       Treatment Issues, Vol 8, No. 10 - November 1994
       Gay Men's Health Crisis

       Table of Contents
       -----------------
       Reports from ICAAC
         Viral Load Dynamics
         Maternal Viral Load Predicts Transmission
         Increased Transmission of AZT-Resistant HIV
         Blood Transfusions May Increase HIV
         CD4 Benefits From d4T
         Protease Inhibitor Studies
         GEM-91 Trials begin
         Preventing Fungal Infections
         Sorivudine (BV-ara-U) for Herpes Zoster
         Famciclovir for Herpes in Women
         Foscarnet
         TB Prophylaxis
         Disappointing Crypto Studies
         "Off-Label" Drugs for HIV

       Validating Viral Load Markers
       Passive Immunotherapy: New Stories, Same Old Data
       Future Uncertain for NIH AIDS Drug Discovery Program
       Treatment briefs by David Gold
       Correction to Ho article, Vol. 8, No. 9 - October 1994

       *****************

       Reports from ICAAC
       by David Gold and Gabriel Torres, M.D.

       The Thirty-fourth Interscience Conference on Antimicrobial
Agents and Chemotherapy (ICAAC) was held this year in Orlando, Florida
from October 4 to 7. ICAAC has become the most important infectious
disease conference in the world, with over 40 percent of the attendees
coming from outside the United States. Below are some of the
conference highlights relating to HIV and AIDS.

       Viral Load Dynamics

       David Ho, M.D., of the Aaron Diamond AIDS Research Center
presented a model that describes the dynamics of HIV replication.1 Dr.
Ho noted that patients given Abbott Laboratories' ABT-538 protease
inhibitor experienced a dramatic decrease in HIV RNA levels within a
matter of days. Based on this observation, he infers that nearly half
the viral population in the plasma is renewed every day. There is also
a constant destruction of CD4 cells in infected persons -- Dr. Ho
estimated that approximately 22 million CD4 cells are destroyed each
day in the blood and 50 times more in the lymphoid tissue.

       According to Dr. Ho, the greatest amount of virus is produced
in the first two to four weeks after a person becomes infected by HIV.
HIV production in that period equals the total amount of virus
produced over the next four to five years. This suggests to Dr. Ho
that intervention with antiretroviral therapy should be instituted as
soon as possible after infection to reduce viral burden and delay
disease.

       In a subsequent presentation, Michael Saag, M.D., of the
University of Alabama emphasized the need for the earliest
intervention possible with as many active drugs as can be tolerated.2
He stressed his view that monotherapy with one drug will soon become a
thing of the past, with combinations of protease inhibitors and
nucleoside and non-nucleoside reverse transcriptase inhibitors
becoming the state-of-the- art in managing HIV infection.

       Maternal Viral Load Predicts Transmission

       A landmark study by a group of New York investigators measured
HIV levels in a small group of pregnant women with a technique known
as QC-PCR.3 The 27 mothers in the study had HIV measurements at the
time of delivery, and their infants were followed prospectively. Eight
of the 27 (29.6 percent) mothers transmitted HIV to their infants. The
eight were among the eleven study volunteers with very high HIV levels
in their blood (more than 175,000 copies of HIV RNA per milliliter of
plasma). None of the sixteen mothers with lower viral loads
transmitted the virus.

       The authors concluded that QC-PCR measurements are a far more
powerful predictor of transmission than CD4 counts or viral cultures
using peripheral blood mononuclear cells. This study provides further
evidence for the need to use viral load measurements in clinical
practice, since the decision to institute antiretroviral therapy may
be guided by the viral load of the mother during pregnancy.

       Increased Transmission of AZT-Resistant HIV

       A study presented by researchers from the Walter Reed Research
Institute indicated that AZT-resistant strains of HIV are increasingly
found in newly infected individuals.4 Three cohorts of patients from
the U.S., Australia and Switzerland were evaluated for transmission of
AZT-resistant virus. HIV isolates were obtained at the time of
seroconversion to assess whether the viral strain was resistant to
AZT. From 1988 through 1991, only three percent of the isolates
demonstrated AZT-resistance, compared to nineteen percent in the Swiss
group and eighteen percent in the U.S. cohort during 1993 and 1994.
This rise in the transmission of AZT-resistant strains will
significantly limit the ability to treat seroconverters with AZT
during acute infection and impair the usefulness of AZT as an early
intervention strategy.

       Blood Transfusions May Increase HIV

       A small study by researchers from two medical centers, Case
Western Reserve in Cleveland and the VA Medical Center in Los Angeles,
suggested that blood transfusions may modestly increase HIV
replication in HIV-positive patients.5 Of five HIV-positive patients
who received blood transfusions, all five had an increase in HIV
levels (measured by p24 antigen) one to two weeks after transfusion.

       CD4 Benefits From d4T

       AZT-Naive Patients: Researchers from Bristol-Myers Squibb,
presented data on d4T (stavudine) in 108 patients, 41 of whom had
never taken AZT or any other anti-retroviral drug.6 Not surprisingly,
AZT-naive patients had a better response in terms of CD4 improvement.
After 24 weeks, these patients had a median increase of 74 CD4 cells.
The researchers then compared this CD4 response to that seen in ACTG
116A, where AZT-naive patients were given either AZT or ddI. The
cross- study comparison revealed that in AZT-naive persons with
similar CD4 counts, d4T produced a CD4 response equal or perhaps
superior to AZT. (Comparisons between studies are always difficult to
interpret, however.)

