   GMHC Treatment Issues, Newsletter of Experimental AIDS Therapies
   Volume 10, Number 4 - April 1996; published by the Gay Men's Health    
   Crisis, Treatment Education Dept., 129 West 20th Street, New York
   NY 10011.
   -------------------------------------------------------------------

   Contents:

     Vaccine Review
     Maternal Viral Load
     Preventing MAC
     Evaluating Government Research
     Treatment Briefs
   -------------------------------------------------------------------

   
       Slow Progress On HIV Vaccines
       by Luis Santiago

       This winter's Conference on Advances in AIDS Vaccine
Development in Bethesda, Maryland was the eighth such meeting
sponsored by the National Institute of Allergy and Infectious
Diseases (NIAID). The yearly event brings together investigators
from NIAID's HIV vaccine testing centers, these centers' community
advisory boards, independent researchers and pharmaceutical
companies.

       Important new developments in basic science were announced
this year, in areas like the mucosal immunity and vaccine delivery
mechanisms. Researchers were excited about a new product, the canary
pox-gp120 prime-boost vaccine, which seems to trigger an impressive
cellular immune response not seen with previous candidates. But the
extremely short list of vaccine candidates under development and the
paltry attendance by pharmaceutical companies signaled a lack of
interest and investment in the field of vaccines.

       One manifestation of this lack of input is that some of the
most central issues remain unresolved. Researchers have yet to agree
on the so-called "correlates of protection," what sort of measurable
immune response -- blood-borne versus mucosal, antibody versus
cellular -- a vaccine should trigger to confer protective immunity
to HIV. Vaccines against other diseases have been developed without
settling the "correlates" question, but human testing of HIV
vaccines remains bogged down by this controversy. Meanwhile,
scientists have not created a generally accepted animal model for
more direct testing of vaccine-generated protection.

       Neutralizing Antibodies in Chimps and Humans

       In June, 1994, following a recommendation of a special
advisory panel, NIAID decided not to proceed with large-scale human
testing of two vaccine products, both of which were genetically
engineered versions of the HIV envelope protein gp120. Among the
panel's most important arguments was the finding that the antibodies
generated by these products were unable to neutralize "primary
isolates" of HIV, that is, virus obtained from infected people (not
laboratory strains).

       At the time, questions were raised about the validity of the
test used to measure viral neutralization. Notably, this assay could
not detect neutralizing antibodies in the blood of several
vaccinated chimpanzees that were shown to be protected from HIV
infection when injected with the virus.

       At the vaccine conference, Susan Zolla-Pazner, Ph.D., from
New York University Medical Center, reported the results of two
blinded studies involving a new, more sensitive test. Both the new
and the conventional neutralization assay work by mixing the virus
with antibodies and putting them in cell cultures to determine if,
and to what degree, the presence of antibodies prevents the
infection of cells. The conventional assay adds PHA to the cultures,
which powerfully stimulates cell proliferation and makes the cells
much more prone to infection with HIV. The new assay, known as the
"resting cell assay," uses no such stimulant.

       With the new test, Dr. Zolla-Pazner's group showed that
antibodies present in the blood of three vaccinated, protected
chimpanzees did indeed neutralize HIV and that these antibodies
persisted for more than a year. Furthermore, her data demonstrated
that there is an "absolute" correlation in the chimpanzees studied
between protection from HIV and the presence of such neutralizing
antibodies.

       In the second study, blood from sixteen human HIV-negative
recipients of several gp120-based vaccines was tested using the
resting cell assay to detect neutralization against an HIV-1 subtype
B primary isolate. A vaccine recipient showing greater than 50
percent neutralization (at a specific dilution level) was defined as
"reactive." Although studies with the conventional assay have never
been able to detect neutralizing antibodies for primary isolates,
ten out of sixteen or 62 percent of the vaccine recipients were
reactive based on the resting cell assay results.

       It is now clear that the gp120 vaccines can induce
neutralizing antibodies. Whether the neutralizing antibodies protect
against infection may depend on whether CD4 cells are in an
activated or resting state when exposed to HIV. However, the
conventional assay may not accurately reflect the immune system even
when activated, so it may be too high a standard for any vaccine.

       The possibility of reconsidering the negative decision made
two years ago remains slim, mainly because the gp120 products alone
do not elicit significant cellular responses, as some of the new
candidates do. Still, Genevax, a Genentech spin- off, and
Chiron/Biocine, which own the two major gp120 products, continue to
collaborate with Thai and U.S. authorities on large trials in
Thailand.

       Infections despite Vaccination

       The gp120 vaccines are clearly not completely protective.
There have been widespread reports of documented new HIV infection
among participants in the existing gp120 vaccine studies. A
preliminary analysis of these cases of acute HIV-1 infection in
individuals participating in Phase I and II trials of the gp120
vaccines was presented in January at the Third Conference on
Retroviruses.

       Biochemist John P. Moore from the Aaron Diamond AIDS Research
Center in New York described nineteen trial participants who had
become infected out of 596 total enrollees. In fourteen of these
cases, individuals had received the full course of immunization,
with four receiving the Genentech MN strain gp120 vaccine, four the
Biocine SF-2 strain gp120 vaccine and the remaining two getting
placebo.

       Researchers concluded that the vaccine-induced antibodies
were transient, type-restricted and of lower magnitude than those
induced by actual HIV infection. In one case presented as an
example, the individual was infected right after a booster shot,
which is usually when the level of antibodies is highest. All
vaccine breakthroughs were typical of community isolates,
genetically different than MN and SF-2. No effect of pre-vaccination
on viral load has been detected so far, and there were no special
qualities that distinguished these cases from non-vaccinated
controls.

       The ALVAC vaccine

       Many researchers believe that a successful HIV vaccine must
be able to stimulate at least two different kinds of immune
responses: a humoral response, which is essentially the production
of antibodies, and a cellular response, mainly the production of
cytotoxic lymphocytes (CTLs). Antibody production helps the body rid
itself of free virus while CTLs destroy infected cells.

