       BETA 28 -- March 1996

       Table of Contents
       _________________

News Briefs
Mark Bowers

Highlights from the FDA Antiviral Advisory Committee Meetings
Ron Baker

Kaposi's Sarcoma
Harvey Bartnof

Report from the 3rd Conference on Retroviruses and Opportunistic Infections
Mary Romeyn

Women and HIV/AIDS: Pelvic Inflammatory Disease
Liz Highleyman and Leslie Hanna

Avoiding Cryptosporidiosis: Safe Food, Safe Water, Safe Sex
Diane Cenko

Scope and Limitations of Gene Therapy for HIV Infection
Henry Chang and Mark Bowers

Sinusitis
Leslie Hanna

AIDS Fraud
Mark Bowers

Research Notes
Mark Bowers

Glossary
Liz Highleyman

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       News Briefs

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       BETA News Briefs
       Mark Bowers

       Mark Bowers is Managing Editor of Treatment Publications and
       a member of the Scientific Advisory Committee of the San
       Francisco AIDS Foundation.

       Protease Inhibitors

       The short-term effects of triple combinations of antiviral
drugs including a protease inhibitor as one element were reported at
the 3rd Conference on Retroviruses and Opportunistic Infections,
held in Washington, DC, from January 28 to February 1, 1996.
Clinical data show dramatic decreases in viral load. Even more
important, data from a randomized, placebo-controlled study of
ritonavir (Norvir) in 1,090 volunteers with CD4 counts less than 100
cells/mm3 showed a striking survival benefit for those taking the
protease inhibitor.

       Abbott Laboratories' large-scale clinical study of ritonavir
tried to replicate the real-life situations in which the drug would
potentially be used. Either 600 mg of ritonavir or placebo was given
to participants twice daily in addition to their current nucleoside
analog therapy. Thirteen percent (13%) of the 543 volunteers who
received ritonavir died or experienced disease progression, compared
with 27% of the 547 volunteers who received placebo. The mortality
rates were 4.8% for the ritonavir group and 8.4% for the placebo
group. See Mary Romeyn's review of the 3rd Conference on
Retroviruses and Opportunistic Infections in this issue.

       Gore Meets Pharmaceutical Firms and Government Researchers

       On February 20, 1996, Vice President Al Gore met with
representatives from 11 pharmaceutical companies, leading AIDS
researchers and officials from the National Institutes of Health
(NIH), the Department of Defense and the Food and Drug
Administration (FDA). The agenda included AIDS vaccine development,
therapeutics and microbicides. This was the meeting that was
promised as a follow-up to the December 1995 White House Conference
on HIV and AIDS. Gore promised the following:

       * The Clinton Administration will work with international
         organizations such as the World Bank to increase investment
         in AIDS vaccine development and trials worldwide;

       * The Administration will help facilitate the development of
         microbicides to enable women to protect themselves from HIV
         infection;

       * The Vice President will facilitate ongoing discussions
         between the government and the pharmaceutical industry to
         identify promising areas of AIDS research that the
         government can support in order to stimulate private sector
         investment in the next generation of AIDS vaccines,
         therapeutics and microbicides;

       * FDA will pursue additional measures to increase the number
         of anti-HIV therapeutics with pediatric indications.

       Generic AZT Prevented from Entering Market

       The U.S. Supreme Court refused to hear a case challenging the
patent on AZT, the most widely used antiretroviral drug, thus
preventing cheaper generic versions from being marketed.
Burroughs-Wellcome, recently acquired by Glaxo, retains exclusive
right of sale in the United States through the patent it has held
since 1987. Generic AZT, at about one-half the price of the Glaxo
product, is available in Canada and elsewhere.

       Baboon Cell Transfer

       On December 14, 1995, Jeff Getty became the first person ever
to receive a bone marrow transplant from another species. Steven
Deeks, MD, of San Francisco General Hospital, and Suzanne Ildstad,
MD, of the University of Pennsylvania, prepared Getty with partial
radiation therapy to remove any immune cells that might compete with
the transplant. He then received stem cells and facilitator cells
from a healthy baboon. The stem cells were expected to produce new
T-lymphocytes that would be resistant to HIV infection; baboon
T-lymphoctyes are not susceptible to infection with HIV. The new
baboon-derived T-cells were expected to engraft (learn to adapt to a
human environment) and begin to fight infections.

       By February 1996, Getty was feeling better than he had for
months. However, Deeks and Ildstad were unable to find signs that
the baboon marrow had engrafted. Getty said that researchers looked
twice for baboon DNA using polymerase chain reaction (PCR) tests,
but found none one time and only a small amount the next.
Nonetheless, Getty's CD4 cell counts returned to 1992 levels.
Researchers now speculate that the radiation therapy that Getty
received before the transplant accounts for his improved health. In
the past, French researchers have used immunosuppressive steroids to
treat people with AIDS with some limited success. The destruction of
immune cells by radiation may have only partly accounted for Getty's
improvement. He also has been on a triple combination antiviral
regimen, which includes 3TC, AZT and the protease inhibitor
indinavir (Crixivan).

       Although the baboon cells apparently did not engraft, Getty
is pleased and relieved that the transplant procedure proved to be
safe and paves the way for future intriguing research. There are
plans for another baboon bone marrow transplant, and interest in
exploring the positive effects of the combination of radiation
therapy and antiviral drugs in people with advanced HIV disease.

       Gene Therapy Recommendations

       The National Institutes of Health (NIH) regulates gene
therapy research through the Recombinant DNA Advisory Committee
(RAC). In 1995, NIH Director Harold Varmus, MD, appointed 2 advisory
panels to assess NIH investment in gene therapy and examine the work
of the RAC. The first panel, co-chaired by Arno Motulsky, MD, from
the University of Washington in Seattle and Stuart Orkin, MD, from
Harvard Medical School, reported their findings to Varmus on
December 7, 1995. Their assessment is that gene therapy has been
over-optimistically reported, and that it is still too early to
expect clinical miracles from this fledgling area of research. None
of the 100 protocols or 600 patents approved by the RAC have proven
efficacy in humans so far. NIH allocates about $135 million to
extramural and $61 million to intramural gene therapy research,
while private industry invests about $200 million. The
Motulsky-Orkin panel does not take issue with the amount spent, but
wants the priorities to reflect the need to develop better gene
transfer technology and animal models. Many studies have been
hindered by an inability to effectively place desired genes into
their target cells. More basic research also needs to be focused on
the mechanisms of acquired and inborn genetic diseases, according to
the report.

       The second panel looked specifically at the scope of the
authority of the RAC: should this body only evaluate the safety of
proposed gene therapy protocols, or should it also evaluate the
science behind the proposals for research? Can the RAC effectively
do one without the other? Francis Collins, MD, Director of the
National Center for Human Genome Research, thinks that the RAC could
do both. Expanded authority for the RAC would place the discussions
of the comparative merit of proposed gene therapy protocols in the
public eye, since the deliberations of the RAC are conducted in
public. Such discussions would possibly begin to temper the popular
impression that gene therapy for HIV/AIDS and other life-threatening
diseases is just around the corner, and would allow for steady, safe
and rational development of the field.

       Both reports agree that human gene therapy will eventually be
a success, but it is now in a difficult stage of development.
Effective technologies are being developed, and even disappointing
clinical results do not mean that gene therapy is a failure.

       Viral Genetics Important in Long-Term Nonprogressors

       Science magazine reported in November on an Australian man,
and 6 people who were infected with HIV through blood or blood
products that he had donated. All of these individuals continue to
have high CD4 cell counts and no symptoms of HIV disease after 10-14
years of infection. Researchers looked at the viral sequence of the
strain of HIV that is common to all 7 people, and found that the nef
gene had 3 deletions, with 2 more deletions in an area where the nef
gene overlaps the long terminal repeat region. These researchers
concluded that disease progression can be determined by the HIV
genome. The intriguing possibility of crafting an effective
attenuated HIV vaccine has also been raised.

       Ganciclovir is an Effective CMV Prophylaxis Drug

       The results from Syntex study 1654, reported at the 3rd
Conference on Retroviruses and Opportunistic Infections, support the
use of oral ganciclovir (Cytovene) in the prevention of primary
cytomegalovirus (CMV) retinitis. The study confirms preliminary data
presented at the 35th Interscience Conference on Antimicrobial
Agents and Chemotherapy last September. In October, FDA approved
oral ganciclovir for the prevention of CMV disease in persons with
advanced HIV infection, based on the final analyses of Syntex 1654.
The study randomized 486 volunteers to oral ganciclovir and 239 to
placebo. Final data demonstrated a 49% risk reduction in the
development of CMV disease compared to placebo.

       Concerns about the development of resistance to ganciclovir
because of the use of the drug for prophylaxis were allayed. Larry
Drew, MD, of the University of California at San Francisco reported
that in vitro testing of 40 CMV-culture isolates from urine showed
less than 1% resistance after prophylaxis for a mean duration of 8.3
months (251 days).

       Doxil Approved for Treatment of KS

       On February 15, 1996, Sequus Pharmaceuticals announced that
FDA and similar approval agencies in 15 European countries have
approved the sale of liposomal doxorubicin (Doxil) for the treatment
of Kaposis sarcoma, a cancerous condition that affects 10-12% of
people with AIDS in the United States. In the U.S., Doxil is
indicated for patients whose disease has progressed despite prior
combination therapy; in Europe, physicians may choose Doxil as a
first-line therapy. Sequus employs a unique strategy (stealth
technology) that helps the drug evade detection by the immune system
longer than other approved chemotherapy drugs, and it remains in the
body long enough to seek out and destroy cancer cells. The drug is
concealed in a liposome (fat coating), then further coated in
polyethelene glycol, an ingredient found in antifreeze. See Harvey
Bartnof's in-depth article on Kaposi's sarcoma, this issue.

       New Preventive Vaccine Study

       The AIDS Vaccine Evaluation Group (AVEG) at the NIH has
approved the initiation of a study of a new genetically engineered
HIV vaccine in 140 volunteers at 6 sites in the U.S. The vaccine is
the result of a collaboration between Pasteur Mrieux/Connaught
Laboratories in Paris, France, and BIOCINE Company in Emeryville,
California. The vector for the vaccine is a canarypox virus, large
enough to accommodate several HIV genes as well as the surface
protein gp120 that has been the hallmark of many previous vaccine
candidates. This vaccine candidate is unique in that it contains HIV
core regulatory proteins that may spur a more vigorous and broader
anti-HIV immune response in vaccinated volunteers. HIV negative men
and women between the ages of 18 and 60 will receive either vaccine
or placebo vaccinations over a 9-month period, and will be followed
for over 1 year. Study sites are in St. Louis, MO; Rochester, NY;
Seattle, WA; Nashville, TN; Birmingham, AL; and Baltimore, MD. Call
the Center for Vaccine Development at (314) 268-5448 for further
information.

       Chiron's Eye Implant Device Is Approved for CMV Retinitis

       The U.S. Food and Drug Administration (FDA) gave approval on
March 5 to Chiron Vision to begin marketing a device that is
implanted in the eyes of people with cytomegalovirus (CMV)
retinitis. The device, called Vitrasert, was approved for use in
combination with ganciclovir, an antiviral drug already approved for
preventing or treating CMV disease. Ganciclovir, made by Hoffmann-La
Roche and marketed under the name Cytovene, is available in oral and
intravenous formulations. The Vitrasert device is surgically
implanted in the eye to provide continuous delivery of ganciclovir
to the vitreous fluid for up to 6 months. Vitrasert will sell for
about $4,000 per implant.

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       Highlights From the FDA Antiviral Drugs Advisory Committee
       Meetings, 2/27 - 3/1, 1996

       * Abbott's Ritonavir Wins Approval
       * Merck's Indinavir Recommended for Approval
       * Serono's Human Growth Hormone on Hold
       * New Indications for ddI and AZT/ddC
       * Review Date Set for Roche and Chiron Viral Load Test Kits

       by Ronald Baker, PhD

       Ronald Baker is Editor-in-Chief of BETA and Director of
       Treatment Education and Advocacy at the San Francisco AIDS
       Foundation. Baker attended 3 days of public review hearings
       held by the FDA Antiviral Drugs Advisory Committee in
       Gaithersburg, MD. Baker also was a guest member of the FDA
       review panel for Abbott's protease inhibitor drug ritonavir.

       Acting with unusual swiftness, the U.S. Food and Drug
Administration (FDA) granted marketing approval to ritonavir (March
1, 1996) and to indinavir (March 13, 1996), the 2 new protease
inhibitor drugs from Abbott and Merck, respectively. The approval of
ritonavir was announced by FDA Commissioner David Kessler, MD, less
than 24 hours after the FDA Antiviral Drugs Advisory Committee
recommended the drug for approval. Ritonavir is now available in
pharmacies across the U.S. at an average wholesale cost of $6,500 a
year.

       FDA approved indinavir in record time --only 42 days after
Merck filed its application for accelerated approval of the drug,
making it the fastest drug approval in the FDA's history. Due to a
shortage of supplies of indinavir for the next few months, Merck is
implementing a temporary plan that limits distribution of the drug
exclusively to Stadtlanders Pharmacy. The average wholesale yearly
cost for indinavir is $4,380 ($12 a day). Beginning Monday, March
25, all prescription orders should be made through Stadtlanders. For
more information,  patients and physicians may call 1-800-927-8888
8:30 am - 9 pm Eastern Time beginning Monday, March 18.

       Abbott's Ritonavir (Norvir)
       ---------------------------

       FDA granted full (traditional) approval for ritonavir alone
or in combination with other anti-HIV therapies for the treatment of
advanced AIDS. The agency granted accelerated (conditional) approval
for ritonavir alone or in combination with other anti-HIV therapies
for the treatment of people at earlier stages of HIV disease who
experience clinical or immunologic decline. The FDA-approved
indications for the use of ritonavir are unusual, and reflect
concerns among members of the Antiviral Drugs Advisory Committee
that more information is needed about the drug's effectiveness in
earlier stages of HIV disease.

       Abbott Laboratories conducted a total of 9 Phase II or III
studies of ritonavir. Data from these studies, in particular the 2
double-blind, randomized, multicenter, controlled Phase III studies
(M-245 and M-247) show that ritonavir significantly decreases viral
load and significantly increases CD4 cell counts in HIV positive
individuals. M-208, an open-label, 6-month study of ritonavir in a
triple combination with AZT and ddC, also demonstrates the potent
anti-HIV activity of ritonavir. Preliminary results of these studies
provided the principal data presented in the application for
approval submitted by Abbott to FDA.

       M-245 compared ritonavir to AZT (Retrovir) and to ritonavir
plus AZT in 356 HIV positive individuals without prior anti-HIV
therapy who had greater than 200 CD4 cells/mm3 and a baseline viral
load of 15,000 copies/mL (milliliter) or greater. Participants took
either 200 mg AZT 3 times/day, 600 mg ritonavir 2 times/day or a
combination of AZT and ritonavir at these same doses. Results of
viral load and CD4 cell count tests were assessed at 2, 4, 8, 12,
16, 20 and 24 weeks.

       In this study of patients without previous anti-HIV
treatment, ritonavir monotherapy produced a more profound decrease
in viral load and a higher increase in CD4 cell counts than did the
combination of ritonavir plus AZT or AZT monotherapy. This somewhat
confounding result of M-245 (monotherapy was more effective than
combination treatment) may be explained by patient non-compliance in
the combination AZT/ritonavir arm, according to Abbott. The reason
for non-compliance may have been due to the high incidence of
gastrointestinal adverse effects (nausea and vomiting) reported by
participants. This study used the notoriously bad-tasting liquid
formulation of ritonavir.

       M-247 was a double-blind, randomized, 2-arm, multicenter
trial comparing ritonavir to placebo in 1,090 HIV positive
individuals with 100 or fewer CD4 cells/mm3 who had prior anti-HIV
therapy. Participants were randomly assigned to either ritonavir 600
mg twice daily or placebo, and were allowed to continue taking up to
2 FDA-approved nucleoside analog reverse transcriptase inhibitors
during the study. (3TC [Epivir] was not approved at this time, and
was not permitted in the study.) The double-blind phase of M-247 was
to be halted when 191 people died or experienced a new AIDS-defining
event beyond the first 4 weeks of the study.

       When 191 cases were documented in December 1995, the study
was unblinded and analyses of the data were begun. The most
significant outcomes of the trial were: (1) the addition of
ritonavir to existing anti-HIV therapy produced a 43% reduction in
the death rate compared to the addition of placebo; and (2)
ritonavir plus existing therapy reduced the risk of disease
progression or death by 56% compared to placebo plus existing
therapy.

       DISEASE PROGRESSION OR DEATH
       Ritonavir  --  86/543 (15.8%)
       Placebo    -- 181/547 (33.1%)

       DEATHS
       Ritonavir  --  26/543 (4.8%)
       Placebo    --  46/547 (8.4%)

The following table summarizes the number and percentage of patients
in each group who experienced the most common clinical events
associated with HIV disease progression.

       MOST COMMON CATEGORIES OF DISEASE PROGRESSION

       Category                    Placebo (n=547)     Ritonavir (n=543)

       Death                       46 (8.4%)           26 (4.8%)
       Esophageal candidiasis      40 (7.3%)           16 (2.9%)
       Cytomegalovirus retinitis   20 (3.7%)           14 (2.6%)
       Other cytomegalovirus       17 (3.1%)            5 (0.9%)
       Kaposi's sarcoma            23 (4.2%)            8 (1.5%)
       Pneumocystis carinii        18 (3.3%)            9 (1.7%)
          pneumonia
       Mycobacterium avium         11 (2.0%)            6 (1.1%)
          complex
       HIV-related wasting          8 (1.5%)            2 (0.4%)

In addition to producing these statistically significant effects on
disease progression and death, ritonavir also consistently produced
significant decreases in HIV RNA levels and significant increases in
CD4 cell counts when compared to placebo during the observation
period.

       M-208 was a 6-month, multicenter, open-label study designed
to evaluate the safety and effectiveness of ritonavir in combination
with AZT and ddC in HIV positive individuals with 50-350 CD4
cells/mm3 without prior anti-HIV therapy. Participants first
received 600 mg 2 times/day of ritonavir for 14 days, followed by
the addition of AZT (200 mg 3 times/day) and ddC (0.75 mg 3
times/day). After 2 weeks of therapy, patients taking ritonavir
experienced significant improvement in both viral load and CD4
counts. At 24 weeks, mean HIV RNA levels decreased from baseline by
2.46 logs. The median increase in CD4 cell count from baseline at 24
weeks was 147 cells/mm3.

       In reporting the preliminary results of studies M-245, M-247
and M-208, Abbott has sought to define a strategy for maintaining
suppression of HIV by combining ritonavir with nucleoside analogs.
Although the results of study M-245 show the potent anti-HIV effect
of ritonavir, using the drug as monotherapy eventually leads to
resistant viral strains that show decreased sensitivity to
ritonavir. The results of M-247 clearly demonstrate the clinical
benefit of ritonavir, even among patients with advanced AIDS. Yet
simply adding ritonavir to existing nucleoside analog therapy is
probably not the best anti-HIV treatment strategy. Results of study
M-208 show that a more powerful anti-HIV effect can be achieved by
the (nearly) simultaneous administration of 3 drugs (in M-208,
ritonavir, AZT and ddC) never previously used by the participants.
The most formidable anti-HIV regimens may be those consisting of
combinations of multiple drugs which the patient has not previously
used.

       Safety of Ritonavir

       At the FDA hearings, Abbott characterized ritonavir as
"generally well tolerated by patients." In all the ritonavir
studies, the most common adverse events were related to the
gastrointestinal tract and the nervous system. Nausea, vomiting and
diarrhea were the most common gastrointestinal complaints. Patients
tended to experience these effects within the first few days of
starting the drug, according to Abbott. Nervous system adverse
events consisted of circumoral (around the mouth) paresthesias
(abnormal tingling or burning sensations), paresthesias elsewhere in
the body and headache. As with the gastrointestinal events, these
effects tended to occur during the first few days following
initiation of ritonavir. Overall, circumoral paresthesias and
headache were the most common adverse events.

       Most participants who experienced an adverse side effect did
not discontinue ritonavir. The adverse side effects that most
commonly did cause discontinuation of the drug were nausea,
vomiting, diarrhea and asthenia (weakness).

       Ritonavir Interactions

       Ritonavir is metabolized by the cytochrome P450 oxidase
system in the liver, and is possibly the most potent inhibitor of
this pathway known. The P450 pathway is shared by many other drugs
used in the treatment of HIV and other diseases. Abbott has
categorized over 200 drugs frequently used in the treatment of
HIV/AIDS with respect to their known or possible interaction with
ritonavir. The company says it is in the process of publishing this
list and will distribute it to physicians. Examples of drugs that
should not be taken together with ritonavir due to toxicity concerns
include codeine, diazepam (Valium), ketoconazole, rifabutin and
piroxicam. There are many others. Physicians should obtain complete
information from Abbott (or from the drug labeling) regarding which
drugs are known to cause adverse interactions when taken with
ritonavir.

       Although inhibition of the cytochrome P450 enzyme system
negatively impacts the simultaneous use of some drugs with
ritonavir, this inhibition also may have an important positive
consequence. Ritonavir taken with the Roche protease inhibitor
saquinavir (Invirase), for example, significantly enhances plasma
drug levels of saquinavir. If saquinavir levels can safely be
increased in this manner, the likely result will be to increase the
anti-HIV effect of saquinavir. Abbott and Roche have recently begun
a study of ritonavir co-administered with the new, more bioavailable
formulation of saquinavir. The first order of business will be to
establish doses that can be safely tolerated, followed by a study of
the effectiveness of the ritonavir/saquinavir double combination.

       Resistance and Cross-Resistance

       HIV has been shown to develop resistance to ritonavir,
especially at suboptimal doses (below 1,200 mg/day). Laboratory
tests demonstrate that ritonavir is cross-resistant to Merck's
indinavir and possibly to other protease inhibitors, but not to
Roche's saquinavir. Unpublished data from Roche showed that 12 of 13
patients treated with saquinavir monotherapy for 6 months exhibited
no cross-resistance to ritonavir.

       The issue of resistance and cross-resistance among the
protease inhibitor drugs is important, and requires further study
and clinical experience. It will be necessary for Abbott to give
appropriate warnings about resistance and cross-resistance in the
drug labeling and to develop educational materials for patients and
physicians.

       Clinical Chemistry Evaluations

       Ritonavir may cause increases in hepatic (liver) enzymes,
lipids and CPK (creatinine phosphokinase, an enzyme that may reflect
toxicity to muscles). Generally, these laboratory abnormalities have
not been associated with clinical abnormalities. However, since
ritonavir is metabolized by the liver, hepatic enzyme tests are
important for monitoring the safety of the drug. Individuals with
prior or current liver disease (e.g., hepatitis) who use ritonavir
should closely monitor hepatic enzyme values.

       Additional Studies of Ritonavir

       Abbott has recently initiated 4 additional studies: 1 for the
treatment of children and 3 to evaluate various combination
regimens. M-310 is assessing the safety, tolerance and anti-HIV
effect of ritonavir in children with HIV infection. Thirty-six (36)
to 70 children (ages 6 months to 18 years) will be enrolled.

       M-313 is planned as a 12-month study to determine the safety
and anti-HIV effect of a triple combination of ritonavir, 3TC and
AZT in people recently infected with HIV.

       NUCB-2019 is an open-label, 1-year combination study of
ritonavir, 3TC and AZT in patients with no history of prior anti-HIV
treatment.

       M-409 will assess the tolerability and pharmacokinetic
interaction of ritonavir and saquinavir in HIV negative subjects.
Doses range from 200-600 mg/day for both ritonavir and saquinavir.

       Abbott also plans the following studies: ritonavir/saquinavir
combination; ritonavir in the treatment of Kaposi's sarcoma;
ritonavir plus ddI/d4T versus ddI/d4T; and ritonavir intervention in
acute opportunistic infections. Abbott has also agreed to provide
"long-term follow-up safety and clinical endpoint data from M-245
and M-247 to assess the comparative clinical efficacy and safety
data in patients with advanced stage disease versus patients with
early stage disease."

       Finally, Abbott says the company will evaluate CD4 cell and
HIV RNA responses and safety among patients with greater than 100
CD4 cells/mm3 in a study comparing ritonavir/saquinavir to
ritonavir.

       Drug Supply

       Abbott says there is currently enough ritonavir available in
the new capsule formulation to treat up to 100,000 people in the
U.S. at the 1,200 mg/day dose.

       Cost

       The average wholesale cost of ritonavir at the FDA-approved
1,200 mg/day dose is $6,500 a year ($17.80 per day). The cost to
patients will be higher, and will vary depending on the retail
markup. For example, Walgreen's Pharmacy in San Francisco is
charging $23.44 for the daily dose ($8,438 yearly). The Castro
Village Pharmacy in San Francisco is charging $25.56 for the daily
dose ($9,304 yearly).

       Indinavir (Crixivan)
       --------------------

       On March 1, the FDA Antiviral Drugs Advisory Committee
recommended accelerated (conditional) approval for Merck and
Company's protease inhibitor drug indinavir (Crixivan). The labeling
will indicate that indinavir is approved for the treatment of HIV
disease in patients for whom anti-HIV therapy is warranted. This
broad indication for indinavir therapy will allow physicians to
prescribe the drug to individuals at all stages of HIV infection.
Commissioner Kessler said the FDA would give final approval to
indinavir following an inspection of their manufacturing site.

       Clinical Efficacy

       To demonstrate the efficacy of indinavir, Merck has conducted
8 multicenter Phase II studies and has 2 ongoing Phase III trials.
The indinavir trials have enrolled HIV positive individuals across
the broad spectrum of HIV disease, including patients with low CD4
cell counts. In general, Merck sought study participants with
moderate to high HIV RNA levels (greater than 20,000 copies/mL), in
order to evaluate the ability of indinavir to reduce viral burden.
Overall, Merck designed the indinavir studies using surrogate
markers (viral load and CD4 cell count) to show a potential clinical
benefit. Significant increases in CD4 cell counts and significant
decreases in viral load (HIV RNA copies) have been associated with a
clinical benefit. An impact on viral load, in addition, may be
predictive of a therapy's clinical utility.

       Early studies explored the effectiveness of several different
doses of indinavir. Merck eventually determined that the optimal
indinavir dose is 800 mg 3 times/day. This dose was used in the
Phase III trials. After selecting 2,400 mg/day as the therapeutic
dose, Merck began several double-blind, randomized Phase III studies
to evaluate the effectiveness of indinavir and the ability of 1 or
more nucleoside analog drugs to increase its anti-HIV effects. These
include studies that focus on surrogate marker results (protocols
033, 037 and 039) and clinical endpoints (protocols 028 and ACTG
320), and ongoing protocol 035.

       Protocol 028

       Protocol 028 is a double-blind, randomized study among 900
patients in Brazil without prior anti-HIV therapy. Study
participants have 50-250 CD4 cells/mm3 and a wide variation in viral
load results (there was no entry criterion for HIV RNA values). The
study is evaluating the effect of indinavir monotherapy versus AZT
monotherapy versus the double combination of indinavir/AZT. CD4 cell
counts and HIV RNA results are available for the first 24 weeks of
treatment. CD4 cell counts are also available for up to 32 weeks in
a small number of patients.

       Both the indinavir and indinavir/AZT groups experienced an
initial increase in median CD4 cell counts of over 100 cells/mm3.
This increase has been sustained for at least 24 weeks. The AZT
monotherapy group experienced only a small increase in CD4 cell
count, which was not sustained at week 24. There was a statistically
significant difference between the 2 indinavir groups and the AZT
group in terms of CD4 cell count, but the difference between the
indinavir monotherapy group and the indinavir/AZT group was not
significant. Preliminary data on 82 patients at week 32 demonstrate
a favorable trend for the 2 indinavir arms.

       In protocol 028, the combination indinavir/AZT group
experienced the greatest decrease in HIV RNA levels. The indinavir
monotherapy group experienced a somewhat lesser decrease, while the
AZT monotherapy group experienced the least decline in HIV RNA
levels. The differences were highly statistically significant
between the indinavir arms and the AZT arm in terms of HIV RNA
results. About 40% of those in the 2 indinavir groups experienced
decreases in HIV RNA levels to below the limit of detection (500
copies/mL) compared to 7% of those in the AZT monotherapy group.

       Protocol 033

       Protocol 033 is a 52-week, double-blind study among 740
individuals with 50-500 CD4 cells/mm3. Underway in the U.S., Europe
and Canada, protocol 033 has no specific

       HIV RNA level entry requirement. The baseline HIV RNA level
and CD4 cell count of participants are 4.34 log copies/mL and 258
cells/mm3, respectively. The study had 3 arms: indinavir
monotherapy, AZT monotherapy, and indinavir plus AZT. Both indinavir
groups experienced median increases in CD4 cell counts of over 90
cells/mm3. These increases were sustained for at least 24 weeks. The
AZT monotherapy group showed much smaller median increases in CD4
cell count. The differences between the 2 indinavir arms and the AZT
monotherapy arm in terms of CD4 cell count were highly statistically
significant, while the difference between the 2 indinavir groups was
not statistically significant.

       The median decreases in HIV RNA values were greatest for the
indinavir/AZT group, somewhat less for the indinavir monotherapy
group and least for the AZT monotherapy group. These decreases were
sustained for the 2 indinavir arms. The differences between the 2
indinavir groups and the AZT group in terms of HIV RNA levels were
highly statistically significant, but the difference between the 2
indinavir groups was not significant.

       About 40% of those in the indinavir monotherapy arm and 50%
of those in the indinavir/AZT arm experienced declines in HIV RNA
levels to below the limit of detection (500 copies/mL) as compared
to 5% in the AZT arm.

       Protocol 035 (Triple Drug Therapy)

       Protocol 035 is a multicenter, double-blind, 52-week study
among 96 individuals with previous AZT therapy. Study participants
were randomized to one of 3 treatment arms: indinavir monotherapy
(800 mg 3 times/day), AZT (200 mg 3 times/day) plus 3TC (150 mg 2
times/day) or a combination of all 3 drugs. Data are available at 20
weeks on 61 participants for CD4 cell counts and on 65 participants
for HIV RNA levels. The median baseline CD4 cell count was 155
cells/mm3 and the median baseline HIV RNA value was 4.6 log
copies/mL.

       About 36% of individuals taking indinavir monotherapy and 91%
(10/11) of patients taking the triple combination of
indinavir/AZT/3TC experienced HIV RNA levels below the level of
detection (500 copies/mL). Triple combination therapy reduced median
HIV levels by greater than 99%. These preliminary data are
impressive, particularly considering that the participants were
AZT-experienced at study entry. However, the data are derived from a
relatively small number of patients (22) who were on drug for 24
weeks.

