       GMHC Treatment Issues, Volume 10, Number 2 - February 1996
       ----------------------------------------------------------

       Table of Contents

       Let There Be Drugs
       Protease Inhibitors Come of Age
       Back to the Nukes
       A Surprisely Potent Nucleoside Analogue
       And also, "Adefovir Dipovixil"
       Nevirapine
       Curcumin Trial Finds No Activity
       Hydroxyurea Continues to Show Promise
       ADAP Financial Abyss

       ------------------
       Let There Be Drugs
       by Dave Gilden

       The Third Conference on Retroviruses and Opportunistic
Infections took place at the beginning of this month in an
atmosphere of unaccustomed optimism. There was a sense that the
conference marked a watershed in the history of attempted therapies
for HIV infection. Now at last, there seem to be some powerful tools
to attack HIV, suppressing virus levels by many orders of magnitude.

       Emilio Emini, M.D., head of antiviral research for Merck &
Co., set the atmosphere for the rest of the conference by describing
these new tools in one of the event's lead-off presentations.
Reviewing the public data on protease inhibitors and their
combination with one or two nucleoside analogs, Dr. Emini urged a
"new paradigm" for AIDS treatment, in which the goal is to
administer combinations of drugs that lower viral loads for as long
as feasible to below current assays' limit of detection. The idea is
to shut down HIV replication as much as possible so as to eliminate
or delay the accumulation of mutations leading to drug resistance,
the chief nemesis of HIV therapy up to this point. (Considering the
source, it is not surprising that Merck's protease inhibitor
indinavir had a featured role in this "new paradigm.")

       The results presented both before and during the conference
concerning such drug combinations are very impressive. Combinations
of some of the new protease inhibitors and the older nucleoside
analogs caused drops in plasma viral loads of a thousand-fold and
more, accompanied by average CD4 cell rebounds of up to two hundred
and, in one trial, a sharp decrease in new AIDS-related diseases and
death. (For details, see Theo Smart's article starting on page 3.)

       Yet many questions persist. The data accumulated so far cover
only six months of treatment and/or a handful of trial participants.
Already it is apparent that there is wide interpersonal variation in
response to treatment, especially to the protease inhibitors.
Conference reports on the various clinical trials commonly lacked
important information on this score, such as baseline viral load and
other characteristics of the best responders.

       The duration of treatment benefit remains unknown and
probably also differs greatly between individuals. When patients
should switch treatment and to what remains the subject of much
speculation. And the extent to which people can tolerate the many,
sometimes interacting, side effects of combination therapy also
remains to be seen.

       New Agents Galore

       There is no question that a new era is dawning for therapy of
HIV and AIDS. As this edition of Treatment Issues goes to press, the
FDA's Antiviral Advisory Committee is poised to take up
consideration of two protease inhibitors, Merck's indinavir (brand
name: Crixivan) and Abbott's ritonavir (Norvir), plus human growth
hormone ("Serostim," from Serono) for AIDS-associated wasting.
Meetings for these three are scheduled for February 28 through March
1. Delavirdine (made by Upjohn) and nevirapine (Boehringer
Ingelheim), two reverse transcriptase inhibitors that are not
nucleoside analogs like AZT, also are expected to go before the FDA
in coming months.

       The FDA reportedly has urged the manufacturers of indinavir,
ritonavir and delavirdine to file as quickly as possible, even if
trials are not completed or manufacturing facilities ready. Judging
by the examples of saquinavir and 3TC, approved last November, the
agency may take only a few weeks to license drugs for market after
its advisory committee has recommended approval.

       By the end of this year, if not this summer, there should be
at least ten anti-HIV therapies on the market, and the FDA is in the
process of approving a variety of new medications for opportunistic
infections, too. All this activity is creating a considerable amount
of confusion about when and how to apply treatment.

       At the Third Conference on Retroviruses, many experts'
inclination seemed to be, don't hesitate, use everything now. In a
review entitled "Antiviral Therapy '96," Australian researcher David
Cooper, M.D., told his audience that 1995 saw the "demise of
monotherapy and the ascendancy of combination therapy." But he
warned that in the absence of hard data, there was a "danger of
patients getting anecdotal combinations" based on physicians'
informal summaries of their own experience.

       Because of the rush to combination therapy and the large
number of available or soon-to-be-available drugs, recruitment for
future clinical trials may be difficult, and dropouts may be common.
Nevertheless, testing of innovative combinations against standard
ones needs to take place.

       One goal would be to find "the most compact, least toxic
combinations with the greatest antiviral activity," to use Dr.
Cooper's words. Combining different protease inhibitors, an
uncharted field so far, would be a particularly fruitful area to
investigate. Another area is the use of maintenance therapy: Once
HIV replication is tightly suppressed for some months, and nearly
all the infected cells harboring the virus are dead, it may be
possible to switch to simpler therapies with fewer drugs to provide
a barrier against a resurgence of HIV.

       Dr. Cooper also proposed looking at disease progression in
people with life-threatening opportunistic illnesses for which there
are no adequate treatment options. Here, investigators would measure
by how much a new anti-HIV therapy increased the time until diseases
such as CMV or lymphoma recurred.

       Trials monitoring the recurrence of OIs might give some quick
answers, or they might have ambiguous results because unhealable
damage inflicted during HIV infection prevents the recovery of
effective immune function (see below). Certainly these trials would
not tell how to best use antiviral therapy earlier in HIV infection.
Efforts to evaluate compact and efficient combinations in a more
complete fashion could perhaps take the form of large treatment
strategy trials involving changing combination therapies as
conditions seem to warrant. Such trials could, and preferably should
be, conducted by community physicians in a real world setting.

       Counting Virions

       The use of viral load assays -- PCR and bDNA -- to measure
changes in the level of free HIV in blood plasma, and hence a drug's
antiviral activity, has been widely proposed as a way to radically
shorten trials. The problem has been that no one has established how
predictive viral load measurements are of a person's long-term
disease course. Even more in question has been the significance of
short-term reductions in circulating HIV induced by a specific
treatment.

       Almost unnoticed among the news about protease inhibitors and
combination therapy were the Conference presentations that promised
to revolutionize trials of anti-HIV compounds by confirming viral
load as a marker for drug effectiveness. The announcements
concerning viral load began in mid-January, when representatives of
the newly merged corporation Pharmacia & Upjohn first broadcasted
the preliminary results from two large trials combining delavirdine
with either AZT or ddI (see last month's Treatment Issues, page 9).

       Researchers found that delavirdine trial participants who
registered a 0.5 log (70 percent) reduction in viral load in their
eighth week of treatment experienced a 50 percent reduction in AIDS
progression (as measured by opportunistic infections or death). In
contrast, a CD4 count increase of 25 or 50 at week eight was not
predictive of improved clinical outcome over the next year. (See
abstract LB8c.)

       But a CD4 count gain of 50 sustained for a year was indeed
accompanied by less illness and death. The Upjohn researchers argue
from their analysis that early viral load changes are nevertheless
more useful for evaluating experimental drugs and managing
individual patient's therapy. In their cohort, though, those people
with reduced viral load tended to keep that reduction for a year's
time, leaving open the question of precisely how long a treatment
has to show antiviral activity before that activity translates into
symptomatic relief for the patient.

       A number of other objections could also be raised concerning
this confusing trial analysis, which easily leant itself to
rationalizing the approval of delavirdine, a drug with modest
antiviral effect when combined with AZT and little effect on CD4
counts. "I'd love to see this in the hands of an objective, outside
statistician," commented one skeptical conference attendee.

