF).

COLPOSCOPY: examination of a tissue surface (particularly the uterine
cervix) with a low-powered, lighted microscope (colposcope) to
identify abnormal cell growth and, if necessary, remove a tissue
sample for biopsy.

COMBINATION THERAPY: simultaneous or alternating administration of 2
or more therapies.

COMPASSIONATE USE: an FDA classification that allows the use of an
experimental drug for a serious illness for which there is no other
suitable treatment.

CONCOMITANT: occurring together.

CONDYLOMATA ACUMINATA: genital and/or anal warts caused by infection
with the human  papillomavirus (HPV).

CONE BIOPSY (CONIZATION): removal of a cone-shaped wedge from the
bottom of the uterine cervix to remove lesions and/or to provide a
tissue sample for biopsy.

CONTRAINDICATION: any circumstance or symptom that makes a method of
treatment inadvisable in a particular case.

CONTROLLED TRIAL: a clinical trial in which a group receiving an
experimental therapy is compared to a control group that is not given
the intervention under study.

CORTICOSTEROID: one of a group of steroid hormones (e.g., prednisone,
cortisone) produced by the outer part of the adrenal gland or
manufactured synthetically; corticosteroids have anti-inflammatory and
immunosuppressive effects.

CROSS-RESISTANCE: the development of resistance to one agent (e.g.,
drug) which also confers resistance to another (often similar) agent.

CRYOTHERAPY (CRYOSURGERY): the use of liquid nitrogen to freeze an
abnormal lesion; the lesion typically forms a blister and then heals.

CRYPTOCOCCOSIS: an infection caused by a yeast-like fungus, typically
Cryptococcus neoformans, found in soil and bird excreta. A common
manifestation is cryptococcal meningitis (CM), an inflammation of the
membranes surrounding the brain and spinal cord; cryptococcosis may
also become disseminated.

CRYPTOSPORIDIOSIS: a disease caused by the protozoan Cryptosporidium
parvum, which is transmitted to humans by contact with animal feces,
contaminated food or water, or oral-anal sexual contact. It can cause
severe, chronic diarrhea, gas, weight loss and lymphadenopathy.

CURETTE: a sharp, spoon-shaped instrument. Curettage is the process of
scraping a cavity with a curette, e.g., to remove abnormal tissue.

CYTOCHROME P450 SYSTEM: a process that metabolizes drugs and other
foreign substances in the liver, by means of the p450 enzymes.

CYTOKINE: an intercellular chemical messenger protein (e.g.,
interleukin) released by white blood cells. Cytokines facilitate
communication among immune system cells and between immune system
cells and the rest of the body.

CYTOMEGALOVIRUS (CMV, HHV-5): a herpesvirus. CMV infection often
occurs in healthy individuals without causing symptoms. In
immunocompromised individuals it may cause retinitis, pneumonia,
colitis and/or encephalitis.

CYTOTOXIC T-LYMPHOCYTE (CTL, T-KILLER CELL): an immune system white
blood cell that targets and kills cells infected with microorganisms.
CTL action is coordinated by CD4 cells via cytokines.

CYTOTOXICITY: the quality of being toxic to or killing cells.

DEMENTIA: chronic loss of mental capacity due to organic causes that
affects social and/or occupational functioning.

DENDRITIC CELL: a type of immune system cell with many branches found
in the skin and mucosal linings.

DESENSITIZATION: the reduction of sensitivity or allergic reactions to
an antigen or drug by administering a very small amount and gradually
increasing the dose.

DISSEMINATE: to spread; a disseminated infection is one that is
distributed throughout the body.

DNA (DEOXYRIBONUCLEIC ACID): a molecule found in the nucleus of cells
that encodes genetic information. The particular sequence of 4
chemical building blocks (nucleotides) determines an individual's
unique genetic code.

DOUBLE-BLIND: a type of clinical trial in which neither the subject
nor the observer knows what treatment, if any, the subject is
receiving.

DYSPLASIA: the abnormal development or growth of cells and tissues;
precancerous tissue changes.

EFFICACY: effectiveness; the ability to achieve a desired effect.

EMPIRIC DIAGNOSIS/TREATMENT: evaluation and/or treatment based on
observation and experience alone, without relying on laboratory test
results or while awaiting lab results.

ENCEPHALITIS: inflammation of the brain.

ENCEPHALOPATHY: any disease of the brain.

ENDOCERVIX: the inner part of the uterine cervix.

ENDOCRINE SYSTEM: a system of ductless glands that regulates bodily
functions via hormones secreted into the bloodstream. The endocrine
glands include the hypothalamus, pituitary gland, thyroid, adrenal
glands and gonads (ovaries and testes).

ENDOMETRIUM: the mucous membrane that lines the uterus.

ENDOSCOPY: a method of examining the interior of a body cavity or
hollow organ (e.g., esophagus, stomach) using an endoscope, a narrow
flexible fiber optic instrument that conducts light.

ENDPOINT: a direct marker of disease progression, e.g., disease
symptoms or death.

EPITHELIUM: the thin layer of cells that covers the internal and
external surfaces of the body, including body cavities, ducts and
vessels.