       Preliminary results of these studies demonstrate that
indinavir monotherapy produces significantly greater increases in
CD4 cell counts and greater decreases in HIV RNA levels than AZT
monotherapy. In addition, indinavir/AZT appears to produce slightly
greater declines in HIV RNA than indinavir monotherapy. However, use
of the 3-drug combination of indinavir/AZT/3TC results in a greater
proportion of patients with HIV RNA levels below the limit of
detection than indinavir monotherapy or AZT/3TC combination therapy.
Those on triple therapy experienced a median increase of 146 CD4
cells/mm3 compared to a median increase of 98 CD4 cells/mm3 among
those on indinavir monotherapy. In patients taking AZT and 3TC, CD4
cell counts increased by a median of 22 cells/mm3.

       Individuals taking indinavir (800 mg 3 times/day) as
monotherapy or in combination with AZT experienced increases in CD4
cell counts of 90-100 cells/mm3 for at least 24 weeks. Those taking
indinavir also experienced decreases in HIV RNA levels of greater
than 1 log for 24 weeks.

       Indinavir Pharmacology

       The results of experiments to determine the bioavailibility
of the 800 mg dose of indinavir in humans are not yet available. In
animals, the bioavailability of indinavir ranges from 72% in the dog
to 19% in the monkey and 24% in the rat. Merck has determined that
indinavir is rapidly absorbed after oral dosing and achieves peak
plasma concentrations in about 1 hour. The drug is eliminated with a
half-life (time required for half of the drug to be metabolized) of
about 1.8 hours.

       High-fat, high-protein food intake (such as a bacon and eggs
breakfast) significantly reduces the absorption of indinavir.
However, it appears that low-fat, low-protein meals produce only a
modest decrease in plasma concentration of the drug (2-8%). For
optimal absorption, indinavir should be taken 1 hour before or 2-3
hours after eating.

       Indinavir is metabolized (like ritonavir) primarily by the
cytochrome P450 enzyme system in the liver. Merck researchers say
that they have found no clinically significant interactions between
indinavir and the following drugs commonly used in the treatment of
HIV disease: AZT, 3TC, d4T, trimethoprim/sulfamethoxazole (Bactrim,
Septra), clarithromycin, fluconazole or isoniazid. However, like
ritonair, indinavir interacts strongly with rifabutin and with
ketoconazole. Dose reduction is recommended for indinavir when
co-administered with either of these 2 drugs.

       There do not appear to be any clinically relevant differences
in the pharmacokinetics of indinavir associated with HIV status,
gender or race.

       Indinavir Safety Data

       Over 1,400 individuals have participated in Phase III studies
where they received indinavir at a dose of 2,400 mg/day. In
addition, about 200 individuals have taken indinavir at a daily dose
of 2,400 mg for at least 24 weeks either alone or in combination
with nucleoside analogs. About 100 of these individuals have been
followed for at least 48 weeks.

       Merck researchers report that indinavir has been generally
well tolerated. Two adverse experiences have been identified as
clearly associated with indinavir treatment: nephrolithiasis (kidney
stones) and hyperbilirubinemia (high bilirubin levels in the blood).
In all indinavir studies, nephrolithiasis has been defined as any
episode of unexplained flank pain with or without hematuria (blood
in the urine). The majority of patients who experience
nephrolithiasis have remained on indinavir during and after an acute
episode, according to Merck researchers.

       Fifty-five (55) of more than 2,000 patients (3%) treated with
indinavir have met the Merck definition of nephrolithiasis. Fifteen
(15) of these 55 cases have been regarded as serious (passing a
stone can be extremely painful). At least 9 of these 55 reported a
past history of nephrolithiasis. Passage of a kidney stone or gravel
or radiographic evidence of a stone at the time of the event
occurred in about 28 cases. Forty-eight (48) of 1,976 people (2.4%)
treated with indinavir at a dose of 2,400 mg/day have developed
kidney stones. Merck says that nephrolithiasis has not been
associated with kidney dysfunction so far. Rarely has the condition
resulted in discontinuation of indinavir therapy. There is some
indication that adequate fluid intake minimizes the incidence of
nephrolithiasis among patients taking indinavir.

       Asymptomatic hyperbilirubinemia is an adverse event
determined by laboratory values that is occasionally associated with
indinavir therapy. Approximately 10% of participants on indinavir
have had bilirubin values greater than 2.5 mg/dL at some point in
their treatment. Clinical adverse events such as jaundice have been
rarely reported. The incidence of hyperbilirubinemia together with
elevated serum transaminases (liver enzymes) is low, according to
Merck.

       There have been 12 deaths of participants enrolled in studies
of indinavir. Two deaths occurred in participants on AZT
monotherapy; 10 deaths were felt to be unrelated to indinavir.

       Researchers have noted a number of non-serious clinical
adverse events among participants in indinavir studies, both among
those on indinavir monotherapy and in those who took indinavir in
combination with nucleoside analogs. The most common of these
experiences in the indinavir monotherapy groups were: abdominal pain
(20%), asthenia/fatigue (31%), diarrhea (36%), dry skin (24%),
headache (46%), insomnia (16%), lymphadenopathy (24%), nausea (34%),
rash (37%) and taste abnormalities (16%). Hematologic abnormalities
were infrequent with indinavir monotherapy: decreased hemoglobin
(5%), hematocrit (red cell count, 6%), neutrophil count (white cell
count, 9%) and platelet count (20%).

       Resistance and Cross-resistance

       In the early Phase I and early Phase II studies of indinavir,
participants received various doses of the drug that eventually were
found to be suboptimal. Resistant virus commonly appeared by week
24. Resistance to indinavir occurs in association with changes at 11
amino acid residue positions. Treatment with lower doses of
indinavir (e.g., 800 mg/day) produces a less potent anti-HIV effect
than that observed at higher doses and selects for viral mutants
that are much less responsive to higher doses of indinavir (2,400
mg/day). Merck scientists believe that use of the 2,400 mg/day dose
as initial therapy produces the strongest anti-HIV effect in more
patients. In addition, the effect is sustained for a longer period
at this higher dose.

       HIV mutants that are resistant to indinavir are also highly
resistant to Abbott's ritonavir. Many ritonavir-resistant HIV
mutants are also cross-resistant to indinavir. About two-thirds of
viral variants tested to date that are resistant to indinavir also
show resistance to Hoffmann-La Roche's protease inhibitor
saquinavir, and one-half of the tested variants exhibit high-level
resistance to saquinavir, according to Merck.

       NOTE: Roche scientists dispute these conclusions by Merck
concerning saquinavir cross-resistance to indinavir. Further
research is necessary to confirm or reject the Merck conclusions on
this subject.

       Implications of Cross-Resistance

       Cross-resistance among the various protease inhibitors has
profound implications for sequential therapy with these agents. The
selection of viral resistance to indinavir in patients will produce
ritonavir resistance. In addition, treatment of patients with
ritonavir will likely produce indinavir-resistant virus. As a
result, sequential treatment with these 2 drugs will probably not be
beneficial.

       The issue of sequential treatment with saquinavir and
indinavir is more complicated. Merck scientists say that individuals
treated first with indinavir may not benefit from subsequent
treatment with saquinavir. Roche scientists disagree. Roche
researchers also say that individuals treated with saquinavir do not
yield variants resistant to indinavir. There are no data on patients
initially treated with saquinavir followed by subsequent treatment
with indinavir. More laboratory research and clinical experience are
required to clarify these important issues.

       The development of resistance to indinavir at the 2,400
mg/day dose is modest and may be further reduced by com-bination
therapy with other anti-HIV drugs, according to Merck.

       Drug Supply

       For information on how to obtain and fill an indinavir
prescription, and for the patient assistance and reimbursement
programs, patients and physicians may call Stadtlanders Pharmacy
beginning Monday, March 18 (1-800-927-8888). Prescriptions will be
filled by Stadtlanders beginning Monday, March 25.

       Cost

       The average wholesale cost for indinavir is $12 a day ($4,380
a year). The retail cost will be higher.

       Future Studies of Indinavir

       Merck is continuing 2 multicenter, double-blind, Phase III
trials (protocols 028 and 033). Protocol 028 will yield additional
clinical endpoint data. Merck will pursue a pediatric study, and
perhaps a trial to test the drug's ability to reduce maternal
transmission of HIV.

       Recombinant Human Growth Hormone (Serostim)
       -------------------------------------------

       A 15-member FDA Advisory panel voted 8 to 7 on March 1 not to
recommend full approval for somatropin (Serostim), the recombinant
(genetically engineered) human growth hormone from Serono
Laboratories, for the treatment of wasting syndrome in AIDS.
Serostim is currently available to people with AIDS-related wasting
through a Treatment Investigational New Drug (IND) program (See BETA
September 1994, page 10 and December 1995, page 3).

       Serono presented the results of 2 Phase III trials of
Serostim in support of its application for full approval. The first
12-week study demonstrated significant weight gain for patients on
Serostim, and showed a marked increase in lean body mass. Patients
on the drug experienced improvements in quality of life and
increased strength and endurance. The second Phase III trial was
designed to confirm safety, and looked only at weight gain, not body
composition (i.e., lean body mass). Weight gain was shown to be
statistically significant after 6 weeks of treatment with Serostim,
but not at 12 weeks.

       The FDA review panel was impressed by the public testimony of
over a dozen patients and physicians who spoke in favor of approval
for Serostim. However, some committee members felt that there were
too many gaps in the data presented by Serono. For example, it is
unknown whether the dose used in the 2 Phase III studies (6 mg
daily) is optimal, or whether a lower dose would be just as
effective. In addition, no data were presented on patients who stop
therapy after 12 weeks.

       Serono is now negotiating with FDA about how best to continue
pursuing approval for Serostim. One possibility is for the company
to apply for accelerated approval rather than full approval. The San
Francisco AIDS Foundation, ACT UP/Golden Gate and other community
groups support this approach. If FDA does not encourage a new
application from Serono, and instead sends the company a
"non-approvable" letter regarding Serostim, access to the drug
through the Treatment IND will be jeopardized, and reimbursers such
as Medicaid will discontinue coverage.

       AZT Plus ddC

       The Antiviral Drugs Advisory Committee on February 28, 1996
unanimously recommended full approval of ddC (Hivid) in combination
with AZT (Retrovir) as an option for initial therapy in HIV
infection. The recommendation was based on a review of 2 studies
that provided clinical endpoint data to support this indication.
Patients on AZT/ddC experienced slower disease progression (fewer
opportunistic infections) and improved survival compared to those
using AZT or ddI monotherapy. As a part of its recommendation, the
committee pointed out that the benefit of the AZT/ddC combination is
observed primarily in individuals without prior AZT use.

       ddI

       The Antiviral Drugs Advisory Committee on February 28, 1996
also unanimously recommended that ddI (Videx) be indicated as a
first-line treatment for HIV infection. ddI appears to be superior
to AZT in delaying disease progression and death, according to the
results of 3 large studies. ACTG 152 compared ddI alone to AZT alone
and to the combination of ddI/AZT in children. Results show that
children receiving ddI alone or in combination with AZT developed
fewer HIV-related illnesses and survived longer than those receiving
AZT monotherapy.

       Studying more than 5,000 patients, the European and
Australian Delta trial and ACTG 175 also found that ddI alone or in
combination with AZT was superior to AZT monotherapy in slowing CD4
cell decline and in delaying disease progression and death.

       "The proven survival benefit of ddI shows that the drug can
be considered an important component of future combinations,
including those with the protease inhibitors," said Paul Volberding,
MD, Director of the AIDS Program at the University of California at
San Francisco/San Francisco General Hospital.

       FDA Review of Viral Load Test Kits
       ----------------------------------

       Viral load testing is a powerful new technology that is able
to directly quantify the amount of HIV in the blood plasma of people
who are HIV positive. Both the reliability of HIV RNA testing and
its practical applications have expanded dramatically in the last
year. These powerful assays already are helping to guide the course
of treatment for HIV infection in a growing number of patients with
HIV disease. Increasingly, researchers and physicians are relying on
viral load tests to determine patients' disease stage, to predict
clinical outcome and to evaluate the effectiveness of therapy for
HIV infection.

       Several companies produce these tests, which are not yet
FDA-approved. However, both Hoffmann-La Roche (Roche Molecular
Systems) and Chiron Corporation have filed recently for FDA approval
of their respective HIV RNA assay kits for widespread use by
physicians and researchers. The Roche test is called "quantitative
competitive polymerase chain reaction" or more commonly
"quantitative PCR (QC-PCR)." The Chiron product is called "branched
chain DNA" or more commonly "branched DNA (bDNA)." Both tests give
comparable results in measuring HIV RNA.

       The FDA review of the Roche and Chiron viral load test kits
will take place on March 21, 1996. If the review committee
recommends approval on that date, an announcement regarding final
approval should come within a couple of weeks thereafter.

       HIV RNA tesing is significantly impacting the treatment of
HIV disease in many ways. It has already changed the way that
researchers test the effectiveness of AIDS drugs in clinical
studies. Several large trials have shown that HIV load (viral load)
correlates with clinical benefit (the lower the load, the better the
clinical prognosis). High viral burden appears to presage disease
progression and clinical decline. Within a short time, HIV RNA
testing will be an FDA-approved method for demonstrating how well a
particular drug (or drug regimen) is working in individual patients.

       With this critically important information in hand, drug
treatment can be better "individualized" for each patient. As a
result, recommendations can be made about continuing, halting,
changing or adding drug treatments early, before patients experience
significant CD4 cell loss and clinical decline. Using HIV RNA
testing in clinical trials to assess the HIV load in patients on
various treatment regimens, researchers may be able to predict with
reasonable certainty which drugs will work best for a particular
patient or group of patients. These new assays may dramatically
shorten the amount of time necessary to test drugs in patients prior
to approval and marketing. One result of this would be tremendous
cost savings in research and more rapid patient access to promising
drugs.

       ****************
       ****************
       Kaposi's Sarcoma

       Harvey S. Bartnof, MD

       Harvey S. Bartnof, MD, has been a member of the Scientific
       Advisory Committee at the San Francisco AIDS Foundation since
       1987. He has been Course Director of  "AIDS-HIV: Overview and
       Update" at the University of California at San Francisco
       School of Medicine since 1985.

       In 1981, the Centers for Disease Control and Prevention (CDC)
published a report of 21 cases of Kaposi's sarcoma (KS) among
previously healthy gay/bisexual men from California and New York
City. This outbreak represented the beginning of the recognized AIDS
epidemic. Even in 1996, KS is the most common tumor in people with
AIDS. When compared with the risk for HIV negative people, HIV
positive people have a more than 20,000-fold increased risk of KS.
The majority of this risk is among men who have sex with men.

       Several advances in KS research and treatment have occurred
in the past few years. These advances include identifying potential
causes and the approval of new treatments.

       Types of KS

       Kaposi's sarcoma can be divided into the following types:

       Classical KS

       Professor Moriz Kaposi Kohn, a Hungarian dermatologist, first
reported the existence of KS in 1872. This relatively slow-growing
type of KS on the legs or feet occurs predominantly among elderly
men aged 50-70 years of Italian (Mediterranean) or Eastern European
(Ashkenazic Jew) descent.

       African KS

       In the 1960s, it was recognized that 9% of all tumors among
men from equatorial Africa were KS. This form of KS is unrelated to
HIV and AIDS. It may be slow-growing like classical KS or it may be
more aggressive, sometimes lethal, particularly among those under 25
years of age.

       Transplant KS

       Transplant patients are given immunosuppressive drugs to help
prevent rejection of transplanted tissue. In 1969, the first case of
KS in a kidney transplant patient was reported; many other such
cases have been reported since. This type of KS also occurs among
patients receiving other types of transplants and among those given
immunosuppressive steroid drugs for other conditions. In some of
these patients, KS regresses when immunosuppressive drugs are
decreased or stopped.

       AIDS-KS

       Between 1992 and 1994 there were over 11,000 reported cases
of AIDS-KS among adults in the U.S. Due to underreporting, the CDC
estimates that there were over 15,000 cases during those 3 years. KS
is the cause of death in approximately 10-12% of people with AIDS.

       Non-AIDS KS in Gay/Bisexual Men

       KS has also been recognized among gay/bisexual men who are
negative for HIV by antibody, p24 antigen, viral culture and PCR
tests. HIV negative KS is slow-growing, similar to classical KS.

       Insights Into the Causes of KS
       ------------------------------

       Relevant Epidemiology

       Population-based studies have provided insights into
potential cause(s) and mechanism(s) of KS:

       Male Predominance

       Male predominance is quite striking in all types of KS. In
classical KS, males outnumber females almost 15 to 1; in African KS,
13 to 1; and in kidney transplant patients, 2.5 to 1. In AIDS-KS,
U.S. men currently have an approximate 10-fold higher risk of KS
than women; it occurs among 9.8% of men and 1.2% of women with AIDS.
The only group with an equal number of males and females with
AIDS-KS is U.S. children under age 13.

       Behavioral Risk Differences

       From 1985 to 1992, KS was the AIDS-defining illness in
approximately 20% of all gay/bisexual men with AIDS. Even more men
developed the tumor at some time during the course of AIDS. This
percentage has decreased as the AIDS epidemic has progressed. During
the 1992-1994 period, 14% of gay/bisexual men with AIDS developed
KS. This reduction may be due to increased safer sex practices
and/or to underreporting of cases.

       All other behavioral risk categories have much lower rates of
KS: injection drug users (2.3%), transfusion recipients (2.1%),
heterosexual contact (1.7%), hemophiliacs (1.1%) and
mother-to-newborn (0.3%). Altogether, 8% of all U.S. adults with
AIDS have KS.

       Risks Among Women

       In the U.S. and Europe, the greatest risk for KS among women
is heterosexual contact with a bisexual man. Women with KS from the
U.S. and Europe were more likely to have been born outside of the
U.S., predominantly in the Caribbean or Africa.

       Risks Among Children

       While not statistically significant, U.S. children with
AIDS-KS were 2.5 times more likely to have a mother who acquired HIV
by sexual contact with a gay/bisexual man than to have a mother who
acquired HIV by other means.

       Geographic Location

       Unlike many AIDS-related conditions that have little
geographic variance, KS patients are 70% more likely to be from a
metropolitan area with a population greater than 1 million. In the
1980s, a risk factor for KS among European and Australian
gay/bisexual men with AIDS was sexual contact in a large U.S. city.

       Genetic Marker Differences

       Studies of KS patients indicate a high prevalence of the
human leukocyte antigen (HLA) markers DR5, B35 and C4. The
protooncogene (cancer gene) c met and the p53 cancer gene mutation
may be also be cofactors in the development of KS.

       Racial/Ethnic Differences

       In the U.S., adult Caucasians have a 3-fold increased risk
for KS compared to African-Americans. The opposite is true for U.S.
children with AIDS: African-American children have a 3-fold
increased risk for KS compared to Caucasian children. In the U.S.,
all other racial/ethnic groups are represented among AIDS-KS cases,
including Latino, Asian/Pacific Islander, Alaskan Native and
American Indian.

       Specific Sexual Practices

       Several epidemiologic studies of gay/bisexual men have
demonstrated that certain practices are associated with an increased
risk for developing KS. Such practices include unprotected: (1)
oral-anal contact (rimming); (2) receptive anal intercourse with or
without rectal gonorrhea; and (3) receptive hand-anal insertion
(fisting). Several studies have linked the recreational use of
inhalant amyl nitrite (poppers) with KS, however not all studies
demonstrate the association, and an association does not indicate
causation. The use of these agents is highly correlated with unsafe
sexual practices that likely facilitate the transmission of sexually
transmitted diseases (STD). Amyl nitrite dilates blood vessels and
is considered a sexual stimulant.

       The combination of these epidemiologic factors leads to the
hypothesis that KS probably involves a sexually transmitted agent or
co-factor under the influence of sex hormones and genetic markers.
The agent may be transmitted from mother to newborn. The possibility
of another mechanism of transmission exists early in life, probably
in childhood, in developing countries.

       A New Herpesvirus: a Cause of KS?

       Certain viruses are known causes of cancer. In the past,
several infectious agents have been hypothesized to be associated
with KS, including cytomegalovirus (CMV), Epstein-Barr virus (EBV),
human papillomavirus (HPV), hepatitis B virus, Mycoplasma penetrans,
human herpesvirus type 6 (HHV-6) and human herpesvirus type 7
(HHV-7). With the possible exception of HPV, none have been
definitively linked with KS.

       In December 1994, a research team from Columbia University
published findings of a new human herpesvirus as the possible cause
of KS (see BETA, March 1995, page 10 and BETA Treatment Alert,
December 20, 1994). Molecular biologist Yuan Chang, MD,
epidemiologist Patrick Moore, MD, and their colleagues published
data in the journal Science. Over the last 14 months, over 35
research papers have appeared on this new herpes virus. It has been
called both Kaposi's sarcoma-associated herpesvirus (KSHV) and human
herpesvirus type 8 (HHV-8). Donald Ganem, MD, and colleagues from
the University of California at San Francisco have isolated and
grown KSHV in vitro.

       The Chang and Moore team used a unique method of amplifying
DNA sequences called representational difference analysis (RDA),
followed by polymerase chain reaction (PCR). The method isolates
unique DNA sequences found only in diseased but not normal tissues
from the same individual.

       Chang, Moore and co-workers isolated the unique herpesvirus
sequences from: (1) 93% of 27 AIDS-KS tissue samples, (2) 11% of 27
AIDS-related lymphoma tissue samples, and (3) 25% of lymph node
samples from people with AIDS who did not have KS. They also found
the sequences in normal appearing skin biopsies adjacent to KS
lesions in 2 patients. They were unable to isolate the sequences
from control samples including other organs from the same AIDS-KS
patients, opportunistic infection biopsies from other AIDS patients
and various biopsies from HIV negative people.

       Chang and Moore noted that the unique sequences were
dissimilar to other human herpesviruses, except for a 56% homology
(similarity) with EBV. EBV is associated with lymphoma, nose-throat
cancer and HIV-related oral hairy leukoplakia. In addition, the new
virus sequence had a 55% homology with herpesvirus saimiri, a cause
of lymphoma in New World monkeys. Chang and Moore concluded that
KSHV represents a new human herpesvirus.

       Since the original report of KSHV, numerous laboratory groups
worldwide have reported finding KSHV DNA sequences in all types of
KS and in various bodily tissues.

       KSHV has been detected in KS tissue from men, women and
children. In the lymph nodes of asymptomatic HIV positive persons
with persistent lymphadenopathy, KSHV has been detected among
gay/bisexual men, but not among injection drugs users or
heterosexual men. In skin cancers (squamous cell and basal cell
carcinomas), KSHV has been detected among immunocompromised
transplant patients, but not among immunocompetent patients.
Similarly, benign skin tumors (actinic and seborrheic keratoses)
from immunocompromised transplant patients contain KSHV, but those
from immunocompetent patients do not.

       The CDC was able to find KSHV in semen samples from 30 of 33
(91%) HIV positive gay/bisexual men. Also, they found the virus in 7
of 30 (23%) control HIV negative healthy male semen donors. The
sexual orientation of the controls was not stated. Half were CMV
positive and half were CMV negative. Preliminary results of this
study were discussed in the December 1995 issue of BETA (page 30).

       Contrasting with the CDC, Jay A. Levy, MD, and co-workers,
from the University of California at San Francisco, have been unable
to isolate KSHV from seminal fluid or cells from AIDS-KS patients.
Neither were they able to isolate KSHV from fluid or cells in
saliva. Levy's group has determined that the blood cells containing
KSHV are B-lymphocytes.

       When examined by the laboratory of D. Whitby, R. Weiss, PhD,
and colleagues, of the University College London School of Medicine,
KSHV was detected in none of 18 stool samples and in only 1 of 21
throat swab samples from AIDS-KS patients (the 1 patient with throat
swab KSHV had KS in the lung). The authors state that the lack of
KSHV in the stool is not inconsistent with the epidemiologic finding
of an increased risk of KS with oral-anal contact. They believe that
the virus would be expected to be found in immune cells of the
rectal lining. Additional studies are necessary.

       Alvin Friedman-Kien, MD, and colleagues from New York
University have found that KSHV DNA is localized to the nuclei of
the abnormal spindle-shaped cells that are characteristic of KS.
Whitby and co-workers have also localized KSHV to KS spindle cells,
in addition to finding the virus in KS endothelial lining cells.

       Robert Gallo, MD, of the Institute for Human Virology at the
University of Maryland, is skeptical that KSHV is the cause of KS
because his laboratory cannot isolate the virus from established KS
cell lines in vitro. However, KS cell lines in vitro appear to be
unable to sustain the virus. C. Lebbe and colleagues from the
Hpital Saint-Louis in Paris, France have found KSHV in original
primary cell cultures of KS cells. However, KSHV recovery decreases
with subsequent passages (growth cycles) in vitro. They found that
KS cell cultures were all negative for KSHV by the third and fourth
passage. Moreover, Yuan Chang agrees with the findings of Lebbe and
colleagues.

       Predicting KS by Finding KSHV in the Blood or Semen

       Researchers from the Institute of Cancer Research and
University College London Medical School have determined that the
presence of KSHV in blood mononuclear cells is predictive of the
future onset of KS. They followed 143 HIV positive people without KS
for a median of 30 months. Eleven of 143 initially were positive for
KSHV by blood testing; 6 of them (55%) developed KS within 30
months. This compared with 12 who developed KS out of 132 (9%) who
initially were KSHV negative. Moreover, those with detectable KSHV
in their blood progressed to KS disease much faster than those
without blood KSHV who progressed to KS disease. Those with KSHV in
the blood had a lower CD4 cell count (median 120 cells/mm3) compared
with those without KSHV in the blood (median 300 cells/mm3). All of
these findings were statistically significant. However, at the time
of blood testing, both the KSHV positive and KSHV negative groups
who later progressed to KS disease were similar in their CD4 counts.
A similar proportion of both groups also had other AIDS diagnoses.
The authors have calculated that 50% of those with KSHV in the blood
will progress to clinical KS within 3.5 years.

       Researchers from the London Children's Hospital detected KSHV
in the blood of a 6-year-old African girl 2 years before she
developed KS. After chemotherapy for the tumor, the KS regressed and
KSHV was undetectable in her blood. When her KS relapsed, her blood
also revealed that KSHV had returned. The authors, D. Shingadia and
colleagues, concluded that not only was blood KSHV predictive of KS
disease, but that it correlated with treatment efficacy and relapse.

       During a 5-year follow-up period, 13 of the 30 men (43%) in
the CDC study described earlier who had KSHV in their semen
developed KS disease. None of the 3 KSHV negative HIV positive
gay/bisexual men developed KS.

       Previously, BETA (March 1995, page 72) reported on research
that indicated that KS disease could be predicted by the finding of
KS spindle cells in the blood. Gallos group found KS-like spindle
cells in the blood of 25 HIV positive gay/bisexual men with KS
disease and in 27 HIV positive gay/bisexual men without KS disease.
When compared with HIV negative controls, those with KS disease had
a 78-fold higher level of KS spindle cells in their blood, while
those without KS disease had an 18-fold higher level. The level
among HIV positive injection drug users was similar to that of
controls. The authors conclude that the presence of KS-like spindle
cells in the blood may be predictive of developing KS disease.

       Is KSHV Treatable with Foscarnet or Ganciclovir?

       Other evidence supporting a viral cause of KS was reported in
1994 by Linda Morfeldt, MD, and colleagues from the Karolinska
Institute in Sweden (see BETA June 1995, pages 58-59). They reported
that KS tumors resolved in 3 of 4 AIDS patients who were treated
with foscarnet (Foscavir), a drug that is FDA-approved to treat CMV
disease. Foscarnet is active against many viruses, including HIV and
5 herpesviruses. Two of the 3 patients were treated for 20 days. The
third patient had two 20-day treatment courses. Resolution of KS
occurred after 1.5 to 13 months.

       In addition, other treatment-related epidemiologic evidence
supports a viral cause of KS. In February 1995, the CDC reported
that AIDS patients who were treated with foscarnet for any reason
were 70% less likely to develop KS than those not treated with the
drug. The findings were statistically significant. There were no
benefits in preventing KS for AIDS patients treated with ganciclovir
(Cytovene) (see BETA, June 1995, page 59).

       Lastly, a report at the September 1995 Interscience
Conference on Antimicrobial Agents and Chemotherapy (see BETA,
December 1995, page 30) also suggested that certain CMV treatments
may help prevent the development of KS. In the Multicenter AIDS
Cohort Study (MACS) from 4 U.S. cities, foscarnet treatment for CMV
disease conferred a 60% decreased risk of subsequent KS. Moreover,
ganciclovir treatment for CMV disease conferred a 44% decreased risk
for subsequent KS. However, these results were not statistically
significant.

       The National Cancer Institute, under the auspices of Robert
Yarchoan, MD, is planning a trial of foscarnet as a treatment for
KS.

       It is unproved whether foscarnet or ganciclovir has activity
against the new KSHV. Before this can be tested, KSHV must be fully
isolated and cultured. KSHV likely represents part of the cause of
KS, probably early in the cascade of events leading to KS tumor
development. Undoubtedly, future research will yield more
information surrounding KSHV and its role in AIDS-KS and other
conditions. One future goal will be the development of a simple
blood test to screen large numbers of people in the general
population and HIV cohort groups.

       Other Causes of KS

       KS is a Disease Due to Abnormal Growth Factors

       Gallo's research group was the first to cultivate KS spindle
cells in vitro. Their research and the research of other groups has
shown that the growth of KS cells in vitro requires specific growth
factors, including cytokines. Some of these factors must be added to
the cultures, while others are derived from the cells themselves.
Removal of 1 or more of these factors causes inhibition of KS cell
growth. Such factors include: platelet-derived growth factor,
platelet activating factor, basic fibroblast growth factor,
transforming growth factor beta, interleukin 1, interleukin 6, HIV
tat protein, tumor necrosis factor, granulocyte-macrophage
colony-stimulating factor, oncostatin M and others. Recognition of
the various factors is important, since the development of drugs
that block their actions would represent viable forms of therapy to
treat KS.

       The proof that these cells can induce KS is shown when they
are injected into an immunodeficient mouse species. At the injection
sites, transient lesions occur that have the clinical and
microscopic appearance of KS. The evidence indicates that the
injected cells secrete factors that recruit local mouse cells to
become KS-like cells. In addition, the factors promote blood vessel
growth, a necessary component of the KS tumor.

       The various growth factors for KS likely represent part of
the cause of KS.

       Hormones as Co-Factors for KS

       The male predominance of almost all forms of KS has led to
the long-held theory that KS may be under the regulatory influence
of sex hormones or some other genetic factors associated with the
sex chromosomes. There are several lines of evidence to support the
sex hormone co-factor hypothesis.

       Beta-HCG

       One line of evidence comes from the clinical observation that
pregnancy caused the resolution of KS in 2 women with AIDS. First
reported by Gallo at the X International Conference on AIDS in 1994,
the published report appeared in the May 4, 1995 issue of Nature.
The first woman's KS lesions were completely resolved 5 months after
delivery, without any treatment. The other woman's KS lesions
resolved after 2 months of pregnancy.