       AZT-Experienced Patients: Lisa Dunkle, M.D., from Bristol-
Myers Squibb reported an update on a trial comparing d4T to AZT in
people with CD4 counts of 50 to 500 and at least six months of AZT
therapy.7 In this trial which is still ongoing, 822 patients were
randomized to receive either d4T (40 mg twice daily) or continued AZT
(200 mg three times daily). An interim analysis of the first 359
patients showed that the CD4 responses and declines in p24 antigen
levels and HIV titers were greater and more sustained in those who
switched to d4T than in those who remained on AZT. Furthermore, those
who switched to d4T had fewer clinical complaints. Peripheral
neuropathy occurred in fifteen percent of those on d4T after one year
of treatment, but only six percent required discontinuation of
treatment, and there were few cases of pancreatitis. The final
analysis of this study will be available after December 1994, when the
trial is scheduled to close.

       Protease Inhibitor Studies

       Data presented at ICAAC emphasized the different anti-viral
effects of the most-studied protease inhibitors: Roche's saquinavir
and Merck's L-735-524. As measured by PCR techniques, Saquinavir can
achieve a two-fold reduction in blood- borne HIV particles (at the
dose currently being studied). The Merck drug can achieve a three-fold
to 1,000- fold reduction (average of 30-fold). But the key question
is: how long can these decreases be sustained? Both companies are
studying higher doses of their drugs to see whether they can achieve
greater and more sustained reductions in HIV levels. Merck Protease
Inhibitor: Merck researchers presented data on sixteen patients who
received the L-524 drug for six months at a dose of 400 mg every six
hours.8 Over 70 percent of the patients achieved greater than ten-fold
reduction in viral titers during the first several weeks. Resistance
to L-524 was noted in five of fourteen patients after six months. (At
a subsequent meeting at Merck headquarters, researchers reported that
within four to twelve weeks after initiation of L-524, HIV levels
start to increase, and by week 24 almost all patients return to
baseline levels.)

       The trial participants entered the study with a median CD4
count of 71 and had increases of 70 to 100 cells after a few weeks.
These increases were maintained for up to six months. In addition,
most patients had improvements in white blood cell counts, neutrophil
counts, platelet counts and hemoglobin levels. Most also gained a
median of eighteen to nineteen pounds in body weight. The only side
effect seen from the Merck protease was a transient increase in blood
levels of bilirubin, which is normally removed by the liver. Abbott
Protease Inhibitor: A "late breaker" session included a report on the
first pharmacokinetic study of ABT-538, the protease inhibitor under
development by Abbott Laboratories.9 Researchers from other companies
consider the Abbott compound, along with Merck's L-524, to be among
the most active and bioavailable of all protease compounds in clinical
trials. ABT-538 exhibited potent activity in the test tube (in vitro)
against HIV-1 and HIV-2 and achieved impressive blood concentrations
when given orally to rats, dogs and monkeys. Humans in phase I trials
absorbed the drug even better than the animals. Resistant virus was
eventually isolated. Further preliminary results from the phase I
trials will be announced at the Second International Conference on
Drug Therapy and HIV Infection in Glasgow, Scotland.

       GEM-91 Trials begin

       GEM-91 is an antisense oligonucleotide being developed by
Hybridon Inc., a Massachusetts-based company. In the first human study
of the drug, GEM-91 was administered to six HIV- positive individuals
by intravenous infusion. No drug-related side effects were seen.10
GEM-91 locks onto and sparks the destruction of exposed HIV RNA within
cells. It reputedly targets a number of steps in the HIV life-cycle,
including the integration of HIV genes into the nucleus of newly
infected cells and the production of new virus particles in cells'
cytoplasm. GEM-91 is now entering Phase I/II trials at a number of
sites, including New York Hospital. For information, call
212/746-4393.

       Preventing Fungal Infections

       William Powderly, M.D., of Washington University in St. Louis
gave an excellent overview of prophylaxis for fungal infections in
HIV-positive patients.11 Between 70 and 90 percent of people with AIDS
will develop oral candidiasis (thrush), about 20 percent develop
esophageal candidiasis, and five to ten percent contract cryptococcal
meningitis. The most widely studied anti-fungal agent in HIV-positive
patients is fluconazole. Itraconazole is another approved anti-fungal
agent. Dr. Powderly described fluconazole as an effective agent in
preventing fungal infections, but also noted that
fluconazole-resistant candidiasis is a significant problem and
itraconazole-resistant histoplasmosis and aspergillus are also
emerging. Once resistance develops, patients are forced to rely on
amphotericin B, an intravenous therapy with major toxicities.

       Dr. Powderly also noted the high cost of fluconazole
(approximately $20 per pill) and remarked that fungal prophylaxis
probably should be considered only for those who are at highest risk
for developing cryptococcal meningitis, such as people with CD4 counts
below 50.

       In a study that demonstrated how common fluconazole-resistant
fungal strains are becoming, Swiss researchers took oral swabs from
401 HIV-positive patients who showed evidence of fungal infections.12
Twenty-eight percent of these samples contained organisms resistant to
fluconazole. AIDS researchers from Bowman Gray School of Medicine in
Winston-Salem followed six patients with less than 50 CD4 cells who
developed fluconazole-resistant thrush while on fluconazole
prophylaxis.13 All six failed to respond to a higher dose of
fluconazole (800 mg per day). Two of the six were susceptible to
itraconazole, but all six ultimately needed amphotericin B therapy.

