Contents
Europeans Eye New Drug Cocktails
by Dave Gilden
The Third International Conference on Drug Therapy in HIV Infection
-- held in Birmingham, U.K. from November 3 to 7, 1996 -- reflected the ongoing
vigorous disputes over how to apply the new anti-HIV combination therapies
from a European point of view. That point of view is difficult to characterize
because some countries are following a relatively conservative strategy
whereas healthcare providers in other countries are much more aggressive in
starting treatment with protease inhibitors plus other drugs in highly potent
"knockout" cocktails.
The British tended to be the most conservative. Ian Weller, M.D., a
noted researcher at the University of London and the chair of the
conference's scientific committee, said at the opening press conference that if
a new patient came to him with a CD4 count of 190 and was otherwise
healthy, the only thing he would prescribe was prophylaxis for pneumocystis
carinii pneumonia. In an interview at the end of the conference, Dr. Weller
elaborated that he was more concerned about the possible long-term toxicities
of the new antiviral agents than about the dangers of irreversible damage to
the immune system if HIV was left unchecked -- a danger he dismissed as
"speculative." At the press conference, Dr. Weller's view was disputed by
Dutch and Swedish colleagues, Dr. Pieter Reiss and Dr. Erik Sandstršm. And
Joep Lange, M.D., of the University of Amsterdam went so far as to declare
during the conference, "Any significant viral load should lead to therapy."
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Paralleling these different national attitudes, Dutch health authorities
have agreed to fund protease inhibitors for early HIV infection whereas the
British government, whose National Health Service is deeply in the red, has
yet to provide any new funds for these drugs. Therapy in the U.K. is mostly
limited to people with CD4 counts under 350.
A critical issue in this debate is how durable is the response to anti-HIV
therapy. Outside of the initial, or acute, phase of HIV infection, no one expects
elimination of the virus, just chronic management of the disease. Precisely
when and under what conditions breakthrough infections of therapy-
resistant HIV occur remain to be seen. David Cooper, M.D., of Sydney,
Australia, warned in an interview at the end of the conference, "We risk
repeating the experience of AZT -- in which people's hopes were raised only
to be dashed a few years later." In contrast, Douglas Richman, M.D., during
one of the conference's final presentations held out the hope that with
enough drugs (at least three new ones at a time in a given patient), the drop
in HIV replication would be so great that drug resistance could be put off
indefinitely in many people.
There were even disagreements about how to prove treatment
concepts: at the conference's opening session, the American Richard
Schooley, M.D., who chairs the National Institutes of Health's AIDS Clinical
Trials Group, gave an impassioned plea for ending the practice of conducting
definitive drug trials based on comparisons of physical disease progression.
He argued that these huge, long-running comparative trials are a waste of
resources, leading to results that are irrelevant because of more recent
advances in treatment and the poor correlation between trial results and
individual patients' experience. Dr. Schooley said, "There is no need to keep
showing the superiority of better viral load reductions." He did advocate a
trial that evaluated individualizing treatment regimens to keep patients' HIV
levels undetectable and allow them to stay "ahead of HIV replication and
resistance." The next day, the British statistician Thomas Peto, Ph.D.,
countered with the argument, "Viral load is okay for phase II [preliminary
efficacy trials] and for checking 'me too' drugs for equivalence, but not for
proving out new classes of drugs or establishing enhanced efficacy."
Clearing the Lymph Nodes?
Central to the debate on the relative merits of data on disease
progression and viral load is the state of HIV infection in the lymph nodes
and other lymphoid tissue. Viral load tests monitor HIV levels in the blood,
but the major population of virus and the damage that the virus wreaks is
concentrated in the lymphoid tissue. Though not formally reported at the
Birmingham conference, a paper then in press by a University of Minnesota
team cast a shadow over the conference proceedings. That paper (published a
week later in the journal Science: Ashley Haase et al., Science. Nov. 8, 1996;
274(5289):985-989) used tonsil biopsies (much easier to perform than lymph
node extractions) to produce graphic photos of the location of HIV virus in
lymph tissue. It turns out that there are 1,000 to 10,000 times more HIV in
lymph tissue than in blood. Plasma viral load does indeed correlate with the
number of HIV-infected cells in the lymph tissue, and these seem responsible
for most of the free virus appearing in the blood. But, 90% to 99% of the HIV
particles in the lymph have been trapped on the surface of the follicular
dendritic cells (FDC) in that tissue. Although coated with antibody, that virus
is still infectious, and its longevity is unknown. As long as there is still some
HIV sticking to the FDCs, HIV infection apparently can rebound should
antiviral treatment be terminated.
The University of Minnesota investigators are now using their
technology to analyze tonsil biopsies taken from participants in a Dutch trial
of the AZT/3TC/ritonavir combination, and the first results from that
analysis were reported at the conference. Participants in the Dutch trial saw
their viral loads drop by 99.8% (2.7 logs) at 16 weeks. (There were 33
treatment-naive individuals, with a median CD4 count of about 155 and
median plasma viral load of about 210,000. They were assigned to one of two
open-label arms, which turned out to have equivalent results: start all three
drugs right away or delay the ritonavir for three weeks.) By week 24, no trial
participant had detectable HIV in their blood plasma (limit of detection was
238 HIV RNA copies/ml). In the first six patients whose tonsil tissue was
analyzed, all had no detectable HIV at week 24.
This report caused a sensation because of the advanced disease status of
the individuals involved. Virus levels in the lymph tissue, including the
FDCs, clearly have been greatly reduced by six months, but Keith Henry, M.D.,
of the University of Minnesota group, noted in a telephone interview, "The
detection limit for this assay is 30 copies per milligram of tissue. Saying that
levels went below detection, doesn't mean that there is not still a fair amount
of virus."
Other conference reports also reported lymph tissue clearance in
parallel with reductions in plasma viral load: Alain Lafeuillade, M.D., of
Toulon, France, used a four-drug combination (AZT/3TC/ddI/saquinavir --
with ketoconazole added to reduce the breakdown of saquinavir in the liver)
that reduced lymph node HIV levels by 99% in 15 patients with baseline CD4
counts averaging 264.
A similar parallel decay in blood and lymph node HIV levels was
found in 15 participants from an international study of AZT/ddI/nevirapine
(participants' baseline CD4 counts averaged 376 -- see the June/July, 1996
Treatment Issues article, Nevirapine Surprise for details of this trial).