       Be that as it may, Upjohn's so far preliminary conclusions
about the value of viral load were reproduced in several other
conference reports, particularly the virologic analysis of a subset
of the participants in the ACTG 175 trial (abstract S24). ACTG 175,
it should be recalled, was a 2,500- person, government-sponsored
trial spanning three years that compared AZT alone, ddI alone, AZT
plus ddI and AZT plus ddC in HIV-positive individuals with and
without prior AZT therapy (see Treatment Issues, October, 1995,
pages 2-4).

       Although CD4 cell count gains sustained for more than a year
seemed to best reflect improved outcome during the course of the
trial, baseline plasma viral load and treatment-induced reductions
at week 8 were more predictive than CD4 count or change in CD4 count
in the first eight weeks of trial observation. A ten-fold drop in
viral load correlated with a 70 to 87 percent decreased risk of
disease progression as measured by various endpoints -- 50 percent
drop in CD4 count, AIDS-defining disease and/or death.

       The ACTG 175 analysis further found that initial,
pretreatment viral load was a good predictor of future health, as
did the Upjohn and several other studies. John Mellors, M.D.,
reported viral load trends seen in a retrospective analysis of 181
gay men with early HIV infection in the years 1984-85 (abstract
S22). (The group was part of the Multicenter AIDS Cohort Study, or
MACS.) Based on these people's experience, Dr. Mellors observed,
"[Plasma viral load] is an earlier and more accurate predictor than
CD4 count--Viral load reflects the balance between the immune system
and the virus. It is the most important determinant of outcome."

       These studies do not establish how well viral load can be
used when making treatment decisions for individual patients. They
are a further indication, though, that in the future, optimum
combination therapies will be formulated for each patient according
to how his or her viral load responds. More and more experts are
concluding that the advantages gained are worth the added complexity
and cost. "I'm a believer in HIV RNA [viral load]," concluded
Harvard's Scott Hammer, M.D., when reporting on ACTG 175.

       Holes in the Defense

       In the great new age of elaborate antiviral combinations that
pack a real wallop, there will be plenty of reason to closely
monitor how well that wallop is reaching HIV. First of all is the
issue of side effects, which may make patients take their drugs
erratically or cease altogether. It is worth noting that in Jacques
Liebowitch's small but highly successful Paris study of
ritonavir/AZT/ddC (abstract 285, see page 2 of this issue), eleven
of 32 volunteers dropped out. Mostly it was the nausea and vomiting
that drove them out, despite almost 1,000-fold drops in HIV levels
and gains in CD4 counts of nearly 300. (The new capsule form of
ritonavir may induce fewer of these adverse effects than the older
liquid formulation used here.)

       Also, ritonavir's particular molecular structure was chosen
for its inhibitory effect on the liver, which stabilizes the drug's
level in the bloodstream. Ritonavir as a result cannot be taken
along with the many drugs that depend on the liver to break them
down and prevent any toxic accumulation in the blood. If prescribed
ritonavir, patients may sometimes be faced with choosing between
their anti-HIV medication and their OI drugs.

       The other way these therapies will fail is through the
development of mutant HIV whose altered enzymes no longer interact
with suppressive compounds like the nucleoside analogs or protease
inhibitors. The ritonavir trial for people with CD4 counts less than
100 (abstract LB6a -- see page 3 of this issue) did find a rapid
reduction in the rates of death and new opportunistic infection, but
the level of HIV went right back up after the second week. At
sixteen weeks, average viral loads were approaching their initial
values, leading one to wonder how trial participants will fare later
on.

       These volunteers merely added ritonavir to their existing
therapy, leading the presenter John Leonard of Abbott Laboratories
to reckon that the trial was "almost sequential monotherapy" since
the other therapies had probably outlived their usefulness because
of drug resistance. Dr. Leonard remarked that it would be preferable
"to start multiple agents simultaneously."

       The futility of monotherapy with even a very potent protease
inhibitor, at least at less than optimal doses, was underscored
further in an analysis of seven participants in an early ritonavir
study using 600 to 900 mg per day (the current dosage is 1200 mg per
day). An outgrowth of HIV with a single specific mutation known to
confer resistance to ritonavir in the test tube led to a rebound in
viral load (abstract 201).

       Disappointing expectations that mutant virus would be somehow
impaired, this ritonavir-resistant HIV had a robust doubling time of
two to four days, perhaps partially due to a second, compensatory
mutation. Worse yet, the mutant HIV was already present in very
small amounts prior to ritonavir treatment. The time to virus load
rebound after therapy began was highly associated with the
pretreatment virus level. It was only weakly associated with the
dose of ritonavir.

       This ritonavir study was remarkable in that it confirmed some
of the predictions made by various scientists, including John Coffin
of Tufts University (abstract L13) and David Ho (abstract S21) in
their reports to the conference on HIV dynamics: there is a close
link between the detection of certain mutations and the rebound in
viral load; mutant HIV is able to establish significant growth rates
only slightly below that of nonmutant virus; and the HIV with point
mutations contributing to reduced susceptibility to particular drugs
exists even before exposure to those drugs.

       Attaining the goals Dr. Cooper set out for ideal antiviral
therapy may require personal modification of proposed treatment
plans based on genetic analysis of the resistance mutations present
in a patient's pool of HIV. Such complex testing would be in
addition to viral load monitoring and the multitude of laboratory
tests needed to check for side effects like liver and bone marrow
damage.

       Holes in the Repertoire

       Time will tell if it is possible with our current technology
to root out absolutely all the HIV in a person and thus avoid the
rise of mutant varieties resistant to treatment.

       There are three distinct "reservoirs" beyond the scope of
present treatment that may preserve some HIV indefinitely. One is
the brain and central nervous system, which is poorly penetrated by
most drugs. The second is chronically infected macrophages, which
store HIV for many months. Finally, there are antibody-coated HIV
particles adhering to the surface of the follicular dendritic cells,
which trap such virus in lymph node fluid.

       The follicular dendritic cells (FDCs) hold HIV for an unknown
length of time, creating a library of the past HIV variants in
someone's body, including any previous drug-resistant variants. A
paper in the journal Nature last fall (SL Heath et al., October 26,
1995, pages 740-4) reported that virus sticking to FDCs easily
infect the circulating immune cells with which they come in contact
despite being covered with what are normally highly neutralizing
antibodies. "Time bombs waiting to explode," is the way one expert
observer, Cecil Fox, Ph.D., characterized them. (Dr. Fox specializes
in the analysis of HIV-infected lymph and other tissue.)

       It could well be that people with established HIV infections
will need some kind of antiviral therapy for the rest of their lives
given the limitations on what current treatments can reach. Besides
their antiviral cover, people with AIDS may continue to need
medications to treat or prevent various infections because they are
unable to recover their complete immune response even with HIV
permanently suppressed.

       Mark Connors, of the National Institute of Allergy and
Infectious Diseases, compared the CD4 cell "repertoire" in ten
HIV-positive and seven HIV-negative individuals (abstract 397). The
people with HIV had a more uniform CD4 cell population containing
cells able to respond to fewer different foreign proteins. In
theory, these HIV-induced "holes in the repertoire" will prevent
their immune systems from recognizing specific pathogens, making
them vulnerable to diseases most people are immune to.

       The gaps essentially persisted in patients even though
antiviral and IL-2 therapy raised their CD4 cell count from about
200 to 1,000. Presumably they could not rebuild their normal CD4
cell diversity because the damage to the thymus and other lymph
organs wrought by HIV infection makes it impossible for fresh CD4
cells to develop and mature.