       Sorivudine (BV-ara-U) for Herpes Zoster

       A new agent for the treatment of herpes zoster called
sorivudine was studied in a randomized, double-blind trial, which
compared it to acyclovir given at a dose of 800 mg five times a day.14
Sorivudine has the advantage of requiring only one daily dose (40 mg
per day). Trial participants receiving sorivudine healed their zoster
lesions quicker, had fewer new lesions and required less use of
analgesics than patients receiving acyclovir. Time to resolution of
the pain associated with the zoster was similar in both groups.
Sorivudine is the second new drug being developed for the treatment of
herpes zoster. Famciclovir (Famvir, manufactured by SmithKline
Beecham) was recently approved. It is similar to acyclovir, but has
the advantage of twice daily administration.

       Famciclovir for Herpes in Women

       According to a study by University of New Mexico researchers,
famciclovir can limit the recurrence of new herpes outbreaks in women
with chronic herpes infections.15 In the double blind, placebo
controlled study, 375 women of unknown HIV status were randomized to
either placebo or six doses of the drug. Women who were given 125 mg
or 250 mg twice per day had a significantly prolonged time before new
herpes outbreaks. When these doses were taken only once daily, no
significant benefit was seen. The median time to recurrence of herpes
outbreaks was 2.7 months on placebo, 3.9 months on 125 mg twice a day,
and greater than four months on 250 mg twice a day.

       Foscarnet

       A study by European researchers suggests that five days per
week treatment with foscarnet may be preferable to seven days in
patients with CMV esophagitis or colitis.16 In the study, 33 patients
were randomized to receive foscarnet either five or seven per week.
Foscarnet was only slightly more effective when given seven days a
week, and the added benefit was not statistically significant.

       Two studies in animals suggest that liposomal formulations of
foscarnet may increase the drug's therapeutic efficacy while
decreasing its renal toxicity.17,18 Clarithromycin for MAC Prophylaxis
A long-awaited trial contrasting clarithromycin (500 mg twice daily)
with placebo for primary prevention of Mycobacterium avium complex
(MAC) was presented by researchers from Abbott Laboratories.19 The
international trial was randomized and double-blinded. It enrolled 684
HIV-positive volunteers with CD4 counts of less than 100. The average
follow-up was eight to nine months. There were fifteen instances (4.5
percent) of MAC bacteremia in the clarithromycin group compared to 42
cases (12.5 percent) in the placebo group, a highly significant
difference. There also were fewer deaths in the treatment group (74)
than in the placebo group (98), a 30 percent reduction in death rate.

       Patients receiving clarithromycin experienced more
gastrointestinal side effects and taste perversion than the control
group. Unfortunately, nine (60 percent) of the fifteen MAC isolates in
the clarithromycin group were resistant to the drug, whereas none of
the isolates in the placebo group exhibited resistance.

       These findings support the use of clarithromycin for MAC
prophylaxis and suggest that it is more effective and less toxic than
rifabutin. MAC breakthrough rates during rifabutin prophylaxis are
approximately eight percent.

       TB Prophylaxis

       A short course prophylactic regimen may be effective in
preventing tuberculosis (TB) in HIV-positive individuals, according to
a study by Spanish researchers.20 Twenty-two of 70 HIV-positive
individuals (who were either positive on the TB skin test or anergic)
received the short course regimen of 300 mg a day isoniazid and 600 mg
a day rifampin for three months. None developed TB. Of those not given
the short term prophylaxis regimen, five developed TB.

       Disappointing Crypto Studies

       Two studies of anti-cryptosporidiosis therapies ended
disappointingly. In a randomized multicenter study of Bovine
Anti-Cryptosporidium Immunoglobulin (BACI), cryptosporidia oocysts
(the parasite's fertilized reproductive cell form ) in patients on
BACI were reduced, but no difference in either stool volume or
frequency was seen.21 BACI is derived from the colostrum of
cryptosporidia-immunized cows. Another study of hyperimmune bovine
colostrum, infused into two people with AIDS-related
cryptosporidiosis, also showed no clinical benefit from the therapy.22

       "Off-Label" Drugs for HIV

       A survey of 386 physicians in the U.S. found that over 40
percent of all drug therapy administered to people with AIDS involves
"off-label" use of medications.23 Drugs prescribed off-label are
compounds approved by the Food and Drug Administration (FDA) for some
situations, but not for the particular one the physician is treating.
According to the survey, over 90 percent of people with AIDS receive
at least one off-label drug.

       Frequently, off-label use of a drug merely anticipated FDA
approval for that use (for example, Bactrim as prophylaxis for
pneumocystis pneumonia). Half of the doctors surveyed nonetheless
reported having problems obtaining insurance reimbursement for
off-label prescriptions. Not surprisingly, patients who had no
insurance or were members of health maintenance organizations (HMOs)
had less chance of receiving off-label therapies, as did
African-Americans.

