      ===============================
      P I Perspective
      Number 13 - February 1993
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      Project Inform - San Francisco. California

      In this issue:

      A Time for Change
      VIIIth International AIDS Conference 
      State of the Antiviral Art 
      New Antiviral Update
      Women and AIDS 
      New Labeling for OTC Products 
      Vaccine Progress
      PML 
      Progress on Opportunistic Infections 
      New AIDS Definition 
      Immune Restoration Think Tank 
      Organizational Update 
      
      **********

      A Time for Change

      AIDS research, now entering its second decade, is at a crossroads.
Despite substantial advances which have extended survival times, no treatment
is uniformly or dramatically effective. Some argue that this should have been
expected in a major disease like AIDS, as decades of work have yet to conquer
cancer or many other serious illnesses. Yet there is little doubt that the
fight against AIDS could be better managed. With a new administration taking
the reins in Washington, there has never been a better opportunity to
implement reforms and initiate new programs.

      Three key initiatives, one already underway, may light the way to a
more hopeful future:

      1. Strengthening the Office of AIDS Research (OAR);

      2. A Call for an Independent Assessment of AIDS Research;

      3. Opening a 'second front' in the war on AIDS.

      Initiative #1: OAR Reform

      If one word characterizes the last several years of AIDS research, it
would be "unmanaged."  It is fair to argue that no one has really been in
charge of the overall effort, and thus no one is truly accountable for
anything. One of the most obvious problems has been a lack of coordination
and strategic planning. It is no one's job to systematically follow-up on the
new leads and insights generated each year. No one is responsible for finding
the common threads which might link the work of hundreds of scientists
working in isolation. Because no one is in charge, no one is responsible for
making sure the right experiments are done to answer key questions and test
new theories.
            With a new administration taking the reins in
            Washington, there has never been a better
            opportunity to implement reforms and initiate new
            programs.

      To a large degree, each of the hundreds or thousands of researchers
working in AIDS is simply doing his or her own thing, pursuing self-selected
paths and often competing, rather than collaborating, with each other. This
is not due to malice or lack of concern - it is simply the tradition of
medical research. Major institutions like the National Institutes of Health
have long operated on the principle of investigator-initiated research, a
process in which individual researchers apply for grants to do the work they
believe is necessary. The only real direction-setting occurs when the
leadership invites applications for study in particular subject areas. While
this is helpful, it is a very imprecise tool, one which at best only gives
gentle direction. There is no strategic plan to coordinate or guide research
efforts toward common goals.

      Currently, US AIDS research is directed by the Office of AIDS Research
of the National Institutes of Health. This office has the power to influence,
but not control, research throughout the many Institutes. In a sweeping
series of reforms proposed by New York's Treatment Action Croup (TAG), this
office may be greatly strengthened in future years. If the legislation passes
as planned, the newly invigorated Office of AIDS Research will:

       work with the Institutes to establish an overall strategic plan 
        and objectives for all AIDS research funded by the federal
        government;

       work with the Institutes to create an annual bud get which implements
        the strategic plan;

       distribute funding according to the plan and negotiate any necessary
        changes with the Institutes, in keeping with the strategic plan;

       evaluate the overall performance of the federally funded groups
        working on AIDS;

       manage a "discretionary fund" for special needs and new opportunities
        as they occur.

      Together, these reforms should go a long way toward creating a greater
sense of focus and unity of purpose in AIDS research. Moreover, it should
give the public greater confidence that the effort will be well-planned and
well-managed. While the reform package was not yet fully approved by the
Congress as of publication date, differences of opinion were rapidly
narrowing and were limited mostly to the question of funds disbursement after
bud gets are approved. In effect, this says that the notions of stronger
management, centralized strategic planning, and meaningful program evaluation
are already agreed to. This is no small matter, as the research community is
unaccustomed to many of these concepts. Once passed, these reforms should
help optimize the federal research bureaucracy and at least create the
opportunity for stronger leadership.

      Initiative #2: An Independent Assessment 

      The Office of AIDS Research reform package lays the framework for
improvement in the fight against AIDS. Once new processes are in place,
however, the second challenge is the substance of reform. In this regard,
there is no shortage of opinions. Researchers, physicians, patients,
politicians, and activists alike have their views on what has been wrong with
past efforts, and what to do next. While some of these views are
complimentary, some others are quite contradictory.

      While everyone has opinions and biases, no one has a lock on the truth.
One of the reasons for this lack of clarity about where we stand is that the
AIDS research program has been essentially unevaluated for the last 8 years.
No serious assessment has occurred, despite the overall size and importance
of the program.

      Thus, before the next major step is taken, Project Inform is calling
for a high level, independent assessment of AIDS research, an assessment
which would address both scientific and management issues. To be effective,
it must be done by a "blue-ribbon" panel of scientists and management
experts, and practical thinkers. The panel should be appointed by the
President, not from within the National Institutes of Health, nor even within
the Department of Health and Human Services.

      What would the 'assessment' process do??

       Constructively assess the strengths and weaknesses, successes and
        failures of the first decade of AIDS research, not to blame or laud
        anyone, but to provide a basis upon which to build new initiatives.

       Define the state of our knowledge of AIDS, across several broad
        scientific fronts.

       Define key unanswered questions which lie ahead, as well as suggest
        general priorities.

       Identify the principle bureaucratic, management, legal, and economic
        obstacles which might be hindering progress.

       Make recommendations for the second decade of AIDS research,
        including giving direction to any special new research program which
        might be initiated.

      Properly managed and given sufficient priority within the government,
the committee process and recommendations could be completed in six months
or
less. Once completed, presidential authority would be required to implement
the Committee's recommendations.

            Just as the military employs "skunkworks" operations
            and "rapid deployment forces" for critical projects,
            just as General Motors created the small nimble
            "Saturn" corporation for making a new line of small
            cars, it may be appropriate to spin off certain key
            aspects of AIDS research to a new kind of
            rapid-response facility.

      This proposal is not a call for just "another committee" or "another
commission. " For the first time, the fight against AIDS has the support of
the President. It is not unreasonable to expect that this could be a
committee with genuine teeth. Previous well-intended efforts, like the two
prior National Commissions on AIDS, were paper tigers because the
administration which created them never had any intention of acting on their
recommendations. They were essentially public relations exercises by the
Administration, no matter how hard the Commission members tried to make them
otherwise. Moreover, the prior Commissions did not focus on questions of AIDS
research, nor were they qualified to do so.

      Despite concerns over the possible time an assessmellt might require,
and despite fear that its recommendation might not be followed up, such an
assessment is an essential step for future progress on AIDS. Before any bold
new initiatives can take place, it is critical to build a consensus about
what has taken place previously and what should happen next. New directions
neither can nor should be dictated, no matter what their source. Even though
many groups have their own visions for the future, and most sincerely believe
their own plan to be the best, there are far too many lives at stake here to
gamble on anyone's individual view. Scientists, politicians, physicians,
activists and patients alike are aU individually capable of being wrong. It
is only by working together through a process of assessment and consensus
building that we can go forward with reasonable assurance we're on the right
track. Without it, the risk of error is high, and the risk of crippling
disunity is near certain.

      Initiative #3: Open A Second Front

      Some researchers argue that science cannot be managed like a military
operation, that creative minds must be given freedom to explore without
excessive direction. They point out that a powerful centralized program could
go off on the wrong track and waste aU its resources and authority. Perhaps,
perhaps not. The same challenge is faced in any kind of a major project
working in unknown territory. But this concern must be balanced against the
fact that AIDS is an infectious, deadly epidemic, not an exercise in academic
freedom. At the very least, a somewhat more managed and better controlled
effort must be possible and must be tried. What could be less promising than
ten more years of the same kind of AIDS research?

      Many voices have long called for a special, focused research project
on
AIDS, frequently called a"Manhattan Project," the name taken from the famed
project which sent hundreds of top scientists off to Los Alamos, New Mexico,
to build the atomic bomb during World War II. Some people believe that a
similar approach is the only thing which will ever solve the problem of AIDS.

      For many reasons, direct comparison to the Los Alamos project of 1943
is inappropriate. However, it has become a truism of modern business and
contemporary project management theory that certain tasks are best done by
smaller groups of highly skilled, highly motivated people working in teams,
freed from the normal bureaucratic overhead. Innovation and flexibility are
simply not characteristics of bureaucracy, and the current AIDS research
program is certainly a bureaucracy. Thus, just as the military employs
"skunkworks "operations and "rapid deployment forces" for critical projects,
just as General Motors created the small nimble "Saturn" corporation for
making a new line of small cars, it may be appropriate to spin off certain
key aspects of AIDS research to a new kind of rapid-response facility.

      What's Needed?

      Calling for a complete dismantling of the current AIDS research effort
and replacing it with a "Manhattan Project" would be politically
futile and probably scientifically unwarranted because of the many
uncertainties which still exist. Much of the work underway today will be
needed no matter what new approaches are tried. Moreover, the efficiency and
value of that work will almost certainly be enhanced by the Office of AIDS
Research reform package. Thus, a "second front on AIDS" is likely
to be an offshoot of the current federal AIDS program, rather than its
replacement.

      Yet, there are many reasons to believe a far more directed and
intensively focused research effort might pay special dividends in certain
aspects of AIDS. These might include the development of such budding new
technologies as gene therapy, antisense therapy, and immune system
regeneration. These critical areas will eventually be addressed within the
broader context of AIDS-research, but perhaps not as quickly as might be
possible in the setting of a more specialized program. Such a program would
differ from the normal processes at the National Institutes of Health in
several key ways:

       Leadership and a strong chain of command would be established, with
        a clear decision-making structure and lines of accountability,
modeled
        after industry or military project management styles, rather than the
        typical science management approach.

       A team would be created including diverse top scientific minds and
        creative thinkers. Such a project could employ a certain type of
        person, one who knows how to get things done while meeting the
        conflicting needs for personal autonomy and leadership authority.

       Program administration could be left in the hands of experienced
        civilian administrators, rather than wasting the time of scientists
        with administrative duties (as is now so much the case in the federal
        AIDS program) . Keeping the scientists out of administrative posts
        would also diminish inappropriate forms of competition between them.

       At least a core of top scientists would come together at a single
        location, from which they could work in collaboration with others
        linked to them in a "distributed" institute.  Much of the need for
        relocation in the original Manhattan Project was for security
        reasons, but it also provided great payoffs in team spirit,
        efficiency, and group focus.

       Scientific makeup of the team should include pathologists, lab
        scientists, virologists, immunologists, and clinicians, each with
        appropriate support staff. By combining laboratory and applied skills
        in a single setting, testing, evaluation, and adjustment could be
        greatly speeded compared to the current system, which establishes
        artificial barriers between these functions and requires separate
        levels of approvals each time a project moves on to the next step.
In
        the history of medicine, most breakthroughs have occurred through the
        work of such integrated teams.

       Key to the concept is the notion of "emergency powers:" the team
        would be empowered to work in unique ways currently not possible
        under the spider's web of federal regulations affecting medical
        research. This would include:

        - a special cooperative relationship with regulatory authorities,
          providing the greatest degree of experimental freedom and minimal
          unnecessary oversight;

        - access to the broadest possible range of public and proprietary
          technologies and products, using, if necessary, the legal
          justification of "eminent domain" (a practice in which government
          sometimes controls or seizes otherwise private property or goods,
          for the national good)

       The team would be responsible to a single institutional review board.
        All levels of experimentation, including clinical research, would be
        conducted without additional oversight from the FDA or the myriad of
        review bodies which currently hamstring NIH and university/academic
        research.

       The entire team would be driven by clear, limited goals, and held
        accountable to them. Accountability, however, would be measured by
        achievement of the goals, not by compliance with paperwork and
        needless regulations, as is now the case.

       Resources would be allocated on a long-term basis, as is often done
        for military programs. Minimizing the annual budgeting process would
        increase the efficiency of researchers.

       Most importantly, the group and any subgroups would function as
        teams, working together from the same operating plan and working to
        achieve group goals. The groups would carry experiments through from
        laboratory observations to clinical testing within a single team,
        with overnight capability to move back and forth between the lab and
        the clinic. Such an approach is not only the most efficient, but also
        the most effective and most satisfying for the scientists.

       Leadership would have direct access to the highest civilian
        authorities, including the President of the United States.

       The entire team, not individuals, would be credited for
        accomplishments. By giving up the right to individual patents and
        personal publication credit, senior-most scientific personnel would
        encourage collaboration and diminish inappropriate forms of
        competition.

      Such an arrangement of personnel and policies would utilize our best
scientific minds under the systems and procedures most likely to produce
results. However rational this sounds, it is quite unlike the ways in which
AIDS research is currently conducted. Such a program, of course, would be an
experiment, and as such reviewed frequently to determine whether or not it
is
producing results.

      Wishful Thinking?

      All of this, of course, is dependent upon achieving the political will
to take a new direction in AIDS research, one based on acknowledgment that
AIDS is an emergency which deserves the highest national attention. Despite
a lot of rhetoric, AIDS does not today have this position, nor does any other
health care problem.

      Government can act decisively when it wants to. Witness its response
to
such events as the 1989 San Francisco earthquake or Hurricane Andrew. Even
though only a relatively small loss of life was involved, compared to AIDS
or
other major diseases, billions of dollars of federal support funds were
appropriated within days, with nary a peep from Congress or the public. No
one denies the suffering caused by these events. But by far the largest price
the government will pay in response to these events will go toward the
restoration of property - not life or health. In comparison, the death toll
from AIDS alone already exceeds that of US citizens in wars in the Gulf,
Korea, and Vietnam combined. By decade's end, there is little doubt that the
toll will exceed that of all combined wars in US history. As in war, most
deaths will occur among the young, people who were expected to contribute to
society for decades to come. Is this not sufficient reason to declare an
emergency and try something new in the "War on AIDS"?