       Gallo also reported that the beta chain of the pregnancy
hormone human chorionic gonadotropin (b-HCG) blocked the growth of
KS cells in vitro. Also, injecting b-HCG into immunodeficient mice
after KS cells were injected blocked the development of KS lesions.
Similarly, pregnant immunodeficient mice injected with KS cells did
not develop KS, whereas non-pregnant mice and male mice similarly
injected with KS cells did develop KS lesions. Gallo's group has
shown that b-HCG leads to KS cell death both in vitro and in vivo
(in mice) by apoptosis (programmed cell death).

       Initial reports of treating AIDS-KS patients with b-HCG have
been mixed. P.J. Harris, MD, from the AIDS Clinical Research Center
of Washington, DC, reported in the July 8, 1995 issue of Lancet on
the use of b-HCG intramuscularly in 6 AIDS-KS patients. Injections
of 150,000-700,000 international units (IU) 3 times per week led to
marked tumor regression in all 6 (time frame was not stated).
Toxicities included injection site pain and skin retraction around
the resolved KS lesions. If the dose was less than 100,000 IU or if
a dose was delayed, KS recurred. Regression persisted until
financial constraints forced a tapering of the dosage.

       Two other research groups from England and Switzerland have
reported no benefits from injected b-HCG for AIDS-KS, although
neither group used doses as high as Harris did.

       The results of the 3 groups of AIDS-KS patients totaling 13
people are not inconsistent. Future trials are certainly
appropriate. Since b-HCG has an 85% homology with the beta chain of
luteinizing hormone (LH), it is possible that LH might achieve
similar anti-KS effects. LH regulates the testes and ovaries. Gallo
hypothesizes that women have lower rates of KS because: (1) LH
levels are higher in women than in men, and (2) women of
child-bearing age have monthly surges of LH that occur with
ovulation.

       Testosterone, Estrogen, DHEA

       The level of male sex hormones in men with AIDS-KS has been
reported to be low by some researchers and high by others. N.
Christoff, MD, and colleagues, from Paris, France, reported in June
1995 that levels of the androgens (male hormones) testosterone and
dehydroepiandrosterone (DHEA) were higher in men with AIDS-KS than
in either HIV positive men without KS or HIV negative control men
(these are considered male hormones although women also produce
small amounts of each). Both the KS group and the HIV positive/KS
negative group had higher levels of the female hormones estradiol
and progesterone than the HIV negative control group. The report was
in Journal of Clinical Pathology (see BETA, December 1995, page 49).

       Nearly opposite findings were reported the September 1995
issue of AIDS by S. Klauke, MD, and colleagues from the Buerger
Hospital in Frankfurt, Germany. Testosterone and estradiol levels
were both significantly lower in men with AIDS-KS than either men
with AIDS who did not have KS or asymptomatic HIV positive men.
Levels of LH and follicle stimulating hormone (FSH) were higher than
they were in either men with non-KS AIDS or asymptomatic HIV
positive men. Like LH, FSH regulates the testes and ovaries. DHEA
levels were not reported. This research group has previously
reported that estrogen levels are similarly low in women with
AIDS-KS.

       The apparently conflicting findings regarding abnormal levels
of sex hormones need to be resolved. It is likely that some
confounding factors are causing the discrepancy. These may include:
patients' medications, current or past KS therapies, individual
variations in hormone levels, sampling differences and/or laboratory
techniques.

       Glucocorticoids

       The glucocorticoid steroid hormones increase the growth of KS
in vivo and in vitro. The first recognition of this was in KS among
transplant patients treated with prednisone, a immunosuppressive
glucocorticoid steroid. Other examples of glucocorticoids include
cortisone, hydrocortisone and dexamethasone (DEX). Clinically,
treatment of AIDS patients with any of these steroids increases the
risk of developing KS. RU-486 is a glucocorticoid receptor
antagonist and an experimental abortion-inducing pill. Adding RU-486
to KS cells in vitro with DEX blocks the stimulatory effects of the
DEX.

       Additional research on sex hormones and other hormones will
probably lead to new treatments for KS in the next few years.

       Is KS a True Cancer?

       The issue of whether KS is a true cancer is controversial. A
true cancer arises from 1 abnormal cancer cell that repeatedly grows
and divides, becoming a clone of cells. The clone in turn will grow
into a tumor mass. In some cancers, a group or groups of cells can
break off, travel and start growing in other bodily locations
(metastasis). However, all the cells in that cancer began from the 1
original malignant cell; that cell type can be seen in the
microscope when a biopsy of the cancer is taken.

       When viewed under the microscope, KS does not have just 1
cell type. There are several cell types in KS, including spindle
cells (the main abnormal cell in KS), fibroblasts, inflammatory
white blood cells and red blood cells that have leaked out of blood
vessels. That there is more than 1 cell type in KS speaks against
its being a true cancer. Microscopic examination also reveals small
blood vessel slits.

       Instead, KS is thought to be a multicentric tumor, that is,
an abnormal proliferation of cells that occurs in several locations
at the same or different times under the regulatory growth of
cytokines, other growth factors, sex and other hormones and possibly
KSHV.

       It is also possible that the slow-growing forms of KS may
represent a hyperproliferative (excessive growth) state under the
regulation of several factors, whereas the more aggressive forms may
result from true malignant transformation (cancer).

       Clinical Manifestations, Symptoms and Diagnosis of AIDS-KS
       ----------------------------------------------------------

       Clinical Manifestations

       KS can occur anywhere on the skin, in the mouth or on any
mucous membrane lining. Common locations are the mouth, neck and
head, particularly the tip of the nose or behind the ears. Common
internal organs involved include the lung and intestines. When found
on the skin, KS also occurs in the intestinal tract 40% of the time.

       KS occurs on the skin most commonly as nodules, raised round
or oval hard lumps. The size of the nodules is usually 0.5-2.0 cm
(3/16-3/4 inches) in diameter. In light-skinned individuals, the
color is usually violet, bluish or reddish (reflecting the presence
of red blood cells). In dark-skinned individuals, the color is more
brown or black. A bruise-like discoloration and minor swelling often
appear at the edges of the KS nodules when they are enlarging. Less
commonly, KS skin nodules can ulcerate, bleed and become secondarily
infected.

       Before the KS has grown to full nodule size, it may first
appear flat with a pink or blood-bruise color (patch stage). Often,
1 or 2 KS lesions in the patch stage may go unnoticed by the
patient.

       When many nodules are present on the skin, they often appear
in patterns, with symmetry on both sides of the body. The patterns
can be linear or slightly curved, following the skin fold lines
(Langer's lines).

       Sometimes, the KS can form large plaques on the skin, with
larger raised areas of skin involved. Common locations are the
thighs and soles of the feet. Often, there is painful swelling
involved.

       KS in the mouth is common, often on the roof (palate) or
gums. The color is usually violet or red. On the roof of the mouth,
KS is usually flat. Sometimes mouth KS can swell, bleed or ulcerate.

       Less commonly, 1 or more lymph nodes may be involved without
skin involvement. This form of KS can also cause potentially painful
swelling.

       The clinical course of AIDS-KS is usually progressive over
time. Flat lesions tend to grow into nodules and new lesions appear.
Often, an opportunistic infection will cause an accelerated growth
of KS. However, there can be periods of weeks to months when the KS
remains stable in size, shape and number.

       KS is not a common cause of death among AIDS patients. In
1987, KS was the cause of death in 10% of AIDS patients. By 1992,
this number increased slightly to 12%. However, death often occurs
when KS is in the lungs.

       Symptoms

       Usually, skin KS does not cause symptoms of pain or itching.
Larger lesions can be painful. There can be associated swelling,
particularly on the face or legs, and this may be painful. KS on the
soles of the feet may be painful when walking.

       When KS occurs in the mouth, usually there are no symptoms.
Sometimes, however, there can be swelling, bleeding and ulcers, with
associated pain. Uncommonly, KS in the mouth or throat may cause
difficulties with chewing or swallowing.

       When KS occurs in the intestines, usually there are no
symptoms. Sometimes, however, internal bleeding or a blockage with
pain can occur. A blockage can also cause nausea and vomiting.
Intestinal KS is associated with malabsorption of nutrients.

       The most serious organ involvement is KS of the lung. There
may be shortness of breath, wheezing and a cough that is usually
dry, but can be bloody. Lung KS is life-threatening.

       Sometimes, KS is associated with fevers, night sweats and
weight loss. However, these symptoms are common in AIDS, and are
often due to an associated opportunistic infection.

       Diagnosis

       The diagnosis of KS usually is made by taking a biopsy or
piece of the KS lesion. On the skin, a small punch biopsy is used.
The biopsy specimen is then examined under a microscope to look for
typical abnormalities. For KS of the internal organs, a biopsy may
be obtained during endoscopy or bronchoscopy. While the patient is
sedated, a narrow flexible tube with a lens tip is inserted into
either the swallowing tube, stomach and small intestines or the
rectum and colon (endoscopy) or the windpipe and lungs
(bronchoscopy). Sometimes, the KS is deep enough under the mucosal
lining that the biopsy misses the KS. Taking a biopsy of the
windpipe or lungs may be risky, sometimes causing a lung to
collapse. This is a treatable complication, however.

       According to CDC protocol, a presumptive diagnosis of AIDS-KS
may be made without a biopsy if: (1) the person has documented HIV
infection, and (2) there is an erythematous (red) or violaceous
(purple) plaque-like lesion on the skin or mucous membrane. Through
1994, 17% of U.S. AIDS-KS cases were made presumptively, while the
remaining 83% were made definitively with a biopsy.

       Routine blood tests are performed, including complete blood
counts, CD4 cell counts and possible viral load testing. Sometimes,
skin tests are done to help measure immune functioning.

       In the future, it is possible that blood levels of KSHV,
spindle cells, growth factors and certain hormones may be measured
to aid in the diagnosis of KS, or to follow up when therapies are
given.

       Treatment for KS
       ----------------

       There is no cure for AIDS-KS, and treatments for KS are not
associated with a prolongation of life. However, KS treatments can
markedly improve the quality of life and ameliorate symptoms caused
by the disease. Improving the cosmetic appearance of KS lesions
often improves peoples outlook as well. KS treatment is helpful
when there are painful lesions, bulky lesions, associated swelling,
lung or intestinal KS symptoms, rapidly progressive disease or
disfigurement.

       After a diagnosis of KS is made, several factors enter into
the decision as to the type(s) of therapy:

       * What is the total KS tumor burden (total quantity or volume
         of KS in the body)?

       * What is the state of the immune system? Is the CD4 cell
         count low or normal?

       * Are there associated symptoms of fever, night sweats or
         weight loss?

       * Were there any prior opportunistic infections?

       * What is the overall functional ability of the patient?

       A better prognosis for KS is expected when: (1) there is a
low tumor burden, (2) the CD4 cell count is normal or only mildly
decreased, (3) there are no associated symptoms of fever, night
sweats or weight loss, (4) there have been no prior opportunistic
infections, and (5) the patient has essentially normal functional
capabilities.

       For those with minimal KS disease that is stable or only
slowly progressive, the choice may be observation only. When the KS
appears to be increasing in number or size, or if there are
associated symptoms, a decision may be made to initiate appropriate
therapy. Treatments for KS fall into 2 categories, local and
systemic.

       Local Therapies

       Due to the disfigurement and stigma of skin and mouth KS,
local therapies are often indicated. One should be mindful, however,
that KS is a systemic disease, and that new lesions are likely to
appear in the future.

       Radiation Therapy

       Localized radiation therapy (radiotherapy) is very effective
for those with a single lesion or a localized group of lesions. It
is effective for relieving localized swelling, particularly on the
face, and less so on the legs. Painful or cosmetically displeasing
lesions are often successfully treated with radiotherapy. The
eyelids and conjunctiva (white parts of the eye) respond well to
radiotherapy. Mouth and throat KS can be treated this way as well,
although painful inflammation of the mucous membranes (mucositis) is
a common side effect. For this reason, many clinicians try to avoid
radiotherapy to the mouth. Toxic side effects limit the use of
radiotherapy for the soles of the feet. Symptoms associated with
lung or intestinal KS can be improved temporarily with radiotherapy.

       Localized Chemotherapy Injections

       Small KS lesions on the skin or in the mouth may be
successfully treated with 1 or more injections of chemotherapy.
Injecting directly into the KS lesion is somewhat painful, and
sometimes repeated injections are necessary for an optimal cosmetic
result. Usually, diluted vinblastine (Velban) is used. Vinblastine
therapy may leave some hyperpigmentation (darkening of the skin),
even after the lesion has resolved. Response rates are 92%, for a
mean duration of 4.5 months (including complete and partial response
rates). Some oral surgeons and dentists may use sodium tetradecyl
(Sotradecol) for lesions in the mouth. Multiple local injections of
interferon alpha (IFN-a) have also led to significant response rates
of individual lesions.

       Cryotherapy

       Freezing a lesion on the skin with liquid nitrogen
(cryotherapy) has also proved successful in treating unsightly skin
lesions, especially on the face. Cryotherapy is usually reserved for
thinner skin areas on the face and the thin skin of the genitals.
Often, the lesion needs more than 1 treatment. Response rates are
88%, including complete and partial responses. Cryotherapy is most
successful if the KS lesion is smaller than 4/5 inch in diameter and
flat, not nodular.

       Systemic Therapies

       When KS is widespread, rapidly progressive or in more than 1
organ, systemic therapy is indicated. Since most of the systemic
therapies for KS have toxic side effects, often to cells of the
immune system itself, sometimes the side effects may outweigh the
potential benefits of therapy. There are several cancer
chemotherapies that lead to significant response rates in KS. The
chemotherapies may be single drugs or combinations of drugs.

       Vincristine and Vinblastine

       Both vincristine (Oncovin) and vinblastine are active against
AIDS-KS. These 2 drugs are often given as a single drug at a time
alternating weekly with the other drug, to minimize toxicities.
Vincristine can cause peripheral neuropathy (pain and tingling in
the feet, legs and hands). This may be increased when taking
anti-HIV therapies that also cause peripheral neuropathy, including
ddI (Videx) and ddC (Hivid). Vinblastine can cause toxicity to the
bone marrow, leading to low white cell counts (neutropenia) and
increased risk of infection. Low white cell counts may be offset by
using the white cell boosters granulocyte colony-stimulating factor
(G-CSF [Neupogen]) or granulocyte-macrophage colony-stimulating
factor (GM-CSF [Leukine]).

       Etoposide

       Etoposide (VP-16) is an active agent against KS, but is not
usually a first choice drug. It is available in an oral formulation,
an attractive characteristic. However, like some cancer therapies,
it can cause reversible hair loss. This side effect makes it
somewhat unattractive when KS is being treated for cosmetic
purposes.

       Doxorubicin

       As a single agent, doxorubicin (Adriamycin) has significant
activity against AIDS-KS. It is helpful for those who have not
responded to other therapies or for those with more advanced
disease. This agent is toxic to white blood cells. Triple
combination therapy with doxorubicin, bleomycin and vincristine
(ABV) is more effective than doxorubicin alone.

       In late 1995, the FDA approved a new formulation of
doxorubicin called Doxil (liposomal doxorubicin). The drug is
encapsulated in liposomes (fat bubbles). This allows for greater
uptake of the drug by KS cells and fewer toxicities. In one study,
the concentration of drug in KS cells was 5-10 times higher with the
new formulation than with the non-liposomal type. Doxil is approved
for those whose KS has progressed while on prior combination therapy
or those who were intolerant to such treatment. Phase II studies
have yielded an 80-100% response rate to the new formulation and its
first cousin, liposomal daunorubicin. A study of Doxil was presented
at the December 1995 American Society of Hematology meeting in
Seattle by Donald Northfelt, MD, and colleagues, from the University
of California at San Francisco. In 228 AIDS-KS patients with
extensive, progressive disease (skin and mouth and/or internal
organs), Doxil was significantly more effective than ABV in
producing partial or stable responses. Also, side effects were more
favorable in the Doxil group. Side effects for Doxil and ABV,
respectively, were: fever (24%, 37%), nausea (31%, 56%), neuropathy
(5%, 9%), leukopenia (low white cells: 44%, 47%), and severe
toxicities (54%, 66%). Bone marrow toxicity appears to be similar
with the liposomal and non-liposomal formulations of doxorubicin.
One Doxil patient and 6 ABV patients had progressive disease.

       Daunorubicin

       FDA approval has been granted for the first liposomal
derivative of daunorubicin (DaunoXome) for advanced AIDS-KS; exact
labelling is now being worked out. It is closely related to
doxorubicin. KS response rates were in the 80-100% range in Phase II
trials of the drug, significantly higher than response rates with
older regimens. Toxicities with liposome-encapsulated daunorubicin
and doxorubicin reveal lower rates of vomiting, mouth inflammation
and hair loss than non-liposomal formulations.

       Doxorubicin plus Bleomycin and Vincristine

       Triple combination chemotherapy with doxorubicin, bleomycin
and vincristine (ABV) is well tolerated and successful in treating
AIDS-KS that is widespread, including cases involving the lung
and/or swelling of the extremities. Sometimes, 1 treatment with the
3 drugs can lead to marked improvement of leg swelling and shortness
of breath. Due to pre-existing low white cell counts, sometimes
bleomycin and vincristine are used as a double therapy without
doxorubicin. Alternatively, GM-CSF or G-CSF may be added to the
triple therapy. Common AIDS drugs that cause low white cell counts
include AZT (Retrovir), ganciclovir (Cytovene) and sulfa-containing
drugs (e.g., Septra, Bactrim).

       Alpha Interferon Alone or with Anti-HIV Therapy

       Alpha interferon (IFN-a [Intron A, Roferon A]) with or
without AZT has shown significant benefit in treating AIDS-KS. It is
used alone for those with progressive disease with minimal or no
symptoms and with a CD4 cell count greater than 200 cells/mm3. The
drug does not work as well when the CD4 cell count is low or if
there have been prior opportunistic infections. IFN-a has anti-tumor
and anti-HIV effects. When used alone, a dose greater than 20
million units/meter2 daily has led to the highest response rate.
However, side effects are significant, including flu-like symptoms
(fever, weakness, sweats, fatigue), loss of appetite and weight
loss. Long-term treatment with the drug can be difficult because
some of these symptoms persist. Response to IFN-a may take as long
as 1-2 months. Optimal response may take 6 months. If patients
respond to the drug and can tolerate it, treatment continues
indefinitely. Otherwise, KS returns when IFN-a is stopped. Patients
can give themselves injections of IFN-a, obviating the need for a
clinic or office visit for therapy.

       Combining AZT with IFN-a is a common drug regimen used to
treat AIDS-KS. When used with AZT, a lower dose of IFN-a is used,
4-18 million units/meter2 daily. Low white cell counts are common
with this regimen, often requiring the use of GM-CSF or G-CSF. Even
though a lower dose of IFN-a is used with AZT, the response rate is
better using the 2 drugs than IFN-a alone.

       One recent study evaluated the use of an even lower dose of
IFN-a with AZT for early limited but progressive KS. In 1995, S.
Mauss, MD, and H. Jablonowski, MD, from the Heinrich-Heine
University in Duesseldorf, Germany, reported their findings in the
Journal of Acquired Immune Deficiency Syndromes and Human
Retrovirology. They treated 17 AIDS-KS patients who had a median of
8 lesions. All had skin KS; 3 also had oral KS, and another 7 also
had lymph node or intestinal KS. The median entry CD4 cell count was
315 cells/mm3. The researchers used an IFN-a dose of 3 million units
injected 3 times weekly along with AZT 250 mg twice daily.

       A complete response occurred in 3 of 17 patients (18%), while
a partial response occurred in 8 of 17 (47%). Stable disease
occurred in 2 of 17 (12%), while progressive disease occurred in 4
of 17 (24%). KS tumor reduction was documented after 6-8 weeks among
responders. Those with complete responses had CD4 counts greater
than 513 cells/mm3, while those with progressive disease had CD4
counts less than 222 cells/mm3. Remissions among responders were
maintained for a median 2.5 years while still taking IFN-a and AZT.
Such responses are similar to or slightly better than responses in
earlier studies using higher doses of IFN-a. Side effects were much
milder than those observed with higher doses of IFN-a. Mild flu-like
symptoms occurred. No patient required white cell boosters since
severe neutropenia did not occur. The authors conclude that this
low-dose regimen of IFN-a plus AZT for AIDS-KS patients with a low
tumor burden and CD4 cell counts greater than 250 cells/mm3 has a
substantial and sustained antiproliferative (anti-KS) effect. They
recommend large scale studies.

       It remains to be seen whether using IFN-a with other anti-HIV
drugs will be better than a combination with AZT alone. It will be
particularly interesting to see whether combining IFN-a with AZT and
3TC (Epivir) and/or a protease inhibitor (e.g., saquinavir
[Invirase]) will yield even better responses than the double
combination of IFN-a and AZT.

       Photodynamic Therapy

       Photodynamic therapy for AIDS-KS, which involves exposure to
ultraviolet light after the ingestion of hematoporphyrin
(Photofrin), has led to disappointing cosmetic results due to
scarring and increased pigmentation. Lower doses may have more
favorable results.

       Experimental Therapies
       ----------------------

       Retinoic Acid Derivatives

       Currently, Phase I/II studies are underway using the oral
form of 9-cis-retinoic acid (ALRT 1057) and Phase II/III studies are
underway using a topical form. Tretinoin (Retin-A) is in Phase I/II
trials.

       All-trans retinoic acid monotherapy followed by dual therapy
with IFN-a has completed Phase I/II trials. The results were
published in August 1995 in the Journal of Clinical Oncology. At the
doses used, little anti-KS activity was demonstrated.

       LGD 1069

       LGD 1069 (Targretin) is in Phase I/II trials in both an oral
and topical form.

       Topotecan

       Phase II trials are underway for topotecan for KS and for
       lymphoma.

       Paclitaxel

       Paclitaxel (Taxol) is derived from the bark of yew trees.
This experimental therapy has led to a major response rate of 59% in
AIDS patients with advanced or refractory KS, according to a paper
presented at the December 1995 American Society of Hematology
meeting in Seattle. None have had progressive disease. Half of 30
patients had more than 50 lesions, and half had significant
swelling. The lungs or intestines were involved in 27%. A 3-hour
infusion was given every 2 weeks for a median of 5 doses. Swelling
was reduced in 95% of patients.

       Foscarnet

       Foscarnet was discussed earlier in this article. The National
Cancer Institute is planning a trial to treat KS with foscarnet.

       Immune Globulin

       Intravenous immune globulins (IVIG) used to treat
polymyositis (muscle inflammation) has been reported to cause
regression of KS. Human trials or retrospective analyses of HIV/AIDS
cohort groups would seem appropriate.

       Apolipoprotein E

       Apolipoprotein E (Apo E), a subtype of which is associated
with Alzheimers disease, has been shown to block the development of
KS in immunodeficient mice. A Phase I trial in humans is indicated.

       bHormone Therapy

       Trials using experimental therapies such as b-HCG, beta-LH,
and possibly glucocorticoid receptor inhibitors will likely progress
in the next few years. Manipulation of testosterone and estrogen sex
hormone profiles will likely lead to new experimental therapies as
well.

       Angiogenesis and Growth Factor Inhibitors

       Tumors require new blood vessel growth in order to receive
oxygen and nutrients from the blood. An intriguing area of cancer
research involves using experimental therapies that block
angiogenesis, or the formation of new blood vessels. This may be
particularly promising for KS, with its high density of microscopic
blood vessels.

       Many of the growth factors discussed previously are potential
targets for anti-KS therapies. Molecules that bind to the RNA
strands of KS growth factors represent viable candidates for
therapies. One antisense molecule that has shown promise in vitro is
a nucleotide that binds basic fibroblast growth factor, a potent
promoter of blood vessel growth. Other growth inhibitor candidates
include sulfated polysaccharide-peptidoglycan (SP-PG), fumagillin
analog TNP-470, platelet factor 4, interleukin 4 (IL-4, an inhibitor
of IL-6) and HIV tat protein inhibitor. Trials of the latter 3 are
underway. Vitamin D3 and its analogs inhibit KS cell growth in
vitro, possibly by inhibiting IL-6 and IL-8.

       Telomerase Inhibitors

       Telomeres are structures at the end of chromosomes in every
cell. With each normal cell division, the telomeres undergo
progressive shortening. After a predetermined amount of telomere
shortening, cell death occurs. This may be a normal part of the
aging process. Many cancer cells are under an abnormal influence of
telomerase, which inhibits the normal shortening of telomeres. Such
cancer cells are immortal, and they continue dividing, leading to
cancerous growth. Isolating inhibitors of telomerase may lead to
potential cancer chemotherapies, including therapies for KS.

       Hyperthermia

       In one report of heat therapy in 31 patients with widespread
KS and severe immune impairment, a partial or complete response was
seen in 69%, 30 days after the 1-hour treatment. After 1 year, 14%
maintained KS tumor regression. One patient remained in complete
remission 26 months after the therapy; he reportedly became HIV
negative by both culture and PCR test after the treatment. Moreover,
this man had a rise in his CD4 cell count from 250 cells/mm3 to
approximately 800 cells/mm3.  The treatment heats the body to 42 C
(107.6 F), while the blood is circulated out of the body and heated
to 49 C (120 F). Two patients died as a result of the treatment: 1
had a stroke and the other had a lethal abnormal heart rhythm. Two
additional cases had severe bleeding from the procedure
(intravascular coagulopathy).

       References

       Chang Y and others. Identification of herpesvirus-like DNA
sequences in AIDS-associated Kaposis sarcoma. Science 266:
1865-1869. December 16, 1994.

       Charnow J. NCI's Gallo downplays evidence that a herpesvirus
causes KS. Infectious Disease News 8(9):3,9. September 1995.

       Chuck S and others. Frequent presence of a novel herpesvirus
genome in lesions of human immunodeficiency virus-negative Kaposi's
sarcoma. Journal of Infectious Diseases 173:248-251. January 1996.

       Denning P and others. Current trends in the epidemiology of Kaposi's
sarcoma. Centers for Disease Control and Prevention. 35th
Interscience Conference on Antimicrobial Agents and Chemotherapy,
San Francisco, CA, September 17-20, 1995. Abstract and poster I23.

       Harris PJ. Treatment of Kaposi's sarcoma and other
manifestations of AIDS with human chorionic gonadotropin. The Lancet
346:118. July 8, 1995. Kaposi M. Archives of Dermatology and
Syphilology 4: 742-749, 1872.

       Levy JA. A new human herpesvirus: KSHV or HHV8? The Lancet
146(8978):786. September 23, 1995.  Lin J-C and others. Is Kaposi's
sarcoma-associated herpesvirus detectable in semen of HIV-infected
homosexual men? The Lancet 346:1601-1602. December 16, 1995.

       Moore, P and others. Detection of herpesvirus-like sequences
in Kaposi's sarcoma in patients with and without HIV infection. New
England Journal of Medicine 332(18): 1181-1185. May 4, 1995.

       Morfeldt L and others. Long-term remission of Kaposi's
sarcoma following foscarnet treatment in HIV-infected individuals.
Scandinavian Journal of Infectious Diseases 26(6):749-752. 1994.

       Northfelt DW and others. Randomized comparative trial of
Doxil vs Adriamycin, bleomycin, and vincristine (ABV) in the
treatment of severe AIDS-related Kaposi's sarcoma. 37th Annual
Meeting of the American Society of Hematology. Seattle, WA, December
1-5, 1995. Abstract 1515.

       Rady PL and others. Herpes-like DNA sequences in non-Kaposi's
sarcoma skin lesions of transplant patients. The Lancet
345:1339-1340. May 27, 1995.

       Schalling M and others. A role for a new herpes virus (KSHV)
in different forms of Kaposi's sarcoma. Nature Medicine 1(7):
707-708. July 1995.

       Whitby D and others. Detection of Kaposi sarcoma associated
herpesvirus in peripheral blood of HIV-infected individuals and
progression to Kaposi's sarcoma. The Lancet 346:799-802. September
23, 1995.

       **************************************************
       **************************************************
       Report from the 3rd Conference on Retroviruses and
       Opportunistic Infections

       Mary Romeyn, MD

       Mary Romeyn is a member of the San Francisco AIDS
       Foundation's Scientific Advisory Board.

       The tone of this year's 3rd National Conference on
Retroviruses and Opportunistic Infections, held January 28 -
February 1, 1996 in Washington, DC, reflected hope and enthusiasm.
Over the past year, there have been great strides in understanding
the mechanisms of viral activity and HIV disease progression as well
as how to treat and prevent secondary infections. The news about
antiretroviral therapy, particularly the protease inhibitors,
sparked great excitement at the conference.

       Pathophysiology

       How the Virus Works

       Anthony Fauci, MD, of the National Institutes of Health,
       proposed an expanded model of HIV infection and progression.

       Primary infection leads to trapping of virus in the dendritic
cells of the lymph nodes; CD4 cell interaction with the trapped
virus results in infection within the node. Massive replication and
widespread dissemination throughout the entire body follows. Intense
immune response permits partial immunologic control of viral
reproduction, but nonetheless allows viral escape. This escape from
immunologic control sets HIV infection apart from most viral
infections and necessitates further research.

       A state of dynamic equilibrium is reached, formerly known as
the "latency" period, during which the infected individual is
generally asymptomatic. In this state, accelerated viral replication
is opposed by rapid immune cell turnover.

       Clonal Exhaustion

       Initial HIV infection causes CD8 cell expansion. There are 24
basic families, or types, of CD8 cells that can respond by clonal
expansion, or proliferation of cells of a certain family.
HIV-specific cells belong to these families in varying numbers, and
are the only cells activated to expand. In some people, cell
expansion may thus be limited to only 1 family or a few families of
CD8 cells. In others, cloning, or cell proliferation, in response to
infection may occur in a broad range of families. Among HIV positive
people whose response is monoclonal, or involves only 1 family, the
expansion of that family is massive. Ultimately, that family
apparently disappears entirely despite the fact that HIV is still
present. No new family appears, so this disappearance does not
reflect mutation. Rather, Fauci proposed, it disappears because it
has been "used up," or completely destroyed.

       Those who respond to infection with massive monoclonal CD8
cell expansion appear to progress quickly, reflected by a rapid and
continuing drop in CD4 count. Those whose CD8 immune response
involves many families do better. CD4 counts drop less, then return
almost to baseline; further losses are delayed and gradual. An
intermediate rate of progression is seen in people whose pattern of
clonal response falls between the 2 extremes.

       Fauci suggested that viral escape was in part a reflection of
clonal exhaustion. Moreover, a person's initial response to
infection may help forecast the speed of their progression.

       Chemokines

       Following sequestration of the virus in the lymph node, local
secretion of cytokines helps to create a delicate balance which
actually favors HIV replication. Once infection is established,
cytokines are released to keep replication down. These include
interleukin 2 (IL-2), IL-4 and the chemokines, which have been found
to influence the rate of viral replication. Chemokines are produced
locally in response to local irritants or other cytokines.

       To summarize, once the virus is established in the lymph
nodes, the immune system fails to ever completely contain or
eradicate it. Rather, a dynamic equilibrium is reached, with
intensive viral replication opposing intensive immune response.
Fauci postulated 2 newly discovered phenomena underlying the
mechanisms that lead to this state: clonal exhaustion, and the
existence of newly identified soluble mediators of immune response.