       1 Ho, D. 34th ICAAC. October 4-7, 1994. Orlando, Florida.
Symposium 1.

       2 Saag, M. Symposium 1.

       3 Fang G, et al. Abstract LB-A6.

       4 Mayers DL, et al. Abstract LB-A11.

       5 Mudido P, et al. Abstract I126.

       6 Anderson RE, et al. Abstract I60.

       7 Dunkle LM, et al. Abstract LB-3.

       8 Deutsch P, et al. Abstract I59.

       9 Kempf D, et al. Abstract LB-A4.

      10 Zhang R, et al. Abstract LB-A5.

      11 Powderly W. Symposium 3-2.

      12 Chave JP, et al. Abstract I219.

      13 Horn CA, et al. Abstract I221.

      14 Dehertogh D, et al. Abstract LB-A7

      15 Mertz GJ, et al. Abstract H3.

      16 Schrappe M, et al. Abstract H99.

      17 Guembel H, et al. Abstract 145.

      18 Dusserre N, et al. Abstract H75.

      19 Pierce M, et al. Abstract LB-A2.

      20 Solera J, et al. Abstract I183.

      21 Fries L, et al. Abstract M21.

      22 Sluiters JF, et al. Abstract M19.

      23 Brosgart C, et al. Abstract I139.

      *********

      Validating Viral Load Markers
      by Dave Gilden

      The most dramatic change in atmosphere between the Ninth
International Conference on AIDS last year and the Tenth International
Conference this year concerned the newly available measurement
techniques for HIV load. The new HIV assays -- involving branched DNA
(bDNA from the Chiron Corporation) and quantitative polymerase chain
reaction (principally Hoffmann-La Roche's RT-PCR, but also Genelab's
QC-PCR) -- for the first time provide a relatively easy, reproducible
way of estimating the amount of HIV in an infected person's
bloodstream.

       PCR and bDNA tests do not count actual HIV particles directly,
but assess the amount of HIV genetic material present. Results are
recorded as the number of viral "copies" or "equivalents" per unit
measure. The tests for HIV RNA discussed here measure free virus
particles in blood plasma. The production of new HIV reflects current
viral replicative activity, which therapy can rapidly inhibit.

       Similar assays for HIV DNA measure the number of infected cells
with HIV incorporated in their genes. Since present and most upcoming
treatments do not directly eliminate infected cells or the HIV
therein, HIV DNA is a more stable quantity less sensitive to changes
in therapy. Infected cells may be actively producing new virus
particles, or, much more commonly, they possess quiescent or defective
HIV genes. The latter cells may live for many months.

       Utilizing Viral Load Assays

       HIV load analyses could be applied in two distinct manners:

       * In medical practice, they could be used to make individual
         treatment decisions. Rising HIV levels in a patient's blood
         could be taken as a sign of increasing failure on the part of
         the immune system or current drug treatment to control the
         virus. A physician could then recommend either beginning
         anti-HIV therapy or altering the present regimen to stave off
         further disease progression. Changing treatment in this
         manner is called a medical strategy approach and involves not
         just prescription of successive single-agent therapies
         against HIV, but juggling any of the proposed multidrug
         combinations as soon as their components are available.

       * In clinical trials, a treatment's antiviral activity could be
         measured in terms of the reduction in the amount of HIV in
         trial participants' blood. Single compounds or multidrug
         combinations that cause the greatest decreases would be
         candidates for further testing and possibly accelerated
         approval by the Food and Drug Administration. The bDNA and
         PCR techniques have an intuitive appeal. The obvious goal of
         antiviral therapy is to inhibit HIV and thus allow an
         infected individual to maintain or recover health. The tests
         can monitor drugs' effect on HIV in an immediate, "real-time"
         fashion that can never be duplicated by CD4 counts, which
         vary more slowly in response to therapy while fluctuating
         sharply for extraneous reasons.

       The Uncertainties

       But serious questions remain concerning the significance of
these tests. It may not be so difficult to establish that rising HIV
levels correlate with and even predict declining immune function and
worsening physical symptoms. (Several reports1,2 already suggest that
this is true.) It is also possible to chart the decline in HIV load
that occurs immediately after someone begins a new antiviral therapy.3
Whether this artificially induced drop in virus produces better health
is a more knotty issue, however. Consistently low CD4 cell counts are
considered a very accurate predictor of future physical symptoms. But
it turns out that raising CD4 count over the short term through
antiviral therapy has had disappointing results. Physical condition
has not improved correspondingly during clinical trials.4 (In one
study of people with advanced disease, though, trial participants
experienced an increase in survival greater than their CD4 count rises
would indicate.5)

       Resolving this issue runs up against the modest, transient
effects that current anti-HIV medications have. Stronger, more
sustained increases in CD4 counts, for example, might have an
incontestably positive effect on physical health. Also, HIV infection
focuses on the center of immune activity in the lymph nodes and other
lymphoid tissue, not in the blood. Detecting a lowering of HIV in the
bloodstream may not reflect what is occurring in the lymph system. One
study presented at the Tenth International Conference6 found that in
people with high CD4 counts (average of 654), initiating AZT therapy
did not alter the production of new HIV particles within lymph nodes
or the number of infected cells. Adding ddI to prior AZT therapy did
decrease new HIV production in the lymph nodes in four of six
patients, but this decrease was not statistically significant.

       An underlying problem is that HIV is a subtle infection because
there are no outward symptoms of immune deficiency per se. Directly
monitoring a treatment's effect requires some way of precisely
describing immune function. CD4 cell count by itself is not sufficient
because it does not indicate how well those cells or the immune system
as a whole are functioning. Even if therapy-induced reductions in the
amount of blood-borne HIV do trigger a rise in CD4 counts, this does
not guarantee that the immune system will recover.