      If the will can be found in the new Administration, all the other
pieces are already in place to begin such a program, including a facility to
house it. The Frederick Cancer Research Center, a privately managed research
facility closely associated with the National Cancer Institute, has an empty,
50,000 square foot facility designed for AIDS research. It currently sits
empty and unused. Management and direction of the complex, which includes
some of the most advanced laboratory facilities in the world, is currently
open for discussion due to the recent death of its chief administrator.
Senior scientists, along with a new generation of creative thinkers, are
ready and able to open a second front against AIDS. Because of the Frederick
facility, little money would be needed to create new labs or purchase new
equipment. It is all sitting there, much of it unused or not used to
capacity.

      The Clinton Administration has dropped broad hints of its interest in
making a bold stand against AIDS, even though it is limited by financial
constraints. A limited, focused research program like that conceived here
could be funded for $50 to $100 million annually, a very modest additional
expenditure on top of the existing AIDS research budget. By limiting the
scope of the new program, no feathers need be ruffled in the existing
research program, which itself will proceed in an improved fashion thanks to
the impending Office of AIDS Research Reforms proposed by TAG.

      Only three things are needed to initiate a program such as this:
       a consensus, built upon assessment of needs

       a national agreement to put an end to AIDS

       a financial commitment from the Administration and the Congress

      The ideas presented here are, of course, but one way of looking at the
problem. What should be clear to all, however, is that there is currently no
real "War on AIDS" and that the present effort to conquer the disease is in
no way guided by the organizational and strategic thinking which directs our
other most pressing emergencies. AIDS is an enemy which can be beaten, but
to
date, we are fighting with tools designed for another task. The sense of
urgency, which seemed once shared at least by some researchers and political
supporters, has never seemed more lost than it is today. Whether it is
through reforms of the Office of AIDS Research, the "special project on AIDS"
envisioned here, or both, we can definitely move faster, more efficiently,
and more productively, but not until the nation develops the will to do so.

      **********

      Reflections on the VIIIth International Conference on AIDS

      Last year's VIIIth International Conference on AIDS in Amsterdam was
similar to past meetings in that there were no major medical breakthroughs
announced, nor even much new information for those who follow the subject
carefully. This is not necessarily a fault of the conference, but simply a
reflection of the fact that information travels so quickly and in so many
other ways. Anything truly newsworthy was addressed earlier or elsewhere.
This doesn't mean, however, that everyone got the news earlier, so the
conference still served an important purpose as a "one-stop-shopping-center"
for AIDS information.

      The conference also offered a much needed platform for a number of
modest advances, giving them the official stamp of approval that so many
doctors and health care workers seem to require before accepting them as
"real." The biggest beneficiaries were combination therapy (primarily AZT
plus ddI), therapeutic vaccines, and several treatments for opportunistic
infections. The fact that these were also the highlights of the 1991
conference in Florence must tell us something about the pace of research in
the last year. The frustrating thing is that so many people still see even
these findings as premature and lacking in data because they have not yet
been published in the major medical journals, or the studies have been "too
small" to please critics. For more on progress with antiviral medications,
see the State of the Antiviral Art in this issue. Likewise, read the latest
on the fight against opportunistic infections in the report on PML and the
Survey of Opporhmistic Infections.

      Far too much of the world's attention was diverted to the supposed
mystery of "non-HIV" cases of AIDS in 1992. Fully three days of International
conference coverage around the world was devoted to this non-event,
non-issue, while truly useful information was ignored. Is it any wonder that
the public is losing interest in AIDS? Little more than a month after the
International conference, most of the reported non-HIV AIDS cases had
evaporated in a puff of steam. We address this issue again only because there
was far too little coverage elsewhere on the resolve of this issue. The
non-HIV AIDS-like condition was subsequently termed Idiopathic CD4+ T
Lymphocytopenia (ICL). Further investigation of potential cases of ICL was
conducted via an examination of not only all 230,179 AIDS deaths reported to
the Center's for Disease Control (CDC) through July 1992, but also by
examining a cohort of 2,268 gay and bisexual high-risk HIV-negative men from
the MACS (Multicenter AIDS Cohort Study) If ICL was infectious via the same
routes as HIV, it would be assumed that this population of high-risk
individuals would demonstrate some prevalence of ICL. The review of the CDC's
230,179 reported AIDS death records revealed, in the final analysis, 2 cases
which possibly fit the definition of ICL. The review of the MAC Study, which
included 23,000 CD4 cell counts taken over a period of time, revealed only
one man with persistently low CD4 counts. Further investigation showed this
man had cancer and was undergoing chemotherapy, which is immunosuppressive.

      The issue again resurfaced at the meeting of the National Cancer
Institute's Tumor Cell Biology Laboratory, and again at the Interscience
Conference on Antimicrobial Agents and Chemotherapy (ICAAC). The majority of
the original cases reported were dismissed as misdiagnosed, while a few
unrelated and dissimilar cases remain a puzzlement. It is not surprising,
however, that a few cases of immunosuppression unrelated to HIV exist.
Immunosuppression existed long before the technology to detect it, and long
before AIDS.

      Certainly one of the most important, and perhaps controversial
discussions of the conference, and indeed the year, centered around the
progress toward a vaccine. The greatest movement was seen in the use of
therapeutic vaccines to boost the immune response in people already infected
with HIV. The Vaccine Progress article in this issue presents the highlights.
On the preventive vaccine front - vaccines intended to prevent infection -
a
lot of new information was announced, but it would be exaggerating to call
it
progress. Many skeptics feel that none of the preventive vaccine approaches
have shown the ability to prevent anything, even though all kinds of
measurements and observations have been reported. A great controversy is
brewing over the steamrolling plans to test preventive vaccines worldwide,
apparently whether they work or not.

      Fortunately, AIDS research doesn't begin and end with the International
Conference. More and sometimes better data come from other conferences, such
as the annual Meeting of the Laboratory of Tumor Cell Biology, the National
Cooperative Vaccine Development Croup Conference, and ICAAC. Project Inform's
coverage of these and other events continues throughout the year.

      **********

      Survey: State of The Antiviral Art

      Behind the various headline grabbing stories from the International
AIDS Conference in Amsterdam, there was a lot of information on the more
mundane area of nucleoside analog antiretrovirals, both approved and in
development. There was also some promising information on antivirals that
work in other ways. On a practical level, these drugs, more than some of the
ambitious high-tech treatments that get the publicity, will offer the real
options for most people in the upcoming year. Understanding the new
information available on AZT, ddI and ddC is key when considering new uses
of
these drugs, possibly in innovative combinations or at different doses.
Various studies have come to light over the past few months which may help
shed some light on shaping treatment strategies and reconsidering current
courses of treatment.

      Early Intervention

      The debate on when to start antiviral therapy is ongoing. Some people
believe that beginning AZT immediately, regardless of CD4 count, is the best
treatment strategy. Others feel that waiting until the CD4 cell count falls
below 500 is more beneficial. A recent report suggesting that the virus is
never latent, or dormant, truly gives credence to the idea of beginning
anti-HIV therapy earlier, perhaps when the body's immune system is still very
healthy and functioning well. Fears around the development of AZT resistance,
however, enter the debate and make the decision more complicated, although
all studies to date have concluded that AZT resistance develops much more
slowly in early disease. Whatever the outcome, the decision to initiate
antiviral therapy must include weighing the pros and cons, considering the
information available, and being aware of the potential risks and benefits.
Regardless what the decision is, careful and ongoing monitoring of general
health and laboratory tests is critical to making wise choices. Moreover,
taking charge of your health, paying attention to nutrition, and considering
options are all things that can be done right away, with very little risk and
a whole lot of benefit.

      The center of this discussion typically falls to the question, "When
should I start taking AZT?" It is important to remember that AZT is not the
only option. More and more there is a growing consensus in the scientific
community that combination antivirals are the way to go. There are no data,
however, on the usefulness of combinations in very early stages of
HIV-disease, although logically it makes sense that aggressive treatment
early may alter the disease course. Because there are no clear data, the
decision as to when to begin therapy, and what therapy to begin, falls mostly
to personal choice and how you feel about it.

      In the April 1992 Perspective, we reported on preliminary information
from a placebo-controlled, 1000-patient European/Australian study of AZT for
early intervention. Study volunteers were asymptomatic with more than 400 CD4
cells, and two-thirds of the volunteers entered the study with between 500
and 750 CD4 cells. The earlier data showed that the placebo group was twice
as likely to progress to symptoms or to significant CD4 cell decline (below
350) as the AZT group, and the side effects were indistinguishable in the two
groups. In Amsterdam there was a final analysis of that study, which was
stopped because it showed that, even leaving aside CD4 decline, people on
placebo were progressing to symptoms twice as often as people on AZT. This
lends weight to the idea of starting antivirals at counts above 500. The
counterpart American study, ACTG 019, is following AZT and placebo groups who
began the study with up to 800 CD4 cells. Thus far, there have been no
definitive answers out of ACTG 019.

      AZT Versus ddI

      As noted in our July, 1992 Briefing Paper, ACTG 116B/117, a large study
of AZT versus ddI in people who had at least four months of prior AZT use,
showed a 33% advantage for ddI in preventing progression to new infections,
and a modest advantage in CD4 counts. The advantage for ddI was the same no
matter how long people had been on AZT, and it was most evident in people who
started the study without a previous AIDS diagnosis. Subsequently,
Bristol-Myers (maker of ddI) asked the FDA to widen the approved indications
for ddI to include anyone with four months of prior AZT use, regardless of
their immune status or how they were responding to AZT. In late September,
1992, the FDA approved an expanded labeling indication for ddI.

      Results of another large AZT-versus-ddI study (ACTG 116A), were
announced on 30 December, 1992. The study, which enrolled 617 volunteers with
CD4 counts of less than 300, randomized study participants to receive either
AZT (600 mg/day) or one of two doses of ddI (500 mg./day or 750 mg./day). It
is worth noting that at the time of the study the powdered formulation of ddI
was still in use and 500 mg./day of the powdered formulation of ddI is
equivalent to 400 mg./day of the current tablet form. Volunteers were
eligible to participate in the study if they had CD4 cell counts of 300 or
less, and symptoms of HIV-disease upon entering the study, or if they had CD4
cell counts of 200 or less and no symptoms.

      Of the 617 study participants, 380 had no previous history of AZT use,
118 volunteers had 8 to 16 weeks of prior AZT therapy, and 119 people had
less than 8 weeks of prior AZT use. Of the 380 people who entered the study
with no prior history of AZT therapy, only 18% of those randomized to receive
AZT progressed in disease or died within one year. In comparison,31% of
persons on the 750 mg./day dose of ddI and 29% of people on the 500 mg./day
dose progressed or died within one year. While there is still more careful
analysis which must be conducted on these data, the immediate take home
message may be that if you are considering initiating single-agent antiviral
therapy, AZT is a reasonable option.

      For the 119 persons who entered the study with less than 8 weeks of
prior AZT therapy, who were then randomized to either continue AZT or
switched to receive one of the two doses of ddI, there were no significant
differences between clinical outcome. For the 118 volunteers who had 8 to 16
weeks prior AZT therapy, however, there was a significant benefit for those
people who were switched to receive ddI. Of these study participants, 33% of
the volunteers who remained on AZT developed a new AIDS-defining condition
or
died within one year, whereas only 11% of people receiving 500 mg/day dose
of
ddI, and 17% of those switched to 750 mg/day did.

      In this study, people taking AZT were more likely to have low white
blood cell counts (e.g. granulocytopenia) than those taking ddI. While there
was a trend toward a higher incidence of peripheral neuropathy (pain, burning
or tingling in the hands and feet) in the group of people who were randomized
to receive the 750 mg/day dose of ddI, there were no significant differences
in the incidence of peripheral neuropathy between the group receiving ddI
versus those who received AZT. If there had been any doubt, it now seems
clear that the lower dose of ddI (500 mg/day which is equal to 400 mg/day
tablet form) seems to be equally beneficial as the higher dose and there is
a trend toward less adverse reactions to the drug with the lower dose. The
optimal dose of ddI may be lower still. Doses of ddI are typically determined
on the basis of body weight.
      Results of this study add to the bulk of information available on AZT
and ddI, and provide additional information by which to make treatment
decisions. However, the best therapeutic strategy may be combination use of
AZT and ddI, or combinations of other antivirals, including ddC or d4T.

      Potential pancreatitis has been a serious obstacle to wider ddI
acceptance, since this life-threatening side effect was seen to a significant
degree in the very sick people who first got the drug. But interim reports,
presented in Amsterdam, from two ddI studies in healthier people (CD4 counts
up to 500) indicated no incidences of life-threatening pancreatitis and a
much lower incidence of elevated amylase levels (a possible marker for
pancreatic abnormalities). Then, in the August 27 New England Journal of
Medicine, the publication of the final data from ACTG 116B/117 showed no
statistically significant difference in pancreatitis between the group
receiving 500 mg. of ddI and the group receiving AZT. People in this study
either had baseline CD4 counts under 300 and a diagnosis of AIDS or ARC, or
less than 200 CD4 cells and no symptoms. People taking ddI who are sicker
than the study group must be considered to be at increased risk for
pancreatitis, but it begins to look as if ddI-related pancreatitis may follow
the pattern of AZT-related anemia, in which the severe anemia seen in sick
people became rare-to-nonexistent as the drug was used in healthier people.