EPSTEIN-BARR VIRUS (EBV, HHV-4): a herpesvirus. EBV infection is
common in children and may cause infectious mononucleosis in young
adults. EBV is associated with oral hairy leukoplakia and some types
of cancer.

ESOPHAGUS (adjective ESOPHAGEAL): the swallowing tube, the portion of
the digestive canal between the oral cavity and the stomach.

ESTROGEN: a female sex hormone; a natural or synthetic substance
(e.g., estradiol) that stimulates the development of secondary sex
characteristics and regulates the reproductive cycle in women.

ETIOLOGY: the cause of a diseases; the study of causes of disease.

EXOGENOUS: originating or produced outside the body.

EXPANDED ACCESS: an FDA program that allows free distribution of
experimental drugs through physicians to people with life-threatening
illness who have failed or cannot tolerate approved therapies.

FIRST-LINE TREATMENT: the preferred standard therapy for a particular
condition.

FOOD AND DRUG ADMINISTRATION (FDA): the federal agency responsible for
regulating the development, use and safety of drugs, medical devices,
food, cosmetics and related products.

FUNGUS: a class of organisms that includes yeasts, molds and
mushrooms, several of which can cause disease (mycoses) in humans,
e.g., candidiasis, cryptococcal meningitis and histoplasmosis.

FUSIN: a protien necessary for HIV fusion with a host cell.

GANGLION: a cluster of nerve tissue primarily composed of neuron cell
bodies.

GASTROINTESTINAL: relating to the stomach and intestines.

GENE (adjective GENETIC): the unit of heredity. A gene contains
hereditary information encoded in the form of DNA and is located at a
specific position on a chromosome in a cell's nucleus.

GENE THERAPY: an approach to preventing and/or treating disease by
replacing, removing or introducing genes or otherwise manipulating
genetic material, e.g., adding a gene to a cell to produce a specific
missing protein.

GENOME (adjective GENOMIC): the unique genetic code or hereditary
material of an organism.

HALF-LIFE: the time required for half the amount of an agent (e.g.,
drug, virus) to be eliminated from the body.

HELPER T-CELL: see CD4 cell.

HEPATITIS: an inflammation of the liver that may be caused by several
agents, including viruses and toxins. Hepatitis is characterized by
jaundice, enlarged liver, fever, fatigue and abnormal liver function
tests. Types include hepatitis A (infectious hepatitis), hepatitis B
(serum hepatitis) and hepatitis C.

HEPATOMEGALY: liver enlargement.

HEPATOTOXICITY: poisonous to the liver.

HERPES SIMPLEX VIRUS (HSV): a herpesvirus that causes blisters and
recurring disease. HSV-1 usually produces lesions on the lips or in
the mouth ("cold sores"). HSV-2 is usually sexually transmitted and
its lesions generally occur in the anal and/or genital area.
Symptomatic disease outbreaks occur at unpredictable intervals of
weeks, months or years.

HERPESVIRUS: a group of viruses that includes herpes simplex virus
types 1 (HSV-1) and 2 (HSV-2), varicella zoster virus (VZV, HHV-3),
Epstein-Barr virus (EBV, HHV-4), cytomegalovirus (CMV, HHV-5), human
herpesvirus types 6 and 7 (HHV-6, HHV-7) and Kaposi's
sarcoma-associated herpesvirus (KSHV or HHV-8).

HERPES ZOSTER (SHINGLES): a skin condition characterized by painful
blisters that appear in a linear distribution following nerve
pathways. Shingles is caused by reactivation of the varicella-zoster
virus (VZV) that causes chickenpox; VZV lies dormant in the nerves and
reactivates when immune defenses are weakened.

HISTOPLASMOSIS: a fungal infection acquired by inhaling spores of the
fungus Histoplasma capsulatum which are present in soil or dust. The
disease is most often found in the lungs, where it produces a
tuberculosis-like inflammation, but it may also disseminate. Symptoms
include cough, fever and weight loss.

HIVIG: concentrated anti-HIV immunoglobulins used in passive
immunotherapy. HIVIG is under study as a treatment for children with
HIV disease and as a therapy to prevent vertical transmission.

HORMONE: a chemical messenger involved in the regulation and
coordination of cellular and bodily functions.

HUMAN GROWTH HORMONE (HGH, SOMATOTROPIN, SEROSTIM): a peptide hormone
secreted by the anterior pituitary gland. HGH enhances growth by
stimulating metabolism and protein synthesis. Recombinant human growth
hormone (rHGH) is a genetically engineered drug used for the treatment
of HIV-related wasting syndrome.

HUMAN LEUKOCYTE ANTIGEN (HLA): a genetic marker of "self" which
prevents the immune system from attacking the body's own tissues.

HUMAN PAPILLOMAVIRUS (HPV): a papova virus, many strains of which
cause warts, including condylomata acuminata (genital warts). Certain
strains (e.g., 16, 18) are associated with cervical, anal and oral
cancer.

HUMORAL IMMUNITY (ANTIBODY-BASED IMMUNITY, TH2 RESPONSE): the immune
response mediated by the TH2 subset of CD4 cells. Humoral immunity is
stimulated by the cytokines IL-4 and IL-10, and carried out by plasma
cells (derived from B-cells) which produce antibodies.

