       GMHC Treatment Issues, Volume 9, Number 6 - June 1995
       -----------------------------------------------------
       The Gay Men's Health Crisis Newsletter of Experimental
       Therapies
       -----------------------------------------------------

       Viral Resistance to Protease Inhibitors
       by Theo Smart

       Just a year or so ago, it was commonly held that HIV could
not rapidly become resistant to protease inhibitors. Reports stated
that the mutations could not occur within HIV's protease enzyme
without reducing the enzyme's activity.[1,2] Even when a mutant but
functional protease was created in the test tube that was resistant
to one inhibitor, it remained susceptible to the other compounds.[3]
Later, there were reports that HIV in some patients had become less
susceptible to protease inhibitors after just a few months of
treatment. Multiple mutations within the protease enzymes in HIV
isolated from these patients enabled the virus to resist the drug's
effect.

       The specific mutations, referred to as patterns of
resistance, that occurred depended upon the drug being used, and it
appeared that there were a couple of patterns that rendered the
virus resistant to more than one compound. Worse yet, after
continued therapy on one drug, Merck's MK-639, researchers
discovered strains in a handful of patients that had decreased
sensitivity to all other protease inhibitors in clinical development
at the time.[4]

       Before panic sets in, remember that the degree of resistance
can vary. One strain of HIV may be highly resistant to a drug in the
test tube while a slightly higher concentration of drug may still
suppress another strain.

       There also is next to no information on the relationship
between drug resistance and physical response to the drug. What
information that does exist is puzzling. For example, the
pharmaceutical companies that make protease inhibitors have reported
rises in CD4 cell counts that are sustained after the development of
resistance and the corresponding rebound in viral load. But the CD4
cell counts do start to drop eventually.

       The Evolution of Resistance

       Some researchers believe that resistance occurs when strains
of the virus that are less sensitive to a drug's effects exist prior
to therapy. A second model maintains that resistance evolves during
therapy, when there is less than enough drug available to completely
shut down viral replication. The virus continues to reproduce
somewhere in the body (perhaps in a cell type into which the drug
does not penetrate) and over time, there is a chance that resistance
could occur. Both mechanisms may play a role, particularly when a
slightly resistant virus evolves into a highly resistant strain.

       HIV's reverse transcriptase enzyme is the root cause of
resistance, whether pre-existing or acquired during therapy. The
enzyme constructs new viral genetic material but often makes
mistakes. About ten percent of the time the result is a virus with a
genetic structure (genotype) that differs from the parent virus.
Sometimes, these genetic variations are substantial enough to change
the physical structure (phenotype) of viral proteins and enzymes.
Some of these phenotypes are resistant to drugs currently being used
in therapy. The higher the viral load, the more opportunities there
are for resistant mutants to develop.

       However, drugs may also be inactivated by host resistance,
which has nothing to do with viral load or changes in the virus.
Host resistance occurs when, over time, the body begins to
discriminate against the drugs, sometimes on the cellular level.
This may occur in cellular factors responsible for converting the
nucleoside analogues into their active form.5 For example, a loss of
antiviral activity is often seen with drugs such as ddI long before
the development of resistant virus is detected. Other factors may
also be at work with different drugs.

       Resistance Data

       Merck's resistance data do sound quite frightening. After
trial participants had been on several months of therapy,
researchers isolated HIV that was resistant to MK-639, but within a
year on continued therapy, the virus appeared to evolve
ever-decreasing sensitivity to other protease inhibitors. The
protease enzyme could successfully make multiple mutations, some of
which were not even in the "active" parts of the enzyme -- the part
that snips out the individual HIV proteins from a long string (see
Treatment Issues, March, 1994, page 1). The authors concluded that a
number of pathways to broad spectrum resistance appeared possible.

       However, the data came from only four individuals treated
with MK-639 as a monotherapy. The virus from these patients seemed
to develop increasing resistance that may have been caused by
sub-optimal dosing. When low-level resistance was seen at the dose
that was too low to be completely effective to begin with, the dose
was raised, but it clearly was not raised enough. This happens to be
a classical way to induce higher levels of resistance to a drug.

       A study from the Aaron Diamond Institute in New York City,
presented at last January's Conference on Human Retroviruses,
reported that high-level resistance to every protease inhibitor
currently in clinical trials could be bred in the test tube.
Investigators could do this by exposing the virus to drug levels
that were not quite enough to completely suppress it. Once they
produced a resistant strain of virus, they increased concentrations
of drug just slightly. After repeated exposure to increasing
concentrations of any single protease inhibitor, the researchers had
produced phenotypes that were less sensitive to almost every known
protease inhibitor.[6] But outside of an occasional clinical trial,
no one administers drugs to people in this manner. It is unknown
what will happen to people who start out on optimal doses of drug or
who take protease inhibitors in combination with other drugs.