      A few additional points can be made about pancreatitis. First: people
on ddI did see more frequent unfractionated amylase elevations than people
on
AZT, but this did not translate into more frequent pancreatic disease.
Doctors whose patients are doing well on ddI but showing elevated amylase
should request fractionated amylase levels, which look separately at amylase
levels in saliva and elsewhere. If the increase is purely in the salivary
amylase, there is little or no reason for concern because this bears no
relation to pancreatic problems (though it may have some relation to dry
mouth, another ddI side effect). Second: aerosolized pentamidine can also
cause pancreatitis, or may contribute to it when used in combination with
ddI. Although this potential side effect has long been reported, it has not
been publicized or well understood, and some knowledgeable researchers
suggest that the problem may be more widespread than most clinicians have
realized. Although it has been common knowledge that pentamidine, when used
intravenously, could cause pancreatitis, most physicians felt this was
irrelevant with the aerosol, in the belief that the aerosolized drug never
left the lung. This is apparently not true. Combinations of ddI and aerosol
pentamidine should at least be watched carefully and avoided if possible,
especially in people with a history of pancreatic disease.

      Finally: in June of this year, the American Journal of Gastroenterology
published a study reporting a 43% pancreatitis rate in AIDS patients on ddI.
This study is two years old, based on a small group in the early
expanded-access program who received higher doses than are now used. There
are various problems with this study's methods and conclusions, which called
any elevated amylase levels "pancreatitis." The reported pancreatitis rate
from the entire ddI expanded-access program and Phase I studies ranged from
five to nine percent and, due to diagnostic inconsistencies, the actual rate
may have been lower still.


      ddI Versus ddC
      Controversial results of a community-based study comparing ddI therapy
to ddC in people who had failed or were intolerant to AZT were amlounced in
late January 1993. The study (CPCRA 002) was an "open-label" study, which
means that volunteers were aware which drug they were given. The study
enrolled 467 people, two thirds of whom had an AIDS diagnosis. The mean CD4
cell count of study participants was 37.

      A first look at the study suggested that there was a slight, but
insignificant, trend toward longer survival in the group of people taking
ddC. A closer look at how the data were analyzed, however, reveals that this
study is inconclusive at best The study was analyzed in such a way that the
statisticians reviewing the data "corrected" for the fact there was a trend
toward higher CD4 cell counts in the group of people who received ddI. This
"correction" is misleading and in fact the actual numbers do not reflect a
trend towards survival in people taking ddC While people who received ddI
reported a higher incidence of stomach pain, diarrhea and symptoms of
pancreatitis, people who took ddC reported a higher incidence of lesions in
the mouth and symptoms of peripheral neuropathy. In both groups, however,
there was an extremely high progression rate, nearly 66%, to a new AIDS
defining illness or death within one year.

      What is most alarming about these results is they call into question
the benefit of current antiviral options for people with more advanced stages
of HIV disease. While it is clearly important to have adequate antiviral
cover in later stages of HIV disease, this study seems to highlight first and
foremost the need for more and better options, perhaps different therapeutic
approaches incorporating new and innovative technologies, and a targeted
research effort into therapeutic strategies for people with lower CD4 cell
counts.

      Combination AZT and ddC

      On June 22, 1992, the FDA approved ddC for combination use with AZT,
the first combination therapy approach to receive FDA approval. The approval
was based on two small studies that showed superiority of combination therapy
over monotherapy in both absolute CD4 increases and in duration of CD4
increases. Unfortunately, the wording of the approval was confusing,
recommending the combination for some people under 300 CD4 cells with
"significant clinical or immunologic deterioration", without defining the
terms or indicating exactly who might best benefit from combination therapy,
and leaving monotherapy as the standard of care. The first hope for clearing
up this confusion may come from ACTG 155, a large study comparing AZT plus
ddC to AZT alone Results from this study should be available soon In the
meantime, with the buyers-club ddC gone and the approved ddC selling at a
wholesale price of $1800 per year, some people are finding ddC less
accessible than it was before it was approved.

      Combination AZT and ddI

      Not surprisingly, the combination of AZT and ddI appears to work at
least as well as the combination of AZT and ddC. There were three studies
presented at the International Conference in 1992, all fairly small, none
very long-term, and all still in progress. Nonetheless, the evidence was
generally comparable to the AZT plus ddC evidence and, in one major respect,
better.

      The first study compared five different combination doses (ranging from
150 mg. AZT and 90 mg. ddI daily to 600 mg. AZT and 500 mg. ddI daily) to an
AZT-only (600 mg.) arm. There were 69 volunteers, who began with CD4 counts
under 400 (mean count: 259); half had less than four months prior treatment
with AZT, half had none. At 24 weeks, all combination doses were
significantly more effective than AZT alone (median CD4 increases: 166 on
combinations, 77 on AZT alone), but there was little difference in response
between the different combination dose levels. In all groups the peak CD4
increase was about twice as high in people who hadn't had previous AZT
therapy, but combination therapy was still superior to monotherapy regardless
of prior therapy. Decreases in viral burden were seen significantly more
often in groups receiving combination therapy than monotherapy.

      The second study compared AZT plus ddI (one dose: 300 mg. AZT and 250
mg. ddI daily) to AZT (600 mg. per day) alternating with ddI (500 mg. per
day) every three weeks. The 41 volunteers, some with AIDS and some without
symptoms of HIV disease, began with CD4 levels below 350 and had less than
three months prior AZT treatment. At week 54, the mean CD4 increase in the
combination therapy group was 74, compared to a drop below baseline in the
alternating therapy group. Of p24 antigen positive patients, twice as many
reversed their positive status on the combination alm as on the altelnating
arm.

      The third study compared three arms of AZT plus ddI (ranging from 150
mg. AZT and 134 mg. ddI daily to 600 mg. AZT and 500 mg. ddI daily) to a
group receiving ddI alone (500 mg. daily). There were 116 asymptomatic
patients with baseline CD4 counts between 200 and 500, with up to 13 months
of prior AZT (but no ddI). At 24 weeks, across all the groups, the median CD4
increase was 64; there was no significant difference between the combination
groups and the ddI-only group, and no significant difference between people
who had previous AZT and people who had not. By 56 weeks, the numbers had
changed somewhat but the basic conclusions hadn't.

      One interesting aspect of the third study is that thus far there is no
apparent difference in benefit between the combination therapy arms and the
ddI alone arm of the study. The study is still underway, however, and the
advantage of a combination in healthier people might be more in how long it
works than in how big the initial CD4 boost.

      An important finding of all these studies is the effectiveness of lower
doses of AZT and ddI. Even at doses as low as 90 mg. ddI and 150 mg. AZT
daily, the effect was as great as at full doses of each drug; whereas, in the
comparable AZT-plus-ddC study, there were two low-dose arms that didn't show
much promise at all. It may be that the synergy is stronger between AZT and
ddI, or it may just be that ddI is a more effective drug than ddC. Time may
change things, but it's reasonable to say, based on these three studies, that
people planning to combine AZT and ddI might talk to health care
professionals about using low doses of each drug: for example 300 mg. AZT and
250 mg. ddI daily (which is the sole dose used in the second study). This may
provide a safety margin between the doses being used and the lowest doses
that showed efficacy. People who have trouble tolerating even half doses of
one or both drugs could experiment with cutting back to the lowest doses with
the fair expectation of getting benefit. In effect, combining very low doses
of AZT and ddI may provide an antiviral therapy for people who otherwise
don't tolerate either drug alone.

      (Important note: all the ddI doses mentioned above refer to
      powdered ddI. Although the powder is still available, most people
      now take the tablet ddI, for which the doses are different. In
      tablets, the proper dose is four-fifths (or .8) of the powdered
      dose. So 500 mg. of powder equals 400 mg. of the tablets, 250 mg.
      of powder equals 200 mg. of tablets, and so on.)

      Dosing matters remain somewhat uncertain. AZT only comes in 100 mg.
pills. ddI tablets and powder come in a variety of doses, as low as 25 mg.,
but at least two tablets need to be taken together, on an empty stomach, to
provide the proper buffering, and a full powder packet should be used for the
same reason. Some sources suggest that neither ddI nor AZT needs to be taken
more than once a day, but this is unproven.

      In short, the case for combining AZT and ddI is strong. As a practical
matter, how to pay for two drugs when insurance or government agencies may
not cover both is a problem; but it helps that only half-doses of each are
necessary. This potential for lower cost must be addressed in any discussion
with insurers.

      **********

      New Antiviral Update

      The saga continues as to the best use of AZT, ddI and ddC, in which
combination, at what dose, and for how long. Throughout the course of debate,
one issue becomes clear there is an urgent need for more and better antiviral
options. Fortunately, there are a number of promising antiviral therapies in
the pipeline, some of which are available through larger trials or expanded
access, such as d4T. Others are expected to enter larger scale testing this
year, such as 3TC. Novel approaches to blocking HIV replication are also
being pursued, with drugs which block HIV at different parts of its life
cycle, such as proteinase and tat inhibitors. Additionally, new information
on innovative strategies for controlling HIV, by targeting the destruction
of
HIV-infected cells or manipulating the immune system to help inhibit HIV
replication, are encouraging and hold great promise.

      Nucleoside Analogs

      There are a number of nucleoside analogs, similar to AZT, ddI and ddC,
which are still in the development pipeline. These include d4T, 3TC, and FLT.
All nucleoside analogs are not the same. Just as the three currently approved
antivirals have a different set of toxicities and indications for use, so too
the antivirals on the horizon have unique features which make them more and
less attractive. While d4T, for example, seems to occasionally cause the same
type of peripheral neuropathy seen with ddI, the early information suggests
d4T may be more potent than the existing antivirals. Preliminary results of
early studies indicate that some study participants experienced 50% CD4 cell
count increases which were sustained for one year. 3TC on the other hand,
does not demonstrate the anti-HIV activity of other drugs but early results
of study show that it is virtually nontoxic. While 3TC may never have its
place among the ranks of first line antiviral therapies, it may prove to have
an important role in combination approaches or for people who cannot tolerate
other antivirals.

      d4T

      In October of 1992, Bristol-Myers began an expanded access program for
d4T, which is now in large efficacy trials at many sites around the country.
(For information on entering these trials, call 1-800-TRIALS-A.) In
uncontrolled studies, d4T has indicated clear anti-HIV activity and the
ability to produce rises in CD4 counts lasting much longer than rises
produced by other single nucleosides. The drug's only serious potential
toxicity seems to be peripheral neuropathy, which, as with ddI, has sometimes
been successfully managed by cutting the doses in half. In one study d4T
produced improvements in neurocognitive functioning equal to those produced
by AZT, suggesting that it may be helpful to some people with HIV-related
dementia (and of special importance to such people if they can't
tolerate AZT.

      The expanded access program provides d4T to people who are intolerant
of both AZT and ddI, or who have failed both drugs. For more information on
d4T and the expanded-access program, a d4T Fact Sheet is available through
Project Inform's toll free hotline.

      A point to remember is that, although the expanded access program
focuses attention on the use of d4T in a specialized, mostly later stage
group, the drug may ultimately take its place among the currently approved
drugs, to be used in ways that can't be foreseen. It may end up being used
in
late disease, in early disease, as first line therapy, as fall back therapy,
alone or in one or more combinations.

      3TC

      Early results from a phase I dose ranging study evaluating the safety
of 3TC were discouraging. Upon closer analysis of the data, however, poor
results were attlibuted to subclinical doses, meaning the doses used in the
trial were too low to be effective. The sponsor, Glaxo, subsequently raised
the doses of drug in the trial. As the doses were increased, so was the
anti-HIV activity of the drug, although never to the level of other approved
antivirals. Despite increasing doses, toxicities were not apparent.3TC is
expected to go into larger scale testing this year.

      The other nucleoside currently in trials, FLT, produced serious
toxicities, adversely affecting red cells, white cells, and platelets. Trials
have been on hold, after two deaths that may or may not be FLT-related, and
the future of the drug is unclear.

      In general, everyone wants to move beyond nucleosides to other kinds
of
drugs. But if d4T and 3TC are in certain ways better than AZT, ddI and ddC,
there could be quite a lot done with five nucleosides to mix and match. As
more nucleosides show efficacy, alone and in combination, people may become
anxious about which is the best option, since there have been no studies
comparing the most promising therapies to each other. Although several
important studies will report data in the coming months, the aggregate
results are unlikely to produce accord on any single superior therapy. A
scientific consensus has developed that combination antivirals are more
effective than monotherapy, but, due to problems with intolerance or access,
a single drug like AZT or d4T may sometimes still be a better option. There
may in the end be a number of valid antiviral strategies, none dramatically
superior to the others. Doctors and patients should always be flexible,
willing to alter therapy according to individual response and in light of new
evidence as it appears.