       The NIAID study contrasted with a report from Australia of
improved CD4 cell response in a few persons with advanced HIV taking
ritonavir in one of the original trials (abstracts 232 and 451 --
see page 3 of this issue). Counts of CD8 cells (which play an
important role in eliminating virus-infected and cancerous cells)
also exhibited a substantial, sustained rise -- the first time this
has been observed in trials of anti-HIV agents.

       The clinical implications of either the Australian reports or
the contrary NIAID study have not been determined and will require
prolonged following of many patients' experience. As reported at the
Second Retrovirus Conference last year, the Australians did see some
resolution in several patients' physical symptoms.

       The hope expressed by one of the Australian observers that
under the influence of ritonavir, "[advanced] patients' immune
profile becomes similar to that of asymptomatic patients" for now
seemed more like a prayer than a realistic assessment to many
observers. But still, it is encouraging that immune improvements
correlated with the depth and length of viral load decrease. Just
getting rid of HIV may turn out to be the linchpin of immune
therapy.

       Who's Footing the Bill?

       Roche's protease inhibitor saquinavir (Invirase) entered the
market in December with a retail price tag of about $7,500 per year,
and Merck and Abbott, though refusing to comment on pricing issues,
can be expected to charge a similar amount. It would be one thing if
a cure for HIV could be procured for a cost of $15,000 or $20,000.
The benefits of combination drug therapy are finite, though. People
with HIV will have to come up with the money for all their drugs and
for monitoring their own HIV over an indefinite period.

       In the U.S., there are a million people, more or less,
infected with HIV. Arguably, they all could profit from the new
therapeutic advances (although this is not yet proven). Who will pay
is going to become a big question, especially when cuts in Medicaid
are in the offing and the states' AIDS Drug Assistance Programs
(ADAPs) are already in financial crisis (see page 11). Effective
treatment requires social commitment as well as technical finesse.

       The experience with tuberculosis, which has some parallels to
HIV, is not encouraging. TB requires six to nine months of daily
treatment, usually with one inexpensive drug if the disease is
latent and with four drugs of moderate price in the case of active,
symptomatic TB. When TB elimination seemed within our grasp, a
concerted effort to finish off the disease was never undertaken. The
result has been incomplete courses of treatment, a resurgence in the
number of cases and the emergence of drug-resistant TB requiring
novel and costly antibiotics. HIV is even more prone to drug
resistance, and its treatment is more complicated and prolonged in
the first place.

       Then there are all the "developing" countries, whose citizens
will have almost no access to the new treatment modalities.
Scientists may worry about the protected reservoirs of HIV within
the body, but political figures will have to worry about the vast
reservoirs of HIV within the planet's human population. Unless the
virus can be controlled worldwide, it will keep coming back to haunt
us, just as TB does.

       Table: Protease Data at a Glance (Omitted from Electronic
       Version)


       *******************************
       Protease Inhibitors Come of Age
       by Theo Smart

       The big news at the Third Conference on Retroviruses was the
extraordinary antiviral and clinical effects achieved by protease
inhibitors when administered along with nucleoside analogs. The
reports, although limited in their scope, suggested that
combinations of anti-HIV drugs now available will be considerably
more effective than the mediocre HIV treatment options of the past.

       In one study, Abbott's ritonavir (brand name Norvir) was
found to dramatically prolong survival and slow disease progression
in people with advanced AIDS. Other trials found that Merck's
indinavir combined with several nucleoside analogs can hold HIV
blood levels for many months below minimum detectable levels (less
than 500 copies of HIV genes (RNA) per ml of plasma).

       Findings from the Ritonavir Clinical Study

       Abbott, which was running behind Merck and Hoffmann-La Roche
in the race to develop protease inhibitors, is so far the first and
only company to show that its drug extends survival and delays
opportunistic infections (abstract LB6a). The company accomplished
this feat by counting the clinical events that occurred in 1090
volunteers with advanced HIV disease -- CD4 cell counts of 100 or
below -- randomized to take either ritonavir (600 mg) or placebo
twice daily. The participants had a history of more than nine months
of prior anti-HIV therapy and added ritonavir to their existing
regimen of nucleoside analogs (most commonly AZT or d4T -- 3TC was
not yet approved).

       At baseline, the median CD4 cell count was 18 in the
ritonavir arm and 22 in the placebo group. The median HIV plasma
viral load was over 250,000 copies per milliliter. After completing
four months on the study, trial participants who reached an
AIDS-defining event were given open-label ritonavir.

       When planning the study, Abbott researchers had calculated
that it would take only 191 clinical events (the appearance of new
opportunistic infections) or deaths to show definitively that
ritonavir had an effect. That figure was reached within one month,
although the trial continued while the company confirmed each event.
When the results were analyzed, it became clear that the people on
ritonavir were doing better than those on placebo within ten days.
After one month, only 69 opportunistic infections or deaths had
occurred in those receiving ritonavir as opposed to 149 in those on
placebo, a statistically significant difference. Forty-four of these
events were deaths -- seventeen on ritonavir, and 27 on placebo.

       After a median of six months follow-up (see table), 26 people
on ritonavir versus 46 people on placebo had died, a 43 percent
reduction in mortality. New OIs or death occurred in 85 people on
ritonavir and 181 on placebo.

       Viral load response was analyzed in 159 patients from the
trial. Levels of virus decreased by 96 percent in the ritonavir arm
but over time returned back upwards toward baseline. The trial's
rapporteur, John Leonard, M.D., of Abbott, argued that virologic
responses might have been more sustained if trial participants had
begun their concurrent therapies at the same time as they started
ritonavir. CD4 and CD8 cell responses (followed in 215 participants)
were also significantly better in those taking ritonavir (47 CD4
cells and more than 200 CD8 cells above baseline at week sixteen).

       An Australian team led by David Cooper, M.D., performed a
more in depth exploration of the immunologic effects of ritonavir in
21 patients from an earlier trial by analyzing the functional
responses of the new CD4 and CD8 cells (abstract 232). The team
determined that the new CD4s acquired during the first four weeks of
therapy were primarily clones of existing memory cells (lymphocytes
that respond to previously encountered pathogens), and that new
"naive" cells (which might be able to mount an immune response to
infections for which there is no pre-existing defense) were noted
only after the first four week period.

       CD8 cells increased here too (abstract 451). Andrew Carr,
M.D., one of the Australian team, noted that ritonavir's ability to
increase CD8 cell counts has no parallels in the CD8 responses
observed for reverse transcriptase inhibitors, whether alone or in
combination. In laboratory tests, the ability of some patient's
cells to proliferate after exposure to certain foreign antigens
improved, as did the ability of cells to secrete the immune
stimulant IL-2. Improvements in a few clinical conditions, such as
KS and oral hairy leukoplakia, were also noted and attributed to a
restored immune response.

       Surrogate Marker Data

       Abbott: A group of French researchers addressed whether
combinations of ritonavir with other antivirals can force the virus
into submission in an open-label study of ritonavir plus AZT/ddC in
21 individuals (abstract 285). The baseline CD4 count was 156 and
viral load was 69,780 copies per ml. Early data suggested that over
time, viral loads dipped below the limit of detectability in a
growing number of patients on the combination (see last October's
Treatment Issues, pages 4-5).

       The combination's antiviral effect, which really improved
only slightly after the first month, may now be dwindling (see
table). Viral load was undetectable in seven patients at month five,
but only in five at month six. The actual change in median viral
load between month five and six is very small, though, (median viral
load merely went from 351 to 892) so it is not clear yet whether the
increase is a random blip or reflects a gradual viral rebound.