       Patterns of Resistance

       Aside from high-level cross-resistant phenotypes, data show
at least three, and probably more, general patterns of resistance to
protease inhibitors. One phenotype confers resistance to saquinavir,
as well as decreased sensitivity to VX-478 (the
Glaxo-Wellcome-Vertex compound), and SC-52151 (Searle's failed
compound). Virus resistant to saquinavir is also three-to-five fold
less sensitive to Agouron's AG1343, which has just been reported to
show antiviral activity in people (see box, page 4). However, the
initial HIV mutations that resist AG1343 in the test tube are not
the same ones conferring resistance to saquinavir.

       Still another series of mutations reduces susceptibility to
the Merck, Abbott, the NCI/Kyoto Pharmaceutical and DuPont Merck
compounds. Other compounds on the horizon such as new drugs from
Upjohn and Searle may induce other mutations. Data on the pattern of
resistance to Upjohn's compounds seen in the test tube will be
presented at an upcoming conference. There is now evidence that some
resistant phenotypes may be pre-existing. Noel Roberts of
Hoffmann-La Roche has reported that blood samples from nearly ten
percent of the patients entering saquinavir studies already
possessed HIV with mutations that are involved in resistance to the
Merck/Abbott group of compounds, and some had mutations associated
with reduced sensitivity to AG1343. He has not found pre-existing
resistance to saquinavir, although after a year of therapy, half of
the patients have HIV with mutations in response to saquinavir.[7]

       Saquinavir appears to lose its antiviral effect in people
before the virus becomes resistant, though. It is unclear what
causes this, but it may be host resistance, or a decrease in
absorption of the compound over time. This may also happen to other
protease inhibitors in development.

       Informed Treatment Decisions

       Up to now, the only access to protease inhibitors has been
through clinical trials, but soon there will be limited expanded
access programs (see page 3), and by the end of the year, saquinavir
may even be approved. In light of the confusing information on
resistance, it is difficult for people with HIV to make informed
decisions about utilizing protease inhibitors in treatment regimens.

       Here is what we know: Resistance to protease inhibitors taken
alone is possible. It happens faster in people with higher viral
loads. If you become resistant to one drug, there are probably at
least a few others to which you simply will not respond. There is
also a remote possibility of insurmountable high-level
cross-resistance to most or all protease inhibitors.

       Many researchers often compare HIV disease to tuberculosis as
both HIV and the tuberculosis bacterium tend to become resistant to
drugs. If they are right, the development of resistance to protease
inhibitors -- the most potent antivirals yet seen -- is indeed cause
for serious concern. When drugs were first being developed for TB,
many were studied as monotherapies. Some worked well for a couple of
months, but then resistance developed. Eventually, it was determined
that combination therapy could permanently keep TB in check.
Tragically, the people who had developed resistance to one of the
available TB drugs derived less benefit from the early combinations.

       Protease inhibitors may face a parallel challenge from HIV.
Taking one drug as a monotherapy may mean losing the opportunity to
use that drug in the future in a potentially more effective
combination strategy that extends the health benefits of available
therapy.

       It must be the right combination of drugs since an inferior
mix may have little effect or could be toxic. The right combination
may significantly delay the development of resistance, but it may
take an almost complete suppression of the virus to achieve this.

       The catch is that we do not know whether such a combination
can be created from the current range of available drugs, whether
protease inhibitors or others. It is unforseeable how long it will
take to develop a really effective combination. And the longer an
individual waits, the higher his or her viral load becomes and the
greater the chance for drug- resistant HIV strains to arise.

       Protease inhibitors may indeed turn out to be a dramatic step
forward in the treatment of AIDS. This is all the more reason to be
careful about how they are used until clinical studies provide us
with more information.

       References

              1 El-Farrash MA et al. Journal of Virology. Jan 1994;
       68(1):233-9.

              2 Sardana VV et al. Biochemistry. Mar 1 1994;
       33(8):2004-10.

              3 Otto MJ et al. Eighth International Conference on
       AIDS Jul 19-24 1992;.1(abstract ThA 1505):Th66.

              4 Condra et al. Nature. Apr 6 1995; 374(6522):569-571.

              5 Antonelli G. AIDS Research & Human Retroviruses. Oct
       1992; 8(10):1839-44.

              6 Mo H et al. The Second National Conference on Human
       Retroviruses and Related Infections. Jan 29-Feb 2 1995;
       (abstract 188):89.

              7 Noel Roberts, Personal Communication. Feb 2 1995.

       ************************************
       The Next Wave of Protease Inhibitors

       Three of the newer protease inhibitors are particularly
interesting in light of cross-resistance, either because they
achieve levels in the blood that may overwhelm low-level resistance
(Agouron's compound) or because data suggest that they will not be
cross-resistant with compounds in current clinical trials (Searle
and Upjohn's products).

       Agouron's AG1343

       Data from a study of AG1343 in people with HIV is beginning
to trickle in. The only information that the company has formally
released comes from the first patient to complete a phase I study.