       Markers

       Multiple studies have shown that viral load is predictive of
clinical outcome in HIV infection. Its reliability is equal or
superior to that of the CD4 cell count. Viral load testing makes it
possible to assess disease course and prognosis earlier than has
been possible using CD4 counts, offering a rationale for
continuation or change of treatment tailored to individual response.
Its use in research permits more timely and efficient study of
antiretroviral therapies, as efficacy can be seen sooner.

       Another important application for viral load testing relates
to prenatal care for HIV-infected women and prenatal prevention of
vertical transmission. Maternal viral load can help predict the
likelihood of transmission of HIV to a child, as well as length of
survival of infected infants.

       Test results were reproducible for a given patient as long as
the same technology was used. A poster presentation by W. A.
O'Brien, MD, of the Department of Veteran's Affairs in Los Angeles,
and others stated that a change in viral load of greater than or
equal to 0.5 log is a useful indicator of response, particularly
when accompanied by a 10% or greater change in CD4 counts.

       Michael Saag, MD, of the University of Alabama, commented
that the cost of the HIV branched DNA (bDNA) assay to participating
laboratories was about $60. Laboratories charging patients $150 or
more should be asked to justify their pricing.

       Nutrition

       Carl Grunfeld, MD, of the University of California at San
Francisco, reviewed the role of cytokines in HIV-associated wasting.
While Grunfeld stated that failure to recover lost lean body mass
(muscle) is due to underlying HIV infection, he emphasized that
secondary infections are the primary precipitants of wasting. Active
secondary infection causes the body to expend more energy and
reduces appetite. Skeletal muscle is the primary source depleted to
provide necessary protein. "Rapid weight loss with anorexia is a
sign of an event, particularly secondary infection in AIDS,"
Grunfeld stated.

       Donald Kotler, MD, of St. Lukes-Roosevelt Medical Center in
New York, discussed the use of medical foods with specialized
nutrients (Advera, Sustecal, Lipisorb, Ensure, etc.) to combat
malabsorption, which he ties to a CD4 count of 200 cells/mm3 or
fewer. He recommended combining medical foods with appetite
stimulants, and judging response by clinical outcome. He urged
consideration of malabsorption in diagnosing HIV-associated wasting.

       Morris Schambelan, MD, of San Francisco General Hospital,
reviewed the successful use of recombinant human growth hormone
(Serostim) to treat HIV-associated wasting. In a study performed by
Schambelan and Kathleen Mulligan, PhD, of UCSF, two-thirds of 178
HIV positive participants with evidence of wasting received growth
hormone for 3 months, while one-third received placebo. Growth
hormone recipients gained weight and lean body mass, while placebo
recipients did not. After 3 months, all subjects received growth
hormone; those who had first received placebo also gained, while the
larger group maintained their initial gains. Reported quality of
life improved, as did exercise capacity measured by treadmill work
output. Schambelan reported that new data suggest a reduced
incidence of secondary infections, particularly Pneumocystis carinii
pneumonia (PCP), in the group originally assigned to growth hormone.

       Schambelan also discussed the role of androgenic steroids
such as testosterone in the treatment of HIV-associated wasting. He
reported on a study by Judith Rabkin, MD, of the New York State
Psychiatric Institute, and Kotler in which HIV-affected men were
given 400 mg of testosterone every 2 weeks. After 11 weeks, average
weight had increased, although not significantly. However, lean body
mass had increased by 2.6 pounds, which was statistically
significant.

       Antiretroviral Therapy

       While information was presented on many drugs currently in
wide use in clinical practice, the real excitement in Washington
centered on protease inhibitors. Drugs in this class are the most
potent antiretroviral drugs to date. Recently released data indicate
that participants in a clinical study who received the protease
inhibitor ritonavir (Norvir) experienced fewer opportunistic
infections and deaths than matched controls who received placebo.

       Emilio Emini, MD, of Merck Research Laboratories, gave the
state-of-the-art lecture on this class of drugs. The goal of an
antiretroviral therapy, he stated, should be to reduce viral load as
much as possible, for as long as possible, while minimizing
resistance, with few or no side effects. Issues to consider are
bioavailability (how much drug gets inside the body for use),
pharmacokinetics (how long a drug lasts in the body, what
concentration it reaches, what compartments or parts of the body it
enters, and how it breaks down), plasma protein binding (how much
drug is bound inertly to other molecules in the blood, and how much
is free), and selection for resistance (how the virus changes to
avoid the effects of a drug, and what impact that change has on
viral response to other drugs).

       While Emini focused on indinavir (Crixivan), Merck's protease
inhibitor, he reviewed studies available for all 3 protease
inhibitors.

       Saquinavir

       Saquinavir (Invirase) is well tolerated and is the only
protease inhibitor currently available by prescription.

       In study SAQV13330, saquinavir was tested against and in
combination with AZT (Retrovir) in people who had never used
antiretroviral therapy. After 16 weeks, viral load was reduced by
0.6 log in the AZT-only group, by 0.2 log in the saquinavir-only
group, and by 1.0 log in the combination group.

       Study ACTG 229 evaluated the effects of saquinavir in
AZT-experienced subjects. The group receiving ddC (Hivid) plus
saquinavir had lower viral load by 0.3 log. The AZT plus saquinavir
group showed no change from baseline; and the group receiving AZT,
ddC and saquinavir showed a reduction of 0.5 log. Less than half of
the patients in the saquinavir plus AZT arm developed resistance at
1 year; even fewer subjects in the other 2 arms were
saquinavir-resistant.

       Ritonavir

       Short term data indicate that Abbott's ritonavir (Norvir)
increased survival, decreased incidences of opportunistic
infections, and decreased viral load in study participants. In one
reported study, ritonavir was studied in patients with CD4 counts
greater than 50 cells/mm3. At doses below 1,200 mg a day, a 1.2 log
drop in viral load occurred initially, but the decrease was not
sustained. At 1,200 mg a day, however, a 1.2 log drop was sustained
for at least 32 weeks. CD4 count rose by an average of 200
cells/mm3, and was also sustained for at least 32 weeks.

       When tested in combination with AZT (200 mg 3 times a day)
and ddC (0.75 mg 3 times a day), a 2.5 log drop in viral load was
sustained at 20 weeks. CD4 count was increased by 100 cells/mm3 from
baseline.

       One newly reported study, presented at a late breaker session
(important studies submitted after the conference deadline), looked
at 1,190 extensively pre-treated subjects with CD4 counts less than
100 cells/mm3 (median CD4 count 19 cells/mm3). Entry requirements
included the receipt of at least 9 months of approved antiretroviral
therapy. Combination therapy, other than ritonavir, was restricted
to a maximum of 2 approved antiretrovirals. Ritonavir or placebo
were added to patients' current regimens. Study participants were
not required to take other antiretrovirals during the study,
although most subjects did so.

       Secondary markers were examined in a nested subgroup study (a
smaller group taken from within a large study, and looked at for a
particular purpose) over 16 weeks. CD4 counts rose by 40-50
cells/mm3 in the ritonavir-treated group, and were unchanged in the
placebo arm. CD8 cell counts also increased in the ritonavir
recipients, and remained high for the 16 weeks of the substudy.

       This important trial showed improved clinical outcome in a
group whose extensive pre-treatment might predict resistance to
therapy, and whose underlying immune competence was poor. In such a
group, because progression of disease was more likely, it was
possible to show clinical benefit in a short period of time.

       Side effects of ritonavir included occasional large increases
in uric acid, which sometimes results from tissue breakdown, as well
as elevations of  AST and SGTP, enzymes which may reflect liver or
biliary tract inflammation or obstruction. Creatinine phosphokinase
(CPK), an enzyme found in many tissues but especially in muscle, was
sometimes transiently elevated. Nausea, vomiting and diarrhea were
reported by some participants. Levels of red blood cells and
neutrophils in the blood were often markedly improved.

       Indinavir

       Indinavir (Crixivan), made by Merck, was approved by the FDA
in March 1996 as monotherapy or in combination with nucleoside
analog drugs for the treatment of late-stage HIV disease.

       Indinavir was tested alone and in combination with other
approved antiretroviral drugs in people who had never taken AZT. In
the indinavir-only group, an initial 2.2 log drop in viral load was
reduced to 1.5 logs at 24 weeks. Forty percent (40%) sustained a
drop of 2 logs or greater, with a viral load below 200 copies/mL in
15%. One of 13 subjects showed AZT resistance.

       The AZT-only group maintained a 0.5 log reduction in viral
load at 24 weeks. None had a viral load under 200 copies/mL. Eleven
of 16 were AZT-resistant at 24 weeks.

       Combination AZT and indinavir caused a 2.5 log drop in viral
load, which was sustained at 24 weeks. Sixty percent (60%) sustained
a greater than 2 log drop; 60% kept viral load under 200 copies/mL.
Only 1 of 13 participants in the combination group developed AZT
resistance. Of those remaining on treatment at 48 weeks, 40% still
show viral load under 200 copies/mL. (These later figures may be
biased by the fact that patients who do well remain on a study,
while those who do poorly tend to drop out.)

       Six of the people in the combination group have had serial
lymph node biopsies. Five showed a 2 log drop in nodal viral load;
interestingly, treatment had been interrupted in the subject who did
not.

       In Merck protocol 19, indinavir alone was tested against a
AZT/ddI combination and against indinavir/AZT/ddI. Viral load
dropped by 2 logs in the indinavir monotherapy group, by 1.6 logs in
the AZT/ddC group, and by 2.9 logs in the triple combination group.
CD4 counts in this last group increased by a median 150 cells/mm3.
White blood cell counts and absolute neutrophil counts increased.
None of the 78 participants developed kidney stones, a known side
effect of indinavir that can be prevented by drinking a lot of
water.

       Roy Gulick, MD, of New York University Medical Center,
reported on an ongoing placebo-controlled indinavir study. This
study is looking at AZT-experienced patients, many of whom have used
other antiretroviral drugs as well. Participants must have CD4
counts between 50 and 400 cells/mm3, a viral load greater than
20,000 HIV RNA copies/mL, at least 6 months of prior AZT experience,
and no history of protease inhibitor or 3TC use. Nonwhite subjects
comprise 28% of the study population, and women 15%. Ninety-seven
(97) subjects are enrolled, grouped into an indinavir arm (800 mg
twice a day), a 3TC/AZT arm (standard doses) and a 3TC/AZT/indinavir
arm.

       While this study is still in progress, the triple combination
arm is showing a profound reduction in viral load. Taking indinavir
alone has reduced viral load by 40% so far in this group; 3TC/AZT
reduces viral load by 20%; the 3 drugs together reduce viral load by
85%, or almost 1 log. At 24 weeks, effects have been sustained, and
the regimen is well tolerated. No clinically significant drug
interactions have been seen. Only 1 subject has withdrawn from the
study. Bilirubin was elevated in 17 of the patients on the indinavir
arms. Kidney stones were found in 2 indinavir patients, but did not
require study withdrawal.

       Based on the promising results of this study so far, all
participants will be offered triple drug therapy at the end of 24
weeks.

       Resistance

       Protease inhibitors are more powerful than the reverse
transcriptase inhibitor drugs which preceded them. They reduce viral
load to a greater degree. Their chance for sustained activity
depends on their power to decimate the population of virus by
limiting viral replication and reducing opportunities for viral
mutation. Subtherapeutic drug levels, whether caused by reduced
dosing, drug interactions, malabsorption or reduced bioavailability
due to other factors, or self-imposed drug holidays, all permit
increased viral replication and increased opportunity for mutation
and resistance.

       Resistance to saquinavir requires 2 viral mutations.
Resistance to indinavir or ritonavir requires multiple sequential
viral mutations at various sites. Indinavir- and ritonavir-resistant
viral strains are cross-resistant to both drugs. Two-thirds or more
of such strains are saquinavir-resistant as well.
Saquinavir-resistant isolates, however, are susceptible to indinavir
and ritonavir.

       Based on early evidence, resistance is best avoided by
maintaining therapeutic drug levels and by using protease inhibitors
in combination with antiretrovirals from other classes. While the
concept of treatment with more than 1 protease inhibitor is
interesting, powerful drug interactions may result. Barring a
clinical trial in a research setting where blood levels can be
monitored, the risks of experimentation are high. As Joseph Eron,
MD, of the University of North Carolina at Chapel Hill, said during
the BETA Live! conference call, "Do not try this at home."

       Drug Interactions

       Protease inhibitors interact with many other drugs. They
increase levels of rifabutin, the use of which is not recommended
with this class of drugs. Drug interactions have also been reported
with rifampin and ketoconazole. Phenytoin (Dilantin), phenobarbital
and other drugs which induce the P450 system (a metabolic pathway
for drug breakdown in the liver) speed clearance of protease
inhibitors, and may drop levels into the subtherapeutic range. Using
protease inhibitors in combination also changes pharmacokinetics and
affects drug levels. Ritonavir, for example, when administered with
saquinavir, can raise saquinavir levels 8 times. Indinavir can
increase saquinavir concentrations even more, to 36 times the
expected level.

       The bottom line, then, on protease inhibitors, can be reduced
to: * Treat early. * Treat consistently. * Use in combination with
other antiretrovirals. * Watch for drug interactions with other
HIV-associated medications.

       Other Antiretrovirals

       A French study reported that d4T in people with early-stage
HIV disease with a measurable viral load showed sustained activity.
While combination therapy emerged from this conference as the clear
treatment of choice, this study showed that benefit can be obtained
from early antiretroviral treatment.

       B. Gazzard, MD, of Chelsea and Westminster Hospital in
London, gave a brief update on the European and Australian Delta
Treatment Group studies. Delta I, which compared AZT monotherapy to
AZT plus ddI in antiretroviral-naive subjects, showed fewer clinical
events and a significant survival benefit in the combination arm.
Delta II, which examined AZT-experienced patients, also showed a
survival advantage with the addition of ddI to AZT.

       Combination ddI and d4T resulted in sustained reductions in
viral load and increases in CD4 count. The regimen was well
tolerated, with no significant increase in toxicity, even where
toxicities overlap.

       W.W. Freimuth, MD, of the Howard Hughes Medical Institute,
reported on an ongoing study of delavirdine, a non-nucleoside
reverse transcriptase inhibitor made by Upjohn Pharmaceuticals,
tested in different doses with or without AZT. Subjects had CD4
counts of 200-400 cells/mm3, were largely asymptomatic and were
divided between AZT-naive (40%) and AZT-experienced (60%). The mean
increase in CD4 count for the combination regimens at 60 weeks was
20-30 cells/mm3 (40-50 cells/mm3 increase in the naive group), with
a 0.6 log reduction in viral load at 52 weeks at the higher doses
studied (300-400 mg 3 times a day).

       Another study, protocol 17, looked at the benefit of
delavirdine/ddI treatment compared to ddI alone in a group of 800
largely symptomatic, AZT-experienced subjects. Twenty-five percent
(25%) were ddI-experienced as well. CD4 counts at entry ranged from
0 to 300 cells/mm3. CD4 counts in the combination arm were increased
by 5-20 cells/mm3 above those in the ddI-only arm at 40 weeks.

       In 366 AZT-naive patients in study NUCA 3001, 3TC/AZT
combination therapy resulted in a peak drop in viral load of 1.5
logs, with a CD4 count rise of 60-80 cells/mm3. At 52 weeks and
beyond, viral load has remained suppressed at 1 log below baseline
and CD4 count elevations were unchanged. Fewer adverse clinical
endpoints were noted than in the AZT-only arm of the study.

       In a follow-up study with AZT-experienced patients, study
NUCA 3002, subjects were randomized to AZT/high-dose 3TC (300 mg
twice a day), AZT/low-dose 3TC (150 mg twice a day), and AZT/ddC.
Both 3TC arms showed decreases in viral load at 52 weeks (about 0.5
log) and increases in CD4 counts (23 cells/mm3 in the high-dose
group and 42 cells/mm3 in the low-dose group). During the 52 weeks
of the study, no significant difference in progression to clinical
events was observed. In sum-mary, in AZT-experienced patients,
treatment with AZT/3TC combination therapy is better than with AZT
alone, and effects appear to last out to 52 weeks.

       When NUCA 3002, a prospective double-blind study, was
unblinded, it was found that those who had dropped off the study
were those whose viral load had returned to baseline. In other
words, the patients clinical judgment mirrored a return to viral
load baseline. Thus another marker for progression, in addition to
viral load and CD4 count, may be patient intuition.

       Resistance to non-protease inhibitor drugs occurs in stepwise
increments. It appears to develop faster when drug levels are lower.
Strains of multidrug-resistant virus may emerge, but the virus which
results will be less fit. For example, development of resistance to
3TC results in an attenuated, less virulent virus with reduced
resistance to AZT. Delavirdine selects for a virus that replicates
less efficiently.

       An interesting study reported by T.G. Tachedjian, MD, of the
Macfarlane Burnet Center for Medical Research, showed that HIV
resistant to AZT will be sensitive to foscarnet; conversely, the
development of foscarnet resistance confers AZT sensitivity.

       Again, the appropriate approach is to treat early, while less
virus is available to mutate; treat aggressively, at the maximum
safe and effective dose; and treat in combination. Convergent
therapies, which attack replication at different points, can box in
the virus, forcing mutations that purchase its survival at the
expense of fitness.

       Women and HIV

       Although many presentations addressed issues of importance to
women, the range of subject matter remained narrow. Most studies
focused on vertical transmission, or infection of the newborn by its
mother. Those studies that addressed diagnosis and treatment of
HIV-affected women for their own sake were chiefly concerned with
gynecological matters.

       Perinatal Transmission

       ACTG 073 examined the role of AZT treatment in perinatal HIV
transmission among 419 mothers with CD4 counts of over 200
cells/mm3. As in ACTG 076 (see BETA, June 1995, pp. 41-43), a 3-fold
decrease in transmission was seen among the mother/infant pairs that
received AZT before, during and after delivery. High maternal viral
load, as well as low CD4 cell count, CD4 percentage, and CD4/CD8
ratio were associated with increased risk of transmission. However,
there were no viral load levels below which transmission did not
occur.

       Other factors believed to influence transmission rate  mode
of delivery (vaginal or Cesarean), duration of rupture of membranes
before birth and gestational age (premature or full-term) were not
found to be predictive of HIV infection in this study. Thus
researchers concluded that there was no way to assure that a fetus
could be protected from transmission. In addition, the benefit of
AZT treatment appeared unrelated to its effect on viral load in the
mother. The value of AZT in blocking transmission may relate more to
its effects during delivery and after birth than its effects on the
mother during gestation.

       The Ariel Project, which also looked at vertical transmission
in 151 mothers, found no evidence of any viral load threshold below
which infants were not infected, or above which infants were
consistently infected.

       Other presentations on perinatal transmission addressed
breast-feeding (which predisposed to HIV transmission), length of
time in birth canal (the first twin born is more likely to be
infected), duration of rupture of membranes (proportional to the
rate of transmission) and type of delivery. Vaginal birth appears to
involve a higher risk of transmission than Cesarean delivery. Data
are blurred, however, as many babies delivered by Cesarean section
still spend a long period in the birth canal. Therefore, the
potential benefit of Cesarean section in reducing transmission may
be understated.

       Recommendations are to minimize invasive monitoring of the
infant, e.g., not using fetal scalp devices, in order to reduce the
risk of infection during birth. An attempt to reduce the rate of
transmission in Africa by cleansing the birth canal prior to
delivery was unsuccessful, despite careful study design.

       Cervical Dysplasia

       The incidence of cervical dysplasia (cell changes which may
indicate cervical cancer) is increased in HIV-infected women;
recurrence after treatment is increased 4-fold when compared to HIV
negative women. While it remains unclear whether cervical cancer
occurs more frequently in HIV positive women, it is clear that, once
present, its course is more aggressive. Cancers of the vagina and
the vulva (the area outside the vagina) are also more frequent in
women with HIV.

       Infections

       Candida, or yeast infections, are often the first sign of HIV
infection in women. Herpes simplex outbreaks occur more often, and
asymptomatic shedding of herpes simplex virus is common. Pelvic
inflammatory disease (PID) occurs more often, can be more severe and
may result from different organisms than those found in PID in HIV
negative women. Genital ulcers are more frequent.

       Menstrual Irregularities

       One study reported no HIV-related increase in menstrual
irregularities or symptoms compared to matched HIV negative
controls.

       Epidemiology

       One interesting study compared length of life after diagnosis
in HIV-infected women and men in Puerto Rico. Although matched for
CD4 count with men in the study, and although they had fewer
AIDS-associated events, women in the study lived only about half as
long as men. A thoughtful analysis of social factors showed that
women were more likely to have contracted HIV by heterosexual
transmission, more likely to be widowed and more likely to live in
rural areas and to have dependents. Researchers postulated that
widows infected by husbands and left to raise the family had less
money, less access to health care and greater responsibilities, and
that these factors directly influenced their survival.

       Opportunistic Infections

       Cytomegalovirus

       Mark Jacobson, MD, of San Francisco General Hospital,
discussed treatment and prophylaxis of cytomegalovirus (CMV).
"Treatment is always required," says Jacobson. "Watchful waiting in
the presence of disease is an invitation to progression."

       Intravitreal implants (drug-containing devices inserted into
the eye) are effective, doubling the time to progression of
retinitis. However, there are considerable risks; vision may be
disturbed or lost as a result of the procedure itself. Jacobson
reports a 10% risk of visual impairment as a result of implantation,
compared to standard intravenous (IV) treatment with ganciclovir or
foscarnet, which offers a 5% risk of blindness. He recommends
systemic treatment for peripheral retinal damage unless Zone 1
(central vision) is threatened, in which case implants may be worth
the risk. In addition, implants provide no systemic benefit against
CMV manifestations in other parts of the body.

       Oral ganciclovir as maintenance therapy is not as successful
as continued IV treatment. Oral ganciclovir allows more disease,
more bilateral disease (in both eyes) and more involvement of Zone
1. However, there may be a role for oral ganciclovir in primary
prophylaxis of CMV once CD4 counts fall below 50 cells/mm3. Jacobson
suggests CMV PCR studies every 3 months after a CD4 count of 50
cells/mm3 has been reached to screen for CMV in those most likely to
benefit from prophylaxis.

       In cases of progression, ganciclovir and/or foscarnet may be
increased or combined. Co-administration of the standard dose of
each has been shown to double the time to progression.

       Parvovirus

       Parvovirus, a viral organism which causes a common childhood
illness, was found in the bone marrow of 16% of AIDS patients at
autopsy in one series. It should be considered when neutropenia (a
shortage of neutrophils, a type of white blood cell necessary for
immune defense) is present and no other cause has been found.

       Cryptococcus

       C. Van der Horst, MD,of the University of North Carolina at
Chapel Hill, reported on new approaches to the treatment of
cryptococcal meningitis. He stressed the importance of relieving
intracranial pressure with repeated lumbar punctures (spinal taps)
or the placement of a shunt. Headaches are relieved and confusion
reduced when pressure is lowered.

       Amphotericin B is the treatment of choice for cryptococcus;
efforts to treat orally with fluconazole or itraconazole have failed
to show a greater than 50% response. Unlike the azole drugs,
amphotericin B actually kills fungal organisms. Studies conducted by
David Stevens, MD, at Stanford University show that there may be
synergy (a combined effect of 2 drugs that is greater than the
separate effects of both added together) when a growth factor,
granulocyte-macrophage colony-stimulating factor (GM-CSF), is used
with fluconazole. Following treatment with amphotericin B,
fluconazole may be used as maintenance therapy, or secondary
prophylaxis; prophylaxis after infection should be at 200 mg per
day.

       A study from Burundi reported the successful administration
of amphotericin B with intralipids (fats used for feeding through
the vein). Side effects of amphotericin (fevers, chills and nausea),
which may be severe, were resolved, although renal function was not
affected.

       Fluconazole and amphotericin B may be used in combination to
treat cryptococcosis, but not to treat aspergillosis, where the
drugs work against each other. Histoplasmosis, when treated with
fluconazole, results in a fluconazole-resistant organism which is
still sensitive to itraconazole.

       Thrush

       Prophylaxis or long-term treatment of thrush, or oral candida
infection, with fluconazole results in resistance. It can be briefly
overcome with high doses; the effect is transient. Studies of daily
vs weekly regimens show more unusual and resistant yeast species,
and more resistant candida in the weekly regimens.

       Tuberculosis

       In the kickoff lecture at the conference, Barry Bloom, MD, of
the Howard Hughes Medical Institute/Albert Einstein College of
Medicine, reviewed the extent of tuberculosis (TB) in HIV/AIDS.
Rates are increasing, largely as a result of decreased funding for
eradication efforts. HIV positive people are 3 times more likely to
be infected; HIV positive Latinos are 5 times more likely.

       Infections previously had represented reactivation; now many
infections are primary, or newly infected, cases. Primary infection
with the same strain can occur in large numbers of HIV positive
people. Homeless shelters have been shown to be instrumental in such
mass infections.

       Mycobacterium avium Complex

       Incidence, severity of illness and deaths associated with
Mycobacterium avium complex (MAC) are increasing. Rifabutin and
clarithromycin are each now approved as monotherapy for primary
prophylaxis. One study has shown that adding rifabutin to
clarithromycin does not improve activity. Clarithromycin or
azithromycin for prophylaxis also reduces community-acquired
pneumonia, and may be synergistic against PCP. Azithromycin at 1,200
mg per week or 500 mg per day, and clarithromycin at 500 mg twice a
day, have been shown to be superior to rifabutin for MAC.

       Drug interactions must be considered. Clarithromycin can
increase rifabutin levels; rifabutin can lower clarithromycin
levels. There are also important drug interactions between these
drugs and protease inhibitors; rifabutin should not be given with
protease inhibitors, and clarithromycin may require dose adjustment.

       While prophylaxis may be more costly than waiting to treat,
it is important to remember that MAC infection triggers an intense
immune response, and hence triggers wasting and viral replication.

       Pneumocystis carinii Pneumonia

       PCP prophylaxis delays progression to AIDS and prolongs
survival. About 50% of breakthrough infections are found in people
with CD4 counts of less than 75 cells/mm3; 75% have counts less than
50 cells/mm3. TMP-SMX (Bactrim, Septra) is better than dapsone,
which is better than aerosolized pentamidine. No studies yet show
the effectiveness of atovaquone (Mepron) compared to the others for
PCP prophylaxis.

       Microsporidium

       Microsporidium can cause intractable diarrhea in people with
advanced HIV infection. There are 2 main species; 1 is sensitive to
some experimental regimens. New studies are available to help
determine the species, and hence guide treatment.

       ***************************
       ***************************
       Pelvic Inflammatory Disease

       Liz Highleyman and Leslie Hanna

       Liz Highleyman is a Treatment, Education and Advocacy
       Assistant at the San Francisco AIDS Foundation. Leslie Hanna
       is Associate Editor of BETA.

       Pelvic inflammatory disease (PID) is an infection of the
female upper reproductive tract. The term actually refers to a broad
range of conditions. Various parts of the upper reproductive tract
may become infected, including the fallopian tubes, the uterus and
the ovaries. Advanced cases may affect the abdominal lining
(peritoneum).

       PID is a serious, potentially life-threatening condition in
any woman. HIV-infected women have some unique considerations and
risks. The 1993 expanded Centers for Disease Control and Prevention
(CDC) case definition of AIDS includes PID as a Category B illness,
or one that is attributable to or complicated by HIV. Although women
with HIV respond as well to treatment for PID as women without HIV,
HIV itself creates a biological environment, especially in the
vagina and lower reproductive tract, that facilitates the
development of PID. This consideration makes prevention of and
screening for PID especially important for HIV positive women.

       Causes of PID

       Except for cases related to abortion, childbirth or pelvic
surgical procedures, PID occurs when infection-causing organisms
(pathogens) spread upward from the vagina through the cervix to the
upper reproductive organs. Anything that facilitates this migration
of pathogens may facilitate the development of PID. HIV-related
physiological changes such as altered mucosal integrity may
encourage PID. HIV-related disruption of the normal vaginal ecology
may contribute to an imbalance that favors the proliferation of some
bacteria over others. Resident bacteria (those that normally live in
the vagina, e.g., Gardnerella vaginalis) may prevail against a
weakened immune system and expand beyond their normal "territory."

       Untreated sexually transmitted diseases (STD) cause most
cases of PID. When STDs go undetected or untreated, the pathogens
may proliferate and spread to infect new areas. Untreated or
undertreated gonorrhea and chlamydia cause an estimated 90% of cases
of PID. As many as 40% of untreated cases of chlamydia ascend to the
upper reproductive tract. Chlamydia often goes undetected in women;
75% of women show no symptoms of chlamydia infection. Because women
with gonorrhea and chlamydia are so often asymptomatic, Risa
Denenberg, FNP, recommends STD screening every 6 months for women
with AIDS and for HIV positive women who are symptomatic or sexually
active. New non-culture-based screening tests for chlamydia have
been developed that use DNA amplification technology and can be used
on a urine sample. In addition, recently reported findings by D.
Dean and colleagues, of the University of California at San
Francisco, suggest that certain types of Chlamydia trachomatis, the
organism that causes chlamydia, are more aggressive than others.

       Advanced PID usually involves more than one pathogen. Some
cases of PID involve infection with bacteria that do not commonly
affect the reproductive tract, such as Mycobacterium tuberculosis.
M. tuberculosis occasionally infects organs in the upper
reproductive tract, after initially infecting the lungs.
Cytomegalovirus (CMV), a common opportunistic pathogen in people
with HIV/AIDS, also has been identified in reproductive organs. A.
Moorman and colleagues, of the Multicenter HIV and PID Study Group,
found higher rates of CMV in the cervical area of HIV positive women
compared to HIV negative women. However, little is yet known about
the clinical significance of the presence of CMV in the endocervix
(upper, inner part of the cervix).

       Certain anatomical or physiological states increase the risk
of an acute episode of PID. Risk for PID is high during or
immediately following the menstrual period, when the cervix is
slightly dilated (more open), making it easier for pathogens to
spread from the vagina to the upper reproductive tract. Seventy
percent (70%) of women with gonoccocal PID develop symptoms during
the first week after menstruation. Risk of PID is higher at points
in the menstrual cycle when the cervical mucous is thinnest and most
penetrable (e.g., during ovulation).

       Oral contraceptives affect risk of PID in complicated,
incompletely understood ways. Their use is associated with some
degree of protection against symptomatic PID, possibly because they
thicken cervical mucous, making it more difficult for pathogens to
spread into the uterus. Conversely, oral contraceptive use appears
to increase the frequency of chlamydia infections by exposing a type
of vaginal tissue, called columnar epithelium, that is particularly
vulnerable to infection.

       PID may also develop following an incomplete or unsterile
induced abortion or following childbirth. This type of PID may be
accompanied by a severe infection of the bloodstream that is
directly related to delivery or to an obstetric procedure (puerperal
sepsis). Premature rupture of membranes or prolonged labor are
particularly associated with PID, usually due to infection with an
organism called Bacteroides. Any procedure in which the cervix is
opened (e.g., using dilating rings) or an instrument is inserted
into the uterus (e.g., a curette) may lead to pelvic infection.
Women who use douches also may be at higher risk of PID. Douching
removes protective mucous and normal bacterial flora, and may
unintentionally flush vaginal bacteria into the upper reproductive
tract.