       Merck: This company may be seeing more sustained results with
a different combination. Roy Gulick, M.D., of New York University
reported on a study comparing Merck's protease inhibitor indinavir
plus AZT/3TC to AZT/3TC or indinavir monotherapy (abstract LB7). The
study enrolled 97 people with at least six months of prior AZT
therapy, CD4 cells between 50 to 400 and a viral load higher than
20,000 copies/ml. The median baseline viral load was 40,000 copies,
and the median CD4 cell count was 142.

       The three drug combination most reduced viral load (by more
than 99 percent -- see table on page 2). The antiviral effect
appears sustained in the combination arm, maybe dissipating slightly
in the indinavir monotherapy arm, but is clearly on the way back to
baseline in the AZT/3TC arm (only 75 percent below baseline). The
results at week 24 are a little shaky, though, since only eight to
ten patients in each arm have been on therapy for that long. Viral
loads at week 24 were below detectable limits in six out of seven
trial participants receiving the triple combination for that long.
CD4 cell responses were greater in the indinavir containing arms.

       Indinavir plus AZT/ddI may not sustain its antiviral effect
as well (abstract 200), but this is a completed study and not merely
an interim analysis. A 24-week study enrolled 78 antiretroviral
naive patients. At study entry, the median CD4 count was 150 and
median viral load was 100,000. Again, the antiviral effect of three
drug combination was greater and more sustained than AZTddI or
indinavir monotherapy (see table for details), although ten patients
dropped out of the study because of ddI's gastrointestinal side
effects.

       Agouron: The company has now shown a dose effect with its
protease inhibitor, nelfinavir, by raising the dose to 2,250 mg a
day. During the conference, Agouron presented data on the
combination of nelfinavir with d4T in a meeting with community
representatives, doctors and stock analysts. An ongoing trial is
comparing d4T to d4T plus nelfinavir (two doses) in people with CD4
cell counts 200 or higher and viral loads above 15,000 copies per
ml. The median baseline viral load in the different trial arms
ranged from 50,000 to 70,000. The two drug combination achieved
dramatic reductions in viral load (more than a 99 percent reduction
day 45 -- see table on page 2) and increases in CD4 cell counts, but
data are available for only seventeen people at day 28 and six to
eight at day 45.

       Duration of Effect

       The Agouron study illustrates the chief problem with the
information available on protease inhibitors -- the effect is
profound, but given the development of resistance, will it last for
more than a few months? Researchers suggest that the combination
therapy approach will postpone resistance, but again for how long?

       There is no way to say until studies longer than six months
are conducted. Some researchers and doctors are pushing patients to
use the combination therapies while they still have low viral loads
and high CD4 cell counts because they reason that the effect will
last longer and that resistance will take still longer to develop
with early treatment. But, again, no one knows how much longer.

       What scant long-term data there is comes from studies of
indinavir. Data out to sixty weeks were presented from an open-label
phase 1 trial of indinavir monotherapy in five volunteers (abstract
147). After 24 weeks, four of the five resumed taking their previous
nucleoside analog therapy in addition to indinavir. Mean CD4 count
for the five at week 60 remained 140 cells above baseline, and viral
load was still 96 percent below baseline -- levels not significantly
different from their peak responses. Weight also had increased an
average of 3.5 kilograms and remained stable.

       Another presentation (abstract 146) had a positive report on
indinavir monotherapy. The dose-ranging study was in 70 infected
people with a median baseline viral load of 126,000 and a median
baseline CD4 count of 250. This baseline CD4 count is about 90 to
100 cells higher than in the combination studies above, and the
viral load response seemed greater and more sustained. There was
little difference between the study arms, but the dose now used in
clinical studies (800 mg every eight hours) at week sixteen reduced
plasma HIV levels by a median of 99.5 percent, and the effect was
sustained out to week 24.

       In a state of the art symposium on protease inhibitors,
Emilio Emini, M.D., of Merck (abstract L1) briefly presented
follow-up data from this study. The suppression of HIV continued
unchanged through week 48 in fifteen people who had at least a 99
percent reduction in viral load at week 24. There clearly is not the
rebound in viral load that was seen in Merck's earlier studies with
lower doses.

       The profound antiviral effect seen with indinavir may even be
depleting the viral reservoirs in the lymph nodes. The lymph nodes
trap large amounts of free virus which can survive for an unknown
length of time and may infect cells passing through the nodes. Dr.
Emini presented data of antiviral activity in the lymph nodes of
five people who had lymph node biopsies after eight weeks on
therapy. The people experienced a 99 percent reduction of infectious
virus in the lymph nodes that matched a 99 percent reduction in
plasma viral loads. Indinavir may also penetrate the brain, another
reservoir for virus, at levels 40 to 50 percent of that achieved in
the blood.

       Side Effects and Drug Interactions

       None of the three potent protease inhibitors have been
directly compared to one another. In a few months, though, ritonavir
and indinavir will be competing for market share, and nelfinavir may
be available, too, by the end of the year. The antiviral activity
reported for these drugs may sound very similar at this point, but
their side effects and drug interactions are distinct.

       Ritonavir appears to be the least well tolerated. In the
French surrogate marker study mentioned above, which used the old
liquid formulation, three-fourths of the study participants
experienced nausea, more than half had diarrhea, and more than a
quarter had episodes of vomiting. One-third dropped out. Likewise,
91 (seventeen percent) of those receiving ritonavir in the clinical
endpoint study for advanced patients stopped taking the drug because
of nausea, vomiting, weakness and diarrhea.

       Few patients seem willing to quit indinavir due to side
effects. The reported elevated levels of bilirubin do not appear to
produce symptoms or discomfort. Nephrolithiasis (accumulation of
drug residue in the kidneys similar to kidney stones) seems more
serious as kidney stones can be extremely painful. In the studies
reported at the conference, though, people with this side effect
continued on drug without dose reduction. Some new side effects were
reported in the indinavirAZT/ddI study: indinavir therapy caused
more cases of dry skin, insomnia, rash, pharyngitis and flank pain.

       Meanwhile, nelfinavir causes grade I/II diarrhea,
characterized as two to six bowel movements per day in 70 to 100
percent of the patients on the three highest doses. The company
claims that this diarrhea is mild, "just loose stools, really" and
that only 40 percent of the patients choose to treat it with
antidiarrhea medication. Convenience of dosing is a factor that
people take into consideration when deciding whether to take a drug.
Here ritonavir wins out, with twice-a-day dosing, although people
have to take six capsules each time. Nelfinavir has to be taken
three times a day with a little food. Conversely, indinavir has to
be taken three times a day on an empty stomach, difficult to do for
patients struggling to keep their weight stable.

       Finally, ritonavir has a powerful inhibitory effect on the
liver's ability to metabolize many drugs, which therefore cannot be
taken concurrently (see last December's Treatment Issues, page 8).

       The Next Generation

       Other companies hoping to cash in on the protease inhibitors
will have to find some marketing advantage for their compounds --
such as lower price, better potency, or fewer burdens for its
recipients. An important positive feature would be that the drug
requires of HIV a unique genetic pattern to protect itself from that
drug. HIV that develops resistance to other protease inhibitors to
which it is exposed would then not be cross-resistant to the new one
even before a patient starts taking it.

       A number of drug developers have already dropped out because
they could not get ahead of the competition. Bristol-Myers did so
after discovering that its compounds were not adequately
bioavailable. Since these drugs did not stand out from the other
current protease inhibitors, the company chose to scrap the whole
program rather than spend more funds on improving them. The reverse
transcriptase inhibitor nevirapine (see page 9) has exhausted
Boehringer Ingelheim's will to do any further AIDS research, so its
protease inhibitors are trapped in the starting gate.

