The Arsenal Files 8/The Arsenal Files Collection #8 (Arsenal Computer) (1996).ISO/health/beta30.txt

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       BETA 30 -- September 1996

       Table of Contents

       News Briefs
       Advocacy
          Access to HIV Viral Load Testing
          The Case for Medical Marijuana
          The HMO Patients' Rights Act
       Impressions from Vancouver
       Highlights from the XI International Conference on AIDS
           Clinical Updates and Basic Science
           Women and HIV
            Epidemiology and Prevention
       Anabolic Steroids in the Treatment of HIV-Related Wasting
       HIV Vaccines
       Critical Issues in Treating HIV During Pregnancy
       Clinical Trials
       The Options Project at SF General Hospital
       Glossary

       *******************************************************

       BETA News Briefs
       Mark Bowers

       **New Formulation of Saquinavir Enters Clinical Trials

       Hoffman-La Roche, Inc. has announced the initiation of a
multisite, randomized, open-label comparative clinical study of 2
formulations of saquinavir. The 48-week study will recruit 140
volunteers to receive either 1,200 mg of soft gel capsules or hard gel
capsules in combination with one or more Food and Drug Administration
(FDA) approved nucleoside analog antiretroviral drugs as chosen by the
investigator and the volunteer. Use of saquinavir as monotherapy or in
combination with other protease inhibitors will not be permitted.
Volunteers will be 13 years of age or older and will not have been
exposed to any protease inhibitor for more than 2 weeks. Contact
information: Los Angeles - Pacific Oaks Medical Group (818-906-6279)
or UCLA AIDS Clinical Research Center (310-206-8359); Sacramento - UC
Davis Medical Center (916-734-3741); San Diego - UC San Diego
Treatment Center (619-543-8080); Boston - Massachusetts General
Hospital (617-726-3815) or New England Medical Center (61!
7-636-7008); Stanford - AIDS Research Center (415-852-3408); San
Francisco - Veterans Administration Medical Center (415-750-6960) or
Mount Zion Hospital (415-885-7737); New York - Beth Israel Medical
Center (212-420-4432); Galveston - University of Texas Medical Branch
(409-772-4979); and Denver - University of Colorado (303-270-7233).

       **Food and Drug Administration Approvals

        *FDA Approves Expanded Access for Nelfinavir

       Beginning on September 16, 1996, an FDA-approved expanded
access program will make Agouron Pharmaceuticals' protease inhibitor
nelfinavir (Viracept) available to people with CD4 counts below 51
cells/mm3. Viracept will be provided free-of-charge to persons who
cannot take the 3 commercially available protease inhibitors,
saquinavir, indinavir and ritonavir. Physicians, health care
professionals and patients may call 1-800-621-7111 Monday through
Friday between 8:00 a.m. and 6:00 p.m. EST.

        *FDA Approves Serostim

       In August 1996, Serono Laboratories was granted accelerated
approval to market recombinant human growth hormone (Serostim) for the
treatment of AIDS wasting or cachexia. Approval was based on data from
studies that showed significant gains in lean body mass or weight,
with decreases in body fat. The impact of Serostim treatment on
survival and morbidity still is not known, but will be addressed in
post-marketing studies. Serono will also conduct studies to evaluate
whether the drug improves physical performance and to substantiate
previous findings of increased lean body mass in persons who receive
injections of Serostim. Under pressure from activists, including ACT
UP/Golden Gate, Serono agreed to a price cap on Serostim of $36,000
per year. Serono expects that Serostim will be available in pharmacies
in November; until then, the Serono treatment IND program will accept
new enrollments. For additional information, call the Serostim Access
Line at 1-800-714-2437 Monday throu! gh Friday between 8:30 a.m. and
5:00 p.m. EST.

        *FDA Approves Azithromycin for MAC Prophylaxis

       In June 1996, Pfizer, Inc. was granted FDA approval to market
azithromycin (Zithromax) for the prevention of disseminated
Mycobacterium avium complex (MAC) disease in people with advanced HIV
infection. A 1,200 mg dose (two 600 mg tablets) of azithromycin once a
week was shown to reduce the risk of developing MAC in 2 randomized,
double-blind studies. Azithromycin reduced by one half the risk of
developing MAC, compared to rifabutin. One study also showed that the
combination of azithromycin and rifabutin was more effective than
rifabutin alone at preventing MAC. The new once-weekly azithromycin
regimen is also more convenient and is expected to be cheaper than
daily rifabutin (two 150 mg capsules per day at approximately $2,600
per year). For patient assistance and further information, physicians
may call 1-800-869-9979 Monday through Friday between 9:00 a.m. and
5:00 p.m. EST. Allow 3-4 weeks for shipment of drug, and reapply every
15 weeks to assure continued supply.

        *FDA Approves Nevirapine

       In June 1996, Boehringer Ingelheim won accelerated approval to
market nevirapine (Viramune) in combination with nucleoside analog
drugs for the treatment of HIV-infected adults who have experienced
clinical or immunologic deterioration. The recommended dosing schedule
is one 200 mg tablet per day for 2 weeks, followed by one 200 mg
tablet twice daily. This schedule reduces the likelihood of developing
rash, which developed in 17% of patients on combination regimens that
included nevirapine in clinical studies. FDA approval was based on
studies that combined AZT and ddI with this new, non-nucleoside
reverse transcriptase inhibitor. For patient assistance, call
1-800-595-5494.

        *FDA Approves Cidofovir

       In July 1996, Gilead Sciences of Foster City, CA, was granted
FDA approval to market cidofovir (Vistide) for the treatment of
cytomegalovirus (CMV) retinitis in persons with AIDS. The dosing
schedule for induction is 1 infusion per week for 2 weeks. Maintenance
infusions are done every other week. The main side effect of the drug
is renal (kidney) impairment, which can be minimized with the
administration of probenecid tablets and hydration on the day of each
infusion. The catalog price is $589 for a 1-week course of induction
therapy or a 2-week course of maintenance therapy. For reimbursement
or financial assistance, call the Support Services Program at
1-800-GILEAD 5 (1-800-445-3235).

       *FDA Approves Urine Test to Detect HIV Antibodies

       In August 1996, Caltype Biomedical of Berkeley, CA, won FDA
approval to market the first urine test to detect antibodies to HIV.
The accuracy of the urine test differs from HIV blood tests in that
the false negative rate is estimated at 1 or 2 in every 100 tests,
while blood tests for antibodies miss 1 or 2 in every 1,000 tests.
Studies also show that 1 or 2 in every 100 tests will falsely register
positive for antibodies. The new urine test may only be administered
by a physician, and positive test results must be verified with a
follow-up blood test (Western blot). Evidence of pre-test counseling
is required before any sample will be evaluated for the presence of
HIV antibodies.

        *FDA Approves Home Access HIV Testing and Counseling Systems

       On July 14, 1996, Home Access Health Corporation won FDA
approval to market 2 HIV testing and counseling systems. Home Access
Express and Home Access allow people to collect blood samples, access
professional pre-test and post-test counseling, and receive test
results in either 3 days or 1 week, depending on which system is
purchased. Counseling is available in connection with both systems 24
hours a day, 7 days a week. For more information or to order a test
system, call 1-800-HIV-TEST.

        *Other News

       One Percent of Caucasians Immune to HIV

       Reports by researchers at the Aaron Diamond AIDS Research
Center published in the August 9, 1996 issue of Cell and by
researchers in Brussels, Belgium published in the August 22, 1996
issue of Nature provide insight as to why some people who are
repeatedly exposed to HIV through sex do not become infected. A newly
discovered gene called CKR-5 makes a protein that is located on the
surface of some immune cells. This protein is necessary for HIV to
enter and infect CD4 cells. People inherit 2 copies of the gene, 1
from each parent. If both inherited copies of the gene are mutants, no
CKR-5 protein is made, and HIV cannot infect immune cells where it is
lacking. Some people inherit 1 copy of the mutant gene. Belgian
researchers suspect that these are often the slow progressors who,
although they may be HIV-infected, do not progress to AIDS.

       Aaron Diamond researchers predict that 1% of people of Western
European heritage have 2 copies of the mutant gene. The Belgian team
found 1 copy of the mutant gene in 20% of 700 healthy Caucasians and
in a much smaller percentage of people who were HIV-infected. Central
Africans and Japanese who were studied did not show evidence of the
genetic mutation. The lack of CKR-5 apparently makes infection with
the most common sexually transmitted varieties of HIV unlikely, but
the effect on the incidence of transmission through blood is not
known.

       Mark Bowers is Managing Editor of BETA.

       *******************************************************

       Access to HIV Viral Load Testing
       Ronald Baker, PhD

       HIV viral load testing is a powerful new technology that is
revolutionizing the medical management of HIV disease and the conduct
of AIDS clinical research. These sensitive assays--branched chain DNA
(from Chiron Corporation) and RT-PCR (from Roche Diagnostics
Systems)--accurately measure the amount of HIV in the bloodstream of
HIV positive individuals and thus provide information about the
patient's disease stage and predict relative risk for progression to
AIDS and death.

       Test Results Guide Decisions About Therapy and Clinical
       Research

       Armed with this invaluable knowledge, patients and their
physicians can make rational, informed decisions about starting,
switching or adding therapy. It has become clear that decreases in HIV
viral load due to drug treatment correlate with decreased disease
progression. Conversely, increases in HIV viral load correlate with
increased risk for disease progression and suggest drug failure. In
AIDS clinical trials, researchers employ HIV viral load testing to
evaluate the effectiveness of the drug regimen(s) under study. FDA
approved the new protease inhibitor drugs based almost exclusively on
their ability to significantly reduce HIV viral load in patients using
the drugs!

       Viral Load Testing Is Standard of Care

       Almost everyone agrees that these tests are now an integral
component of the standard of care for HIV disease. Individuals denied
access to these tests are receiving substandard care. Most private
insurers, Health Maintenance Organizations (HMO) and Medicaid will
reimburse for or provide viral load testing. That's the good news.
Unfortunately, thousands of HIV positive individuals are underinsured
or uninsured, do not belong to an HMO or are not covered by Medicaid.
These individuals urgently require access to HIV viral load testing
through some sort of patient assistance program. In San Francisco and
in New York City, such individuals may take advantage of established
programs that provide them access to the tests. But in many other
areas of the country, no such programs exist.

       Who Is Responsible for Providing Access to the Tests?

       The San Francisco AIDS Foundation believes that it is the joint
responsibility of federal, state and city governments, the test
manufacturers and the manufacturers of anti-HIV drugs to create
mechanisms for uninsured and underinsured individuals to access HIV
viral load testing. It is unacceptable that any of these parties
should refuse to contribute financial and other resources to ensure
access for disadvantaged patients.

       A working group comprised of people with HIV/AIDS and
representatives of community-based AIDS organizations is continuing to
meet with representatives of 3 test manufacturers and 10 drug
manufacturers to find an at least temporary solution to this pressing
problem. The Foundation calls on all parties to continue to work in
good faith to quickly establish compassionate access to HIV viral load
testing to all HIV positive individuals who need it.

       The Case for Medical Marijuana:

       Vote Yes on Proposition 215

       Apart from its recognition by many civilizations throughout
history as a medicinal herb, marijuana has been used more recently in
our own culture to alleviate serious illnesses such as AIDS-related
wasting, glaucoma, epilepsy, multiple sclerosis, arthritis and the
nausea and vomiting associated with cancer chemotherapy. Anecdotal
evidence of the plant's therapeutic value is overwhelming. Yet the
U.S. government persistently refuses to allow licensed physicians to
prescribe marijuana in small amounts for their patients.

       Adding insult to injury, the Drug Enforcement Administration
(DEA) has steadfastly refused to allow recognized medical researchers
to conduct an FDA-sanctioned clinical study of smoked marijuana's
safety and potential benefit to HIV positive patients.

       Donald Abrams, MD, of San Francisco's Community Consortium, an
Association of Bay Area Health Care Providers, has attempted for 3
years to carry out such a study. His efforts have been met with
disdain from DEA officials who have rejected the research proposal
without offering any opportunity for dialogue or compromise.

       California's Proposition 215

       To create a safe and affordable mechanism through which
seriously ill individuals can access marijuana, proponents of its
legitimate use for medical purposes have placed Proposition 215 on the
California state ballot. If passed, the measure would legalize use of
marijuana by any resident of California whose physician determines
that the patient's health would benefit from such use. The medical
uses listed on the ballot measure are cancer, anorexia, AIDS, chronic
pain, spasticity, glaucoma, arthritis, migraine or "any other illness
for which marijuana provides relief."

       Under the proposed measure, a patient or primary caregiver may
grow marijuana for personal use. Patients and their caregivers would
not be subject to criminal prosecution and no physician could be
punished or sanctioned under state law for recommending marijuana.
Although Proposition 215 will not completely solve all problems
related to Californians' access to marijuana for medical use, it
decriminalizes its prescription and use as a treatment for serious
illnesses. The San Francisco AIDS Foundation supports passage of
Proposition 215 and other efforts to change state and federal laws
that make medical use of marijuana illegal.

       San Francisco's Healing Alternatives Foundation

       For about 2 years, over 10,000 people procured medicinal
marijuana through the Cannabis Buyers Club (CBC) in San Francisco. On
August 4, 1996, the state Bureau of Narcotics Enforcement raided the
CBC headquarters, and a Superior Court judge has prohibited further
sale or storage of marijuana at the club. Despite protests and
demonstrations, the CBC operation appears shut down for good.
Operators of the club may face fines and imprisonment.

       San Francisco's Healing Alternatives Foundation (HAF), a
non-profit group that has operated for several years as a buyers' club
for certain AIDS drugs and alternative AIDS treatments, has announced
that it will offer medical marijuana for sale to San Franciscans who
qualify. Matthew Sharp, Director of HAF, said that when prospective
buyers come to HAF's office, they will be given a letter for their
doctor to copy onto official letterhead and sign. The doctor's
documentation of the patient's illness and need for medical marijuana
will be required. Once the letter is verified by HAF, patients will be
told where to go to purchase medical marijuana. For more information
about this program, call HAF at 415-626-2316.

       The HMO Patient Rights Act:

       Vote Yes on Proposition 214

       The San Francisco AIDS Foundation endorses Proposition 214 on
the November 1996 ballot in California. Also known as the HMO Patient
Rights Act, Proposition 214 protects consumers who rely on their
physicians and managed care organizations for ethical and quality
health care and services. As more people living with HIV infection
enroll in managed care programs, it is increasingly important to enact
legislation to protect the best interests of patients.

       Proposition 214 does not impose new taxes, create new agencies
or establish unnecessary regulations. The proposed measure ensures
direct and open communication between doctors and patients, prohibits
gag rules and bans financial incentives to providers for denying or
delaying appropriate patient care. In addition, Proposition 214 would
limit the rationing of care for those with chronic, expensive-to-treat
illnesses such as HIV disease. The measure also would mandate written
criteria for denial of care, quality standards, financial reports,
staffing standards and complaints and arbitration. Finally,
Proposition 214 requires health care insurers to disclose how much of
consumers' premiums is spent for patient care and how much for
salaries and overhead.

       If you would like to receive more information on Propositions
214 and 215 as well as other November 1996 election recommendations
from the San Francisco AIDS Foundation, please call the Foundation's
Public Policy Department at 415-487-3080. Ronald Baker is
Editor-in-Chief of BETA and Director of Treatment Education and
Advocacy at the San Francisco AIDS Foundation.

       *******************************************************

       Impressions from Vancouver
       Ronald Baker, PhD

       The XI International Conference on AIDS held July 7-12, 1996 in
Vancouver, British Columbia generated more hope and optimism about
progress toward controlling HIV disease than any other AIDS conference
in the history of the pandemic. In addition to presenting important
confirmatory data on treatment-related subjects, researchers for the
first time spoke openly about topics which 6 months earlier were
considered wildly speculative or even taboo.

       This commentary outlines 5 important subjects addressed by
researchers and clinicians at the Vancouver meeting: HIV viral load
testing, treatment during early HIV infection, treatment of
asymptomatic individuals, possible eradication of HIV from the body,
and HIV suppression. For a comprehensive report on these and other
treatment developments presented by AIDS researchers and clinicians in
Vancouver, see "Highlights from the XI International Conference on
AIDS" in this issue.

       HIV Viral Load Testing

       * Increased baseline HIV viral load predicts increased risk for
         disease progression and death.

       * A decrease in HIV viral load from drug treatment correlates
         with decreased disease progression.

       * Each 1 log copies/mL reduction in HIV RNA correlates with a
         66% reduction in the risk of AIDS and death.

       * A baseline HIV viral load of 30,000 copies/mL or greater
         suggests a 13-fold increased risk of progression to AIDS and
         an 18-fold increased risk of death over a 10-year period,
         compared to a baseline value of less than 500 copies/mL.

       * A baseline HIV viral load between 500-3,000 copies/mL
         suggests only a 2.5-fold increased risk of progression to
         AIDS or death over 10 years compared to a baseline HIV viral
         load less than 500 copies/mL.

       * Higher baseline HIV RNA values predict a greater annual
         decline in CD4 cells.

       * Higher HIV viral load among pregnant women at the time of
         delivery correlates with an increased likelihood of HIV
         transmission to infants.

       * HIV viral load testing is probably the quickest way to
         diagnose HIV infection among infants and seroconverters.

       Treatment During Early HIV Infection

       * The time from initial exposure to HIV until primary HIV
         infection (PHI) typically ranges from 2 to 4 weeks, although
         longer periods have been reported. During PHI, people often
         experience mild to severe flu-like symptoms that may include
         rash, fever, sore throat, muscle aches and swollen lymph
         glands. When present, these symptoms indicate the
         newly-infected individual is experiencing acute retroviral
         syndrome (ARS). Clinical illness usually lasts from 1 to 2
         weeks. Not all newly-infected individuals experience ARS.

       * Treatment during PHI can decrease HIV in the blood to
         undetectable levels. Successful regimens include AZT plus
         ddI, AZT plus 3TC and AZT plus 3TC plus indinavir;
         interestingly, the use of protease inhibitors is not always
         needed to reach undetectable HIV levels.

       * Treatment of 2 infants (twins) with AZT plus ddI plus
         nevirapine for 11 months led to undetectable HIV levels, HIV
         negative blood cultures and negative antibody tests; however,
         the twins tested positive for HIV DNA using an experimental
         PCR test.

       * Triple therapy with AZT plus 3TC plus ritonavir begun 65 days
         after PHI led to undetectable viral load after 12 weeks among
         12 men (mean viral load of 91,389 copies/mL); in this ongoing
         study, new subjects are using indinavir rather than
         ritonavir.

       * Use of 4- and 5-drug therapy (AZT plus ddI plus ddC plus
         alpha interferon with or without 3TC) by 6 patients during
         PHI led to a maximum decrease in HIV viral load of 4.5 log
         copies/mL, which was sustained over a mean of 30 weeks. When
         treatment was s topped in the longest-treated patient (over 2
         years), viral load rebounded to 10,000 copies/mL.

       * 6-drug therapy with AZT plus ddI plus ddC plus 3TC plus alpha
         interferon plus saquinavir in patients HIV positive for
         greater than 6 months also produced "extreme suppression" of
         HIV.

       * Among men treated during PHI, very large decreases in HIV
         viral load may occur without the use of protease inhibitor or
         non-nucleoside reverse transcriptase inhibitor drugs.

       * Combination treatment with AZT plus 3TC plus d4T plus
         saquinavir (7,200 mg/day) during PHI (started 26 days after
         exposure) may resolve severe PHI symptoms. In one 35-year-old
         Australian man, HIV RNA decreased from 3 million copies/mL to
         undetectable from week 10 to week 17; this 6 log HIV viral
         load decrease is the largest ever reported.

       * Treatment during early HIV infection may significantly reduce
         HIV infection of the lymph nodes.

       * Treatment for HIV during early infection likely will become
         the standard of care.

       Treatment of Asymptomatic Individuals

       * The question of when to initiate anti-HIV therapy among
         asymptomatic individuals remains the subject of debate among
         researchers and clinicians.

       * Recent guidelines from San Francisco General Hospital call
         for consideration of starting therapy among asymptomatic
         individuals if (1) HIV viral load is greater than 5,000 -
         10,000 copies/mL, regardless of CD4 cell count, or (2) if the
         CD4 cell count is less than 350 cells/mm3, regardless of
         viral load.

       * Some researchers and clinicians recommend initiation of
         therapy if the HIV viral load is at all detectable by one of
         the currently-used assays (e.g., greater than 200-500
         copies/mL).

       * Treatment of 151 treatment-naive, asymptomatic individuals
         with the triple combination of AZT plus ddI plus nevirapine
         in the Boehringer Ingelheim 1046 trial showed impressive
         results: 60% of participants had undetectable viral load and
         a mean increase of 120 CD4 cells/mm3 after 12 months on this
         regimen. Nevirapine has the advantage over protease
         inhibitors and most reverse transcriptase inhibitors of
         readily crossing the blood-brain barrier and the placenta (to
         the fetus). Nevirapine is now FDA-approved for use in
         combination regimens; monotherapy leads to the rapid
         development of high level resistance.

       Is Eradication of HIV Possible?

       * For eradication of HIV to be possible, combination treatment
         must reduce HIV replication to zero and keep it there for an
         extended period. Using a mathematical model, David Ho, MD, of
         the Aaron Diamond AIDS Research Center, theorizes that
         combination therapy would be necessary for about 1.5 to 3
         years, during which time all infected cells would die and be
         replaced by new, uninfected cells. These calculations do not
         account for the possibility that HIV might remain ╥hidden╙ in
         the body in "sanctuaries" such as the brain, lymph nodes and
         spleen.

       * The earlier combination treatment is started, the higher the
         chances for eradication of HIV. The best chance for success
         may be to treat with a combination of drugs very soon (within
         the first few hours) after exposure to HIV, before the virus
         has the opportunity to "seed" the lymph organs (lymph nodes
         and spleen) or the brain.