      Other Antivirals... GLQ223

      Two studies of GLQ-223 (compound Q, or trichosanthin) were presented
at
the International AIDS Conference in Amsterdam, one from Project Inform and
one from the manufacturer, Genelabs (including data from San Francisco
General Hospital and several other sites). The Project Inform study of 29
volunteers, which has completed,reported on doses escalating to 100
micrograms/kg., over a 2-year period. The Genelabs study of 54 study
participants reported on doses escalating to 200 mcg./kg., over the same
time. The Project Inform study allowed simultaneous use of AZT, ddI, ddC, PCP
prophylaxis and acyclovir; the Genelabs study allowed only Q initially, and
later added AZT. Both studies showed that, as doses increased, and as the
total dose each volunteer had taken increased, there tended to be rises in
CD4 and CD8 cells, with a concurrent trend to improved general health. The
positive correlation was almost identical in the two studies. An interesting
feature of the Project Inform study (which included people defined as having
AIDS or ARC) was the virtual absence of severe side effects not just to Q,
but to any of the other drugs people were on.

      None of this is really new, and the Genelabs study has since gone on
to
higher doses of 500 mcg/ kg. The principal measure of the efficacy of aLQ-223
will come from the current controlled trial, now under way in San Francisco
and other cities.

      Pentoxifylline

      Pentoxifylline (Trental) is a prescription drug that reduces a natural
substance called tumor necrosis factor (TNF), which is elevated in people
with HIV. High TNF levels are associated with increased HIV replication and
with decreased activity of concurrent nucleoside analogs. In Amsterdam a
study of 25 people on pentoxifylline reported reduced TNF (but not below
normal levels) and HIV titers. There was no reported increase in CD4 counts.
Since there were no severe side effects, the next round of trials will double
the dose (from 1200 mg to 2400 mg per day) to look for stronger anti-HIV
action. There are some east coast cities where pentoxifylline is a relatively
popular community drug. It's a blood thinner, used mostly for leg cramps in
older people, and is a reasonable alternative for people looking for
something different and easily available, with some science behind it.
Because pentoxifylline is approved, people considering off-label use of the
drug should talk to their doctor and continue careful monitoring. A plan for
a larger study of pentoxifylline is in the works. Another compound in human
trials, N-acetylcysteine (NAC), has also been shown to reduce TNF levels in
laboratory studies. The major rationale behind the development of this
compound, however, is to raise glutathione levels, which may be decreased in
people in later stages of HIV-infection. A more in-depth analysis of NAC is
warranted, but for lack of space in this issue of the PI Perspective, people
interested more in this subject should call the Project Inform Hotline .

      Proteinase and Tat Inhibitors

      Proteinase inhibitors and TAT inhibitors are new kinds of antivirals
that have been widely publicized for years without moving along very quickly.
Hoffman LaRoche has both a TAT inhibitor and a proteinase inhibitor, and both
have been in safety and pharmacokinetics trials for some time, in both the
United States and Europe. Hoffman LaRoche says that there are no data at all
on whether either drug has any antiviral effect in humans, but trials to
determine efficacy are expected to begin shortly. Thus far it is believed
that if Hoffman really had something with their proteinase, they would be
forthcoming with information. Other companies, including Abbott Laboratories
and Merck, have proteinase inhibitors in development as well. Abbott's
intravenous (IV) proteinase, which was under study in the Netherlands, ran
into difficulties due to side affects, most notably liver toxicities.  While
Abbott will continue the study at lower doses in hopes of answering some
pathogenic questions about proteinase in humans, they have decided to abandon
their IV proteinase program. Abbott will still continue their efforts on an
oral proteinase inhibitor, however, which is expected to enter human studies,
in Amsterdam and Paris, in April of this year.

      Ateviridine

      Upjohn's BHAP-compound, U-87201E, is a non-nucleoside reverse
transcriptase inhibitor. A small trial of U-87201E, which has recently been
given the generic name ateviridine, has, as we go to press, just completed.
This study was small and involved 15 volunteers, with CD4 cell counts less
than 500. The goal of the study was to determine the safety and
pharmacokinetics of ateviridine in combination with AZT, and to determine if
resistance to ateviridine develops if taken in combination with AZT. More
information about this study will be available soon. In test tubes
ateviridine has an antiviral effect, but it's unknown whether it does much
in
people. Further small studies are proceeding.

      Three-Drug Combinations

      A current trial is combining AZT, ddC, and alpha interferon, based on
laboratory studies of increased anti-HIV effect with the three drug
combination. Two-drug combinations with alpha interferon have never shown
much increased efficacy (nothing that most people would consider
justification for using an expensive injectable drug with unpleasant side
effects). These drugs are all approved, and some doctors have been
experimenting with AZT/ddC/alpha interferon or AZT/ddI/alpha interferon, but
none have reported their results. The trial is using standard doses of AZT
and ddC and 3 million units a day of alpha interferon, which is low but not
low enough to escape side effects.

      The idea of three-drug combinations may be on the cutting edge of
future research. If two drugs work significantly better than one, then three
or more may work significantly better than two.

      A laboratory study presented at the International AIDS Conference in
Amsterdam showed that a combination of AZT, ddI and a non-nucleoside reverse
transcriptase inhibitor, nevirapine, hitting the virus at essentially the
same point (the formation of reverse transcriptase), caused the virus to
mutate in away that rendered it completely inactive, even after the drugs
were withdrawn. It is unclear whether this would happen in humans, but it's
another possible path, and could represent a use for the otherwise
disappointing non-nucleoside reverse transcriptase inhibitors. As we go to
press, a study of this three drug combination is about to begin in humans,
through the AIDS Clinical Trials Group (ACTG).

      The other three-drug combination reported at the conference featured
AZT and alpha interferon, plus thymosin, a thymic peptide that's also been
studied for use against hepatitis. A small Italian study of people with up
to
500 CD4 cells compared AZT alone to AZT plus alpha interferon to AZT plus
alpha interferon plus thymosin; after 18 months, the one-drug and two-drug
groups were below baseline in CD4 counts, while the three-drug group showed
"a substantial and sustained increase" from a mean of 324 to a mean of 582.
This three-drug group also showed greater decreases in viral load and
increases in measures of CD4-cell function. This particular study is really
too small to be considered conclusive, but clearly the idea of combining
antivirals with immune-based therapies represents, as Project Inform has long
maintained, a major area for further research.

      **********

      Women and HIV/AIDS
      by Tonisa Clardy

      During all the previous International Conferences on AIDS, the amount
of research presented on the natural history and spectrum of diseases found
in HIV-positive women was virtually nonexistent. The small amount of data
that were available focused on epidemiology and women as vectors of infection
to the next generation and as vessels by which heterosexual men might acquire
HIV. In 1992 atAmsterdam, however, the cloud began to lift.

      It began with an International Pre-conference for Women Living with
HIV/AIDS attended by 51 women from 29 countries. At the press conference held
at the close of the three day workshop, the participants presented their
eleven point statement of need for clinical research, treatment, and care.
These needs are as diverse as the women themselves; among them a woman's
right to reproductive autonomy; recognition of the fundamental human rights
of all women with special consideration for those in prison, substance users
and sex workers; research on woman-to-woman transmission; recognition and
support for lesbians living with HIV/AIDS; and equitable, accessible and
affordable treatment for, and research on, pathogenesis in women.
Additionally, women researchers, program workers, and those living with
HIV/AIDS continued the worldwide coalition building and organizing with
meetings focusing on women's issues and the 1993 International Conference in
Berlin.

      During the conference presentations were made on gender variations in
natural history, progression, and survival; epidemiology; prevention and
transmission; gynecological manifestations; reproductive rights;
maternal-fetal transmission; and access to care.

      In the next section, the issues of gender variations in opportunistic
infections and survival, gynecological manifestations, as well as some
political issues will be addressed. This is a review of data presented in the
last year concerning women and HIV.

      Gender Variations - OIs and Survival

      Several presentations from a variety of countries show that when women
receive standard of care therapies at the same rate and under the same
criteria as their male counterparts, there are rarely significant differences
in the incidence and type of AIDS-defining opportunistic infections OIs),
clinical disease progression, or survival. One study concluded after
enrollment women who were diagnosed with AIDS during follow-up were diagnosed
significantly later (8.2 months vs. 6.9 months) than men would be as
predicted by baseline CD4+ counts. There were no significant differences in
risk of Ols when stratified by baseline CD4+ counts. Overall the estimates
of
survival were the same, however women with less than 100 CD4+ cells at
baseline showed a shorter median survival time (25 months vs. 29 months) than
men did.  

      In women the first sign of clinical progression with CD4+ counts
greater than 200 can be oral or esophageal candidiasis.  Vaginal candidiasis
may occur at any CD4 level and is often a chronic problem, as well as
persistent generalized lymphadenopathy (swollen lymph glands).  Still the
single most common fist AIDS-defining OI in both men and women is PCP.  The
importance of PCP prophylaxis [preferably oral] cannot be overstated - PCP
is
life-threatening and can be prevented in most cases.  Toxoplasmosis occurs
at
about the same CD4 levels as PCP and prophylaxis with Bactrim/Septra for PCP
appears to provide coverage for toxo as well.  Testing for exposure to
tuberculosis should be done on a yearly basis as part of standard of care. 
Women should also consider prophylaxis for other common OIs as CD4+ counts
decline below 100-75 CD4+ cells.  Women should also receive treatment for any
active infections in the same manner as men.  The take home message is women
DO NOT have to die faster.

      The one difference in OIs occurs based on both geography and gender.
In
Africa Kaposi's sarcoma is prevalent in both HIV infected and noninfected men
and women. The incidence of KS in women living in the US is about 1%,   while
gay men often present with KS as the first AIDS defining Ol and may occur
with relatively normal immune status. 

      Gynecological Manifestations

      There were several presentations dealing with the frequency,
usefulness, and reliability of PAP smears and colposcopic exams; the role of
human papillomavirus (HPV) as a cofactor in cervical cell growth
abnormalities; and the relationship of CD4+ counts and gynecologic
manifestations.

      A large study done at Montefiore Medical Center looked at PAP and
colposcopy in 111 HIV+ and 107 HIV- women.  Those with squamous
intraepithelial lesions (SIL) on PAP smear (25% HIV+, 10% HIV-) were referred
for colposcopic exam.  Results indicated that PAP smear reliably predicts
colposcopic findings/histological outcomes.  In both groups standard
gynecological care of early lesions made rapid progression to severe genital
disease uncommon.  In the HIV+ group persistent recurring disease without
progression occurred.  This highlights the need for further research for new
treatments to effect a cure in HIV+ women.  Co-infection with HPV was more
common and somewhat predictive for abnormal cervical cell growth in HIV+
women. Several other papers confirmed the correlation between
genital/cervical disease, HPV, and HIV.

      Another paper presented concluded that in men anal cell abnormalities
and HPV infections of the anus are associated with HIV infection and CD4+
counts of less than 200/mm3. Additionally, smoking (one pack/day) and genital
herpes infection may play a role in progression to cancer. There were thirty
four HIV positive and 28 HIV negative homosexual men enrolled. Of the HIV+
men, 28% showed anal cell abnormalities with 64% having anal HPV infection.
The HIV- men presented with 7% anal abnormalities with a 37% anal HPV rate.
Women should take note of this as there is some indication from studies
presented elsewhere that women develop anal cell abnormalities at the same
or
possibly higher rates than gay men do.

      A large study done at Bronx-Lebanon looked at the relationship of CD4+
counts to cervical cell abnormalities and gynecologic infections in HIV+
women. The most common gynecologic infections were vaginal candidiasis,
trichomonas, bacterial vaginitis and pelvic inflammatory disease (PID).
Advanced cervical abnormalities (CIN I, II, III, & CIS) are associated with
advanced HIV disease as measured by CD4+ counts and disease stage with
abnormalities occurring in approximately half of the women. There was no
association between CD4 counts and gynecological infections.

      Considering all the data presented it makes sense for women to have a
complete pelvic examination every six months as their standard of care. This
is especially true for those who have a history of sexually transmitted
disease (STD) and/or are not using barrier precautions when having sex. The
pelvic exam should include at least a cervical PAP smear and possibly an anal
PAP if there is a history of HPV infection. Follow-up of abnormal PAP results
with colposcopic exam is essential, as is more frequent PAP smears after
treatment for disease. Testing for other STDs should be done at entry into
care with follow-up testing when needed

      "Women die faster" is the most common statement made about women and
HIV/AIDS, however the data clearly shows this is not the case. Women die
faster when they have little or no access to testing or when they do not
receive the same standard treatment and care as men do upon entry into the
health care system .

      There are two messages; the first is women do not have to die faster!!
The second is that "it's never too early to take charge of your health".

      *********

      New Labeling for OTC Products
      
      In June of 1992, the FDA approved the nonprescription sale of creams
and suppositories for the treatment of vaginal candidiasis. These products
include Monistat-7, Gyne-Lotrimin, FemCare and Mycelex-7. These products
contain a warning that states that recurrent yeast infections may result from
hormonal changes or use of oral contraceptives or antibiotics. The activist
community has been actively lobbying the FDA and the pharmaceutical
manufacturers to add an additional warning to the label concerning the risk
of HIV infection in women with chronic or recurring yeast infections. After
much resistance we have won a victory.

      The FDA has asked manufacturers to add the following additional warning
to the package insert: In women with frequently recurrent vaginal yeast
infections, especially infections that do not clear up easily with proper
treatment, the vaginal yeast infections may also be the result of serious
medical conditions, including infection with HIV, that can damage the body's
normal defenses against infection. ' This new label will reach packages on
the shelves within the next month or two. The importance of alerting women
that chronic yeast infections could be a sign of HIV infection can not be
overstressed. In one study it was reported that 38% of women diagnosed with
HIV-related immunosuppression suffered recurrent or persistent cases of
vaginal candidiasis as their first symptom. The same study indicated that the
principle reason that women were tested for the presence of HIV antibodies
was their own perception of risk. This was true for all categories of
transmission, with half of all heterosexual transmission testing being driven
by self perception. Since most studies looking at survival differences in
women and men conclude that if women are tested and then treated in the
earlier stages of infection they will survive as long, perhaps longer, than
men, it is imperative that women with chronic or recurrent yeast infections
seriously consider anonymous HIV testing and seeking primary care if found
to
be HIV positive.