       The vaccine products furthest ahead in clinical studies
(Genentech's and Chiron/Biocine's versions of gp120), stimulate
strong antibody responses, but they do not elicit the production of
CTLs. A new vaccine product, recently renamed the ALVAC vaccine,
seems to be able to elicit both a cellular and a humoral response.
This vaccine consists of Pasteur-Merieux-Connaught's live canary pox
virus (harmless to humans) carrying portions of several HIV genes
(for eliciting the cellular response) plus a "booster" of
Chiron/Biocine's gp120 (to trigger the humoral response).

       ALVAC is still in early safety and immunogenicity studies,
but the data have created a lot of enthusiasm among the vaccine
research community. By the time of the vaccine conference, close to
50 percent of the trial participants in one of the studies had new
cellular responses to HIV. If this pattern is sustained, it is very
likely that a larger Phase II study will be initiated in the U.S.
early next year, with even larger Phase III studies in 1998.

       Mucosal Immunity

       HIV usually enters the body through the mucosal surfaces
lining the reproductive and gastrointestinal systems. It is likely
that CTLs in the bloodstream are not enough to achieve full
protection from sexual exposure to HIV. The activation of specific
mucosal responses will be required, too.

       A study reported by Max Essex, director of Harvard
University's AIDS Institute, underscored the importance of ensuring
mucosal protection, whether through vaccines or topical anti-HIV
microbicides. Researchers experimented with isolates of HIV-1 type B
recovered from gay Americans and type E recovered from
heterosexually infected Thais. The scientists introduced these two
isolates into two different immune cell cultures: peripheral blood
mononuclear cells (PBMCs, mostly lymphocytes and macrophages) and
Langerhans' cells (an antigen presenting cell existing on the skin
and oral and genital mucosa, but absent from the rectal mucosa).

       Both HIV subtypes replicated similarly in PBMCs, but type E
alone replicated at particularly high rates in the Langerhans'
cells. Since Langerhans' cells are located on mucosal surfaces, they
can be infected there directly. PBMCs are subject to viral attack
only if HIV reaches lower tissue layers, most commonly by crossing
mucosal membranes through abrasions or lesions.

       Scientists have identified a specific type of antibody, known
as IgA, as the main actor in defending mucosal surfaces. When an
infectious agent reaches certain areas in the mucosal membranes
called Peyer's patches, cells known as the M cells initiate a
complex process resulting in the massive production and secretion of
IgA. These antibodies migrate to other mucosal tissues where they
block mucosal infection and eliminate the invading pathogen before
it can enter the bloodstream.

       Studies in monkeys show that systemic HIV immunity (usually
accomplished by injecting a vaccine into the blood) does not
automatically grant protection from mucosal infection. In human
studies, systemic immunization has failed to produce HIV-specific
IgA in external secretions, particularly saliva. In order to develop
vaccines that can effectively trigger this line of defense, a
vaccine must be able to reach the Peyer's patches and stimulate the
M cells to generate IgA against HIV. Researchers are studying
different vaccination routes (oral, nasal, vaginal, rectal), as well
as novel delivery mechanisms (microspheres, bacteria/viral vectors,
liposome encapsulation) that can effectively do this.

       Oral and Lymph Node Vaccines

       A study presented by Marian R. Neutra, Ph.D., from Harvard
Medical School and Children's Hospital, looked into the potential
benefits of rectal or vaginal vaccination, since it is thought that
oral immunization may not give optimal rectal and vaginal mucosal
protection. In mice, rectal vaccination increased the induction of
secretory IgA in both the rectal and the vaginal/cervical regions.
But only vaginal, not rectal, immunization raised IgA in women's
reproductive tract.

       AVEG (AIDS Vaccine Evaluation Group) Study 023 is a human
trial focusing on mucosal immunity. In this safety/immunogenicity
study, participants are "primed" with an intramuscular injection of
United Biomedical's peptide immunogen followed by oral boosting with
the same peptide combination encased in time-release
"microparticles." The trial's main objective is to compare this
regimen to other oral/intramuscular and oral/oral regimens
previously studied.

       All 35 participants in AVEG 023 had mucosal reactions, and
some anti-viral responses were found in pre-seminal fluid and feces.
Two other AVEG mucosal immunization protocols (027 and 028) are
planned to evaluate different vectors and routes of administration
and their effect on mucosal immune responses.

There also has been positive experience injecting vaccines directly
into lymph nodes to stimulate mucosal immunity. This technique is
known as "targeted lymph node immunization," or TLN. A British study
described at the conference administered a vaccine against SIV to
thirteen macaque monkeys. Seven animals were inoculated in the iliac
(groin) lymph nodes, three intradermally, and three
nasally/rectally. Eight monkeys functioned as controls.

       All animals were rectally exposed to SIV. Of the seven
animals inoculated directly into the lymph nodes (TLN vaccination),
four resisted infection and the remaining three had low viral loads.
None of the animals vaccinated via other routes, and just one of the
untreated animals were able to resist infection. The TLN-vaccinated
animals had higher antibody levels in rectal washings and urine and
far higher T-cell proliferation than those vaccinated by other
means.

       New Goal: Prevent "Disease," Not Infection

       The traditional view of an HIV/AIDS vaccine required that it
provided "sterilizing immunity," which means that it would prevent
an individual from becoming infected with the virus. Vaccines for
other viral diseases only prevent the development of acute illness,
not infection itself, but this approach has been perceived as
extremely risky in the case of HIV.

       Data from studies of HIV plasma viral load (level of virus in
the blood) and its relationship to disease progression, have led
some to openly challenge this fear. At the vaccine conference, John
Mellors, M.D., of the University of Pittsburgh, presented an
analysis from the Multicenter AIDS Cohort Study (MACS) relevant to
this debate. The MACS analysis looked at the HIV "setpoint," which
is the HIV level attained after primary infection and reflects the
balance reached between virus activity and the immune response.

       The MACS investigators observed that a high HIV setpoint is
associated with rapid disease progression, while a low setpoint is
associated with slow progression. If a drug or vaccine is developed
that can push down this initial steady state, disease progression
might be slowed to a very low rate, even though an individual would
remain chronically infected. Since viral load also is associated
with infectiousness, a vaccine that merely limited the HIV setpoint
would have substantial epidemiological impact by reducing the rate
of HIV transmission.