HYPERPLASIA: excessive growth of normal cells (i.e., not tumor or
cancer cells); an increase in the number of normal cells in a tissue
or body part which may increase its size.

HYPERTHERMIA: abnormally high body temperature. Also refers to an
experimental AIDS therapy in which blood is removed from the body,
heated, and returned to the circulation, or in which the patient's
whole body is heated.

HYPOGAMMAGLOBULINEMIA: low levels of immunoglobulins (antibodies) in
the blood.

HYSTERECTOMY: surgical removal of the uterus. A radical hysterectomy
includes the removal of  the upper vagina, fallopian tubes, and
possibly the ovaries and lymph nodes.

IATROGENIC: refers to an unfavorable response to medical or surgical
treatment; symptoms attributable to a medical therapy, e.g.,
peripheral neuropathy caused by an antiviral drug.

IDIOPATHIC: refers to a disease or condition of unknown cause or
origin.

IMMUNE SYSTEM: the body's defense system that protects against foreign
invaders (e.g., microorganisms) and cancerous cells. There are 2
branches: cell-mediated (TH1) and humoral (antibody-based or TH2).
Organs of the immune system include the lymph nodes, spleen, thymus,
tonsils and bone marrow.

IMMUNIZATION: a process by which a person is protected against the
adverse effects of infection by a disease-causing microorganism.

IMMUNOGEN: an antigenic agent or substance that stimulates an immune
response.

IMMUNOGLOBULIN (IG): see antibody.

IMMUNOMODULATOR (IMMUNE MODULATOR): a substance or process capable of
modifying functions of the immune system. Immune modulators include
cytokines (e.g., IL-2, gamma interferon) and broad-acting agents
(e.g., hormones such as endorphins).

IMMUNOSUPPRESSION (IMMUNOCOMPROMISE): reduced function of the immune
system; a state in which the immune system defenses have been
suppressed or weakened.

IMMUNOTHERAPY (IMMUNE BASED THERAPY, IMMUNE MODULATING THERAPY): a
therapy that attempts to modify or enhance immune response or
reconstitute a damaged immune system, e.g., active immunization
(vaccination), cytokine therapy.

INDUCTION: the phase of initiation of a particular therapy.

INFLAMMATION: the body's response to tissue injury or infection, which
typically includes increased vessel dilation and permeability
resulting in redness, swelling, heat and pain.

INTEGRASE: an enzyme produced by HIV that allows the integration of
HIV DNA into the host cell's genetic material.

INTENT-TO-TREAT: a method of analysis of medical trials that groups
each participant according to the treatment arm to which they were
initially assigned (e.g., experimental drug, standard therapy,
placebo), regardless of whether they remained in that arm for the
duration of the study.

INTERFERON: a cytokine (messenger protein) that plays a role in immune
response. Interferons are secreted by infected cells and help protect
other cells from infection. There are 3 major classes: alpha, beta and
gamma.

INTERLEUKIN (IL): a cytokine secreted by immune system cells. Various
interleukins (e.g., IL-1, IL-2, IL-12) regulate a range of immune
system functions.

INTOLERANCE: the inability of the body to appropriately metabolize an
agent or drug.

INTRAVENOUS (IV): introduced directly into a vein.

INVESTIGATIONAL NEW DRUG (IND): an FDA classification applied to
experimental drugs undergoing trials to assess safety and efficacy
prior to marketing approval.

IN UTERO: in the uterus; refers to events that occur in the womb
before birth.

IN VITRO: Latin for "in glass"; refers to work done in a test tube or
culture medium in the laboratory.

IN VIVO: Latin for "in the body of a living organism"; refers to work
done using human (or animal) subjects.

IVIG (INTRAVENOUS IMMUNE GLOBULIN): broad-spectrum concentrated
immunoglobulins adminstered intravenously to treat conditions in which
the body does not produce enough of its own antibodies.

KAPOSI'S SARCOMA (KS): an abnormal or cancerous proliferation of cells
with increased blood or lymph vessels of the skin, mucous membranes
and/or internal organs. KS typically appears as pink or purple flat or
raised lesions on the skin or in the mouth.

KAPOSI'S SARCOMA-ASSOCIATED HERPESVIRUS (KSHV, HUMAN HERPESVIRUS TYPE
8): a recently discovered herpesvirus that is found in samples of
tissue from Kaposi's sarcoma lesions and may be a causal agent or
co-factor.

KILLER T-CELL: see cytotoxic T-lymphocyte.

LESION: any abnormal change in tissue caused by disease or injury.

LEUKOCYTE: any immune system white blood cell (e.g., monocyte, CD4
cell). Many types of leukocytes are involved in the body's defense
against infection and disease.

LEUKOPENIA: an abnormally low number of white blood cells in the
circulating blood.

LIPOSOME (LIPID VESICLE): a spherical particle of fat suspended in a
liquid medium. Liposomes may be used to carry drugs or other
substances to cells or tissues.