       Surrogate Marker Conference Reports

       In an effort to find a way out of this labyrinth, many of the
chief contributors to recent developments in the surrogate marker
field -- including various measurements of HIV activity and immune
function -- attended a three-day conference in Arlington, Virginia
from October 12 to 14, 1994.

       The presentations at the conference comprised a vast review of
the subject, although many of the data had been released previously,
at the Tenth International Conference and elsewhere. [The studies
mentioned below were reported at both conferences, although in greater
detail at the October surrogate marker event. Footnote references will
refer to the International Conference Abstract Book, volumes I and II,
because this is a published, publicly available source.]

       Walter Reed Army data: One of the chief reports supporting the
utility of viral load assays comes from a. U.S. Army study7
investigating the relationship between HIV level and the emergence of
AZT resistance in those on long-term AZT therapy. The 100 trial
participants had a mean CD4 count of 252 and were followed for two to
three years. As reported by Douglas Mayers, M.D., of the Walter Reed
Army Institute of Research, researchers found that emergence of AZT
resistance was associated with HIV levels of more than 100,000 copies
of HIV RNA per milliliter of blood plasma.

       The strongest predictors of death in the group turned out to be
low CD4 count and even more significantly, HIV levels of more than one
million HIV RNA copies per milliliter of plasma. Another Army study8
presented by Dr. Mayers followed 32 individuals over two to three
years after they had switched from AZT to ddI monotherapy. In this
group, only low CD4 count (less than 100) was a statistically
significant predictor of death, with high plasma HIV load (an RNA copy
number of greater than 300,000 per milliliter) being not quite
significant.

       Veteran Affairs review: A report9 suggesting that reductions in
HIV level brought on by therapy do indeed lead to clinical improvement
has been prepared by William O'Brien, M.D., of the Veteran Affairs
Medical Center in Los Angeles, and his colleagues in a nationwide
trial known as VA CSP 298. The group analyzed old blood samples from
this trial, whose original results were published two years ago.10 (VA
CSP 298 was the first major study to conclude that AZT therapy early
in HIV infection, before CD4 count drops below 200, delayed
progression to AIDS but did not prolong survival compared to later
treatment, starting when CD4 count falls below 200.)

       Using a statistical model, investigators found that increases
in CD4 count in response to treatment could account for only 37
percent of the observed delay in progression to AIDS from early AZT
therapy. By comparison, meaningful reduction in virus levels seemed to
account for 67 percent of the clinical benefit. But the study could
say nothing about the association between reducing HIV load and
prolonging survival. AZT's inhibition of HIV is too temporary to make
a judgment on this score, according to Dr. O'Brien. "It's not just how
low virus load goes, but for how long," he notes.

       (Trial participants in the early treatment arm started AZT at
the beginning of the trial and experienced a 70 percent average
decrease in HIV level by the second month. This level returned to
baseline by the eighth month on average.) ACTG look-back: Another
review of an older study came to similar conclusions as the VA CSP 298
review. At the October surrogate markers meeting, Seth Wells, Ph.D.,
Sc.D., a senior statistician at the Harvard University AIDS Clinical
Trail Group Analysis Center, described findings gleaned from blood
samples taken in the course of the ACTG trial 116B/117. This trial
tracked the effect of switching to ddI after at least four months of
AZT therapy. High HIV levels at study entry were associated with more
advanced disease and quicker disease progression, and those whose HIV
levels increased had a greater risk of further progression regardless
of their initial viral load.

       Trial participants who continued to receive AZT experienced on
average a persistent increase in HIV load whereas those who were
changed to ddI had a modest reduction (of one-half logarithm or about
three-fold) that bottomed out at week eight. Interestingly, this
decrease was not reflected in any appreciable CD4 cell augmentation.
This result differed from the results in ACTG 116A and VA CSP 298,
which included people who had not yet started therapy and whose immune
deficiency was less advanced.

       In an interview, Dr. Wells observed, "I'm encouraged by the
data, but the patients in the 116B/117 trial were a very select
population [with advanced disease] and you can't generalize from that
data to other groups, including the people in 116A."

       Complicating Factors

       An indicator that works on a generalized population level might
not work when applied mechanically to individuals because each
personal response to HIV infection differs from the composite average.
One of the co-investigators in ACTG 116-117, Robert Coombs, M.D.,
Ph.D., of the University of Washington, described some of the
interacting factors that might explain different individual and
subgroup outcomes to changing HIV burden.

       The first factor is initial virus load. In people with low
levels of HIV particles in their blood -- RNA copy numbers of less
than 10,000 per milliliter -- there is little detectable
treatment-induced reduction, and changes in CD4 count are related to
changes in CD4 proliferation rates and the virulence of a patient's
particular viral strain. (The appearance of a so-called
syncytia-inducing, or SI, strain of HIV is one major sign of increased
virulence.) In ACTG 116B/117 (remember, these were people who were
previously taking AZT and had advanced immune deficiency), many of the
patients who were switched to ddI experienced some reduction in HIV
load and an accompanying increase in CD4 count. The trial participants
kept on AZT largely saw just the reverse: a continuing increase in
viral load and a decrease in CD4 count. This is a sign of AZT's waning
benefit over time.