       Use of contraceptive intrauterine devices (IUD) is associated
with a 3-fold increased risk of developing PID. The string of the
IUD, which is left hanging through the cervix into the vagina,
provides a conduit for pathogens to reach the upper reproductive
organs. Therefore, IUDs increase the likelihood that an STD will
progress to PID. If a woman using an IUD develops symptoms of PID,
the device should be removed immediately. Because HIV positive women
are especially susceptible to infection, this form of birth control
is not recommended for them.

       Barrier methods of contraception (e.g., condom, diaphragm)
can help protect women against the organisms that cause PID.
Test-tube studies show that spermicides kill Neisseria gonorrhoeae
and C. trachomatis, the organisms that cause gonorrhea and
chlamydia, respectively. Therefore, use of contraceptive foams and
jellies made with these spermicides may help protect women against
PID.

       Consequences of PID

       Untreated PID has serious consequences. The fallopian tubes
and ovaries may become inflamed, swollen and covered with pockets of
pus, becoming what are called tubo-ovarian abscesses; these
abscesses occur in 10% of cases of PID. Pelvic pain may become
chronic. Untreated PID related to gonococcal infection can lead to
Fitz-Hugh-Curtis syndrome, or perihepatitis, an inflammation of the
covering of the liver. Other potential outcomes are intestinal
blockage, sepsis (the presence of bacteria or their toxins in the
blood) and death.

       Adverse reproductive consequences include infertility and
ectopic or tubal pregnancy (in which the embryo begins to develop
outside the uterus, e.g., in a fallopian tube). Infertility is due
either to inflammatory changes in the uterine lining, which make it
resistant to implantation of an embryo, or to scar tissue that
blocks the reproductive organs. Significant pelvic scarring occurs
in at least 20% of women who have had PID; some degree of scarring
is likely to occur in nearly all cases. A woman who has had PID is
6-10 times more likely to have an ectopic pregnancy, a
life-threatening condition that is the leading cause of maternal
death among African-American women. Ten percent (10%) of women who
have had PID will have an ectopic pregnancy when they become
pregnant for the first time following an episode of PID. As many as
1 in 3 women have repeat episodes of PID after initial treatment.
The rate of infertility is near 10% after 1 properly treated PID
episode, near 20% after 2 episodes and near 50% after 3 episodes.

       Symptoms of PID

       Although the symptoms of PID may vary, they generally include
moderate to severe pain, abdominal tenderness, inflammation of the
cervix (cervicitis), pain during intercourse and fever. Vaginal
discharge may be unusual, possibly pus-containing (purulent);
non-menstrual bleeding may also occur. Urination may be painful
and/or frequent. A palpable pelvic mass may be present.

       Early symptoms are often absent or mild, and PID may progress
to an advanced stage before it is diagnosed. PID due to chlamydia is
less acute and less symptomatic than PID due to gonorrhea or other
pathogens, but causes a more protracted illness than does gonorrheal
infection. Chlamydial PID presents a greater potential for missed
diagnosis and permanent damage.

       PID Diagnosis

       PID can be a challenge to diagnose, since obtaining culture
specimens from the upper reproductive tract is invasive and
difficult. Organisms responsible for upper tract infection may not
appear in vaginal or cervical samples. Therefore, PID is usually
diagnosed on the basis of clinical findings. Since clinical
diagnosis may be imprecise, many cases of PID go undetected. Because
the consequences of untreated PID are so serious, the CDC recommends
that healthcare providers "maintain a low threshold of diagnosis."

       The CDC recommends empiric treatment for PID if all 3 of the
following symptoms are present in a woman with no established cause
of pelvic inflammation: lower abdominal tenderness, adnexal
tenderness (tenderness of the pelvic reproductive organs) 
especially bilateral tenderness (on both sides of the body)  and
cervical motion/manipulation tenderness. The following additional
criteria may be used to make a more specific diagnosis: oral
temperature greater than 38.3 C (100.9 F) and abnormal cervical or
vaginal discharge. Laboratory blood tests such as elevated blood
erythrocyte sedimentation rate (ESR), elevated levels of C-reactive
protein and increased white blood cell counts, as well as laboratory
detection of N. gonorrhoeae or C. trachomatis, also may support a
diagnosis of PID.

       Additional diagnostic methods that are sometimes used include
laparoscopy, biopsy and culdocentesis. Laparoscopy is a procedure in
which a small, lighted lens-tip instrument is inserted through a
narrow abdominal incision to allow visual examination of internal
organs and tissue sampling. In an endometrial biopsy, a sample of
tissue from the uterine lining (endometrium) is extracted and
examined under a microscope. Culdocentesis is the removal
(aspiration, via suction) of uterine fluid from the cul-de-sac, a
recess between the uterus and the rectum, through a puncture of the
vaginal wall. Ultrasonography (imaging using sound waves) may also
be used to help diagnose PID, and can be especially useful for
detecting fluid-filled tubo-ovarian abscesses and ectopic
pregnancies. Because these procedures are potentially inconclusive
and, except for ultrasonography, invasive, they should not be
routinely substituted for clinical diagnosis.

       PID in HIV Positive Women

       There are no data to establish conclusive differences in
clinical manifestations and course of PID in HIV positive women
compared to HIV negative women. Large, controlled, unbiased studies
have been difficult to conduct. However, anecdotal reports and some
studies suggest that PID may be more common and more severe in women
with HIV, and especially in women with AIDS. Abner Korn, MD, of San
Francisco General Hospital, and colleagues note that "decreased
mucosal and systemic immune function due to HIV could lead to
increased ascent of pathogenic organisms from lower to upper genital
tracts and lowered response to antimicrobial therapy once upper
tract disease is established."

       Some recent small studies have gathered data on immune
responses to PID in HIV positive and HIV negative women. A central
finding is that HIV-infected women with PID may not have elevated
white blood cell counts in response to infection the way HIV
negative women do. B. Hoegsberg and coworkers, C. Barbosa and
coworkers, and Korn and coworkers have all reported relatively lower
white blood cell counts (leukopenia) in HIV positive women with PID.
Korn believes that this is partly related to the relatively lower
incidence in HIV-infected women with PID of gonoccocal infections,
which are associated with high white cell counts. The significance
of this finding is that laboratory markers such as elevated white
blood cell count and ESR cannot be considered reliable diagnostic
indicators of PID in HIV positive women.

       Hoegsberg's group reported a trend toward more PID-related
surgical intervention in HIV positive women than in HIV negative
women in Brooklyn (p=0.058; n=15 HIV positive, 95 HIV negative), as
well as a trend toward more recurring infections. Korn and
colleagues also found a higher incidence of surgical intervention in
HIV positive women in San Francisco (p<0.05; n=23 HIV positive, 108
HIV negative). It appeared that the incidence of surgery increased
as immune function decreased. Among asymptomatic HIV positive women
with PID, there was no increase in surgical intervention, while 3 of
5 women with AIDS required surgery. Korn suggests that this higher
incidence of surgery may be due to inadequate response to antibiotic
therapy among HIV positive women. Still, Korn's study did not find a
greater length of hospitalization or a greater incidence of
tubo-ovarian abscesses in HIV positive women with PID compared to
HIV negative controls. Barbosa and coworkers found that the
incidences of tubo-ovarian abscesses and surgical intervention were
the same in HIV positive women (n=13) and HIV negative women (n=138)
with PID.

       In a large, multicenter study sponsored by the CDC, Kathleen
Irwin and colleagues, of the Multicenter HIV and PID Study Group,
examined the clinical presentation and course of PID in HIV positive
and HIV negative women (n=43 HIV positive, 162 HIV negative). HIV
positive women had slightly more severe initial symptoms and were
slightly more likely to have had PID in the past. Irwin found that
HIV positive and HIV negative women had similar amounts of pain and
cervical discharge, but that HIV positive women had significantly
lower white blood cells counts.

       In a microbiological substudy of tissue samples from the same
women, Moorman and coworkers identified N. gonorrhoeae, C.
trachomatis and various other types of bacteria in uterine lining
(endometrium) and endocervical tissue at equal rates in HIV positive
and HIV negative women. In these studies, HIV positive women were
significant-ly more likely to have recently taken antibiotic drugs.
Among women who had not recently used antibiotics, infection of the
endometrium (endometritis) was indeed more common in women with HIV
(65%) than in HIV negative women (30%), a statistically significant
difference. Irwins group found that 4-10 days after antibiotic
therapy was completed, the HIV positive and HIV negative women were
similarly improved.

       Irwin's group found that initial symptoms and course of PID
in HIV-infected women did not differ based on CD4 count. Irwin and
colleagues attribute to bias the greater differences between HIV
positive and HIV negative women found in previous studies; for
example, the lower pain scores reported by HIV positive women with
PID noted by Korn may be related to their use of opiate drugs.

       Some investigators have reported lower rates of gonorrhea and
chlamydia in HIV positive women with PID. Korn and coworkers
postulate that this may be because PID in HIV-infected women is more
often due to the ascent of resident vaginal organisms (e.g.
Bacteroides, Staphylococcus, Streptococcus, Escherichia coli), which
the compromised immune system can no longer keep in check. However,
Irwin and R. Rice have countered that the lower rates of gonorrhea
and chlamydia in HIV positive women may be due to their more
frequent use of antibiotic drugs.

       Treatment of PID

       PID is typically treated with a combination of antibiotics.
It is important to select an initial treatment regimen that provides
broad activity against the range of organisms likely to cause
infection, including various resident bacteria. It is also crucial
to treat any initial infection such as gonorrhea or chlamydia. Since
specimens are difficult to obtain, cultures take time and most cases
of PID are polymicrobial (more than one pathogen is present), it is
recommended that broad-spectrum combination antibiotic therapy not
be delayed while awaiting laboratory results. Various studies,
including the Irwin study discussed previously, have found that HIV
status does not appear to influence cure rates of bacterial PID, and
that HIV infection does not appear to negatively affect response to
therapy.

       PID treatment may be administered on an inpatient (in the
hospital) or outpatient basis. Some studies have shown that PID may
be more difficult to treat in women with HIV, and treatment may be
more likely to fail. Thus, the CDC currently recommends
hospitalization and intravenous (IV) antibiotic therapy for women
with HIV infection and PID. Inpatient treatment is recommended for
any woman who does not respond to outpatient therapy, in whom pelvic
abscesses are suspected or who is too ill to take oral medication.
Inpatient IV treatment is also recommended for pregnant and
adolescent women. Two regimens for IV use are 1) cefoxitin and
doxycycline, and 2) clindamycin and gentamycin. Cefoxitin and
cefotetan are effective against gonococci and many other bacteria;
doxycycline is active against chlamydia, mycoplasma and various
resident bacteria. IV antibiotic treatment should continue for at
least 4 days, and should continue for 2 days after fever subsides.
Hospitalized patients should begin to improve in 2-3 days. By the
seventh day of therapy, 80% of effectively treated women will have a
normal pelvic exam. After IV therapy, according to an article in
Scientific American Medicine, "a 14-day antibiotic course can be
completed with the administration of doxycycline."

       Because PID infection can be persistent, the CDC recommends
re-examination 7-10 days following the completion of therapy to
ensure that infectious organisms have been eradicated. Some
physicians also recommend further follow-up at 4-6 weeks. Also,
effective treatment for a woman with PID includes treating sexual
partners for gonorrhea and chlamydia, even if partners are
asymptomatic.

       Severe, difficult to treat cases of PID often involve
disturbances of the bacteria that normally reside in the vaginal
area. For these cases, as well as cases that involve tubo-ovarian
abscesses, IV clindamycin and gentamicin may be effective. Doses of
gentamicin can be adjusted as needed relative to kidney function.

       If a tubo-ovarian abscess does not respond to antibiotic
therapy, surgical drainage may be required; immediate surgical
intervention is needed if an abscess threatens to rupture. The most
severe cases of PID may necessitate surgical removal of the uterus
(hysterectomy), fallopian tubes and/or ovaries.

       Non-steroidal anti-inflammatory drugs (NSAID) are often
effective for the management of chronic pain due to PID; acupuncture
may be a useful adjunct therapy. For more severe pain, narcotic pain
medication such as codeine may be necessary.

       Outpatient treatment is really only recommended for
ambulatory (able to walk and move about normally, i.e., with
relatively low-level pain and symptoms) HIV negative women with mild
PID. Two recommended outpatient regimens are 1) an injected
cephalosporin such as cefoxitin or ceftriaxone plus oral doxycycline
or tetracycline (and possibly metronidazole), or 2) oral ofloxacin
plus clindamycin or metronidazole. Ofloxacin is effective against
both N. gonorrhea and C. trachomatis, and IV ofloxacin has been
studied as monotherapy. However, at this time, the CDC does not
recommend single-agent treatment for PID. Treatment should last at
least 10-14 days. A follow-up examination should be done within 72
hours of the initiation of therapy to check for improvement. It is
important that the full course of antibiotic therapy be taken, even
if symptoms clear.

       Conclusion

       The conflicting findings on the clinical symptoms and course
of PID in HIV positive women point to a need for continued research
in this area, including how HIV-related immunosuppression influences
the acquisition and course of STDs. Research is also needed on
better methods to protect women from infection with the pathogens
that can lead to PID.

       Early treatment of PID is successful in HIV positive as well
as in HIV negative women. It is therefore important that regular STD
screening and thorough evaluation of pelvic pain and other symptoms
be a part of the healthcare regimen of all women with HIV.

       References

       AIDS Weekly. Chlamydia causes infertility and increases risk
of HIV transmission. Report of a CDC national interactive satellite
symposium. 1995.

       Barbosa C and others. Clinical course of pelvic inflammatry
disease in HIV-infected women. Infectious Disease Society for
Obstetrics and Gynecology. Stowe, VT. August 1993.

       Boston Women's Health Book Collective. The New Our Bodies,
Ourselves. Touchstone, New York. 1984, 1992.

       Centers for Disease Control and Prevention. 1993 Sexually
Transmitted Diseases Treatment Guidelines. Morbidity and Mortality
Weekly Report 42:RR-14. September 24, 1993.

       Dean D and others. Major outer membrane protein polymorphism
of Chlamydia trachomatis is associated with severity of genital
tract infections in San Francisco. ICAAC. San Francisco, CA.
September 17-20, 1995. Abstract K89.

       Denenberg R. Gynecological Care Manual for HIV Positive
Women. Essential Medical Information Systems, Inc., Durant, OK.
1993.

       Hoegsberg B and others. Sexually transmitted diseases and
human immunodeficiency virus infection among women with pelvic
inflammatory disease. American Journal of Obstetrics and Gynecology
163(4): 1135-1139. 1990.

       Irwin K and others. The clinical presentation and course of
pelvic inflammatory disease in HIV+ and HIV- women: preliminary
results of a multicenter study. IX International Conference on AIDS.
Berlin. June 1993. Abstract WS-B-07-1.

       Irwin K and others. The influence of HIV on initial
presentation and course of pelvic inflammatory disease: Final
results of a multicenter study. ICAAC. San Francisco, CA. September
17-20, 1995. Abstract K95.

       Irwin K and R Rice. Pelvic inflammatory disease in human
immunodeficiency-infected women (letter). Obstetrics and Gynecology
83(3): 480-481. 1994.

       Karchmer AW. Sexually transmitted disease. Scientific
American Medicine 7: XXII:11-13. June 1994. Kirkman R and Chantler
E. Contraception and the prevention of sexually transmitted
diseases. British Medical Bulletin 49(1):171-181. 1993.

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

       Korn A and others. Pelvic inflammatory disease in human
immunodeficiency virus-infected women. American Journal of
Obstetrics and Gynecology 82:765-8. 1993.

       Mesiwala S and V Parks. Guidelines for women with HIV/AIDS.
Project Inform Fact Sheet. October 1994.

       Moorman A and others. The influence of HIV infection on the
microbiology and histopathology of acute pelvic inflammatory disease
(PID): Final results of a multicenter study. ICAAC. San Francisco,
CA. September 17-20, 1995. Abstract K94.

       Safrin S and others. Seroprevalence and epidemiologic
correlates of human immunodeficiency virus infection in women with
acute pelvic inflammatory disease. Obstetrics and Gynecology
75:666-670. 1990.

       *********************************************************
       Avoiding Cryptosporidium: Safe Food, Safe Water, Safe Sex

       Diane Cenko

       Diane Cenko is a volunteer on the Project Inform Treatment
       Hotline and a director of the Andrew Ziegler Foundation.

       Cryptosporidium, or "hidden spore," is a microscopic,
protozoan parasite 1/25,000 of an inch in size, capable of causing
gastrointestinal disease. It is recognized as one of the 3 most
common diarrhea-causing intestinal pathogens in the world.
Cryptosporidiosis, the disease caused by the organism, can vary
significantly from self-limiting to life-threatening, depending on
the immune status of the individual. Persons with greater than 300
CD4 cells/mm3 are more likely to have self-limited disease, while
those with fewer than 200 CD4 cells/mm3 almost always have
persistent disease. Mortality from cryptosporidiosis approaches 80%
in the immunocompromised. The current lack of a cure and standard
effective treatment makes avoiding exposure to this pathogen highly
desirable.

       Transmission of cryptosporidium is by the oral-fecal route
and occurs when the oocyst, a small hard-shelled capsule formed
during one stage of the parasite's life cycle, is ingested. The
oocyst is extremely tenacious, highly resistant to disinfectant and
capable of living outside the host for 2-6 months in a moist
environment. Symptoms of infection vary, but most commonly include
abdominal cramps and diarrhea. Nausea, vomiting, malaise and
low-grade fever may also be present. In the presence of HIV
infection, cryptosporidiosis can become a protracted disease from
which recovery may be difficult.

       Prevention Strategies

       Recognizing the importance of reducing the risk of exposure
to this disease, the Centers for Disease Control and Prevention
(CDC) in September 1995 issued prevention guidelines for HIV
positive individuals. These include:

       * Wash hands with soap and water before eating anything,
         after touching children in diapers or after touching
         clothing, bedding or surfaces soiled by someone with
         diarrhea. Washing hands frequently may be the most
         important prevention activity. Often overlooked as a source
         of Cryptosporidium, garden soil may become contaminated by
         neighborhood pets or by farm animals in rural areas. Wear
         gloves while gardening and wash hands after gloves are
         removed. Always wash hands before preparing food. A
         responsible adult should supervise hand-washing in
         children.

       * Practice safer sex. Cryptosporidium can be found on the
         skin in the genital area, including thighs and buttocks, of
         an infected person. It cannot be seen, and an infected
         person may be asymptomatic; therefore, safer sex practices
         should be strictly observed. Mouth-to-anal contact can
         spread cryptosporidiosis, even in the presence of
         meticulous hygiene. Wash hands after any sexual activity.

       * Always wash hands after touching any animal. Farm animals,
         particularly young ones, should be considered a source of
         infection. Contact should be followed by careful hand
         washing. Most house pets are safe. Young puppies or kittens
         should be examined by a veterinarian for infection. An HIV
         positive person should avoid cleaning cat litter boxes or
         disposing of pet stools. If help is not available, gloves
         should be worn and hands washed after the gloves are
         removed.

       * Wash and or cook all food. If safe water is a concern, wash
         in water that is known to be Cryptosporidium-free. Peeling
         fresh fruits and vegetables that will not be cooked reduces
         the risk of exposure, and some kinds of cooking eliminate
         the risk. Unless processed food has been contaminated by an
         infected food handler after processing, it is probably
         safe. Unpasteurized drinks are not safe. In 1994, 160 cases
         of cryptosporidiosis were reported among persons who
         attended an agricultural fair in Maine and drank freshly
         pressed, unpasteurized apple juice. Investigation revealed
         that the apples were collected from an orchard where calves
         from a neighboring farm had contaminated the ground where
         the apples had fallen.

       * Evaluate water safety. Although the CDC does not consider
         it to be the primary method of cryptosporidiosis
         transmission, waterborne transmission has recently resulted
         in thousands of cases. In 1993, an outbreak of
         Cryptosporidium in the Milwaukee municipal water supply
         infected 400,000 people and killed more than 100, most of
         them immunocompromised individuals with HIV. This was
         followed by a l994 outbreak in Las Vegas which killed 19
         people. Cryptosporidial outbreaks have occurred in other
         U.S. cities, such as Denver, and there is considerable
         evidence that non-epidemic transmission of Cryptosporidium
         through drinking water may be occurring throughout the U.S.
         Outbreaks have also been associated with swimming pools,
         wave pools and water slides, and care should be taken to
         not swallow water from these sources. Untreated water in
         rivers and lakes should be considered contaminated and also
         avoided.

       Waterborne Transmission

       Studies reported by the Environmental Protection Agency (EPA)
indicate that Cryptosporidium oocysts are present in 65%-97% of
untreated water supplies tested throughout the country. Because the
parasite is highly resistant to the chemical disinfectants used in
the treatment of drinking water, including bleach, filtration may
play an important role in the water treatment process. Filtration
systems must be scrupulously maintained and specifically designed to
remove these organisms. Nevertheless, all waterborne outbreaks of
cryptosporidiosis detected to date have occurred in communities
where water utilities met current state and federal standards for
acceptable quality of water. A filtration system was in use during
both the Milwaukee and Las Vegas outbreaks. Data from these
outbreaks may indicate that simply complying with existing standards
is not adequate to protect individuals from waterborne
cryptosporidiosis. Available information also indicates that oocysts
were able to breach filters in communities where water was both
disinfected and filtered.

       Some communities may filter only some of the municipal
drinking water. Usually this is because the source water is
considered to be sufficiently guarded from contamination. San
Francisco, New York, Boston, Seattle and Portland are among these
cities. While small numbers of oocysts have been detected in
drinking water in these cities from time to time, no designated
outbreaks have been reported. Some communities use a combination of
filtration, sedimentation and ozonization in an effort to reduce the
presence of oocysts. Testing water for the presence of
Cryptosporidium is currently a labor-intensive, hit-or-miss
proposition, according to The Wall Street Journal, which recently
reported on the development of new methods for detecting this
parasite. First, hundreds of gallons of water must be passed through
filters which collect particles of dirt and microorganisms. Then,
the collected material must be stained with a dye which recognizes
the oocyst and it is then examined under a microscope. This process
may take several days, and results can be extremely variable from
one laboratory to another. Dr. Victor Tsang, chief of the CDC
Immunology Branch, is currently examining methods of identifying
Cryptosporidium that are more accurate and less time-consuming. Dr.
Tsang's research is challenged by federal budget uncertainties at
this time.

       Because the health risk associated with exposure to very
small numbers of oocysts is uncertain, especially with regard to HIV
positive individuals, a June 1995 CDC workshop studying these issues
stopped short of making official recommendations for drinking water
safety, but suggested that immunocompromised individuals take
special precautions during known waterborne outbreaks or periods of
"Boil Water Advisories." Many AIDS clinicians and activist groups,
however, have subsequently advised HIV positive individuals to
follow those precautions even in the absence of official advisories.

       The number of oocysts needed to infect a healthy person has
been suggested to be very small, 132 in one study of healthy
volunteers. The number needed to infect an immunocompromised
individual is unknown, but is suspected by some investigators to be
as low as 1 oocyst.

       Safer Water

       Drinking water safety can be enhanced by boiling water,
filtering water or drinking safe bottled water. Boiling water for 1
minute at sea level or 3 minutes at altitudes above 6,500 feet will
kill Cryptosporidium and completely eliminate the risk of infection.
Filtering water with an appropriate water treatment unit can reduce
the risk of infection.

       Before buying or installing a home water treatment unit, a
number of factors should be considered. Not all water treatment
units are effective against Cryptosporidium; in fact, most are not.
CDC guidelines of September 1995 recommend only 3 categories of
filters: 1) microstraining filters that can remove particles 0.1-1
micron in size, 2) units that work by reverse osmosis or 3) units
that meet National Sanitation Foundation International (NSF)
Standard 53 for "cyst reduction."

       In the first category, the units must be labeled "absolute" 1
micron, not "nominal" 1 micron, as the second group is not
standardized and may allow small particles the size of
Cryptosporidium oocysts to pass through. Reverse osmosis units, the
second category, work by passing water through a tightly stretched
membrane. While preventing the passage of undesirable organisms,
there exists the possibility of a membrane rupture, especially with
changes in water pressure, which would cause release of high
concentrations of captured pathogens. These units must be
scrupulously maintained and carefully monitored.

       In the third category are water treatment units which have
been voluntarily submitted by their manufacturers for testing and
certification by the NSF International. NSF is an independent
organization that develops industry standards, then tests and
evaluates products to determine compliance with those standards.
Since there are no governmental regulations or mandatory standards
for these products, NSF certification is the only currently
available method for consumer guidance.

       NSF certification covers many areas, including aesthetic
effects and health effects. Standard 53, which covers health
effects, includes 21 separate categories, of which "cyst reduction"
is only one. This can be somewhat confusing, since a particular unit
may be labeled as meeting Standard 53 "lead reduction" and not
reduce cyst exposure adequately. Units must specifically indicate
certification for "cyst reduction" to be effective against
Cryptosporidium.

       All units have removable filters which must be changed on a
regular basis, usually dependent upon volume of water used. The CDC
recommends that these filters not be handled by an immunocompromised
person because they collect and concentrate potential pathogens. If
someone else is not available to assist with the changing process,
then gloves and a face mask should be worn.

       A few cautions should be kept in mind. Because NSF
certification requires ongoing, random inspection of certified
products, the approved list changes regularly. It is possible that
an individual may purchase a unit in August, and find that it is no
longer approved in December. Some manufacturers have a longer
history of continuous certification, and these should be sought out.
Another caution is the following: "NSF does not assume or undertake
to discharge any responsibility of the manufacturer or any other
party. NSF shall not be responsible to anyone for the use of or
reliance upon this standard by anyone." It should be noted that to
meet the established standard, a treatment unit must be shown to
reduce evidence of cysts by 99.95%.

       In January 1996, 26 manufacturers had approved devices for
cyst reduction. Some of these appliances are readily available from
retail outlets (PUR-brand, for example, sold in many drug and
department stores, has 5 models that meet NSF standards). Some
manufacturers sell their products only through distributors who are
available to properly install the devices. Some even provide a
service for filter replacement at an additional charge (Multi-Pure
Drinking Water Systems has a comprehensive package which includes
initial purchase, replacement filters and installation).

       All of the filters examined and certified under NSF Standard
53 are mechanical filters. Individuals who are considering the
purchase of a water treatment device should contact NSF at
800-NSF-MARK for a current list of certified units.

       Drinking bottled water is suggested as a possible
alternative, but because no consistent standards exist in this area,
the consumer must be careful to select a product that is safe.
Products labeled "drinking water" may simply be local tap water in a
container. According to the CDC, "the origin, microbial flora and
treatment of water before it is bottled vary considerably between
bottled water companies and between brands of water produced by the
same company. In general, bottled water obtained from underground
sources, i.e., springs or wells, is less likely to be contaminated
with Cryptosporidium than bottled municipal water derived from
rivers or lakes. Persons who use bottled water as an alternative to
tap water that has been boiled must carefully research and choose
their supplier."

       Bottled water that is distilled is free of Cryptosporidium.
There is currently debate over whether carbonation is capable of
killing the oocyst. While some reports indicate that it is, further
research is needed.

       Portable water filters and purifiers are also available for
travelers. Ranging in weight from 7-22 ounces, they are designed to
transport water while camping, hiking or trekking, but some models
may be adapted for use in a contained space such as a sink. All
models claim to remove "cryptosporidia, giardia and bacteria" but,
as with in-home units, there are no mandatory standards for
operation of these devices. Regardless of what method of water
treatment is used by an immunocompromised individual to reduce the
risk of exposure to Cryptosporidium, it must be used consistently
and in all cases where water is ingested, including reconstituted
juices, ice cubes and brushing teeth.

       Incidence and Diagnosis

       The incidence of cryptosporidiosis in the HIV positive
population is a subject of some controversy. While cryptosporidiosis
is an AIDS-defining condition, reporting of the disease is not
mandatory in all states. In California, where reporting has been
required since 1989, different reporting criteria may contribute in
part to the controversy over disease incidence. For example, the
California Department of Health Services, Office of AIDS reports
zero (0) cases of cryptosporidiosis for San Francisco County for the
year 1995. However, the San Francisco Department of Public Health
Seroepidemiology and Surveillance Branch reports 71 cases for the
same year. The difference is that the former reports
cryptosporidiosis only as an AIDS-defining condition, while the
latter reports all incidences of cryptosporidiosis. These differing
reporting criteria may contribute to a less than accurate perception
of the frequency of this illness.

       Annual data from the California Department of Public Health
Division of Communicable Diseases indicate either a growth in
incidence or  changes in reporting criteria from 1989 to 1994 with
the following figures: 1989 -- 46 cases 1990 -- 165 cases 1991 --
210 cases 1992 -- 276 cases 1993 -- 372 cases 1994 -- 477 cases.

       It is estimated by some epidemiologists that worldwide, the
incidence of cryptosporidiosis in the HIV positive population may
reach 50%. John Cello, MD, a gastroenterologist at the University of
California/San Francisco General Hospital, believes that fully 25%
of AIDS-related diarrhea is caused by Cryptosporidium. Difficulty
identifying the pathogen may also be partly responsible for the
controversy over reported incidence. Diagnosis is typically made by
acid-fast stool staining. The fewer organisms present, the more
difficult the diagnosis. Excretion of the oocyst can be intermittent
and the parasite may not be present in every stool sample. A minimum
of 3 separate samples is recommended. Cello advises that stool
samples will identify Cryptosporidium only 75% of the time, and that
a colonoscopy with intestinal biopsy is necessary to identify the
remaining 25%. Cryptosporidium oocysts often "hide" in an area of
the intestine called the terminal ileum. This area must be carefully
examined during a colonoscopy. Use of a flexible sigmoidoscope to
examine the lower portion of the intestine, a less invasive and less
expensive procedure, is not as likely to result in identification of
the pathogen (35-40% will be completely missed).

       Treatment

       Cryptosporidium has only been known to cause disease in
humans since 1976. Between l976 and l982, it was thought to be of
only marginal importance, and this may account for a lack of
investigation into treatment options. The lethal course of the
disease in the presence of HIV, however, has prompted an exploration
of a plethora of drugs and biological agents as potential
treatments.

       Standard anti-diarrheal medications, intravenous fluids,
electrolyte management and oral rehydration therapy with appropriate
fluids such as juice, broth or commercially available products are
usually recommended, but there is no recognized, effective treatment
at this time. Since 1988, several drugs have been reported as
treatments for cryptosporidiosis, with success varying from
nonexistent to encouraging (see chart below).