LIVER ENZYME: a protein produced by the liver (e.g., SGOT, SGPT).
Abnormally high levels in the blood indicate liver disease or damage
(e.g., hepatitis, drug-related liver toxicity).

LOG: refers to quantities in factors of 10. A log change is an
exponential or 10-fold increase or decrease (e.g., 10 to 100 is a 1
log increase).

LONG-TERM NONPROGRESSOR (LTNP): an individual who has been infected
with HIV for 7-10 years or more but does not exhibit immune system
decline or opportunistic diseases. Long-term survivor refers a person
who has lived 7-10 or more years with HIV, but who may or may not have
symptomatic disease.

LOOP ELECTROSURGICAL EXCISION PROCEDURE (LEEP, LOOP DIATHERMY):
utilization of a heated wire loop to remove a cone-shaped wedge from
the bottom of the cervix and around the os for biopsy; the loop seals
off blood vessels as it cuts.

LYMPH NODE: a small, bean-sized organ located throughout the body with
concentrations in the neck, groin and armpits. Lymph nodes are the
sites of antigen presentation and immune activation.

LYMPHADENOPATHY: any abnormality of the lymph nodes. Usually refers to
swollen and tender lymph nodes due to, e.g., an infectious disease
such as AIDS or mononucleosis.

LYMPHATIC SYSTEM (adjective LYMPHOID): a network of vessels, ducts,
nodes and organs that help maintain the fluid environment of the body
and coordinate immune response. The lymphoid organs include the lymph
nodes, spleen, thymus and tonsils.

LYMPHOCYTE: a type of white blood cell (e.g., T-cell, B-cell)
responsible for immune defenses.

LYMPHOMA: a malignant disease (cancer) originating in the lymph nodes.

MACROPHAGE: a large scavenger white blood cell that ingests
degenerated cells and foreign particles and secretes messenger
proteins (monokines) involved in a variety of immune system responses.

MAINTENANCE THERAPY (SECONDARY PROPHYLAXIS): preventive therapy that
follows successful initial treatment of an illness.

MAJOR HISTOCOMPATIBILITY COMPLEX (MHC): cell surface markers (also
known as HLA markers) that determine receptor shape and allow immune
cells to recognize components of the body (i.e., to distinguish "self"
from "non-self"). MHC molecules are necessary for antigen presentation
and recognition of antigens by  immune system cells.

MALIGNANCY (adjective MALIGNANT): cancer; a neoplasm or tumor that
grows in an uncontrolled manner, invading nearby tissue or spreading
to other sites through the bloodstream.

MARKER: lab result or symptom observation used to measure a
treatment's effectiveness or an individual's immune system status.
Also, a unique identifier on a cell's surface.

METABOLISM: the process of building the body's molecular structures
from nutrients (anabolism) and breaking them down for energy
(catabolism).

METASTASIS (adjective METASTATIC, verb METASTASIZE): secondary cancer
that has spread via the blood or lymph vessels from the primary or
original site to another part of the body.

MICROCEPHALY: a birth defect characterized by an abnormally small
head, incomplete development of the brain and usually mental
retardation.

MONOCYTE: a large white blood cell that plays a role in immune defense
by acting as a scavenger that destroys invading microorgnisms.
Monocytes circulate in the bloodstream; when they migrate to the
tissues they mature into macrophages.

MONOTHERAPY: use of a single drug or other therapy for treatment.

MORBIDITY: sickness.

MUCOUS MEMBRANE (MUCOSA): a moist layer of semi-permeable tissue
lining the gastrointestinal, respiratory and genitourinary tracts.

MUTATION: a change in the character of a gene that is perpetuated in
subsequent cell divisions.

MYCOBACTERIUM AVIUM COMPLEX (MAC): a disease caused by Mycobacterium
avium or Mycobacterium intracellulare, bacilli found in soil and
water. In immunosupressed persons, the bacteria can infect lymph
nodes, bone marrow, liver, spleen, spinal fluid, lungs and the
gastrointestinal tract. Symptoms in-clude diarrhea, wasting, fever,
fatigue and spleen enlargement.

MYCOPLASMA: a microorganism, of which there are many varieties (e.g.,
Mycoplasma penetrans), that usually does not cause disease in people
with healthy immune systems. Mycoplasma is thought by some to be a
cofactor in the development of AIDS.

NAIVE: inexperienced. Used to describe an individual who has never
taken a certain drug or class of drugs (e.g., AZT-naive,
antiretroviral-naive).

NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES (NIAID): a
component of the National Institutes of Health that conducts
federally-funded research aimed at preventing, diagnosing and treating
infectious diseases such as AIDS and tuberculosis.

NATIONAL INSTITUTES OF HEALTH (NIH): a large biomedical research
organization that is part of the U.S. Public Health Service. NIH
includes 24 institutes, centers and divisions, several of which
perform AIDS-related research.

NATURAL KILLER CELL (NK CELL): a type of lymphocyte that attacks and
kills cells infected with microorganisms.

NECROSIS: localized tissue death.

NEF: a gene of HIV that influences viral replication; also the protein
produced by that gene.

NEOPLASM: a tumor or growth; tissue that develops abnormally or grows
more rapidly than normal. A neoplasm may be benign or malignant
(cancerous).