      Elsewhere in this issue is a short article on the new CDC Case
Definition of AIDS.

      **********

      Vaccine Progress
      by Brenda Lein and Jesse Dobson

      AIDS vaccines are being studied in two ways: first for their potential
to prevent HIV infection, as prophylactic or preventative vaccines, and
second for their ability to stop or slow disease progression in people who
are HIV-positive, as therapeutic vaccines. If successful, these vaccines will
offer the possibility of controlling HIV, perhaps without the need for toxic
drugs. Therapeutic vaccines may be the first therapy available for people
with greater than 500 CD4 cells.

      A vaccine is a preparation intended to produce or increase the immune
system's ability to respond to a particular disease. Vaccines are typically
prepared through the use of a damaged virus, part of a virus, a weakened or
"attenuated" virus, or through the use of a full virulent virus. The possible
uses of vaccines for AIDS are varied and many. Influenza vaccines, for
example, are recommended for people who are HIV-positive to prevent flu
infections.[1]  Work is being done on the development of a type of
cytomegalovirus (CMV) vaccine which could potentially prevent relapses of CMV
infection.[2] Extensive effort is being put into the development of a vaccine
that targets the underlying cause of AIDS, HIV infection. AIDS vaccines
currently in development are being studied for their ability to prevent HIV
infection in people who are HIV-negative and for their ability to stop or
delay progression of HIV-disease in persons who are HIV-positive. The AIDS
vaccine furthest along in development in HIV-positive persons is
MicroGeneSys' gp160. Other products, such as Genentech's gp120 vaccine, have
been tested less extensively in HIV-positive persons but are demonstrating
results similar to the MicroGeneSys product. AIDS vaccine products appear to
be safe, toxicities noted thus far are minor, including pain at injection
site and very mild flu-like symptoms. While none of the products currently
being tested are a cure, therapeutic AIDS vaccines may become an important
component in the management of HIV-disease, especially in early stages of
disease while CD4 cells are above 400.

      Most of the AIDS vaccines in development are envelope vaccines, using
part of the viral envelope, for example, gp160 or gp120, in order to elicit
an immune response. gp 160 and gp120 are proteins on the envelope of HIV.
Other vaccines utilize proteins from the HIV core, such as p17 or p24. Once
the virus infects the DNA of immune cells, the immune system has difficulty
recognizing the infected cells, which enables HIV to replicate despite the
initial natural immune response. It is hoped that by introducing a synthetic
viral protein into the system, the production of antibodies to neutralize the
virus and cells directed at killing HIV infected cells will be stimulated to
enhance the body's ability to detect HIV and keep the virus in check. It may
be that the best use of any of these vaccine products will be in combination
with antivirals, such as AZT and ddI and other types of immune based
therapies, such as IL-2 and pentoxifylline.

      What Does The Research Show?

      There are numerous AIDS vaccine products being tested in HIV-positive
individuals.  How some of these products compare to one another is being
studied in a clinical trial about to start in the AIDS Clinical Trials Group.

      An open label study of MicroGeneSys' gp160 vaccine, conducted by Robert
Redfield of the Walter Reed Army Institute, suggests that by utilizing
vaccine therapy it is possible to redirect the immune system and create new
responses against HIV. This is a critical first step in the development of
a
therapeutic vaccine that can effectively create an immune response capable
of
neutralizing the virus. In Redfield's initial dose escalating study of 30
patients with CD4 cells greater than 400, volunteers were randomized to
receive two different dose schedules of gp160. Nineteen of 30 people
developed new immune responses to HIV.[3] Twenty-eight of the original thirty
volunteers reenrolled in a continuation trial and the original
"non-responders" received a series of higher dose injections of gp 160 (640
micrograms). All but one trial participant have since developed new immune
responses to HIV. It is unknown if these responses are beneficial. The
duration of vaccine-induced immune responses varies between people, however.
Study participants have demonstrated proliferation of HIV-specific cytotoxic
lymphocytes, cells that specifically target and destroy HIV infected cells
as
well as a trend toward CD4 cell percentage stabilization.[4] In the course
of
researching therapeutic vaccines it has been noted that the immune system is
much more resilient than previously believed. Even persons with low CD4 cell
counts are developing responses to vaccination and demonstrating increased
immune response and trends toward CD4 cell percent stabilization. Because
this is not a controlled study, however, it cannot be said for certain that
this is a real response to the vaccine. Some of Dr. Redfield's patients have
been on the study drug for over three years and thus far there have been only
minor side effects which include pain at injection site and mild malaise.[5]

      In an open label Canadian study, 21 volunteers were randomized to
receive one of two doses of MicroGeneSys' gp160 [160 or 320 micrograms),
monthly for 5 months to evaluate the safety and toxicity of the product.  All
volunteers tested positive for HIV-1, had CD4 cells greater than 500, were
aymptomatic and p24-negative.  People were not allowed to be on antiviral
therapy or other immune based therapies.  Ninety percent of study volunteers
developed new and broadened immune responses to HIV.  Of those who responded,
all demonstrated absolute CD4 cell count and percentage stabilization or
increases over time.  After two years of follow-up, volunteers have shown a
mean absolute CD4 cell increase of 117 and a mean increase in CD4/CD8
percentage of 2.  Side effects of gp160 were limited to transient pain at the
site of injection.[6]

      In a randomized controlled trial conducted through the NIH, 52 HIV-
positive asymptomatic volunteers with CD4 cells greater than 400 received
either placebo (hepatitis B vaccine) or one of four doses of the
MicroGeneSys' gp160, regardless of dose, demonstrated increased cellular
recognition of HIV and increased cellular anti-HIV activity. Some volunteers
developed cellular recognition of a number of strains of HIV.  Side effects
were minimal and limited to pain at the site of injection.[7]

            It remains unclear which immune responses are
            beneficial to enhance and which are harmful, which
            types of responses should be stimulated and which
            should be suppressed. While these concerns highlight
            the need for further research into HIV disease,
            vaccine development must move forward with these
            concerns unanswered.

      In an open label study of 30 HIV-positive people receiving
MicroGeneSys' gp160 envelope and p24 core vaccines, analysis was conducted
with respect to CD4 cell count.  The study was open to anyone, regardless of
stage of disease.  Fourteen volunteers had CD4 cell counts less than 200 and
sixteen volunteers had counts greater than 200.  Trial participants with
greater than 200 CD4 cells have demonstrated a progressive increase in CD4
cells that peaked at month 5 with a mean increase of 108 over baseline which
at twelve months remain 42 above baseline. Of the fourteen volunteers with
less than 200 CD4 cells, eight died while on study. Of the remaining six
volunteers, there was no significant stabilization of disease or immune
response. There were individuals, however, within this group who showed signs
of clinical stability, CD4 cell count improvements and the development of new
immune responses.[8]

      While these studies look promising, they were not designed to look for
effectiveness, and the majority were not controlled trials. Many healthy
asymptomatic people are stable or have increasing CD4 cell levels. In ACTG
O19, for example, asymptomatic volunteers who received placebo had a mean CD4
cell rise over a two year period. It is important not to draw too many
conclusions about the benefit of vaccine therapy based on CD4 cell levels at
this time. Larger trials designed to look at efficacy will better answer the
question of whether or not vaccine therapy has an effect on CD4 cell counts.

      A double blind placebo controlled trial of Genentech's gp 120,
randomized 42 volunteers to receive one of three doses (100, 300 or 600
micrograms) of Genentech's product or placebo. Preliminary results of the
trial show that volunteers receiving higher doses had stronger responses to
the vaccine and respondents demonstrated cross reactivity to a variety of
laboratory strains of HIV.[9]

      In an early animal study, vaccinated chimps who failed to resist
challenge with HIV were further studied. The infected animals, when
inoculated with a host of different vaccines, including AIDS vaccines,
demonstrated high viral activity after each inoculation.[10] This study
suggested that antivilal therapy should be administered with vaccine therapy.
Preliminary results of a Swedish trial of MicroGeneSys' gp160 demonstrated
that volunteers given vaccine plus placebo did clinically better than
volunteers receiving vaccine plus AZT. In the forty person study, three
volunteers demonstrated an increase in viral load after being administered
vaccine. Two of these volunteers were receiving vaccine with AZT and one was
not.[11] These early results may change with the continuation of the study
and will need to be confirmed with further research.

      Access and Availability

      Therapeutic vaccines are only available through small clinical trials.
Trials enrolling throughout the country. Most of these trials are only open
to people with greater than 500 CD4 cells. Some will be open to people with
as low as 50 CD4 cells, but there will be limited space. Most trials of
vaccines for people with less than 500 CD4 cells will allow concurrent use
of
antiviral therapy.

      At this point there are no expanded access or compassionate use
programs established for people who do not qualify for trials or for people
who live in areas where there are no clinical trials for vaccines.

      Commentary

      There are a number of vaccine products currently in human testing,
including products from MicroGeneSys, Genentech, Immuno AG, and Chiron. Many
questions remain unanswered about the effectiveness of therapeutic vaccines,
despite the enthusiasm of some researchers. Researchers are looking for a
number of immune markers, including antibody production, increases in T-cell
specific response, decreases in viral load and increases in absolute CD4 cell
counts in order to determine the benefit of vaccine therapy . Potential risks
of vaccine therapy include activating cells and potentially making them
targets for infection, activating HIV infection, and enhancing autoimmune
reactions. Results of current studies, demonstrating absolute CD4 cell
stabilization and increases, CD4 cell percentage stabilization and increases
and stabilization in disease progression are clearly encouraging, but are
short term, and show no evidence of the feared problems.

      Testing AIDS vaccine products in people with less than 500 CD4 cells
is
long overdue. A few companies have agreed to add arms to existing trials in
order to begin to get some answers about the benefit of vaccines for people
with low CD4 cells. "Salvage" protocols, or studies which make these vaccines
available to people with low CD4 cells are necessary in order to give people
with HIV more options as well as real answers about vaccine therapy in the
spectrum of HIV disease. By conducting studies in people with lower CD4 cell
levels, it is possible that answers about the benefits of vaccine therapy
will be achieved more quickly, and if successful could lead to earlier
approval of vaccine therapies.

      In October, the Senate Armed Services committee appropriated $20
million to the Army to conduct an efficacy trial of therapeutic vaccines.
This appropriation was advanced by the successful lobbying efforts of
ex-Senator Russell Long, who was hired by MicroGeneSys, the company which is
developing the gp160 product tested in the trials described above. The
legislation stipulated that if the heads of the NIH, the FDA and the
Department of Defense could not agree that such a trial was currently
scientifically justifiable, the money would revert to DoD's HIV research
program. The FDA and NIH held a series of meetings to develop a recommended
design for such a trial . The Army held a separate meeting on this subject.
After much work, the NIH/FDA panel has written a concept sheet for the study.
The design calls for a comparison of three vaccine candidates and a placebo
arm in 12,000 patients with between 200 and 500 CD4 cells. The candidate
vaccines have not yet been identified, but products from MicroGeneSys, Chiron
and Genentech are leading contenders. The group decided this was the best use
of the limited resources, since a study in those with >500 CD4 cells would
take at least five years and would probably be interrupted by the development
of new therapies. The majority of patients will only be followed for changes
in survival on the drugs, while a smaller group (about 500 patients/arm) will
be followed for clinical disease progression and surrogate markers such as 
CD4 or viral load changes.  While Project Inform applauds increasing moneys
for the study of therapies for HIV, we question the methods by which this
appropriation was made. It is probably unwise to bring Congress into the
setting of scientific priorities, especially since it is obvious by this
example that these priorities are easily influenced by outside interests. The
trial as designed will definitely further the understanding of how these
vaccines work and help determine if they have therapeutic benefit. Therefore,
we support the trial, since we have no input into what the Army would come
up
with on its own. The Army has not committed to execute the trial. The panel
also felt it was critical that the manufacturers of the products should
donate them for study. The trial would be conducted in a variety of settings,
including community doctors' offices. The smaller clinical progression
studies would be carried out in existing HIV research networks.

      More aggressive and innovative strategies for vaccine development are
necessary in order to fully realize the best uses of vaccine therapy in HIV
disease. The development of AIDS vaccines puts a magnifying glass on the need
for increased research into the basic science of HIV disease. It remains
unclear which immune responses are beneficial to enhance and which are
harmful, which types of responses should be stimulated and which should be
suppressed. While these concerns highlight the need for further research into
HIV disease, vaccine development must move forward with these concerns
unanswered.
      Several issues need to be kept in mind when deciding whether or not to
participate in a vaccine study. Vaccine trials typically require numerous
visits to the trial site for injections and follow-up lab work after each
injection. Some trial sites have transportation services and childcare
availability, others do not. Making arrangements beforehand and planning for
appointments can make it easier to stay in these trials. Many of these trials
are placebo controlled and there is no guarantee that participants will
receive vaccine. Also, trial participants should be aware that participation
in trials of existing vaccines may prevent them from being eligible for
future anti-HIV trials. As with any trial, you can stop participating at any
time.

      References

      1. Steinhoff, M and others Letters -H Influenzae vaccines in HIV. New
England Journal of Medicine, v. 3226, n. 28, pp 1569-1571, June 4, 1992.