       The most immediate implication for HIV vaccine research is
the possibility of using plasma viral load as an endpoint
measurement for vaccine evaluation studies in primates. A candidate
product that does not prevent infection but keeps viral load at a
minimum would qualify for further testing in humans.

       From "Vaccine Trials" to "Preventive Trials"

       In another retreat from the absolutism of sterilizing
immunity, NIAID is now talking of "preventive trials" as opposed to
"vaccine trials." Purportedly, this new emphasis is a recognition
that behavioral modification and physical and chemical barriers are
also keys to preventing HIV infection.

       Peter Piot, from the United Nations AIDS Program, reported at
the conference that the acceptance of female condoms has been higher
than expected and called for a stronger push for their distribution.
U.S. AIDS Policy Coordinator Patsy Flemming emphasized the need to
strengthen research on vaginal or rectal microbicides against HIV.

       Dr. Sharon Hiller from the University of Pittsburgh reported
on the vaginal ecosystem and its impact on HIV infectivity. She
identified several species of lactobacilli, a type of bacteria
present in healthy vaginal environments, whose presence is directly
correlated to a decreased incidence of gonorrhea or bacterial
vaginosis. Moreover, these lactobacilli (L. crispatus and L.
jensenii) produce natural microbicides that have been shown to kill
HIV.

       Studies of commercial sex workers in Thailand have found an
association between the lack of these lactobacilli and increased
prevalence of HIV. In the U.S., it has been found that
African-American and Latino women are more likely to lack these
lactobacilli, and Dr. Hiller is developing a program that offers
them along with physical and chemical barriers, such as condoms and
nonoxynol-9 (N-9). Dr. Hiller stressed the need to insure that
microbicides do not adversely affect the vaginal ecosystem. High
doses of N-9 have been found to cause genital ulcerations which
increase the risk of HIV infection.

       Dextran sulfate, a sulfated polysaccharide, is another
candidate microbicide. It is currently in safety studies, both alone
and in combination with nonoxynol-9. A second candidate mentioned at
the vaccine conference was the buffer gel known as Reprotect, which
lowers pH levels in the vaginal walls (lower pH, or greater acidity,
is thought to kill HIV). A large number of potential microbicides
including other sulfated polysaccharides and extracts from
pomegranates, are in preclinical testing.

       Partnership with Industry

       When the decision was made in 1994 not to go ahead with
large-scale trials of gp120, some of the companies involved
complained of being "cheated" by the government. They had invested
money under the assumption that their vaccines would be
"appropriately" tested if they showed any potential. These
complaints have little merit since the government's refusal to
proceed had strong scientific rationale. It is a fact, though, that
many companies are wary of entering the AIDS vaccine field without
some safeguards for their investments. A number of companies have
dropped out of the field altogether.

       In his Special Plenary lecture at the vaccine conference,
NIAID chief Anthony Fauci, M.D., called for "nontraditional
partnerships" between government and industry to give new impetus to
HIV/AIDS vaccine research. NIAID's strategy mainly consists of
establishing concept-specific milestones or targets through
negotiation between government and industry. If the targets are
achieved, the product moves to the next phase.

       The new ALVAC vaccine has become a test case for this
strategy. NIAID, Pasteur-Merieux and Chiron/Biocine have an
agreement to move ALVAC into larger Phase II trials if at least 90
percent of the participants in the initial Phase I studies develop
humoral responses (antibodies), and at least 30 percent develop
cellular responses (CTLs). At least one study must show too that the
ALVAC regimen protects nonhuman primates (gp120 by itself already
has protected chimpanzees from getting infected with HIV).

       In a follow-up meeting at the While House, Vice President Al
Gore held a discussion with NIAID officials and representatives from
eleven pharmaceutical and biotech companies on ways to speed up the
development of vaccines, microbicides and other anti-HIV products.
Whether these negotiations lead to a real turnaround remains to be
seen. The stakes are enormous for the millions of people around the
globe at risk of contracting the disease, most of whom will never be
able to afford the extremely expensive antiviral treatments now
entering the AIDS marketplace.

       --------------------------------
       The (Viral) Burden of Motherhood
       by Dave Gilden

       One of the lasting controversies emanating from the Third
Conference on Retroviruses and Opportunistic Infections held this
winter (see Treatment Issues, February, 1996) was the relationship
between a pregnant woman's plasma HIV levels (viral load) and
transmission of the virus to her baby. With the Roche PCR and Chiron
bDNA assays for measuring viral load under review by the FDA (see
last month's Treatment Issues), viral load assessment may soon play
a major role in patient management. The disagreements that
unexpectedly arose over this reputed association have important
implications for how well these tests can be relied upon for
predicting the future course of disease and the influence various
treatments will have on that course.

       Four studies on mother-to-child (vertical) HIV transmission
were presented at the Conference, with three so newly completed that
they appeared among the event's "late breakers." These studies
looked at whether higher HIV levels in blood plasma correlated with
greater mother-to-child transmission. They sought to ascertain
whether a threshold viral load existed below which HIV transmission
did not occur. A related question was also under examination:
whether an AZT-induced reduction in a woman's viral load leads to a
reduced risk of her baby contracting HIV before and during birth.

       The first report (abstract S25) was presented by Yvonne
Bryson, M.D., of the University of California Los Angeles, and has
recently been published.1 The UCLA investigators found that women
who transmitted HIV to their babies prior to or during birth tended
to have higher viral loads at delivery than those that did not (a
median of 94,000 copies of HIV RNA per milliliter of plasma for the
transmitters versus 4,600 copies/ml for the nontransmitters -- a
highly significant difference). No one with a viral load below
25,000 copies/ml transmitted HIV, and a viral load at delivery of
greater than 50,000 was the single best predictor of transmission
among the many variables analyzed. AZT-treated nontransmitting
mothers generally experienced reduced viral loads during pregnancy
(an eight-fold, or 0.9 log, median decrease), and their viral loads
at delivery had a distribution similar to that of untreated
nontransmitters.