NEPHROTOXICITY: the property of being poisonous to the kidneys.

NEUROPATHY (adjective NEUROPATHIC): any abnormal, degenerative or
inflammatory condition of the nerves. See also peripheral neuropathy.

NEUTROPENIA: an abnormally low number or a decrease in the number of
neutrophils, a type of white blood cell involved in defense against
bacteria and fungi.

NEW DRUG APPLICATION (NDA): an application made by a drug sponsor to
FDA to request marketing approval.

NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR (NNRTI): a drug (e.g.,
delavirdine, nevirapine) that inhibits the action of the retroviral
reverse transcriptase enzyme, thus blocking viral replication, yet
works in a different way than nucleoside analog drugs.

NOSOCOMIAL: refers to the acquisition of a new disease or condition
within a healthcare setting.

NUCLEOSIDE: a precursor to one of the building blocks or bases
(adenine, cytosine, guanine, thymine or uracil) that make up genetic
material (DNA and RNA).

NUCLEOSIDE ANALOG (NA): a synthetic compound (e.g., AZT, ddI, ddC,
d4T, 3TC) that mimics one of the building blocks of DNA (nucleotides).
These compounds suppress retroviral replication by interfering with
the reverse transcriptase enzyme; the synthetic nucleosides cause
premature termination of the viral DNA chain.

OFF-LABEL: use of an FDA-approved drug for an indication other than
that for which the drug was approved.

OFFICE OF AIDS RESEARCH (OAR): a federal agency created to coordinate
AIDS research done by various federal departments, institutes and
agencies.

ONCOGEN: an agent (e.g., virus. toxin) that is able to cause
neoplastic cell growth, or cancer.

ONCOLOGY: the study and treatment of cancer.

OPEN LABEL: a drug trial in which both participants and investigators
know what drug is being tested and what dose is being used.

OPPORTUNISTIC INFECTION (OI): an illness (e.g., PCP, MAC, CMV disease)
caused by a microorganism that usually does not cause disease in
persons with healthy immune systems, but which may cause serious
illness when the immune system is suppressed.

ORAL HAIRY LEUKOPLAKIA: a condition thought to be caused by the
Epstein-Barr virus characterized by white, raised, usually painless
lesions on the sides of the tongue and/or elsewhere in the mouth.

OTITIS MEDIA: inflammation of the middle ear.

P24: a core protein of HIV produced by the gag gene. Detection of the
p24 antigen in the blood or tissues indicates that HIV is actively
replicating and may predict disease progression.

PANCREATITIS: inflammation of the pancreas, a digestive gland in the
abdominal cavity. Symptoms may include intense abdominal pain, nausea,
constipation and possibly jaundice. Pancreatitis may be a side effect
of some anti-HIV drugs (e.g., ddI).

PARENTERAL: given by injection, bypassing the enteral
(gastrointestinal) tract.

PAROTITIS: inflammation of the parotid gland, the largest of the
salivary glands.

PATHOGEN (adjective PATHOGENIC): any disease-causing agent, especially
a microorganism.

PATHOGENESIS: the development of a particular disease, including the
specific events involved, bodily tissues or systems affected,
mechanisms of damage and timing of the course of disease.

PATHOLOGY (adjective PATHOLOGIC): the study of disease, focusing on
causes, development and progress, and how the body is affected.

PCR: see polymerase chain reaction.

PERINATAL: referring to the period around the time of birth.

PERINATAL TRANSMISSION: see vertical transmission.

PERIPHERAL NEUROPATHY: a disorder of the nerves usually involving the
feet and/or hands and sometimes the legs, arms and face. Symptoms may
include numbness, tingling or burning, weakness and partial paralysis.
It can be a side effect of some anti-HIV drugs (e.g., ddC, ddI).

PHARMACOKINETICS: the action of drugs in the body, including the
processes of absorption, transformation, distribution to tissues,
duration of action and elimination.

PHARMACOLOGY: the science of drugs, their sources and how they work;
the specialty of preparing and dispensing drugs.

PHASE I TRIAL: the first step in human testing of a new drug; these
trials evaluate drug safety and toxicity at different dose levels in a
small number of volunteers.

PHASE II TRIAL: the second step in the evaluation of a new drug in
humans; these trials evaluate drug effectiveness and involve more
participants than Phase I studies. Phase II studies proceed only if
Phase I studies have shown that a drug is acceptably safe.

PHASE III TRIAL: the third step in human drug testing; these trials
are designed to support and verify information gathered in Phase I and
II trials and involve many more volunteers (up to several thousand).
Phase III trials may compare the drug being tested to other therapies
or to placebo.

PLACEBO-CONTROLLED TRIAL: a trial of an experimental therapy in which
an inactive substance or mock therapy (placebo) is given to one group
while the treatment being tested is given to another, and the results
obtained in the different groups are compared.

PLACENTA: the vascular organ that connects the fetus and the mother's
uterus, through which metabolic exchange between the fetus and mother
occurs. Some pathogenic organisms and maternal antibodies may be
transfered across the placenta.