      2. Cino, T and others. Prevention of The Cylomegalovirus Infection With
The Early Administration of Anti-CMV Human Immunoglobulin in HIV Positive
Patients. VIII International AIDS Conference, Amsterdam, Netherlands,
abstract POs 8267, July, 1992.

      3. Redfield, R and others. A Phase I Evaluation Of The Safety and
Immunogenicity of Vaccination With Recombinant gp160 In Patients With Early
Human Immunodeficiency virus Infection. The New England Journal of Medicine,
v 324, n. 24. pp 1677-1684, June, 1991.

      4. Redfield, R.  Active Vaccination. Project Inform's Immune
Restoration Think Tank, oral presentation, April 25, 1992.

      5. Redfield, R and others. HIV Vaccine Therapy: Phase I Safety and
Immunogenicity Using gp160 VIII International AIDS Conference, Amsterdam,
Netherlands, abstract TuB0563, July, 1992.

      6. Tsoukas, C and others Specific Active Immunotherapy in Asymptomatic
HIV-Disease Using Recombinant gp160  VIII International AIDS Conference,
Amsterdam, Netherlands. abstract TuB0560. July, 1992.

      7. Valentule, F and others. A Randomized Controlled Study of gp160
Vaccine in HIV-Infected Subjects. VIII International AIDS Conference,
Amsterdam, Netherlands, abstract TuB0561, July, 1992.

      8. Blick G and others. A Phase 1/ 11 Study of the Toxicity,
Immunogenicity and Efficacy of Recombinant gp160 and p24 Vaccines (Vaxsyn)
in
HIV-infected Individuals Regardless of CD4+ Cell Count. VIII International
AIDS Conference, Amsterdam, Netherlands, abstract TuB0562, July, 1992.

      9. Bird, DL and others. Immunogenicity and Safety of rgp120 (lai) in
Early Stage HIV Positive Patients. VIII International AIDS Conference,
Amsterdam, Netherlands, abstract TuB0564, July, 1992.

     10. Fultz, PN and others. Transient Increases in Numbers of Infectious
Cells in an HIV-infected Chimpanzee Following Immune Stimulation. AIDS
Research and Human Retroviruses, v.8, n.2, pp 313-317, 1992.
     11. Wahrell, B and others. High Affinity and Cellular Immunity By Post
exposure HIV Vaccination. NCI's Tumor Cell Biology Laboratory Meeting.
Bethesda, MD. oral presentation, August, 1992.

      **********

      PML (Progressive Multifocal Leukoencephalopathy)
      by Matt Chappell

      PML is a progressive demyelinating disease of the Central Nervous
System (CNS) that is opportunistic in immune-compromised individuals. PML is
caused by the reactivation of a common papovavirus, the JC. virus (JCV). JCV
infects brain cells called oligodendrocytes. Oligodendrocytes wrap around
nerves to produce myelin, a substance that protects nerves. Without
protection, nerves quickly become dysfunctional. Small lesions may also form.
Inactivated JCV is harbored in the kidneys, but when the immune system
malfunctions, JCV somehow moves to the bone marrow. B lymphocytes transport
JCV to the brain from bone marrow.

      PML probably occurs in 5% of people with AIDS I (estimates are as high
as 7%) but is likely to be under reported. Clinical signs of PML include
generalized or localized weakness of one side of the body or limbs (sometimes
very severe), blurred vision or loss of vision (possibly on one side),
lethargy, and cognitive impairments that may range from language impairments
(aphasia) to memory loss, confusion, disorientation, or a loss of balance.
Symptoms usually progress rapidly. Prognosis following diagnosis is poor and
mortality is likely within one year. Some studies indicate a mean survival
of
4 months.[2]  Approximately 10% of people with PML have recovered with or
without treatment. Spontaneous recovery or stabilization is more likely to
occur in patients with CD4 counts greater than 2003. This unpredictability
presents a perplexing challenge to clinicians treating PML.

      Diagnosis

      Signs of PML include white matter lesions below the outer layer of the
brain, both focal and diffuse. There is a focal loss of oligodendrocytes with
remaining oligodendrocytes in surrounding areas exhibiting enlargement of the
nucleus and nuclear inclusions. Some astrocytes~ within lesions become
infected abortively and become enlarged taking on bizarre cellular
manifestations. Many PML manifestations are similar to toxoplasmosis, CNS
lymphoma, AIDS Dementia Complex (ADC), cryptococcal meningitis, and CMV
infection of the CNS. Therefore, consultation with a neurologist is important
upon onset of neurological symptoms to assure an accurate diagnosis. PML is
most often mistaken for toxoplasmosis. Typically PML may be suspected if
treatments for other complications fail. PML can occur in conjunction with
HIV encephalopathy and toxoplasmosis.

      Leading neurologists agree that a brain biopsy is the most accurate
means of diagnosis of PML. Brain biopsy is becoming increasingly more
important in the accurate detection of neurological complications. Incidence
of brain biopsies may vary due to the reluctance of patients, and the
reluctance of surgeons to operate if they believe that no treatment may be
helpful. Other methods of neurological evaluation remain valuable tools.

      In certain cases, Magnetic Resonance Imaging (MRI) scans may not
adequately distinguish between PML and other complications. Computed
tomographic (CT) scanning may also indicate myelinic abnormalities of CNS
disorders, but is not as sensitive as MRI scanning. Tests for JCV antibodies
in peripheral blood or urine are not a valid means for detection of active
virus, since up to 80% of adults will have JCV antibodies, with or without
HIV infection. Polymerase chain reaction (PCR ) tests are currently being
explored as a possible way to measure the amount of JCV in the cerebrospinal
fluid (CSF).

      PML is difficult to study. Factors that contribute to this difficulty
include the rapid onset of symptoms, similarities to other complications
(usually toxoplasmosis), and the fact that some people spontaneously recover
or stabilize for unknown reasons. Neurological manifestations of HIV
infection are further complicated by the lack of an animal model to test
potentially effective treatments. The National Institute of Neurological
Disease and Stroke (NINDS) is conducting research to develop an animal model
for neurological diseases. Human trials are currently the only means to test
potential agents. The improved ability to diagnose PML by brain biopsy has
increased the reported number of cases, and should allow for clinical trials
large enough to provide definitive answers. Most information concerning PML
treatments now comes from small studies and anecdotal reports.

      Treatment

      As it is now, many doctors assert that PML is not treatable. But some
individuals have responded to various treatments. However, it is important
to
consider that stabilization or partial resolution of symptoms is different
from complete resolution of symptoms; an individual may experience permanent
severe localized or generalized weakness of one side of the body or limbs
and/or permanent impairment of thought and/or movement, even if survival is
extended.

      In some cases, anti-HIV drugs have had some effect. The tat protein
which is translated during HIV replication is able to transactivate PML in
oligodendrocytes.[6] Therefore, the ability of antiviral treatments to slow
the replication of HIV, and consequently inhibit the translation of the tat
protein, may stabilize the immune system and indirectly slow the replication
of JCV. Experienced neurologists who choose to treat PML aggressively begin
with 1000 to 1200 mg. of AZT daily (lower doses are not as effective at
crossing the blood-brain barrier). Doses may be adjusted according to
tolerance. Other antiviral treatments may be substituted if an individual is
AZT-intolerant. The antiviral d4T, now available through an expanded-access
program from Bristol Myers, has been shown to cross the blood brain barrier.
Published reports estimate ddI and ddC are somewhat less permeable though the
blood brain barrier.

      Another compound of potential benefit is cytosine arabinoside (ara-C,
cytarabine), an inhibitor of DNA biosynthesis, currently used as a
chemotherapy for leukemia and lymphomas. ara-C has both antiviral and
antitumor activity. ara-C is commonly administered intrathecally, through a
shunt into the brain, and/ or intravenously. Intrathecal administration,
which requires hospitalization, has shown the most effective results. This
is
due to a low level of enzymatic deaminase in CSF, which quickly metabolizes
ara-C in peripheral blood to a nontoxic form of uracil, ara-U. Unfortunately,
the same low level of this enzyme may necessitate consistent, long-term
cycles of administration to achieve beneficial levels of ara-C in the CNS7.
Experienced neurologists may administer 10 mg/m2 for three days, followed by
10 mg/m2 twice a week for two weeks, then 20--30 mg/m2 weekly. The most
common intravenous dose of ara-C is 2 mg/kg in 5-day cycles, either every 15
days or monthly.

      Side effects of ara-C include nausea, consistent fevers, and bone
marrow toxicity. These effects are dose- and schedule-dependent, and vary in
severity. Ara-C can cause fetal damage in pregnant women. Hematopoietic
monitoring is necessary, including daily platelet and leukocyte counts, and
bone marrow examinations throughout treatment. Some doctors administer a dose
of Granulocyte Colony Stimulating Factor (G-CSF) for one week prior to ara-C
treatment, to relieve bone marrow toxicity. Prednisone may be administered
for inflammatory side effects as well.

      Carolyn B. Britton, M.D. of Columbia University, presented results of
a small study involving 26 individuals diagnosed with PML at the Neuroscience
of HIV conference and the VIII International Conference on AIDS (abstract ThB
1512 ). Dr. Britton treated 13 of 26 PML patients (diagnosed by brain biopsy)
with araC and the maximum tolerated dose of either AZT or ddI. Ten
individuals had CD4 counts under 50; the mean CD4 count of this group was
106, ranging from 7 to 690. Britton reported that eight treated patients
stabilized or improved: four for seven months to two years, and another four
for six weeks to six months. Dr. Britton stated that the individuals who did
not respond to ara-C treatment had large lesions, major deficits, or
brainstem disease. She suggested that a patient with a CD4 count greater than
200 may have a better chance for stabilization of symptoms, spontaneously or
with antiretroviral treatment.

      Other studies indicate that there may be no difference in survival time
with ara-C use, but partial resolution of symptoms may occur with multiple
cycles.[8,9,10,11,12,13,14] ara-C deserves a well-designed clinical trial to
evaluate its efficacy administered both intrathecally or intravenously, and
in combination with various anti-HlV treatments such as AZT, d4T, ddI,
combination regimens, and new compounds such as 3TC. Study design of any
trial for PML is of extreme importance. Researchers need to develop a
structure to adequately study the perplexing complications of PML.

      Another trial evaluated the combination of alpha interferon and AZT,
and produced no observed improvement. Anecdotally, heparin, an anti-
coagulant, may be a potential agent for therapy in combination with other
regimens such as ara-C, high-dose acyclovur, and an antiretroviral regimen.
The theory behind the use of heparin as a therapy for PML is that low doses
will somehow interfere with the mechanism by which B lymphocytes transport
JCV into the brain. The effects of high-dose acyclovir on PML are unknown.
However, the action of acyclovir is specific to Herpes virus therefore, many
neurologists believe acyclovir is not effective against JCV. Future treatment
possibilities may include the HIV tat inhibitor, and genetic therapy such as
an antisense oligonucleotide.

      Recent research presented at the Neuroscience of HIV and Clinical
Frontiers Conference in Amsterdam, Netherlands, July, 14-17, 1992, found
HIV-infected macrophages located in close proximity to JCV-infected
oligodendrocytes[5] in areas of the brain. The tat protein of HIV is able to
transactivate PML[6] in vitro; therefore, a tat gene inhibitor may have value
for treating PML. Future genetic treatments may involve an antisense
oligonucleotide and compounds to inhibit viral binding of JCV both inside and
outside cells.

      As a final note, Peter and Lisa Brosnan of Los Angeles have published
a booklet entitled "PML, Case Studies and Potential Treatments." The booklet
includes case histories, journal articles, and commentary on potential
treatments for PML. For more information, write Peter and Lisa Brosnan, 3031
Angus St., LA, CA 90039, or call (213) 666-0751.

      References

      1. Berger, J. Progressive Multifocal Leukoencephalopathy with HIV
infection. Neuroscience of HIV Infection Basic and Clinical Frontiers 1992.
Abstract page 14.

      2. Berger J and Mucke, L. Prolonged survival and partial recovery in
AIDS-associated progressive multifocal leukoencephalopathy. Neurology 38,
July, 1988.

      3. Britton, C. VIII International Conference on AIDS, abstract ThB
1512.

      4. A type of large non-neuronal cell found in the central and
peripheral nervous systems, astrocytes are found in gray matter and in white
matter in the brain and spinal cord .

      5. Aksamit, A. Interaction of HIV and JCV in the Brain. 1992, abstract
page 68.

      6. Tada, H. Trans-activation of the JC virus late promoter by the tat
protein of type 1 human immunodeficiency virus in glial cells. Proceedings
of
the National Academy of Sciences USA, v. 87, pp. 3479-3483.

      7. Drug Facts and Comparisons 1991 Edition, pp. 2285-2289, J.B.
Lippincott Co.

      8 Sweeney, B. Progressive Multifocal Leukoencephalopathy. p. 137,
poster presentation Neuroscience of HIV Infection Basic and Clinical
Frontiers 1992.

      9. Portegies, P. Response to cytarabine in PML in AIDS . Lancet 337.
pp. 680-681, 1991.

     10. Lidman, C and others. PML in AIDS. AIDS, v. 5, n. 8, pp.
1039-311,1991.

     11. Nicoli, F. Efficacy of cytarabine in PML in AIDS . Lancet 339,
p.306, 1992.

     12. Britton, C. Abstracts from the Neuroscience of HIV Basic and
Clinical Frontiers 1992, page 40, VII International Conference on AIDS,
abstract ThB 1512.