       "Patient 001" came into the study with oral leukoplakia, a
CD4 cell count of 368 and a plasma HIV level around 40,000 copies
per ml. After two weeks on drug, his HIV level had dropped by 99 to
99.7 percent, and his CD4 count went up by 120. At 28 days, patient
001's viral load was undetectable by current tests and his CD4 count
was up by more than 300 cells. His oral leukoplakia had resolved.

       Agouron will not release surrogate marker data on other
patients in the study, but Dr. Neil Clendeninn, Vice President of
Clinical Affairs, did comment that: 1) some responses were more
modest than what was seen in patient 001, although his response was
not unique; and 2) he has yet to see resistance in people or any
rebounds in viral load. Also, two patients had resolutions of severe
seborrheic dermatitis and one patient's recurrent oral candidiasis
went away. Researchers have not observed any serious side effects,
Agouron claims.

       Searle's S338

       Searle will not discuss the status of its compound or whether
it is even still in the game since its first generation drug failed.

       Upjohn

       Upjohn's protease inhibitors are small molecules and should
be much easier to manufacture than most other protease inhibitors.
It is too bad that two of these compounds have already failed in
preliminary clinical studies. The most recent compound was toxic to
the liver. Extremely high doses (up to eight grams a day) were
required because this class of compounds has a high affinity to the
human blood protein albumin. This binding inactivates the drug and
increases the blood levels needed to achieve an antiviral effect.
The company hopes that a third, and reportedly much more potent,
compound will be in human studies soon. It is undergoing toxicity
testing in animals at present.- TS

       **********************************
       Protease Inhibitor Expanded Access
       by Theo Smart

       The makers of the protease inhibitors furthest along in
development insist their drugs are so difficult to manufacture that
they barely have enough for their clinical trials, not to mention
expanded access. Nevertheless, Merck and Hoffmann-La Roche have now
announced small access programs (Roche's is the larger one with
slots for 4,000 persons), while Abbott, whose drug supply problems
are supposedly not as great, has refused. Abbott's stance finally
provoked an activist response.

       Hoffmann-La Roche/Saquinavir

       Hoffmann-La Roche plans to open a worldwide 4,000-person
compassionate use protocol of saquinavir in August, 1995. Slightly
over half (2,280) of the participants will be in the U.S. Sixty
percent of the slots will be for people with CD4 cells below 50. The
remainder will be in people with CD4 cell counts between 50 and 300.
Since the company anticipates more demand than supply, the slots
will be distributed through a lottery system. Gail Levinson of Roche
says the company hopes to increase the size of the study as more
drug becomes available. Physicians who want to register patients can
call 800/332-2144.

       The program is significantly different in Canada, which is
only allotted drug for 96 people. It is open to anyone with HIV
older than thirteen, regardless of CD4 cell count. A tier system
will be implemented to distribute the drug first to those most ill.
The first tier will be patients with less than 50 CD4 cells and two
concurrent opportunistic infections. Interested Canadians can call
800/257-3741.

       The allocations of drug in both the U.S. and Canadian systems
were devised with input from representatives of the respective AIDS
communities. It is interesting to note the differences in
priorities.

       Merck/MK-639

       Merck initially claimed it would not have enough drug for
expanded access, but the company unexpectedly found enough drug for
1,400 people. Merck's program is an adaptation of a 300-person study
in individuals with less than 50 CD4 cells, which is starting this
month (see table). A new study arm will be open-label MK-639 for
patients who are intolerant to AZT or who have been on 3TC for an
extended period (which is not defined). The first participants
should receive drug sometime in August, and Merck plans to enroll at
least 1,400 by end of the year.

       Abbott/ABT-538

       Abbott has not announced plans for expanded access. The
company is running a study in 900 people with less than 100 CD4
cells, and after four months on study, everyone will get ABT-538.
This did not satisfy an ad hoc Protease Working Group (PWG), made up
of representatives of major AIDS organizations including Treatment
Action Group (TAG), GMHC, ACT UP/New York and ACT UP/Golden Gate. In
May, the PWG called for a week-long fax zap of numerous Abbott
officials. Jules Levin of the PWG said the company has since
communicated that it is considering expanded access and should give
the community an answer by July. Depending on the company's
response, further action is contemplated.

       In the meantime, members of the community are still urged to
contact Abbott and express their feelings about this matter. Fax
Andre Pernet, Abbott Laboratories vice president for pharmaceutical
research, at 708/938-1797.

       Others

       Most of the newer protease inhibitors, such as Agouron's,
Upjohn's and Vertex's, are in early stages of development, but are
reputedly much easier to manufacture than the older drugs.

       AG1343 has shown antiviral activity in people and seems
poised for rapid clinical development. Representatives of Agouron
have stated that the company intends to implement a program
eventually, contingent on drug supply. Although Agouron is well
funded, it owns no production facilities. The company is currently
negotiating manufacturing arrangements with other companies.