PLASMA: the fluid, non-cellular portion of circulating blood that
carries blood cells and nutrients throughout the body.

PNEUMOCYSTIS CARINII PNEUMONIA (PCP): a life-threatening type of
pneumonia thought to be caused by a protozoan. PCP is a common
opportunistic infection and a leading cause of death in people with
AIDS.

PNEUMONIA: an inflammatory condition of the lungs in which they become
obstructed with fluid, causing difficult breathing and possibly
suffocation. Pneumonia may be caused by bacteria, viruses or fungi.

POLYMERASE CHAIN REACTION (PCR): a highly sensitive test that uses an
amplification technique to detect minute amounts of DNA or RNA in
blood or tissue samples.

PRENATAL: the period preceding birth, during which the fetus develops
in the uterus.

PRESUMPTIVE DIAGNOSIS/TREATMENT: treatment based on an assumed
diagnosis, prior to receiving confirmatory laboratory test results.

PRIMARY INFECTION: the initial introduction of an infectious organism
into the body.

PRODRUG: a drug that exerts its effects after metabolic changes within
the body convert it to a usable or active form.

PROGESTERONE: a female steroid hormone with anti-estrogenic effects.
Progesterone prepares the uterus for the development of the fertilized
ovum and maintains the uterus throughout pregnancy. Synthetic
progesterone is used as a contraceptive.

PROGNOSIS (adjective PROGNOSTIC): a forecast of the probable course
and/or outcome of a disease.

PROPHYLAXIS: a treatment that helps to prevent a disease or condition
before it occurs (primary prophylaxis) or recurs (secondary
prophylaxis).

PROTEASE (PROTEINASE): an enzyme that cleaves the large precursor
proteins produced from viral RNA into the component parts (e.g.,
enzymes and structural proteins) that are then assembled into new
viral particles; protease is essential for the replication new of
infectious viruses.

PROTEASE INHIBITOR: a drug (e.g., saquinavir, indinavir, ritonavir)
that blocks the action of the protease enzyme that breaks up large
proteins produced from viral RNA, thereby preventing HIV replication.

PROTEIN: a large molecule consisting of sequences of amino acids.
Proteins are major components of living cells and compose hormones,
enzymes and immunoglobulins; they are essential for most life
functions.

PROTOZOAN: an acellular or 1-celled microorganism, some of which can
cause disease in humans.

PROVIRUS: a viral state in which viral DNA has been inserted into the
chromosome of the host cell.

PULSE OXIMETRY: a method of measuring the amount of oxygen in the
blood by means of a clip-like instrument that attaches to the finger.

PURULENT: characterized by the accumulation of pus.

PSYCHOPHARMACOLOGY: the use of drugs that affect the psyche or
personality.

QUANTITATIVE COMPETITIVE POLYMERASE CHAIN REACTION (QC-PCR): a
refined, sensitive version of the PCR assay used to detect DNA or RNA
(viral load) using competitive RNA samples for comparison.

RANDOMIZED TRIAL: an experiment arranged so as to produce a chance
distribution of subjects into different treatment groups or arms.

RECEPTOR: a specific protein-binding site on a cell's surface or
interior. Many drugs exert their effects by binding to receptors and
altering normal cellular communication. Viruses enter cells by fusing
with receptors on the cell surface and then passing into the interior
of the cell.

RECOMBINANT: produced by genetic engineering in the laboratory.
Recombinant products are designated by a lower-case r (e.g., rHGH).

REFRACTORY: resistant to treatment.

REMISSION: a lessening of the severity of disease symptoms; a period
of time during which symptoms are abated or eliminated.

REPLICATION: duplication or reproduction.

RESERVOIR: a site where an infectious agent collects and multiplies,
e.g., the macrophages and lymph nodes are reservoirs for HIV.

RESISTANCE: the ability of a microorganism (e.g., a virus) to lose its
sensitivity to a drug. Microorganisms mutate to function and reproduce
despite the presence of a drug.

RETINITIS: inflammation of the retina, the light-sensitive tissue at
the back of the eyeball that transmits visual impulses to the brain.

RETROVIRUS: a class of enveloped viruses that have their genetic
material in the form of RNA and use reverse transcriptase to translate
their RNA into DNA. The retrovirus family includes oncoviruses (e.g.,
HTLV-1) and lentiviruses (e.g., HIV-1, HIV-2).

REVERSE TRANSCRIPTASE (RT): a viral enzyme that allows a retrovirus to
translate its genetic material, in the form of RNA, into DNA, which is
then integrated into the host cell's chromosomes.

REVERSE TRANSCRIPTASE INHIBITOR (RTI): a drug that blocks retroviral
replication by interfering with the reverse transcriptase enzyme. RTI
include nucleoside analogs (e.g., AZT, ddI) and non-nucleoside reverse
transcriptase inhibitors (e.g., nevirapine).

RNA (RIBONUCLEIC ACID): a single-stranded nucleic acid made up of
nucleotides. RNA is involved in the transcription of genetic
information; the information encoded in DNA is translated into
messenger RNA (mRNA), which controls the synthesis of new proteins.
RNA takes the place of DNA in retroviruses such as HIV.