       Also reported frequently since 1988 has been treatment with
biological agents such as chicken immunoglobulin (IGX), bovine
anti-cryptosporidium immunoglobulin (BACI), bovine collostrum and
bovine transfer factor. Studies of the efficacy of these products
have had mixed results, ranging from disappointing to nearly
complete success. Studies have been mostly with very small
populations and have been difficult to design, according to Cello.
Nevertheless, recently completed Phase I trials with a newly
formulated high-titer bovine immunoglobulin have been very
encouraging. Dr. Paul Greenberg, also involved in the initial
trials, is very optimistic about the results. A new double-blind,
placebo-controlled Phase II trial is currently scheduled to begin at
San Francisco General Hospital. Any HIV positive individual with a
diagnosis of cryptosporidiosis who would like more information may
call Lisa Thurber at 415-206-4746.

       References

       Bartlett JA. Cryptosporidiosis. Project Inform Hotline
Handout. Reprinted from PAAC Notes 120: 110-113. March 1993.

       Cello J. UCSF/San Francisco General Hospital Department of
Gastroenterology. Personal communication. December 1995.

       Centers for Disease Control and Prevention. Assessing the
public health threat associated with waterborne cryptosporidiosis.
Workshop report. MMWR 44, #RR6. June 16, l995.

       Centers for Disease Control and Prevention.
Cryptosporidiosis: Fact Sheet. Document #578000. September 28, 1995.

       Centers for Disease Control and Prevention.
Cryptosporidiosis: A guide for persons with HIV/AIDS. Document
#578001. September 25, 1995.

       Ciesielski C and others. Cryptosporidiosis in AIDS patients
in the United States: relationship to municipal water supplies? 2nd
Conference on Human Retroviruses and Related Infections. January
29-February 2, 1995. Abstract #UI95920339.

       Clavel A and others. Evaluation of the optimal number of
fecal specimens in the diagnosis of cryptosporidiosis in AIDS and
immunocompromised patients. European Journal of Clinical, Microbial
and Infectious Diseases 14:46-49. January 1, 1995.

       Coates T. San Francisco Department of Public Health Monthly
Rounds. Center for AIDS Prevention Studies, San Francisco. November
30, 1995.

       Cryptosporidiosis:a growing public health concern. California
Morbidity. May 5, 1995.

       Culotta N. National Sanitation Foundation International.
Personal communication. December 1995. Current WL and others.
Cryptosporidiosis. Eli Lilly and Company, Clinical Laboratory
Medicine 11:873-97. December 1991.

       Fenton M. Safe Drinking Water. AIDS Project of Los Angeles.
1995.

      Gilson I and others. Impact of a community-wide outbreak of
cryptosporidiosis on patients with AIDS. X International Conference
on AIDS. August 7-10, 1994. Abstract U194371610.

       Greenberg P. UCSF/San Francisco General Hospital Department
of Gastroenterology. Personal communication. January 1996.

       Hanna L. Cryptosporidium and other environmental pathogens.
BETA. December 1994.

       Hicks M. System Water Quality Superintendent, East Bay
Municipal Water District. Personal Communication. October 1995.

       Hsu K. Deadly parasite in water spurs scientists to improve
detection. Wall Street Journal. August 8, 1995. James J.
Cryptosporidium in water: CDC guidelines on how to protect yourself.
Aids Treatment News 227:7-8. 1995.

       Juranek D. Cryptosporidiosis: Sources of infection and
guidelines for prevention. Centers for Disease Control and
Prevention, Division of Parasitic Diseases. Document #578003.
October 2, 1995.

       Kreiger J. California Department of Health Services, Office
of AIDS. Personal communication. January, 1996.

       Lambert G. Cryptosporidium. The Alternative. Baltimore, MD.
September 1995.

       Lutz H. Preventing Cryptosporidiosis. Positive Nutrition.
Autumn 1995.

       McKinney K. Field Unit AIDS Surveillance Coordinator, San
Francisco Department of Public Health/AIDS Office. Personal
communication. January 1996.

       Petersen C. Cryptosporidium and the food supply. The Lancet
345: 1128-1129. May 6, l995.

       Ritchie DJ and ES Becker. Update on the management of
intestinal cryptosporidiosis in AIDS. Annals of Pharmacotherapy 28:
767-78. June 1994.

       Rosenberg J. California Department of Health
Services/Communicable Disease Control. Personal communication,
December 1995.

       Sears CL. Cryptosporidiosis: epidemiology, pathogenesis and
treatment. Interscience Conference on Antimicrobial Agents and
Chemotherapy. October 4-7, 1994. Abstract U195921037.

       United States Environmental Protection Agency, Office of
Water. EPA efforts to control microbial and byproduct risk. EPA
811/F-94-005. June 1994.

       *******************************************************
       *******************************************************
       Scope and Limitations of Gene Therapy for HIV Infection

       Henry E. Chang and Mark Bowers

       Henry E. Chang is Vice President of Clinical Research and
       Development at Kraus Medical Partners in Los Angeles, CA,
       where he monitors the development of promising HIV/AIDS
       therapies. Mark Bowers is Managing Editor of Treatment
       Publications at the San Francisco AIDS Foundation.

       During the last few years, considerable progress has been
made in gene therapy technology for HIV infection and AIDS. Reports
of extremely rapid progress in this high-tech arena have distorted
public opinion by catapulting expectations, while at the same time
some researchers have called for a renewed emphasis on basic
research. This article will review some of the key issues in gene
therapy as it relates to HIV disease, and will report early results
from some of the more than 100 studies currently approved by the
Recombinant DNA Advisory Committee (RAC) at the National Institutes
of Health (NIH).

       What is Gene Therapy?

       Gene therapy is the descriptive term for a method which seeks
to correct a disease by genetic manipulation. Genes, the basic units
of heredity, consist of a long stretch of deoxyribonucleic acid
(DNA), which forms a part of the chromosome, a body in the nucleus
that is the bearer of genetic information. Human DNA contains all of
the information that the body needs to form new cells and tissues,
to communicate with other cells, and to regulate the continued
existence and biological evolution of humankind. Human beings have
between 50,000-100,000 genes (the collection is called a genome).
The Human Genome Project is working now to characterize all human
genes; several thousand are known so far.

       Each gene contains the information required to make a
protein. Human cells contain an abundance of different proteins,
each with a different job to do. If even a single gene is damaged in
some way, the production of the protein that is made by that gene
will be changed. The changed or missing protein could then change
the way the cell functions, ultimately leading to genetic disease.
Many diseases are possible when proteins are not produced in the
right amounts, are produced at the wrong time or are not produced at
all.

       One goal of gene therapy is to replace a gene that has become
defective. Another goal is to put new working genes into the human
body that do specific useful things, such as increase the immune
system's ability to find and neutralize HIV. In order to accomplish
either of these goals, the gene must first be delivered to the right
cell by a process called gene transfer. There are many technical
difficulties in accomplishing gene transfer, and much basic research
focuses on safe methods to put genes into human cells. Once the gene
has been successfully inserted in the right place in the target
cell, the gene must produce enough protein to bring about some
therapeutic effect. Again, protein production presents many
technical challenges. Finally, the whole procedure must result in
clinical benefit to patients.

       Gene Transfer Methods

       Once an appropriate gene has been identified, it needs to be
put into the right cell. Viruses have a natural ability to insert
their own genes into the chromosomes of cells. The virus takes over
the cellular machinery, inducing the cell to make the proteins the
virus needs to survive and reproduce. Gene therapy researchers have
genetically engineered several different kinds of modified viruses
to carry desired genes into target cells. This involves removing
some of the virus's genes and replacing them with genes that make
proteins that may provide therapeutic benefit.

       So far, researchers have identified 3 broad problems with
using viruses as transferring vehicles, or "vectors." First, the
virus that has had modifications in its DNA must effectively and
reliably put the target gene into a host cell. Once that happens,
the cell is permanently modified, as are all cells produced by the
subsequent division of that cell. The second problem is that host
cells need to be infected outside the body with the virus that
transfers the desired genes. Once the DNA is incorporated into the
host cell's genetic material, the cells are encouraged to divide
many times (a process referred to as "cell expansion"). Finally,
cells are tested for contaminants and viruses that could reproduce
and cause disease. Only after all the steps have succeeded are the
modified cells put back into the body.

       The Recombinant DNA Advisory Committee (RAC) of the Food and
Drug Administration (FDA) has approved studies of viral gene
transfer approaches. Practical difficulties and high costs have
spurred researchers to look for alternative ways to move desirable
genes into target cells. One strategy is to deliver the genes of
interest directly into a living person, using either modified
viruses or other transfer technologies. Mouse retroviruses are
considered safe for moving genes into the cells of living humans.
The use of mouse retroviruses also results in stable long-term
expression of proteins that have a therapeutic effect. Direct gene
transfer of pure DNA without the intermediary use of a virus has
also been attempted. The arguments for this kind of transfer are
that it is safer, more convenient and cheaper than using viruses.

       Antiviral Gene Therapies

       Antiviral gene therapy is a strategy that is being developed
to interfere with the reproduction of HIV. Some gene therapy
techniques are designed to enhance or modify the human immune
response to HIV infection. The information that will come from early
studies of immune enhancement will yield important information about
how to restore lost immune functions that result from advanced HIV
disease. Recent experience with gene therapy approaches to HIV
disease has also taught researchers about immune responses to gene
therapy itself, and has given some clues about how to best use these
immune responses.

       CD8 HIV-Specific Cytotoxic T-Cells

       Stanley Riddell, MD, and colleagues at the Fred Hutchinson
Cancer Research Center in Seattle reported the results of a small
gene therapy study in the February issue of Nature Medicine. These
researchers infused 6 HIV positive individuals 4 times with
genetically altered cytotoxic T-cells (CTL), immune cells with CD8
markers that can destroy the virally infected cells that they find.

       The new cells were specifically targeted at gag, a gene of
HIV, and also contained a "suicide gene" that produces an enzyme for
which a powerful drug already exists. If the new cells were to prove
to be a problem for any reason, the drug could be administered to
effectively destroy them. Each time the volunteers received an
infusion of altered cells, their bodies mounted a defensive immune
response that eliminated the altered cells.

       In 5 of the 6 participants, the cells either disappeared
rapidly or were found in much decreased numbers after the third and
fourth infusions. Was the study a failure or a qualified success?
Certainly, new and important questions arise because of these study
results. There must be a way around the generation of a strong
anti-CTL response in almost all of the HIV positive volunteers.

       Researchers are now considering using drugs or antibodies to
block the immune response that destroyed most of the infused cells.
Also under consideration is the use of certain cytokines (chemical
messengers) such as interleukin 10 (IL-10) to dampen the vigorous
immune response to the transplanted cells. Researchers have also
begun to wonder if adding CTL to existing antiretroviral therapies
(such as nucleoside analogs and protease inhibitors) will be enough
to halt disease progression.

       Ribozymes

       Flossie Wong-Stahl, MD, and her colleagues at the University
of California in San Diego have developed an RNA molecule called a
ribozyme that can bring about certain chemical reactions; it can cut
HIV's genetic material at a certain point and prevent the production
of new HIV in treated cells. This is an interesting avenue of
research, because the creation of ribozymes, or "molecular
scissors," is not limited to a single strain of HIV, and because
ribozymes can successfully be put into human T-cells from HIV
negative as well as HIV positive individuals. A Phase I clinical
study was developed and approved by the RAC in 1993. The study is
designed to find out if a double ribozyme can safely and effectively
be introduced into human volunteers. The study has not yet opened.
Nonetheless, researchers are optimistic that they will be able to
justify the clinical use of ribozymes in treating HIV disease.

       Transdominant Negative Mutants

       As in the previous 2 examples of gene therapy, transdominant
negative mutants are introduced to target cells by viral vectors, or
delivery systems. This particular approach takes advantage of a
phenomenon that has been frequently observed in nature: mutant
proteins can interfere with a large number of wild-type proteins.
Wild-type means the kind of protein that HIV normally produces.
Transdominant negative mutants include altered forms of the HIV
genes gag, rev, tat and env.

       Gary Nabel, MD, and his colleagues at the University of
Michigan at Ann Arbor have chosen to develop one transdominant
negative mutant called Rev M10. This mutant has been able to
suppress HIV replication in chronically infected cells. Rev binds to
an area of genetic material called the Rev Response Element (RRE).
Mutant rev binds to the same place and creates a backlog of HIV RNA
in the nucleus of the cell. The RNA cannot leave the nucleus, and
thus no new HIV proteins can be made. Nabel's group has begun a
Phase I study of Rev M10. Two different delivery systems are being
used: viral and microparticle. The study is expected to provide data
about the safety of the 2 procedures and some hints as to the
effectiveness of the overall strategy.

       Conclusion

       Gene therapy, an exciting and promising field of research,
has not yet produced any striking therapeutic benefits. Both
researchers and the public have been enthusiastic about the
possibilities of correcting or compensating for disease at the
genetic level, but some of the more fundamental problems -- delivery
and continued existence of altered cells -- remain incompletely
solved. Gene therapy is an infant science, and like an infant, the
first steps are halting. Gene therapy will one day be used with
currently approved drugs -- nucleoside analogs and non-nucleoside
reverse transcriptase inhibitors, protease inhibitors, and others
not yet imagined -- to control HIV disease and restore immunity, but
the process will take time. In 3-5 years, the tools should be
available, and several years after that, widespread use of gene
therapy may be a reality. For now, gene therapy research is
progressing no faster than vaccine research. Answering key questions
must precede widespread clinical adoption of any specific gene
therapy strategy.

       References

       Afton E. Gene therapy. New England Journal of Medicine
334(5):332. February 1, 1996.

       Fox J. One panel tells NIH not so fast on gene therapy;
another says streamline RAC. ASM News 62(2):66-67. February 1996.

       Friedman T. Human gene therapy:an immature genie, but
certainly out of the bottle. Nature Medicine 2(2):144-147. February
1996.

       Koenig S. A lesson from the HIV patient: the immune response
is still the bane (or promise) of gene therapy. Nature Medicine
2(2):165-167. February 1996.

       Leiden J. Gene therapy: promise, pitfalls, and prognosis. New
England Journal of Medicine 333(13):871-873. September 28, 1995.

       Riddell S and others. T-cell mediated rejection of
gene-modified HIV-specific cytotoxic T lymphocytes in HIV-infected
patients. Nature Medicine 2(2):216-223. February 1996.

       Touchette N. Gene therapy: not ready for prime time. Nature
Medicine 2(1):7-8. January 1996.

       *********
       *********
       Sinusitis

       Leslie Hanna

       Leslie Hanna is Associate Editor of BETA.

       Fever, facial pain, nasal discharge, postnasal drainage,
headache and congestion: especially during the winter months, these
symptoms of sinusitis are perhaps all too familiar. Although
intermittent sniffling and fishing through pockets in search of a
tissue may seem to be simple, inescapable seasonal rituals, these
common, nonspecific signs may actually signify a variety of
conditions that warrant equally various treatment approaches. But
what differentiates a "common cold" from other conditions such as an
allergic reaction, or the more serious infection known as sinusitis,
all of which can cause similar symptoms?

       Sinusitis is generally manageable in HIV negative and HIV
positive individuals alike. In HIV positive persons, especially
those with advanced HIV disease, the management of sinusitis may be
more difficult. Sinusitis is more likely to become chronic; serious,
even life-threatening complications may arise. What should persons
with HIV know about pathology and treatments? This article will
address these questions and related issues.

       The Paranasal Sinuses

       The paranasal sinuses are air spaces or cavities within the
skull, or facial skeleton. Lined with a special tissue called
ciliated respiratory epithelium, the paranasal sinuses drain through
tiny passageways into the nasal cavity (nose). The ciliated
epithelium lies on top of a mucous membrane in the paranasal sinuses
and is continuous with the membrane of the nose. The mucous membrane
is well supplied with blood and mucous-secreting goblet cells that
normally keep the membranes very moist. By warming and hydrating air
as it is inhaled, the mucous membranes help protect the lungs. In
addition, the mucous covering the membrane captures small inhaled
particles, which the cilia (hair-like projections) move toward the
back of the throat, where the entrapped material may be coughed out
or swallowed.

       Four individual sinuses collectively compose the paranasal
sinuses, named for the skull bones that contain them. The frontal
sinuses are located approximately above the eyebrows. The maxillary
sinuses, the largest, extend from the eye orbit (the bony cavity
where the eye is located) on both sides of the nose to the upper
jaw. The sphenoidal sinuses are in the sphenoid bone, somewhat below
and behind the eye orbits, toward the base of the skull. The ethmoid
sinuses are in front of and below the sphenoidal sinuses, flanking
the nose.

       One or multiple sinuses may be the site(s) of infection. The
most common sites of infection are the maxillary sinuses, followed
in descending order of frequency by the ethmoid, frontal and
sphenoidal sinuses.

       Mechanisms of Infection

       Sinusitis is an upper respiratory tract infection (URI),
usually bacterial, of the paranasal sinuses that often develops
secondarily, after an allergic reaction or primary viral URI.
Allergies or common respiratory infections such as colds inflame the
mucous membranes of the nasal cavity; blood vessels enlarge, causing
membranes to swell and mucous secretion to increase. The resulting
congestion makes breathing difficult and causes a "runny nose."
Since the membrane lining the nose is continuous with the membrane
of the sinuses, infection spreads fairly easily from the nasal
cavity into the paranasal sinuses. In approximately 20% of cases of
bacterial sinusitis, rhinovirus (which causes the common cold),
adenoviruses (which cause various respiratory infections) and
influenza viruses can also be recovered. (For more information on
bacteria and other pathogens that cause HIV-related sinusitis, see
the charts.) When the tiny interconnecting passageways that normally
allow the sinuses to drain into the nose become blocked, mucus and
debris become trapped in the sinuses, creating an ideal environment
for the development of secondary bacterial sinusitis.

       Impaired immune defenses contribute to the development of
sinusitis. Normal mechanical immune functions such as mucous
secretion or ciliary action may be disrupted. Levels of
immunoglobulin A (IgA), an infection-fighting antibody that protects
mucosal surfaces, may be reduced in respiratory secretions. Levels
of bloodborne infection-fighting white blood cells such as
phagoctyes, which consume and destroy antigens, may be altered.

       URI, Acute and Chronic Sinusitis Usually, people with acute
sinusitis have had either a recent viral URI or an allergic reaction
that caused mucosal inflammation and irritation (rhinitis). One
simple approach to differentiating between a primary URI and
secondary sinusitis relates to the duration of symptoms; respiratory
symptoms that continue without improvement after 10 days suggest
possible secondary bacterial infection. What about differentiating
between acute and chronic sinusitis? While that distinction can be
difficult to make, symptoms that continue after 30 days suggest
chronic rather than acute sinusitis. Another definition for chronic
sinusitis is the persistence of signs and symptoms despite 4-6 weeks
of antibiotic treatment; especially in a person with HIV, this
condition is likely to involve different bacteria and a different
type of mucosal inflammation than acute sinusitis.

       Symptoms and Diagnosis

       The signs and symptoms of acute and chronic sinusitis differ
slightly. Signs and symptoms of "acute purulent" sinusitis include
nasal congestion, purulent (characterized by pus) nasal discharge
and often fever. Facial pain often increases when bending or
stooping forward, and in severe cases may increase with nearly any
movement. Pain and tenderness can be focused in different regions
around the face and head; an individuals perception of the locus of
pain may suggest which of the sinuses are infected. For example,
sinusitis pain that occurs primarily around the mouth, cheeks and
upper teeth suggests maxillary sinus infection. Sphenoid sinusitis
causes sensations of generalized facial pain, and pain behind and
between the eyes; people with sphenoid sinusitis sometimes report
that their eyes are sensitive to light and watery, or teary. Ethmoid
sinusitis causes pain that is perceived as close to or behind the
nose, especially the upper nose, and headache that may be perceived
as continuing inward from the temples to the region behind the eyes.

       The symptoms of chronic sinusitis may be fewer and milder or
blunted, compared with those of acute sinusitis. Chronic sinusitis
involves nasal congestion and discharge, intermittent pain (patients
may report vague pressure rather than sharp pain), but rarely
fever. Postnasal drip often causes a chronic, nonproductive cough.
People with chronic sinusitis often have a history of allergies, and
an estimated 25% of those with chronic maxillary sinusitis have an
underlying dental infection. Staphylococcus aureus and gram-negative
bacteria often factor in chronic sinusitis. Evaluation of a person
with chronic sinusitis should include routine sinus x-rays, computed
tomography (CT scan) and tests for granulomatous disease, ciliary
dysfunction and hypogammaglobulinemia (depressed levels of serum
antibodies, associated with immunodeficiency).

       Diagnosis of sinusitis is usually based on signs and symptoms
rather than on laboratory tests and data. Cultures are not routinely
made, since the relative inaccessibility of the paranasal sinuses
makes taking specimens difficult. Over the past several years,
however, standard office nasal endoscopy (use of an instrument that
allows the examination of the interior of a canal or passageway) has
become one of the most valuable tools for diagnosing sinusitis,
especially in HIV positive persons. The areas of drainage for most
of the sinuses are accessible by this method, and cultures made from
these sinus outflow areas provide good bacteriologic information
on the sinuses themselves. Other helpful diagnostic tools include
radiographs (x-rays) to confirm actual cases and to help identify
the cause(s) of recurrent or chronic sinusitis, CT scans and
magnetic resonance imaging (MRI) to help determine bone and fungal
involvement or tumors.

       Other Causes

       In addition to a previous URI or allergic reaction, anything
that blocks drainage of the sinuses may also promote their
infection: nasal polyps (growths), a deviated septum (malformation
of the thin wall that separates the 2 nasal cavities) or adenoids
(enlarged tonsils or lymph glands located near the nasal and
paranasal cavities). Other possible causes of sinusitis include
cigarette smoking, intranasal cocaine use, overuse of decongestants
or nasal sprays, rapid changes in altitude (airplane travel) or
pressure (deep sea diving) and other medical conditions, such as
cystic fibrosis. Persons with URI or allergies who must travel by
airplane are advised to take a decongestant one hour before
departure to avoid pressure change-related sinus inflammation and
irritation.

       Nosocomial sinusitis, or infection that is acquired in the
hospital (usually the intensive care unit) while the person is being
treated for another, unrelated condition, usually results from the
prolonged use (greater than 48 hours) of tubes in the nose or
through the mouth, e.g., for feeding. Patients become colonized with
organisms present in the environment. Since tubes are used only when
deemed necessary, little can be done except to remove the tubes and
treat the patient with decongestants and the appropriate
antibiotics.

       Complications

       Life-threatening complications of sinusitis have been
infrequent since the development of antibiotics. Still, serious
complications occasionally occur. Osteomyelitis (bone infection) of
the frontal bones sometimes follows frontal sinusitis; it is more
common in children. Pott's puffy tumor is another bone condition
that may follow sinusitis. Generally, the organism that caused the
sinusitis also causes the following disease, with a few exceptions.
For example, S. aureus tends to be found more commonly in
later-developing osteomyelitis than in the preceding bout of
sinusitis. Antibiotic treatment is usually required, and a CT scan
to rule out brain involvement is recommended.

       Since the paranasal sinuses nearly surround the eye socket,
orbital involement sometimes results. Swelling of the eyelids and
interference with eye movement may indicate orbital involvement in
people who are feverish and, generally, very ill. Pressure on the
optic nerve can lead to irreversible vision loss. A thorough
clinical evaluation and antibiotic treatment are essential if any of
these symptoms are present.

       Central nervous system involvement may also follow sinusitis,
causing a variety of conditions including brain abscesses and
meningitis. Headache, subtle personality changes, alterations of
consciousness (caused by increased pressure) and/or visual symptoms
may indicate neural involvement, which can lead to seizures, coma
and death. Such serious complications necessitate high-dose
antibiotic therapy and, often, surgery.

       HIV-Specific Considerations

       Sinusitis is a common bacterial infection in people with HIV.
Actual incidence rates are unknown, but estimates range from 10-16%
of people with AIDS in retrospective studies, and up to 70% in
prospective studies. HIV-infected children, especially those with
hypogammaglobulinemia, appear particularly susceptible to sinusitis.
People with fewer than 200 CD4 cells/mm3 are most likely to develop
sinusitis. As HIV-related immunosuppression increases, cases of
sinusitis are more likely to become severe, difficult to treat and
chronic. In people with low CD4 cell levels, sinusitis is more
likely to involve multiple (rather than single) sinuses and to fail
to respond to antibiotic treatment. Thus, chronic management often
becomes the critical issue in the context of HIV.

       HIV-infected people are at increased risk for bacterial
infection, due to HIV-related impaired humoral immunity. Impaired
humoral immunity has itself been linked to sinus infection,
regardless of HIV serostatus. Persons with HIV who have a history of
previous sinus problems, lower respiratory infections (bronchitis,
bacterial pneumonia), allergy and even dental infections should
report these to their healthcare providers, since their history puts
them at additional risk for sinusitis.

       Most sinusitis as well as pneumonia are bacterial infections
associated in the context of HIV with community-acquired organisms
such as Streptococcus pneumoniae, Haemophilus influenzae, Moraxella
catarrhalis and Mycoplasma pneumoniae. Coagulase positive as well as
negative staphylococcus organisms also are seen in people with AIDS.
The bacterial pathogens most frequently implicated in HIV-related
sinusitis are Streptococcus pneumoniae and Hemophilus influenzae.
Viruses, such as adenovirus or influenzavirus, often the cause of a
preceding URI, are also frequently present. Anaerobic bacteria and
recently, increasingly, Pseudomonas aeruginosa have been implicated
as pathogens in sinusitis in people with HIV. See the charts of
pathogens for details.

       Sinusitis also may signal the presence of another, more
serious condition such as the fungal infection aspergillosis. While
fungal infections occasionally cause sinusitis in HIV negative
persons, the risk is higher for people with HIV. Fungal sinusitis
can be allergic or invasive. Aspergillosis in particular, when
infecting the lung, may cause sinusitis, in addition to serious bone
or central nervous system complications. Candidiasis also may be
involved in chronic sinusitis. Although Candida albicans is
extremely common in the oral cavities and throats of people with
AIDS, it does not often cause sinusitis.

       Although fungal sinusitis is relatively uncommon, the
incidence appears to be increasing. Heightened awareness on the part
of physicians of the possibility of sinusitis among their HIV
positive patients and increasing use of nasal endoscopy both result
in more diagnoses. Sinusitis expert Thomas Tami, MD, Associate
Professor in the Department of Otolaryngology-Head and Neck Surgery
at the University of Cincinnati, told BETA that he attributes the
increase he has seen in aggressive fungal sinusitis to neutropenia
(low levels of infection-fighting white blood cells). Neutropenia in
any population, regardless of HIV serostatus, is a very high risk
factor for invasive fungal infections. Patients with fungal
sinusitis usually also have very advanced HIV disease and
immunosuppression, and have been taking antivirals, antibiotics and
other medications for extended periods. It is not surprising to see
neutropenia in this group of long-term survivors, Tami notes, adding
that formal studies have not yet been conducted to test these
observations.

       These patients with fungal sinusitis are generally very
symptomatic, but CT scans reveal relatively little about fungal
pathogens. Therefore, Tami states, an HIV positive person with
advanced HIV disease who has severe, unremitting pain that is
disproportionate to the clinical and radiographic findings would
immediately prompt him to consider and evaluate for fungal sinusitis
using endoscopy and culture.

       Another factor contributing to chronic sinusitis in people
with HIV may be the "hyperallergic" state associated with immune
dysregulation in some individuals. Elevated levels of immunoglobulin
E (IgE) reflect this hyperallergic state. People who have lower CD4
cell levels and high serum IgE levels, which appear to increase with
progression of HIV disease, are at greater risk for chronic
sinusitis that is related to allergy rather than to bacterial
infection.

       HIV-Related Clinical Presentation and Evaluation

       The signs and symptoms of sinusitis in HIV positive people
are similar to those in HIV negative people. However, chronic
sinusitis in people with HIV may be less symptomatic than in HIV
negative people. Also, concomitant infections in people with HIV
sometimes mask chronic sinusitis. Sinusitis should be considered in
the differential diagnosis of HIV positive individuals with low CD4
cell counts who have fever and/or headache. Uncommon presentations,
including pulmonary signs and sepsis (the presence of pathogens in
the blood), have been reported, but are rare.

       CT scans and MRI are considered more helpful in diagnosing
sinusitis in HIV-infected people than in HIV-uninfected people,
since radiographs often miss the posterior sinus involvement that
occurs more frequently in people with HIV. Similarly, microbiologic
diagnosis may be more useful in diagnosing sinusitis in people with
HIV. Again, nasal endoscopy has emerged as an essential tool for
diagnosing sinusitis among persons with HIV, as well. Tami
recommends nasal endoscopic evaluation of the middle meatus and
sphenoethmoid recess for both diagnosis and follow-up.

       There have been suggestions that taking
trimethoprim/sulfamethoxazole (TMP/SMX; Bactrim, Septra) for PCP
prophylaxis reduces the incidence of sinusitis, but no prospective
studies have tested this observation. Individuals with later-stage
HIV disease may be taking various potent medications, including
antibiotics, which make oral and respiratory flora more resistant to
standard antibiotics. Such persons are at relatively high risk of
having unusual pathogens such as Pseudomonas aeruginosa, which is
known to colonize people with AIDS. Again, microbacteriologic
diagnosis is helpful in devising the most appropriate treatment
regimen.

       Treatment

       Treatment regimens vary somewhat, depending on whether
sinusitis is acute or chronic. Treatment for acute sinusitis usually
involves antibiotic therapy; regimens are generally the same for HIV
negative and HIV positive persons. Treatment for chronic sinusitis
for a person with HIV is somewhat more specialized, and depends on
several factors, such as the severity of the condition, whether
recurrence is due to antibiotic resistance, whether another
opportunisitic pathogen is involved, etc.

       Acute Sinusitis

       Again, acute sinusitis is a secondary bacterial infection
that follows a primary viral URI. Antibiotic treatment is
appropriate for the bacterial sinusitis but not for the viral
condition; thus, optimal treatment requires accurate diagnosis of
acute sinusitis.

       Treatment of acute sinusitis is aimed at promoting proper
drainage and decreasing nasal swelling. Decongestants are helpful
adjuncts to antibiotic treatment. Nasal swelling may be decreased by
using topical nasal sprays such as oxymetazolin that constrict blood
vessels. Their use should be restricted to the first 4-5 days of
antibiotic therapy to avoid a rebound effect of worsened congestion.
Systemic agents such as pseudoephedrine or phenylpropanolamine are
considered very helpful.

       Adequate hydration helps thin mucous secretions, which aids
in drainage. Inhaling steam from a basin of hot water or cool-mist
humidifier or while taking a shower helps loosen mucus. Oral
antihistamines are not helpful, since they thicken material in the
sinuses. Guaifenesin (e.g., Humibid LA) helps to thin mucus; Tami
recommends relatively high-dose guaifenesin equal to 1,200 mg every
12 hours. Mild analgesics like aspirin or Tylenol and heat may
relieve discomfort.