       New and Improved Saquinavir Formulation

       Saquinavir is one of the most potent protease inhibitors in
the test tube, but not in people. The poor bioavailability
(absorption) of saquinavir is probably to blame. Roche now has a new
"enhanced oral formulation" (EOF) that is reportedly seven times
more bioavailable.

       "The 600 mg three times a day dose [of the current
formulation] is probably not the optimal dose for monotherapy,"
according to Miklos Salgo, Roche's Director of Clinical Research and
Virology. Why didn't Roche wait until the EOF was available? "We
want to get the 600 mg dose approved first. If we had to wait for
the EOF, we will be the number eight or number ten protease
inhibitor."

       To get the EOF approved, Roche needs safety data on several
hundred patients for six months. Initial dose-ranging studies will
start in July. The next study will begin in November and evaluate
the safety of the EOF combined with nucleoside analogues.

       ****************
       Washington Watch
       by Derek Hodel

       FDA Reform Floated in DC

       Legislative proposals to significantly reshape the mandate of
the Food and Drug Administration (FDA) are now receiving serious
attention in Washington. Many of the proposals capitalize on the
current Republican drive to deregulate American industry and to
reduce federal bureaucracy. Although such deregulation has long been
a goal of the pharmaceutical and medical device industries, some of
the changes now under consideration would, if implemented, reshape
the agency to a greater extent than at any time since the Kefauver
Amendments were passed by Congress in 1962. (This legislation first
vested the FDA with the responsibility to ensure the efficacy of
drugs in addition to their safety. It is the cornerstone of drug
regulation today.)

       AIDS activists will occupy an unusual position in this
debate, as much of the charged rhetoric now employed by the
conservative right substantially echoes the arguments crafted by the
activists themselves during past well publicized debates with the
agency concerning the approval of AIDS drugs.

       Many activists are understandably ambivalent about rushing to
the defense of the government agency that had been the focus of
their ire only a few years ago. But most AIDS organizations also
agree that their intention was never to debilitate the agency, and
like many more traditional consumer groups, they are now worried
that the so-called reform proposals would do just that -- and what
is worse, might actually diminish the number of effective drugs
developed in the future.

       Accordingly, many AIDS groups, including Gay Men's Health
Crisis as well as ACT UP (New York and Golden Gate chapters), AIDS
Action Council, American Foundation for AIDS Research, Human Rights
Campaign Fund, National Minority AIDS Council, Pediatric AIDS
Foundation, Project Inform and Treatment Action Group (TAG), have
formed an ad hoc coalition to participate in the FDA reform debate.
The group is drafting principles for evaluating FDA reform proposals
from the standpoint of people with life-threatening disease.

       Although the FDA has always claimed a mandate to advance the
public health, the responsibility to keep harmful products off the
market has always taken precedence over ensuring that helpful
products reach the market. Of course, the consequences of the former
are also much more immediate and severe -- rarely do Congressional
hearings or media exposs concern drugs that have yet to reach the
market.

       Now the balance is starting to shift the other way. Many of
the current suggestions for reforming the FDA would significantly
alter its authority. To date, proposals have been advanced mainly by
conservative think tanks and drug industry associations. Also, Rep.
Ron Wyden (D-OR) has just introduced the "FDA Modernization Act of
1995" (HR-1742). Among the items under discussion are measures that
would:

       *  Shift more efficacy studies to a "post-marketing" setting.
          The FDA's determination of efficacy (whether a drug
          "works" or not) is, in some ways, a judgment call.
          Clinical trials after a drug is approved are called
          post-marketing studies. Most are designed to study side
          effects that occur so infrequently as to go unnoticed
          during clinical trials. By approving drugs earlier (when
          less efficacy data are available), many more people could
          take the drug, even though substantially less would be
          known about its effects.

       Pros: Drugs reach the market much faster, so more people have
       access sooner.

       Cons: The risks are greater, because many more people take
       drugs with even less data about the tradeoff between hazards
       and benefits in new drugs.

       *  Utilize local Institutional Review Boards (IRBs) to review
          proposals for the early human testing (phase I clinical
          trials) of drugs. Presently, the FDA must approve an
          Investigational New Drug Application (an IND) before a
          manufacturer (or research scientist) can conduct studies
          in humans. Additionally, a local IRB (usually composed of
          scientists, physicians, ethicists, clergy and lay persons)
          must examine and approve the human subjects protections in
          all human research protocols. Current reform proposals
          would shift to local IRBs the whole responsibility to
          evaluate INDs.

       Pros: More than half of the INDs under review at the FDA are
       submitted by individual research scientists who are seeking
       to increase knowledge about a given drug. The considerable
       FDA resources allocated to these reviews could be diverted to
       more critical questions.

       Cons: IRBs are not currently constituted with appropriate
       expertise (animal toxicologists, for example) to evaluate
       critical data prior to commencing initial human studies.
       Additionally, local IRBs sometimes reach contradictory
       conclusions -- employing them to review INDs would subvert
       national coordination of drug trials.