       For others, the work on perfecting their protease inhibitors
continues. Glaxo Wellcome's 141W94 compound, purchased from Vertex,
has the advantage of already being in human trials. It also has the
distinction of accumulating in the brain -- cerebrospinal fluid
levels of 141W94 reach about 170 percent of the levels in the blood.

       Upjohn continues preliminary testing of its protease
inhibitors, with the first safety and metabolic trial of the
discontinued U-103017 in HIV-negative humans reported on at this
conference (abstract 153). Upjohn's compounds are known for the
unique resistance pattern HIV develops in response to them. They do
not suffer from cross-resistance with the more established protease
inhibitors. Gilead Sciences has temporarily delayed clinical studies
of a potent class of protease inhibitors because the company's
chemists believe they can make a few modifications to the lead
compound so as to eliminate cross-resistance.

       Parke-Davis has a class of novel compounds (abstract 149)
that are currently hampered by binding to blood plasma proteins. The
Parke-Davis compounds are similar to Searle's second generation
compounds, which were reported to have little cross-resistance.
Parke-Davis is currently trying to ascertain whether its drugs are
active against virus resistant to the Merck and Abbott drugs.

       The only new compound entering clinical trails in the near
future is Ciba-Geigy's lead compound CGP 61755. A dose- ranging
study and a fourteen day viral load study will begin shortly in the
Netherlands.

       CGP 61755 is potent in the test tube and synergistic with
saquinavir (abstract 150). Animal studies suggest that it is safe
and highly bioavailable. Plasma protein binding appears to have
little effect on its antiviral activity. Unfortunately, there may be
cross-resistance problems between CGP 61755, ritonavir and
indinavir, which give rise to similar resistance patterns in HIV.
CGP 61755's chief advantage is that it is easy to manufacture. That
should translate into lower retail costs, one hopes.

       *****************
       Back to the Nukes
       by Theo Smart

       Clinical and surrogate data were released at the Third
Conference on Retroviruses from various studies of nucleoside
analogs, as monotherapies or in combination with each other. In
light of the profound activity of the soon to be available protease
inhibitors, it may seem as though data on this more modest class of
drugs is moot. But given the development of resistance to protease
inhibitors, there clearly remains a role for these drugs as a means
of maximizing the antiviral response and forestalling viral
resistance to protease inhibitors. Besides the question of
resistance, there will also be a sizable number of people who fail
or cannot tolerate protease inhibitors due to drug-drug interactions
and gastrointestinal or liver issues (poor absorption or rapid
breakdown of protease inhibitors as well as the drugs' toxic
effects) -- and then there is protease inhibitors' high cost.

       The Old Guard Combinations

       New data from various studies largely paralleled the
previously reported results from ACTG 175 and Delta 1 trials (see
last October's Treatment Issues, pages 2-4). Robert Schooley, M.D.,
presented data from a Burroughs Wellcome sponsored study of AZT
versus AZT/ddC and AZT/ddI (abstract 202). The trial enrolled people
with CD4 cell counts below 300 and less than four weeks of prior
AZT. The primary goal was to see whether the addition of ddI (at
half dose) or ddC delayed the development of resistance to AZT. They
did not, but AZT/ddI was associated with a significantly enhanced
suppression of HIV and extension of life as compared to AZT alone.

       AZT/ddI also produced a significant survival advantage over
AZT monotherapy in people with prior nucleoside analog experience in
the Delta 2 study, now that more deaths have occurred during the
long-term follow-up (abstract LB5). Most of the people who died had
entered the study already diagnosed with AIDS.

       The Community Programs for Clinical Research on AIDS (CPCRA)
network sponsored the NuCombo study, which also compared AZT against
AZT/ddI and AZT/ddC. For the trial cohort as a whole, NuCombo found
only a marginal survival benefit for AZT/ddI after two years of
observation (abstract LB4). The 1,113 participants in this study had
more advanced disease status than those in Delta or ACTG 175.
NuCombo participants entered the trial with an average CD4 cell
count of 119.

       In the subset of trial enrollees who were initially AZT-naive
(about 23 percent of the total enrollment), combination therapy had
a significant clinical benefit over AZT alone. There was no benefit
to combination in the AZT-experienced patients. Combination therapy
also was poorly tolerated, calling into question the wisdom of
adding ddC or ddI to AZT in people with very advanced disease. For
ddI, in particular, tolerance and compliance were lower because of
gastrointestinal side effects.

       3TC

       Long-term follow-up of NUCA 3001 and 3002 (AZT/3TC studies in
antiretroviral naive and experienced patients, respectively) shows
that viral load and CD4 cell responses in the 3TC- containing arms
at week 24 were sustained in a high proportion of persons who
continued treatment out to 68 weeks in NUCA 3001 and 52 weeks in
NUCA 3002 (abstracts 198 and 199). In NUCA 3002, no difference in
clinical endpoints was seen between arms. The clinical endpoint
differences in NUCA 3001 were not statistically significant.

       Two posters addressed the effect or safety of 3TC in people
with advanced disease. A French group evaluated two doses of 3TC
combined with AZT in seventeen people with less than 50 CD4 cells
(abstract 299). Both doses lowered viral load and increased CD4 cell
counts. In eight patients at the month one timepoint, viral load
decreased by more than 90% or became undetectable. This was
sustained at month three in four trial participants. At month six,
fifteen out of the seventeen 3TC- treated volunteers were alive,
only one had had an opportunistic infection.

       A Toronto physician, I. W. Fong, M.D., reported that 3TC is
not as well tolerated in advanced HIV disease as in earlier stages
of the disease and can cause serious side effects (abstract 134).
His data came from 36 of his advanced patients enrolled in the 3TC
compassionate use program (mean CD4 count at baseline was 80 cells).
Fifteen took 3TC as a monotherapy, and the rest used it in
combination with AZT, ddI or ddC. Seventeen patients reported
serious side effects, with seven discontinuing 3TC as a result.
Among the side effects were five cases of hair loss (13.9 percent),
five cases of neuritis (13.9 percent), four cases of anemia (11.1
percent), four cases of leukopenia, or low white blood cell count
(11.1 percent), including two cases of severe neutropenia (less than
500 of the infection-fighting neutrophil cells per mm3 of blood),
and three cases of nausea and vomiting (8.3 percent). More side
effects were reported on monotherapy (12 of the 21 events) than on
combination treatment.

       d4T and d4T/ddI

       Christine Katlama, M.D., presented data from a placebo-
controlled dose-ranging study of d4T (abstract 196). The trial
enrolled 66 people with more than 350 CD4 cells (baseline median
527). Viral load (4.2 log or 15,900 copies/ml of plasma at baseline)
decreased by 0.8 log (84 percent) on the high dose (80 mg per day),
and 0.6 log (75 percent) on the low dose (40 mg per day). These
reductions were sustained for the duration of the twelve week study.
Average CD4 cell counts at week twelve were 35 cells over baseline
on the high dose and twenty cells over baseline on the low dose.
These increases compare with a decline of 45 cells in the placebo
group, but the CD4 cell changes were not considered significant.

       Forty patients continued with open-label low-dose d4T. Those
who had been on placebo had a seventy percent reduction (one- half
log) in viral load. The antiviral responses were sustained through
month twelve, although viral load rose slightly in the patients
randomized to high dose when crossed over to low dose d4T. During
the follow-up period, there were nine cases of peripheral
neuropathy, leading one patient to stop the d4T.