       * The U.S. Centers for Disease Control and Prevention (CDC) in
         June 1996 issued new recommendations for post-exposure
         prophylaxis (PEP) following occupational exposure to HIV
         using the triple combination of AZT plus 3TC plus indinavir.
         Presumably, treatment with the same or a similar regimen
         would be appropriate very soon after known sexual exposure to
         HIV.

       Complete Suppression of HIV

       * Complete suppression of HIV replication is not the same as
         eradication of the virus. Eradication means that all HIV is
         cleared from the body, and the possibility of renewed
         replication is removed.

       * Complete suppression implies that HIV still is present, but
         viral replication is halted by the successful action of drug
         therapy (or perhaps through the body's own anti-HIV
         defenses). If the suppressive effect of a drug regimen
         diminishes over time (due to drug resistance) or if therapy
         is halted, it is likely that HIV replication will resume and
         viral load will rebound to high levels.

       * A few available combination drug regimens (with and without
         protease inhibitors) appear to have produced complete
         suppression of HIV, reducing the virus to undetectable levels
         for up to 2 years; only time and further study can tell us
         how long the suppressive effects of these regimens will endure.

       * It is unlikely that currently available drug regimens can
         eradicate HIV from the bodies of individuals who have been
         HIV positive for over one year. However, complete suppression
         of HIV for an extended period may be possible among these
         individuals, especially if they are "treatment naive" (no
         previous use of anti-HIV drugs) and thus less susceptible to
         developing drug resistance.

       * Among HIV positive individuals with extensive previous use of
         anti-HIV drugs, successful long-term suppression of HIV will
         likely depend on their ability to find drug combinations to
         which their viral pool is not already resistant.

       * Even partial suppression of HIV can lead to slower disease
         progression, improved quality of life and prolonged survival
         among treatment-experienced individuals.

       * If HIV viral load can be reduced to below 10,000 copies/mL,
         there is significantly less likelihood of progression to AIDS
         and death over a 10-year period (see BETA. June 1996, pages 9
         -11).

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


       *******************************************************
       Highlights from the XI International Conference on AIDS
       Harvey S. Bartnof, MD, Leslie Hanna and Liz Highleyman

       This report from the XI International Conference on AIDS is
presented in 3 parts: I. Clinical Updates and Basic Science (Bartnof),
II. Women (Hanna) and III. Epidemiology and Prevention (Highleyman).
Bartnof╒s reports that appear outside of part I are indicated by the
initials HB.

       A more extensive conference report may be found on the BETA Web
Page at http://www.sfaf.org/beta.html.

       The XI International Conference on AIDS was held in Vancouver,
British Columbia July 5-12, 1996. It was the largest of its kind since
the first international AIDS conference in Atlanta in 1985. There were
a record 14,137 registered attendees from over 125 countries, and
5,252 abstracts were presented. The conference was divided into 4
concurrent themes: Basic Science, Clinical Science (including
treatment), Epidemiology and Public Health, and Social Science:
Research, Policy and Action.

       The conference was marked by cautious optimism regarding the
beneficial effects of new combination therapies for HIV. That optimism
was balanced against the reality that over 90% of the world's HIV
positive people will never receive those therapies because they live
in developing nations that lack adequate resources. Other main themes
included: (1) the clear value and importance of HIV viral load testing
in a variety of clinical settings; (2) nutrition and wasting; (3)
alternative therapies; and (4) women's issues, particularly research
into vaginal microbicides. A new theme at this year's conference was
treatment for early HIV infection.

       Part I: Clinical Updates and Basic Science

       **Viral Load Testing

       The clinical benefits and utility of HIV viral load testing
were demonstrated in numerous presentations. HIV viral load was a
topic in 213 abstracts. This year and this conference will undoubtedly
be remembered for the unequivocal establishment of HIV viral load
testing as part of HIV/AIDS care in developed countries.

       **Predicting HIV Progression And Survival

       The value of HIV viral load in predicting the future course of
HIV/AIDS progression and survival was expanded and demonstrated in
several different groups of patients.

       * Gay/bisexual men

       John Mellors, MD, from the University of Pittsburgh, expanded
his group's research on viral load and disease progression from the
Pittsburgh arm of the Multicenter AIDS Cohort Study (MACS) to the
entire 4 city study. The update included 1,064 HIV positive
antiretroviral-naive men. (See also BETA, June 1996, pages 9-10,
41-42.) The most commonly shown slide at the conference was the
Mellors group's graph demonstrating increased progression to AIDS and
death with increasing baseline HIV viral load.

       Those HIV positive men who entered the MACS with a baseline RNA
viral load of greater than or equal to 30,000 copies/mL had a 13-fold
increased relative risk of progression to AIDS over 10 years, and an
18-fold increased risk of death, when compared with those who had less
than 500 copies/mL at baseline. Those who entered with a baseline
viral load between 500-3,000 copies/mL had only a 2.5-fold increased
risk of AIDS progression or death over 10 years, when compared with
those with a baseline viral load under 500 copies/mL.

       Mellors provided new analyses indicating that higher baseline
HIV RNA viral loads predicted a greater annual CD4 cell decline. For
example, those with a baseline HIV viral load less than 500 copies/mL
lose a mean of 36 CD4 cells/mm3 annually. Those with a baseline viral
load greater than 30,000 copies/mL lose a mean 76 CD4 cells/mm3
annually. There were intermediate annual CD4 cell losses in those with
baseline viral loads between 500-30,000 copies/mL.

       Mellors cautioned that the exact RNA copy numbers from the MACS
study are likely to be 30-50% lower than would be expected due to the
use of heparin-containing tubes and processing delays when the blood
samples were drawn in 1984-1985.

       Five other gay/bisexual male cohort studies reported
correlations between baseline viral load, HIV disease progression and
mortality. Those studies included: San Francisco Men's Health Study,
the Swiss HIV Cohort Study, the Vancouver Lymphadenopathy AI

       DS Study, CPCRA 007 and NuCombo. The Swiss HIV Cohort Study
found that in late stage HIV disease (AIDS), CD4 cell count is a
better predictor of death, while HIV plasma viral load is a better
predictor of HIV progression.

        * Women

       The ALIVE study from Baltimore included women, and 26% of the
Swiss HIV Cohort are women.

        * Injection drug users

       The ALIVE study from Baltimore is comprised of injection drug
users(IDU).

        * Hemophiliacs

       The Multicenter Hemophilia Cohort Study data was presented by
Thomas O'Brien, MD, MPH, from the National Cancer Institute. The study
was also published in the July 10, 1996 issue of the Journal of the
American Medical Association. In addition, a report from Japan
confirmed similar observations among hemophiliacs there.

        * Infants and children

       Lynne Mofenson, MD, from the National Institutes of Health,
presented data demonstrating the predictive value of HIV viral load in
infants and children infected during pregnancy and delivery. In
children under age 1 year, HIV viral loads tend to be higher than in
adults, with averages approaching 1 million copies/mL. Also, after
initial infection, there is a much slower decline of viral load to the
"set-point" in this group, when compared with adults. The set-point
reached a plateau at age 2-3 years, whereas adults establish their
set-point within 6-12 months after infection. Since enrollment in
1988-1991, only 3% of those with a baseline RNA level under 5 log
copies/mL died, while 13% of those with levels between 5 and 6 log
died, and 33% of those with a baseline over 6 log died.

       Elaine Abrams, MD, from Harlem Hospital Center in New York
City, reported that the HIV RNA viral load in infants at age 2-3
months was an excellent predictor of clinical outcome and death. A
viral load above 1 million copies/mL (6 log) at age 2-3 months
predicted a 50% mortality by age 1 year. She stated, "Effective
interventions to lower viral load may therefore need to be initiated
during infancy."

       William Shearer, MD, from Texas Children's Hospital, reported
that higher HIV RNA plasma viral loads in infancy were correlated with
faster HIV disease progression in 102 infants from the Women and
Infants Transmission Study. Shearer found that viral load peaked at
1-2 months of age for the infants.

       Increased maternal viral load near the time of delivery also
was found to be associated with rapid HIV progression in the infant
when transmission did occur, according to a presentation by Jeremy
Weedon, PhD, from Medical and Health Research Associates in New York
City.

       Abrams EJ and others. HIV viral load early in life as a
       predictor of disease progression in HIV-infected infants. Oral
       presentation and abstract We.B.311.

       BETA 9-10, 41-42. June 1996

       Craib KJP and others. Post-seroconversion HIV-1 viral load
       predicts progression to AIDS and death among seroconverters in
a prospective study of homosexual men. Late breaker presentation and
abstract Mo.C.902,

       Galetto-Lacour and others. Prognostic value of viremia in
       patients with long-standing human immunodeficiency virus
       infection. The Journal of Infectious Disease
       173:1388-1393(Swiss). June 1996.

       Graham NMH and others. Infectious HIV viral load predicts
       clinical progression and survival among HIV infected adults.
       Oral abstract We.B.411.

       Lambert G, Weedon J and others. The effect of maternal CD4
       count, AIDS and viral load on disease progression in infacts
       with perinatally acquired HIV-1 infection. Poster presentation
       and abstract We.C.3461.

       Mayers DL and others. Viral burden measurements in CPCRA 007.
       Late breaker presentation and abstract Th.B.911.

       Mellors JW and others. Prognostic value of plasma HIV-1 RNA
       quantification in seropositive adult men. Oral presentation and
       abstract We.B.410.

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

       Mofenson LM and others. Relationship between serum HIV-1 RNA
       copy number and mortality in HIV-infected children followed in
       the NICHD IVIG clinical trial. Oral presentation and abstract
       We.B.315.

       O'Brien TR and others. HIV-1 RNA levels in early chronic
       infection: association with AIDS and long term non-progression.
       Oral presentation and abstract Mo.C.323.

       O'Brien TR and others. Human immunodeficiency virus type-1
       serum RNA levels and time to AIDS in the Multicenter Hemophilia
       Cohort Study. Journal of the American Medical Association
       276(2):105-110. July 10,1996.

       Schearer WT and others. Prospective evaluation of plasma HIV-1
       RNA copy number in 106 HIV-infected children from the Women and
       Infants Transmission Study. Late breaker presentation and
       abstract Th.B.910.

       Sheppard HW and others. Determinants of long-term
       non-progression: the relative contribution of viral burden and
       strain variation. Oral presentation and abstract Mo.A.390.

       Yerly S and others. HIV viremia influences survival in HIV
       infected patients. Oral presentation and abstract We.B.413.

       Yamamoto Y and others. A decade of HIV-infected hemophiliacs:
       low virus burden in non- and slow progressors of HIV infection
       in 1985. Poster presentation and abstract Mo.B.1259.

       **Diagnosis of HIV Infection

        * HIV RNA viral load may be the best way to diagnose HIV
          infection in infants and seroconverters

        * RNA viral load tests turn positive before antigen, antibody
          or DNA PCR tests

       Teresa Brown, MD, from the Centers for Disease Control and
Prevention(CDC), presented a report indicating that HIV RNA viral load
tests become positive before any other HIV tests in infants, including
DNA tests using polymerase chain reaction (PCR). Due to the fact that
a positive RNA viral load test represents active replication
(transcription) of the virus, it may also be more specific than other
tests. Positive HIV antibody tests in infants often reflect maternal
antibodies that crossed the placent a during pregnancy. Thus, a
positive RNA viral load in an infant may represent active and true HIV
infection. However, this would not rule out the possibility of
subsequently "clearing" the virus and the "seroreversion" that has
been documented in a few HIV-infected infants.

       Michael Busch, MD, PhD, from Irwin Memorial Blood Center in San
Francisco, also reported on the order in which HIV blood tests turn
positive, using stored samples from 376 adult seroconverters. The
results were similar to Brown's report. Busch reported that RNA viral
load tests become positive 3-4 days before p24 antigen and DNA PCR
tests become positive. Five days after that, the first screening
antibody test becomes positive.

These results indicate that the first test to turn positive is the RNA
viral load test. This information has direct application for
diagnosing people during their acute (primary) HIV infection with
flu-like symptoms, diagnosing newborns, and even screening the blood
supply and organ/tissue donors. Nonetheless, the p24 antigen test is
less expensive than a viral load test.

       Brown TM and others. Early diagnosis of perinatal HIV infection
       comparing DNA-polymerase chain reaction and plasma viral RNA
       amplification. Poster presentation and abstract Tu.B.2374.

       Busch M, Schumacher RT and others. Consistent sequential
       detection of RNA, antigen and antibody in early HIV infection:
       assessment of the window period. Oral presentation and abstract
       Tu.A.153.

       **Measuring Response To Anti-HIV Therapy

        * Correlation with HIV progression

        * Measuring HIV viral load in lymph organs

       Several presentations documented that the decrease in HIV viral
load due to the use of HIV therapies statistically correlates with a
decrease in disease progression. A few showed that the same decrease
in viral load correlates with increased survival. Those studies
include ACTG 175 (disease progression or death); NUCA 3001 and 3002
(disease progression), VA 298 (disease progression), Delta 1 (disease
progression) and CPCRA 007 NuCombo (disease progression or death).
David Katzenstein, MD, of the ACTG 175 study, reported that for every
1 log copies/mL reduction in HIV RNA viral load, there is a 66%
reduction in the risk of AIDS and death over time.

       In several of the HIV combination treatment studies for early
or acute HIV infection (see below), blood plasma HIV levels are driven
to undetectable for months and even up to 1-2 years. In those
situations, it will become necessary to determine the pres-ence of HIV
RNA and DNA in the lymph organs after it has been eradicated from the
blood. This is because approximately 98% of lymphocytes reside in
lymph organs, compared with only 2% in the blood.

       In a late breaker presentation John Todd, MD, of Chiron
Corporation in Emeryville,CA, presented a method whereby lymph organs
could be tested for HIV RNA viral load levels using branched-chain
DNA(bDNA) technology. The authors tested lymph nodes, tonsils and
spleen. Only 5-10 mg of tissue is needed. Todd noted that the average
viral load in lymph organs ranges from 1 million to 1 billion HIV RNA
copies per gram of tissue in untreated HIV positive people. This
represents approximately 3 log copies/mL more than is present in the
blood plasma.

       Brun-Vezinet F and others. HIV viral load changes in Delta
       patients. Oral presentation and abstract Mo.B.292.

       Harris M, Todd J and others. Quantification of HIV-1 RNA in
       lymphoid tissues: the next step. Late breaker presentation and
       abstract Th.B.915.

       Katzenstein DA and others. Suppression of plasma HIV RNA by
       reverse transcriptase inhibitors prevents AIDS and death in
       ACTG 175: combination and monotherapy with ZDV, ddI, and ddC.
       Oral presentation and abstract Mo.B.293.

       Mayers DL and others. Viral burden measurements in CPCRA 007.
       Late breaker presentation and abstract Th.B.911.

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

       Phillips AN and others. Effects of nucleoside analog RT
       inhibitors on plasma HIV RNA and CD4 count as an indicator of
       clinical effect. Oral presentation and abstract Mo.B.290.
       Facilitating Diagnosis Of AIDS Dementia Complex

       Bruce Brew, MD, from the University of South Wales, reported
       that worsened states of AIDS dementia complex statistically
       correlate with increasing levels of HIV RNA viral load in the
       cerebrospinal fluid (fluid around the brain and spinal cord),
       and are unrelated to blood plasma HIV viral burden.

       Brew, BJ and others. Cerebrospinal fluid (CSF) HIV-1 RNA levels
       correlate with AIDS dementia complex. Oral presentation and
       abstract Mo.B.314.

       **Early Treatment for HIV Infection

       Several oral and poster presentations addressed trials that
treat people with HIV shortly after infection, ranging from treatment
during the acute (primary) flu-like illness during the months after
becoming HIV positive to treatment within the first 1-2 years after
infection. Currently, none of these studies is able to demonstrate a
slower progression to AIDS or increased survival. However, all of them
were able to demonstrate marked decreases in HIV viral load (often to
undetectable levels) and, usually, increases in CD4 cell counts. Given
the new understanding of the prognostic value of viral load, the
beneficial effects on surrogate markers will likely translate into
decreased HIV disease progression, increased survival and possibly a
prolonged period of years to decades free from HIV disease.

       Research has demonstrated that the treatment benefits of
combination anti-HIV therapy (decreased HIV progression and increased
survival) correlate with treatment-induced reductions in HIV viral
load.

       Some of the authors of the early treatment trial reports spoke
of the possibility of an HIV "cure," or "complete eradication of the
virus," if long-term suppression of HIV replication is accomplished.
However, measuring the presence or absence of HIV genetic material in
immunologically protected sites, including the brain, remains
problematic. A healthy, asymptomatic HIV positive person probably
would not want to undergo a spinal tap or brain biopsy to determine
whether HIV has been eradicated from the brain.

       Lange, J. Can HIV be eradicated from an (HIV) infected
       individual? Late breaker session 436.

       **Triple Therapy with Nevirapine, AZT and ddI in Asymptomatic
         Individuals

        * 60% have undetectable HIV viral loads after 1 year
        * CD4 cell counts increase a mean 120 cells/mm3 after 1 year
        * Non-compliance with dosing schedule is associated with
          nevirapine resistance

       Impressive results of the BI 1046 (Incas) trial of drug
combinations in 151 asymptomatic HIV positive people were presented by
Julio Montaner, MD. Participants in the 1 year, randomized,
placebo-controlled, international study had baseline CD4 cell counts
between 200-600 cells/mm3. All had no prior HIV treatments.

       The participants had been HIV positive for a mean of only 1.5
years. Baseline demographics, CD4 cell counts and viral loads were
similar in the 3 treatment arms. For the triple therapy group, the
mean baseline CD4 cell count and percentage were 367 cells/mm3 and
21%, respectively. The mean baseline HIV RNA viral load was 4.2 log
copies/mL.

       The 3 treatment arms were: (1) triple therapy with nevirapine
(NVP) 200 mg twice daily plus AZT 600 mg daily and ddI 250 or 400 mg
daily; (2) AZT plus ddI; and (3) NVP plus AZT.

       After 1 year of treatment, the mean reduction in HIV viral load
RNA was 1.5 log copies/mL for the triple therapy arm, 1 log for the
AZT/ddI arm and a return towards baseline in the NVP/AZT arm. The
results were statistically significant. In addition, HIV viral load
was below the limit of detection (200 copies/mL using the Roche
Amplicor test) in 60% of the triple therapy arm, in 30% of the AZT/ddI
arm and in none of the NVP/AZT arm. Moreover, using an ultrasensitive
viral load test, two-thirds of the triple therapy arm had an HIV viral
load below 20 copies/mL. None in the other 2 arms had HIV RNA levels
below 20 copies/mL.

       The 1 year CD4 cell count changes were greatest in the triple
therapy arm, with a mean increase of 120 CD4 cells/mm3, and counts are
still increasing. The AZT/ddI arm sustained a 20 cell/mm3 increase,
while the NVP/AZT arm had a CD4 cell count that returned towards
baseline.

       Interim results of the study also documented that maximum viral
load suppression was not achieved in triple therapy enrollees who were
not compliant in taking their medication. Moreover, no compliant
triple therapy enrollees had NVP-resistant isolates.

       Noncompliant triple therapy enrollees had documented
NVP-resistant isolates after 6 months.

       The most significant side effect of NVP was rash, which
occurred in 30% in each of the 2 NVP arms (13% in the AZT/ddI arm). In
both of the NVP arms, 8% discontinued therapy due to severe rash.

       A similar trial using the same triple therapy in HIV positive
people with 6 months or more of prior nucleoside analog therapy was
published in the June, 1996 issue of Annals of Internal Medicine. The
398 enrollees from ACTG 241 had more advanced baseline disease, with a
mean entry CD4 cell count of 139 cells/mm3. After 48 weeks of triple
therapy, the mean HIV viral load was 0.25 log copies/mL lower and the
mean CD4 cell count was 18% higher than in the double therapy arm of
ddI plus AZT.

       The Incas Trial and other studies presented in Vancouver
suggest that the non-nucleoside reverse transcriptase inhibitors
(NNRTIs), which include NVP, represent the "rising of the Phoenix,"
due to their significant beneficial anti-HIV effects, which are only
evident when the drugs are used in combination therapies. NVP used as
monotherapy leads to the rapid development of resistance to HIV.

       NVP has distinct advantages over the currently available
protease inhibitors (PIs) and the reverse transcriptase inhibitors
(RTIs). Unlike the PIs and RTIs, NVP does not require any metabolism
by human cells to become active. NVP is already in its active form
after absorption. In addition, NVP readily crosses the blood-brain
barrier into the brain (achieving even higher penetration levels than
AZT), crosses the placenta to the developing fetus and is secreted in
breast milk.

NVP was granted FDA approval on June 1, 1996 and became available in
August. Other larger trials of NVP and other NNRTIs are ongoing. Other
NNRTIs include loviride, delavirdine and atevirdine.

       D'Aquila RT and others. Nevirapine, zidovudine, and didanosine
       compared with zidovudine and didanosine in patients with HIV-1
       infection. Annals of Internal Medicine 124:1019-1030. June 15,
       1996.

       Montaner JG. NNRTIs (non-nucleoside reverse transcriptase
       inhibitors) in naive patients. Non-nucleoside reverse
       transcriptase inhibitors, the new class of antiretrovirals.
       Satellite symposium. Vancouver, B.C. July 9, 1996.

       Myers MW, Montaner JG and others. A randomized, double-blinded
       comparative trial of the effects of zidovudine, didanosine and
       nevirapine combinations in antiviral-naive, AIDS-free,
       HIV-infected patients with CD4 counts between 200-600
       cells/mm3. Oral presentation and abstract Mo.B.294.

       **Triple Therapy for New HIV Infection in 12 Gay Men

        * Ritonavir, AZT and 3TC started 65 days after acute HIV
          infection
        * After 4 months, HIV viral loads were undetectable
        * After 4 months, HIV cultures of mononuclear cells were
          negative
        * HIV cultures of blood mononuclear cells and plasma continue
          to show no growth for up to 9 months

       Martin Markowitz, MD, from the Aaron Diamond AIDS Research
Center in New York City, presented interim data on the treatment of 12
recently HIV-infected gay men with the triple therapy of ritonavir
plus AZT plus 3TC (Epivir). All 12 men had had prior symptoms of acute
(primary) HIV infection. A precise time of HIV infection that preceded
the onset of flu-like symptoms by 15 days (range 6-20) was identified
by 9 of the 12 men. Triple therapy was started a mean of 65 days after
the onset of flu-like illness. All 12 had detectable HIV RNA at
baseline, with a mean viral load of 4.9 log (91,389; range
1,420-953,200) copies/mL. The mean baseline CD4 count was 633
cells/mm3 (range 312-916 cells/mm3). The drug doses were: ritonavir,
600 mg twice daily, AZT, 200 mg 3 times daily, and 3TC, 150 mg twice
daily.