     13. Nicoli, F. Efficacy and treatment with cytarabine for progressive
multifocal leukoencephalopathy. Neuroscience of HIV Basic and Clinical
Frontiers 1992, poster, page 118.

     14. Brosnan, L and Brosnan P. PML case studies and Potential Treatments.
case histories #1,2,5,9.

      **********

      Progress on Opportunistic Infections
      by Denny Smith

      While not the scene of dramatic research breakthroughs, the Amsterdam
Conference was at least a forum for sharing the small steady advances made
possible by a decade of tedious laboratory research and hard-won clinical
experience. Following is a survey of the notable studies of opportunistic
cancers and infections presented in the basic science, clinical science, and
epidemiology abstracts at Amsterdam.

      KS and Lymphoma

      A report from New York renewed a mystery that has concerned experts for
several years. Six of 350 men diagnosed with Kaposi's sarcoma were determined
to be HIV-negative.[1]  Although they were considered to have less extensive
disease than the HIV-positive men, this phenomenon suggests that KS may be
associated with an infectious agent separate from HIV. A German KS study
found that a liposomal formulation of the chemotherapy agent daunorubicin was
less toxic, but somewhat less effective, than a standard three drug
combination of adriamycin, vinblastine and bleomycin for treating advanced
KS.[2]  Other studies from France and the U.S. also reported positive results
with liposomal daunorubicin.[3] Another German report discussed the value of
treating advanced KS with liposomal doxorubicin.[4]

      New liposomal formulations of established chemotherapies are a
promising technology. Liposomes are essentially microscopic globules of fat
that can be impregnated with a particular therapeutic agent; they "deliver"
that agent to diseased tissues more effectively than standard intravenous
formulations, which simply pour into the bloodstream and saturate the entire
body. Consequently liposomal drugs tend to produce less toxicity, if
sometimes less potency. Liposomes have also been studied in combination with
alpha interferon for KS,[5] amphotericin B for leishmaniasis[6] and
cryptococcal infections[7] (see below), gentamicin for MAC, intravitreal
ganciclovir for CMV,[8] and even AZT for HIV infection.[9]

      In a separate daunorubicin study, researchers from Quebec found it to
be an inhibitor of HIV replication.[10]  Interestingly, a number of other
drugs used in AIDS care, including amphotericin, rifabutin and foscarnet,
have also been described as having some anti-HlV activity.

      Studies of lymphoma in laboratory mice as well as in human patients
bolstered the accumulating evidence that the Epstein-Barr virus (EBV) is
implicated in the development of some lymphomas, and that the immune
impairment caused by HIV infection further enhances such development.[11] An
especially interesting U.S. study found that ganciclovir, but not acyclovir,
inhibited lymphoproliferation in laboratory mice who were inoculated with
EBV-involved lymphoma cells.[12] The authors suggest that ganciclovir may
have a role in the prophylaxis and treatment of HIV-associated lymphoma.

      CMV and Other Herpesviruses

      In the ongoing effort to contain cytomegalovirus infection, as well as
the toxicities caused by treating the infection, German researchers reported
the effective use of combined ganciclovir and foscarnet in a three-week
induction therapy, followed by a reduced-dose maintenance regimen which
alternated the drugs every other day.[13]  Another report, from U.S.
researchers, noted that high levels of CMV-specific neutralizing antibodies
prolonged the stabilization of retinitis following treatment with
foscarnet.[14]  They propose further studies administering such antibodies
as
a complementary treatment, an idea already tried with anecdotal success by
some AIDS clinicians.

      For some time now, many physicians have offered acyclovir, as well as
AZT, ddI or ddC, to their patients with CD4 cell counts below 500. While
acyclovir has no demonstrable activity against HIV, it has been considered
effective for preventing or treating flare-ups of herpes and shingles, and
possibly, CMV infections. But according to a joint Australian/European study,
800 mg. of acyclovir given four times daily was found not to prevent CMV
disease in persons with CD4 counts below 150.[15]  These latest studies add
weight to the notion that acyclovir has some beneficial, if poorly
understood, role in HIV intervention strategies.

      In a related U.S. study, published in the New England Journal of
Medicine (January 23, 1992), ganciclovir was compared to foscarnet in the
treatment of 234 people with CMV retinitis.[16] Although no difference was
observed in the progression of retinitis, the foscarnet group showed a
significantly lowered mortality rate-34% compared to 51% in the ganciclovir
group. The implication that foscarnet provides benefits beyond controlling
CMV infection is intriguing, but complicated by the fact that the difference
in toxicities between the two treatments means that more people on foscarnet
can, and in this study they did, take (nucleoside) anti-HIV drugs. In other
words, survival might have been enhanced for anyone who could simply add AZT
to their CMV therapy. Yet even allowing for that advantage, the authors of
this report found a survival difference. Could foscarnet, like acyclovir in
the above study, simply have contributed to the suppression of the "cofactor"
activity of herpes infections? Foscarnet does have effective activity against
other herpesviruses, and in fact is sometimes used to treat serious herpes
infections which no longer respond to the milder acyclovir. Foscarnet is one
of several opportunistic-infection drugs that have been found in test-tube
studies to be active against HIV itself. Dr. Jabs proposes that this activity
on the part of foscarnet, when compared to ganciclovir, may explain the
improved survival found in these individuals. That theory is buttressed by
a
new report in the September issue of The Journal of Infectious Diseases:
a multicenter study of foscarnet maintenance therapy in 22 patients revealed
a sustained decrease in p24 antigen levels (a protein marker for HIV).

      In a development noticed by Project Inform hotline volunteers, but
apparently not addressed at the Conference, some physicians have reportedly
been choosing to delay treatment for CMV eye infections. When asked about
this, Dr. Jabs told us that he sometimes identifies retinitis that has not
approached the macula (that area of the eye responsible for direct vision,
such as for reading) closely enough to be immediately sight-threatening, and
appears to be progressing slowly. Since the benefits of any treatment are
necessarily balanced against the long-term risks, he said patients in this
situation might be offered the option of postponing treatment (and the
attendant toxicities of ganciclovir or foscarnet, such as bone-marrow
suppression or kidney damage). But he warned that any damage caused by the
infection, including loss of peripheral vision, is irreversible, and that
genuine choices for treating CMV retinitis can be assessed only by an
ophthalmologist with HIV expertise, and that these patients' clinical
progress must be checked at least monthly.  Another study, from Germany,
asserted that foscarnet effectively crosses the blood-brain barrier, ensuring
that it would be a suitable treatment for encephalitis caused by herpes or
CMV.[17]

      An exciting report from the U.S. described how "behavioral
intervention" programs of aerobic exercise and stress management actually
resulted in significantly decreased titers of EBV and HHV-6 (another
herpesvirus).[18] The authors refer to the association between HIV
progression and herpesvirus reactivation, and the possible value of these
behavioral interventions to thus affect HIV.

      Fungal Infections

      As mentioned above, amphotericin B is under study in a liposomal
formulation, by at least three pharmaceutical manufacturers. Several studies
at Amsterdam reported liposomal amphotericin to be -- safe and fairly
effective for treating cryptococcal meningitis,[19] and two others reported
the same for treating leishmaniasis.[20]


      A U.S. study described several instances of tracheobronchitis caused
by
infections of the fungus Aspergillus. The authors suggest that itraconazole
may provide an altemative to amphotericin for treating this infection.[21]
A
German report describing the emerging incidence of aspergillosis named
amphotericin (both the conventional and liposomal formulations), flucytosine,
and itraconazole as possible treatments.[22]

      Pneumocystis, Toxoplasmosis,
      Cryptosporidiosis, Microsporidiosis

      Two interesting studies regarding Pneumocystis carinii pneumonia (PCP)
may help refine treatment for that infection. Researchers from Canada and
France found that oral corticosteroids (prednisone) were helpful to persons
being treated for mild episodes of PCP.[23] Corticosteroids are already
well-established as an important adjunct for treating moderate to severe
bouts of PCP. In a Canadian/U.S. study, trimethoprim-sulfamethoxazole
(TMP-SMX, also known as co-trimoxazole, Septra, and Bactrim) was compared to
an experimental antiprotozoal drug, atovaquone, in the treatment of PCP.[24]
Atovaquone was found to be less effective overall than TMP-SMX, but also less
toxic. Subsequently, atovaquone has been approved as salvage option for
treating PCP. (It has also been under study for the treatment of
toxoplasmosis and cryptosporidiosis.) Italian physicians reported five cases
of pneumonia caused not by Pneumocystis but by Rhodococcus equi.[25] They
caution that the relative infrequency of this infection may contribute to its
misdiagnosis, even while its severity possibly qualifies it as an AIDS
"index" diagnosis.

      A U.S. study of new potential agents to treat toxoplasmosis found that
azithromycin, clarithromycin, and atovaquone each had synergistic activity
in
combinations with the older drugs--pyrimethamine, sulfadiazine or
dapsone.[26]  All six of these drugs were known to have anti-Toxoplasma
activity, and this is one more of a number of studies indicating that some
optimal combination of these drugs will probably become a reliable approach
to this infection. Even though combination therapy is considered the ideal,
another U.S. study described clinical stabilization of toxoplasmosis in
eleven of fourteen patients who were given atovaquone alone, after becoming
intolerant of pyrimethamine and sulfadiazine.[27]  TMP-SMX, used as a
prophylaxis against PCP, was reported by French researchers to be associated
with a decreased incidence of active toxoplasmosis.[28]

      The debilitating intestinal infection cryptosporidiosis has always
proved difficult to treat. The current contending therapies include
octreotide (Sandostatin), paromomycin (Humatin) and azithromycin. A report
from Argentina described surprisingly good results in four patients with a
chemical cousin of azithromycin called roxithromycin, a drug that has been
the object of both encouraging and discouraging studies in the past. Results
of extremely small studies must be considered very cautiously, and are not
nearly as dependable as larger, controlled trials. In the Argentine study,
all four patients found relief from diarrhea, and posttreatment stool tests
for the parasites were negative in three of them.[29] British physicians
reported a substantial mean decrease in diarrhea in 34 patients using
aminosidine; later stool examinations found nine to be negative.[30] 
Letrazuril, a new version of the once-promising diclazuril, obtained a
substantial decrease in diarrhea in four Spanish patients who had already
tried other drugs, including paromomycin and octreotide.[31]  Diarrhea
returned in all four when the drug was discontinued.

      Another major diarrhea-causing infection is microsporidiosis. New York
researchers reported a dramatic reduction in diarrhea in five of thirteen
patients who were treated with albendazole.[32]  Again, diarrhea tended to
return when treatment was stopped. Australian physicians found that less than
a quarter of patients with microsporidiosis responded to either albendazole
or metronidazole.[33]

      Mycobacterium avium complex (MAC/MAI), Tuberculosis

      The studies focusing on MAC therapies presented mostly familiar data.
Clarithromycin continues to look useful for treating this infection, although
more likely so in combination with other antibiotics.[34] As a prophylaxis,
rifabutin, which recently received FDA approval for the prevention of MAC,
appears to be effective in inhibiting MAC bacteremia in persons with less
than 200 CD4 cells.[35]  Because MAC is in the same family of diseases as
tuberculosis, and because rifampin, a treatment for tuberculosis, is in the
same family of drug as rifabutin, people considering initiating preventative
therapy with rifabutin should be tested, and if necessary treated, for
tuberculosis prior to beginning rifabutin. For more information on rifabutin,
call the Project Inform Hotline.

      One Belgian and one German report each suggested that when treatment
of
tuberculosis is initially successful, maintenance therapy may be unnecessary
contrary to the case of most opportunistic infections.[36]  The expansion of
tuberculosis in medically underserved communities, especially a drug-
resistant version of the infection, was perhaps the single most ominous topic
at Amsterdam.[37] Especially disturbing was an abstract suggesting that
Mycobacterium tuberculosis may accelerate the progression of HIV.[38]

      HIV seems to enjoy a cooperative relationship with other pathogens as
well. Italian researchers reported that a gene in the Epstein-Barr virus
transactivates HIV, and a Dutch report asserted that Cryptococcus neoformans,
the fungus that causes cryptococcal meningitis, enhances HIV replication in
laboratory cultures.[39]  The authors of the latter report speculated, as
many have before them, that opportunistic infections in general may quicken
the progression of HIV disease. This may relate to cytokine imbalances that
are associated with many infections.

      Neurological Concerns

      Long considered the most challenging of opportunistic infections,
progressive multifocal leukoencephalopathy (PML) is a life-threatening viral
infection of the brain. (See extended article on PML by Matt Chappell in
elsewhere in this issue).

      Although emotional depression is not usually considered
life-threatening, San Francisco researchers found a dramatic correlation
between depression and the rate of decline in CD4 cells.[40] In a cohort of
291 gay and bisexual men followed over a period of four years, clinical
depression preceded a decline in CD4 counts that was 50% greater than that
in
non-depressed men. And although the progression to an actual AIDS diagnosis
was not different, the depressed group nevertheless experienced a greater
mortality--28% vs 19%.