       Meanwhile, Swiss researchers reported on a study in 23
persons with late-stage disease and a long history of prior
nucleoside use (abstract 136). d4T had only a minor effect on viral
load (0.2 log or 37.5 percent reduction) after one month, and that
effect was lost by month three. As with the NuCombo study, this may
be another case of a nucleoside analog not performing well in
heavily pretreated patients. Finally, the results reported on the
antiviral activity in an ongoing study of the combination of d4T
with ddI (abstract 197) were less robust than reported to activists
last November (see the November, 1995 Treatment Issues, page 3). The
data from this trial is in a constant flux as more people reach
later timepoints.

       Ninety-four patients have been randomized into the study; 71
are evaluable at present. Viral load responses were presented only
for 54 people who entered the study with plasma viral load of over
1,000. The median CD4 cell count in these 54 patients was 310
(average CD4 count: 327), and the median viral load was 4.6 log
(39,800 copies/ml). The median CD4 cell count at entry in all 71
evaluable patients was slightly higher at 325 (the average was 336).

       More than half of the study participants have had at least 28
weeks of treatment. The average reduction in viral load was 1.4 log
(96 percent) in the 32 on treatment at week 28. Contrary to
appearances last November, the average viral load response is not
increasing over time, but it was sustained at 1.5 log (97 percent)
below baseline in the fourteen patients with measurable viral load
that have completed 52 weeks of treatment. So far, there have been
no statistically significant differences between the various dose
arms of the study. The variation in individual response was great,
though, with reductions in viral load ranging between 0.29 log (50
percent) and 2.9 log (99.8 percent).

       Overall, 26 patients have completed 52 weeks of treatment and
their CD4 counts are up by a mean of 68. At present, there appears
to be a CD4 response favoring the high dose. Counts increased by 141
cells in the four on this arm at week 52, as opposed to a loss of
more than twenty cells on the low dose. Again, these as yet
nonsignificant differences are sure to change as more people
complete the study.

       d4T and ddI both cause peripheral neuropathy as a side
effect, but only one episode has been noted in this trial. Six
patients discontinued therapy due a variety of other side effects,
including increases in liver function tests, abdominal pain,
neutropenia and depression.

       *****************************************
       A Surprisingly Potent Nucleoside Analogue
       by Gabriel Torres, M.D.

       1592U89 is a new nucleoside analogue under development by
Glaxo-Wellcome (see Treatment Issues, June 1995, page 12). It is
known to have potent in vitro activity against HIV and to be
synergistic with all other nucleoside analogues and protease
inhibitors.

       At the Retroviruses Conference, Michael Saag, M.D., of the
University of Alabama presented the highly encouraging first in vivo
efficacy data for this compound (abstract 195). These were the
interim results from the international phase 1/2 trial underway in
Europe and the United States. The study is a dose-ranging one in
HIV-positive adults with less than twelve weeks prior AZT therapy
and CD4 counts between 200 and 500.

       After four weeks, the average HIV viral load dropped in
continuing trial participants by a median 1.9 logs (98.7 percent),
and after a further eight weeks, in which participants received
either AZT or placebo in addition to 1592U89, the viral RNA level
was down by 2.1 logs -- representing a 99 percent reduction from
baseline at twelve weeks. CD4 counts had increased by an average of
122 at week twelve.

       This first cohort of nineteen patients received 1592U89
monotherapy at an oral dose of 200 mg thrice daily. The group's
average CD4 count at entry was 352, and its average viral load was
5.1 logs. All but one of the patients were AZT-naive.

       Two participants withdrew from the study, one after
developing fever, rash and tingling thought to be due to the drug.
The main side effects of 1592U89 were nausea in 28 percent of
volunteers, headache in 17 percent and rash in 11 percent. One
person had an elevation in liver function tests. The exceptional
results for this nucleoside analogue have prompted the investigators
to continue the trial. At present, they are enrolling three
additional cohorts for higher doses. Since the drug penetrates into
the central nervous system, trial participants are asked to allow
spinal taps in order to measure the concentration of the drug in the
cerebrospinal fluid.

       Pivotal trials in AIDS-related dementia also are being
developed for 1592U89, as are novel trials that will combine the
drug with AZT and 3TC. The new trials are due to begin once the last
of the present cohorts has finished. For more information, call
Glaxo at 800/437-0992.

       ******************************
       And also, "Adefovir Dipovixil"
       by Theo Smart

       Adefovir dipovixil (formerly bis-POM PMEA) is an experimental
anti-HIV drug made by Gilead Sciences, which presented data on it at
the Retroviruses Conference (abstract 407). It has the advantages of
a very long half-life within the body (leading to a once-a-day
dosing regimen) as well as broad spectrum antiviral activity against
hepatitis B and herpes viruses -- particularly CMV and Epstein Barr
-- in addition to HIV.

       Adefovir (and PMPA, a new derivative now entering clinical
studies -- see December's Treatment Issues, page 3) is a nucleotide
analog that is similar to nucleoside analogs such as ddI but does
not need to undergo as much processing within cells to become
active.

       Both nucleotide and nucleoside analogs attack reverse
transcriptase, so HIV resistance can cover drugs in both classes at
once. In particular, HIV mutations that confer a ten-fold loss of
susceptibility to adefovir in the test tube also reduce
susceptibility to ddI and ddC by four fold and to 3TC by 40 fold.
These laboratory derived mutations have not been observed yet in any
patients treated with adefovir. Data from a twelve week
placebo-controlled study of adefovir, at 125 or 250 mg per day, were
presented during the Retrovirus Conference. Both doses reduced viral
load by 70 percent, (roughly equivalent to the effect of AZT), and
viral load rebounded when treatment stopped. The CD4 cell response
was greater on the lower dose, a boost of 57 versus 27 for the high
dose. CD4 counts decreased by 41 in those on placebo. Side effects,
mostly nausea and diarrhea, happened more frequently in the
high-dose arm.

       Researchers at one study site found that adefovir treatment
reduced levels of CMV in the semen by more than 50 percent in four
out of seven patients. In test tube studies, adefovir is as active
against CMV as ganciclovir, while it is much more bioavailable in
people than oral ganciclovir. Gilead Sciences plans to look at
adefovir both for HIV and CMV in upcoming large phase 3 studies.

       Ironically, broad spectrum antiviral drugs like adefovir are
a cause of concern for some researchers. They fear that those who
take drugs like adefovir for HIV disease risk developing
breakthrough CMV infections cross-resistant to adefovir and other
CMV medications as well. As of yet, there is no data on whether CMV
can evolve resistance to adefovir, but it would be surprising if it
could not, especially should the drug enter widespread use. If
CMV-resistance to adefovir confers cross-resistance to the other CMV
treatments, it might be best to limit CMV's exposure to the drug by
reserving adefovir for those needing CMV prophylaxis.

       *********
       Nevirapine
       by Theo Smart

       Several poster presentations at the Conference on
Retroviruses tried to make a case for the HIV reverse transcriptase
inhibitor nevirapine (brand name: Viramune). Richard Pollard, M.D.,
reported on a study comparing AZT to nevirapine plus AZT in 60
AZT-experienced volunteers (abstract 325). The nevirapine plus AZT
cohort saw viral load reduced by a median of over 1.57 log (98
percent), but viral load was on its way back to baseline by week
four and at baseline by week fourteen. CD4 cell counts had increased
by a median of 60 at week eight but were back to baseline by week
28.

       Nevirapine's developer, Boehringer Ingelheim also presented a
paper on the duration of the drug's effect (abstract 141) based on
an analysis of three separate studies including ACTG 241 -- a
"convergent combination" study of nevirapine/AZT/ddI. The addition
of nevirapine to AZT or AZT/ddI regimens did delay the "return of
viral load to baseline" by a few months. Viral loads may linger
slightly below their pretreatment value for months without being
significantly different from that value.