       Of the 10 patients who completed 3 months of triple therapy, 8
had undetectable HIV viral load (as measured by the Chiron second
generation assay, which can detect as few as 500 copies/mL). Of the 3
patients who completed 7 months of therapy, all had undetectable viral
load. All 9 patients who completed 4 months of uninterrupted triple
therapy had undetectable viral load. Moreover, all 9 patients had
undetectable HIV in cultures of blood mononuclear cells and plasma.
HIV cultures continue to remain negative for the farthest collection
points of the study (7 patients completing 5 months of therapy, 6
completing 6 months of therapy, 3 completing 7 months, 2 completing 8
months, and 1 who completed 9 months of triple therapy). Of the 4
patients who completed 6 months of triple therapy, the mean CD4 cell
count was over 850 cells/mm3.

       Three patients withdrew from the study, 1 due to intolerance of
all 3 drugs and 2 due to non-compliance. Another patient developed an
allergy to ritonavir and was switched to indinavir after 7 months.
Lymph node biopsies will be performed after 12 months of triple
therapy.

       The study is ongoing and the researchers anticipate enrolling
more patients close to the time of seroconversion to HIV, which is
often accompanied by symptoms of acute HIV infection. Further study of
the participants may determine whether HIV can be "eradicated" from
their bodies, according to Markowitz.

       Markowitz emphasized the rationale for very early treatment of
HIV infection. He stated that therapy is more likely to be successful
if started while the HIV viral population is relatively homogeneous
and if the treatment consists of multiple drugs that do not share
cross-resistance or overlapping toxicities. He added that early
complete suppression of virus will likely prevent drug-resistant virus
from emerging.

       Markowitz M and others. Triple therapy with AZT, 3TC, and
       ritonavir in 12 subjects newly infected with HIV-1. Late
       breaker oral presentation and abstract Th.B.933.

       Markowitz M. Treatment intervention in newly infected patients.
       Emergence of a new approach in HIV disease management.
       Satellite symposium. Vancouver, B.C.. July 10, 1996.

       The Aaron Diamond AIDS Research Center. Norvir, AZT, 3TC
       regimen renders patients aviremic. News release. July 11, 1996.

       **Four- and Five-Drug HIV Therapy for Newly HIV-Infected Men

        * Mean HIV viral load reduction of 4.5 log copies/mL observed
        * No protease inhibitors used

       Brad Saget, PhD, Steve Scheibel, MD, and colleagues from San
Francisco authored an oral presentation about treating 6 gay men from
San Francisco who had been HIV positive for less than 6 months. The
treatment consisted of AZT plus ddI (Videx), ddC (Hivid), and
interferon-alpha, with the subsequent addition of 3TC. The doses of
AZT, ddI and ddC were reduced to 50-66% of the usual doses. The
interferon-alpha dose was low, 2 million units self-administered 3
times weekly. Five of the 6 patients never had prior anti-HIV therapy.
Baseline HIV viral load ranged from 17,000 to 227,000 copies/mL.
Baseline CD4 cell counts ranged from 193 to 1,005 cells/mm3. Baseline
HIV viral cultures were all positive.

       There was an initial "precipitous drop" in HIV plasma RNA
within the first 2 weeks of therapy, followed by a slower decline,
resulting in an undetectable HIV viral load in all 6 patients (using
the Roche "ultradirect" assay which can measure as few as 10
copies/mL). The maximum decline in HIV viral load was a mean 4.5 log
copies/mL, which was sustained over a mean of 30 weeks. The CD4 cell
count increased a mean of 121 cells/mm3 over a mean of 29 weeks. After
therapy, cultures of blood mononuclear cells for HIV were negative in
5 of 6 patients.

       The 1 patient who had had prior anti-HIV therapy sustained a
total decline of 5.37 log copies/mL in HIV RNA. Another patient had
been treated for over 2 years. A lymph node biopsy after 1.5 years of
therapy was negative for HIV RNA and revealed normal lymph node
architecture. Therapy was temporarily stopped, and HIV viral load
increased again. When combination therapy was reintroduced, viral load
returned to undetectable levels again. Ongoing observation of the
patients is continuing. It should be noted that these impressive
levels of HIV viral load reduction were accomplished without protease
inhibitors or non-nucleoside reverse transcriptase inhibitors. The
large log decreases in RNA levels achieved in this small study support
the canon of several AIDS researchers, "treat early and treat hard."
It also supports the concept that early in HIV infection, whole body
HIV viral load (including all lymph organs) has not yet reached its
peak. It may take many months or longer for the full comple-ment of
HIV viral replication to reach a maximum in terms of HIV DNA and RNA.
In addition, there have been fewer cycles of HIV replication to
establish mutant or resistant viral strains.

       Saget B and others. Dramatic suppression of HIV-1 plasma RNA
       using a combination of zidovudine, didanosine, zalcitabine,
       lamivudine, and interferon- alpha in subjects with recent HIV-1
       infection. Oral presentation and abstract We.B.533.

       Scheibel S and others. Extreme suppression of HIV-1 plasma RNA
       using a combination of zidovudine, didanosine, zalcitabine,
       lamivudine, saquinavir, and interferon-alpha in subjects with
       HIV-1 infection. Poster presentation and abstract We.B.3128.

       **Combination Treatment During Acute HIV Infection

        * Viral loads driven to undetectable in the majority of
          subjects
        * Protease inhibitors not always needed
        * Symptoms of acute infection resolve with treatment
        * One patient sustained a 6 log decrease in HIV viral load

       Several presentations addressed the experimental treatment of
primary HIV infection (PHI). Luc Perrin, MD, from University Hospital
in Geneva, Switzerland, reported on using 2-5 different anti-HIV
therapies for the very early manifestations of HIV infection. Most
patients were treated with low dose AZT (250 mg every 12 hours) plus
ddI (200 mg twice daily). Some were treated with the triple
combination of AZT plus ddI plus 3TC, while others were treated with
AZT plus 3TC plus indinavir. A total of 18 treated PHI patients were
compared with untreated PHI patients and with AZT monotherapy-treated
historical controls.

       For the AZT/ddI combination therapy group, the mean baseline
HIV RNA viral load was 5.1 log copies/mL, which decreased to a mean of
1.7 log copies/mL after 6 months and 1.3 log copies/mL after 1 year.
Approximately 75% of the enrollees had undetectable HIV viral loads
after 2-3 months that persisted for 1 year (using the Roche Amplicor
research test, which can measure as few as 20 copies/mL. Undetectable
viral loads were found in only 3% of the untreated or AZT monotherapy
control groups. The CD4/CD8 ratio tended towards normal in the
combination therapy arm.

       Perrin noted that the glycoprotein (gp) 41 band on one
patient's Western blot confirmatory antibody test began to diminish
after combination therapy. He commented on another patient who
discontinued therapy after 6 months, and whose viral load increased to
baseline 2 weeks later. Twelve patients have continued combination
therapy for 10 months.

       Perrin stated that aggressive treatment during PHI is extremely
important to limit HIV spread into the lymph nodes before it
establishes itself. Perrin further believes that an aggressive therapy
approach with 3 (or more) anti-HIV drugs for an unspecified time
period starting with PHI might be able to be followed by a
"maintenance" treatment period, in which fewer drugs could be used.

       A second report about treating primary HIV infection was
described by Brian Conway, MD, from the British Columbia Center for
Excellence in HIV/AIDS. A vigorous campaign targeting emergency rooms
and clinics for gay/bisexual men and injection drug users found 18
persons experiencing PHI. The researchers screened referrals with the
HIV p24 antigen and enzyme-linked immunosorbent assay (ELISA) antibody
tests. The 18 had positive antigen tests, usually with a negative
antibody test.

       Seven of 8 gay/bisexual men and 1 of 10 injection drug users
consented to enroll in the pilot, open-label trial of combination
therapy for PHI. Four were treated with AZT plus ddI, while 3 others
were treated with AZT plus 3TC. The eighth subject remained on AZT
monotherapy due to intolerance of other antiretroviral therapies. The
mean CD4 cell count at baseline was 510 cells/mm3. The median baseline
HIV RNA viral load was 139,305 copies/mL.

       All participants demonstrated a marked reduction in viral load,
with a mean decline of 3.7 log copies/mL for combination therapy
patients. Half achieved an undetectable viral load after 8 weeks of
treatment (using the Roche Amplicor test, which can measure as few as
500 copies/mL). At baseline, most patients had fatigue and loss of
appetite. One had oral thrush (candidiasis), while another had
cytomegalovirus (CMV) infection of the rectum. All patients
experienced resolution of all PHI symptoms within 1-2 weeks after
starting therapy. Conway and colleagues are continuing their study.

       A late breaker poster described the resolution of severe PHI
symptoms in a man after only 5 days of combination therapy. The lead
author was Cassy Workman, MD, from Australia. The subject was a
35-year-old man who presented to Workman with a 4 day history of
severe PHI symptoms. Combination therapy was started 26 days after his
behavioral exposure to HIV. Therapy included AZT 500 mg daily, 3TC 600
mg daily, and saquinavir 7,200 mg daily. d4T (Zerit) 80 mg daily was
added 53 days after the triple combination was started.

       HIV RNA viral load decreased from over 3 million copies/mL at
baseline to 2,000 copies/mL at week 4, to 400 copies/mL at week 7 and
to undetectable from weeks 10-17. This represents a 6 log decrease in
HIV viral load, the largest ever reported. The baseline CD4 count of
574 cells/mm3 increased by 220 cells/mm3 after therapy. Similar to the
report by Perrin (above), Workman also reported that the antibody
bands on the Western blot antibody test were very atypical, with many
having decreased intensity or never developing. The patient in this
report tolerated the therapy extremely well, according to Workman.

This series of reports describing treatments for PHI and early HIV
infection represent major ground-breaking efforts in HIV/AIDS clinical
care. Even though the numbers of patients in the studies are small,
the emerging pattern is clear. Since treatment-induced reductions of
viral load in other studies have translated into slower HIV
progression and increased survival, it is likely that early treatments
for HIV will accomplish the same thing. Therefore, it is extremely
likely that early treatments for HIV will one day become the standard
of care. This is particularly the case for primary HIV illness, when
the virus has not yet seeded the entire lymph system. Otherwise,
during early HIV infection (after PHI), an elevated viral load
represents a clear indication for early intervention with combination
therapy. (See BETA, June 1996, pages 10, 39-41 for new SFGH/SFDPH
Guidelines).

New public information campaigns in all urban areas should be
undertaken to find people in the midst of seroconversion illness and
give them combination HIV therapy. (These seroconverters should be
followed in observational studies so that the best drug combinations
can be determined and long term outcomes can be documented. The
pharmaceutical industry should provide financing for the drugs used
until FDA approves the drugs for PHI.) A few years or more of
combination therapy after PHI will decrease the transmission of HIV,
slow the epidemic, decrease HIV progression, save lives and save money
in the long run by avoiding the high cost of AIDS care and drugs for
opportunistic infections, cancers and wasting.

       Azar R, Conway B and others. Combination antiretroviral therapy
       for the treatment of acute HIV infection. Oral presentation and
       abstract We.B.531.

       BETA 10, 39-41. June 1996.

       Holodniy M and others. A pilot study to evaluate the efficacy
       of zidovudine versus placebo in primary HIV infection (Datri
       002): a preliminary analysis. Late breaker poster and abstract
       LB.B.6022.

       Perrin L and others. Reduced viremia and increased CD4/CD8
       ratio in patients with primary HIV infection treated with
       AZT-ddI. Oral presentation and abstract We.B.532.

       Workman, C and others. Rapid viral load decrease in primary
       infection associated with aggressive therapy. Late breaker
       poster and abstract LB.B.6021.

       **Triple Therapy with Nevirapine, AZT and ddI in Infants

        * 2 infants become negative for HIV in viral load assays,
          cultures and ELISA antibody tests

       A most interesting report on the beneficial effects of triple
therapy with nevirapine plus AZT plus ddI was presented by John
Sullivan, MD, from the University of Massachusetts. A subset analysis
of HIV positive infants from ACTG 180 was presented. Eight
HIV-infected infants aged 2-16 months were treated with the triple
therapy. Two of those infants were twins who started the triple
therapy at age 2 months. Their baseline HIV RNA viral loads were
295,000 and 331,036 copies/mL, respectively.

       After 22 weeks of triple therapy, both of their viral loads
were undetectable (less than 200 copies/mL). Testing of the twins
after 11 months of triple therapy revealed that both infants had
negative HIV cultures from their blood plasma and blood mononuclear
cells. Their ELISA HIV antibody blood tests became negative and their
confirmatory Western blot antibody tests became indeterminate (loss of
several antibody bands). In addition, the twins╒ blood immunoglobulin
type G (IgG) levels normalized (most infants with HIV have abnormally
high IgG levels). Lastly, the twins had normal antibody responses to
standard infant vaccinations. However, a sensitive research PCR test
for HIV genetic material remained positive. The infants were healthy
and thriving, without any signs or symptoms of HIV disease.

       Sullivan believes that the impressive results indicate that
here was not enough HIV genetic material present in the twins to
stimulate an antigenic response by their immune systems to make enough
HIV antibodies, leading to the lack of measured HIV antibodies on the
ELISA tests. In addition, the results represent evidence of a
sustained reduction of HIV viral replication. Sullivan indicated that
only time will tell whether the twins will be "cured" of their HIV
infection.

       Sullivan J. NNRTI (non-nucleoside reverse transcriptase
       inhibitor) pediatric experience. Non-nucleoside reverse
       transcriptase inhibitors, the new class of antiretrovirals.
       Satellite symposium. Vancouver, B.C. July 9, 1996.

       **Can HIV be Eradicated from HIV Positive Persons?

        * One and a half to 3 years of complete HIV inhibition
          necessary to eradicate HIV from latently infected cells,
          excluding sanctuary sites
       * HIV drugs in liposomes may help target lymph organs

       David Ho, MD, from the Aaron Diamond AIDS Research Center in
New York, summed up current dogma regarding HIV and disease:

       * No HIV - No AIDS
       * Attenuated (weakened) HIV - No progression
       * Constant HIV replication - Constant CD4 cell destruction
       * Increased HIV replication - Fast progression
       * Decreased HIV replication - Slow progression
       * No HIV replication - No progression

       Ho also commented that therapies to treat HIV during acute or
primary HIV infection may be different from those used during later
stage HIV disease. The latter group of patients may also need immune
modulation therapy in addition to combination anti-HIV therapies.
During PHI, perhaps only antiretroviral therapies are needed, as
already suggested by the above studies. This is probably the case,
because during PHI the immune system is still intact.

       In a separate presentation, Ho addressed the issue of how long
combination anti-HIV therapy would need to be given before HIV
"eradication" would be possible. Ho and his colleagues used
mathematical models to make predictions. One assumption is that
combination HIV therapy would need to drive HIV viral replication to
zero, i.e., zero viral load, and keep it there for an extended time
period.

       Ho remarked that combination therapy leads to a fast decline in
viral load (days to weeks), followed by a slower decline (weeks to
months). He believes that the first decline represents the loss of
activated lymphocytes that produce HIV particles. Those lymphocytes
have a mean half-life of 1.25 days. The second, slower decline
probably represents persistent viral production from long-lived cells,
i.e., macrophages, infected before HIV therapy was started. He
calculated that these long-lived cells have a mean half-life of 13.3
days.

       Using the estimates that a person has approximately 1 trillion
(1012) lymphocytes and 100-300 billion (1011) macrophages, Ho
estimated that 30-120 weeks is the minimum time needed to eradicate
HIV from those 2 groups of cells. Therefore, he hypothesizes that
completely inhibitory treatment using combination therapy would need
to be given for approximately 1.5 to 3 years. He adds that the
calculations do not consider a possible, even slower, third phase of
viral decay, or the "possibility of a sanctuary site," such as the
brain.

       Ho's hypothesis also assumes that all latently infected cells
eventually divide, reproduce or die. The current combination therapies
merely block HIV infection of new cells and do not "seek out" or
target all HIV-infected cells. Central nervous system cells are not
known to divide or reproduce.

       The prospect of eradicating HIV from infected persons clearly
involves targeting the virus in many different organs, particularly
the lymph organs (lymph nodes and spleen), as well as immunologically
protected sites like the brain. Harvie Pierrot, from Universite Laval
in Quebec, presented a paper entitled, "Targeting Lymphoid Organs in
HIV Disease." He stated that incorporating antiretroviral drugs in
liposomes (fat globules) improves drug accumulation in lymph nodes and
spleen, associated with a longer drug half-life. This also allows for
less frequent dosing of drugs. Liposomal drugs have already been
approved by FDA for AIDS-related Kaposi╒s sarcoma (see BETA, June
1996, pages 7 and 11).

       In a related late breaker presentation, John Todd, from Chiron
Corporation in Emeryville, CA, presented a method whereby lymph organs
could be tested for their HIV RNA viral load levels using bDNA
technology. The authors tested lymph nodes, tonsils and spleen. Only
5-10 mg of tissue is needed. They noted that the average viral load in
lymph organs ranges from 1 million to 1 billion HIV RNA copies per
gram of tissue in untreated HIV positive people. This represents
approximately 3 log copies/mL more than in the blood plasma.

       BETA, pages 7 and 11, June 1996.

       Harris M, Todd J and others. Quantification of HIV-1 RNA in
       lymphoid tissues: the next step. Late breaker presentation and
       abstract Th.B.915.

       Ho DD. Pathogenesis: resolved that viral factors, and not host
       factors, are the primary determinants of pathogenesis,
       affirmative. Plenary session 400.

       Perelson AS, Ho DD and others. How long should treatment be
       given if we had an antiretroviral regimen that completely
       blocks HIV replication? Late breaker presentation and abstract
       Th.B.930.

       Pierrot H and others. Targeting lymphoid organs in HIV disease.
       Oral presentation and abstract Th.A.155.

       Protease Inhibitors with or without Reverse Transcriptase
       Inhibitors

       **Saquinavir plus Ritonavir Combination Shows Synergy

       In patients with past therapy with reverse transcriptase
       inhibitors:

       * 6 week viral load reduction of 2.4 log copies/mL
       * 6 week viral load undetectable in 86%
       * 6 week CD4 cell count increase of 98 cells/mm3 and increasing

       D. William Cameron, MD, from the University of Ottawa,
presented interim results of an open-label, multicenter, dose-ranging
study in the U.S. and Canada using the protease inhibitors saquinavir
and ritonavir. A total of 120 HIV positive patients with CD4 cell
counts ranging between 100-500 cells/mm3 received 1 of 4 regimens
combining saquinavir plus ritonavir. Data were presented for 43
patients who received 6 weeks of therapy with either saquinavir 400 mg
twice daily plus ritonavir 400 mg twice daily, or saquinavir 400 mg
twice daily plus ritonavir 600 mg twice daily. The mean baseline HIV
RNA viral load was 4.6 log copies/mL, while the mean baseline CD4 cell
count was 268 cells/mm3. All enrollees were required to discontinue
their reverse transcriptase inhibitor therapy before starting the
study. None of the patients had prior therapy with PIs.

       After 6 weeks of therapy, the median reduction of HIV viral
load was 2.4 log copies/mL of RNA, with a median increase of 98 CD4
cells/mm3. Moreover, 86% of participants had an HIV viral load below
detection (200 copies/mL). These changes are greater than would be
expected from either drug alone (synergy). Only 3% of patients
discontinued treatment due to adverse effects, mostly
gastrointestinal. The study will continue for a total of 1 year.

       The 2 other doses in the study are saquinavir 600 mg twice
daily plus ritonavir 600 mg twice daily, and saquinavir 400 mg 3 times
daily plus ritonavir 400 mg 3 times daily. Results from these latter 2
dosing groups were not presented. Saquinavir and ritonavir are the 2
protease inhibitors that have independently demonstrated decreased HIV
disease progression and increased survival. Their resistance patterns
are somewhat different. Combining the 2 appears to allow for twice
daily dosing with saquinavir. Observation is continuing.

       Cameron DW and others. Combination use of ritonavir and
       saquinavir in HIV-infected patients: preliminary safety and
       activity data. Oral presentation and abstract Th.B.934.

       Cameron DW. Synergistic action between ritonavir and
       saquinavir: implications for treatment. Emergence of a new
       approach in HIV disease management. Satellite symposium.
       Vancouver, B.C. July 10, 1996.

       **Triple Therapy: Indinavir, AZT and 3TC

       After 11 months (48 weeks) in AZT-experienced subjects:

        * HIV viral load reduced by 2.3 log copies/mL (7 patients)
        * 86% have undetectable viral loads in blood (7 patients)
        * CD4 cell counts increase by a median of 218 cells/mm3 (at 44
          wks)
        * HIV resistance occurs least often with triple therapy

       Condra JH and others. Bi-directional inhibition of HIV-1 drug
       resistance selection by combination therapy with indinavir and
       reverse transcriptase inhibitors. Oral presentation and
       abstract Th.B.932.

       Emini EA and others. Maintenance of long-term virus suppression
       in patients treated with the protease inhibitor Crixivan
       (indinavir). Oral presentation and abstract Mo.B.170.

       Gulick R and others. Potent and sustained antiretroviral
       activity of indinavir, zidovudine and lamivudine. Oral
       presentation and abstract Th.B.931.

       Merck and Company, Inc. Late breaker abstracts for protease
       inhibitor Crixivan. News information. July 1996.