       There were some participants in 116B/117, though, who
perversely had an increase in both viral load and CD4 count. Dr.
Coombs thought this phenomenon was due to higher CD4 cell replication
rates in such people. Another subgroup witnessed a simultaneous
decline in both viral load and CD4 cell count. Most of these people
possessed a virulent SI strain of HIV, Dr. Coombs noted.

       All these interacting elements make it hard to determine the
role viral load can play in clinical trials, and harder still in
individual treatment decisions. Dr. Wells' group at Harvard is
formulating ways to validate viral load as a surrogate marker. He
says, "Viral load seems like a great marker for phase I and II testing
[for screening new drugs for anti-HIV activity]. But we will need to
follow extraordinary numbers of people to assess how well viral load
works as a surrogate for [clinical] outcomes. The size of the studies
has to do with the magnitude of the treatment effects we're
observing."

       Dr. O'Brien concurs in this assessment. "There is not enough
data to change our whole policy," he says. Before viral load can enter
into wide-scale use as a predictor of increasing immune deficiency in
HIV infection, its relationship to physical symptoms will have to be
convincingly demonstrated. The rate of opportunistic conditions has
long been considered the "gold standard" for gauging therapies'
benefits. Given the lack of a more direct measure of immune function,
it is considered a real measurement of disease progress and ranked as
a "clinical" endpoint rather than a surrogate.

       Difficulties with Clinical Endpoints

       Frank Rhame, M.D., an AIDS researcher who heads the HIV clinic
at the University of Minnesota, goes a step further and argues, "You
have to ground surrogates in studies showing a survival difference not
in those counting up AIDS-defining events, which is itself a surrogate
marker." At the October surrogate marker conference, Dr. Rhame
explained in great detail the practical problems that have arisen when
relying on the incidence of new opportunistic conditions to decide the
outcome of clinical trials.

       One of the major difficulties encountered when interpreting
data on opportunistic conditions is that there is no ranking system
for judging the seriousness of illnesses, which can range from
comparatively minor candida infections to life- threatening
conditions. Also, trials usually count only the first event during
follow-up, ignoring whether a given individual experiences a whole
string of infections or not. Finally, trial sites may misdiagnose
illnesses or miss them entirely when trial participants fail to return
for follow-up -- frequently because they are too sick.

       Unfortunately, survival has its own drawbacks for evaluating
the effect of antiretroviral drugs. It is time-consuming and unethical
to wait for a sufficient number of deaths before judging the utility
of a therapeutic technique. In addition, death depends on the history
of opportunistic conditions, not just on HIV, and this history is
affected by therapies unrelated to antiviral medications and their
effect on surrogate markers for immune decline. Another concern is
that focusing on survival really focuses on the rapid progressors who
provide a disproportionate number of a trial's fatal events. Rapid
progressors' performance in a trial may not be representative of what
happens in other subgroups.

       Many Markers, Few Treatments

       The surrogate marker conference heard presentations describing
the utility of at least seventeen candidate surrogate markers,
including various measurements of HIV level and virulence, lymph node
condition and immune status. Different kinds of therapy affect the
AIDS disease process in different ways, so probably no one marker will
prove universal enough to be used alone. Viral load and CD4 count for
now promise to be the most applicable and informative combination, but
it will take considerable effort to sort out the contribution all
these different lab values can make, both for testing new drugs and
determining patients' individual treatment strategies.

       Thomas Merigan, M.D., a co-chair of the surrogate marker
conference, said, "We're trying to use surrogate markers to license
drugs with slight effect. How can we be definite?" Evaluating strong
treatments can be accomplished in a clear- cut manner. The lack of
such treatments creates both the need for surrogate markers and the
uncertainties concerning their application.

       1 Saksela K et al. Proceedings of the national academy of
science USA. Feb 1 1994; 91(3):1104-8.

       2 Mellors J et al. First National conference on human
retrovirus infections. Dec 1993; (abstract 274):103.

       3 Dewar RL et al. Journal of infectious diseases. Nov 1994;
170(5)1172-9.

       4 Fleming T. Statistics in medicine. Jul 30 1994;
14(14):1423-35.

       5 De Gruttola V et al. Journal of acquired immune deficiency
syndromes. Apr 1993; 6(4):359-65.

       6 Cohen O et al. Tenth international conference on AIDS
abstract book. Aug 7-12 1994; I(abstract 001B):7.

       7 Vahey MT et al. Tenth international conference on AIDS
abstract book. Aug 7-12 1994; I(abstract 253B):75.

       8 Mayers DL et al. Tenth international conference on AIDS
abstract book. Aug 7-12 1994; II(abstract 359B):17.

       9 O'Brien WA et al. Tenth international conference on AIDS
abstract book. Aug 7-12 1994; I(abstract 254B):75.

      10 Hartigan PM et al. New England Journal of Medicine. Apr 16
1992; 326(16): 1037-42.

       **********

       Passive Immunotherapy: New Stories, Same Old Data
       by Dave Gilden

       A conference in London sponsored last month by proponents of
passive immunotherapy (PIT) sparked a new round of interest in the
therapy, with reports appearing on both CBS and BBC television.
Because of the interest that has been generated by these reports,
Treatment Issues is providing a brief report on PIT.

       What is Passive Immunotherapy?