       Antibiotic treatment is often needed and, reportedly, usually
at least partially effective. In the seminal sinusitis study by
Godofsky, 79% of participants had at least a partial response,
meaning documented full or partial resolution of signs and symptoms.
Purulent nasal discharge and fever indicate antibiotic treatment,
which often lasts 2-4 weeks. Common antibiotics for primary therapy
include amoxicillin and TMP/SMX; amoxicillin-clavulanate (Augmentin)
or an oral cephalosporin are preferred. Cefuroxime axetil (Ceftin)
or cefpodoxime (Vantin) also are considered very good treatments for
HIV-related sinusitis. If acute sinusitis fails to clear after 2-4
weeks, the patient should be re-evaluated and referred to an
otolaryngologist (an ear, nose and throat specialist, or ENT).

       If sinusitis develops in the intensive care unit, nasal tubes
should be removed if possible and antibiotics administered, usually
oxacillin or vancomycin, as well as a third-generation cephalosporin
or sulbactam-ampicillin. An attempt to culture the sinus drainage is
always helpful in determining the appropriate antibiotics.

       Chronic Sinusitis

       Research data suggests that severe chronic sinusitis is
almost exclusive to those with severe immunosuppression. Since
unusual pathogens may be involved, particularly Pseudomonas, Tami
suggests covering all the bacteriologic bases by using combination
antibiotic therapy with ciprofloxacin and clindamycin. Standard
nasal endoscopy and culture are recommended.

       Tami described a typical case: a frustrated infectious
disease or primary care doctor refers to an otolaryngologist a
patient with a low CD4 cell count who has failed on several courses
of standard sinusitis therapy. After first performing an endoscopy
and culture, Tami recommends beginning empiric treatment with
combination clindamycin and ciprofloxacin. These drugs will kill
Pseudomonas, Staphylococcus and most possible pathogens. If the
culture results are negative, Tami suggests keeping the patient on
the combination because it usually resolves symptoms; if a positive
culture result is returned, there may be evidence suggesting the use
of other, more appropriate drugs. Although the combination tends to
cause diarrhea, Tami recommends it for its extreme anti-sinusitis
potency.

       Chronic, persistent sinusitis due to allergy may require
identification and elimination of allergens, which are often in food
or airborne (e.g., hayfever). Local applications of heat to the area
of the face over the sinuses are often helpful.

       Intranasal steroids are a very useful and non-antimicrobial
method for managing chronic sinusitis, decreasing chronic
inflammation and reducing mucosal swelling. Antibiotics should be
used only when infection is also present. Some theoretical concern
over the use of intranasal steroids in immunocompromised people
exists, due to the local immunosuppressive effect of steroids, which
may cause a subsequent local proliferation of fungi. Still, Tami
considers the risks low and the use of intranasal steroids in people
with HIV "very safe."

       Chronic fungal sinusitis usually responds to treatment with
an antifungal agent aimed at the causative organism or with
intravenous amphotericin B. Allergic fungal sinusitis is treated
symptomatically, often with glucocorticoids. In the rare case of
candidiasis-related sinusitis, treatment for candidiasis should
alleviate the sinusitis.

       Another experimental treatment is the administration of
intravenous gamma globulin (IgG), a concentrated solution of
antibodies, in an attempt to counterbalance deficits in humoral
immunity.

       Occasionally treatment requires endoscopic sinus surgery
(ESS) to allow tissue sampling and diagnosis, as well as to remove
polyps and establish proper ventilation of infected sinuses.
Surgery, which involves widening the passageways for drainage, is an
aggressive intervention. Generally regarded as a last resort,
surgery is reserved for those who fail antibiotic treatment and
especially when sinusitis may involve extra-sinus complications.
Surgery does not always effect a cure, but may provide some
symptomatic relief and improve the quality of life for people with
late-stage AIDS.

       Acupuncture and Herbal Treatments

       According to Tom Sinclair, a licensed acupuncturist (LAc)
with the Immune Enhancement Project (IEP) in San Francisco, the
moderate efficacy of standard Western or allopathic treatments for
HIV-related sinusitis have led many people to explore alternative
medical approaches. Holistic measures that may help alleviate acute
sinusitis include bed rest and drinking lots of fluids such as
diluted vegetable juices, soups and herbal teas. Other suggestions
include limiting sugar consumption and eliminating common food
allergens (milk, wheat, eggs, citrus, corn and peanut butter).
Supplementation of vitamins such as C, A and beta carotene has been
recommended, along with zinc and bioflavonoids. Goldenseal is
regarded as the most effective botanical for acute bacterial
sinusitis; it can be taken as a tincture (added to liquid and
drunk), as a fluid or powdered solid extract, or as a dried root
prepared as a tea. Local alternative treatment recommendations
include applying menthol or eucalyptus packs over the sinuses and
swabbing nasal passages with oil of bitter orange. Application of
hot packs may help, but should be discontinued if pain increases but
drainage does not.

       One promising alternative approach under formal study is
Traditional Chinese Medicine (TCM). According to TCM, sinusitis is
one of various "bi-yuan" conditions, which involve nasal discharge
and interference with the normal nose/lung connection, the nose
being regarded as the opening to the lung. Sinusitis signifies a
problem with the flow of energy that moves from and through the lung
(Lung Qi). In addition, the independent sinuses are related to other
internal organs, which merit evaluation in the event of sinusitis.
According to the TCM school of thought, the large intestine is most
frequently implicated as a source of sinusitis-related problems.

       To treat sinusitis, TCM uses acupuncture and herbs that dry
and move, cleanse, open and circulate the lung energy. TCM also
recommends taking vitamin supplements and botanicals such as
goldenseal. IEP provides clients with a handout on sinusitis
"homework."

       Sinusitis in the general population has been treated with
acupuncture and herbs in the past. Improvement has been anecdotally
reported but actual efficacy is unclear. The IEP wrote a protocol
for studying acupuncture and herbal treatment for chronic
HIV-related sinusitis. Funded by the National Institute of Health,
the study is now underway and several participants have been
enrolled. The non-blinded study compares TCM with standard Western,
allopathic approaches to treating sinusitis by randomizing
participants with CT-confirmed sinusitis to receive either
acupuncture and herbal treatment or antibiotic and decongestant
treatment. Outcome measurements include symptomatic relief and
radiographic improvement. Data from this comparative study should
provide valuable insights into the role and efficacy of TCM in
treating sinusitis.

       Table 1. Unusual pathogens causing chronic sinusitis in HIV
disease Pseudaliesheria boydii (Sooy, 1987) Alternaria alternata
(Wiest, 1987) Aspergillus (Carranza, 1987) Cryptococcus (Choi, 1988)
Candida (Colmenero, 1990) Acanthamoeba (Gonzales, 1986) Legionella
pneumophillia (Schlanger, 1984) Cytomegalovirus (Brillhart, 1991)
Zygomycosis (Blatt, 1991)

       Table 2. Bacteriology of HIV-related sinusitis [from
Godofsky] Based on 11 positive cultures from 18 patients

       7----Staphylococcus epidermidis
       3----Pseudomonas aeruginosa
       2----Streptococcus viridans
       1----Streptococcus pneumoniae
       1----Aspergillus fumigatus
       1----Cytomegalovirus

       Table 3. Bacteriology of HIV-related sinusitis (endoscopic
cultures)[from Tami]

       Based on 11 positive cultures from 14 patients

       5---Coagulase negative Staphylococcus
       2---Pseudomonas aeruginosa
       2---Streptococcus pneumoniae
       2---Streptococcus (other)
       1---Staphylococcus aureus
       1---Enterobacter
       1---Klebsiella pneumonia
       1---Aspergillus fumigatus
       1---Scedosporium inflatum

       HOLISTIC INTERVENTIONS FOR SINUSITIS

       The following information has been excerpted from a
"sinusitis homework" sheet that the Immune Enhancement Project in
San Francisco provides to their clients with sinusitis. Immune
Enhancement Project (415-252-8711) offers alternative treatments
including acupuncture, herbal therapy and massage to people with
HIV/AIDS.

       Mucous membranes are like muscles--they function better when
they've been "stretched and exercised." To strengthen mucous
membranes and release pressure in the head, perform the following
massages 10 times each, 1-3 times a day. The whole procedure should
take about 5 minutes.

       1) Pinch the tip of the nose and move it back and forth.

       2) Pinch the area between the cartilage and hard bone and
          move back and forth.

       3) Push the tip of the nose upward.

       4) Massage the sore spots on your cheeks. Search for them in
          the entire zone from the bottom edge of your nose, under
          and on top of the cheekbones and under, over and on the
          eye socket.

       5) Massage the sore spots along the hair line and slightly in
          back of that. Push toward the face. Notice whether you
          feel a change in pressure as you would in an airplane.

       6) Massage behind the muscle that runs from behind your ear
          diagonally forward to your breast bone. Push or pull
          forward toward the throat.

       7) With thumb or index finger, massage the soft palate at the
          back part of the top of your mouth with a sweeping side to
          side motion.

       8) To assist in the drainage of "stuck energy" and fluids
          from the head, massage the hollows on the sides of the top
          of your breast bone, the webs of your thumbs and any sore
          spots along the thumb edge of your wrists.

       Things to do once a day or 2-5 times a week during acute
       phases:

       1) Apply a paste made with dry ginger and water or pureed
          lotus root (available at health food or Asian food stores)
          to the skin over the sinus areas below and above the eye.
          This will feel very hot, but it does not burn the skin and
          relieves sinus pressure and dries up congestion.

       2) Boil water, add 1-2 drops of thyme or eucalyptus essential
          oil (available at health food stores) to the water, put a
          dry towel over your head and the pot, and inhale through
          your nose. Repeat for 4-6 breaths. This opens the
          passageways, and may help to prevent bacterial
          complications in your lungs and sinuses. Be cautious at
          first--it's very strong.

       3) Lie on your back with your knees up and massage sore spots
          around your navel, pointing 45 degrees down and under the
          navel 1-1.5 inches deep.

       From Immune Enhancement Project, Winter 1995-95.

       Sources

       Dobson JC. HIV-related sinusitis. Critical Path AIDS Project
2(9-10): 1-4. December 1991.

       Godofsky EW and others. Sinusitis in HIV-infected patients: a
clinical and radiographic review. The American Journal of Medicine
93: 163-170. August 1992.

       Lee K. Personal communication. January 18, 1996. Simon HB.
Infections of the upper respiratory tract. Scientific American
Medicine: 7:XIX:3-5. June 1994.

       Spence AP. The respiratory system. Chapter 19, Basic Human
Anatomy, third edition. Benjamin/Cummings Publishing Company, Inc.
Redwood City, CA. 1990.

       Tami TA. The management of sinusitis in patients infected
with the human immunodeficiency virus (HIV). ENT Journal 74 (5). May
1995.

       Tami TA. Personal communication. January 18, 1996.

       Zurlo JJ and others. Sinusitis in HIV-1 infection. The
American Journal of Medicine 93: 157-162. August 1992.

       **********
       **********
       AIDS Fraud

       Mark Bowers

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

       Throughout recorded history, whenever there have been
epidemics people could neither understand nor cure, unscrupulous
hucksters have taken advantage of widespread credulity and
desperation to sell unproved "cures." The AIDS epidemic has produced
its share of fraudulent treatments and questionable healthcare
strategies. The current gamut of HIV/AIDS treatment quackery runs
from drinking amaroli (one"s own urine) to deliberately infecting
oneself with malaria, a strategy championed by the otherwise
credible Harry Heimlich, MD.

       AIDS fraud may be difficult to identify. The Food and Drug
Administration (FDA) established a definition of health fraud on
June 17, 1993: "The deceptive promotion, advertisement, distribution
or sale of articles, intended for human or animal use, that are
represented as being effective to diagnose, cure, treat or mitigate
disease (or other conditions), or to provide a beneficial effect on
health, but which have not been scientifically proven safe and
effective for such purposes. Such practices may be deliberate, or
done without adequate knowledge or understanding of the article."
Many of the people responsible for such fraud are impostors who pose
as physicians or scientists. Vast sums of money can be made in
exchange for the right marketing ploy and a veneer of scientific
credibility. Confidence men (and women), with and without medical
degrees, can often effectively conceal fraud behind the respectable
mantle of caring physician.

Why Do People Turn to Charlatans?

       Increasing barriers to medical access and burgeoning mistrust
of physicians have encouraged many to take desperate measures to
manage serious and incurable disease. The current climate of
suspicion and conflict can be traced to recent political events.
Last year, universal health care in the United States was rejected
in favor of a corporate takeover of health care. Partisan rhetoric
predicted that universal health care would lead to an assembly-line
system where choice is lacking and care is rationed and subject to
spending limits. These predictions have in fact come true under
today's for-profit system. Meanwhile, the ranks of the uninsured
have swelled by an additional 2 million, to total more than 41
million Americans today. Bureaucracy has intervened in the
physician-patient relationship. Corporations impose gag rules on
physicians, preventing them from disclosing the existence of some
medical treatments, in direct violation of the principle of informed
consent. Cases have been brought against corporate giants for
failure to provide needed drugs, tests and procedures. Americans now
need legal protection from their HMOs. In this climate of aggressive
cost-containment at the expense of patient rights, people
increasingly turn to alternative medicine for the emotional and
psychological support that their physicians can no longer provide in
the 7 minutes typically allotted to a primary-care visit. Thus they
put themselves at increased risk of exposure to AIDS fraud. Those
who seek to persuade patients to rely on fraudulent cures take their
time, listen sympathetically, say what patients want to hear and
provide hope, however illusory and misplaced that hope may be.

       Opportunists who sell "cures" seldom offer more than one
specific product. Some products may be recycled, having previously
been sold illicitly to cure cancer, but with no results. One such
drug is laetrile, once offered as a "safe and effective cure for
most types of cancer" at border clinics in Mexico; widespread
publicity and government intervention eventually discredited the
drug, but not before millions of dollars were ill-spent. Laetrile
resurfaced in the early 1990s as a cure for AIDS. It was not. Some
products are new and have not been rigorously evaluated in carefully
controlled clinical studies. These products may be harmless, but
they could also result in fatalities.

       AIDS Fraud Task Forces

       AIDS fraud in California is not a crime in itself, but rather
is controlled by the application of state and federal laws that
govern other crimes and the permissible uses of unapproved drugs and
substances. Because of the broad range of possible fraudulent
activities, FDA initiated the formation of the California AIDS Fraud
Task Force (CAFTF) in 1990. Members include representatives of local
community AIDS organizations throughout the state, physicians and
representatives of public health and law enforcement agencies. For 4
years, discussions about what constituted AIDS fraud were heated.
The issue was resolved when an informational brochure was created
and distributed throughout the state. The philosophy of the task
force is that people can and do make wise and informed decisions for
themselves about their HIV/AIDS healthcare if they are given
complete information about strategies and products they might
choose. HIV/AIDS fraud in California is subsumed under the broader
category of false advertising. AIDS fraud task forces in 10 states
(see sidebar) investigate reports of AIDS fraud and refer them to
law enforcement agencies when appropriate.

       A national consortium of state task forces meets annually to
discuss incidents of fraud and their resolution, and to increase
outreach efforts to prevent AIDS fraud before it occurs. Each state
provides information to its residents via statewide hotlines.
Illinois and California have established targeted outreach to
communities of color. These communities are considered to be at
greater risk for AIDS fraud; they have historically had less access
to healthcare in the United States.

       A Case of Fraud

       When opportunists sell a harmful substance of no proven
therapeutic benefit as a medical cure, law enforcement agencies may
prosecute. The Consumer Protection Unit in San Diego has prosecuted
2 cases of HIV/AIDS fraud in the last 10 years. Tricia Johnson,
deputy city attorney, handles the criminal prosecution of fraudulent
claims for San Diego. She emphasizes that people are not prosecuted
for injecting, ingesting or applying unapproved substances to
themselves. Her office and others like it around the state focus on
false advertising claims and the illegitimate exercise of the profit
motive. Making false statements about the effectiveness of
substances that are sold for profit is consumer fraud. For example,
false claims that FDA has tested and approved a substance, or claims
that a substance will cure a wide range of diseases when the only
evidence consists of unverifiable anecdotes, would constitute fraud.
Usually such claims are accompanied by exorbitant prices and
requests that information about the products not be shared with
other physicians.

       Johnson has recently completed the successful prosecution of
the operators of the Taylor-Stacey Center for Advanced Medicine.
William Stacey and Lawrence Taylor, MD, were charged, tried and
convicted of selling and injecting Immunostim to more than 108
patients with severe diseases, including AIDS. According to written
testimony by a relative of one man who received Immunostim, "David
and I were assured of several things: that Immunostim was
'FDA-approved,' 'completely safe,' 'contained 4 common ingredients,'
one of which was Bill Stacey's own 'discovery,' and that Bill had
documented case histories of 'cures'. David died March 4, 1995, just
4 days short of his 36th birthday." According to the testimony of
Donald Stevenson, MD, Chairman of the Department of Medicine at
Scripps Clinic in La Jolla, Immunostim is composed of quaternary
amines that "have never been approved for injection into veins. [It]
caused inflammation in the veins as it was dripped into [patients']
bodies...The inflammation in the veins led to painful swellings and
then a complete closure of the veins with a resulting hard knot
where a vein had previously existed." Quaternary ions are the basis
for some household cleansers.

       The original complaint against Stacey was lodged with the USA
Television Network as part of a program called "Case Closed.". The
program series invited viewers to describe wrongs that remained
unresolved. The mother of a North Carolina man who had been "cured"
with Immunostim injections at great financial expense called the
network to fulfill a promise she made to her son on his deathbed:
she would see that his tormentor, Stacey, would be punished for his
cynical exploitation of her son during his desperate quest to locate
an AIDS cure. Alerted to Stacey's sale of Immunostim and potentially
illegal activities, the San Diego Office of Consumer Protection
located him at the Taylor-Stacey Center for Advanced Medicine in San
Diego. In February 1994, a sting operation was set up. On 3
occasions, hidden cameras recorded Stacey's and Taylor's miraculous
claims about Immunostim. By March, search and arrest warrants were
issued, and the 2 were taken into custody. In May 1995, pleas were
entered, and plea bargaining led to a reduced charge for Taylor:
maintaining a nuisance. He was sentenced on August 18, 1995 to pay
restitution to his victims, serve 150 days in jail and pay a $2,000
fine. He is on probation for 3 years, during which time the court
has directed him not to treat anyone with AIDS or cancer unless they
are referred to him by another physician. The California Medical
Association subsequently withdrew Taylor's license to practice
medicine in the state.

       Stacey jumped bail, left the state and set up shop in South
Carolina. He continued to sell Immunostim to desperate and
vulnerable people as far away as Australia and Bermuda. Stacey was
finally extradited and imprisoned in December 1995. At that time, 55
of the 108 patients who had been "cured" with Immunostim were dead.

       How Can Fraud Be Avoided?

       The Immunostim example illustrates many important
considerations about AIDS fraud. FDA-approved drugs are listed in
the Physicians' Desk Reference (PDR) and other standard
pharmaceutical reference works. Dosages, routes of administration,
side effects and pharmacological properties are fully disclosed.
Immunostim is not included in the PDR, and no clinical testing had
been done. The product was available from only one source. The claim
that Immunostim was FDA-approved was not substantiated by any
published research. The ingredients were never approved for any use
other than household cleansers. Verify claims that a product is
FDA-approved.

       Products that are sold to cure or prevent cancer and other
illnesses as well as AIDS are always suspect. Immunostim was
guaranteed to "cure" any fatal illness. There is no treatment so
effective that it can cure all fatal illnesses. Anyone who makes
such claims intends to take advantage of people who are desperate
and willing to suspend rational judgment and disbelief. On one
occasion, Stacey paraded a woman patient through the crowded waiting
room at his clinic, proclaiming that she was being sent home because
her cancer was now cured. She died of cancer shortly thereafter.

       Printed material about Immunostim was available, but it only
included personal success stories and testimonial evidence, claims
which could not be independently verified. Potential consumers
should carefully question any product or treatment that relies on
personal success stories or testimonials. Promotion for a product
that relies on testimony from people who are not medically or
scientifically trained is a warning sign of AIDS fraud. Look for
objective data.

       Immunostim was very expensive. In 22 months, Taylor collected
$238,181.10 and Stacey received $431,945.40 from the sale of
Immunostim. However, some AIDS treatments that are legitimately
approved or at some stage of the approval process are also
exorbitantly expensive: foscarnet (Foscavir), a treatment for CMV
retinitis, costs about $26,000 a year before additional infusion
costs, and human growth hormone (Serostim), an experimental drug for
AIDS wasting, costs $60,000 a year. The more a treatment costs, the
more evidence one should demand that the product works.

       Be wary of the promotion of a therapy for uses other than
those for which the therapy was approved. Sometimes, the "off-label"
use of a drug can be beneficial and is supported by published
research and wide community experience. Usually, such use is not
reimbursed by insurance carriers. In early 1995, Taylor placed
advertisements in San Diego newspapers promoting chelation therapy
for heart disease, high blood pressure, arthritis, impotency and
other conditions. None of these were approved uses, and a court
order was issued against Taylor, ordering him not to perform that
therapy. Off-label use of any drug should be carefully researched
and evaluated.

       Be suspicious of any drug or treatment that requires you to
stop taking other prescriptions or seeing other healthcare
providers. Fraudulent practitioners often argue that anything that
they did not sell or create must be bad for people. They may ask for
secrecy and exclusive medical control for fear of confrontation with
other accredited physicians who may reveal their fraud.

       Insist on full disclosure of the risks and benefits of any
drug or treatment. Informed consent is the cornerstone of patient
rights in the United States. No physician may legally prescribe any
drug or perform any procedure without fully informing you of the
associated risks, benefits and alternatives.

       Reliable treatment information can be obtained from national
treatment hotlines and from treatment publications. When unsure
about a drug or treatment, seek a second opinion. Consult the CDC
Drug Information and Clinical Trial Hotline at 1-800-874-2572,
Project Inform at 1-800-822-7422 or your local AIDS hotline.

       If you think you have been the victim of AIDS fraud, contact
your state's AIDS task force or Attorney General's office (see
sidebar) or the California AIDS Fraud Task Force at 1-800-459-4503.
The best defense against fraud is knowledge.

       *******************
       *******************
       BETA Research Notes

       Mark Bowers

       Mark Bowers is Managing Editor of Treatment Publications at
       the San Francisco AIDS Foundation. He has been a member of
       the Scientific Advisory Committee of the San Francisco AIDS
       Foundation since 1994.

       HIV Pathogenesis
       ----------------

       Two Studies Show Some Infants Can Beat HIV

       * 299 children became HIV-antibody negative

       * 2 European studies support the notion of natural immunity

       Two recently reported European studies lend support the
long-debated assertion that there is natural immunity to HIV. In the
European Collaborative Study of children born to HIV positive
mothers, 299 children became negative for the HIV antibody test. 264
of these children were tested by polymerase chain reaction (PCR) for
the presence of virus in the blood. 219 children were tested at
least twice. PCR detected HIV in 9 children who subsequently were
found to have undetectable levels of virus. These children appear to
have seroreverted: they were exposed to HIV, were infected for a
short time, then cleared the virus.

       In December 1995, French researchers found another 12
children whose initial PCR tests were positive for HIV, and who then
apparently cleared the virus before their first birthday. A
retrospective study of 188 children born to HIV positive mothers
over a 6-year period detected HIV by coculture of cord blood, direct
culture or PCR. These tests are used because children naturally
acquire antibodies from their mothers whether or not they also are
infected with HIV. Five of the 12 children who seroreverted had
tested positive by no method of detection other than by PCR.

       Researchers are now trying to reach consensus on acceptable
criteria for determining if children have been transiently infected
with HIV. Individual PCR tests may be associated with false-positive
results because of laboratory contamination, but repeated PCR tests
results are unlikely to be false. If these children are naturally
immune, as they appear to be, the data suggests that such immunity
is rare. The seroreversions suggest that there is an immunologic
mechanism for controlling and eliminating HIV. If researchers can
determine what that mechanism is and how it works, they may be able
to duplicate it in others, design an effective vaccine and fill in
the blanks in understanding HIV pathogenesis.

       Roques T and others. Clearance of HIV infection in 12
              perinatally infected children: clinical, virological
              and immunological data. AIDS 9(12): FF19-F26. December
              1995.

       Newell ML and others. Detection of virus in vertically
              exposed HIV-antibody-negative children. The Lancet
              347:213-214. January 27, 1996. HIV Suppression:Two
              Groups Identify


       Chemical Messengers that Inhibit HIV

       For many years, Jay Levy, MD, at the University of California
in San Francisco, has looked for a soluble factor, secreted by CD8
cells, that suppresses HIV replication. The CD8 factor is predicted
to be initially present and then decrease in rapid progressors, and
to be important in long-term non-progressors. Two groups have
recently laid claim to the identity of this soluble factor. Robert
Gallo, MD, and colleagues, of the Institute for Human Virology,
found that 3 chemical messengers produced by CD8 cells could
together inhibit different strains of HIV-1, HIV-2 and simian
immunodeficiency virus (SIV) in the test tube. The factors have been
named RANTES, MIP-1 alpha and MIP-1 beta. Gallo speculates that this
discovery could lead to the development of effective therapeutic
approaches to AIDS.

       Michael Baier, PhD, and fellow researchers in Germany contend
that the elusive factor is the newly isolated interleukin 16
(IL-16). The presence of IL-16 in African green monkeys is credited
with controlling SIV and preventing the development of simian AIDS.
Both groups now must determine whether production of these chemical
messengers is defective in rapid progressors. If so, clinical
studies in human subjects will soon follow. Baier M and others. HIV
suppression by interleukin-16. Nature 378(6557): 563. December 7,
1995.

       Cocchi F and others. Identification of RANTES, MIP-1alpha,
              and MIP-1beta as the major HIV-suppressive factors
              produced by CD8+ T-cells. Science 270:1811. December
              15, 1995.


       HIV Concentration During Acute Infection

       The currently accepted model of early infection with HIV
holds that the concentration of virus in the plasma increases for a
few weeks after initial infection, then begins to decrease when the
body develops an HIV-specific immune response. British researchers
have challenged this model, suggesting that population dynamics, and
not the immune system, accounts for sharp decreases in viral load.
They argue that measurable virus decreases because HIV runs out of
suitable uninfected cells to infect, not because the body has
mounted a partially effective immune response to the infection. In
fact, in some individuals, viral load was seen to decrease
dramatically despite the absence of any measurable antibody or
cytotoxic T-cell responses.

       Phillips A. Reduction of HIV concentration during acute
              infection: independence from a specific immune
              response. Science 271:497-499. January 26, 1996.


       Predicting Progression to AIDS
       ------------------------------

       Polymerase Chain Reaction Found to Predict Progression

       The search for a surrogate marker that reliably predicts HIV
disease progression has returned mostly disappointing results.
Beta-2 microglobulin, neopterin and HIV p24 antigenemia have all
been of limited value. CD4 counts and percentages are commonly
accepted, but not entirely correlative with disease progression. The
latest of 4 studies that support the use of PCR RNA tests for
predicting disease progres- sion was reported in Annals of Internal
Medicine in November 1995.

       A distinction is drawn between 2 kinds of PCR messenger RNA
measurement, in plasma and in peripheral blood mononuclear cells
(PBMC). Plasma viral load measures, according to Nobel Prize winner
Warner Greene, "probably reflect a dynamic balance between the daily
production of nearly 1 billion new virions [virus particles]
countered in part by the destruction and physical trapping of these
virions in the dendritic cell network of the lymph node or other
lymphatic tissues." RNA in PBMCs reflects trafficking in and out of
lymph nodes and the effects of other infections. Finding HIV
messenger RNA in PBMCs strongly predicts future progression to AIDS.
Greene said in summary, "For the HIV infected person, the clinician
providing care and the scientist attempting to unravel the mysteries
of the HIV virus, the identification of an assay potentially capable
of predicting future progression or nonprogression to AIDS is very
good news indeed."

       Greene W. Predicting progression to AIDS. Annals of Internal
              Medicine 123(9):727-728. November 1, 1995.

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


       Typical Progressors, Rapid Progessors and Nonprogressors

       In the January 19, 1996 issue of Science, Barton Haynes, MD,
Giuseppe Pantaleo, MD, and Anthony Fauci, MD, reported on current
understanding of the genetic, immunologic and virologic factors in
HIV infected individuals who do or do not progress to AIDS. From 5%
to 10% of all HIV infected individuals are asymptomatic after 7-10
years and their CD4 cell counts are stable (nonprogressors); 10%
progress to AIDS within 2-3 years (rapid progressors); the rest will
on average progress to AIDS about 10 years after initial infection
(typical progressors).

       Typical progressors characteristically are infected with HIV
strains that are homogeneous, that target monocytes, that do not
induce syncytia formation (cell clumping) and that replicate slowly
during the clinically latent stage. During progression to AIDS, HIV
isolates increase their speed of replication and target T-cells.
Rapid progressors tend to have an initial high viral load that does
not fall to the same lower levels as seen in typical progressors.
There are higher levels of HIV messenger RNA compared with other
groups, and some people may be infected with rapidly replicating,
virulent strains of HIV. Nonprogressors on average have lower viral
loads than either of the other 2 groups, and some may be infected
with less pathogenic strains of HIV.

       A clear set of research priorities is established in the
article summary. The key question to be answered is how a low viral
load in nonprogressors relates to the pathogenicity of the HIV
strain and to anti-HIV immune responses. The next priority is to
determine genetic influences on anti-HIV responses and find ways to
rebuild the immune system, including use of bone marrow and thymus
transplants. The third goal is to understand the role of protective
neutralizing antibodies in nonprogressors. The fourth key question
is whether a particular interaction between a strain of HIV and a
specific host can explain nonprogression. Fifth, immune responses at
the mucosa, the most common portal for HIV entry during sexual
transmission, need to be adequately characterized in animal models.
Sixth, attenuated virus vaccines need to be explored and understood
in both newborn and adult rhesus monkeys. Finally, the role of the
newly isolated soluble factors secreted by CD8 cells in
nonprogression needs to researched. These 7 research priorities will
no doubt constitute a blueprint for future HIV research at the
National Institutes of Allergy and Infectious Diseases, where Fauci
is responsible for setting research policy.

       Haynes B and others. Toward an understanding of the
              correlates of protective immunity to HIV infection.
              Science 271:324-328. January 19, 1996.


       HIV Treatments
       --------------

       People of Color Experience Same AZT Side Effects as Whites

       There is no significant increase in adverse side effects from
AZT (Retrovir) use among African-Americans or Hispanics, according
to results of a recent University of California at San Francisco
study. The study was based on reports from patients about pain or
discomfort while using AZT. These results do not mean that these
groups do not experience side effects from the use of AZT, only that
these effects are the same as those experienced by whites who use
the drug.

       Jacobson M and others. Zidovudine side effects as reported by
              black, Hispanic, and white/non-Hispanic patients with
              early HIV disease: combined analysis of two
              multicenter placebo-controlled trials. Journal of
              Acquired Immune Deficiency Syndromes and Human
              Retrovirology 11(1): 45-52. January 1996.