       **Indinavir Monotherapy: Continued Benefits at 48 Weeks

        * 54% have undetectable HIV RNA viral loads (63 patients)
        * Viral load reductions greater than 2.3 log copies/mL
        * CD4 counts increase over 80 cells/mm3
        * Daily doses greater than 2.4 grams provide no added benefits

       Steigbigel R and others. Extended follow-up of patients in a
       study of indinavir at 800 mg every 8 hours (2.4 grams per day),
       1000 mg every 8 hours (3 grams per day) and 800 mg every 6
       hours (3.2 grams per day). Oral presentation and abstract
       Mo.B.412.

       **Triple Therapy: Ritonavir, AZT and ddC

       After 14 months in 17 subjects without prior HIV treatment:

        * HIV viral load reduced by 1.9 log copies/mL
        * 59% have undetectable HIV viral loads in blood
        * 60% have negative HIV blood cultures
        * CD4 cell counts increase by a mean of 180 cells/mm3

       Katlama C. Triple therapy with ritonavir, ddC, and AZT: study
       update. Emergence of a new approach in HIV disease management.
       Satellite symposium. Vancouver, B.C. July 10, 1996.

       Mathez D and others. A triple combination of ritonavir plus AZT
       plus ddC as a first line treatment of patients with AIDS:
       update. Oral presentation and abstract Mo.B.175.

       Abbott Laboratories. Triple therapy benefits with Norvir
       sustained at 60 weeks. News release. July 8, 1996.

       **Ritonavir Plus Other Anti-HIV Treatments Increases Survival

        * After 1 year, 33% reduction in deaths
        * After 1 year, 55% decreased HIV disease progression or death
        * Increased quality of life

       BETA, page 44, June 1996 and pages 7-8, March 1996.

       Cameron W and others. Prolongation of life and prevention of
       AIDS complications in advanced HIV immunodeficiency with
       ritonavir: update. Oral presentation and abstract Mo.B.411.

       Danner S. Ritonavir Phase III studies: overview. Emergence of a
       new approach in HIV disease management. Satellite symposium.
       Vancouver, B.C. July 10, 1996.

       Heath-Chiozzi M and others. Ritonavir clinical benefit
       correlates with HIV RNA and CD4 cell levels in advanced HIV
       illness. Poster presentation and abstract We.B.3127.

       Nabulsi A and others. The use of Euroqol preference scale in
       AIDS; results from two clinical trials. Late breaker poster and
       abstract LB. B.6046.

       Nabulsi A and others. Quality of life consequences of adding
       Ritonavir to current

       *****************************************************

       Anabolic Steroids in the Treatment of HIV-related Wasting
       Mark Bowers

       Researchers and clinicians have increasingly recognized and
described endocrine abnormalities in people with HIV infection. Men
with HIV, particularly men with AIDS, are likely to be hypogonadal.
Serum levels of testosterone are found to be below average in up to
50% of these men. Several strategies have been considered and
implemented to restore testosterone levels to the normal range,
including the use of testosterone and other anabolic agents.

       Clinicians who specialize in HIV disease have begun to
appreciate the early manifestations of HIV-related wasting and the
correlation between wasting and the loss of lean body mass (muscle).
Many clinicians intervene early in the course of HIV infection to
ensure that lean body mass is preserved for the longest possible time.
Some of the more commonly prescribed interventions to restore or
increase lean body mass include testosterone and other anabolic
agents. Researchers at the XI International Conference on AIDS in
Vancouver (July 7-12, 1996) suggested that combinations of
testosterone and one or more other anabolic agents may provide the
most effective intervention for HIV-related wasting.

       This feature will briefly describe the history and biology of
anabolic steroids for HIV-related wasting and hypogonadism in the
United States, the use of established and novel anabolic agents in the
treatment of hypogonadism and wasting, side effects, legal
considerations, current clinical research and development, and the
contribution of progressive resistance exercise to increasing lean
body mass when anabolic agents are used.

       History of Anabolic Steroids

       Anabolic steroids are synthetic derivatives of testosterone.
Testosterone itself is the sex hormone produced by specialized cells
in the testes of males and in smaller quantities by the adrenal glands
of both males and females. Charles Edouard Brown is credited with the
discovery of testosterone and with helping to found modern
endocrinology with his 1889 report that he had reversed the aging
process by injecting himself with liquid derived from the testicles of
dogs and guinea pigs.

       The first real synthesis of testosterone was accomplished in
1935 by 3 different European research teams. Noting that androgens (of
which testosterone is one) could relieve pain, increase appetite and
promote a sense of well-being, researchers in the 1940s studied
testosterone therapy in the treatment of hypogonadism, impotence,
metastatic cancer and even attempted to change the sexual orientation
of male homosexuals (the intervention increased libido but did not
change orientation).

       Since the 1940s, testosterone and synthetic derivatives, now
collectively referred to as anabolic steroids, began to be used to
stimulate growth and initiate puberty in boys whose development is
slowed, to treat chronic wasting in survivors of concentration camps
and to reduce trauma associated with burns, surgery and radiation
therapy. Until the development of synthetic erythropoietin and the
perfection of bone marrow transplants, anabolic steroids were widely
used for increasing red blood cell production in the treatment of
anemia.

       Investigation of testosterone derivatives for increasing muscular
capacity in soldiers, athletes and bodybuilders began in earnest in
the 1940s and continues today, mostly supporting a $1 billion
international black market. Since 1970, drug-testing programs have
been initiated by Olympics governing committees and by sports
organizations to discourage use of anabolic steroids. In March 1991,
the Federal Anabolic Steroid Control Act went into effect. Anabolic
steroids were classified with narcotics and drugs with serious
addictive potential, despite a lack of clinical data to support such a
classification. Also in the 1990s, anabolic steroids have been used
medically to decrease bone resorption (the decrease in bone mass that
increases with age), increase reported sexual desire and function, and
improve spatial cognition and word memory. Aware that consistent use
of anabolic steroids reduces sperm production, the World Health
Organization conducted a 10 center global study of! anabolic steroids
as a male contraceptive.

       Biologic Effects

       The endocrine system of the body provides fine tuning of the
activities of bodily systems through the release of various hormones,
including amines, amino acids, polypeptides, proteins and steroids.
The slow process by which the body breaks down carbohydrates, fats and
proteins to make energy is called catabolism, while the process by
which the body uses energy to create new protein, fats and complex
carbohydrates is called anabolism. Anabolic steroids are the hormones
(and synthetic hormones) that build new lean body tissue, among other
functions.

       Androgens are hormones secreted by the gonads and adrenal
cortex that masculinize, while estrogens are hormones that bring about
female secondary sexual characteristics. Androgens increase the body's
retention of nitrogen and increase lean body mass and body weight. No
androgen is completely anabolic; all stimulate male secondary sexual
characteristics to some degree, although some do so to a lesser extent
than others. Androgens include dihydroepiandrosterone (DHEA), DHEA
sulfate, androstendione and testosterone, all of which are anabolic to
some extent. The class of anabolic steroids includes drugs that are
more or less anabolic and more or less androgenic.Estrogens are not
anabolic.

    Androgens and estrogens do not work in isolation in the body.
Hormones are secreted by many endocine glands in the body, and each
hormone potentially affects the release of many other hormones by
feedback loops or direct inhibition. Endocrinologists are trying now
to completely understand and manipulate the feedback loops that are
relevant to many different diseases and syndromes, including thyroid
disease, obesity, diabetes, hypogonadism and HIV-related wasting.

       An important hormone that can affect levels of testosterone
production in males is gonadotropin-releasing hormone (GnRH), produced
by the hypothalamus in the brain. When GnRH is released into the
blood, it targets cells that produce gonadotropins, luteinizing
hormone (LH) and follicle-stimulating hormone (FSH). LH binds to
receptors on the Leydig cells of the testes to increase the metabolism
of cholesterol (from which steroid hormones are made) and thereby
initiate production of testosterone. Follicle-stimulating hormone
finds receptors on the Sertoli cells of the testes to produce 5
necessary proteins and to initiate sperm production.

       Androgens and estrogens have an effect on gonadotropin
regulation by either increasing or decreasing the amount of GnRH, LH
or FSH that is released, and in so doing, decreasing or increasing the
amount of testosterone that is produced and released. High enough
levels of testosterone will suppress the release of LH, in turn
shutting down production of new testosterone. Moreover, the
administration of exogenous (not produced by the body) testosterone or
estrogens (such as are found in megestrol acetate or crude marijuana)
and some drugs (notably ketoconazole, ganciclovir and cancer
chemotherapeutic agents) can also affect feedback loops and decrease
testosterone production.

       Testosterone either binds to target cells or is converted to
dihydrotestosterone (DHT) or estradiol. DHT binds to androgen
receptors better than testosterone, and is more androgenic. Both
androgens maintain the tissues of the testes, penis, epididymis,
seminal vesicles and prostate. Other binding sites for androgens
include muscle cells, sebaceous (oil) glands and body hair follicles.
Additionally, elevated testosterone or DHT increases the synthesis of
blood clotting factors, decreases high-density lipoprotein
concentrations and maintains or increases bone mass.

       Clinical Considerations

       HIV disease is increasingly associated with decreases in
anabolism and increases in catabolism in the body. The number of HIV
positive men who complain of decreases in libido and impotence
increases with their stage of disease. Testosterone levels in such men
are found to be significantly lower than normal reference levels, and
in many communities including San Francisco, it is standard of care to
restore levels of testosterone to normal physiologic ranges by
administering either periodic intramuscular injections of testosterone
derivatives (see below for types and doses) or by transdermal patch
delivery of testosterone (Testoderm or Androderm).

       A more complicated syndrome often present in HIV disease is
HIV-related wasting. Wasting is usually defined as unintentional loss
of 10% or more of usual body weight. Such weight loss may be explained
by several factors, including malnutrition, malnourishment and chronic
severe diarrhea, as well as increased catabolism that selectively
seems to target lean body mass while sparing fat stores. A clinically
important consideration is that the amount of lean body mass
correlates with survival, while the amount of fat mass does not.
Studies strongly suggest that moderate to severe weight loss before an
AIDS diagnosis independently predicts survival after AIDS; those with
greater weight loss have significantly poorer survival times after
developing AIDS than those with no such weight loss.

       A logical paradigm for evaluating weight loss in the context of
HIV disease is to first assess nutritional status and supplement where
it is found to be deficient. Megestrol acetate (Megace, made by
Bristol Labs, 100 20mg tablets for $69.86) and dronabinol (Marinol,
made by Roxane Labs, 25 5mg capsules for $160.89) are both approved
appetite stimulants for treating HIV-related weight loss. A common
observation about such weight gain, however, is that seldom is lean
body mass increased by the use of these 2 approved drugs.

       Donald Kotler, MD, of Columbia University College of Physicians
and Surgeons, suggests evaluating patients who are wasting for
malnutrition related to oral, pharyngeal or esophageal problems
resulting from medications or other factors. Patients whose metabolic
rate is increased should be evaluated for possible systemic
infections, and treated if they are found. Kotler suggests that
patients who do not respond to appetite stimulants may require
nonvolitional approaches (e.g. parenteral nutrition) to offset eating
disorders or malabsorption. When intake is judged to be adequate,
Kotler suggests that anabolic agents may be useful.

       Many physicians who provide exogenous testosterone to patients
who are mildly to severely hypogonadal find that lean body mass
increases, particularly when testosterone supplementation is
accompanied by progressive resistance exercise. In cases where frank
hypogonadism is not found, some physicians will choose another
anabolic steroid to increase the ratio of lean body mass to fat and
promote survival. Although the hormone is only available through
expanded access and is not yet FDA-approved for HIV wasting, some
physicians rely on human growth hormone (HGH) to respond to wasting in
their patients who are losing weight too rapidly and fail to respond
to other interventions. Anecdotally, combinations of testosterone,
other anabolic steroids and growth hormone yield the greatest gains in
lean body mass, but this strategy has not yet been evaluated in
rigorously controlled clinical studies.

       An important hormone that regulates the production of
testosterone is human chorionic gonadotropin (HCG, made by Steris
Labs, 10ml at 10,000 units/vial for $22.71), administered as treatment
for hypogonadism in some instances. Most information about the use of
HCG is anecdotal, and involves periodic injections at the end of a
"steroid cycle," a period of several weeks during which combinations
of testosterone and anabolic steroids are taken to increase lean body
mass. HCG is thought to provide the needed hormonal impetus to restart
endogenous testosterone production after exogenous steroids have
down-regulated testicular production for several weeks. HCG has not
been evaluated in treating hypogonadism in HIV positive individuals.

       What is Available?

       Testosterone is available in oral, intramuscular, transdermal,
subcutaneous and sublingual preparations. Oral preparations of
testosterone are quickly inactivated by the liver and may have
unacceptable liver toxicities. However, some oral anabolic steroids
such as Winstrol (stanozolol, made by Sanofi Winthrop, 100 2mg tabs
for $65.87), and Oxandrin (oxandrolone, made by BTG Pharmaceuticals,
100 2.5mg tablets for $375.00) are not as quickly broken down in the
liver and may be useful in repleting lean body mass. Anadrol
(oxymetholone, made by Syntex, 100-50mg tablets for $88.06) and
Halotestin (fluoxymesterone, made by Upjohn Pharmaceuticals, 100-5mg
tablets for $109.96) are very toxic to the liver.

       Esters of testosterone in an oil base are available by
prescription for intramuscular injection: propionate or
phenyl-propionate (short range of effectiveness, injections 5 days
apart), cypionate (mid range of effectiveness, injections about 7 days
apart) and enanthate, decanoate or undecanoate (longer range of
effectiveness, injections 10-14 days apart). Many synthetic anabolic
steroids are also intended for intramuscular injection: nandrolone
decanoate (Deca-Durabolin, made by Organon, 1 ml injection at 200mg/ml
for $19.30 or made by Steris Labs, 1 ml at 200mg/ml for $6.29) or
nandrolone phenylpropionate (Durabolin, made by Organon, 2 ml
injection at 50mg/ml for $14.15 or made by Haber Pharmaceuticals, 2 ml
injection at 50mg/ml for $4.75).

       What to Measure?

       Only 1 to 2% of all testosterone in circulation is free; the
rest is bound to sex hormone-binding globulins, which cannot bind to
target cells. Clinicians measure total testosterone, including both
bound and free fractions, to determine whether an individual is
hypogonadal.

       Data reported by Adrian Dobs, MD, of Johns Hopkins University
in Baltimore, at the 10th annual meeting of the International Congress
of Endocrinology in San Francisco June 12-15, 1996, suggest that
declining levels of testosterone in HIV positive men may predict
weight loss and wasting. Twenty-six participants in the Multicenter
AIDS Cohort Study were tested to see if decreases in testosterone
levels preceded or were linked with wasting or if weight loss caused
decreases in testosterone levels. Baseline measures showed 13 men had
lost more than 10% of their original weight independent of diarrhea or
opportunistic infections, while 13 men gained weight. After 6 months,
testosterone levels decreased in the 13 who had significant weight
loss, and remained stable in those with stable weight. Dobs concluded
that decreases in testosterone levels may predict which male patients
are at risk for rapid weight loss and wasting.

       A related study reported at the same meeting suggested that the
loss of testosterone may contribute to decreased lean body mass, and
further suggested that increased resistance to growth hormone
accompanies testosterone decreases. From a field of 65 men with AIDS,
20 hypogonadal men were selected for study. Free testosterone levels
were highly correlated with lean mass, and increased growth hormone
levels were inversely correlated with weight. Acquired growth hormone
resistance is considered a classical factor in the loss of lean body
mass. Both studies suggest that monitoring an HIV positive man's
testosterone levels and supplementing when they are deficient may be
an easy, cost-effective means of preventing HIV wasting syndrome.

       A study of the nutritional and testosterone status of HIV
positive women, done by Donald Kotler, MD, and colleagues at St.
Luke's-Roosevelt hospital in New York and reported at the XI
International AIDS Conference in Vancouver, concluded that serum
testosterone levels are frequently low in pre-menopausal HIV positive
women and are associated with malnutrition defined by low body cell
mass (Tu.B.2382).

       Side Effects and Risks

       The number of side effects associated with the use of anabolic
steroids varies depending on the source and the individual steroid.
Entries in the Physician's Desk Reference may pre-date newer research
and may incorrectly portray the primary and side effects of anabolic
steroids. The most complete list of side effects appears in Anabolic
Reference Guide, which lists skin reactions (acne, virilization,
hirsutism, male pattern baldness and seborrhea), endocrine, urinary
and genital involvement (gynecomastia, enlarged prostate, sterility,
adrenal genital syndrome, excessive frequency of urination and
duration of penile erections), fluid and electrolye effects (sodium,
chloride, water, potassium, calcium and inorganic phosphate
retention), gastrointestinal effects (stomach aches, nausea), hepatic
effects (alterations in liver function tests, hepatocellular neoplasms
and peliosis hepatitis), hematologic effects (suppression of clotting
factors II, V, VII and X, bleeding in users w! ho also take
anticoagulants, and polycythemia), cardiac effects (hypertension,
cardiovascular disease, palpitations, enlarged heart), cancer,
headaches, muscle tears, immune system depression, insomnia and
anaphylactic shock as independent risks associated with the use of
steroids.

       Not all synthetic testosterone derivatives have the same safety
profile. Oral steroids are associated with reduced high-density
lipoprotein cholesterol, increased low-density lipoprotein cholesterol
and increased risk of liver damage. Jaundice, a yellowing of the skin,
the whites of the eyes and other tissues because of excess circulating
bilirubin (a waste product resulting from the breakdown of red blood
cells), may be a sign of toxic side effects from the use of an
anabolic steroid or a symptom of liver disease, such as hepatitis.

       Novel delivery systems for anabolic steroids are accompanied by
additional novel side effects, including rare incidences of rash,
rectal lesions over the prostate, scrotal cellulitis and papilloma on
the scrotum associated with the use of Testoderm subscrotal
testosterone patches. Androderm, which is applied to non-scrotal skin,
is associated with the additional side effects of pruritis (itching),
blister reactions, erythema (redness), allergic dermatitis, burning or
vesicles at the patch application site.

       Most anabolic steroids are delivered by intramuscular
injection; they must not be injected into veins. Testosterone is
suspended in cottonseed oil or sesame oil so that the hormone diffuses
slowly. Oil is thicker than most fluids that are injected, so the
delivery needle should be larger, preferably 21 or 22 gauge, and
longer, 1 or 1.5 inches. The needle should be used only once, then
safely discarded or exchanged. Needle exchange programs frequently
exchange appropriately sized syringes and needles.

       Sharing needles can result in the transmission of many
infections, including HIV, hepatitis, papilloma virus, cytomegalovirus
and others. Proper injection techniques will help to avoid several
risks associated with injecting steroids. Counterfeit steroids
frequently contain impurities that cause infection or abscesses. Too
frequent injection in one area may also result in the formation of
abscesses. Failure to thoroughly clean the injection site with an
alcohol swab before injection may allow skin bacteria to be injected
along with the steroid; the resulting infection may be difficult to
treat and disfiguring. Incorrect selection of an injection site may
lead to the disruption of a major nerve, such as the sciatic nerve,
with considerable pain and temporary paralysis in the area served by
that nerve.

       Recent innovations in the delivery of testosterone are
subcutaneous pellets and transdermal patches. One patch, Testoderm
(Alza Pharmaceuticals, 30 patches 4mg/24hr $71.76) is in clinical
studies for the treatment of HIV weight loss in men. The patch is
applied to the subscrotal area (which is one reason why women are
excluded from the study) and delivers physiologic levels of
testosterone over 24 hours, then is replaced. An advantage of both
delivery systems is that there is no immediate rise in serum
testosterone levels to supraphysiologic (higher than naturally
occurring) levels, which occurs after intramuscular injections. Some
evidence has accrued that supraphysiologic levels of testosterone
trigger a feedback mechanism that down-regulates end ogenous (natural,
made within the body) production of testosterone and may perturb the
levels of other important hormones in the feedback loop. Another
patch, Androderm (Smith Kline Beecham, 60 patches of 2.5 mg at $97.50)
is also! available and can be worn elsewhere than on subscrotal skin;
5mg (2 patches) per day are recommended to produce results equivalent
to a 200 mg injection of testosterone. Testosterone cyclodextrin
(Androtest SL, Biotechnology General) is a short-acting sublingual
(under the tongue) testosterone preparation that circumvents most
problems with liver toxicity. A clinical study compared sublingual
testosterone at either 2.5 mg or 5 mg 3 times a day to intramuscular
injections of 200 mg of testosterone enanthate every 20 days over a
total of 60 days. The sublingual preparation was found to be as
effective as intramuscular injections for restoring sexual function
without significant side effects. An advantage to the sublingual pill
is that testosterone levels do not become supraphysiologic; however,
the effectiveness of sublingual testosterone in maintaining bone
density and muscle mass has not yet been proven.

       Legal Risks

       Anabolic steroids are Schedule III controlled substances. The
Anabolic Steroids Control Act of 1990 that added 28 anabolic steroids
to Section 102 of the Controlled Substances Act made it a felony in
the United States to distribute or possesss with intent to distribute
any anabolic steroid or human growth hormone for any use other than
the treatment of a disease or other recognized medical condition,
punishable by not more than 5 years in prison or, if a minor under 18
years of age is involved, not more than 10 years in prison. Legally,
"anabolic steroid" means any drug or hormonal substance (other than
estrogens, progestins and corticosteroids) that promotes muscle
growth.

       The legal system is clear that anabolic steroids promote muscle
growth, a position more clear than the official policy of the Food and
Drug Administration.

       Progressive Resistance Exercise

       Anecdotal evidence has accumulated for many years that shows
that persons who are receiving anabolic steroids increase their lean
body mass much more quickly when they perform progressive resistance
exercise than when they do not. A study by Shalender Bhasin, PhD, of
the Charles R. Drew University of Medicine and Science in Los Angeles,
compared lean body mass gain of 43 HIV negative men in 4 treatment
groups. The 30 week, double-blind study compared testosterone
enanthate to placebo, with or without progressive resistance exercise.