SALVAGE THERAPY: emergency treatment with an experimental drug of a
disease or illness that has not responded to standard therapy.

SECOND-LINE TREATMENT: the second preferred therapy for a disease or
condition.

SECONDARY INFECTION: infection with a second or subsequent infectious
organism (e.g., bacteria) during the course of an initial infection
with another organism (e.g., a virus).

SENSITIVITY: the ability of an organism to be affected by a drug or
other agent, e.g., a virus is senstive to AZT if AZT is able to
prevent viral replication. Also refers to a statistical measure of the
accuracy of a screening test, i.e., how likely a test is to label as
positive those who have a disease or condition.

SEPSIS: the presence of pathogenic (disease-causing) organisms or
their toxins in the blood or tissues, and the associated bodily
reactions.

SEQUELAE: conditions resulting from a disease or injury.

SEROCONVERSION: the change in a person's antibody status from negative
to positive.

SEROPREVALENCE: the rate of HIV-infected individuals in a certain
geographic location or population as measured by blood tests.

SEROSTATUS (ANTIBODY STATUS): the presence or absence of antibodies in
the blood serum. If antibodies are present, a person is said to be
seropositive; if no antibodies can be detected, they are said to be
seronegative.

SERUM: the fluid portion of blood after coagulation; lymphatic fluid.

SEXUALLY TRANSMITTED DISEASE (STD, VENEREAL DISEASE): a disease (e.g.,
syphilis, chlamydia) that is transmitted through sexual contact.

SIDE EFFECT: an action or effect of a drug other than that which is
intended. The term usually refers to undesired or negative effects
such as headache, skin rash or liver damage.

SIMIAN IMMUNODEFICIENCY VIRUS (SIV): a viral infection endemic to
African green monkeys and similar to HIV-2.

SINUSITIS: acute or chronic inflammation or infection of the sinuses
(cavities behind the forehead and cheekbones).

SPECIFICITY: a statistical measure of the accuracy of a screening
test, i.e., how likely a test is to label as negative those who do not
have a disease or condition.

SPLENOMEGALY: enlargement of the spleen.

SPUTUM: mucus or other matter ejected from the bronchi and lungs by
coughing or spitting.

SQUAMOUS CELL: flat, thin cells that comprise the surface of the skin
and the lining of the esophagous, vagina and rectum.

SQUAMOUS INTRAEPITHELIAL LESION (SIL): abnormal growth of squamous
cells. SIL particularly refers to abnormal cell changes at the
squamo-columnar junction of the uterine cervix. Low-grade SIL is
considered a precancerous condition. See also cervical intraepithelial
neoplasia.

STANDARD THERAPY: a therapy that is FDA-approved for a given condition
and is widely used as first-line treatment.

STATISTICAL SIGNIFICANCE: the probability that an observed outcome of
an experiment or trial is due to chance alone. In general, a result is
considered to be statistically significant if there is a less than 5%
probability that the difference observed would occur by chance alone
if the two treatments being compared were equally effective (e.g., a
p-value of less than .05).

STEM CELL: a precursor cell from which all blood cells are derived. As
they mature, stem cells evolve into various types of red and white
blood cells. Bone marrow, the site of blood cell production, is rich
in stem cells.

STENOSIS: the narrowing or tightening of an opening or passage in the
body.

STEROID: a family of substances that share a similar chemical
structure, including many hormones (e.g., testosterone), vitamin D and
various drugs. Some steroid drugs are used to lessen inflammatory
reactions.

STEVENS-JOHNSON SYNDROME: an unusual, severe reaction characterized by
blistering and sloughing of the mucous membranes; the visceral organs
may also be involved, and the condition can be fatal. The syndrome may
result from the use of certain medications such as TMP-SMX.

STOMATITIS: inflammation of the mucous membranes of the mouth.

STRAIN: a specific genetic variant of a particular organism.

SURROGATE MARKER: a marker or sign that can serve in place of a
clinical endpoint, e.g., viral load or CD4 cell count.

SYNCYTIUM (plural SYNCYTIA): a mass or clump of cells that fuse
together to form one "giant cell." In HIV infection syncytium
formation can may lead to direct cell-to-cell infection.

SYNERGY (SYNERGISM): the action of 2 or more agents (e.g., drugs)
working together that produce an effect greater than the combined
effect of the same agents used separately.

SYSTEMIC: affecting the whole body; not localized.

T-CELL (T-LYMPHOCYTE): a type of white blood cell derived from the
thymus that participates in a variety of cell-mediated immune
responses. There are 3 major types of T-cells: T-helper (CD4),
T-suppressor (CD8) and T-killer (cytotoxic T-lymphocytes or CTL).

T-HELPER CELL: see CD4 cell.

T-KILLER CELL: see cytotoxic T-lymphocyte.

T-SUPPRESSOR CELL: a type of T-cell that bears the CD8 surface marker
and helps to regulate the immune response.

TESTOSTERONE: a steroid hormone produced by the testes, essential for
sperm production and the development of reproductive organs and
secondary sexual characteristics in males. Testosterone is under study
as a therapy for HIV-related wasting syndrome.