      Unusual Diagnoses, Newly Described Infections

      As is well-known by now, the symptoms of opportunistic infections can
be atypical and misleading. Perhaps the most notorious are symptoms of the
central nervous system and the gastrointestinal tract. In both cases,
biopsies can be the most reliable diagnostic tool, if also the most invasive.
An abstract from Argentina described the usefulness of liver biopsies in 46
patients with fevers of unknown origin and persistently elevated liver
enzymes.[41]  Researchers in Brazil found that biopsies identified
opportunistic infections in 19 (38%) of 50 patients whose symptoms had eluded
diagnosis.[42]  In a third such study, from Germany, 40% of liver biopsies
led to an AIDS-defining diagnosis, and another 40% revealed liver problems
that had not been previously diagnosed.[43]  The collective import of these
studies suggests that the decision to biopsy greatly clarifies the decision
to treat.

      Physicians from two U.S. studies discussed unusual situations of
intestinal disease caused by CMV, including three instances of
gastrointestinal lesions.[44] They warned that the symptoms can mimic
malignancies, and may call for surgical resection of the affected tissues.
On
the other hand, an abstract from Brazil alerted clinicians to the possibility
that retinitis and other ocular problems may not always be caused by CMV
infection. In a study of 146 patients, toxoplasmic retinitis and tuberculous
choroiditis were determined to be at least as common as retinitis due to
CMV.[45]

      Another U.S. study described toxoplasmosis of the lungs in three
patients who had been presumed to have Pneumocystis pneumonia.[46] The
authors urge the consideration of pulmonary toxoplasmosis in persons who have
evidence of toxoplasmic infection and who do not respond to pentamidine.

      Thai researchers described the emergence of infections of Penicillium
marneffei in 41 patients.[47]  The clinical symptoms included cough, fever,
and skin lesions. They propose naming this infection an "AIDS-defining"
diagnosis.

      Azithromycin, one of the most promising new antibiotics for treating
toxoplasmosis, MAC and cryptosporidiosis, was found to be useful for treating
primary or secondary syphilis in persons who cannot take penicillin.[48]

      Bacillary angiomatosis (BA) is an infection that can cause bacteremia,
peliosis hepatis and skin lesions that very much resemble KS. In fact, BA is
often misdiagnosed as KS. Just recently, the bacterium that probably causes
BA was isolated and named Rochalimaia henselae. San Francisco researchers
described pathology work that also implicates a closely related species,
Rochalimaia quintana.[49]  It is now incumbent on AIDS health providers to
familiarize themselves with the manifestations and possible treatments, such
as doxycycline, for BA.

      HIV infection is known to involve the heart in some people, but the
exact incidence and consequence are not very well understood. Portuguese
physicians studying cardiac abnormalities in thirty patients at varying
points of HIV disease found auliculo-ventlicular valve insufficiency in 15,
pericardial effusion in 17, and outright symptoms of congestive heart failure
in three.[50]  Since some heart dysfunction may be asymptomatic, the authors
suggest that persons with HIV receive regular echocardiograms to detect and
treat cardiac problems early. Certain AIDS treatments can themselves be
damaging to the heart; intravenous pentamidine was named in at least two
reports of cardiac emergencies.[51]

      Endocrine, Pediatric Studies

      Encompassing as HIV infection is for adults, it is even more so in
children. During the ages of physical development, HIV poses risks that
adults will have escaped. For example, physicians from Uganda discussed a
study of 386 infants that revealed prominent physical stunting in infected
babies beginning around one and a half months of age.[52]  Rather than
attributing the slowed growth to inadequate nutrition, the authors of the
report thought the stunting was the result of a postnatal neuroendocrine
insult." Another study, from the U.S., offered similar data: following 44
HIV+ children, researchers found them to be smaller in height and weight
percentiles than the uninfected control group.[53] However, the authors of
that report also note that the appearance of individual kids with HIV is
appropriate, since their proportion of weight for height is normal.

      The phenomenon of stunted childhood growth may be mirrored in the role
of endocrine insufficiencies in HIV-associated wasting in adults. Whether
because or in spite of endocrine problems, the children in the Ugandan study
were also generally undernourished, despite continuity of care and
nutritional intervention. An Italian study took these concerns a step
further, saying that since the clinical health of HIV-infected children
declines when their height, weight and endocrine indices decline, the latter
can be used to monitor the course of perinatal HIV infection.[54]

      Various endocrine problems may play a critical role in the metabolic
dysfunction that fosters HIV-related wasting. Nutritional therapies can often
provoke simple weight gain, but tend to do so by increasing fat levels rather
than reversing the loss of cell protein. Growth hormone is known to promote
body cell mass, and San Francisco researchers reported promising results with
the use of growth hormone to treat wasting.[55]

      Swedish doctors presented an abstraet that reaffirmed the emerging
interest in adult endocrine insufficiency. After testing patients who had
symptoms of fatigue and weight loss, they found that insufficient adrenal
production of cortisol was common, and in this group at least, always
associated with some evidence of CMV infection--either retinitis, colitis or
encephalitis.[56]  They added that adrenal insufficiency is easily treated
with hydrocortisone.

      For some time, intravenous immunoglobulin (IVIG) has been given to
children with HIV to protect against various bacterial infections. IVIG has
also been tried in adults for bacterial pneumonias and chronic sinusitis, but
those applications are not as well documented and are sometimes resisted by
insurance providers. Immunocompromised people in general are prone to
bacterial infections, but children are especially susceptible, because unlike
adults, they have not had time to accumulate a dependable reservoir of
antibodies to the many bacteria commonly present in the environment. A U.S.
study of 376 symptomatic children presented at the Conference revealed that
in those with CD4 cells above 200, immunoglobulin not only helped to prevent
bacterial infections, but also curiously slowed the decline of CD4 cells.[57]

The principal author of the abstract, Lynne Mofenson, M.D., spoke with
Project Inform and shared some possible reasons for the serendipity. The
easiest explanation is that by controlling bacterial co-infections,
immunoglobulin was functionally controlling some potential "cofactors" that
enhance HIV-progression--and the consequent loss of CD4 cells. The other
possibilities concern the role of anti-idiotypes (antibodies that develop in
response to other antibodies) and super-antigen in HIV infection.

      Referenced abstracts

      1. ThB 1543 
      2. ThD 1545 
      3. PoB 3106, 3119, 3123 
      4. PoB 3108 
      5. PoB3120 
      6. PoB 3203, 3341 
      7. PoB 3132, 3156, 3706 
      8. PoB3131 
      9. PoB 3024 
     10. PoA 2306 
     11. PoA 2075, PoB 3104, 3128 
     12. PoA 2362 
     13. WeB 1054 
     14. WeB 1053 
     15. MoB 0056 
     16. PoB 3193 
     17. PoB 3189 
     18. PoB 3794 
     19. PoB 3132, 3156, 3706 
     20. PoB 3203, 3341
     21. PoB 3196 
     22. PoB 3337 
     23. WeB 1016 
     24. WeB 1019 
     25. PoB 3169 
     26. PoB 3137 
     27. PoB 3185 
     28. PoB 3166 
     29. PoB 3209
     30. PoB 3229
     31. PoB 3257
     32. PoB 3333
     33. PoB 3344
     34. WeB 1052, PoB 3667
     35. WeB 1055, PoB 3081
     36. PoB 3096, 3347
     37. PoB 3076, 3085
     38. PoA 2154
     39. PoA 2270, 2268
     40. WeC 1031
     41. PoB 3183
     42. PoB3221
     43. PoB 3722
     44. PoB 3195, 3233
     45. PoB 3136
     46. PoB 3236
     47. PoB 3559
     48. PoB 3376
     49. PoB 3339
     50. PoB 3227
     51. PoB 3287, 3320
     52. PoB 3630
     53. PoB 3643
     54. PoB 3659
     55. PoB 3835


      Immune Restoration Think Tank
      by Jesse Dobson

      On the weekend of January 23, approximately thirty of the world's
leading AIDS researchers gathered in Rutherford, CA at the estate of Francis
Ford Coppola to develop a strategic research agenda to restore the immune
systems of people with advanced AIDS. The event was coordinated, organized
and sponsored by Project Inform with the generous support and participation
of Mr. Coppola and his wonderful staff. The meeting was assembled to focus
attention on restoring immunity in late-stage HIV, especially by methods
other than direct antivirals to HIV. This conference shows once again that
Project Inform is not content with merely reporting progress in AIDS
treatment research, but is involved in making this progress happen.

      At the meeting, scientists were divided into small working groups and
given the charge of outlining comprehensive scientific agendas for developing
therapies for immune restoration in AIDS. Each draft approach was evaluated
by the entire group, which then addressed prioritization and implementation
strategies. Meeting participants included government, academic and industry
researchers and clinicians, along with a representative of the FDA and
selected community activists. Steering committees were established to
follow-up on the implementation of the detailed plans. Two approaches were
developed having different time frames (approximately 12 and 36 months) for
implementation. Both combine basic research with clinical trials. Details of
carrying out the plans and coordinating efforts will be directed by the
steering committees through Project Immune Restoration of Project Inform.
These plans offer arational, directed, and most importantly, doable program
for dealing with the immune loss in AIDS. Project Immune
Restoration was established at Project Inform about 2 years ago to help
promote development of immune based therapies for HIV disease. The plans, due
to their different time frames, obviously emphasized different aspects of
immune restoration. The 12 month effort emphasized the optimization of things
that are currently being tested in humans, building upon solid foundations
of
optimal nutrition and antiviral therapy. Agents such as the tat inhibitor and
protease inhibitor would be combined with existing antivirals. Maximum
prophylaxis would also be emphasized, including anti-MAC drugs and unproved
but logical adjuncts like high dose acyclovir and CMV antibody rich IVIG.
Strategies which focused on immune reconstitution include cell line
expansion, which involves removing cells, such as CD8 or CD4 cells, growing
them outside of the body and reinfusing them. If this technology can be
developed, it may be possible to grow cells which have strong anti-HlV
activity, and cells which help protect against opportunistic infections.
Moreover, exploration of anti-TNE compounds, which reduce levels of a
chemical found in the blood thought to increase HIV-replication. was
recommended.

      Like the 12 month plan, the 36 month plan builds upon a solid
foundation of antiviral therapy, encouraging further exploration of
combination approaches. The additional time for the 36 month program allowed
for consideration of additional technologies. The strongest take home message
from this group was the need to store immune cells by cryopreservation
(freezing), especially CD8, CD4, and bone marrow from people with healthier
immune systems (e.g., >300 CD4) for use later, as a person's own cells are
more likely to produce benefit than those from a donor. Despite this,
technologies involving donor cells both from humans and other species were
considered reasonable technologies to explore. These included thymus, bone
marrow and immune cells. Development of genetic manipulation of cells,
especially stem cells, which are considered to be the 'mother of all cells'
as a single stem cell may be capable of differentiating into the entire
spectrum of immune system cells, was felt to be a high priority. This program
also emphasized optimization of prophylaxis therapies. In prophylaxis, the
idea of immunizing a relatively healthy person against HIV (therapeutic
vaccines) and opportunistic diseases, such as CMV, before storing cells may
be an important strategy.

      Scientists at the meeting were enthusiastic about the possibilities
discussed. Nobel prize winner Dr. David Baltimore praised the meeting saying
that such meetings should have been taking place for the last twelve years.
Researchers agreed that focused cooperation was the best approach to
developing therapies. Dr. Robert Schooley of the University of Colorado
added. "This is not a time for pessimism. This is the time for optimism. This
is the time to really use all these new tools in as innovative and
imaginative ways as we can, removing the barriers that have slowed us down
in
the past. "Some researchers felt that other participants would be needed to
implement the plan."  If we don't get the same sort of collaborative support
from the pharmaceutical companies and regulatory agencies, these plans will
be difficult, if not impossible, to move forward at a reasonable speed,"
noted Dr. John Dwyer, an AIDS researcher from the University of South Wales
in Australia.

      Future meetings of the group are scheduled to allow evaluation of the
progress of the existing plans and to bring in new ideas as the understanding
of immune dysfunction in HIV improves. Project Immune Restoration will also
be attempting to bring about the sort of academic, regulatory and industry
cooperation needed for the project. Based on the success of the meeting,
Project Inform is considering sponsoring meetings to promote furthering other
areas of HIV research.

      **********
      Board of Directors

      Curtis Ponzi, Esq., 
      President'

      Joe Brewer, M.S., M.F.C.C., 
      Vice President

      Steve Wilson, 
      Secretary/Treasurer

      Kim Corsaro
      Martin Delaney
      Randy Miller
      Joel Thomas
      Paul Wisokky
      
      National Board

      Lynda Dee, Esq.
      Kenneth Hill
      Adan Rios
      
      Staff

      Executive Director       Founding Director
      Steve Wilson             Martin Delaney

      Accounting               Administration
      Mark Rogers              Bill Stibich
                               Gordon Hibbs

      Advocacy/Publications    Constituent Services
      Brenda Lein              Sue Bradley

      Development & Finance    Hotline
      Bill Rosen               Mark Frey
      David Evans
      Maureen Brownsey

      Outreach                Program/Volunteer
      Alfredo Flores          Ben Collins

      Public Policy           Research
      Anne Donnelly           Tonisa Clardy

      Volunteer Groups

      Grant Management Team
      Hotline Computerization Project
      Hotline Operators
      Institutional Review Board
      Mailing and Otfice Assistants
      Media Comminee
      Project Immune Restoration
      Project OI
      Research and Writing Teams
      Speaker's Bureau
      Treatment Action Network


Copyright San Francisco Project Inform, 1994

Project Inform
1965 Market St., Suite 220, 
San Francisco, CA 94103, 
Offices 415-558-8669
Fax, 415-558-0684
Hotline Number 800-822-7422 or 415-558-9051
Hotline hours: Mon - Sat, 10am - 4pm Pacific standard time.

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