       *  Privatize certain drug safety reviews, by relegating them
          to independent testing or accrediting institutions. Many
          proposals would shift responsibility for determining a
          drug's toxicology (and thus safety), a critical early part
          of the review process, and other manufacturing standards
          to private vendors, much like Underwriter's Laboratory
          evaluates the safety of electrical appliances.

       Pros: Much of the backlog at the FDA is a result of these
       early, often technical reviews -- privatizing them could
       significantly speed the process.

       Cons: It is difficult to establish independence and avoid
       conflict of interest in for- profit organizations.

       *  Permit the promotion of FDA-approved drugs for "off-label"
          uses. In general, drugs are approved by the FDA for a
          narrow range of use, specified in the so-called label
          indication. Doctors, however, are free to prescribe
          FDA-approved drugs for uses not described in the label or
          validated by the FDA. Such "off-label" use is not only
          common, but for many diseases represents the
          standard-of-care. Manufacturers are prohibited from
          promoting off-label uses of drugs, however, and must apply
          again to the FDA before modifying a label to include a new
          use. This prohibition prevents manufacturers from making
          unsubstantiated claims, but critics claim that doctors and
          patients are denied state-of-the-art information
          concerning the clinical application of drugs.

       Pros: Because manufacturers have an incentive to promote the
       use of their products, up-to-date information concerning
       innovative uses of approved drugs would become available much
       more quickly.

       Cons: As described earlier, the determination of efficacy is
       not absolute, but rather represents a subjective decision
       that balances risk and benefit -- leaving the decision in the
       hands of manufacturers seems to invite conflicts of interest.

       *  Impose statutory time limits on FDA reviews. Most FDA
          reviews are already subject to statutory time limits, some
          of which the agency habitually misses. Most analysts agree
          that the problem is a result of insufficient resources,
          not statutory deficiencies.

       *  Improve harmonization with international standards.
          Because the FDA maintains the highest standards for drug
          safety and efficacy in the world, drug approval in the
          United States is often out-of-sync with the international
          community. In a majority of cases, drugs are approved
          abroad before the FDA allows them in the United States. By
          agreeing with other countries to jointly review drugs, or
          to use common standards, the FDA could utilize safety and
          efficacy data generated overseas.

       Pros: The duplication of efforts in multinational drug
       approvals would surely diminish, speeding up the drug testing
       process and saving manufacturers money.

       Cons: The FDA rejects foreign data in part because it is
       unable to sufficiently monitor the quality of foreign
       clinical trials. International agreement would likely require
       extensive negotiations and oversight.

       *  Remove export barriers for non-FDA-approved drugs.
          American companies currently are prohibited from exporting
          drugs that are not licensed by the FDA, regardless of
          whether they are approved for use in the country of
          import. Present proposals would remove these barriers.

       Pros: Business opportunities for American manufacturers would
       increase substantially. The United States would respect other
       countries' sovereignty in setting their own standards for
       safety and efficacy.

       Cons: There is a risk that the United States could be held to
       blame for dangerous drugs that are exported as a result of
       weak international standards.

       Although administrative agency reforms are all the rage in
Washington, the authorizing committees in both the House and Senate
seem to harbor particularly focused, long-standing resentments
toward FDA Commissioner David Kessler. Kessler enraged many
tobacco-state members (including Thomas Bliley, R-VA, now chair of
the House Commerce Committee) by his attacks on cigarette
manufacturers. Speaker Newt Gingrich clearly has the commissioner in
his sights when he claims that the "FDA is the biggest job-killer in
America." How far reforms go is still up in the air, but it is safe
to say that insofar as AIDS activists sparked much of the discussion
in the first place, we will continue to play a major role in the
debate.

       Derek Hodel is GMHC's director of federal affairs.

       ****************
       Treatment Briefs
       by Dave Gilden

       A Monumental Struggle for Sufficient Nutrition

       As Treatment Issues went to press last month with a long
section on therapies for AIDS-related wasting, a study appeared in
the Journal of Acquired Immune Deficiency Syndromes (R.S. Hogg et
al., June, 1995) that indicated just how desperate are the body's
efforts to replenish its nutritional stores during HIV infection.
The study was based on questionnaires filled out by HIV-positive gay
men without clinical AIDS and HIV-negative ones participating in the
Vancouver [Canada] Lymphadenopathy-AIDS Study (VLAS). The men were
interviewed about their diet over the previous 24 hours.

       The HIV-positive men reported a 24-hour consumption of 2,239
calories versus 1,989 calories for the negative men. The
distribution of calorie intake among protein, fat, carbohydrates and
alcohol was the same for the two groups. Average weight was stable
over the last year in the two groups, but at the time of the
interviews, the HIV-positive men weighed five percent less than the
HIV-negative men, and their body mass index, a measure of the lean
tissue to fat ratio, was four percent less. There were no
differences in food consumption or composition between men with less
than or more than 200 CD4 cells per milliliter of blood.