       The three late breaker presentations were not so sanguine
about viral load's predictive power. Richard A. Koup, M.D.,
reporting for the Pediatric AIDS Foundation's Ariel Project,
described the findings that viral load was a poor predictor of HIV
vertical transmission in a group of 151 pregnant women (LB2). The
transmission rate in this cohort was thirteen percent. (Eighty-three
percent of study participants were taking AZT.) There was a trend
toward higher viral load in the HIV-transmitting mothers --
transmitting mothers' viral loads averaged 5,200 copies/ml, compared
to 2,600 for the nontransmitters -- but there was a large overlap
between the two groups and the difference was not quite
statistically significant. Vertical transmission occurred even in
women with HIV levels so low that their virus was unculturable.

       The Woman Infant Transmission Study Group (WITS) also found
that there was only a weak association between viral load and
vertical transmission (abstract LB3). Transmission was seen at all
plasma HIV levels, except under 1,000 copies/ml, and although
transmitting mothers had slightly higher viral loads than
nontransmitting ones at delivery, this difference was not
statistically significant.

       Rhoda Sperling, M.D., (abstract LB1) summarized the long-
awaited virologic results from ACTG 076, a study of reducing
mother-to-child HIV transmission by administering AZT to pregnant
women and, starting immediately after birth, to their babies. Use of
AZT in this double-blind, placebo- controlled trial reduced the rate
of vertical transmission by about 70 percent (see Treatment Issues,
March 1994, pages 15- 16). In both the study group receiving AZT and
that receiving placebo, HIV transmission took place at all
detectable viral loads (but not in women with undetectable levels of
HIV). The pregnant women receiving AZT saw their viral load drop by
a median of only 0.2 log (37 percent), and differences in the
magnitude of this reduction did not correlate with any difference in
transmission rate.

       The 076 team concluded that the fall in HIV levels with AZT
could not explain the entire decline in mother-to-child transmission
of the virus. Dr. Sperling conjectured that the AZT given in 076 to
the newborn babies, as a kind of immediate post-exposure prophylaxis
for those babies contracting HIV during delivery, played a major
role in lowering transmission rates.

       One limitation of these last three studies is that the
observed viral loads in the women they followed were remarkably low
(the means or medians were below 10,000 copies/ml). Any differences
in HIV levels were relatively small, as was any effect AZT could
have on these levels.

       But the measured viral loads may not have been accurate. They
could have been reduced by the way blood samples were processed: the
three late breaker studies all used heparin as an anticoagulant in
the blood samples collected. Dr. Bryson contends that heparin
results in an immediate 30 to 38 percent loss in viral load values.
(Dr. Bryson's group at UCLA processed their samples mostly with
EDTA.) Storage of samples could also be a problem: a delay in
separating plasma from whole blood can lead to lower viral loads as
can a postponement in freezing the processed samples. (The Ariel
Project shipped its samples to New York for overnight processing
whereas the 076 and WITS studies batch-processed their samples well
after the studies were terminated.)

       Finally, researchers are attempting to divide up mother-to-
child transmission by stage -- during pregnancy (in utero) or during
labor (intrapartum). In utero HIV transmission is considered to have
taken place if the infant is PCR- or culture-positive for HIV within
48 hours after birth, according to Dr. Bryson's working definition,
for example. Such early transmission seemed to be promoted by high
maternal viral load in her study, as it did in the WITS. (Note that
a low viral load early in pregnancy is not sufficient to establish
low transmission risk since viral load can rise abruptly.)

       Intrapartum transmission, a much more common occurrence than
in utero, is not necessarily tied to high maternal viral load during
delivery. Events during delivery that expose the baby to maternal
blood or cervicovaginal secretions might promote transmission. For
example, the UCLA group detected a tendency for intrapartum
transmission to occur in women whose uterine membranes ruptured well
in advance of delivery. This trend did not reach statistical
significance, though, and the ACTG 076 investigators did not notice
any correlation between vertical transmission and such "obstetrical
factors." The WITS researchers are continuing to look at maternal
cofactors that promote vertical transmission, and the 076
researchers are now analyzing whether the particular infectivity of
a woman's HIV strain influences the risk of transmission during her
pregnancy.

       Reference:

              1 Dickover RE et al., Journal of the American Medical
       Association. Feb. 28, 1996; 275(8):599-605.

       -------------------------
       MAC Prophylaxis Revisited
       by Gabriel Torres, M.D.

       MAC (mycobacterium avium complex) infection occurs in
eighteen to 40 percent of people with AIDS. It is most common in
those with CD4 counts under 50. The symptoms and signs are quite
nonspecific and protean: they can mimic those of many other
infections and tumors in patients with advanced AIDS. Several lines
of evidence seem to indicate that a few individuals develop MAC from
reactivation of an old infection. The preponderance of evidence,
however, indicates that most individuals develop MAC following
recent acquisition of a virulent MAC strain. Epidemiological studies
have found evidence that many patients who contract MAC had new
exposure to the bacterium from environmental sources such as tap
water or soil.1 The sum of this evidence is inconclusive, and there
is no recommendation as to how an individual can avoid exposure to
MAC from environmental sources.

       The MAC bacteria infects the respiratory system and the
gastrointestinal tract, initially forming colonies without causing
symptoms. This asymptomatic colonization can lead to dissemination
of MAC through the bloodstream (MAC bacteremia) and more aggressive
disease. Many experts support treatment of patients who are
MAC-colonized but without signs of dissemination in order to prevent
spread of the infection via the bloodstream. Virulent MAC strains
seem to bind tightly to cells in the gastrointestinal walls or
respiratory tree, invading macrophages and triggering the generation
and/or release of such inflammatory cytokines as interferon gamma,
IL-2, IL-6, IL-12, GM-CSF and TNF, which may promote HIV
replication.

       Most of the anti-MAC research effort is focused on
prophylaxis with drugs that directly kill the organism. The Food and
Drug Administration has approved both rifabutin and clarithromycin
(the latter just at the end of last year) for the primary prevention
of MAC, as placebo-controlled studies have shown a reduction in the
rates of MAC bacteremia and symptoms related to MAC disease.