In the lymph node substudy, three of the four fully compliant participants on
triple therapy had undetectable lymph node viral loads after over a year of
therapy, but the limit of detection with bDNA assay used was 10,000 copies of
HIV RNA per milligram of lymph tissue, a fairly high amount.
AZT/ddI/nevirapine could leave substantial amounts of replicating and
increasingly resistant HIV in the lymph nodes. This may be why HIV levels
in the blood seem to be creeping up, judging by the one-year overall trial
results. At six months, those on AZT/ddI/nevirapine had undetectable
plasma viral loads (limit of detection: 200), compared to 57% after one year.
Potent Combinations
If AZT/ddI/nevirapine is not potent enough for many people, maybe
the ritonavir/saquinavir protease inhibitor combination will do. Additional
results, out 12 to 20 weeks, were released in Birmingham for a pilot study of
140 people with CD4 counts of between 100 and 500 and no prior protease
inhibitor exposure. Due to ritonavir's inhibition of liver metabolism, blood
levels of saquinavir are raised 20-fold by the combination. After 12 weeks of
treatment, median viral loads declined by up to 1,000-fold (3 logs) in those
receiving any of the four different combination regimens, with no regimen
being clearly superior to the others. In the two trial arms with data now
available for week 20, viral loads continued to decline a little further, and the
median drop now clearly exceeds 1,000-fold. This compares with a mean viral
load drop of 25-fold (1.4 log) for AZT/ddI/nevirapine at 28 weeks. For those
out to 20 weeks in the ritonavir/saquinavir trial, the median viral load now
measures only about 20. Detecting that small amount is quite a trick
considering that the limit of detection is 200 for the PCR assay used to
evaluate viral load in the trial's participants. The nevirapine triple
combination trial used the same assay and counted everyone testing out at
below 200 as having a viral load of 200.
It turns out that the ritonavir/saquinavir study included actual viral
load values obtained down to 20, even though the test was not considered
accurate at these levels. The ritonavir/saquinavir investigators effectively
(and tacitly) imposed a lower limit of 20 rather than 200, and by this
contrivance, allowed their treatment to achieve an extra ten-fold (one log)
apparent drop in viral load. It is therefore impossible to take their results at
face value. According to John Sninsky of Roche Molecular Systems, which
developed the PCR assay, the test is not appropriate for low viral loads
because its variation at these levels has not been established.
Roche has developed an ultra-sensitive test, now available for research
purposes, that is accurate down to 20 HIV RNA copies per milliliter of
plasma. That was the test recently used to recheck the lowest viral loads in the
nevirapine trial, and these data were summarized in Birmingham. With the
ultra-sensitive PCR assay, 51% of the trial participants receiving
AZT/ddI/nevirapine had undetectable viral loads at one year, just 6% less
than with the standard PCR. Using a lower limit of detection would have
increased the observed viral load drop for the nevirapine triple combination
by a considerable amount -- with Roche's ultrasenstive test, the mean viral
load drop was 2.25 logs (178-fold) at six months and 1.8 log (63-fold) at one
year. In the ritonavir/saquinavir trial, it will be difficult to evaluate the trend
in HIV levels between six and 12 months because of the unknown, but
assumed to be large, amount of error in the standard PCR assay at low viral
loads.
It remains that ritonavir/saquinavir is one of the most powerful
combinations, and many doctors are trying to use it as salvage therapy for
people failing other therapies. It is not for everyone, though. The trial data
reveal a huge range in responses to the two protease inhibitors, which may be
partly due to interpersonal differences in the extent that ritonavir raises
saquinavir levels. At a press conference in Birmingham, Richard Haubrich,
M.D., of the University of California San Diego described the experiences of
seven of his private patients taking ritonavir/saquinavir, two of whom did
not improve to any appreciable degree. In the discussion following Dr.
Haubrich's account, it was commonly felt that the population in whom
ritonavir/saquinavir was less likely to provide benefit includes those with
higher viral loads (100,000 or above), concurrent illnesses or prior treatment
with ritonavir or saquinavir -- or a lengthy history of HIV treatment in
general. (Other, as yet undefined, personal characteristics no doubt also play a
role.) For such people, the combination of the two protease inhibitors is
probably not sufficient. They need at least a third new drug to which their
HIV is not yet resistant.
Resistance and Cross-resistance
In regard to new drugs, the news from the Birmingham conference was
mixed. There was a detailed description of the mutations that arise after 18
months in trial participants on AZT/3TC in the pivotal American trials for
the combination. Earlier reports claimed that resistance to 3TC somehow
reduced resistance to AZT, but this analysis found extensive dual resistance to
the two drugs, involving both classic AZT mutations and several novel ones.
Cross-resistance to ddI or ddC did not appear to be a major issue, though, as
has sometimes been feared to arise from 3TC resistance.
In one session, Emilio Emini of Merck (makers of the protease
inhibitor Crixivan) pronounced that general cross-resistance exists for
nucleoside analogs and it is now appearing for protease inhibitors. Later on,
Amy Patick from Agouron Pharmaceuticals, which is developing the new
protease inhibitor nelfinavir (Viracept), disagreed. Citing her study of
resistance to nelfinavir in 16 people with up to one year on nelfinavir, she
claimed that cross-resistance rarely occurs between nelfinavir and other
protease inhibitors. This observation needs further confirmation with more
patients and longer follow-up. Further, it has not been determined at all
whether people starting to fail on other protease inhibitors can switch to
nelfinavir without encountering drug resistance on the part of their HIV.
Emilio Emini warned, "If selection for resistant virus occurs, future
therapeutic options may be very limited." Multi-drug resistant HIV is an
increasing problem as mutations accumulate. These mutations both provide
for drug resistance and compensate for any slowing of viral replication due to
the resistance mutations. Fear of forcing HIV on such an evolutionary
pathway was a decisive reason for the many Birmingham attendees who
wanted to put off therapy in "healthy" people, at least until more information
is available.
Nevirapine Trial Confirms Dr. Schooley's Point
The mortality results of ACTG 193A, an early large anti-HIV
combination therapy study in very advanced disease, were finally released at
the December meeting of the AIDS Clinical Trial Group. The study compared
AZT/ddC, AZT and alternating ddI, AZT/ddI and AZT/ddI/nevirapine in
1,314 subjects with a median CD4 cell count of 20 -- most of whom had prior
treatment with nucleoside analogs. The study found that there were
significantly fewer deaths on the three drug arm (118) as compared to
AZT/ddC (142) or AZT alternating with ddI (148). However, the reduction in
deaths was not statistically significant when the triple therapy was compared
to AZT/ddI (128 deaths) -- and the AZT/ddI arm, in turn, was not
significantly better than the two arms of the study with the poorest
performance. There was also a trend toward longer median survival on the
triple combination.