       The authors concluded that the HIV-positive men should have
weighed ten kilograms (22 pounds) more assuming that their reported
diet had been the same over the past year. They considered the fact
that they did not a sign of the increased basal metabolic rate that
occurs during chronic HIV infection. These men also had already lost
a disproportionate amount of their lean tissue despite adequate
protein intake. Nutritionally, these relatively healthy men with HIV
were precariously balanced. Any subsequent illness that made it hard
to eat or absorb nutrients, or just placed additional metabolic
demands on the body, could have disastrous consequences in terms of
wasting.

       R U Ready for This?

       Cortisol is an important glucocorticoid hormone secreted by
the adrenal gland to moderate stress. Among other things,
glucocorticoids promote the breakdown of protein stores in the body
to produce sugar (glucose) and can decrease the immune system
activity. Cortisol levels are high in people with HIV infections,
and the hormone has been implicated in wasting syndrome. In
addition, blocking cells' glucocorticoid receptors was found
recently to reduce the proliferation of Kaposi's sarcoma tissue
(W.X. Guo and T. Antakly, American Journal of Pathology, March,
1995). Now a study has found that blocking these receptors also
might inhibit HIV itself.

       The HIV study, by a group of University of Pennsylvania
researchers (Y. Refaeli et al., Proceedings of the National Academy
of Science, April, 1995) investigated the function of the Vpr
protein, produced within cells by a relatively obscure HIV
"accessory" gene. Vpr appears to mildly stimulate HIV replication by
combining with the long terminal repeat genetic sequence at the end
of the HIV gene set. The researchers have deduced that Vpr forms a
complex with a cellular protein they call Rip and the intracellular
receptors for glucocorticoids. The complex is able to transport Vpr
into the cell nucleus where the HIV gene set resides.

       This process seems to be promoted by synthetic
glucocorticoids such as dexamethasone. In laboratory cultures, HIV
production was reduced 70 percent by a glucocorticoid receptor
blocker -- RU486. RU486 is well known for its use as an
abortion-inducer. Pressure from anti- abortion groups has delayed
its availability in this country.

       To underscore the fact that nothing concerning HIV is ever
straightforward, a group of French researchers reported in March
(J.M. Andrieu et al., Journal of Infectious Diseases) on successful
results from a preliminary trial of glucocorticoid therapy in HIV
infection.

       Forty-four asymptomatic trial participants with CD4 counts
between 200 and 800 took 25 to 40 mg of the drug prednisolone daily,
depending on their weight. After one year, no major new disease had
occurred. CD4 counts were up by an average of 119. Immune activation
markers were down while tests of immune function held stable.
Interestingly, HIV levels did not decrease in response to therapy
but remained constant.

       The researchers noted a decrease in spontaneous cell death
(apoptosis) in peripheral blood mononuclear cells (lymphocytes and
macrophages). They felt this effect might be a major reason why
glucocorticoid therapy had beneficial results in the face of
unchanged HIV levels.

       *********************
       Future of ICC Debated
       by Theo Smart

       The Inter-Company Collaboration for AIDS Drug Development
(ICC) was created with great fanfare over two years ago. Its purpose
is to foster cooperation between pharmaceutical companies with
antiviral drugs in clinical development so as to more rapidly
develop therapies for people with AIDS. At a meeting with community
representatives on May 11, 1995, the ICC presented an update on the
organization's recent activities, including advances in
collaboration on basic research, a review of the ICC's current
clinical trial program, and a discussion of alternative trial
designs to rapidly find the more active antiviral combinations.

       Basic Science

       The companies of the ICC have made a commitment to extend
their collaboration into basic research. They agreed that: 1)
companies would share animal models they develop; 2) they will share
biologic data (lab samples) for drug resistance studies; 3) they
agree to exchange biochemical assays (drug screening tests); and 4)
companies will share data on compounds that failed in pre-clinical
development, to help keep other companies from repeating similar
mistakes.

       Clinical program

       ICC-001 is the first of the ICC's proposed clinical studies
evaluating the surrogate marker effect of two separate three- drug
combinations, AZT/ddC/Invirase and AZT/ddC/nevirapine compared to
AZT/ddC, in 225 patients. The rate of accrual has been very rapid,
and the trial is now fully enrolled, although the number of female
participants is quite low. Representatives from the community are
forming a committee to find solutions for this problem.

       ICC-002 is scheduled to begin enrolling June 12. It compares
AZT/ddI/nevirapine and AZT/ ddI/3TC to AZT/ddI, again in 225
patients. For the location of the nearest trial site, call the
National AIDS Clearinghouse at 800/TRIALS-A.

       Alternative Trial Designs

       Two activists at the meeting were given an opportunity to
propose clinical trial designs for the ICC's consideration. Jules
Levin recommended that the collaborative run combination protease
inhibitor studies, specifically of Merck's MK-639 and Roche's
Invirase (saquinavir). Representatives from the two companies said
they plan to do that, but not until the new formulation of
saquinavir (designed to be better absorbed) is ready for clinical
development (next year at the earliest).