       Clarithromycin vs. Rifabutin

       At the Third Conference on Retroviruses and Opportunistic
Infections this winter, the results of the first MAC prophylaxis
study comparing clarithromycin, rifabutin and the combination of the
two were presented by Connie Benson, M.D., from Rush Medical College
in Chicago (abstract 205). In this phase III double-blind study,
1,216 volunteers were randomized to clarithromycin (500 mg twice
daily), rifabutin (450 mg/day) or a combination of the two. The dose
of rifabutin was subsequently lowered to 300 mg/day, due to an
unacceptably high incidence (three percent) of uveitis (inflammation
of the eye's iris and associated tissue). A second study sponsored
by the National Institute of Allergy and Infectious Diseases showed
that there was a drug-drug interaction resulting in higher plasma
levels of rifabutin when clarithromycin was administered
concomitantly.

       The results of the comparative study found rates of MAC
disease to be nine percent in the clarithromycin arm, fifteen
percent in the rifabutin arm and seven percent in the combination
arm, a highly significant difference in favor of the
clarithromycin-containing arms. The death rates were similar in all
three arms. The percentage of patients requiring treatment
discontinuation was higher in the combination arm (31 percent) than
in either monotherapy arm (sixteen percent for clarithromycin and
nineteen percent for rifabutin). The most common side effects were
nausea and vomiting, diarrhea, abdominal pain, anemia, neutropenia,
thrombocytopenia and elevation of alkaline phosphatase blood levels
(indicative of liver inflammation).

       Preliminary drug susceptibility analysis for isolates
recovered from patients who developed MAC bacteremia during the
study indicates that 27 percent, zero percent and 24 percent of
isolates from patients assigned to clarithromycin, rifabutin or the
combination, respectively, were definitely resistant to
clarithromycin. In the same three arms, only four percent, two
percent and none of the isolates, respectively, were resistant to
rifabutin.

       The researchers concluded that clarithromycin alone was more
effective than rifabutin alone in reducing the incidence and
delaying the time to development of MAC disease. Clarithromycin
alone also was as effective as the combination but less toxic.
Finally, the use of rifabutin alone did not appear to select for
rifabutin resistance while the use of clarithromycin did appear to
promote clarithromycin resistance. Combining both drugs did not
significantly reduce the rate of clarithromycin resistance.

       The true impact of clarithromycin resistance is not clearly
understood. Clarithromycin's manufacturer Abbott Laboratories found
in a previous prophylaxis trial that those patients who developed
clarithromycin-resistant MAC while on clarithromycin had the same
survival time as those who developed MAC on placebo. But resistance
to clarithromycin creates azithromycin resistance, too. This
cross-resistance severely limits a patient's treatment options. A
number of studies have shown that effective treatment of
disseminated MAC requires a combination of drugs that includes one
of these two "macrolide" antibiotics.

       Azithromycin Once a Week

       A study involving prophylactic azithromycin was also
presented at the Third Conference on Retroviruses and Opportunistic
Infections (abstract 204). It was conducted by Diane Havlir, M.D.,
and her colleagues from the University of California San Diego and
sponsored by Pfizer, maker of azithromycin. In this study, 669
persons with CD4 counts less than 100 were randomized to receive
either azithromycin (1,200 mg once weekly), rifabutin (300 mg/day)
or the combination (using the same doses). The rates of MAC disease
were 15.3 percent in the rifabutin arm, 7.6 percent in the
azithromycin arm and 2.7 percent in the combination arm -- a
significant difference favoring the combination. There were no
differences in survival or dose-limiting toxicities, although the
incidence of side effects (mostly gastrointestinal) was highest in
the combination arm (22.7 percent). Half of the volunteers receiving
azithromycin had diarrhea at least once, but only 3.8 percent of
those taking the drug had to discontinue it.

       Only two of eighteen (eleven percent) of the MAC isolates
obtained from patients in the azithromycin arm were resistant to
both azithromycin and clarithromycin. None of the five isolates from
the combination arm had resistance to macrolide antibiotics.

       This study found that the azithromycin/rifabutin regimen was
associated with the lowest rate of MAC breakthrough. The rates of
other bacterial infections in this study were similar among the
three groups. In contrast, another Pfizer- sponsored,
placebo-controlled study of once weekly azithromycin (1,200 mg/week)
in patients with CD4 counts below 100 found that azithromycin also
protected against other bacterial infections (abstract 203). MAC
breakthrough rates in this study were 8.2 percent with azithromycin
and 23.3 percent with placebo. Eighty-three percent of the
volunteers on azithromycin reported gastrointestinal side effects
compared to 44 percent of the patients on placebo. Only 8.2 percent
discontinued azithromycin treatment due to toxicity, compared to 2.3
percent of the placebo group.

       Clarithromycin and azithromycin are closely related drugs,
with similar anti-MAC activity and toxicity. What sets the two apart
is their durability in the blood and cells and hence their dosing
regimens. Once weekly azithromycin may be both cheaper and more
convenient than twice daily clarithromycin. Without a head-to-head
clinical trial, though, it is hard to determine whether one regimen
is more effective or less toxic than the other, although it is
unlikely that this trial will occur. Pfizer anticipates FDA approval
in mid-May for azithromycin at the 1,200 mg once weekly dose. The
price is expected to be about $1,000 a year.

       Deciding on Prophylaxis

       The overall conclusion from these MAC prophylaxis trials is
that either clarithromycin (500 mg twice daily) or azithromycin
(1,200 mg once a week) are the most effective regimens, with a
potential survival benefit reported for clarithromycin in an earlier
study.2 Yet those with breakthrough MAC while on either of these
macrolide antibiotics have a relatively high rate of MAC resistant
to both drugs.

       Rifabutin is less effective in preventing MAC, but
breakthrough isolates have lower rates of resistance. Rifabutin also
interacts with many other common drugs used in HIV disease,
including protease inhibitors (saquinavir and ritonavir). It can
lower other drugs' blood levels, thus decreasing their
effectiveness.