       The greatest gains (an average of 13.5 lbs) were seen in men
who received testosterone (600 mg per week intramuscular injections)
and exercised, followed by the group that received only testosterone
(an average gain of 7 lbs), then the placebo plus exercise group (an
average of 4 lbs). The smallest gains were registered in men who
received only placebo injections. All participants ate a controlled
diet based on body weight for 2 weeks prior to the 10- week course of
treatment, and were monitored during the 10 week treatment period to
adjust caloric intake in response to increases in body weight. Liver
enzymes, hemoglobin, hematocrit and red blood cell counts remained
unchanged in the groups receiving testosterone injections.
Standardized mood and anger inventories were completed for all
participants, and no statistically significant differences were noted
among the treatment groups.

       Poster presentations at the XI International Conference on AIDS
revealed that both doctors and their HIV positive patients are
beginning to recognize the importance of weight training or
progressive resistance exercise in building and maintaining adequate
stores of lean body mass and increasing weight, strength and endurance
before symptoms of HIV-associated wasting appear.

       In opposition to generally accepted data that indicate that
androgen use without exercise generally does not produce increases in
muscle mass and strength, a Melbourne, Australia study of 13 healthy,
non-exercising men who received 200 mg of testosterone enanthate once
a week for 6 months showed that lean body mass increased about 10%
while fat mass decreased about 16%. The Bhasin study (above) also
illustrated gains in muscle strength and lean body mass among men who
received testosterone, but did not engage in progressive resistance
exercise. It is not known whether any of these results generalize to
HIV infected individuals.

       Future Directions and Conclusions

       The underlying cause of HIV-related wasting should be
clinically identified as soon as possible. Nutritional strategies
should be exhausted first, if appropriate to treat the underlying
cause. Then, as with antiretroviral therapy and the treatment for many
opportunistic infections, the best approach to increasing lean body
mass in response to HIV-related wasting may be a strategy that
combines available anabolic agents. Testosterone replacement is
appropriate for males with hypogonadism. If a hypogonadal man or a
woman with HIV also experiences unplanned, unexplained weight loss,
the periodic administration of an additional anabolic steroid may help
to replete lean body mass more quickly, reliably and durably than
testosterone alone. Severe cases of AIDS-related wasting should prompt
the treating physician to consider more heroic rescue efforts,
including administration of human growth hormone (Serostim, made by
Serono Laboratories). Marc Hellerstein, MD, of the University of
California at San Francisco, believes that combinations of
testosterone, anabolic steroids and growth hormone may be the most
logical and physiologically appropriate means to reverse HIV wasting.

       Combination therapies for HIV wasting are being evaluated in
clinical studies. Currently, one prospective, placebo-controlled study
will evaluate the body╒s ability to create lean body mass in response
to concurrent administration of megestrol  and either testosterone
patches or intramuscular injections. Combinations of testosterone and
other anabolic steroids or growth hormone have not yet been evaluated
clinically.

       The safety of the anabolic steroid nandrolone decanoate was
prospectively evaluated in HIV positive volunteers in a 12 week,
randomized, double-blind, placebo-controlled study reported by Gary
Bucher, MD, at the AIDS Conference. Volunteers who had no prior use of
anabolic steroids were randomized to nandrolone (53 volunteers) or
placebo (17 volunteers). There was no detrimental effect on CD4 or CD8
cell counts or on HIV RNA levels, and significant increases in
hemoglobin and hematocrit in the treatment group. White blood cell
counts reflected no changes. One person in the treatment arm was
diagnosed with new Kaposi's sarcoma (KS) lesions during the 12-week
study; Bucher reacted to this occurrence by suggesting that nandrolone
decanoate should be used with caution in patients with KS until larger
studies determine the relationship of anabolic steroids to KS.

       Oxandrolone has been proven to be an effective oral therapy to
promote weight gain after extensive surgery, chronic infections and
severe trauma, and offsets protein catabolism associated with long-
term use of corticosteroids. Studies of the effects oxandrolone in HIV
positive individuals with wasting are planned for 1996, but the drug
is FDA-approved, available and can be prescribed now.

       Interesting studies that have not been done include the
combination of one or more of the above modalities with anti-catabolic
agents, such as tamoxifen citrate (Nolvadex, Zeneca Pharmaceuticals,
60 10mg tablets at $86.14). Anti-catabolic agents may reduce unwanted
side effects of the breakdown of testosterone into estrogen, such as
gynecomastia (enlargement of breast tissue), and may prolong the
useful effects of exogenous testosterone. Careful consideration of the
effects of anti-catabolics should include possible drug interactions,
side effects, adrenal insufficiency and long term effects on costisol
production in the body. Also of interest are drugs that are banned by
Olympic Committees because of their anabolic effects: beta 2 agonists
(used in the treatment of asthma) such as clenbuterol, terbutaline
sulfate, salmeterol and salbutamol.

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

       References

       Anabolic Steroids Control Act of 1990. Public Law Number
       101-647, Title XIX, 104 Stat. 4851 (November 29, 1990).

       Bhasin S and others. The effects of supraphysiological doses of
       testosterone on muscle size and strength in normal men. New
       England Journal of Medicine 335(1): 1-7. July 4, 1996.

       Berger JR and others. Effect of anabolic steroids on
       HIV-related wasting myopathy. Southern Medical Journal 86:
       865-866. 1993.

       Dobs A and others. Endocrine disorders in men infected with
       human immunodeficiency virus. The American Journal of Medicine
       84: 611-616. March 1988.

       Fox M and others. Oxandrolone: a potent anabolic steroid of
       novel chemical configuration. Journal of Clinical Endocrinology
       and Metabolism 22(9): 921-924. September 1962.

       Goldberg L. Adverse effects of anabolic steroids. Journal of
       the American Medical Association 276(3): 257. July 17, 1996.

       Grinspoon SK and others. HIV disease and the endocrine system.
       New England Journal of Medicine 327(19): 1360-1365. 1992.

       Hoberman JM and others. The history of synthetic testosterone.
       Scientific American 272(2): 76-81. February 1995.

       Karim A and others. Oxandrolone disposition and metabolism in
       man. Clinical Pharmacology and Therapeutics 14(5): 862-869.
       September 1973.

       Kotler DP. Nutritional effects and support in the patient with
       AIDS. Journal of Nutrition 122: 723-727. 1992.

       Kotler DP. Wasting syndrome: nutritional support in HIV
       infection. AIDS Research and Human Retroviruses 10(8): 931-934.
       1994.

       Laudat A. Changes in systemic gonadal and adrenal steroids in
       asymptomatic human immunodeficiency virus-infected men:
       relationship with the CD4 cell counts. European Journal of
       Endocrinology 133: 418-424. 1995.

       McClure D and others. Hypogonadal impotence treated by
       transdermal testosterone. Urology 37(3): 224-228. March 1991.

       Palinicek J and others. Weight loss prior to clinical AIDS as a
       predictor of survival. Journal of Acquired Immune Deficiency
       Syndromes and Human Retroviruses 10:366-373. 1995.

       Phillips WN. Anabolic Reference Guide. Mile High Publishing,
       Golden, CO. 1991. Poretsky L and others. Testicular dysfunction
       in human immunodeficiency virus-infected men. Metabolism 44(7):
       946-953. 1995.

       Salehian and others. Pharmacokinetics, bioefficacy and safety
       of sublingual testosterone cyclodextrin in hypogonadal men:
       comparison to testosterone enanthate - a clinical research
       study. Journal of Clinical Endocrinology and Metabolism 80(12):
       3567-3575. 1995.

       Scott MJ and others. HIV infection associated with injections
       of anabolic steroids. Journal of the American Medical
       Association 262: 207-208. 1989.

       Spangelo BL. The thymic-endocrine connection. Journal of
       Endocrinology 147: 5-10. 1995.

       Stuenkel and others. Sublingual administration of
       testosterone-hydroxypropyl-cyclodextrin inclusion complex
       simulates episodic androgen release in hypogonadal men. Journal
       of Clinical Endocrinology and Metabolism 72 (5): 1054-1059.
       1991.

       Wood Alastair. Androgens in men ╤ uses and abuses. New England
       Journal of Medicine 334(11): 707-714. March 14, 1996.

       Young HWG and others. Body composition and muscle strength in
       healthy young men receiving testosterone enanthate for
       contraception. Journal of Clinical Endocrinology and Metabolism
       77(4): 1028-1032. 1993.

       ***************************************************

       HIV Vaccines
       Mark Bowers

       Vaccination is the simplest, safest and most effective way to
prevent many diseases. Vaccines for many viral diseases are routinely
given to children and adults in all countries of the world. These
vaccines, including smallpox, polio and measles vaccines, are both
cheap and effective. Yet former Surgeon General C. Everett Koop told
the American public not to expect a vaccine for HIV before the end of
the century, and Margaret Johnston, PhD, who spearheads the new
International AIDS Vaccine Initiative (IAVI), told the XI
International Conference on AIDS in Vancouver that current research
and development efforts are unlikely to yield an effective vaccine for
6 more years. What is holding back research? Where are the candidate
vaccines that were so widely publicized in the early 1990s?

       Drug companies have backed away from HIV vaccine research for
the last several years for a number of reasons. The failure of
envelope glycoprotein (gp) 120 subunit vaccines to neutralize primary
isolates of the virus (strains of HIV taken from the blood of infected
individuals, rather than developed in the laboratory) led to a pivotal
decision in June 1994 not to pursue wide-scale vaccine trials in the
United States. In response, biotechnology and pharmaceutical companies
reduced their commitment to vaccine research and development.
Genentech, where vaccine researcher Donald Francis, MD, for years has
championed wider testing of his gp120 vaccine candidate, created a
smaller, vaccine-focused company named Genenvax, then backed away from
AIDS vaccine research in general. Merck and Repligen suspended work on
their candidate vaccine in 1994. And MicroGeneSys, maker of a
controversial baculovirus-grown subunit gp 160 vaccine candidate,
ceased further vaccine research when that ! candidate failed to
demonstrate positive effect in clinical studies.

       The focus of vaccine testing then shifted to the developing
world. In Thailand, increasing infection rates created the political
will to test candidate vaccines that certainly will not be 100%
effective. However, it is felt that even a modest rate of protection
would have a major impact on diminishing new infections. A wide-scale
study of a Genenvax vaccine candidate is slated for Thailand in 1997.
Later this year, a Chiron gp120 subunit vaccine candidate based on the
subtype of HIV prevalent in Thai land will enter Phase I testing.

       Primary concerns regarding the development of a vaccine
intended for wide use in developing countries are low cost and ease of
administration. A cheap and easily administered vaccine is considered
the only possible means of containing burgeoning infections in most
third world nations. Unfortunately, potential vaccine makers have
chosen to direct their research and development efforts elsewhere,
fearing potential financial losses.

    Also of concern is the huge variability of HIV, both in
infected individuals (more than 660 variants are known) and in
infected populations (subtypes or clades). HIV-1 has been classified
in 2 groups, M and O; 9 subtypes have been identified within group M,
and only a few in group O. Subtypes in a group differ genetically from
one another by about 30%. A successful HIV vaccine would need to
elicit immunity to all the HIV subtypes to which a vaccinee may be
exposed.

       Two major initiatives to bolster vaccine research were revealed
at the Vancouver conference. The director of the Office of AIDS
Research at the U.S. National Institutes of Health, William Paul, MD,
announced an increased allocation of funds for research on vaccines
and a "restructured, redirected vaccine research program." Moreover,
efforts by Seth Berkley at the Rockefeller Foundation in New York to
raise $600 million over 7 years to fund the IAVI have borne fruit.
IAVI, incorporated in January 1996, now has $5 million in its coffers
for its first year of operation. Under the leadership of scientific
director Johnston, formerly deputy director of the Division of AIDS,
IAVI will support vaccine research and development in areas where
there are currently gaps. IAVI also plans to work with the World Bank,
governments, private industry, funders and regulatory agencies to
increase investment in vaccine research and development. Perhaps the
most important mission of IAVI is to foster the creation of
coordinated global vaccine efforts to make vaccines that can be
effectively and cheaply used in the developing world.

       Preventive Vaccine Candidates

       The AIDS Vaccine Evaluation Group (AVEG), sponsored by the
National Institute of Allergy and Infectious Diseases (NIAID), has
conducted 25 clinical studies of candidate HIV vaccines, involving
more than 1,900 seronegative adults. A table of completed, current and
planned trials is shown below. Results of AVEG 201, the only study in
Phase II, were reported at the Vancouver conference. A total of 296
adult heterosexuals, gay or bisexual men and intravenous drug users
received either 600 mg of the recombinant gp120 MN vaccine candidate
(made by Genenvax) in alum adjuvant, MF-59 adjuvant alone or alum
alone, or 50 micrograms of the recombinant gp120 SF2 vaccine candidate
in MF-59 adjuvant (made by Chiron Biocene). Comparisons of
neutralizing antibody were made between the groups, and it was
concluded that 4 rather than 3 immunizations may be the optimal dosing
schedule to elicit antibody responses. The participants in the study
did not increase their risk behaviors because they were in a vaccine
study. Also reported were the results of Phase I/II trials of a
"prime/boost" strategy employing a recombinant canarypox vaccine
candidate designated ALVAC-HIVgp160 (Virogenetics/Pasteur Merieux) as
the prime followed by the Chiron Biocene gp120 candidate as the boost.
The strategy has proven safe and capable of inducing not only
neutralizing antibodies, but also cytotoxic lymphocyte responses in
vaccinees. This shows that the humoral and cell-mediated (B-cell and
T-cell) types of immunity can be induced by intramuscular injection of
the 2 candidate vaccines. Different doses and dosing schedules were
compared. Participants were vaccinated at baseline, 1 or 2 months
later, 6 or 9 months later, and 12 months later. Ten participants
received 106 50% tissue culture infectious doses of ALVAC-HIVgp160
alone while 9 also received 50 micrograms of Chiron's gp120; 18
received 107 50% tissue culture infectious doses of ALVAC-HIVgp160
alone while 29 also received 50 micrograms of Chiron's gp! 120; and 9
participants received only 50 micrograms of Chiron's gp120.

       Those participants who received prime/boost developed
antibodies that could neutralize both the MN and SF2 strains of HIV.
The 4-dose schedule appeared to be better than the 3-dose schedule,
and a current study will assess if even higher doses enhance the
immune responses that were found.

       AIDS Vaccine Evaluation Group Completed, Current and Planned Vaccine
       Trials

       Completed Trials

       Envelope alone:

       Product: gp160 IIIB
       Sponsor*: MicroGeneSys
       Number of volunteers: 128

       Product: gp160 IIIB and MN
       Sponsor*: Immuno-AG
       Number of volunteers: 159

       Product: gp 120 (yeast)
       Sponsor*: Biocene
       Number of volunteers: 78

       Product: gp 120 IIIB
       Sponsor*: Genentech
       Number of volunteers: 28

       Live pox virus envelope:

       Product: Vaccinia -env envelope boosts
       Sponsor*: Bristol-Myers
       Number of volunteers: 217

       Product: Vaccinia-env(gag)pol
       Sponsor*: Therion
       Number of volunteers: 14

       Current Trials

       Envelope alone:

       Product: gp 120 MN
       Sponsor*: Genentech
       Number of volunteers: 211

       Product: gp 120 SF2
       Sponsor*: Biocene
       Number of volunteers: 205

       Product: gp120 (new formulation)
       Sponsor*: Biocene
       Number of volunteers: 30

       Product: gp120 + novel adjuvants
       Sponsor*: Genentech/Biocene
       Number of volunteers: 311

       Live pox envelope:

       Product: Canarypox env  gp120
       Sponsor*: PMC/Biocene
       Number of volunteers: 131

       Product: Low-dose canarypox env/gag  gp120
       Sponsor*: PMC/Biocene
       Number of volunteers: 76

       Peptide:

       Product: V3 peptide
       Sponsor*: UBI
       Number of volunteers: 137
       Method: intramuscular, intramuscular + oral

       Particle:

       Product: p24 virus-like particle
       Sponsor*: British Biotech
       Number of volunteers: 36
       Method: intramuscular + mucosal

       Planned Trials

       Live pox  envelope:

       Product: High dose canarypox env/gag  gp120
       Sponsor*: PMC/Biocene

       Product: Canarypox env/gag mucosal
       Sponsor*: PMC

       Product: Canarypox env/gag/pol gp120
       Sponsor*: PMC/Biocene

       Product: Number of volunteers:
       Sponsor*: Therion

       Peptide:

       Product: T-B peptide
       Sponsor*: Lederle

       Particle:

       Product: Pseudovirion
       Sponsor*: PMC

       Live bacteria:

       Product: Salmonella gp160
       Sponsor*: University of Maryland

       *Sponsors:
       MicroGeneSys, Wallingford CT, USA
       Immuno-AG, Vienna, Austria
       Biocene, Emeryville, CA, USA
       Genentech, South San Francisco, CA, USA
       Bristol-Myers, Wallingford, CT, USA
       PMC (Pasteur Murieux Connaught), Swiftwater, PA, USA
       UBI (United Biomedical, Inc.) Hauppauge, NY, USA
       British Biotech, Ltd., Cambridge, UK
       Lederle/Praxis, Rochester, NY, USA
       University of Maryland, Baltimore, MD, USA.

       BETA thanks Patricia Fast, MD, PhD, for permission to reprint
       this chart.

       Laboratory and Animal Studies

       Considerable interest has been generated by the news shared at
the international AIDS conference by Robert Gallo, MD, of the
Institute of Human Virology in Baltimore. Gallo and Paolo Lusso, MD,
of the San Raffaele Scientific Institute, described 3 chemokines
(pro-inflammatory chemicals made by the immune system) that may play
an important role in the way that HIV infects cells. These chemokines,
according to Daniel Zagury, MD, at the Pierre and Marie Curie
University in Paris, are more highly concentrated in HIV positive
non-progressors. Gallo argues that a strategy that can artificially
boost the chemokines (MIP-1a, MIP-1b and RANTES) or down-regulate
their receptors (designated cysteine-cysteine chemokine receptor 5,
CKR5) might protect against infection with HIV. The theory is so far
untested, but warrants closer scrutiny and research.

       Several vaccine researchers have been pursuing "naked DNA"
approaches to vaccine development. Over the last 3 years, DNA vaccines
have increasingly been constructed and tested for HIV, as well as
hepatitis B, tuberculosis and influenza. Upon injection, DNA vaccines
apparently incorporate their genetic material into cells near the site
of injection and begin producing their gene products (proteins) more
efficiently than was predicted by tissue culture experiments. DNA
vaccines can be simply and cheaply produced in large quantities, and
are free of contaminants. Further, this type of vaccine remains very
stable by comparison with other vaccine modalities, increasing the
likelihood that they can be transported and utilized anywhere in the
world.

       Intramuscular injections of DNA expressing either gp120 or
gp160 have been found to induce significant titers both of
neutralizing antibody (a strong humoral response) and cytotoxic
T-lymphocytes (cellular immunity). According to a research team headed
by Britta Wahren, MD, of the Karolinska Institute in Stockholm,
Sweden, immune responses to DNA that expresses regulatory genes of HIV
are stronger than the responses to DNA based on HIV structural genes.
Still, both types of genes may be needed to bring forth the wide
immune response to HIV challenge that may be necessary to protect
people from infection. Naked DNA vaccines are now established as
players in the field of HIV vaccine candidates, despite the fact that
little is known about the mechanisms by which they activate immune
responses.

       A collaboration between the University of Pennsylvania and
Apollon, Inc. of Malvern, PA, funded by a $4.2 million grant from
NIAID, has yielded a DNA vaccine candidate that expresses the envelope
glycoprotein and rev protein of HIVMN. The first clinical study of
this vaccine candidate demonstrated the safety of 3 doses (30, 100 and
300 micrograms) in 15 asymptomatic HIV positive volunteers. The
volunteers received 3 intramuscular injections each at 10-week
intervals. No trends were noted in CD4 or CD 8 cell counts or viral
load. This study is the precursor to more elaborate planned studies;
it is thought that the immunogen may be useful as both a therapeutic
and prophylactic vaccine for HIV.

       The most positive news in pre-clinical research on vaccines is
data from a study of an attenuated (weakened) version of simian
immunodeficiency virus (SIV) in monkeys. The vaccine was made by
deleting the nef gene and injecting it, followed by a challenge that
consisted of high intravenous doses of a lethal strain of SIV
different from the one from which the vaccine was made. While the
monkeys were protected from infection, control animals were not.
Asakura Yusuke, PhD, and colleagues from Yokohama University in Japan,
who constructed the DNA, saw production of nef-specific cytotoxic
lymphocytes and no pathogenesis in vaccinated monkeys.

       Burt Dorman, PhD, of Acrogen in Oakland, CA, believes that a
whole inactivated (killed) HIV vaccine candidate would be likely to
generate wide-ranging immune responses and might be as successful in
reducing HIV infection rates as the killed polio vaccine was 4 decades
ago. Dorman's team has proposed to identify appropriate strains of
HIV, inactivate them, and test them in pre-clinical settings. This
research has not been done because of the many attendant concerns that
a vaccine based on whole HIV, if incompletely inactivated, could lead
to infection, and because of the associated liability concerns.
However, about one-third of all currently used viral vaccines are
based on "whole-killed" technology.

       The proposal to identify and perform rigorous scientific
testing on whole-killed HIV vaccine candidates is currently the first
proposal to be reviewed by the Scientific Advisory Committee (SAC) of
the IAVI. The SAC is enthusiastic about advancing the concept of
whole-killed HIV or another particle design to Phase I studies. The
SAC additionally felt that an approach to distinguish between the
vaccine strain of the virus and other HIV in an infected vaccinee
needs to be conceptualized before initiating development of a
whole-killed virus. This concern is shared by many potential HIV
vaccine trial volunteers, who worry that health insurance and
employment may be out of reach if a vaccinee cannot be distinguished
from a person with active HIV infectio n. Correlates of Protection An
effective preventive vaccine would have to protect people from
transmission of HIV by 2 very distinct routes: intravenous and sexual.
Sexual transmission can be further divided into transmission through
oral, rectal and vaginal mucosal surfaces. Can a single vaccine
candidate protect against challenge by both intravenous and sexual
routes of transmission? Recently published information shows that
immunization that protects monkeys from SIV injected directly into a
vein does not protect against vaginal challenge. This finding suggests
that mucosal immunity differs from systemic immunity, and supports the
creation and testing of hybrid combinations of vaccine candidates to
induce immune protection from infection by both intravenous and sexual
routes of transmission.