If anyone is particularly interested in these outdated results -- since
therapy including protease inhibitors has been shown to be dramatically
better than nucleoside analog combination therapy in this population -- the
data should nevertheless be viewed with skepticism, since 74% of the patients
went off study treatment for reasons other than death, drug toxicity or
completion of the study. (The median time on treatment was only 45 weeks
in the study, which lasted roughly three years.) Ongoing subset analyses and
comparisons of the effect on progression may yet yield some interesting
minutiae, but this lengthy trial serves to buttress Robert. Schooley's polemic
in Birmingham (see main story above) about the futility of clinical endpoint
trials in the current environment.
- Theo Smart
Nevirapine's Effect on Indinavir Levels
Nevirapine generally lowers blood levels of indinavir according to
newly released data from the nevirapine/indinavir drug interaction study.
The results are not completely unexpected because nevirapine is known to
induce liver activity that breaks down drugs such as the protease inhibitors.
Though significant, the effect on indinavir blood levels is not dramatic, and
varies from person to person -- in fact a couple of trial participants actually
saw increases in blood levels of indinavir.
The study was in 24 HIV-positive adults (19 available for analysis) who
were treated with standard doses of indinavir for seven days before receiving
nevirapine. Nevirapine was administered according to the dose-escalation
schema recommended to reduce the incidence of drug-related rash: 200 mg a
day for 14 days, followed by 200 mg twice a day. Data to day 36 was available
for the drug interaction analysis.
Nevirapine reduced the mean peak levels of indinavir by only 11%,
but the mean area-under-the-curve concentrations (a measure of the drug's
total presence in the body between doses) and trough levels (minimum level
between doses) were significantly reduced -- by 28% and 38% respectively.
There was a slight reduction in nevirapine area-under-the-curve
concentrations. Both drugs were well tolerated together. Of the five patients
who discontinued, three were due to toxicity -- two in response to nevirapine-
related rashes, and one participant developed kidney stones on the first day of
indinavir treatment.
The degree of interaction was slightly greater than hoped, but virtually
identical to the interaction observed between nevirapine and saquinavir. The
stakes are higher with indinavir, though, since a substantial number of
people who develop resistance to this drug appear to lose susceptibility to
most of the other protease inhibitors available or in development. Increasing
the indinavir dose to 1,000 mg three times a day may achieve blood levels of
indinavir closer to what is achieved by standard dose in the absence of
nevirapine. Upping the dose costs more, though, and runs the risk of more
side effects given the variation of indinavir blood levels among individual
patients.
Of course, the combined antiviral effects of the two drugs may
substantially reduce the incidence of resistance. This study is collecting
resistance data, but the median starting viral load was very low (4,000 copies
per ml) as many of the volunteers were on nucleoside analog background
therapy before and during the study. Virologic data out to day 96 is available
on sixteen patients (three more have discontinued the study). Fourteen have
viral load below 400 copies, and two have rebounding viral load. Clearly,
larger trials will be needed to adequately address the effectiveness of this
combination.
Data from an open-label study of indinavir/nevirapine/3TC will be
presented at the Conference of Human Retroviruses this January.
- Theo Smart
Delavirdine Dilemma at the FDA
by Theo Smart
For the first time ever, the Food and Drug Administration (FDA)
Antiviral Advisory Committee found itself unable to recommend approval
of an anti-HIV drug. Amid complaints that the data from studies of
delavirdine (brand name Rescriptor) were contradictory and inconsistent, the
committee reached a four-to-four tie vote on Pharmacia and Upjohn's
application to market this nonnucleoside reverse transcriptase inhibitor
(similar in action to the approved NNRTI nevirapine) for use in combination
with other antivirals. Committee chair Fred Valentine, M.D., illustrated his
panel's mixed feelings when he declared, "Right now, I don't believe the data
supports approval, though I do believe the drug probably deserves it." It
remains to be seen what final action FDA officials will take on the company's
application.
The case for approval was based primarily upon data from three
studies, two large clinical endpoint studies (which measure disease
progression in terms of opportunistic infections and death) and one surrogate
marker study (which checked only on CD4 count and viral load changes) --
see the box for a detailed summary of the clinical endpoint studies. Although
there were modest positive changes in CD4 cell counts and viral load in the
pivotal clinical endpoint studies, in the third study, ACTG 261, there was no
significant difference in the surrogate marker changes between
AZT/ddI/delavirdine and AZT/ddI. (But these are very preliminary results.
ACTG 261, which is just winding up, is a one-year, 550-person trial in people
with CD4 counts between 100 and 500 and little or no previous anti-HIV
treatment.) The worst stumbling block was that in one of the large trials, the
transient surrogate marker benefit provided by the addition of delavirdine to
ddI monotherapy did not translate into less disease progression.
The Advisory Committee also was concerned that the data on drug
interactions with protease inhibitors were derived from studies in HIV-
negative people, so there was no clear data on the safety or effect of
delavirdine with protease inhibitors in HIV-positive patients over time. (For
more specifics on the interaction of delavirdine and protease inhibitors see
September 1996 Treatment Issues article, Delavirdine/Protease Inhibitor
Interactions. Delavirdine inhibits the breakdown of many drugs in
the liver, including the protease inhibitors. This may raise drug levels
dangerously in some circumstances.
Even Committee members who favored approving delavirdine were
underwhelmed by the trial results. "I am dismayed at the modest data seen in
the studies especially when compared to AZT or ddI monotherapy," said
Wafaa El-Sadr, M.D., of Harlem Hospital. Nevertheless, she and others felt
that there was a role for the drug in combination therapy, particularly in
patients who could not tolerate other options.
Diane Murphy, M.D., of the University of Florida commented, "Maybe
these were just the wrong drugs to use in combination. There was always a
positive trend in CD4 cell counts and viral load - It would be wrong to [block
approval] because of the clinical endpoint study," she said.
It is now recognized that few anti-HIV drugs produce more than a
temporary effect when used alone or in suboptimal combinations.
Nevirapine, a very similar drug to delavirdine, looked much better when it
was combined with two other drugs in previously untreated patients. There
are similar studies underway for delavirdine, but no data are available yet.