       In March, Boehringer Ingelheim, intends to request FDA
marketing approval for nevirapine. While awaiting approval, the
company has announced plans to proceed with an expanded access
program to provide nevirapine to people with CD4 counts below 50.
For more information on eligibility, call 800/595-5494.

       Note: Due to an error in the trial announcement, last month's
Treatment Issues published an incorrect telephone number for
information on the currently enrolling large clinical trial of
nevirapine. The correct number is 919/544-3170.

       ********************************
       Curcumin Trial Finds No Activity
       by Dave Gilden and Theo Smart

       Curcumin, a component of the spice turmeric and popular
herbal medicine, has no anti-HIV activity in people according to a
study presented by the Community Research Initiative of New England
(CRINE) at the Retrovirus Conference (abstract 140). The report
stands in contrast to an earlier, smaller study by the Search
Alliance (now the AIDS ReSearch Alliance) of Los Angeles which
observed a reduction in viral load. Interest in curcumin increased
when Search Alliance announced that 2,500 mg per day of curcumin
produced a "modest" reduction in viral load over twenty weeks.

       Researchers at CRINE attempted to reproduce these results by
enrolling 40 people in an eight-week trial. Two doses were used,
2,700 mg/day and 4,800 mg/day, and enrollees were allowed to take
concurrent antiviral drugs.

       The results were nil for both doses. Viral load (an average
of 61,000 copies/ml at baseline) did not change significantly over
the eight weeks, nor did CD4 count (baseline average of 236).

       It is not clear why the two community-based research
organizations came to such different conclusions. Ten of the
eighteen Search volunteers received flu shots during the trial,
which probably distorted the viral load data. The accuracy of the
Search trial's viral load testing also has been questioned. (See
AIDS Treatment News, May 6, 1994, pages 1-7.)

       The reason for curcumin's lack of activity may be that it is
very poorly absorbed by the digestive tract, according to animal
studies. Levels of curcumin in the blood were not measured in either
study. CRINE plans to do this shortly.

       *************************************
       Hydroxyurea Continues to Show Promise
       by Luis Santiago

       Further human trial data on hydroxyurea and compounds with
similar effect were presented at the Third Conference on Human
Retroviruses and Opportunistic Infections. The new data confirm the
positive impression that hydroxyurea, especially, has made in past
investigations (see the September, 1995 Treatment Issues, pages 1,
2-4).

       Hydroxyurea and the related drugs act by restricting the
cellular pathways by which new DNA nucleotides are made. These
gene-creating building blocks are taken up by the HIV enzyme reverse
transcriptase as HIV infects new cells. The resulting scarcity of
natural nucleotides allows nucleoside analog drugs like ddI or AZT,
which are defective nucleosides, to play a greater role in
disrupting HIV.

       Canadian Study

       The most significant new piece of information on hydroxyurea
(abstract 406) was presented by Julio Montaner, M.D., head of a
Canadian pilot study of hydroxyurea among a group of patients with
CD4 counts between 100 and 350 (average CD4 count of 241) and at
least six months prior ddI experience. The objective of the study
was to assess the viral load effect of adding hydroxyurea to ddI
monotherapy.

       The study was set up as follows: all trial participants (26)
received ddI monotherapy for four weeks (200 mg twice a day). The
ddI alone therapy was followed by four weeks of ddI plus
hydroxyurea, with half of the group (13) assigned randomly to a low
dose (500 mg once a day) and the other half to a high dose (500 mg
twice a day) of hydroxyurea. For the last four weeks of the
twelve-week study, everyone was put back on ddI monotherapy. Viral
load (plasma levels of free HIV) and CD4 counts were measured on a
daily basis.

       For study purposes, an individual was defined as a
"responder" if he or she registered an HIV viral load reduction
greater than one log (90 percent). Based on this definition the
investigators found that during the four weeks on ddI/hydroxyurea
combination, nine out the 26 patients were responders. Six out of
the nine responders were on the hydroxyurea high dose, with the
remaining three on the low dose. This difference is only great
enough to statistically suggest, but not demonstrate, that a greater
viral burden reduction can be achieved with the higher dose.

       The average viral load reduction (70 percent and 90 percent
at week seven in the low and high dose arms, respectively) was
statistically significant, as was the viral load rebound after
discontinuation of hydroxyurea therapy at week eight. This return to
baseline HIV levels occurred during the first week off hydroxyurea.

       In the initial laboratory experiments at the National Cancer
Institute, inhibition of HIV-1 was still seen several weeks after
stopping drug treatment. The rapidity of the rebound in the present
human trial indicates that continued viral suppression after
withdrawal of hydroxyurea may not occur, at least in this population
with advanced HIV infection and high CD4 turnover. (The CD4 cells
arising after treatment cessation would be unaffected by the
previous exposure to hydroxyurea.)

       Many hydroxyurea researchers argue that the ddI/hydroxyurea
combination will be of significant benefit only for a relatively
healthy, ddI-naive population since this is where a synergistic
effect would be seen and toxic side effects (bone marrow
suppression) should be minimal.

       Considering the advanced disease status and long treatment
history of the trial cohort, the viral load reductions were
impressive. Investigators are currently analyzing the prevalence of
ddI resistance in study participants' HIV and its association, if
any, with the magnitude of the response. No serious toxicities were
reported in the study, although some conference attendees pointed
out that the time on hydroxyurea was too short to evaluate any
negative effects on blood cell counts. Likewise, no change was
observed in CD4 counts probably because of the trial's brevity.

       Follow-up to the French Trial

       Interest in hydroxyurea had been considerably heightened by
the results of a French study involving twelve asymptomatic
HIV-positive patients (CD4 count above 250) with no previous
anti-HIV therapy. (See the September, 1995 Treatment Issues, page
1.) The group received ddI (200 mg twice a day) and hydroxyurea (500
mg twice a day) for three months.

       In a follow-up report (abstract 291), researchers presented
data on those twelve patients, six of whom stopped the study regimen
at the end of the three-month observation period. They also reported
on an additional group of six patients that started treatment with
this combination since then and also have completed three months of
therapy.

       At eight months, HIV viral load increases were reported in
five out of the six persons that stopped treatment. The other one
was stable. CD4 counts held more or less steady in four of them. Of
the six patients who have remained on therapy, two have stable HIV
levels, one had a major increase and two had slight increases. (No
data were reported for one member of the group.) CD4 counts
continued to increase in three members of this group.

       Of the six patients that started the combination recently,
two had HIV levels below detectable limits at three months, one
experienced a two log (99 percent) decrease, and the other three a
one log (90 percent) decrease. This study is not a rigorous clinical
trial and leaves a lot of room for argument over its interpretation.
Along with the Canadian trial, it does at least provide a basis for
more sophisticated testing of hydroxyurea

       Where's the Placebo?

       Here in the U.S., ACTG 307, a pivotal ddI/hydroxyurea study,
was due to start last fall. According to the trial's principal
investigator, Joseph Eron, M.D., the lack of a placebo has been a
big stumbling block. Bristol-Myers Squibb, producer of hydroxyurea
(brand name: Hydrea) has yet to provide the placebo pill, which has
to resemble the real thing. A company in Maryland is currently
working on it, but researchers are not ready yet to start
recruiting. For the latest information and current trial sites, call
800/TRIALS-

       A. Other Compounds

       Alternative experimental medications utilizing the same
strategy as hydroxyurea are also waiting for more extensive testing.