TH1/TH2 IMMUNE RESPONSE: 2 branches of the immune system. The TH1
response involves a subset of CD4 lymphocytes called TH1 cells that
secrete IL-1, IL-2 and gamma interferon, which enhance the
cell-mediated immune response. The TH2 response involves the TH2
subset of CD4 cells that secrete IL-4 and IL-10, which enhance the
humoral (antibody-based) immune response.

THROMBOCYTOPENIA: a condition marked by an abnormally low number of
platelets, blood cells that facilitate normal blood clotting; the
condition may result in abnormal bleeding and bruising.

THRUSH: see candidiasis.

THYMUS (adjective THYMIC): a lymphoid organ in the upper chest cavity
that is the source of lymphocytes in children, but which generally
shrinks during adolescence. The thymus is the site of lymphocyte
differentiation where lymphocytes learn to recognize antigens. The
thymus produces some 30 hormones or thymic factors (e.g., thymodulin,
thymopentin, thymostimulin) that are involved in the regulation of
immune function.

TOLERANCE: a condition in which the body becomes accustomed to an
agent (e.g., drug) so that the previous dose no longer produces the
desired effects.

TOXICITY (adjective TOXIC): the quality of being poisonous or harmful;
often used to refer to side effects of drugs.

TOXOPLASMOSIS: an opportunistic infection caused by the microscopic
parasite Toxoplasma gondii, found in raw or undercooked meat and cat
feces. Symptoms may include headache, lymphadenopathy, malaise, muscle
pain, fever and dementia. Toxoplasmosis may lead to brain swelling,
coma and death in persons with suppressed immune systems.

TRADITIONAL CHINESE MEDICINE (TCM): an Asian system of healing that
focuses on achieving internal balance using methods such as
acupuncture, heat application (moxibustion), herbal preparations and
exercises (e.g., tai chi, qigong) to restore the flow of qi ("vital
energy") and the balance of yin and yang.

TRANSFORMATION ZONE: the area of the cervix where squamous cells and
columnar cells meet; a common site for dysplasia.

TREATMENT IND (TIND): an FDA protocol that allows patients with
life-threatening disease to obtain experimental drugs through their
physician free of charge from the drug's manufacturer.

TUBERCULOSIS (TB): an infectious disease caused by Mycobacterium
tuberculosis that typically affects the lungs but may occur in other
organs (extrapulmonary TB). Transmission generally occurs through
inhalation of aerosolized sputum droplets. Multidrug-resistant
tuberculosis (MDR-TB) is resistant to some of the standard drugs and
requires more aggressive treatment.

TUMOR NECROSIS FACTOR (TNF, CACHECTIN): a cytokine produced by
activated monocytes and macrophages that can destroy tumors. When
chronically elevated, TNF may lead to fever, anorexia, hypermetabolism
and wasting.

UVEITIS: an inflammation of the membranes (uvea) of the eye.

VACCINE: a preparation that contains an infectious agent or its
components which is administered to stimulate an immune response that
will protect a person from illness due to that agent. A therapeutic
(or treatment) vaccine is given after infection and is intended to
reduce or arrest disease progression. A preventive vaccine is intended
to prevent initial infection.

VARICELLA-ZOSTER VIRUS: a virus in the herpes family that causes
chickenpox (varicella). VZV may lie dormant for years and reactivate
later in life to cause shingles (herpes zoster), especially in
immunosuppressed individuals.

VECTOR: an agent used as a vehicle for transfer. A disease vector is
an agent that transfers a pathogen from one organism to another (e.g.,
an insect). A viral vector is an engineered virus used to introduce
genes into cells or a live virus used as an antigen delivery vehicle
in a vaccine.

VERTICAL TRANSMISSION (PERINATAL TRANSMISSION, MATERNAL-FETAL
TRANSMISSION): the transmission of an infectious organism from a
mother to a fetus or neonate (newborn). Vertical transmission may
occur in utero (in the womb), during birth or via breastfeeding.

VIRAL LOAD (VIRAL BURDEN): the amount of virus in the blood or other
tissues. The presence of HIV RNA indicates that the virus is
replicating; changes in viral load may be used to gauge drug
effectiveness and disease progression. Viral load is measured using
assays such as QC-PCR or branched-chain DNA, and is expressed as the
number of copies of RNA per milliliter (mL) of blood.

VIREMIA: the presence of virus in the blood or plasma.

VIRION: a complete virus particle.

VIRULENCE (adjective VIRULENT): aggressiveness, ability to cause
disease.

VIRUS: a group of minute organisms that are unable to grow or
reproduce outside the body of a host. During replication a virus
integrates its genetic material (DNA or RNA) into a host cell and
takes over the cell's biological mechanisms to reproduce new virus
particles.

VULVA: the external female genitalia, including the clitoris and the
inner and outer labia (lips) surrounding the urethral and vaginal
openings.

WASTING SYNDROME: a condition characterized by atrophy of lean body
mass and involuntary weight loss of more than 10% of normal body
weight.

WILD-TYPE: the normal, typical phenotype of a virus or other organism
before genetic mutation or manipulation takes place.  Back to the BETA
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