A final issue that plagued the panel was the absence of any data on use
of this drug in the pediatric population. During the public comment session
of the hearings, pediatric activists from across the nation complained that
pharmaceutical companies are ignoring this population, and that the FDA
has been complicit by not requiring companies to investigate drugs in
children with HIV. The most moving statements at the hearing came from
HIV-infected mothers of such children, many of whom said that their health
was improving on the new HIV combination regimens and that they could
no longer stand by and watch their children go untreated. The mothers
demanded that the FDA not countenance applications for drug approval in
adults from companies that were not submitting data in pediatric populations
as well.
Delavirdine Data at the FDA
Trial 017 compared the ddI and delavirdine combination to ddI plus
placebo in a group of patients with a mean CD4 count of 135 cells/mm3 (entry
CD4 count between 0 and 300) and an average viral load of 5.8 logs (630,000
HIV RNA copies/ml of plasma). All patients had prior AZT experience, and
25% had received ddI in the past. Three hundred ninety volunteers were
enrolled, of whom 13% were women, 32% non-white and 11% injecting drug
users. The study compared the rates of death, clinical progression defined as
time to AIDS or death, and disease progression (defined as time to AIDS,
death or 50% drop in CD4 cell count).
The peak viral load reduction (0.8 logs, or 84%) at week four was
significantly greater for the delavirdine/ddI arm, but did not persist and was
not different at subsequent points in time. After 92 weeks of follow-up, there
was no significant difference in clinical efficacy between ddI/delavirdine and
ddI alone. The number of deaths were similar in both arms (ddI arm: 61,
combination arm: 66). Yet the number of opportunistic infections while on
study medication were fewer for the combination arm (n=63) as compared to
ddI monotherapy arm (n=90).
Trial participants with entry CD4 counts greater than 50 had a slightly
better CD4 and viral load response. This enhanced effect may have been due
to higher delavirdine plasma concentrations: Trial participants who achieved
nevirapine concentrations of at least 7.5 micrograms/ml had better results,
and these people tended to be the ones with an initial CD4 count above 50.
Another trial, 021, which compares AZT plus placebo to AZT plus one
of three doses (200 mg, 300 mg, or 400 mg three times per day) of delavirdine,
remains active and has not been terminated. This trial enrolled over 700
patients with CD4 counts between 200 and 500 (mean ranging from 325 to 340,
depending on the trial arm) and an average viral load of 5.2 logs (160,000), of
whom 60% were antiretroviral naive, 14% women, 31% non-white and 10%
injecting drug users. Over 75% of patients in each arm had a detectable
delavirdine plasma concentration. In terms of CD4 responses, after 62 weeks,
the groups with the two higher doses had approximately a 20 point CD4 count
difference as compared to the lower dose group or the AZT monotherapy
group. In addition, there was a sustained 0.5 log difference in HIV RNA
between the 300 mg or 400 mg delavirdine dose groups and the two other
groups at 62 weeks of follow-up. In this trial, the rate of treatment emergent
medical adverse events was similar in all arms, although again the rate of
drug-related rashes was greater in the delavirdine groups (22% to 31% as
compared to 16% in the AZT monotherapy group).
Future studies will combine delavirdine with AZT/3TC, as well as
protease inhibitors, and will investigate the use of delavirdine in preventing
maternal-fetal transmission and needlestick exposures. A five-drug
combination trial including hydroxyurea also is being considered.
- Gabriel Torres, M.D.
Novel HIV Strategies Previewed
by Theo Smart
Attacking new critical points in the HIV lifecycle is vital to finding
cheaper, more effective and resistance-defying antiviral therapies. On
November 20 to 21, a symposium, "Novel HIV Therapeutic Strategies,"
covering such innovative approaches was held in McClean, Virginia,
sponsored by the Cambridge Healthtech Institute. Attendees reviewed targets
for drug therapy revealed by recent progress in the understanding of how HIV
infects cells and replicates in those cells, interacting with cellular proteins and
the immune system in the process. Many of the compounds mentioned have
been covered previously in Treatment Issues, but there were several truly
novel drug leads that have received little attention in the past.
The Glove Fits
The reverse transcriptase enzyme, which converts HIV's RNA gene set
into DNA before the virus inserts itself into cells nuclei, often has been
compared to a hand, complete with a palm, fingers and thumb. The fingers
and thumb grab a hold of the nucleotide building blocks and attach them to
the growing strand of HIV DNA, lying in the "palm" of the enzyme. This
analogy was first made several years back, when the three-dimensional
structure of the reverse transcriptase enzyme was discovered.
Knowing the enzyme's structure could have important implications in
the design of new, more potent reverse transcriptase inhibitors. Ten years ago,
discovery of the three-dimensional structure of the protease enzyme led to
the discovery and development of protease inhibitors.
A group at State University of New York (SUNY), Buffalo has used
reverse transcriptase structure to design a chemical, DNP-poly-A, that fills the
entire nucleotide binding region of the enzyme, in a fashion similar to how
protease inhibitors fill the active site of the protease enzyme. When DNP-
poly-A was added to HIV-exposed cells, the cells did not become infected.
DNP-poly-A is a sequence of nucleotides (an oligonucleotide). Usually,
if strands of such material are found floating around in the blood or outside
of protected areas like the cell nucleus or mitochondria, they are treated by the
body as noxious garbage or enemy viral genes and quickly destroyed by special
enzymes. Most oligonucleotide drugs similarly are broken down before they
can reach their targets. The researchers from SUNY do not believe that this
will be a problem with DNP-poly-A, because the drug was stable even after
prolonged incubation in cell cultures with a variety of enzymes known to cut
up strands of nucleotides.
Next, the researchers administered the drug as an injection to mice
with murine leukemia virus, which has a reverse transcriptase enzyme very
similar to HIV's. Viral load dropped to undetectable levels in the mouse
blood, and there was little toxicity. One problem with the compound, is that
even though the team has modified it to increase its absorption from the
digestive tract, it still looks as though DNP-poly-A will have to be
administered as an injection.
There is no word yet if any pharmaceutical company is interested in
developing this compound.
RiboGene's RG 501
Ribosomal frameshifting is a process unique to viruses. It occurs as the
viral genetic material is translated into proteins that eventually will be
incorporated into new virions. In HIV, frameshifting is carefully orchestrated
to produce an exact ratio of 'gag' gene proteins (the core proteins of the virus)
to 'pol' gene proteins (the reverse transcriptase, integrase and protease
enzymes). If the virus produces too much gag in relation to pol, or visa versa,
new infectious virions cannot be properly assembled.