       MAC prophylaxis is now recommended for patients with CD4
counts below 75. Many clinicians keep patients on prophylaxis even
if their counts climb above this threshold due to protease
inhibitors or other drugs. Whether effective anti- HIV therapy can
make MAC prophylaxis superfluous is one of the great unanswered
questions.

              1 von Reyn CF et al., Lancet. May 7, 1994; 343(8906):
       1137- 41.

              2 Pierce M et al. Tenth International Conference on
       AIDS. Aug. 7-12, 1994; 10(2):70(abstract 558B).


       -------------------------------------
       OAR Puts AIDS Research under Scrutiny
       by Derek Link

       On March 14, a federal scientific advisory panel released its
final report recommending sweeping changes in the nation's AIDS
research effort. Under the leadership of Princeton University
virologist Arnold Levine, Ph.D., the AIDS Research Program
Evaluation Working Group spent fifteen months examining the $1.4
billion AIDS research program at the National Institutes of Health
(NIH). Its evaluation of the entire NIH AIDS research program was
the first by an expert, non-government body.

       The NIH AIDS effort, which incorporates funding for outside
investigations as well as for projects within the Institutes' walls,
accounts for more than 85 percent of the world's publicly funded
AIDS research. Twenty-four separate programs, conducted by each of
the NIH's independent research institutes, make up the overall
undertaking. The AIDS program at the National Institute of Allergy
and Infectious Diseases (NIAID) is the largest and most prominent,
but NIAID's endeavors account for only 40 percent of the entire NIH
AIDS research budget.

       The report assessed how the 24 AIDS research programs fit
together and determined whether NIH AIDS research as a whole is
moving effectively and efficiently toward an AIDS cure and vaccine.

       The Working Group found that the NIH has made substantial
progress over the last fifteen years, helping to identify the
causative agent of AIDS, establish AIDS research as a scientific
discipline, and improve treatment of HIV and associated infections.
But a cure and vaccine remain elusive. The panel concluded that the
federal government must restructure its AIDS research effort to meet
the scientific challenges posed by AIDS.

       The evaluation panel was convened by the new NIH Office of
AIDS Research (OAR) in late 1994. In 1993, the Congress commissioned
the OAR to review how prudently the NIH spent its AIDS research
money and strengthened the OAR's authority to coordinate and plan
this spending. Since the 1994 Congressional elections, when
Republicans won majorities in both houses of Congress, the OAR's
authority has been under constant assault. Ironically, just as the
Working Group was releasing its findings, Congressional leaders were
trying to strip the OAR of its authority to implement the report's
recommendations. As Treatment Issues goes to press, the OAR's
authority remains an unresolved issue.

       Promoting the Nongovernmental Sector

       Six themes emerged from the OAR review. First and foremost is
the need for stronger oversight and participation by non- government
scientists (such as the academic researchers constituting most of
the OAR Working Group). Further concerns were better integration and
coordination of the NIH's individual AIDS programs; more
collaboration between NIH and the drug industry; an increased
emphasis on basic research initiatives; and more research on the
prevention of HIV transmission, including both biomedical and
behavioral approaches. The Working Group's final overarching point
was expressed by a strong statement advocating greater involvement
of affected communities in the research process.

       From these general themes came fourteen specific
recommendations:

       Increase support for and improve peer-review of investigator-
       initiated research.

       "Investigator-initiated research" refers to research that is
developed and conducted by independent scientists. It stands in
contrast to "directed research," which is controlled and designed by
staff scientists of the NIH. Investigator-initiated research is
advanced in the report as the best way to enhance the diversity and
productivity of scientific investigations. The report calls for
doubling the level of investigator-initiated AIDS research over five
years. It notes that only twenty percent of NIH AIDS research is
investigator-initiated, far less than the approximately 50 percent
that occurs other fields.

       Restructure the nation's AIDS vaccine research.

       Calling an AIDS vaccine a crucial public health priority, the
report calls for a national task force to guide all government AIDS
vaccine research programs and urges that distinguished non-
government scientists be placed in control of the program. The
report sharply criticizes HIVNET, an NIH-funded network of research
sites working on an AIDS vaccine, and calls for a comprehensive plan
for its organization, governance, research priorities and funding.

       Develop an HIV prevention science agenda.

       The report suggests the creation of a prevention science
agenda that is practical and evidence-based. It says an "ideal"
strategy would include behavioral and social interventions and
biomedical technologies (topical microbicides, anti-addiction
treatments, etc.) in addition to vaccines.

       Augment research efforts to better understand the human
       immune system.

       More research into the human immune system is critical for
the development of an AIDS vaccine and better therapies. The report
recommends more research on human and primate immunity, noting a
heavy emphasis to date on mouse immunity.

       Integrate all adult clinical trial programs into a single
       network.

       The NIH maintains twelve adult trials networks to test
therapies for HIV and related conditions. Among the most prominent
are the ACTG and CPCRA at NIAID; the Study of the Ocular
Complications of AIDS, or SOCA, at the National Eye Institute; and
the AIDS Malignancy Consortium, or AMC, at the National Cancer
Institute. Currently, there is no mechanism for cooperation and
collaboration between them. The report observes that "there has been
overlap and, in some instances, unnecessary competition between
these diverse programs that are funded by different institutes with
different self- defined missions. The scientific productivity of
these independent clinical trials efforts has been quite variable."
A single clinical trials network should be run by NIAID with support
from other institutes, and the network's scientific leadership
should be provided by non-government scientists.

       Refocus and restructure the drug discovery research effort.

       The NIH drug discovery effort for AIDS includes many
different programs in different scientific areas. Some programs,
such the National Cooperative Drug Discovery Groups and the HIV
structural biology program, are praised by the Working Group. The
panel singles out the National Cancer Institute's Developmental
Therapeutics Program (DTP) for particular criticism. The DTP
annually screens thousands of compounds, both natural and synthetic,
for activity against HIV, but the report finds that this vast effort
is hobbled by antiquated techniques and a lack of follow through on
the potential antiviral drugs it uncovers. The DTP's AIDS resources
and enormous collection of compounds should be restructured, serving
as a resource for the entire NIH AIDS program.

       Augment basic research on AIDS-associated infections and
       facilitate transfer of new findings for early clinical
       evaluation.