       These differences in transmission and in probable means of
protection help to highlight the importance of finding out what
exactly does protect people against HIV infection. Many researchers
have attempted to find correlations between various blood cells,
cytokines and other factors and protection against HIV infection by
studying people who are at risk for HIV infection, are frequently
exposed to it, and yet never seroconvert.

       Progress in answering this central question has been very slow.
Studies done at Chiang Mai University in Thailand and in Zambia reveal
that there are no apparent differences in CD4 cell counts, CD8 cell
counts or CD4/CD8 percentages between people who are at risk but do
not seroconvert and people who do. Furthermore, levels of MIP-1a,
MIP-1b and RANTES (the cytokines recently described by Gallo), beta 2
microglobulin and neopterin levels do not illuminate any fundamental
differences between the groups. The Chiang Mai University study did
detect a statistically significant difference in levels of natural
killer (NK) cells, but this was the first report of such a difference
and needs to be independently validated. In summary, according to the
National Institute of Allergy and Infectious Diseases, "whether a
natural protective state against HIV can exist remains unknown."

       Future Plans

       Much depends on public support for the development of an
effective HIV vaccine. The current lack of interest in HIV vaccine
research at pharmaceutical companies advances the field of vaccine
research too slowly. On the other hand, current efforts to attract
more research and development funding may offset the current lull.
There are now only 4 major pharmaceutical companies that make
vaccines. Private funding may help open up the field and bring more
bright investigators into the crusade. With more investigators, the
chance of a new, unusual idea changing the landscape of vaccine
research increases, but the means to develop an effective HIV vaccine
may already be in hand. Whole-killed vaccine candidates have not been
made (the technology is now 40 years old) and no vaccine candidate has
yet advanced to wide-scale (Phase III) testing.

       It is hoped that surveys of the preparedness of potential
vaccine study volunteers to participate in HIV vaccine trials, such as
the survey currently underway at the Center for AIDS Prevention
Studies at the University of California in San Francisco, will
identify stumbling blocks and highlight the concerns of AIDS-affected
communities. It is clear that not enough research is being devoted to
this critically important area of AIDS research, and that fundamental
changes in funding research and development coupled with community
involvement will help.

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

       References

       Enger C and others. Survival from early, intermediate and late
       stages of HIV infection. Journal of the American Medical
       Association 275(17): 1329-1334. May 1, 1996.

       Gorse GJ and others. A dose-ranging study of a prototype
       synthetic HIV-1MN V3 branched peptide vaccine. Journal of
       Infectious Diseases 173: 330-339. February 1996.

       Gorse GJ and others. Antibody to native human immunodeficiency
       virus type 1 envelope glycoproteins induced by IIIB and MN
       recombinant gp120 vaccines. Clinical and Diagnostic Laboratory
       Immunology 3(4): 378-386. July 1996.

       Lehner T and others. Protective mucosal immunity elicited by
       targeted iliac lymph node immunization with a subunit SIV
       envelope and core vaccine in macaques. Nature Medicine 2(7):
       767-775. July 1996.

       Levine A and others. Initial studies on active immunization of
       HIV-infected subjects using a gp120-depleted HIV-1 immunogen:
       long-term follow-up. Journal of Acquired Immune Deficiency
       Syndromes and Human Retrovirology 11(4): 351-364. 1996.

       Miller CJ and others. Progress towards a vaccine to prevent
       sexual transmission of HIV. Nature Medicine 2(7): 751-752. July
       1996.

       Pardoll DM and others. Exposing the immunology of naked DNA
       vaccines. Immunity 3: 165-169. 1995.

       Trauger R and others. Safety and immunogenicity of a
       gp120-depleted, inactivated HIV-1 immunogen: results of a
       double-blind, adjuvant controlled trial. Journal of Acquired
       Immune Deficiency Syndromes and Human Retrovirology 10(Suppl.
       2): S74-S82. 1995.

       Wrin T and others. HIV-1MN recombinant gp120 vaccine serum,
       which fails to neutralize primary isolates of HIV-1, does not
       antagonize neutralization by antibodies from infected
       individuals. AIDS 8(11): 1622-1623. August 1994.

       ****************************************************

       Women and HIV/AIDS: Critical Issues in Treating HIV During
       Pregnancy
       Ellen J. Landsberger, MD

       This article originally appeared on the Internet via Medscape,
       and is based on the author's presentation at the AIDS Journal
       Club of the Department of Medicine at the New York-Cornell
       University Medical College.

       Abstract

       When the AIDS Clinical Trial Group broke the code for Protocol
076, researchers discovered that giving AZT (Retrovir) to HIV-infected
women during pregnancy (100 mg orally 5 times daily) and labor (2
mg/kg of body weight intravenously, given over 1 hour, then 1 mg/kg hr
until delivery), plus to the newborn (2 mg/kg, orally, every 6 hours
for 6 weeks), could cut the perinatal HIV transmission rate by
two-thirds. Now, further studies are adding to the databank of
information about HIV in pregnancy. For example, one study has shown
that pregnancy does not hasten the progression of HIV; another has
indicated that, although vertical HIV transmission often occurs late
in gestation, it also can occur as early as 8 weeks. One group of
researchers discovered that AZT is highly effective in blocking viral
transmission but also that, when the mother develops resistance, she
is likely to pass the resistant viral strain to the fetus. The
importance of measuring viral load has been suggested by research
demonstrating that the number of HIV RNA copies can help predict which
women are most likely to transmit the virus to the fetus. In one
study, all women with more than 80,000 RNA copies/mL transmitted the
virus, whereas none with less than 20,000 copies/mL transmitted. Of
great interest is that the 22 women in this study who took AZT showed
an 8-fold median decrease in plasma RNA levels.

       Introduction

       In examining how best to treat an HIV-infected woman during
pregnancy, the first point of concern often is how to prevent the
vertical transmission of HIV from mother to child during pregnancy.
Today, most clinicians are guided by the results of the AIDS Clinical
Trial Group Protocol 076 (ACTG 076), which demonstrated that giving
AZT to HIV-infected women during pregnancy (100 mg orally 5 times
daily) and labor (2 mg/kg body weight intravenously, given over 1
hour, then 1 mg/kg per hour until delivery), plus to the newborn (2
mg/kg orally every 6 hours for 6 weeks), could cut the perinatal HIV
transmission rate by two-thirds (Connor and others).

       Other issues concerning perinatal HIV care are also important.
One concern is the high rate of HIV infection in pregnant teens;
another is the relationship between HIV infection and reproductive
choice. In "Pregnancy Rates Among Women Infected With HIV," Susan Chu
and others, from the Centers for Disease Control and Prevention (CDC)
and the Adult and Adolescent HIV Spectrum of Disease Project Group,
discussed data from an ongoing survey of the medical records of 3,915
women, 15 to 44 years old, who were infected with HIV and receiving
care in 90 centers in 11 cities between January 1990 and August 1994
(Chu and others). At the time they entered the project, 570 (14.5%)
women were pregnant. Women who were pregnant upon enrollment had
higher CD4 counts than women who were not pregnant; hence, pregnancy
generally occurred in healthier HIV positive women without
AIDS-related symptoms.

       More than 90% of the pregnancies were unplanned. Also, the
pregnancy rate varied significantly by age: of the teenagers who
entered, almost half (47% of the 15- to 19-year-olds) were pregnant at
the time of enrollment. Most of the teens were identified as HIV
positive because they had become pregnant. During each year of care,
however, only 5.8% of the women became pregnant, which is about 12%
lower than the pregnancy rate of all women in the U.S. from the ages
of 15 to 44. New pregnancies were evenless common among women with an
AIDS-related opportunistic infection (OI). This finding speaks to
reproductive choice and to the importance of HIV counseling and
testing as a regular part of gynecologic care. A central point is that
early identification of HIV in a gynecologic practice could
potentially decrease unwanted pregnancies.

       Does Pregnancy Hasten Decline from HIV Infection?

       Another key issue is the effect of pregnancy on HIV infection.
In a prospective cohort study conducted in France, researchers
compared 57 women who completed pregnancy during the course of their
infection with 114 HIV-infected women who had never conceived (Hocke
and others). The 2 groups were matched on CD4 cell counts, age and
year of HIV diagnosis. Each woman was followed until she reached the
first of 3 endpoints: CD4 count below 200 cells/mm3, the first
AIDS-defining event or death. The results indicated no significant
differences in the endpoints between the pregnant and nonpregnant HIV
positive women; pregnancy did not accelerate HIV progression to AIDS
or death. AZT, prescribed only for women with a CD4 count less than
200 cells/mm3, was used in 57.7% of the pregnant women versus 45.6% of
nonpregnant women. Although CD4 counts were not significantly
different, there was a significant difference in clinical symptoms at
the time of HIV diagnosis. Ninety percent (90%) o! f the pregnant
women compared with 76% of the nonpregnant women were asymptomatic at
the time of HIV diagnosis, which is similar to what was seen in the
Chu study.

       Previous studies, especially those conducted early in the AIDS
epidemic, had suggested that pregnancy had an adverse effect on the
progression of AIDS. More recent studies, such as this one from France
(Hocke), indicated that pregnancy really may not have a detrimental
effect on HIV-infected women.

       Vertical Transmission of HIV from Mother to Child

       Another study, by Soeiro and colleagues, is important in the
discussion of vertical transmission of HIV from mother to baby and its
prevention. These researchers were among the first to prove fetal
infection in utero when they identified HIV in 7 of 23 fetuses from
pregnancies interrupted before the third trimester. Investigators
primarily looked at liver, lung and brain tissue. Positive
maternal-fetal transmission was defined as the presence of at least 10
genome equivalents of viral DNA in at least 1 fetal tissue sample.
Thirty percent (30%) of the fetuses had evidence of infection,
including 1 fetus in the first trimester. This study suggests that any
approach used to decrease viral transmission must be multipronged, and
must begin early in pregnancy. Using only measures that attempt to
block HIV transmission during and after delivery will fail to prevent,
according to some estimates, as much as 50% of HIV transmission from
mother to fetus.

       The importance of early interventions to block the vertical
transmission of HIV to the fetus is further supported by a report on
excess intrauterine fetal deaths/losses associated with maternal HIV
infection (Langston and others). Although there is much evidence to
support that most transmission of HIV to the fetus occurs late in
gestation (Alimenti and others; Lewis and others), studies have
identified HIV infection in fetuses as early as 8 weeks (Ehrnst and
others). Today, it remains easiest to treat HIV at the end of
gestation, around the time of delivery. Still, timing of fetal HIV
infection is a concern that mandates finding ways to block
transmission early on, before the virus becomes established in fetal
tissue. The group from Baylor College in Texas and Texas Children's
Hospital in Houston (Langston and others) studied seropositive
pregnant women who had 109 live births and 16 fetal losses. Of the
fetal losses, 2 were therapeutically induced in ill women but 14 were!
spontaneous, representing an 11% spontaneous intrauterine fetal loss
rate. Of the 14 spontaneous fetal losses, 7 were positive for HIV by
in situ hybridization. In 3 of the early losses, fetal tissue was not
examined, but the chorionic villi, endometrium and desidual tissue
showed heavy viral burden at the implantation site in 2 out of the 3
placental tissues. Fetal-placental tissue pairs were available in 10
pregnancies; 8 fetal-placental tissue pairs were concordant for HIV
status by in situ hybridization. In 6 of the 10 lost pregnancies,
fetal tissue was HIV positive, but only 4 of the associated placentas
showed chorionic villi positivity.

       Impact of Drug Resistance

       In the well known double-blind AZT trials, the risk of vertical
transmission was reduced from 26% among asymptomatic HIV-infected
pregnant women on placebo to 8% among those receiving AZT (Connor and
others). But what about viral resistance, which has been a
long-standing critical concern in AZT therapy? In immunocompromised
individuals, resistance to AZT typically develops after about 6 to 12
months of therapy; then, primary infection can occur with the
resistant virus. What negative impact might there be from treating
women with AZT during pregnancy, only to have them develop resistance
to the drug? Would the women's resistance to AZT facilitate the
transmission of AZT-resistant virus to the fetus?

       To address such questions, a group from the Department of
Pediatrics at the University of Rochester in New York reported a study
of drug resistance and vertical transmission of drug-resistant HIV
strains when AZT was given during pregnancy (Frenkel and others). The
Rochester group retrospectively reviewed 62 infants who were followed
from birth to over 6 months of age. Only 1 of the 20 infants born to
AZT-treated mothers became HIV-infected, and this infant's isolate was
resistant to AZT, like its mother's. That is, both mother and baby had
resistant infection.

       By contrast, 11 of the 42 women (26%) who did not take AZT
transmitted HIV to their fetuses. Among the 20 women taking AZT -- all
of whom had been taking the drug for more than a year -- 4 women had
resistant isolates. Although this is of concern, not everyone
transmitted to the baby, even if they developed the resistant virus.
In the AZT group, only 1 woman with a highly resistant strain
vertically transmitted the virus, and her infant's viral strain was
also highly resistant to AZT. It remains to be seen what will happen
as more and more women take AZT during pregnancy. This study suggests
that, although maternal treatment with oral AZT reduces the rate of
vertical transmission of HIV-1, transmission that does occur may
involve transmission of virus that is resistant to AZT.

       Interestingly, AZT and other antiviral drugs do not seem to be
harmful. The Acyclovir Registry, which has existed for years for
pregnant women on acyclovir, has not shown any harmful effects of this
drug to the fetus, even though the drug is used fairly frequently. To
date, there are no data on the effects of protease inhibitors on
pregnant women. A general approach, subscribed to in our practice, has
been that women who need drugs get the drugs they need, unless there
is a specifically known fetal toxicity.

       FDA Pregnancy Risk Categories

       The risk posed by maternal drug use to a fetus bears closer
examination in a discussion of fetal risk in general. The FDA has
established Pregnancy Categories A, B, C, D and X, according to an
assigned risk. But what do these categories really mean? According to
the FDA, category A consists of drugs for which controlled studies in
women have failed to demonstrate a risk to the fetus in the first
trimester (or subsequent trimesters), and thus the possibility of
fetal harm appears remote. Although very few drugs have ever had
controlled studies that "prove" no fetal harm in the first trimester,
this does not mean that they are harmful.

       Category B consists of drugs for which either (1) animal
reproduction studies have not demonstrated a fetal risk, but there are
no corresponding human studies, or (2) animal studies have shown
adverse effects that have not been confirmed in controlled studies of
women in the first trimester (or subsequent trimesters). Category B
means that there really is not enough information.

       Category C means that (1) animal studies have revealed adverse
fetal effects but that no controlled studies in women have been done,
or (2) no studies in women or animals are available.

       Category D means that there is clear evidence of human fetal
risk, but the benefits derived from using these drugs in pregnant
women may outweigh the risks (e.g., these are drugs that may be used
to treat a pregnant woman with a life-threatening or otherwise serious
condition when there is no other effective alternative).

       Acyclovir is an interesting example. Reviews of acyclovir, a
category C drug, have been available for more than 10 years; it is
known to be fairly "safe." Famciclovir, a relatively newer drug and a
relative of acyclovir, for some reason has been assigned to category
B. Someone called our clinic and asked, "Why are you using acyclovir
when it is more dangerous than famciclovir?" The point is that, if one
does not really consider what is behind the assignment of the
category, these categories can be misleading.

       Finally, category X encompasses drugs in which human and animal
studies (or actual human experience) have demonstrated fetal
abnormalities. The risk of using a category X drug in a pregnant woman
clearly outweighs any benefit.

       Impact of Immunologic, Virologic and Placental Factors on
       Vertical Transmission

       One of the larger studies on vertical transmission examined the
immunologic, virologic and placental factors associated with
transmission (St. Louis and others). Conducted in Zaire, it was a
prospective, observational, cohort study of more than 324 HIV positive
women who were matched with 254 HIV negative controls. This group of
researchers found that the highest transmission rate was associated
with maternal p24 antigen; 71% of the children born to women with p24
antigenemia were HIV positive, compared with 23% born to women without
p24 antigenemia.

       Researchers also found that high maternal CD8 cell counts were
associated with high levels of vertical transmission. Among women with
CD8 counts of less than 1,800 cells/mm3, CD4 counts below 600
cells/mm3 were a risk factor. In women with neither high CD8 nor low
CD4 counts, inflammation in the placenta was the crucial factor
associated with a higher rate of vertical transmission: the vertical
transmission rate was only 7%. However, when p24 antigen was absent,
CD8 count was lower than 1800 cells/mm3, CD4 count was higher than 600
cells/mm3 and the placenta was uninflamed.

       Significance of Viral Load

       Another key question is how important it is to measure viral
load. In a study of 19 mother-child pairs, HIV transmission occurred
in 5 pairs (Weiser and others). Researchers used an endpoint dilution
culture of the peripheral blood mononuclear cells to determine viral
titers as a measure of the viral load. They found that, of 6 women
with viral titers greater than 125 HIV-infectious units per 106 cells,
4 (67%) transmitted HIV to their infants. On the other hand, of 13
women who had low viral titers, only 1 (7.7%) transmitted the virus to
the infant. This finding demonstrates the importance of examining
viral titers and shows that a high viral load promotes transmission.

       Although HIV load varied greatly among the women, viral load in
each woman remained stable over time during pregnancy. This
observation, coupled with the finding that the greater the maternal
viral burden, the more likely that viral transmission would occur, led
researchers to conclude that determination of titers early in
pregnancy may predict which women are at risk for vertical
transmission.

       The Weiser study offers a scientific rationale for therapeutic
strategies based on lowering the viral load, as well as a quantitative
virologic foundation for directly linking the risk of vertical
transmission to the severity of maternal primary infection, advanced
disease and surrogate markers such as p24 antigen and low CD4 counts.
Arguably, obstetricians should measure viral load in pregnant HIV
positive women.

       A prospective cohort study by Dickover and associates addressed
the concern regarding viral load measurement in HIV positive pregnant
women. In this study, 92 HIV positive women who had 95 pregnancies and
97 infants were examined. In 20 of 97 infants, there was vertical
transmission. The most striking difference among the virologic and
immunologic variables was in the number of HIV RNA copies at delivery.
Transmitting mothers were more likely to have plasma HIV RNA levels
higher than 50,000 copies/mL at delivery. Of 20 transmitting mothers,
15 (75%) had high HIV RNA copy levels compared with just 4 out of 75
(5%) of the nontransmitters, a highly significant difference.

       None of the 63 women who had fewer than 20,000 copies/mL of HIV
RNA transmitted the virus to the fetus. Plus, there was a clear
cut-off-all of the women with more than 80,000 copies/mL transmitted
the virus to their infants, whereas none of the women with less than
20,000 copies/mL did. Of great interest is that 22 women who took AZT
showed an 8-fold median decrease in the plasma RNA levels from an
average of 43,043 RNA copies/mL before AZT therapy to 4,238 copies/mL
at delivery; none of these 22 women transmitted the virus to the
fetus. Thus, if AZT was effective, the women did not transmit the
virus. In ACTG 076, the women took AZT, on average, for 12 weeks. In
this study, the women took the drug for an average of 8 weeks (median,
7 weeks; range, 4-11 weeks). Four AZT-treated women with high HIV
levels transmitted the virus to their newborns, even though the HIV
virus in both mothers and infants was AZT-sensitive. Those who
transmitted in utero had the highest viral load,! and those who
transmitted during delivery had higher HIV RNA levels than the
nontransmitting women.

       [Ed. note: The SFAF Scientific Advisory Committee comments that
       data from the XI International Conference on AIDS do not
       clearly support the association of any specific viral load with
       the certainty of vertical transmission.]

       Which Fetuses Get Infected: In Utero versus Intrapartum?

       The issue of which infants get infected and when again raises
the question of where to try to block transmission. A study published
in The American Journal of Public Health showed that events around the
time of delivery that increased the infant╒s exposure to the birth
canal, to maternal blood or to vaginal secretions increased vertical
transmission (Kuhn and others). In this study, epidemiologists
compared the New York City birth records of 632 children with AIDS to
5 controls per case, matched for race, year of birth and institution
of birth, and reviewed complications and risk factors during the
deliveries.

       They found that children born via cesarean section (C-section),
in women who had no placenta previa, abruptions or other complications
that would have increased exposure to maternal blood, had the lowest
rate of transmission. Vaginal deliveries with risk factors had the
highest rate of transmission (Kuhn and others).

       An estimated 50% to 70% of vertical viral transmission occurs
during intrapartum events (i.e., during birth). This estimate is based
on studying the children after birth to see whether the virus can be
cultured. In other words, if the infant was infected at the time of
birth, the HIV culture was negative at birth but positive later. These
data have added to the argument in favor of performing C-sections to
protect infants from intrapartum HIV transmission. From Italy, there
is a review of 1,624 children born to HIV-infected women (Tovo and
others). These infants were prospectively followed from birth to age
18 months, unless they died of HIV-related illness before the study╒s
end. A significantly higher rate of vertical transmission was shown in
children delivered vaginally by women who were symptomatic at the time
of delivery. Multivariate stepwise analysis showed that vaginal
delivery and development of symptoms in the mother were significantly
and independently associated with a high transmission rate. This study
is being cited, as well as others such as the European Collaborative
Study, as demonstrating that C-sections help prevent vertical
transmission of HIV virus.

       In our practice, we are very liberal about doing C-sections
with HIV positive women. Although we have no adopted policy of
C-sections for these patients, we do try to avoid prolonged ruptured
membranes, and we will not use forceps or a vacuum on these babies.

       Could Antiretrovirals Damage Fetal Hearts?

       HIV in children can be complicated by the development of
cardiac disease. In adults, decreased left ventricular function has
been associated with AZT use. The question that arises is, can the use
of antiretrovirals in an attempt to prevent vertical transmission
damage the fetal heart in the process? Or, are the cardiac problems
seen in HIV-infected patients related to the viral infection rather
than to the antiretroviral therapy?