A start-up biotech concern, RiboGene, Inc., has developed a laboratory
test that screens for products that affect frameshifting either by inhibiting it
(no pol enzymes) or inducing it (little gag core protein). Another researcher
present at the conference, Louis Henderson of the National Cancer Institute,
suggested yet another mechanism for interfering with frameshifting to
disrupt the delicate balance of viral production. Premature frameshifting will
prevent production of the last portion of the gag precursor protein. This
would eliminate HIV's "zinc fingers" (see Treatment Issues October, 1995
article, Zinc Fingers - The Next Antiviral Target, pages 7-8), without which
the virus cannot package its genetic material into new virions.
RiboGene's test screen has found several distinct classes of chemicals
that induce frameshifting, though none have been found that inhibit the
process. One of these compounds, RG 501 blocks viral replication in cell
cultures at doses that do not kill or slow the growth of these cells. The
company is currently pursuing analogs of RG 501 in animal models and is in
talks with a number of major pharmaceutical companies interested in buying
or co-licensing the compounds.
Androvir
One of the few compounds reviewed at the meeting that has already
made it into human trials is Paracelsian's PN355, now named androvir. The
compound is derived from an herb used for colds and the flu in Chinese and
Ayurvedic medicine. Androvir inhibits HIV replication in cell cultures and
appears to trigger the death of HIV-infected cells.
Androvir's mechanism of action is complex. When a virus or cancer
takes over a cell, the cell life cycle is altered in such a way as to encourage the
production of viral materials and cancer-promoting proteins. In other words,
the virus shifts the cell's gears into drive. The virus recruits certain cellular
factors to do this. Androvir blocks the activation of these cellular factors,
which slows this viral or cancer-driven cell maturation, thereby stopping
viral replication. Since androvir's target is cellular, the virus may not be able
to mutate to escape the drug's effect.
The company has now studied the drug at doses up to 60 mg per kg per
day in over 30 volunteers with HIV or cancer. One study in HIV-infected
patients was recently completed at Bastyr University in Seattle, Washington.
Viral load was reduced by 38% (which is not a significant amount given the
variability of viral load tests), and CD4 count increases averaged about 30%
over baseline. Dr. John Babish, chief science officer and senior vice president
of Paracelsian also said that there were several unusual changes observed
very early within the study, such as rapid, dose-related improvements in
serum cholesterol levels, which returned to baseline when therapy was
discontinued. The company plans future studies to find a more effective dose.
More on Human Chorionic Gonadotropin
Anecdotal observations and laboratory studies indicated previously
that human chorionic gonadotropin (HCG) might have an anti-KS and anti-
HIV effect. See Treatment Issues July/August 1995 article, Human Chorionic
Gonadotropin, page 15, and Pamela Harris, M.D., in AIDS Patient Care and
STDs, March, 1996, concerning systemic KS treatment with massive amounts
of HCG.
Now, the October 24 New England Journal of Medicine has reported on
the first human trial in Kaposi's Sarcoma for this pregnancy-related
hormone. Investigators documented that intralesional injection of a
formulation of HCG reduces the size and occasionally leads to complete
regression of the treated KS lesions.
The new results come from two small studies performed by Parkash
Gill, M.D., and colleagues. In the first 24-patient study, three lesions per
patient were treated -- one with a placebo, and two with HCG at doses of 250,
500, 1,000 or 2,000 IU (12 lesions at each dose) three times per week for two
weeks. A significant dose-effect was seen, with one, five, five and ten of the 12
injected lesions responding at each dose, respectively. The non-responding
lesions at the highest were in one patient that stopped treatment after one
dose due to pain at the site of injection. Complete tumor regression was
observed in five of the lesions treated at the highest dose, two at the 1,000 IU
dose, and one each at the two lower doses. However, some of the placebo-
treated lesions located near treated lesions had responses as well.
Because of the effect on nearby lesions, the researchers ran a second
study with twelve patients who were randomized to have two lesions treated
with either 2,000 IU HCG or placebo. None of the placebo patients responded,
while ten of the twelve HCG-treated lesions responded. Five out of six lesions
were shown to be complete responses by biopsy. In each of the trials, the side
effects were mild, and included dizziness, nausea, headache, anxiety and pain
at the site of the lesion.
Before conducting the clinical studies, Dr. Gill's team, working in
collaboration with Dr. Robert Gallo, screened four commercial HCG
preparations to determine which had the greatest anti-KS effect in the test
tube. The greatest activity was found in Wyeth-Ayerst's preparation of HCG
called A.P.L., but this may not be because it had the highest concentration of
HCG.
Dr. Gallo observed, "The active material is not the normal HCG
molecule, but something that accompanies it in the crude material, in the
pregnant women's urine." (Commercial HCG preparations are derived from
the urine of pregnant women.) The active component may be a peptide
produced by the degradation of HCG.
"One of the most important concerns about this paper is that people
will rush out and start taking HCG. The problem with doing that is that the
amount of this crude fraction varies from commercial source to commercial
source. Even the most active preparations vary by lot. It probably depends on
what stage the urine is collected during pregnancy -- there is probably more of
it early in the course of pregnancy,"said Dr. Gallo.
Whatever the active component, it appears to induce apoptosis (a form
of cell suicide induced) in the lesion. Dr. Gallo believes that this component
probably acts as both a growth and rejection factor early in the growth of the
fetus. He also promises that more will be published on the anti-HIV activity
of the HCG extract in the near future.
- Theo Smart
Honing the Immune Attack on HIV
by Dave Gilden
In October's Treatment Issues, we looked at the current record of IL-2
research. This immune stimulant may help to ensure stability and even
reinforcement of available immunity by increasing the sheer numbers and
concentration of existing CD4 cells, but it does little to influence the quality of
immune defenses. The response against new opportunistic infections could
in this way be strengthened and accelerated, but the response against
previously encountered microbes, including HIV itself, likely will show no
signs of recovery. HIV presumably has killed off most of the cells that became
activated to fight off prior infections, leaving holes in the immune system's
repertoire of responses.
But then again, who knows how much IL-2 helps? The data on IL-2
remain extremely sketchy after all these years. Clifford Lane, M.D., at the
National Institutes of Health, who has conducted the only long-running IL-2
trial in HIV,1 insists that opportunistic infections only occur at the traditional
CD4 counts among people on IL-2 therapy. This statement implies that the
OIs are restricted almost entirely to nonresponders since IL-2, when
successful, keeps CD4 counts from falling to a perilous level. The basis for Dr.