       PIT involves the transfer of plasma (the fluid portion of the
blood without the cells) from asymptomatic HIV-infected donors with
high HIV antibody levels to individuals with advanced HIV infection or
AIDS and low levels of HIV antibodies. The hope is that the HIV
antibodies in the transferred plasma will help preserve the
recipient's health. PIT's originator and chief promoter is Abraham
Karpas, Sc.D., an AIDS researcher from the University of Cambridge in
Britain. Dr. Karpas published his first paper on PIT in 1988.1

       No New News

       There is actually little new to report on PIT at the moment.
The occasion of the conference was the publication in Blood2 of the
results of a PIT study conducted by a small California company known
as HemaCare. (HemaCare is not a research company. Its main business is
blood tests.) The study was originally released two years ago, at the
1992 National AIDS Update Conference in San Francisco. Since then,
HemaCare has been negotiating with California health authorities to
allow a larger phase III trial including up to 900 persons. The
interchange proved fruitless and HemaCare is now seeking approval from
the U.S. Food and Drug Administration. One of HemaCare's problems may
be the equivocal conclusion of the previous study. Half of the 220
trial participants had baseline CD4 counts of under 50, and for them,
there was no evidence of benefit. The same was true for the trial as a
whole. HemaCare then analyzed the 72-person subgroup with CD4 counts
of 50 to 200. The company found slight advantages in terms of CD4
count and survival after twelve months of "full- dose" PIT (a monthly
500 ml plasma infusion) compared to half-dose PIT or placebo. No
reduction in opportunistic infections was observed in any group.

       A number of concerns have been raised about the way HemaCare
handled this study -- including breaking off relations with its
original statistician. His analysis of the study data was less
positive than the published one described here. (For further details
on the initial problems, see this author's article in AIDS Treatment
News, number 165, December 18, 1992, pages 1-3.)

       A small French PIT study presented at the London conference,
and also a year ago in Washington, D.C.,3 did find a two- thirds drop
in the incidence of AIDS-related opportunistic infections. The 82
participants had less than 200 CD4 cells per milliliter of blood and
symptoms of advanced immune deficiency. The 40 people in the placebo
arm received plasma from HIV-negative donors. A published report on
this study has not yet appeared, so interpreting its findings is
difficult.

       Future Studies of PIT

       The London conference could be dismissed as a public relations
move designed to garner support for further research. The studies may
be weak, but the data they contain plus various anecdotal reports do
provide argument for further research on PIT, especially in people
with fewer symptoms.

       PIT has no well-funded backer, nor is it cheap. One U.S.
practice that performs this technique is the Southern New England
Community Consortium (SNECC) in Greenwich, Connecticut. SNECC charges
recipients $900 a month. The organization's director, Gary Blick,
M.D., claims that even at this price, PIT has been a financial
disaster. Finding enough eligible plasma donors also has been
difficult. Dr. Blick and HemaCare both have suggested that there may
be some benefit for those who are donating plasma with HIV antibodies.
(The benefits are certainly not financial -- SNECC does not pay donors
for their plasma). There is little data, however, to indicate that
donating plasma either helps or hurts donors.

       1 Karpas A et al. Proceedings of the national academy of
sciences of the United States of America. Dec 1988; 85(23):9234-7.

       2 Levy J et al. Blood. Oct 1 1994; 84(7):2130-5.

       3 Vittecoq D et al. First National conference on human
retrovirus infections. Dec 1993; (abstract L12):153.

       ************
       Commentary

       Future Uncertain for NIH AIDS Drug Discovery Program
       by Vincent Pieribone, Ph.D.

       The National Institutes of Health (NIH) appears to be stifling
one of the most important AIDS drug development programs with hardly a
murmur of protest from AIDS activists. The program -- the $10 to 15
million dollar a year National Cooperative Drug Discovery Groups for
the Treatment of HIV Infection (NCDDG-HIV) -- has been the
responsibility of the National Institute of Allergy and Infectious
Diseases (NIAID), the NIH branch that conducts the bulk of AIDS-
related research. NIAID's plans to curtail its support for this
program will increase the distance between the Institute's growing
basic research portfolio and its large, albeit inefficient, system for
clinical trials of new antiviral drugs.

       The NCDDG-HIV was established in 1986 specifically to provide
financial support for scientists interested in developing innovative
anti-HIV therapies. Scientific investigations into the virus's
lifecycle are largely performed at academic research institutes
supported by the NIH. Drug screening and clinical trials are performed
by sponsoring drug companies and NIAID's AIDS Clinical Trials Group.

       Very often, though, observations made about the HIV lifecycle
that might have therapeutic application go unexplored by academic
researchers and drug companies. This large gap, between studying the
virus's lifecycle and screening candidate drugs, is where the
NCDDG-HIV stepped in. By nurturing collaborations between basic
scientists and drug companies, NCDDG grants attracted proven
researchers with sound therapeutic concepts into embarking on risky
drug discovery projects. Collaborating companies could guide the
scientists until their concepts were ready for the company to test.

       The progress made through NCDDG-funded grants have been
substantial. Research funded by this program has resulted in the
development of assays for measuring gag-gag and integrase-integrase
interactions (both necessary for viral infectivity) that are now used
to screen potential treatments. A screen for novel reverse
transcriptase inhibitors created through an NCDDG-HIV grant identified
inophyllum B as a potent inhibitor. This compound is now in
pre-clinical trials at the National Cancer Institute. Many grant
recipients consider NCDDG-HIV funding to have been indispensable to
their projects' advancement. One such researcher is Jef D. Boeke from
Johns Hopkins University, who is investigating capsid-targeted viral
inactivation mechanisms (which destroy the HIV genes within the viral
core). Dr. Boeke was unable to obtain any funding to work on HIV drug
discovery until his group received an NCDDG-HIV award. He then
obtained further support and transformed an interesting idea into a
novel and exciting therapeutic possibility.