       A study done to determine whether cardiac disease in children
is related to antiretroviral therapy or to HIV disease progression
could provide some clues (Domanski and others). Researchers
retrospectively reviewed echocardiograms, clinical information and
laboratory data from 137 HIV-infected children who were treated with
AZT and/or ddI (Videx).

       Despite correction of the echocardiogram results for
HIV-disease severity with markers such as CD4 cell counts, time since
infection, mode of acquisition and age, children who were treated with
AZT had a lower average fractional shortening than those who were not
treated with AZT. The odds that a cardiomyopathy [heart muscle
disease] would develop were 8.4 times greater in children who had
taken AZT than in those who had never taken AZT; ddI was not
associated with the development of cardiomyopathy.

       The U.S. Public Health Service now recommends routinely
offering AZT to all HIV-infected women during their pregnancy. What is
the effect of this drug on the fetus? Even though AZT appears to be
remarkably safe, fetuses not prone to sickness may be being exposed in
utero to a drug that may give them heart disease at a later time. Will
evidence of heart disease emerge in the first year of life, or will
the children be 10 years old when they start to present with
cardiomyopathy?

       Discussion

       What obstetric principles can be followed at this time? One
clear principle is that viral load has a real effect. If babies are
identified as being at relatively high risk or low risk for infection,
interventions can be "bull's-eyed" with a timely course of antivirals.

       Another principle stems from the finding that all women with
more than 80,000 RNA copies/mL vertically transmitted the virus to
their child (Dickover and others). This finding, coupled with the
observation that the viral load tends to remain stable throughout
pregnancy, suggests that another obstetric principle may be to measure
viral load and target interventions early in pregnancy in order to
lower the RNA count to prevent vertical transmission.

       On the other hand, if 50% to 70% of the transmission occurs
during the intrapartum period, what about routinely delivering infants
of HIV-infected women via C-section? Personally, I would prefer drug
treatment over C-section. Giving a C-section to women who have a high
viral load may mean that the sickest patients are being given an
operation that may be essentially unnecessary, particularly if the
virus has already been transmitted. I am certainly not opposed to
C-sections. In fact, we have a 30% C-section rate in our HIV
population. However, C-sections are not routine, and we do not always
know when it is the best procedure to follow.

       Ideally, ACTG 076 would have given us the answer about timing.
Unfortunately, it did not. The researchers who formulated the study
apparently felt that it would take too long for them to be able to
determine whether intrapartum versus antepartum [before birth] AZT
worked best. If we knew the answer to that question, we could monitor
our therapy and direct it toward the antepartum period, the late third
trimester, or during labor and delivery -- whenever it would be most
effective.

       Currently, an objective is not to start too early. Starting AZT
after the first trimester could mean that babies will be born right
about the time that they are developing drug resistance. Furthermore,
it may be important to boost them during delivery.

       Although some of these babies may already be infected, 50% to
70% may not be infected. We also need to look at using the protease
inhibitor drugs during pregnancy. These drugs have not yet been
studied in pregnant women, and we need to study if and when to use
them. As obstetricians, we are extremely reticent about starting new
drugs. But since HIV is a killer disease, we need to consider any drug
in the armamentarium that may help combat it.

       Dr. Landsberger is the Director of the High-Risk Obstetrics
       Clinic at The New York Hospital-Cornell Medical Center in New
       York City.

       Copyright, Medscape, Inc., 1996 , all rights reserved.
       Medscape, the online resource for better patient care, can be
       accessed at http://www.medscape.com.

       References

       Connor EM and others. Reduction of maternal-infant transmission
       of human immunodeficiency virus type 1 with AZT treatment. The
       New England Journal of Medicine 331: 1,173-1,780. 1994.

       Chu SY and others. Pregnancy rates among women infected with
       human immunodeficiency virus. The American Journal of
       Obstetrics and Gynecology 87(2): 195-198. 1996.

       Hocke C and others. Prospective cohort study of the effect of
       pregnancy on the progression of human immunodeficiency virus
       infection. Obstetrics and Gynecology 86: 886-891. 1995.

       Soeiro R and others. Maternofetal transmission of AIDS:
       frequency of human immunodeficiency virus type 1 nucleic acid
       sequences in human fetal DNA. The Journal of Infectious
       Diseases 166(4): 699-703. 1992.

       Langston C and others. Excess intrauterine fetal demise
       associated with maternal human immunodeficiency virus
       infection. The Journal of Infectious Diseases 172: 1,451-1,460.
       1995.

       Alimenti A and others. Quantitation of human immunodeficiency
       virus in vertically infected infants and children. Journal of
       Pediatrics 119(2): 225-229. August 1991.

       Lewis SH and others. HIV-1 in trophoblastic and villous
       Hofbauer cells, and haematologic precursors in eight-week
       fetuses. The Lancet 335(8689): 5,465-5,468. March 10, 1990;
       erratum in The Lancet 335(8696): 1,046. April 28, 1990.

       Ehrnst A and others. HIV in pregnant women and their offspring:
       evidence for late transmission. The Lancet 338(8761): 203-207.
       July 27, 1991.

       Frenkel LM and others. Effects of AZT use during pregnancy on
       resistance and vertical transmission of perinatal HIV type 1.
       Clinical Infectious Disease 20: 1,321-1,326. 1995. St. Louis ME
       and others. Risk for perinatal HIV-1 transmission according to
       maternal immunologic, virologic, and placental factors. Journal
       of the American Medical Association 269(22): 2,853-2,859. June
       9, 1993.

       Weiser B and others. Quantitation of human immunodeficiency
       virus type 1 during pregnancy: relationship of viral titer to
       mother-to-child transmission and stability of viral load.
       Proceedings of the National Academy of Sciences USA 91(9):
       8,037-8,041. 1994.

       Dickover RE and others. Identification of levels of maternal
       HIV-1 RNA associated with risk of prenatal transmission: effect
       of maternal treatment on viral load. Journal of the American
       Academy of Medicine 275: 599-605. 1996.

       Kuhn L and others. Maternal-infant HIV transmission and
       circumstances of delivery. American Journal of Public Health
       84: 1,110-1,115. 1994.

       Tovo PA and others. Mode of delivery and gestational age
       influence perinatal HIV-1 transmission: Italian Register for
       HIV Infection in Children. Journal of Acquired Immune
       Deficiency Syndromes and Human Retrovirology 11: 88-94. 1995.

       The European Collaborative Study: Cesarean section and risk of
       vertical transmission of HIV-1 infection. The Lancet 343(8911):
       1,464-1,467. June 11, 1994.

       Domanski MJ and others. Effect of AZT and didanosine treatment
       on heart function in children infected with human
       immunodeficiency virus. Journal of Pediatrics 127: 137-146.
       1995.

       ******************************************************

       Open Clinical Trials for HIV/AIDS Treatments
       Leslie Hanna

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

       *AZT cessation and effect on viral load

       ACTG 304 is a multicenter study that will evaluate the effects
on viral load of temporarily suspending AZT monotherapy. As more
antiretroviral drugs become treatment options, at least in clinical
trials, more and more people with HIV are being required to undergo
washout periods. That is, people are required to stop taking their
current antiretroviral regimens for a period before beginning a new
one, in order to obtain a drug-free viral load. However, the time it
takes for drugs to properly wash out is not clearly known. This study
will examine viral load fluctuations over a 28-day washout period.
Eligible persons have 500 or fewer CD4 cells/mm3, at least 12 months
of prior AZT use, 2 months of continuous AZT monotherapy before study
entry, and must not have had any vaccinations within 1 month before
beginning the study.

       *Early infection: the Options Project

       Researchers at San Francisco General Hospital (SFGH) recently
began an effort to identify, recruit and treat with a 3-drug regimen
(AZT, 3TC and indinavir) newly infected people with HIV. For details,
see article in this issue.

       *F-ddA

       Sponsored by the National Cancer Institute (NCI), this 8-week
Phase I study will evaluate the safety, tolerance, pharmacokinetics
and antiviral potential of F-ddA. Different doses will be tried in an
escalating pattern until the maximum tolerated dose is established.
Eligible participants have 100-400 CD4 cells/mm3 and symptomatic HIV
disease or AIDS, but have not had hepatic cirrhosis, heart disease or
pancreatitis. Current use of foscarnet or ganciclovir is prohibited.

       *Filgrastim (G-CSF) and stem cell harvesting

       ACTG 285 is a 24-week pilot study of the safety of stem cell
harvesting, after taking granulocyte colony-stimulating factor (G-CSF)
to mobilize bone marrow stem cells. Participants will be randomized to
receive 7 daily subcutaneous injections of 10 mcg/kg G-CSF. Doses may
be raised to 20 mcg/kg. On days 5 and 6 of G-CSF administration
participants will have leukapheresis (peripheral blood mononuclear
cell harvesting). Participants will be stratified by CD4 cell count
and clinical health. There are various requirements based on CD4 cell
count, e.g., persons with greater than 500 CD4 cells/mm3 must be
asymptomatic and must not have used antiretroviral therapy in the past
60 days. Prior malignancy, active alcohol or illicit substance use and
central nervous system (CNS) disease or seizures within the past year
are not allowed.

       *Nelfinavir (Viracept) and nucleoside analogs

       This study will evaluate nelfinavir, Agouron╒s protease
inhibitor, in combination with nucleoside analogs in people with 100
or fewer CD4 cells/mm3. Participants will be randomized to either
continue on the stable regimen of nuceloside analogs they are already
taking, or switch to a new regimen of nuceloside analogs. Nuceloside
analogs include AZT, ddI, ddC, d4T and 3TC. All participants will take
750 mg of nelfinavir, 3 times daily, and must already be on a stable
nucleoside regimen. There are 9 study sites (Berkeley, Chicago,
Dallas, Fort Lauderdale, Los Angeles, New York City [2], San Francisco
and St. Paul); for more information, call 800-501-2474, extension 1.

       *141W94, AZT and 3TC

       This study will compare the safety, tolerability and efficacy
of different dosing regimens of 141W94 in combination with AZT and
3TC. All participants take 3TC and AZT, and will be randomized to 4
treatment arms to receive either one of 3 doses of 141W94 or placebo.
The study lasts 12 weeks, and may be extended for an additional 12
weeks. Eligibility criteria include having at least 150 CD4 cells/mm3,
a viral load by PCR of at least 10,000 copies/mL, no prior treatment
with 3TC or protease inhibitors and no active opportunistic infections
(OI). In the San Francisco Bay Area, call ViRx at 415-353-5623.

       *1592U89 and other antiretroviral therapy

       This open-label study evaluates the safety, tolerability and
antiretroviral activity of 1592U89 when used in combination with other
antiretroviral drugs. All participants will add 300 mg 1592U89 to
their current antiretroviral regimen, such as AZT, ddI, ddC, d4T or
3TC. The 24-week study is open to people with 100 or more CD4
cells/mm3, a viral load of 30,000 copies/mL or more and a history of
antiretroviral use. In the San Francisco Bay Area, call ViRx at
415-353-5623.

       *Ritonavir (Norvir), 3TC and AZT in moderately advanced HIV
        disease

       ACTG 315 is a 48-week, open-label pilot study of the efficacy
of a potent triple combination antiretroviral regimen in persons with
moderately advanced HIV disease. Participants will first undergo a
5-week antiretroviral washout period and then will take ritonavir for
9 days, before adding 3TC and AZT. Eligible persons have 100-300 CD4
cells/mm3 and have had at least 3 months of prior AZT use. Active OIs
are not allowed, nor is a history of pancreatitis within the past 2
years, nor prior use of either 3TC or protease inhibitors. Thalidomide
and rifabutin, as well as other drugs contraindicated with ritonavir,
are not allowed.

       *Saquinavir (Invirase), hard and soft capsules, and indinavir
        (Crixivan)

       ACTG 333 is a Phase II multicenter study of the antiviral
effect in people who have been taking the original, hard-capsule
formulation of saquinavir, who switch to the newer, soft-gelatin
capsule formulation or switch to indinavir, Merck's protease
inhibitor. Objectives of the study include learning whether switching
will decrease viral load (plasma HIV RNA) and evaluating
antiretroviral activity in sequential use of protease inhibitors. The
study will randomize persons who have taken 1,800 mg/day of
hard-capsule saquinavir for at least one year to (1) continue taking
hard-capsule saquinavir, (2) switch to soft-gelatin capsule
saquinavir, or (3) switch to indinavir. After 8 weeks, the people
randomized to continue receiving hard caps will switch to open-label
indinavir for the next 4 months. People randomized to the other 2 arms
will either continue on assigned therapy or, if they have had no
virologic response by week 8, will cross-over to open-label treatment
with the alte! rnate drug. The study lasts 6 months.

       *SPC3

       This Phase I/II clinical trial is the first U.S. trial of SPC3,
a multichain peptide designed to block HIV from attaching to cell
receptors, thereby preventing it from entering cells. The study will
evaluate the safety and efficacy of different doses of SPC3 for
lowering blood levels of HIV. Laboratory studies indicate that SPC3
blocks cell infection by diverse strains of HIV, including
AZT-resistant HIV. Since SPC3 binds to the cell rather than to the
virus, HIV is not expected to be able to develop resistance to it. All
participants receive active drug for 3 weeks, at either the 20 mg or
40 mg daily dose level. Higher doses may be tried, depending on
preliminary results. Drug is administered intravenously for 1 to 2
minutes; participants are monitored after receiving the drug. Eligible
participants have 100 or more CD4 cells/mm3, have been on any
antiretroviral treatment regimen for at least 8 weeks (or no
treatment), have a viral load by RNA PCR of at least 10,000 copies/!
mL, and have no clinically active AIDS-defining OIs or tumor.
Available only at Roger Williams Medical Center in Providence, RI;
call Grace Accetta, RN, or Gail Skowron, MD, at 401-456-2437.

       *Treatment for Opportunistic Infections

       Cryptosporidiosis: BIC-C parvum

       This Phase II study will randomize participants with
cryptosporidiosis to receive 4 daily doses of a powder formulation of
BIC-C parvum (bovine immunoglobulin concentrate-C. Parvum) or placebo
for 4 weeks. Cryptosporidiosis must be diagnosed by stool or biopsy
culture, and participants must have diarrhea. Par-ticipants also must
have 180 CD4 cells/mm3 or fewer and must not have active CMV colitis.
In Los Angeles, call Jennifer Ida at Tower Infectious Diseases at
310-358-2300, extension 228.

       Cytomegalovirus (CMV) retinitis: natural history

       This NIAID study, in its current incarnation, is a modification
of an earlier study that would have evaluated asymptomatic CMV viremia
(when CMV is present in the blood but before disease symptoms have
developed) and its response to oral ganciclovir. Since enrollment
began, oral ganciclovir has been dropped from the study, and now,
participants will be followed with regular viral load tests for CMV,
over 9 weeks, to evaluate several PCR methods of measuring CMV viral
load and also to look at fluctuations.

       CMV retinitis: ganciclovir and neupogen (Amgen)

       This open-label Phase I study will involve increasing the dose
of ganciclovir to maximum levels for each individual. Additional doses
of filgrastim will be taken to protect neutrophil counts. Persons with
active CMV retinitis must have finished a 2-week induction course with
ganciclovir. In Los Angeles, call Connie Olsen at LAC-USC at
213-343-8279.

       Treatment for Malignancies and Cancers

       Kaposi's sarcoma (KS): Virulizin

       In Montreal, Canada, a phase I/II trial of Virulizin for
treating drug-resistant KS has begun. Laboratory studies indicate that
Virulizin stimulates macrophages (immune system white blood cells) to
kill tumors; data in people with KS receiving the drug through a
compassionate use program indicates clinical response. The trial will
evaluate the anti-tumor activity of the drug in people with HIV, KS
and extreme immunosuppression, by evaluating tumor response, survival
and quality of life in 16 participants. The trial is conducted by Dr.
Christopher Tsoukas at the Immune Deficiency Treatment Center at
Montreal General Hospital.

       KS: oral thalidomide

       Sponsored by the NCI, this Phase II study will evaluate the
safety, pharmacokinetics and efficacy of oral thalidomide in people
with KS. Since thalidomide has been shown to inhibit angiogenesis
(growth of blood vessels), one of the main ways KS develops, it may
inhibit KS tumor growth. Eligible participants have KS outside the
lungs that has progressed over the 2 months prior to study entry but
is not life-threatening. Grade 2 or worse peripheral neuropathy is not
allowed. Thalidomide is taken daily, orally, at 200 mg, to be
increased by 200 mg every 2 weeks to a maximum of 1,000 mg. Treatment
lasts for at least 6 months, and may be continued for an additional 6.

       Treatments for Wasting Syndrome and Myopathy

       Nutritional supplements

       This prospective, double-blind Phase IV trial will compare the
effects of oral nutritional supplements with different fat contents on
lean body mass, weight and quality of life in people with AIDS. The
goal is to determine which type of supplement is more effective for
promoting weight gain; other studies have shown that supplements
containing fat in the form of medium-chain triglycerides may be better
absorbed and cause less gastrointestinal distress than standard,
long-chain triglyceride supplements. Participants are randomized to
receive either Lipisorb (medium-chain triglycerides) or Sustacal PLUS
(long-chain triglycerides). Both are liquid nutritional supplements
that come in 8 oz. cans, 3 of which are used daily. Treatment duration
and follow-up last 6 months each. Participants must be clinically
stable, have equal to or less than 100 CD4 cells/mm3, and must not be
taking ganciclovir, appetite stimulants, corticosteroids or anabolic
agents. Quality of life questionnaires and bioimpedance analysis (BIA)
will be used. There are several trial sites.

       Immune Enhancement

       Epithyme

       This is a Phase I study of epithyme in severely
immunocompromised people with HIV. The drug is taken by subcutaneous
injections. The study is open to people with 100-250 CD4 cells/mm3.
Antiretroviral use is permitted as long as the person has been on a
stable regimen for at least 2 months. In Los Angeles, call Corie
Castro 310-358-2429.

       Gene therapy in identical twins

       This Phase I/II NIAID pilot study will evaluate the safety,
efficacy and immunotherapeutic effects of a gene therapy for AIDS.
This treatment involves removing CD4 cells from an HIV negative
identical twin and transfusing them into the HIV positive twin. Before
transfusion, cells are expanded in culture and genetically altered
with anti-HIV genes (antisense tar and transdominant rev) that,
ideally, will provide intracellular protection against HIV. The cells
are intravenously infused, then monitored through blood studies to see
how long they live. A total of 4 infusions will be given during the
12-month study. The HIV negative twin must be healthy and seronegative
for CMV or Epstein-Barr virus (EBV) if the other twin is, and negative
for hepatitis B and C. The HIV positive twin must have greater than 50
CD4 cells/mm3, must not ever have had lymphoma and must not be
undergoing systemic KS treatment.

       Interleukin 2 (Aldesleukin) and standard-of-care antiviral therapy

       This Phase II multicenter open-label study will evaluate the
tolerability, toxicity and utility of subcutaneous interleukin 2
(IL-2) plus antiviral therapy vs antiviral therapy alone. Participants
take antiviral therapy for at least 2 weeks before beginning the
study, then are randomized to receive IL-2 or no IL-2 every 8 weeks.
Participants are followed every 4 weeks for 14 months. Eligible
persons have 200-500 CD4 cells/mm3, no history of AIDS-defining OI, no
prior use of IL-2 and no use of systemic corticosteroids or
chemotherapy within the month prior to entry.

       Perthon/Abavca

       Advanced Plant Pharmaceuticals Inc., manufacturer of
Perthon/Abavca, is sponsoring a Phase II clinical trial at Albert
Einstein College of Medicine. Perthon/Abavca is a ╥whole plant╙
pharmaceutical, with FDA-approved Investigational New Drug (IND)
status. This study will evaluate it as an immune system booster, to
see if it can delay time to AIDS and increase survival.

       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 1-800-TRIALS-A can identify which adult
studies permit adolescents.

       HIV infection: bis-POM PMEA

       ACTG 310 is a Phase IA multicenter study of the safety,
toxicity and pharmacokinetics of a single dose of the antiviral drug
bis-POM PMEA in children. The study will determine age-related dose
differences for children, and try to establish a dosage to be studied
in multiple doses. Participants will be stratified by age to receive
either a single 1.5 or 3.0 mg/kg dose. The lower dose is given to
children aged 3 months to 17 years, first; if this dose is acceptable,
the higher dose will be tried. Blood levels will be monitored for 8
hours following administration. Children aged 1 day to 17 years are
eligible, with any CD4 cell count, but they must be either
asymptomatic or only mildly symptomatic.

       HIV infection: ritonavir (Norvir)

       This is a Phase I/II study to determine the safety, tolerance
and pharmacokinetics of 4 doses of a liquid formulation of Abbott╒s
protease inhibitor, ritonavir, alone and in combination with AZT
and/or ddI. Antiviral and clinical efficacy will be determined by
monitoring viral load and clinical status in 2 age groups. The study
has 3 parts: pre-treatment evaluation, 12 weeks of treatment at 4 dose
levels, then a combination phase where AZT or ddI will be added, or
ritonavir monotherapy continued, if the participant has a history of
intolerance to both AZT and ddI. There is a long list of drugs that
cannot be used concurrently. Call the NCI at 301-402-1391/1387.

       Lymphoproliferative disorders: all-trans-retinoic acid and
       interferon-alpha

       This study of the natural course of lymphoproliferative
disorders in children with HIV has 2 parts: an observation period,
without intervention, and a 6-month treatment period with
all-trans-retinoic acid and interferon-alpha, as well as
antiretroviral therapy. The 48-week study requires tissue biopsy at
entry and after 12 weeks. Treatment can be repeated if the child
declines after treatment ends. Children with rapidly growing,
previously untreated malignant lymphomas are excluded. Call the NCI at
30 1-402-1391/1387.