       Although opportunistic infection treatment and prevention
have achieved impressive gains over the last decade, few new drugs
have been developed specifically for AIDS OIs. (Most OI drugs were
first developed for other more common maladies.) The panel concluded
that an increased emphasis on the fundamental biology of these
pathogens is necessary, given that drug companies have limited
incentive to investigate these normally uncommon diseases. Its
report specifically recommends greater use of Small Business
Innovation Research grants to facilitate transfer of NIH basic
science research to the pharmaceutical industry.

       Strengthen the scientific base for the assessment of
       alternative therapies for HIV disease.

       The panel found that alternative therapies are widely used by
people with HIV and that alternative therapies have the potential to
both benefit and harm recipients. To collect more information on the
effects of such therapies, the report urges greater collaboration
between the AIDS research effort and the NIH Office on Alternative
Medicine.

       Reorganize the Regional Primate Research Centers to ensure
       they are responsive to outside scientists.

       The RPRCs are a crucial national resource, especially for
research into primate models of HIV infection. The panel found the
RPRCs do not always support the most meritorious research, and
recommends that their resources be refocused on the most promising
research ideas. The RPRCs should develop a competitive process to
ensure that the best science is supported and allow outside
scientists greater access to their primate resources.

       Strengthen AIDS Research Centers to foster multidisciplinary
       research on the disease.

       The sixteen NIH-supported AIDS research centers are
multidisciplinary organizations that bring together basic and
clinical researchers from many medical sub-specialties. The centers
"provide a central pool of resources, capable of a flexible and
coordinated response to scientific opportunities." The report
advocates doubling the funding for AIDS Research Centers.

       Ensure that central repositories of biomedical specimens and
       databases are of the highest quality and accessible to
       qualified investigators.

       Over the last decade, the NIH has generated enormous
repositories of specimens and large databases, which represent a
"potential national treasure" for AIDS research. But, the report
says that these repositories and databases are poorly coordinated,
and many investigators have little or no access to them. It
recommends that databases use a common, user-friendly information
system, and that access to them be peer-reviewed and open to all
scientists with meritorious research ideas.

       Upgrade the NIH AIDS Research Information System and increase
       the information base.

       The panel said its review was hampered by the lack of an
adequate information system at the NIH for AIDS research. Available
databases do not accurately and thoroughly track all AIDS research
expenditures at the Institutes, producing many gaps in grasping the
nature of AIDS research there.

       Develop and implement a clear definition of AIDS and AIDS-
       related research through an evolving process.

       The panel found that each NIH institute has its own
definition of what constitutes "AIDS research." A clear NIH-wide
definition of AIDS research is urgently needed, because, in some
institutes, inappropriate classification has led to allocation of a
significant amount of AIDS funding toward activities with little or
no relevance to AIDS (see Treatment Issues, October, 1995, page 9 on
the National Cancer Institute's misallocation of tens of millions of
dollars). The panel urges that these funds be redirected to more
appropriate projects.

       Preserve a strong Office of AIDS Research to provide
       leadership and coordination to the entire NIH AIDS research
       program.

       The panel "unanimously agreed" that the NIH AIDS research
program needs central leadership and oversight. In particular, the
panel emphasized that the OAR will be crucial for implementing the
recommendations in its report.

       ----------------
       Treatment Briefs

       Starting Ritonavir

       Abbott Laboratories claims that the nausea commonly
associated with its protease inhibitor ritonavir (brand name:
Norvir) goes away after the first few weeks in most people. The
digestive upset can be minimized by progressively increasing the
initial dose. But the initiation regimen contained in the package
insert is too quick, Abbott officials now indicate.

       The following schedule is now thought to be the best way to
begin ritonavir (the drug is supplied in 100 mg capsules): First and
second day: Take 300 mg twice a day. Third and fourth day: 400 mg
twice a day. Fifth and sixth day: 500 mg twice a day. If you are
having a problem, stay at this dose. If not, go up to 600 mg twice a
day by the end of two weeks. These instructions will not necessarily
do away entirely with the gastrointestinal upset. What you eat with
ritonavir is important as well. Take ritonavir with a full meal,
particularly a fat-rich meal. Ingest the capsules one at a time with
a generous quantity of milk or whatever you find most useful. At
least one person with AIDS washes down his ritonavir with yogurt
rather than a fluid drink.

       Matching up Ritonavir with Saquinavir

       A trial to study the much heralded protease inhibitor
combination of ritonavir and saquinavir is now screening applicants.
Because of its liver-inhibiting properties, full dose ritonavir will
raise blood levels of saquinavir about ten-fold and make this drug
much more effective. Conversely, increasing saquinavir's
effectiveness may allow a reduction in the dosage of ritonavir, thus
reducing side effects. The combination also might be less prone to
trigger the emergence of treatment-resistant HIV than either drug
alone.

       At first, the volunteers will receive saquinavir at 400 mg
twice daily plus ritonavir at 400 or 600 mg twice daily. Once safety
is established, the doses will increase to saquinavir at 800 mg
twice daily plus 400 mg ritonavir twice daily or saquinavir at 600
mg twice daily plus 600 mg ritonavir twice daily. Everyone will
receive both drugs in this open-label, 48-week trial.

       This 120-person trial (in Annandale (Virginia), Boston, Los
Angeles, New York, Ottawa, Pittsburgh and San Francisco) is open to
volunteers with CD4 counts between 100 and 500, any viral load and
no previous protease inhibitor experience. One or two concomitant
nucleoside analogs will be allowed if an individual's viral load
rebounds to within one log (ten percent) of the pre-trial value.
Otherwise, no other anti-HIV drugs will be allowed during the trial.

       "This might be a powerful combination. If people are on
nucleoside analogs and failing, then this is a great study for
them," commented Marty Markowitz, M.D., the trial's New York City
investigator.

       Further information on this trial may be obtained from the
Abbott Laboratories consumer hotline, 800/441-4987.