       Dr. W-Y Gao of the National Cancer Institute described
compounds that block the cellular enzyme known as thymidylate
synthase (abstract 5). This enzyme helps process the nucleotides for
which AZT and d4T are defective analogs. (See Treatment Issues,
September 1995, page 5. Hydroxyurea inhibits a different enzyme,
ribonucleotide reductase.) In the test tube, very low concentrations
of the anticancer drugs FUdR (floxuridine) and 5-FU (fluorouracil)
potentiated both AZT and d4T as predicted. FUdR raised d4T's potency
eight times, and AZT's effect was six times greater in its presence.

       Dr. Gao's presentation was seconded by a report from the
Robert Johnson School of Medicine in New Jersey and the University
of Rochester (abstract 344). This group used FUdR to potentiate AZT
in the test tube.

       Both FUdR and 5-FU are extremely toxic, which could limit
their use. These drugs' success as antiviral agents depends on their
effectiveness within the body at the very low, presumably nontoxic
concentrations used in the laboratory experiments.

       **************************
       ADAP Faces Financial Abyss
       by Derek Link

       As the good news on protease inhibitors and viral load
testing was broadcast from the Third Conference on Retroviruses last
week, the ability of low-income people with HIV to access these
promising developments was dealt a major blow. The states' AIDS Drug
Assistance Programs (ADAPs) are running out of money, and no
solution is in sight. Increased caseloads and drug usage, higher
drug costs, and more expensive combination therapies coupled with
stagnant financial resources have placed ADAPs across the country in
jeopardy.

       ADAPs are the most heavily utilized AIDS programs in the
nation, with over 50,000 people with HIV or AIDS enrolled. The
federally funded ADAP system began in 1987 as a way of providing
free AIDS drugs to low- or moderate-income people not covered by
Medicaid or third-party insurance. Since 1990, ADAPs have been
funded by the Ryan White CARE Act, the main source of federal funds
for AIDS care. Each state administers its own ADAP, so eligibility
criteria and formularies (the list of covered drugs) vary from state
to state. Some states, like New York, have run generous programs
that cover most AIDS-related medications, while other states have
restrictive programs that cover only a few (usually AZT, aerosolized
pentamidine and Bactrim).

       The Gathering Storm

       In the last several months, two state ADAPs (Colorado and
Missouri) have run out of money and others have cut services,
limited enrollment or canceled formulary expansions in the face of
growing budget shortfalls. The budget problems with the ADAPs appear
certain to grow in the coming fiscal year as new protease inhibitors
gain FDA approval and multi-drug combination therapies are
prescribed earlier in disease, increasing the cost and use of
antiretroviral drugs.

       Use of antiretroviral agents has increased dramatically over
the last twelve months, following a period of decline after the
Concorde study results in 1992. In New York State, for example,
expenditures on antiretroviral drugs from fiscal year 1993 to 1996
are projected to almost double, rising from $5.9 million to $11.2
million. 3TC is one significant case.

       Twelve hundred people obtained 3TC through New York ADAP in
the month following its approval in November, and the state ADAP
spent $300,000 on the drug in its first month alone. The demand for
3TC represented a record level of interest in a new therapy. 3TC,
which is used mostly in combination with AZT, is also associated
with increased AZT expenditures.

       The National Association of State and Territorial AIDS
Directors (NASTAD), a lobbying group, surveyed state ADAPs in
January. Forty-two states responded to the survey. NASTAD found
nineteen state ADAPs had or will have budget shortfalls this fiscal
year. The budget gaps ranged from $5.9 million in New York to
$15,000 for Nebraska. NASTAD calculated that a total of $12 million
would be needed just to make up the budget gaps this fiscal year.
States have implemented a variety of measures to reduce ADAP
expenditures, the most common of which are delaying or canceling
formulary expansions (twelve states), removing drugs from the
formulary (seven states) and establishing waiting lists (seven
states).

       New York Cuts Back

       On January 1, New York State implemented drastic cost-cutting
measures for its ADAP. Over 70 percent of the drugs covered by New
York ADAP have been eliminated from the program, including critical
medications such as Neupogen, Epogen and many antibiotics. In
addition to the cuts, New York ADAP is unable to cover any new
therapy. Saquinavir, the first approved protease inhibitor, is not
covered, and other new protease inhibitors will not be covered when
they receive marketing approval later this year.

       Despite the budget problems, interest in protease inhibitors
remains high in New York State. New York ADAP administrators say
that they have received approximately 120 phone calls a week asking
for saquinavir since it was approved late last year. New York
State's Clinical Advisory Committee for HIV Uninsured Programs,
which advises ADAP on clinical issues, this month recommended
protease inhibitors be covered by ADAP but not at the expense of
other cuts in the program. With more cases than any other state, New
York is the epicenter of the HIV/AIDS epidemic. New York's ADAP is
accordingly the largest in the country. Since its inception, New
York ADAP has covered over 32,000 New Yorkers with HIV. Its current
enrollment exceeds 10,000. About 70 percent of New York ADAP
recipients live in New York City, and over 60 percent earn less than
$10,000 per year. Seventy-five percent of NY ADAP participants use
the program while their Medicaid applications are being processed,
which often takes six months, and the remaining 25 percent are
uninsured or underinsured.

       New York State estimates it needs $49 million in 1996 to
maintain ADAP at its current reduced level. The state will need an
additional $9 million to keep the current level of service while
adding the protease inhibitors. Seventy-five million dollars is
required to restore all cuts and add the protease inhibitors, too.

       Lobbying For ADAP

       The ADAP funding shortfall has led AIDS organizations to
press for more funds at the state and federal level. Nationally,
funding for ADAP is part of the debate on reauthorization of the
Ryan White CARE Act. The CARE Act is stalled in committee, and many
AIDS lobbyists worry that it may remain stalled because the 104th
Congress has had a very difficult time passing any legislation. If
the CARE Act is not reauthorized soon, an even deeper funding crisis
may occur in all CARE Act programs, including the ADAPs. In any
event, NASTAD and other groups have called on the Congress and the
Administration to increase the CARE Act appropriation for ADAPs. An
"ADAP Future Funding Working Group" has also formed in Washington.
This working group is composed mostly of lobbyists who represent the
companies that make and sell medications for AIDS and HIV.

       The Health Resources Services Administration (HRSA), the
federal office that administers Ryan White programs, is also
developing a national "core formulary" for ADAPs. The goal is to
standardize ADAP coverage in all states so that an even level of
service can be provided nationwide, among other things allowing for
more accurate planning. HRSA expects to have elaborated the "core
formulary" by early summer.

       In New York State, a group of AIDS organizations and
legislators have joined together in a campaign to save ADAP. The New
York State group is pressing the government in Albany to supplement
the ADAP budget with state funds -- right now, New York uses none of
its own funds for ADAP. A bill that would use state funds to fill
any shortfall in the state ADAP budget has 31 sponsors in the
Assembly but has yet to be introduced in the Republican-controlled
Senate.

       State funds do subsidize ADAP in California, where ADAP is
running a $4-8 million deficit and is estimated to need an extra $18
million annually just to maintain current service and add 3TC and
saquinavir. Activists are trying to gain extra budgetary
allocations. At the same time, they fear bringing ADAP to the
attention of the new conservative Republican majority in the state
Assembly.

       Two-Tiered Access

       ADAP's woes underscore a frightening reality in the American
health care system. More and more people with HIV who rely on
government health care or managed care plans may find that newer and
more expensive drugs remain unreimbursed.

       Breakthrough drugs that have a major life-prolonging
potential for people with HIV, like protease inhibitors, may only be
available to the very few who have jobs that offer top-of-line
insurance coverage. A concerted effort is still needed for
comprehensive health care reform, but in the meantime AIDS groups
must focus attention on the growing numbers of persons with low and
even moderate incomes who cannot gain access to protease inhibitors
and other innovative HIV therapies.
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