Lane's assertion is unconvincing, though -- only seven actual opportunistic
infections among 60 volunteers who started IL-2 at different timepoints in the
trial and have been on therapy for varying lengths of time. Meanwhile, there
has been little sign of reduction in HIV levels, except perhaps in a few people
with early HIV infection -- and even then, only over the very long-term.
Since general immune stimulation via IL-2 or other agents has not offered
much hope of directly restricting HIV, researchers all along have been
considering ways to construct a strong specific anti-HIV immune defense.
Therapeutic vaccines are the major strategy that has been proposed to
preferentially increase surviving CD4 cells that could orchestrate a new
defense against HIV.
After introduction of new foreign proteins (antigen) to the body, naive
CD4 cells sensitive to portions of that protein eventually are activated and
multiply to construct new immune defenses. The therapeutic vaccine concept
is to improve on the immune defense against a particular already-existing
infection by inoculating pieces of the infectious agent's protein presented in a
way to trigger new naive cell activation. An immune-enhancing adjuvant is
frequently used to help this process along. Just this fall, investigators
presented evidence that therapeutic vaccines can reduce the extent and
duration of genital herpes outbreaks in people with frequent eruptions2 and
in infected guinea pigs.3
Trials Confirm the Naysayers
Most prominent researchers have always been skeptical of the validity
of the therapeutic vaccine approach for HIV, though. David Ho, M.D., director
of New York's Aaron Diamond AIDS Research Center, echoed a common
argument when he quipped, "Vaccines are not promising because the body
already sees lots of HIV antigen. Adding a little extra is not likely to make any
difference."
There is also a serious objection concerning viral diversity: Even if an
induced immune response is effective, won't HIV merely mutate to
rearrange the bit of viral protein that triggers the attack?
And indeed the field of therapeutic vaccines for HIV is littered with
failures, despite clear demonstrations that the vaccines provoke new
immune responses against HIV. The most extensively tested product has
been a gp160 (HIV envelope protein) inoculant made by bioengineered insect
cells, developed by MicroGeneSys. This gp160 had the amino acid sequence,
but not the folded structure, of the envelope found on a particular laboratory
strain of HIV (LAV). Periodic injections in people with early HIV infection
were found to induce new varieties of anti-gp160 antibodies as well as strong
immune cell proliferation when white blood cells taken from inoculated
HIV-positive volunteers were exposed in the test tube to more MicroGeneSys
gp160.4 Though clearly "immunogenic" the MicroGeneSys vaccine
completely flopped in a placebo-controlled trial coordinated by the Walter
Reed Army Institute of Research. After following 608 volunteers (with a
starting CD4 count of at least 400) for three to five years, researchers concluded
that the bimonthly injections of the vaccine were safe, but no difference
existed between the placebo and vaccine groups in terms of occurrence of
opportunistic infections, drop in CD4 count, rise in plasma HIV levels or
other measures of disease progression.5 A similar 278 person, three-year
Canadian trial had equally negative results.6
Recent reports at various conferences have also detailed the failures of
three other, more naturally structured vaccine products (Immuno AG's gp160
produced by mammalian cell cultures, a hybrid canary pox virus with a gp160
envelope, and British Biotech's virus-like particles consisting of yeast protein
particles coated with HIV p24 core protein). A published report on an earlier
trial involving Genentech's gp120 (an envelope component) therapeutic
vaccine also just appeared.7 The trial, involving 573 volunteers with initial
CD4 counts over 600 and followed for 15 months, also could detect no
difference in terms of CD4 decline or HIV plasma viral load reduction
between the vaccine and placebo groups.
Yet hope springs eternal in those interested in this approach. After the
failure of the MicroGeneSys vaccine, Fred Valentine, M.D., of New York
University commented, "We still have an enormous amount to learn about
what makes a protective immune response. I'm willing to have a more open
mind than most folks. If these vaccines don't work, let's try some new ones."
Ongoing Trials
One of the surviving therapeutic vaccines is the so-called Salk
immunogen (sponsored by the Immune Response Corporation under the
brand name Remune). First proposed ten years ago by Jonas Salk, this vaccine
consists of inactivated HIV stripped of its envelope. HIV's internal proteins
are more conserved (less variable), making for a vaccine capable of creating
immune responses that interact with a wide variety of HIV strains and
perhaps less subject to mutational escape by the virus. Surrounding the HIV
particles in the vaccine is a special mineral oil adjuvant known as Incomplete
Freund's Adjuvant (IFA) that is supposed to increase processing of the
vaccine material by the immune system. Past trials have shown at best slight
improvements in HIV levels and percent of CD4 cells along with enhanced
response to p24 antigen over a one year period8 (in 103 volunteers with
starting CD4 counts above 550). There has been no proof of real clinical
improvement, and one long-term observational report of 25 of the original
volunteers who received Remune (a median of eight inoculations over three
years) noted that eight had died. But unlike the sorry state of IL-2 testing (see
Treatment Issues November 1996 article, Outrunning HIV to Protect Immune
Defenses, Remune's corporate sponsor has invested in a large clinical
endpoint trial to confirm the product's value.
This trial, launched after protracted controversy with the FDA over
manufacturing and protocol details, will include 3,000 HIV-positive
participants with CD4 counts of between 300 and 549. They will be vaccinated
every three months for three years with either the Remune vaccine or IFA
alone (the control arm). Even if Remune proves to have little benefit, the
trial is not very risky for participants in that they may take any antiviral
therapy they please, and Remune seems to have little toxicity. Other
immune-based therapies, such as IL-2, are not allowed. It should be noted,
too, that enrollment in the Remune trial will make individuals ineligible for
most other trials. A small preliminary pediatric trial and an adult expanded
access program (for those who cannot participate in the clinical endpoint trial)
also exist -- for further information on any of these projects call 800/684-8624.
In Los Angeles, the AIDS Research Alliance is in the middle of a 24-
person, one-year trial of "HGP-30" in people with HIV and CD4 counts
ranging from 50 to 750. HGP-30 is a portion of HIV p17 core protein that is
considered particularly immunogenic and little subject to mutational
alterations. This 30 amino acid peptide is joined to "keyhole limpet
hemocyanin," or KLH, which originated in a type of mollusk and contains
many sequences of its own that are highly immunogenic. In a study presented
at last summer's International Conference on AIDS, researchers reporting on
a preventive HGP-30 vaccine in 11 HIV-negative volunteers found evidence
(in cell culture assays) of increased anti-HIV antibody production or T-cell
proliferation in six and four of the volunteers, respectively.9 Although KLH's
broad immune stimulation may be helpful in a preventive vaccine, that
stimulation risks triggering heightened HIV replication when used in a
therapeutic vaccine.