       Adefovir Dipivoxil Data Released

       A Phase I/II study of adefovir dipivoxil, an oral prodrug
from the nucleotide analog family, compared 125 mg per day or 250 mg
per day to placebo in 72 volunteers with CD4 counts above 200
cells/mm3. Viral load decreased by 0.5 log at the 125 mg dose, and
by 0.4 log at the 250 mg dose. Mean CD4 cell counts increased at 12
weeks by 57 cells/mm3 at the 125 mg dose and by 27 cells/mm3 at the
250 mg dose, compared to a loss of 41 cells/mm3 in the placebo
group.

       Risk Factors for Neuropathy

       A comparative study of 103 people who took either ddI (Videx)
or ddC (Hivid) assessed whether other risk factors influence the
development of peripheral neuropathy. The group under study had a
mean age of 39 years and a median CD4 count of 59 cells/mm3. Of the
51 people taking ddC, 14 developed neuropathy, compared to 7 of 55
taking ddI. No independent risk factors were associated with
developing neuropathy from ddI, but a history of nervous system
disease, heavy alcohol consumption or low serum cobalamin (vitamin
B12) levels distinguished those who were at higher risk of toxic
neuropathy from ddC.

       Fichtenbaum C and others. Risk factors for
              dideoxynucleoside-induced toxic neuropathy in patients
              with the human immunodeficiency virus infection.
              Journal of Acquired Immune Deficiency Syndromes and
              Human Retrovirology 10:169-174. October 1995.


       3TC and AZT Combination Synergistic

       According to a study of 362 people with CD4 cell counts
between 200-500 cells/mm3 and little or no prior experience with
antiretrovirals, the combination of 3TC (Epivir) and AZT produces
more improvement in CD4 percentages and lower viral load than either
drug alone. The double-blind comparative study of 300 mg of 3TC
every 12 hours, 200 mg of AZT every 8 hours, 150 mg of 3TC every 12
hours plus AZT, or 300 mg of 3TC every 12 hours plus AZT showed that
both combination regimens were superior to either drug taken alone.
Lower plasma HIV RNA levels and increased percentage of CD4 cells
were maintained through 52 weeks.

       Eron J and others. Treatment with lamivudine, zidovudine, or
              both in HIV-positive patients with 200 to 500 CD4+
              cells per cubic millimeter. New England Journal of
              Medicine 333(O25):1662-1669. December 21, 1995.


       DNCB Shows No Clinical, Viral or Immunological Effect

       Two small studies assessed the impact of the application of
DNCB (dinitrochlorobenzene, a photographic solvent) on viral load,
cytokine expression and HIV disease progression. In the first study,
28 asymptomatic HIV positive volunteers with variable CD4 cell
counts and no antiviral treatment in the previous 3 months were
randomized to receive topical DNCB or placebo for 6 months. All also
received Chinese medicine and acupunture. All those who received
DNCB developed evidence of skin delayed-type hypersensitivity
(rashes) but no major systemic side effects. CD4 counts increased
slightly for both placebo and DNCB treated volunteers; CD8 counts
increased more in the placebo group than in the DNCB group. DNCB did
not produce a significant difference in clinical or immunologic
outcomes.

       The second study reviewed 8 HIV-infected volunteers who
received weekly DNCB applications and oral Chinese herbs, and 3 who
received only oral Chinese herbs. Lymph node biopsies were performed
at baseline and at 6 months. CD8 cell losses were similar for both
groups. CD4 counts in the DNCB group fell from a mean baseline of
448 to 289 cells/mm3 at 6 months (a net loss of 159); CD4 counts in
the untreated group fell from 398 to 277 cells/mm3 (a net loss of
121). Because the DNCB group lost more CD4 cells, their percentage
of CD8 cells was higher. DNCB did not affect viral burden, viral
replication or cytokine expression.

       Cohen O and others. Effects of dinitrochlorobenzene therapy
              on viral load and cytokine expression in lymphoid
              tissue of HIV-infected individuals. Infectious
              Diseases Society of America 33rd Annual Meeting. San
              Francisco. September 16-18, 1995. Abstract 475.

       Loveless M and others. Effect of dinitrochlorobenzene (DNCB)
              cutaneous sensitization on HIV disease progression.
              Infectious Diseases Society of America 33rd Annual
              Meeting. San Francisco. September 16-18, 1995.
              Abstract 471.


       Opportunistic Infections
       ------------------------

       NTZ for Cryptosporidiosis

       UNIMED Pharmaceuticals announced that a compassionate access
program has been established for the experimental drug nitazoxanide
(NTZ) for the treatment of cryptosporidiosis (call 1-800-864-6330
for more information). A small clinical study in Mexico evaluated
500 mg of NTZ twice a day in 14 people. At 2 weeks, all 14 were
negative for stool cultures of Cryptosporidium. The best dose for
the drug is not yet established; a clinical study at Cornell Medical
Center in New York City will compare 14 days of treatment with 500,
1000, 1500 or 2000 mg daily in 30 volunteers. Treatment extension of
2 or 4 weeks will be made available to those who do not have a
complete response.

       James J. NTZ: cryptosporidiosis new treatment. AIDS Treatment
              News 239:1-2. January 19, 1996.


       Cryptosporidiosis and Biliary Disease

       In March 1993, a waterborne outbreak of cryptosporidiosis
occurred in Milwaukee, WI. Of the more than 400,000 people who were
affected by drinking water from the contaminated municipal water
supply, a significant number were HIV- infected. Researchers
evaluated the signs and symptoms of HIV disease, CD4 cell counts and
survival in a group of 82 HIV-infected people whose infection with
cryptosporidi- osis was documented by finding Cryptosporidium in
their stools.

       Researchers noted a sharp increase in HIV-infected
individuals with cryptosporidiosis. Biliary disease was present in
24 people, of whom only 4 (17%) were still alive after 1 year.
Biliary disease in people with AIDS can be caused by both
Cryptosporidium and cytomegalovirus (CMV), and affects the tracts
that carry bile from the liver through the gallbladder to the
intestine. Of the 58 people without biliary disease, 30 (52%) were
still alive 1 year after the cryptosporidiosis outbreak. Twenty-one
of the people with biliary symptoms had CD4 cell counts less than 50
cells/mm3, compared to 36 of the 57 without symptoms.

       Researchers conclude that HIV-infected people with CD4 counts
less than 50 cells/mm3 who are exposed to Cryptosporidium are at
increased risk for biliary symptoms and for death within 1 year of
infection. Researchers further caution that "Public water supplies
that meet current federal and state standards for drinking water may
still become contaminated with cryptosporidial oocysts and cause
large outbreaks, as occurred in Milwaukee."

       Vakil N. and others. Biliary cryptosporidiosis in
              HIV-infected people after the waterborne outbreak of
              cryptosporidiosis in Milwaukee. New England Journal of
              Medicine 334:19-23. January 4, 1996.


       3TC Suppresses Hepatitis B Virus

       In a randomized, double-blind, dose-ranging trial of 3TC in
32 people with chronic hepatitis B, participants received either 25,
100 or 300 mg of drug daily for 12 weeks. The drug was well
tolerated, and reduced viral RNA levels as measured by PCR to
undetectable levels in 70% of those taking 25 mg doses and in all of
those taking the higher doses. Traces of hepatitis B virus could be
found again in most people after 3TC was discontinued. Larger
studies are being planned.

       Dienstag J and others. A preliminary trial of lamivudine for
              chronic hepatitis B infection. New England Journal of
              Medicine 333(25):1657-1661. December 21, 1995.


       Famciclovir Suppresses Recurrent Genital Herpes

       Famciclovir (Famvir) was approved for the treatment of herpes
zoster (shingles) in 1994. A recent randomized, double-blind study
of 48 HIV positive individuals with recurrent genital herpes simplex
found that 500 mg of famciclovir twice a day reduced viral shedding
significantly more than placebo. When people are shedding virus,
they can potentially spread the disease to others. Volunteers
received either famciclovir or placebo for 8 weeks, took no drug for
a week, then crossed over to the alternate treatment for another 8
weeks. Famciclovir also appears to reduce the frequency and severity
of HSV infection recurrences.

       Schacker T and others. Efficacy of famciclovir for
              suppressing HSV-2 infections among HIV+ persons. 3rd
              Conference on Retroviruses and Opportunistic
              Infections. Washington DC. January 28-February 1,
              1996. Abstract 13.


       Foscarnet Cream for Acyclovir-Resistant Herpes Simplex

       Foscarnet (Foscavir) cream (1%) was applied 5 times a day to
herpes simplex virus lesions that had previous not responded to
acyclovir treatment. Twenty HIV positive people were treated for
6-60 days (the mean number of days was 34.5).

       Of the 20 lesions treated, 9 healed completely, 3 showed
excellent response (greater than 75% decrease in lesion size), 2
showed good response (greater than 50% decrease), 4 showed partial
response (greater than 25% decrease) and 2 had no response. Pain was
reduced for 11 of 15 participants who reported pain associated with
lesions. Topical 1% foscarnet cream appears to be a safe and
effective therapy for acyclovir-resistant herpes simplex lesions in
people with HIV.

       Hardy D and others. Phase I pilot study of the safety and
              efficacy of foscarnet (PFA) cream for treatment of
              acyclovir-unresponsive herpes simplex. 3rd Conference
              on Retroviruses and Opportunistic Infections.
              Washington DC. January 28-February 1, 1996. Abstract
              167.

       ********
       ********
       Glossary

Compiled by Liz Highleyman


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

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

ACUPUNCTURE: a traditional Chinese medicine technique that involves
inserting very thin needles into different acupuncture points
(meridians) on the body.

ACUTE: rapid in onset, aggressive.

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.

ALLERGEN: an agent or substance that stimulates an allergic or
hypersensitivity reaction.

ALLOPATHY (adjective ALLOPATHIC): "Western medicine." A therapeutic
system in which illness or disease is treated by producing a second
condition that is incompatible with the first, e.g., an antibiotic
drug used to treat infection with a microorganism.

ANALGESIC: a drug that reduces sensibility to or perception of pain.

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

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

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

ANGIOGENESIS: the growth and proliferation of blood vessels.

ANOREXIA: the lack or loss of appetite for food.

ANTAGONIST: an agent that prevents or reverses the action of another
agent.

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: the presence of an antigen in the blood.

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

ASPERGILLOSIS: an uncommon life-threatening infection caused by the
fungus Aspergillus that typically infects the lungs and sinuses, but
may become disseminated.

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

ASYMPTOMATIC: not feeling or showing outward signs of illness.

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

BACTEREMIA: the presence of bacteria in the blood.

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

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.

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

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

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

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

BONE MARROW TRANSFER (BMT): a graft of bone marrow, the spongy
tissue within certain bones that is the site of blood cell
production, from one individual to another.

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

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

CANDIDIASIS: a disease caused by 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. Vaginal and oral candidiasis, or
thrush may be early signs of immune impairment in HIV positive
individuals.

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

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

CD4 (OR CD8) CELL PERCENTAGE: the number of CD4 (or CD8) cells
compared to the number of all lymphocytes.

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.

CHEMOKINE: a chemical produced by cells that stimulates the activity
of other cells.

CHLAMYDIASIS (CHLAMYDIA): an infection, usually sexually
transmitted, with the bacteria Chlamydia trachomatis. Infection may
be asymptomatic or include symptoms such as genital inflammation and
discharge, pelvic pain and fever. Untreated chlamydiasis may lead to
pelvic inflammatory disease (PID) and infertility.

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

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

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

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

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

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

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.

CORD BLOOD: blood taken from the remains of the umbilical cord after
birth; cord blood is rich in stem cells.

C-REACTIVE PROTEIN: a protein often found in the serum of people
with inflammatory and other diseases; the protein reacts with the C
polysaccharide of pneumococci.

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

CRYOTHERAPY (CRYOSURGERY): the use of liquid nitrogen to freeze a
lesion.

CRYPTOCOCCOSIS: an infection caused by a yeast-like fungus,
typically Cryptococcus neoformans, found in soil and bird excreta. A
common manifestation is cryptococcal meningitis.

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

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

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

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

CYTOPLASM: the gel-like substance that makes up cells outside the
nucleus.

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

DEHYDROEPIANDROSTERONE (DHEA): a weak androgenic steroid produced by
the adrenal cortex.

DENDRITIC CELL: a type of immune system cell with many branches
found in the skin and mucosal linings. Dendritic cells are the first
to arrive at sites of injury or infection, where they bind to
invaders and transport them to the lymph nodes.

DIFFERENTIAL DIAGNOSIS: a method of diagnosis that involves
determining, often by a process of elimination, which of a list of
diseases is the probable cause of a patient's symptoms.

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

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

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

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

ECTOPIC PREGNANCY: a pregnancy in which a fertilized egg begins to
develop outside the uterus, e.g., in a fallopian tube. Ectopic
pregnancy can result in tubal rupture, hemorrhage and death.

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

EMPIRIC DIAGNOSIS/TREATMENT (PRESUMPTIVE DIAGNOSIS/TREATMENT):
evaluation or treatment based on observation alone, without relying
on laboratory test results or while results are pending.

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

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

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

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

ERYTHROCYTE: a mature red blood cell that contains the hemoglobin
molecule. Erythrocytes transport oxygen and carbon dioxide between
the lungs and the tissues of the body.

ERYTHROCYTE SEDIMENTATION RATE (ESR, SED RATE): a blood test that
measures the speed at which red blood cells settle in a test tube.
The test is used to detect immune response to an infection.

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.

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

FALLOPIAN TUBE (OVIDUCT): 1 of the 2 tubes leading from the ovaries
to the uterus through which an ovum (egg) travels.

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

FOLLICLE STIMULATING HORMONE (FSH): a hormone produced by the
pituitary gland that stimulates the ovarian follicles to mature and
produce ova (eggs) in women and induces sperm production in men.

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

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

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

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

GIARDIASIS: a common infection with a Giardia protozoan (e.g.,
Giardia lamblia), which is spread via contaminated food and water
and by fecal-oral contact. Giardia infects the intestines and
produces nausea, cramping and diarrhea.

GLUCOCORTICOID: a steroid-like substance (e.g., cortisol) capable of
influencing metabolism, regulating the immune system and exerting an
anti-inflammatory effect.

GONORRHEA: a sexually transmitted disease caused by the bacteria
Neisseria gonorrhoeae. Gonorrhea may be asymptomatic or may include
symptoms such as urethritis, discharge, pelvic pain and inflammation
of the tissues of the genitals, rectum and/or throat. Untreated
gonorrhea may lead to pelvic inflammatory disease (PID) in women.

GROWTH FACTOR: a factor responsible for regulating cell
proliferation, development, migration, differentiation and/or
activity.

HEPATITIS B (HBV): a viral liver disease that may be acute or
chronic and can be life-threatening. Symptoms include fever,
headache, muscle and joint pain, malaise, nausea and jaundice. Some
individuals are asymptomatic carriers; chronic HBV may result in
liver cirrhosis and/or cancer.

HEPATOTOXIC: poisonous to the liver.

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

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

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 Kaposis
sarcoma-associated herpesvirus (KSHV or HHV-8).

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

HOLISTIC: an alternative treatment system that focuses on the whole
person rather than on specific diseases or disorders, and considers
physical, emotional, social, environmental and spiritual factors.

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

HUMAN CHORIONIC GONADOTROPIN (HCG): a hormone secreted by the
placenta that maintains pregnancy during the early development of
the embryo. The beta subunit of HCG (bHCG) has been shown to
suppress the development of Kaposis sarcoma cells in vitro.

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

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

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

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

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

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

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

IMMUNOGLOBULIN (IG): see antibody.

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.

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.

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

INTERFERON: a cytokine that plays a role in immune response.
Interferons are secreted by infected cells and help protect other
cells from infection. There are 3 major classes: alpha, beta and
gamma. Genetically engineered interferon-alpha is FDA-approved for
the treatment of Kaposis sarcoma, anogenital warts and hepatitis B
and C.

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

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

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

KAPOSI'S SARCOMA-ASSOCIATED HERPESVIRUS (KSHV, HUMAN HERPESVIRUS
TYPE 8): a recently discovered herpesvirus that is found in samples
of tissue from Kaposis sarcoma lesions.

LAVAGE: the washing out of an organ or cavity, e.g., to obtain a
sample for diagnosis.

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

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

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

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

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

LONG-TERM NONPROGRESSOR (LTNP): an individual who has been infected
with HIV for 7-10 years or more but does not exhibit immune system
decline or opportunistic diseases.

LUTEINIZING HORMONE (LH): a hormone that stimulates the final
ripening of ova (eggs) and their release in females and the
production of testosterone in males.

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

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

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

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

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

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

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

MENINGITIS: an inflammation of the meninges, the membranes covering
the brain and spinal cord.

METABOLISM: the process of building the bodys 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.

MICROSPORIDIOSIS: infection with a protozoal parasite of the
Microsporidia family (e.g., Enterocytozoan bieneusi, Septata
intestinalis), which may affect the sinuses, lungs and intestines in
immunocompromised persons, and may become disseminated.

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

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

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

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

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

NATIONAL INSTITUTES OF HEALTH (NIH): a large biomedical research
organization that is part of the U.S. Public Health Service. NIH
includes 24 institutes, centers and divisions, several of which
perform AIDS-related research.

NATURAL KILLER CELL (NK CELL): a type of lymphocyte that attacks and
kills cells infected with microorganisms.

NEF: a gene of HIV that influences viral replication; also the
protein produced by that gene.

NEOPLASM: a tumor or growth; tissue that develops abnormally or
grows more rapidly than normal. A neoplasm may be benign or
malignant (cancerous).

NEPHROLITHIASIS: kidney stones.

NEPHROTOXICITY: the property of being poisonous to the kidneys.

NEUTROPENIA: an abnormally low number or a decrease in the number of
neutrophils, a type of white blood cell involved in defense against
bacteria and fungi.

NEW DRUG APPLICATION (NDA): an application made by a drug sponsor to
FDA to request marketing approval.

NITRITE INHALANT (POPPERS): a volatile (easily evaporated) chemical,
e.g., amyl nitrite, with vasodilating (blood vessel expanding)
properties.

NODULE (NODULAR LESION): a hard, raised rounded area of the skin or
a mucous membrane; a knot or swelling.

NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR (NNRTI): a drug
(e.g., nevirapine, delavirdine, HBY 097) that inhibits the action of
the HIV-1 reverse transcriptase enzyme, thus blocking viral
replication, yet works in a different way than nucleoside analog
drugs.

NON-STEROIDAL ANTI-INFLAMMATORY DRUG (NSAID): a drug (e.g., aspirin,
ibuprofen) that relieves pain and reduces inflammation and fever,
but which is not a steroid or a narcotic.

NOSOCOMIAL: refers to the acquisition of a new disease or condition
within a healthcare setting.

NUCLEOSIDE ANALOG (NA): a synthetic compound (e.g., AZT, ddI, ddC,
d4T, 3TC) that mimics one of the building blocks of DNA
(nucleotides). These compounds suppress retroviral replication by
interfering with the reverse transcriptase enzyme; the synthetic
nucleosides cause premature termination of the viral DNA chain.

NUCLEOTIDE: one of the building blocks that make up the genetic
material (DNA and RNA). Nucleotides consist of a base (adenine,
cytosine, guanine, thymine or uracil), a sugar and a phosphate
group.

NUCLEOTIDE ANALOG: a compound (e.g., cidofovir, PMPA) similar to a
nucleoside analog, but which is already "primed" and available to be
added to a DNA chain.

ONCOGENE (PROTOONCOGENE): a gene (e.g., p53) that facilitates the
development of cancer by regulating cell growth, either by actively
turning on abnormal cell growth or failing to turn off normal
cell growth.

OOCYST: the earliest stage of life of a parasitic protozoan (e.g.,
Cryptosporidium) in which it is enclosed in a hard-shelled capsule.

OPEN LABEL: a drug trial in which both participants and
investigators know what drug is being tested and what dose is being
used.

OPPORTUNISTIC INFECTION (OI): an illness (e.g., PCP, MAC, CMV
disease) caused by a microorganism that usually does not cause
disease in persons with healthy immune systems, but which may cause
serious illness when the immune system is suppressed.

ORAL HAIRY LEUKOPLAKIA: a condition thought to be caused by the
Epstein-Barr virus, characterized by white, raised, usually painless
lesions on the sides of the tongue and/or elsewhere in the mouth.

OVARY: 1 of the 2 female gonads located within the abdomen on either
side of the uterus. The ovaries are the site of ova (egg) storage
and maturation.

OZONIZATION: the addition of ozone, a reactive form of oxygen, e.g.,
to disinfect a water supply.

p24: a core protein of HIV produced by the gag gene. Detection of
the p24 antigen in the blood or tissues indicates that HIV is
actively replicating and may predict disease progression.

PARALLEL TRACK: a system of distributing experimental drugs to
individuals who are ineligible for or unable to participate in
clinical trials.

PARESTHESIA: an abnormal burning, tingling or prickling sensation.

PARVOVIRUS: a family of viruses, several species of which infect
humans, including the adeno-associated viruses which are used as
vectors in biotechnology. Symptoms of infection include fever,
malaise and possibly a rash.

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

PATHOGENESIS: the development of a particular disease, including the
specific events involved, bodily tissues or systems affected,
mechanisms of damage and timing of the course of disease.

PELVIC INFLAMMATORY DISEASE (PID): an infection of the upper female
reproductive tract including the uterus, fallopian tubes and
ovaries. Symptoms may include pain, fever and vaginal discharge.
Without treatment PID can become chronic and severe and may lead to
infertility, ectopic pregnancy, septicemia and death.

PERIPHERAL BLOOD MONONUCLEAR CELL (PBMC): a single-nucleus white
blood cell (e.g., monocyte, lymphocyte) that circulates in the
blood.

PERIPHERAL NEUROPATHY: a disorder of the nerves usually involving
the feet and/or hands and sometimes the legs, arms and face.
Symptoms may include numbness, tingling or burning, weakness and
partial paralysis. It can be a side effect of some anti-HIV drugs
(e.g., ddC, ddI).

PHAGOCYTE: a scavenger white blood cell (e.g., neutrophil,
macrophage) that engulfs and destroys dead cells, bacteria and other
debris.

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 verify information gathered in Phase I and II trials
and involve up to several thousand volunteers. Phase III trials may
compare the drug being tested to other therapies or to placebo.

PLACEBO-CONTROLLED TRIAL: a trial of an experimental therapy in
which an inactive substance or mock therapy (placebo) is given to
one group while the treatment being tested is given to another, and
the results obtained in the different groups are compared.

PLASMA: the fluid, non-cellular portion of circulating blood that
carries blood cells and nutrients throughout the body.

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

POLYMICROBIAL: containing or caused by more than one microorganism,
e.g., bacteria.

POLYP: a mass of tissue that bulges or projects outward or upward
from the normal surface level; may be a precursor to cancer.

PREMATURE RUPTURE OF MEMBRANES: a condition in which the amniotic
sac surrounding the fetus breaks open prior to the start of labor
and delivery.

PRIMARY INFECTION: the initial introduction of an infectious
organism into the body.

PRODRUG: a drug that exerts its effects after metabolic changes
within the body convert it to a usable or active form.

PROGESTERONE: a female steroid hormone with anti-estrogenic effects.
Progesterone prepares the uterus for the development of the
fertilized ovum and maintains the uterus throughout pregnancy.

PROGNOSIS (adjective PROGNOSTIC): a forecast of the probable course
and/or outcome of a disease.

PROPHYLAXIS: a treatment that helps to prevent a disease or
condition before it occurs (primary prophylaxis) or recurs
(secondary prophylaxis).

PROSPECTIVE STUDY: a study that follows an individuals or groups
progression over a period of time.

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

PROVIRUS: a viral state in which viral DNA has been inserted into
the chromosome of the host cell.

PUERPERAL SEPSIS (PUERPERAL FEVER): an infection acquired during
childbirth, e.g., with streptococci bacteria. Puerperal fever is an
outcome of puerperal sepsis and is characterized by fever, rapid
heartbeat and inflammation of the uterus.

PURULENT: characterized by the accumulation of pus.

QI (CHI, XI): the vital energy believed to be responsible for health
and disease in Traditional Chinese Medicine.

QUANTITATIVE COMPETITIVE POLYMERASE CHAIN REACTION (QC-PCR): a
refined, sensitive version of the PCR assay used to detect DNA or
RNA using competitive RNA samples for comparison.

RADIOTHERAPY (RADIATION THERAPY): the use of radiation, e.g.,
X-rays, to treat cancer or other diseases.

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

REFRACTORY: resistant to treatment.

REPRESENTATIONAL DIFFERENCE ANALYSIS (RDA): a method that can detect
unique genetic sequences in a tissue sample.

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 looking backward in time using a
individual's or group's medical records or recall.

RETROVIRUS: a class of enveloped viruses that have their genetic
material in the form of RNA and use reverse transcriptase to
translate their RNA into DNA. The retrovirus family includes
oncoviruses (e.g., HTLV-1) and lentiviruses (e.g., HIV-1, HIV-2).

REV: a gene of HIV; also the protein produced by the gene, which
regulates the construction of the structural components of HIV and
is necessary for the production of new virus particles.

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 then integrated into the host cell's
chromosomes. RTI include nucleoside analogs (e.g., AZT, ddI) and
non-nucleoside reverse transcriptase inhibitors (e.g., nevirapine).

RIBOZYME: RNA with enzymatic activity that can break down (cleave)
and piece together (splice) genetic material (DNA or RNA), thus
modifying the genetic instructions it carries. Ribozymes, e.g., the
hairpin ribozyme, are used as "molecular scissors" in genetic
engineering.

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.

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).

SEPSIS: the presence of pathogenic organisms or their toxins in the
blood or tissues, and the associated bodily reactions.

SEROREVERSION: the change of serostatus from positive to negative.

SERUM: the fluid, non-cellular portion of blood after coagulation;
lymphatic fluid.

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

SIMIAN IMMUNODEFICIENCY VIRUS (SIV): a viral infection endemic to
African green monkeys and similar to HIV-2.

SINUSITIS: acute or chronic inflammation or infection of the
sinuses, which may be characterized by nasal congestion and
discharge, fever and headache.

STEM CELL: a precursor cell from which blood cells are derived. As
they mature, stem cells evolve into various types of red and white
blood cells.

STEROID: a family of substances that share a similar chemical
structure, including many hormones (e.g., testosterone), Vitamin D
and various drugs. Some steroid drugs are used to lessen
inflammatory reactions.

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

SYNCYTIUM (plural SYNCYTIA): a mass or clump of cells that fuse
together to form one "giant cell." In HIV infection syncytium
formation can may lead to direct cell-to-cell infection.

SYNERGY (SYNERGISM): the action of 2 or more agents (e.g., drugs)
working together that produce an effect greater than the combined
effect of the same agents used separately.

SYSTEMIC: affecting the whole body; not localized.

T-CELL (T-LYMPHOCYTE): a type of white blood cell derived from the
thymus that participates in a variety of cell-mediated immune
responses. There are 3 major types of T-cells: T-helper (CD4),
T-suppressor (CD8) and T-killer (cytotoxic T-lymphocytes or CTL).

TELOMERE: a complex of repetitive DNA sequences that caps the ends
of chromosomes. Telomeres play a role in cellular replication, via
the telomerase enzyme, which helps determine whether cells are able
to replicate.

TESTIS (TESTICLE, plural TESTES): 1 of the 2 male gonads located in
the scrotal sac, where sperm is produced.

TESTOSTERONE: a steroid hormone produced by the testes and adrenal
glands, needed for sperm production, the development of reproductive
organs and secondary sexual characteristics in males, and the
buildup of lean muscle mass. Testosterone is under study as a
therapy for HIV-related wasting syndrome.

TH1/TH2 IMMUNE RESPONSE: 2 branches of the immune system. The TH1
response involves a subset of CD4 lymphocytes called TH1 cells that
secrete IL-1, IL-2 and gamma interferon, which enhance the
cell-mediated immune response. The TH2 response involves the TH2
subset of CD4 cells that secrete IL-4 and IL-10, which enhance the
humoral (antibody-based) immune response.

THROMBOCYTOPENIA: a condition marked by an abnormally low number of
platelets, blood cells that facilitate normal blood clotting; the
condition may result in abnormal bleeding and bruising.

THRUSH: see candidiasis.

THYMUS (adjective THYMIC): a lymphoid organ located in the chest
behind the sternum. The thymus is a source of lymphocytes in
children; in adults, immature T-cells differentiate and learn to
recognize antigens in the thymus. The thymus produces some 30
hormones or thymic factors (e.g., thymodulin, thymostimulin) that
regulate immune function.

TOXICITY (adjective TOXIC): the quality of being poisonous or
harmful; often used to refer to side effects of drugs.

TRADITIONAL CHINESE MEDICINE (TCM): an Asian system of healing that
focuses on achieving internal balance using methods such as
acupuncture, heat application (moxibustion), herbal preparations and
exercises (e.g., tai chi, qigong) to restore the flow of qi ("vital
energy") and the balance of yin and yang.

TRANSDOMINANT MUTANT (TRANSDOMINANT PROTEIN): genetically engineered
non-functional copies of HIV viral proteins that compete with
functional HIV proteins for the various molecules the virus needs to
complete its life cycle.

TREATMENT IND: an FDA classification that allows physicians to
prescribe certain promising experimental drugs prior to marketing
approval for patients with life-threatening diseases who lack
alternative treatments.

TUBERCULOSIS (TB): an infectious disease caused by Mycobacterium
tuberculosis that typically affects the lungs but may occur in other
organs (extrapulmonary TB).

TUMOR NECROSIS FACTOR (TNF, CACHECTIN): a cytokine produced by
activated monocytes and macrophages that can destroy tumors. When
chronically elevated, TNF may lead to fever, anorexia,
hypermetabolism and wasting.

ULTRASONOGRAPHY (ULTRASOUND): a method of visualizing the internal
parts of the body using sound waves; also used to monitor a fetus
within the uterus.

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.

VECTOR: an agent used as a vehicle for transfer, e.g., an engineered
virus used to introduce genes into cells, or a live virus used as an
antigen delivery vehicle in a vaccine.

VERTICAL TRANSMISSION (PERINATAL TRANSMISSION, MATERNAL-FETAL
TRANSMISSION): the transmission of an infectious organism from a
mother to a fetus or neonate (newborn). Vertical transmission may
occur in utero (in the womb), during birth or via breastfeeding.

VIRAL LOAD (VIRAL BURDEN): the amount of virus in the blood or other
tissues. The presence of HIV RNA indicates that the virus is
replicating; changes in viral load may be used to gauge drug
effectiveness and disease progression.

VIREMIA: the presence of virus in the blood.

VIRION: a complete virus particle.

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 cells 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.

WILD-TYPE: the normal, typical genetic profile of a virus or other
organism before genetic mutation or manipulation takes place.

       Copyright (c) 1996 - San Francisco AIDS Foundation, Bulletin
       of Experimental Treatments for AIDS.  Distributed by AEGIS,
       your online gateway to a world of people, knowledge, and
       resources.  714.248.2836 * 8N1/Full Duplex * v.34+ / ISDN