       Nevirapine and Delavirdine Plus Protease Inhibitors

       Expanded access programs for the two nonnucleoside reverse
transcriptase inhibitors (NNRTIs) nevirapine and delavirdine are now
up and running (call 800/595-5494 for nevirapine and 800/779-0070
for delavirdine), and an FDA advisory committee hearing is scheduled
for June 7 to review nevirapine's marketing application. People may
be tempted to combine the NNRTIs with protease inhibitors to achieve
greater, more durable HIV suppression. Like the protease inhibitors,
nevirapine and delavirdine are metabolized by the liver, though, and
so such combinations may alter the normal blood levels of each
component drug.

       Delavirdine inhibits the way the liver breaks down certain
drugs and may raise blood levels of protease inhibitors. Nevirapine,
an inducer of liver activity, could have the opposite effect.
Changing protease inhibitor blood levels can sharply alter their
activity and side effects, thus, necessitating dose adjustments (as
with the ritonavir/saquinavir combination above).

       Pharmacia & Upjohn, the maker of delavirdine, and Boehringer
Ingelheim, maker of nevirapine, both predict that their drugs will
most likely affect the blood levels of saquinavir and are now
conducting pharmacokinetic studies of these combinations. More
information will be available by this summer.

       Co-administration of delavirdine and ritonavir may increase
blood levels of either drug. Given the toxicity of ritonavir, it is
advisable to wait before trying the combination until safety and the
necessary dose adjustments are established. The pharmacokinetic
study to accomplish this should be underway in May, Pharmacia &
Upjohn says.

       Liposomal KS Drugs Approved

       On April 8, 1996, the FDA granted NeXstar's DaunoXome full
approval as first line therapy in people with advanced HIV-
associated Kaposi's Sarcoma. DaunoXome is a liposomal (lipid-
encapsulated) formulation of the anticancer compound daunorubicin
and is similar to Doxil (liposomal doxorubicin). Doxil (from Sequus)
received FDA "accelerated" approval last November for use only in
people with advanced KS who could not tolerate or did not respond to
standard chemotherapy. Doxil could be used "off-label" as first line
therapy, too, but the comparative effectiveness of Doxil and
DaunoXome is unknown.

       Liposomal drugs tend to be safer and more stable in the body
than standard formulations. Doxil is administered by infusion only
once every three weeks, and DaunoXome is infused every other week.
The drugs' main side effect is bone marrow suppression, which leads
especially to low neutrophil counts. The wholesale price of four
month's worth of DaunoXome is $4,300, close to the $3,500 cost of
ABV, the old standard chemotherapy combination for KS. Doxil costs
about $6,400, but the longer interval between infusions considerably
reduces the difference in total treatment costs. NeXstar has a
DaunoXome reimbursement hotline and indigent program that can be
reached at 800/226-2056. A similar program exists for Doxil -- call
800/375-1658.

       Still Looking for the Real GEM

       A persuasive presentation at the 1993 International
Conference on AIDS excited many about GEM 91, the first antisense
drug targeted against HIV. Antisense compounds are synthetic
segments of nucleic acid that bind to viral genetic material and
disrupt the viral life cycle at multiple points. In the lab, GEM 91
blocks HIV when the virus infects new cells, when the cell's
machinery is commandeered to produce viral protein, and when
complete HIV gene sets are transcribed and packaged in new virions.

       Clinical trials reported last September (Interscience
Conference on Antimicrobial Agents and Chemotherapy abstract I86)
dampened the excitement. They found that the body breaks down GEM 91
too quickly for it to reach effective concentrations in people.
Despite two-week continuous infusions, volunteers received no
benefit. Hybridon, Inc., GEM 91's developer, now has a new
concentrated formulation that is administered as a subcutaneous or
intramuscular injection. A French phase I study of the improved GEM
91 is scheduled for this month, and an AZT/GEM 91 drug interaction
study will begin soon afterwards in Britain.

       Rev-ing Up

       Another slowly advancing high-tech antiviral strategy is the
"rev mutant" gene therapy investigated by Gary Nabel, M.D., of the
University of Michigan. Some mutant versions of the rev protein
hobble production of new HIV particles in cells by blocking the
transport of necessary material from the nucleus. Dr. Nabel found
that cells grown with HIV in the lab survived longer when the gene
for this protein had been added to their normal gene set.

       In the new study, CD4 cells were extracted from three HIV-
infected people. Half of each person's cells were injected with the
antiviral mutant gene and half with a neutral mutant gene. Gold
microparticle "bullets" successfully implanted the genes in ten
percent of the cells. Altered cells were treated with delavirdine to
eliminate any HIV present and IL-2 to stimulate rapid proliferation.
They were then reinfused into the source patient.

       After the first infusion, only very small numbers of the
cells could be detected. Patients no. 2 and no. 3 then received a
second treatment utilizing ten billion, rather than one billion,
cells. In patient 2, the half-life of the cells with the antiviral
gene was four days versus one day for the control cells. In patient
3, the half-lives were around fifteen and 3.5 days for the anti-rev
and control cells, respectively.

       The slowed but relentless drop in the anti-rev cells may be
due to instability of the transferred genes, or because even
non-infected CD4 cells are subject to elimination in people with
HIV. This issue may be resolved as Dr. Nabel's study continues,
using different gene transfer methods to achieve a more stable
integration of the protective gene in a higher proportion of cells.

       Thalidomide for Diarrhea

       Celgene is beginning a phase II study of thalidomide as a
treatment for chronic diarrhea in people with HIV. Thalidomide,
already under testing for AIDS-associated wasting, commonly causes
constipation as a side effect. This unwanted activity actually can
be advantageous in people with untreatable diarrhea. A recent open
label study in London found that thalidomide reduced the number of
bowel movements, increased weight and reduced levels of TNF in
patients with severe diarrhea (mostly from microsporidiosis) who had
failed all other available treatments.

       The 28-day trial will randomize 120 people to placebo or 100
mg of thalidomide daily at bedtime. Besides diarrhea, the trial will
monitor changes in body weight, quality of life and TNF in small
bowel tissue. Enrollment already has begun in London. Other sites
are expected to open soon in Mexico and the U.S. (St. Luke's
Hospital in New York). 

        Copyright (c) 1996 - GMHC Treatment Issues.  Distributed
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