Another pilot therapeutic vaccine trial is winding up at Duke
University and is sponsored by the National Institute of Allergy and
Infectious Diseases' special program for expediting innovative therapies, the
Division of AIDS Treatment Research Initiative (DATRI). The vaccine agent
consists of a special mixture of peptides representing known immunogenic
sequences (epitopes) from two regions of gp120 (C4 and V3) plus the same IFA
adjuvant used in Remune. The selection of the peptides is based on a theory
that antibody and cytotoxic lymphocyte (CTL) responses to certain HIV
epitopes in humans suppress other immune responses that are necessary
later on, as HIV alters its envelope protein to escape immune attack. This
phenomenon, observed in experiments with mice,10 may be the reason that
the immune system eventually loses control of HIV. The C4-V3 peptide
mixture is designed to avoid this occurrence while containing epitopes
representing the major varieties of HIV found in North America and Europe.
An analysis of the trial results should be available this winter, but the
investigators are skeptical: "The likelihood of success with therapeutic
vaccines is decreasing," said John Bartlett, M.D., of Duke.
New Concepts
Inclusion of the new highly active antiretroviral drug combinations
(HAART) could be essential to the success of therapeutic vaccines. As is
probably also true with IL-2, HIV replication may have to be maximally
suppressed before the cells responsible for new immune responses can
replicate without impediment and without stimulating additional HIV
replication. Maximal HIV suppression could prevent the appearance of escape
mutants no longer susceptible to the therapeutic vaccines. HAART's virtual
elimination of HIV might be necessary before the benefits of the new
immune responses elicited by the vaccines will have an observable effect --
they might be best at preventing breakthrough infections by drug resistant
virus.
There are at present two upcoming trials that plan to combine a
therapeutic vaccine with HAART. At New York University, Dr. Valentine
has drawn up a protocol with the Remune vaccine plus AZT, 3TC and the
protease inhibitor indinavir. He commented, "This trial is directed toward
basic immunogenicity questions in people who are quite healthy. We are
asking whether you get new and better immune responses with less HIV, the
logic being the HIV screws up the immune response." The eight-month
study, expected to commence this winter, will enroll 150 participants
randomized to receive either Remune alone, IFA plus AZT/3TC/indinavir,
or Remune plus the triple combination.
A second exploratory trial has already started at Stanford University
and when fully enrolled will include 30 HIV-positive volunteers with CD4
counts of between 200 and 400. After a nine-week introduction to a
d4T/ddI/ritonavir combination, the trial participants will be assigned to
receive either the vaccine or placebo for a total of seven monthly injections.
This trial, ACTG 246, also has a placebo-controlled, 16-person subset for
people with CD4 counts over 500, and these volunteers will not be taking
anti-HIV drugs. The vaccine administered in this trial, Immuno AG's gp160,
is similar to one reported this fall to have failed in a 208-person trial covering
a similar population.11 A higher dose and a different version of gp160 (based
on a more representative strain of HIV) are being used this time.
In the completed trial there was a tendency for vaccine recipients on
anti-HIV drugs to experience deeper reductions in plasma HIV levels than
the reductions experienced by those taking anti-HIV drugs alone. The
Stanford trial started out as a study of how HIV mutates around immune
defenses. HAART was added to the protocol when it became available to see
how greatly boosting CD4 count improves immune responsiveness.
Finally, researchers at the Food and Drug Administration recently
announced further tests in mice of a new concept for a therapeutic vaccine.12
The HIV-derived immunogen is a segment of HIV gp120 protein (an 18
amino acid peptide from the V3 loop) that contains epitopes capable of
exciting both antibody and CTL responses. This amino acid string is coupled
to the walls of heat-inactivated Brucella abortus bacteria (a cow pathogen that
causes undulant fever in humans). This bacterium is capable of eliciting both
antibody-producing B-cells and CD8 cells (including CTLs) that attack virus-
infected cells in a manner partially independent of the CD4 T-helper cells.
(Some other bacteria can do this too; inactivated B. abortus just happens to be
relatively innocuous in humans. This type of immune stimulation is a result
of properties of the polysaccharides on bacterial cell walls.)
If it works, the Brucella abortus based vaccine might have special
therapeutic properties in people whose immune response to HIV is waning
due to the virus-induced destruction of their CD4 T-helper cells. The latest
mouse experiments found that vaccination created a pool of anti-HIV CTLs
even in mice whose CD4 T-helper cells had been artificially depleted.
Previous experiments had also found production of both interferon gamma
and certain types of antibodies (immunoglobulin G2a) that are associated with
the "TH1" immune profile. This cytotoxic lymphocyte oriented pattern of
immune response is thought to be particularly effective against HIV. Many
questions obviously remain concerning the safety as well as the formulation
of this type of vaccine. It is not clear which HIV-derived peptides coupled
with Brucella abortus, if any, would achieve an effective defense against real
HIV infection in humans. Here, too, there is no way to rationally design a
therapeutic vaccine, since what constitutes a protective immunity against
HIV remains unclear.
The immune system suppresses other viral infections, though, and it
seems to contribute to the longevity of most HIV-infected long-term
nonprogressors. Perhaps further observation of such nonprogressors will
indicate how to improve the naturally arising immune defense against HIV
to create an immunity analogous with what develops in other diseases.
Despite generating new immune responses, therapeutic vaccines' record in
controlling HIV has been unsuccessful so far. This failure does not rule out
other attempts using either radically altered versions of present vaccine
designs or completely different strategies -- if only there was some guide as to
how to proceed.
References
1. Kovacs JA et al. New England Journal of Medicine. Oct. 31, 1996;
335(18):1350-6.
2. Straus SE et al. Thirty-sixth Interscience Conference on Antimicrobial
Therapy and Chemotherapy. September 15-18, 1996; abstract H083.
3. Harrison CJ et al. Thirty-sixth Interscience Conference on Antimicrobial
Therapy and Chemotherapy. September 15-18, 1996; abstract H121.
4. Valentine FT et al. Journal of Infectous Diseases. June, 1996; 173(6); 1336-46.
5. Birx D et al. Eleventh Interantional Conference on AIDS. July 7-12, 1996;
(abstract TU.A.275).