       Bill Bahlman proposed that the ICC run open-label studies of
a new three-drug combination in 30 patients every month in order to
quickly discover more potent combination therapies. Each study would
last six to ten weeks, and would include groups with CD4 cell counts
greater than and less than 300. To be considered successful, a
combination would have to be safe and show dramatic activity
(reducing viral load, and boosting CD4 cells) in 70 to 90 percent of
the study participants. The degree of activity that would be
considered dramatic remains to be defined.

       The community members present were very supportive of the
concept in principle. However, some voiced concerns that if a new
three-drug combination is not compared to a two-drug combination,
there would be no way of telling whether the addition of the third
drug was helpful or harmful. Also, since it is unknown whether the
magnitude or duration of antiviral effect is more important for
clinical benefit, such short-term studies could reject important
combinations with less effect on viral load but a longer period of
activity than some other combinations. (The Treatment Action Group
is now drafting a variation of this proposal that addresses these
concerns.)

       David Barry, M.D., of the Burroughs Wellcome Co. (and chair
of the ICC's clinical trials subcommittee) felt that Mr. Bahlman's
concept could be accepted by the ICC with slight modifications, but
only if it were run in people with HIV resistant to AZT. He said
that he would draw up his proposal and present it to the ICC's
members at the consortium's next meeting, slated for June.

       Dr. Barry also presented a proposal to establish an
observational database that would gather data on every person with
HIV under treatment by a physician. He suggested the creation of a
standardized data collection form for use by AIDS care providers.
Each patient could be given a fourteen digit code (to protect
confidentiality) and his or her medical history entered into the
national database.

       [Dr. Barry resigned from Burroughs Wellcome as Treatment
       Issues went to press. It is unclear how his departure will
       affect ICC plans.]

       ****************
       Reappraising d4T
       by Gabriel Torres, M.D.

       d4T (also known as stavudine or Zerit) may be getting a new
lease on life with the recent release of new data showing its
beneficial effects in patients with prolonged previous treatment
with AZT. The FDA approved d4T (a nucleoside analogue like AZT) in
June, 1994 as a second or third line agent for patients with a
history of intolerance or failure on AZT therapy. The agency based
its action on a preliminary analysis of a randomized trial comparing
the two drugs, which showed a beneficial effect on surrogate markers
(CD4 counts and HIV levels). The data available at the time may have
underestimated d4T's value.

       Final Analysis of the 019 Study

       The final analysis of this trial, known as 019 and sponsored
by the d4T's developer, Bristol-Myers Squibb (BMS), was recently
announced at a meeting in San Francisco. This double-blind
randomized trial enrolled 822 people with HIV and CD4 counts between
50 and 500 and at least six months of prior AZT therapy.

       The primary endpoint of the trial was treatment failure,
defined as a drop in CD4 count to 50 percent of baseline, a new or
recurrent AIDS-defining event or death. Ninety-two percent of the
patients were followed for two years, even after the development of
a clinical or CD4 cell endpoint.

       The trial participants who received d4T remained on the drug
longer than those continuing to receive AZT (79 versus 54 weeks).
The results of the comparative analysis demonstrated that the time
to treatment failure was longer for those on d4T, as was the time to
AIDS-defining events or death. This delay in clinical disease
progression had not been seen in trials involving switching from AZT
to ddI, ddC or combination therapy with AZT and ddC. Time to death
(survival time) alone was prolonged by switching to d4T, although
this difference was not statistically significant.

       The rates of peripheral neuropathy were higher for d4T (ten
percent) than for AZT (four percent) as were the rates of liver
enzyme elevations, but there were more cases of bone marrow toxicity
(anemia and neutropenia) among those receiving AZT. No differences
in the rates of pancreatitis were observed.

       In terms of quality of life, the group taking d4T scored
better in all areas than those taking AZT. The daily functioning and
well-being of those switched to d4T were improved, and they reported
fewer drug reactions overall with less asthenia (weakness),
anorexia, abdominal pain, nausea/vomiting and anemia in particular.

       Parallel Track

       Other important d4T data are those from the parallel track
program which enrolled 12,551 patients between October, 1992 and
May, 1994 by 1,244 physicians who enrolled patients from their
offices. This large simple trial compared two doses of d4T (20 and
40 mg twice daily) and measured survival as its primary parameter.

       Participants were 94 percent males and only sixteen percent
non-white, demonstrating again the lack of access of expanded access
trials to women and minorities. The average CD4 count was 45 and the
median duration of prior AZT therapy was 96 weeks. There was a
non-significant survival trend favoring the higher dose of d4T, as
well as more improvements in hemoglobin and neutrophil counts
(indicating better recovery of bone marrow function), increased
weight and fewer hospitalizations. The overall conclusion of this
trial was that d4T can be administered safely to patients with
advanced disease and that the higher dose may be slightly superior
to the lower dose.