       Oral candidiasis: cyclodextrin itraconazole

       This multicenter, open-label study will evaluate 2 doses of
cyclodextrin itraconazole (CD-itraconazole) for treating oral
candidiasis, including refractory cases. Participants take the drug
for 15 days, then are on follow-up for another week. If the child
benefits from the drug, she or he may continue for another 5 months,
with monthly evaluations. The study is open to children aged 6 months
to 18 years, with culture-proven Candida and clinical symptoms.
Children with a history of azole intolerance are excluded, as is the
concurrent use of several other drugs. Call the NCI at
301-402-1391/1387.

       Varicella-zoster virus (VZV) disease: BV-ara-U (Sorivudine)

       This Phase I study will evaluate the safety, tolerance,
pharmacokinetics and efficacy of BV-ara-U in children with VZV of the
skin, viscera or eyes, who have failed on or are intolerant of the
standard treatments, acyclovir or foscarnet. In laboratory studies,
BA-ara-U appears 1,000 times more active against VZV than acyclovir.
Participants will receive 1 dose daily of oral BA-ara-U. The study is
open to children under 18 years of age who weigh 15 kg or more, with
documented VZV infection and a clinical history of continuous or
recurrent VZV despite full-dose, standard therapy. Exclusion criteria
include use of 5FC or 5FU, high-dose prednisone or probenecid. Call
the NCI at 301-402-1391/1387.

       Varicella vaccine (Varivax)

       ACTG 265 is a Phase I/II study of the safety and
immunomodulating potential of a live-attenuated vaccine against VZV in
children with HIV. Infection with VZV (chickenpox) can be extremely
hazardous, often involving complications, in children with HIV.
Children who are VZV-naive and who have not been exposed to either
chickenpox or shingles will receive Varivax vaccinations at weeks 0
and 12, with possible boosts at week 52 if they are still negative for
VZV as well as CMV.

       Women

       Oral isotretinoin for low-grade cervical dysplasia

       ACTG 293 is a Phase III multicenter trial of oral isotretinoin
(Accutane) versus observation for low-grade cervical dysplasia (CIN
I), to evaluate whether it may be more beneficial to wait to see if
lesions resolve without treatment, or to use oral isotretinoin to
prevent lesions from progressing in severity, in women with HIV.
Participants will be randomized to receive oral isotretinoin for 6
months or to be observed only, with 12 additional months of follow-up.
Eligible women have biopsy-proven grade I CIN; the biopsy must have
been performed within the past 3 months. Participants must be at least
13 years old and not pregnant. Exclusion criteria include malignancies
requiring chemotherapy within the past 3 months, hysterectomy within
the past 4 months and prior treatment for grade II or higher CIN.
Neither tetracycline nor vitamin A may be taken at the same time as
isotretinoin.

       Miscellaneous

       SNX-111 for chronic pain

       FDA 256A is a multicenter Phase II/III study of the safety and
efficacy of different doses of SNX-111, a calcium channel blocker, for
controlling severe, chronic pain. The drug is administered
intrathecally, which involves inserting a catheter into the spinal
canal. Participants will receive drug or placebo, both administered
intrathecally. People who respond to their treatment after 5 days will
continue at home for another 5; those who do not respond will be
switched to the other regimen for the next 5 days. After the first 10
days, responding participants will have a permanent pump implanted
under the skin for long-term administration. Eligible participants may
have any CD4 cell count, but have chronic pain related to HIV or
cancer which has not been satisfied by opioid treatment, either
because side effects have been intolerable or pain has not been
relieved.

       *********************************************
       The Options Project
       Leslie Hanna

       Researchers at San Francisco General Hospital (SFGH) recently
began an effort, called the Options Project, to identify, recruit and
treat with a 3-drug regimen people newly infected with HIV. Currently,
all participants are taking AZT, 3TC and indinavir; other combinations
are possible. Each year in San Francisco, 600-1,000 people become
infected with HIV. Many are young (18-24 years of age) gay and
bisexual men.

       The aim is to find people early in infection, give them
powerful antiviral drugs that will complement the immune system's
anti-HIV action and, ideally, eliminate HIV from the individual. The
events that occur in the first few weeks following infection are very
important. During initial infection, HIV replicates at extremely high
rates, and there are accompanying high blood levels of HIV. Symptoms
(including fever, rash, sore throat, muscle aches, swollen lymph nodes
and mouth or genital ulcers) may be absent, mild or severe, and
characterize acute retroviral syndrome (ARS). Studies indicate that
initial blood levels of HIV, as well as the intensity of symptoms in
ARS, have predictive value; high blood levels of virus and severe
illness are associated with more rapid HIV disease progression.

       One goal of the Options Project is to improve the course of
disease in persons who have become HIV-infected, particularly those
with severe ARS. Another goal is to explore the possibility of
preventing long-term infection. This aspect of the work at SFGH has
grown out of research showing that use of potent antiviral drugs can
reduce HIV in the blood to undetectable levels. In the AIDS Clinical
Trials Group (ACTG) study 076, when AZT was given orally to pregnant
women in the third trimester, intravenously during labor and delivery,
and then to both mother and infant after birth, perinatal infections
were reduced from 25% to 8%.

       If a single drug like AZT can do that, more potent drugs used
in combination should be even more effective at preventing the
establishment of viral infection. Another important, case-control
study involved healthcare workers. Healthcare workers with a deep
wound infection due to injury from an HIV-contaminated implement who
took AZT were less likely to become HIV-infected than healthcare
workers with a deep wound infection who did not take AZT. These 2
studies suggest that treating someone early is important and that, if
1 drug has such a profound effect, 3 drugs should work even better.

       Housed at SFGH, the Options Project is a broad collaborative
effort involving the San Francisco AIDS Foundation, Project Inform,
Prevention Point, 18th Street Services and other AIDS service
organizations, as well as private practitioners. Collaborators seek to
identify people with new, acute HIV infection. This refers to
infection in persons who until recently were known to be HIV negative
or whose status is unknown who have engaged in high-risk behavior(s)
associated with transmission of the virus (such as anal or vaginal
intercourse without a condom or with a condom that breaks or sharing
equipment for injecting drugs), and who then develop the symptoms of
ARS.

       Such individuals may call the Options Project Hotline at
415-502-8100. Those who decide to enroll come into the clinic to be
seen immediately, free of charge. HIV antibody and viral load testing
are also free, and processed immediately; an initial follow-up
appointment is scheduled for approximately 72 hours later. The viral
load test results quickly identify who has actually become
HIV-infected.

       In addition to people with acute infection, treatment through
the Options Project is available to people known to be newly infected,
defined as people who have received a newly positive HIV test result
within the past 6 months, after a previous test that was negative for
HIV antibodies.

       A unique and special feature of the Options Project is that
people who are found to be HIV-uninfected after evaluation (perhaps
they are found to have mononucleosis or strep throat) are referred to
community programs like the Center for AIDS Pre-vention Studies
(CAPS), where they can learn strategies designed to help them modify
the behaviors that put them at risk for HIV infection. Thus, these
individuals can learn how to avoid subsequent exposures.

       So far, without any advertising, the Options Project in the
past 2 months has screened 29 people and identified 9 who are newly
infected. Currently, all 9 are taking AZT, 3TC and indinavir, and
"tolerating them well," according to James Kahn, MD, project director.
"We may increase to 4 drugs if we can find a regimen that looks more
promising," he adds.

       Kahn cautions that the results of this novel approach are not
yet known. "Eradication may not be possible, but it certainly bears
trying; certainly, we'll never know if it works if we don't try. It is
not a cure; still, I am very hopeful that early intervention and
treatment with powerful antiviral combinations and behavioral
interventions, as offered by this project, will reduce the rate of new
infections in the community. Finding people early in infection, before
the virus has had a chance to destroy the immune system, at the least
provides an important pathway for a person to effectively fight HIV."

       Sources

       Case-control of HIV seroconversion in healthcare workers after
       percutaneous exposure to HIV-infected blood: France, United
       Kingdom, and United States, January 1988-August 1994.

       Morbidity and Mortality Weekly Report 44(9): 29-33. December
       22, 1995. O'Connor EM and others. Reduction of maternal-infant
       transmission of human immunodeficiency virus with zidovudine
       treatment. New England Journal of Medicine 311: 1173-1180.
       November 1994.

       Kahn J, MD. Personal communication. August 23, 1996.

       ***************************************
       Glossary
       Compiled by Liz Highleyman

ABRUPTION: tearing away, separation or detachment.

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

ACUTE RETROVIRAL SYNDROME (ARS): a combination of flu-like symptoms
(e.g., fever, sore throat, skin rash, headache, nausea, muscle or
joint pain) that accompanies or occurs shortly after primary HIV
infection.

ADJUVANT: an additive (e.g., alum) incorporated into or injected
simultaneously with a vaccine to potentiate (increase) the immune
system response.

ADRENAL-GENITAL SYNDROME: a condition in which excess output of
androgens from the adrenal gland causes virilization.

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 VACCINE EVALUATION GROUP (AVEG): a NIAID-sponsored network that
conducts trials of experimental HIV vaccines at 5 research centers
called AIDS Vaccine Evaluation Units (AVEU).

AMENORRHEA: absence of menstruation or decreased menstrual flow.

ANABOLIC STEROID: a hormone (e.g., testosterone, oxandrolone) that
promotes the synthesis of proteins and the building of muscle mass.
Side effects may include masculinization (e.g., body hair growth) and
liver toxicity.

ANABOLISM (adjective ANABOLIC): the cellular synthesis of organic
molecules; the building of proteins and muscle mass.

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

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

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

ANOREXIA: lack or loss of appetite for food.

ANTEPARTUM: before birth.

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.

ANTIGEN: any agent or substance that stimulates an immune response,
e.g., microorganisms or the substances they produce. Antigenemia is
the presence of antigen in the blood serum.

APOPTOSIS: programmed cell death.

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

ASYMPTOMATIC: not feeling or showing outward signs of illness.

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

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.

BASELINE: a known value to which later measurements can be compared.

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

BODY MASS INDEX (BMI): a measure of mass calculated as weight divided
by height squared.

BOOST: a subsequent dose given after initial administration of a
vaccine or drug to enhance or restore its effectiveness.

BRANCHED DNA ASSAY (bDNA): a test that measures the amount of virus in
plasma or tissue.

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

CANARYPOX: a poxvirus that typically infects canaries and is used in
human vaccine research.

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.

CATEGORY A, B, C, D, X: FDA "pregnancy risk" categories that indicate
risk to a fetus from use of a drug based on controlled studies in
animals or humans.

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 ran

ge of immune activity. The CD4 cell count is the number of CD4
lymphocytes present in a cubic millimeter (mm3) of blood.

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-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.

CHEMOKINE: a chemical (e.g., RANTES, MIP-1 alpha, MIP-1 beta, IL-2)
produced by cells that stimulates the activity of other cells,

CHLAMYDIASIS (CHLAMYDIA): an infection, usually sexually transmitted,
with the bacteria Chlamydia trachomatis. Symptoms may include genital
inflammation and discharge; untreated chlamydiasis may lead to pelvic
inflammatory disease and infertility.

CHORION (adjective CHORIONIC): one of the membranes that encloses the
fetus within the uterus. Human chorionic gonadotropin (HCG) is a
hormone secreted by the placenta that maintains pregnancy during early
development.

CKR5 (CC CKR5): a newly discovered chemokine co-receptor which HIV
uses to infect a cell.

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

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: a steroid hormone (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.

CRYPTOSPORIDIOSIS: a disease caused by the protozoan Cryptosporidium
parvum, often transmitted through contaminated food or water or via
oral-anal sexual contact. It may cause severe, chronic diarrhea weight
loss and lymphadenopathy.

CYTOCHROME P450 SYSTEM: a process by which drugs and other foreign
substances are metabolized 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.

DERMATITIS: inflammation of the skin.

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.

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

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

ENDOGENOUS: originating within or produced by the body.

ENDOMETRIUM: the mucous membrane that lines the uterus.

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

ERYTHEMA (adjective ERYTHEMATOUS): red, especially an inflammatory
redness of the skin.

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.

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

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. The genotype is
the specific genetic "blueprint" of an individua

l.

GENE THERAPY: an approach to preventing and/or treating disease by
replacing, removing or introducing genes or otherwise manipulating
genetic material.

GENITAL ULCER DISEASE (GUD): one of several, usually sexually
transmitted, diseases (e.g., syphilis, chancroid) that are
characterized by the development of ulcers on the skin or mucous
membranes.

GESTATION: pregnancy.

GLYCOPROTEIN (GP): a small unit (e.g., gp 120) made of a sugar and a
protein molecule, often part of a cell╒s membrane; they are used in
vaccine development.

GRANULOCYTE MACROPHAGE COLONY-STIMULATING FACTOR (GM-CSF, LEUKINE): a
hormone that stimulates growth of granulocytes and macrophages, types
of white blood cell.

GYNECOMASTIA: greater than normal breast development in males.

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.

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 gen

ital area.

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 Kapo

si╒s sarcoma-associated herpesvirus (KSHV or HHV-8).

HIRSUTISM: excess growth of bodily and facial hair in a male pattern.

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

HUMAN GROWTH HORMONE (HGH, SEROSTIM): a peptide hormone secreted by
the pituitary gland. HGH stimulates metabolism and protein synthesis
and is used to treat HIV-related wasting syndrome.

HUMAN PAPILLOMAVIRUS (HPV): a virus of the papova family. Many strains
of HPV cause warts, including Condylomata acuminata (genital warts).
Some 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 a

ntibodies.

HYPOGONADISM: inadequate function of the gonads (ovaries or testes)
characterized by deficient hormone secretion and gamete (ova or sperm)
production.

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 node

s, 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.

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.

INCIDENCE RATE: the rate of occurrence of new cases (e.g., HIV
infections) in a given population over a period of time.

IN SITU HYBRIDIZATION: a method used to detect and locate specific DNA
or RNA sequences on chromosomes or in tissues.

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

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

INTRAPARTUM: during birth.

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.

ISOLATE: a specific individual microbe (e.g., an HIV virion) and its
genetically identical progeny. A primary isolate refers to an isolate
derived from human blood or tissue, rather than a laboratory-grown
strain.

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, HHV-8) is a recently
 discovered herpesvirus that may be a causal agent or co-factor.

KILLER T-CELL: see cytotoxic T-lymphocyte.

LACTATION: milk production.

LEAN BODY MASS: muscle tissue.

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

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 NON-PROGRESSOR (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.

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.

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

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.

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.

MICROBICIDE: an agent that inactivates, kills or destroys microbes.

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

MULTIVARIATE ANALYSIS: a statistical technique in which multiple
variables are analyzed separately to determine the contribution made
by each variable to an observed result.

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 immunosuppressed persons, the bacteria can infect lymph
nodes, bone marrow, liver, spleen, spinal fluid, lung

s and the gastrointestinal tract, causing diarrhea, wasting, fever and
fatigue.

NAIVE: inexperienced; used to describe a person who has never taken a
certain drug.

NAKED DNA VACCINE: purified DNA used as a vaccine to insert into cells
genes that produce specific proteins.

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.

NEOPTERIN: a substance produced by macrophages in response to a
foreign agent.

NEUTRALIZATION: a process whereby antibodies bind to an antigen (e.g.,
HIV) to prevent infectious or toxic processes.

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.

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 and causing pr

emature termination of the viral DNA chain.

ONCOGEN: an agent (e.g., virus. toxin) that causes neoplastic cell
growth, or cancer.

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.

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.

PANCREATITIS: inflammation of the pancreas, a digestive gland in the
abdominal cavity.

PATHOGEN (adjective PATHOGENIC): any disease-causing agent, especially
a microorganism.

PELVIC INFLAMMATORY DISEASE (PID, SALPINGITIS): infection of the upper
female reproductive tract including the uterus, fallopian tubes and
ovaries.

PERINATAL: around the time of birth.

PERINATAL HIV TRANSMISSION (PHT, VERTICAL TRANSMISSION, MATERNAL-FETAL
TRANSMISSION): the transmission of an infectious organism from mother
to child. Perinatal transmission may occur in utero (in the womb),
intrapartum (during birth) or postpartum (aft

er birth, via breast-feeding).

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, burning, pain, weakness and partial
paralysis.

PHARMACOKINETICS: the action of drugs in the body, including the
processes of absorption, transformation, distribution to tissues,
duration of action and elimination.

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 t

ested 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 compar

ed.

PLACENTA: the vascular organ that connects the fetus and the mother╒s
uterus, in which metabolic exchange occurs.

PLACENTA PREVIA: a condition in which the placenta is implanted in the
lower section of the uterus.

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.

POLYCYTHEMIA: abnormally high level of red blood cells in the
circulating blood.

POLYMERASE CHAIN REACTION (PCR): a highly sensitive viral load test
that uses an amplification technique to detect minute amounts of DNA
or RNA in blood or tissue samples.

POSTPARTUM: following childbirth.

PREVALENCE: the number of individuals with a condition in a specific
population.

PRIMARY HIV INFECTION (PHI): the initial stage of HIV infection which
may be accompanied by an acute flu-like syndrome.

PROGESTERONE: a female steroid hormone with anti-estrogenic effects.

PROPHYLAXIS: a treatment that helps to prevent a disease or condition
from occurring (primary prophylaxis) or recurring (secondary
prophylaxis).

PROSPECTIVE STUDY: a study that looks forward in time. A prospective
cohort study follows a specific group of people over a period of time.

PROTEASE INHIBITOR: a drug (e.g., saquinavir, indinavir, ritonavir)
that blocks the action of the protease enzyme, which breaks up large
proteins produced from viral RNA, thereby preventing HIV from
producing complete new viruses.

PRURITUS (adjective PRURITIC): a condition characterized by itching.

RANDOMIZED TRIAL: an experiment arranged so as to produce a chance
distribution of subjects into different treatment arms.

RECEPTOR: a specific protein-binding site on a cell╒s surface or
interior.

RECOMBINANT: produced by genetic engineering in the laboratory.

REPLICATION: duplication or reproduction.

RESERVOIR: a site where an infectious agent collects and multiplies,
e.g., the 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.

RETROSPECTIVE STUDY: a study based on the medical records of patients,
looking backward in time at events that happened in the past. A
retrospective cohort study uses the records of a specific group of
patients.

RETROVIRUS: a class of enveloped viruses (e.g., HIV) that have their
genetic material in the form of RNA and use reverse transcriptase to
translate their RNA into DNA.

REVERSE TRANSCRIPTASE INHIBITOR (RTI): a drug that blocks retroviral
replication by interfering with the reverse transcriptase enzyme,
which allows a retrovirus to translate its genetic material (in the
form of RNA) into DNA which is integrated into the

 host cell's chromosomes. 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.

RUPTURE OF MEMBRANES: the breaking open of the amniotic sac
surrounding the fetus prior to the start of labor and delivery.

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 sensitive to AZT if AZT is able to
prevent viral replication.

SEPSIS: the presence of pathogenic (disease-causing) organisms or
their toxins in the blood or tissues, and the associated bodily
reactions.

SEROCONVERSION: the change in a person's antibody status from negative
to positive.

SEXUALLY TRANSMITTED DISEASE (STD, VENEREAL DISEASE): a disease (e.g.,
gonorrhea, syphilis, chlamydia) that is transmitted through sexual
contact.

SQUAMOUS INTRAEPITHELIAL LESION (SIL): abnormal growth of squamous
cells, particularly cell changes of the uterine cervix (cervical
intraepithelial neoplasia).

STATISTICAL SIGNIFICANCE: the probability that an observed outcome of
an experiment or trial is not due to chance alone. In general, a
result is considered to be statistically significant if there is a
less than 5% probability that it occurred by chance

 (i.e., a p-value of less than .05).

STEROID: a family of substances that share a similar chemical
structure, including many hormones (e.g., testosterone), Vitamin D and
various drugs.

STRAIN: a specific genetic variant of a particular organism.

SUBCUTANEOUS: beneath the skin; subdermal.

SUBTYPE (CLADE): a distinct variant of a microorganism. There are two
main groups of HIV subtypes, group M (which includes subtypes A-J) and
group O. Subtype B is predominant in the U.S.

SUBUNIT: a piece or small part of a larger unit.

SURROGATE MARKER: a marker or sign (e.g., viral load, CD4 count) that
can serve in place of a clinical endpoint.

SYNCYTIUM (plural SYNCYTIA): a mass or clump of cells that fuse
together to form one "giant cell."

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 C

TL).

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.

THRUSH: see candidiasis.

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
protozoan Toxoplasma gondii. Symptoms may include headache,
lymphadenopathy, malaise, muscle pain and fever. The disease commonly
manifests as toxoplasmic encephalitis.

TREATMENT IND (TIND): an FDA protocol that allows patients with
life-threatening disease to obtain experimental drugs through their
physician from a drug manufacturer.

TRIMESTER: a 3-month period, usually referring to the three stages of
a human pregnancy.

TROPHOBLAST: the layer of cells covering the embryo that later
develops into the placenta.

TUBERCULOSIS (TB): an infectious disease caused by Mycobacterium
tuberculosis that typically affects the lungs but may occur in other
organs (extrapulmonary TB). Multidrug-resistant tuberculosis (MDR-TB)
is resistant to some of the standard anti-TB drug

s.

UTERUS (WOMB): the muscular pelvic organ of the female reproductive
system in which the fetus develops.

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
 (prophylactic) vaccine is intended to prevent initial infection.

VIRAL LOAD (VIRAL BURDEN): the amount of virus in the blood or other
tissues. The presence of viral RNA or DNA indicates that the virus is
replicating. Viral load is measured using assays such as PCR or bDNA,
and is expressed as the number of copies of

viral genetic material per cubic milliliter of blood (mL3).

VIREMIA: the presence of virus in the blood or plasma.

VIRILIZATION: development of mature masculine characteristics in a
girl, woman or prepubescent boy.

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.

WASTING SYNDROME: a condition characterized by atrophy of lean body
mass and involuntary weight loss of more than 10% of normal body
weight.

       Copyright (c) 1996 - San Francisco AIDS Foundation.  Contact
       Liz A. Highleyman, San Francisco, CA [e-mail] for
       permission to redistribute.  Distributed, with permission, by
       by AEGIS, your online gateway to a world of people, knowledge,
       and resources.  Direct Dial: v.34+: 714.248.2836; v.120/ISDN:
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