6. Tsoukas C et al. Eleventh Interantional Conference on AIDS. July 7-12, 1996;
(abstract Tu.A.274).
7. Eron J et al. Lancet. Dec. 6, 1996; 348(9041):1547-1551.
8. Trauger RJ et al. Journal of infectious Diseases. June, 1994; 169(6):1256-64.
9. Kahn J et al. Eleventh International Conference on AIDS. July 7-12, 1996;
(abstract Th.B.944).
10. Golding Basil et al. Journal of Virology. June, 1995; 69(6):3299-33017.
11. Goebel F.-D. et al. Third International Conference on Drug Therapy in HIV
Infection. Nov. 3-7, 1996; (abstract OP6.4).
12. Lapham C et al. Journal of Virology. May, 1996; 70(5):3084-92.
AIDS Issues Face a More Hostile Congress
by Derek Link
The 1996 elections will mean big political changes for AIDS in
Washington. The balance of power between the parties remains the same, but
mass retirements in the Senate and shake-ups at the committee level mean a
more difficult climate for AIDS in the new Congress. This session of
Congress, the 105th, will no doubt revisit all the unresolved AIDS
controversies of the last one.
Debates likely to take place include the structure and final budget
authority for AIDS research at the National Institutes of Health, where the
preservation of the independent Office of AIDS Research in its current form
is in question. FDA reform is certain to be taken up again, too, and especially
with FDA commissioner David Kessler resigning, an outcome that favors
rapid drug development with little consideration for patient protection is all
the more probable. The struggle over providing adequate, ensured funding
for the state AIDS Drug Assistance Programs and for Medicaid, which are
facing increased demands due to the new HIV drugs, also will continue. (And
remember that the new FDA commissioner will have to be approved by the
Senate Labor Committee and then the full Senate.) Lastly, AIDS advocates
shiver over the prospect of having to fight the Coburn Bill. Introduced into
the last session of Congress by Rep. Tom Coburn, Republican of Oklahoma,
who is expected to introduce it again in some form, the Coburn Bill contains a
slew of measures for mandatory HIV testing and registration of those who
test positive.
The Senate
The Senate has changed the most since the elections. Republicans
increased their majority in this chamber by two seats. The split is now 53-47,
with Democrats maintaining power to protect a filibuster by blocking a cloture
vote, which requires 60 votes. Many moderate Republicans and AIDS allies
retired from office, making this session's Senate more ideologically
conservative than its predecessor. In total, 14 senators retired in 1996,
resulting in the highest number of "open seats" since the 1914 elections.
Two committees with jurisdiction over most AIDS programs, the
Appropriations and Labor committees, have new chairmen and several new
members. Since the vast majority of legislative action is made at the
committee level, these changes will have a huge impact on AIDS issues.
The Labor Committee is the main authorizing committee in the Senate
for most AIDS programs, including AIDS research, the Ryan White CARE
Act, AIDS prevention, etc. Authorizing committees create federal programs,
and determine their structure and purpose. Formerly chaired by moderate
Republican Nancy Kassebaum of Kansas, who retired, the committee now
will be lead by James Jeffords of Vermont. Sen. Jeffords appointment is
perhaps the best news AIDS advocates have had all month. He is a liberal
Republican, an AIDS ally, and he often bucks his party's leadership on
important issues.
Other developments on the Labor Committee are not so welcome.
Three new Republican members on the committee, Mitch McConnell of
Kentucky, Mike Enzi of Wyoming, and Tim Hutchinson of Arkansas, are
very conservative and not known for their leadership on AIDS. (Neither
New York nor California, the two states with the largest AIDS epidemics, are
represented on the Labor Committee.) Also, a new Public Health
Subcommittee, which may have jurisdiction over some AIDS programs, has
been created. It will be lead by Bill Frist, a conservative Republican from
Tennessee, who also happens to be a heart surgeon.
The Appropriations Committee is the other key committee for AIDS.
This committee controls the federal purse strings, allocating money to federal
programs each year. Formerly chaired by moderate Republican Mark Hatfield
of Oregon, another retiree, it is now led by Ted Stevens, a conservative
Senator from Alaska. AIDS advocates will have their work cut out for them
trying to influence Sen. Stevens. Sen. Stevens is joined on the committee by
three conservative colleagues: Kay Bailey Hutchinson of Texas, Larry Craig of
Idaho, and Lauch Faircloth of North Carolina. Barbara Boxer, the California
Democrat and a leader on AIDS issues, will join the committee minority.
Arlen Spector, a moderate Pennsylvania Republican, will keep his
chairmanship of Appropriation's Labor Subcommittee, which is also good
news for AIDS advocates.
The House
House Republicans were chastened in this election, but they still
maintain a majority. The final tally in the House is 227 Republicans and 207
Democrats, the slimmest margin in the House in the past 40 years. Several
right-wing members, particularly from the Northeast and West Coast were
defeated. The best news in the House races was the narrow victory of
Democrat Linda Sanchez over Bob Dornan in Orange county, California,
ending a long and ugly legislative career. A would-be Presidential candidate
and the House's leading homophobe, "B-1 Bob" was known both for his
reactionary theatrics and his devotion to expensive military gizmos. His
departure will remove a source of continuous tension in the House.
Fewer changes have occurred in the House committees than in the
Senate. The two committees crucial for AIDS in the lower chamber, the
Commerce and Appropriations Committees, retain most of their old
character. The leadership of both remains unchanged.
The Commerce Committee is the authorizing committee in the House
for the majority of AIDS bills. Thomas Bliley, a Republican from Richmond,
Virginia, will stay in charge of the committee, and most key members won re-
election. Henry Waxman, the Los Angeles Democrat, stepped down as the
ranking member on the Health And Environment Subcommittee, which
oversees most AIDS programs, for the ranking post in the Government
Oversight Subcommittee. This is probably the biggest blow for AIDS
advocates. His AIDS leadership at the subcommittee level will not easily be
replaced. Meanwhile, Eliot Engel, a Bronx Democrat and another AIDS
advocate, joined the committee minority, increasing New York City's
representation on the committee to three.
The House appropriations committee is also largely unchanged. Bob
Livingston, the New Orleans Republican, remains as chairman, although he
may face a leadership fight from fellow Republican Joseph McDade of
Pennsylvania. Rep. McDade was forced to step aside as chairman in the last
Congress because he was under indictment for campaign finance violations.
His recent acquittal of these charges means he is eligible again for a leadership
post.
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