       Therapy-Naive Patients

       Few studies of d4T are available in people without previous
anti-HIV therapy, mostly because the sponsor delayed development of
the drug in favor of its sister drug, ddI, which is also made by
BMS. But a retrospective analysis examined AZT-naive individuals
with CD4 counts below 300 who received d4T in Phase I/II and
compared them to a similar matched group of trial participants who
received AZT in an ACTG study (116A). The mean change in CD4 counts
was higher and more sustained for 48 weeks in the d4T group. Though
intriguing, these data from studies which were done with different
groups of volunteers at different times have to be interpreted very
carefully. Certainly they suggest that additional studies of d4T
should be carried out to see if d4T indeed is a better drug than AZT
in persons without previous anti-HIV therapy.

       Viral Load Analyses

       Viral load measurements are also generally lacking from d4T
trials. In several small studies conducted at Yale University, d4T
has been shown to reduce viral load, as measured by peripheral blood
mononuclear cell cultures, by 90 to 99 percent, with a 90 percent
reduction maintained up to five weeks. In contrast, a quantitative
PCR assay found only a 70 percent reduction in blood plasma levels
of HIV (viral load).

       In the BMS 019 study mentioned above, the plasma samples for
the viral load assay were not handled and processed adequately at
most of the participating sites. Only a small sample of assays was
available for analysis, and this sample size was insufficient to
ascertain whether viral load changes correlated with enhanced
clinical health.

       Combination Studies

       Combination studies of d4T and AZT were completely stalled
because of a report finding that the two drugs were antagonistic
when used together in cell culture. Data from four laboratories
subsequently indicated that both drugs can be synergistic or
additive in their anti-HIV effects. An ACTG study due to begin
enrolling patients in June 1995 compares d4T to ddI and the
combinations AZT/ddI and AZT/d4T in patients with greater than six
weeks of AZT and CD4 counts between 300 and 600 (ACTG 290). Another
ACTG study will compare the combination AZT/d4T to either drug alone
as first-time therapy for patients with CD4 counts of 300 to 600.

       The ddI/d4T combination also is under study in a pilot trial
comparing high and low doses of both drugs. An interim analysis of
the first 55 patients in this trial could not find a significantly
higher incidence of predictable toxicities such as peripheral
neuropathy, even in volunteers receiving the higher doses of both
drugs together. The study remains blinded and will continue until 75
persons have participated.

       Finally, an analysis of the 114 patients in the parallel
track program who reported taking AZT and d4T together indicated a
survival benefit for those taking the higher dose (40 mg twice
daily) of d4T, no increased incidence of adverse effects and a lower
incidence of dementia.

       Resistance

       The information on the emergence of d4T-resistant strains of
HIV is limited, but it appears that such resistance is slow to
develop. In test tube experiments, Douglas Richman, M.D., from the
University of California San Diego was able to isolate viral strains
resistant to d4T. These were not cross- resistant to other
nucleoside analogues.

       Bristol-Myers Squibb researchers reported last fall that of
eleven individuals with eighteen to 22 months on d4T monotherapy,
decreased susceptibility to d4T occurred in only two persons. The
two had started d4T with HIV that was extraordinarily sensitive to
the drug.

       No particular viral gene mutations were associated with d4T
use. In this study, sensitivity to d4T was determined directly by
viral culture, not indirectly by analysis of genetic mutations.

       The low frequency of clinical d4T resistance is encouraging
although renewed declines in CD4 cells and rises in HIV levels are
still seen with long-term d4T use. This loss of benefit may not be
due to drug resistance as much as with AZT.

       CNS Affects

       The only data available on penetration of d4T into the brain
comes from two small studies that measured blood levels of the drug
in the cerebrospinal fluid (CSF). One study done in four children
reported that drug levels 38 to 97 percent of those in plasma were
attainable in the CSF, and the other one in nine volunteers observed
levels 16 to 72 percent of those in plasma. These levels are
significantly higher than those seen with ddI or ddC.

       No studies of d4T in demented patients have been done. In the
BMS 019 study, no one in the d4T arm developed dementia, as compared
to four persons on AZT, suggesting a protective effect.

       d4T's Potential

       D4T definitively seems to be superior to ddI or ddC in terms
of both efficacy and toxicity given the results of the BMS 019 study
of AZT pre-treated patients. But the paucity of data on AZT-naive
persons or the use of d4T in combination is very disappointing.

       Some clinicians prescribe the drug as a first-line agent in
naive patients who adamantly refuse to take AZT; others are
combining it with 3TC in advanced patients who have failed or are
intolerant to all other approved drugs. Scattered anecdotal reports
of 99 percent or more reductions in viral load from d4T and 3TC in
combination argue that this regime should be studied urgently.

       It remains to be determined how d4T will fare when combined
with protease inhibitors or non-nucleoside reverse transcriptase
inhibitors (nevirapine, delavirdine and loviride). A trial using d4T
along with the Merck protease inhibitor is already in progress.

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