       Restrictions on the NCDDG-HIV will lead to the loss of crucial
and rare collaborations. Although the program is not being killed
outright, it faces two severe constraints: a phased-in reduction in
the number of projects supported and a loss of the special "set-aside"
fund that maintained the program as a whole.

       A 1991 ad hoc NIAID committee reviewing the NCDDG unanimously
concluded that "investigator initiated, collaborative, consortium type
research directed at drug discovery should be fostered." But the
review committee recommended that NIAID should decrease number of
groups funded by the NCDDG-HIV from 27 in 1991 to eight to twelve. Its
reasoning was that the "present numbers of grants of high quality do
not appear to support [the current] level of funding."

       The lack of quality proposals may be a sad reflection on the
NIH's ability to inspire clinically related research from the hundreds
of HIV basic research grantees. The agency's ability in this respect
will further diminish under the current NIAID proposal to eliminate
the special budgetary allocation reserved for financing the NCDDG-HIV.

       In defense of this move Jack Killen, M.D., director of NIAID's
Division AIDS (DAIDS) said, "We are committed to maintaining a program
of eight to twelve NCDDG-HIV grants. We used to set aside money to get
the program running. There is no need for that now that the program is
set up. We will issue a program announcement, now being prepared,
saying we welcome NCDDG-type drug design applications involving
collaborations with industry."

       NIAID insists that researchers who no longer obtain funding
from the NCDDG-HIV can apply for traditional researcher- initiated
grants (R01, or program project, grants) to continue their research.
But the NCDDG was established precisely because the usual
researcher-initiated granting scheme generally does not fund drug
discovery research. The standard R01 review process is much too
conservative to properly assess exploratory research that seeks to
develop assays and therapeutic agents. R01 grants also are highly
competitive. Only ten to fifteen percent (or less) of the R01 grant
applications judged to have merit actually receive funding.

       The worst scenario would be to require the R01 grant reviewers
to evaluate all NCDDG-type research, as is now under consideration.
The NCDDG-HIV had specific requirements for grants that narrowed the
field of applicants, thereby increasing each applicant's chance of
success. The ad hoc review committee report on the NCDDG-HIV
commented, "It was agreed that the proposed cooperative agreement
(U01) objectives, including 1) therapeutic endpoint, 2) multiple
institution collaboration, 3) added value achieved by the
collaborations, and 4) high risk innovative research, clearly
distinguished this funding mechanism from R01 funded research."

       Nonetheless, Dr. Killen's statement appears to represent an
improvement in NIAID's position on the NCDDG-HIV. In July of this
year, DAIDS' therapeutics development chief Carl Dieffenbach, Ph.D.,
reportedly told the National Task Force on AIDS Drug Development that
the NCDDG-HIV was being phased out and that researchers could apply
for other grant programs. When reproached that obtaining many grants
involved a lengthy process, Dr. Dieffenbach responded that the grants
he was referring to took "only two years."

       NIAID furthermore recently announced a new program know as
SPIRAT (Strategic Program for Innovative Research on AIDS Treatment)
that is also designed to fill the gap between basic research and
clinical studies. Though AIDS researchers and activists applaud the
SPIRAT program, it is clear from the design of this program that the
majority of projects now funded by the NCDDG-HIV would not be eligible
for SPIRAT money. SPIRAT is focusing on a narrower, purportedly more
advanced range of products and emphasizes phase I human trials of gene
transfer and immune modulation research. In a letter sent to NIH
officials Drs. William Paul (director of the Office of AIDS Research),
Anthony Fauci (director of NIAID) and Harold Varmus (overall NIH
director), the Treatment Action Group (TAG) expressed its surprise and
dissatisfaction at the unwarranted loss of the critical NCDDG-HIV
program. (This writer was one the letter's co- authors.) TAG asked for
renewed set-aside funds for the NCDDG-HIV or establishment of a
similar program.

       Ironically, NIAID is pruning the NCDDG-HIV just at a time when
the blue-ribbon National Task Force on AIDS Drug Development is
concluding that bridging basic and clinical research should be a major
priority for NIAID and the NIH as a whole. David Ho, M.D., director of
the Aaron Diamond Center for AIDS Research and a member of the Task
Force, recalled a variety of extremely promising targets in the HIV
lifecycle that at present are ignored. (See Treatment Issues, October
1994, for an interview with Dr. Ho).

       Very few anti-HIV approaches are available to succeed the
current crop of new reverse transcriptase inhibitors and protease
inhibitors, which have not yet shown a long term anti-HIV effect in
initial clinical trials. The present situation is very grave: NIAID
should rescue the NCDDG-HIV program by restoring funding levels and
actively promoting new research in this vital area. In doing so, the
Institute will renew its commitment to bridge the gap between basic
and clinical HIV/AIDS research and encourage the more rapid
development of anti-HIV therapies beyond reverse transcriptase and
protease inhibitors.

       ************

       Treatment briefs by David Gold

       Consensus Statement to Save CPCRA Sites

       A coalition of organizations, including GMHC, is circulating a
consensus statement calling for refunding of the four sites in the
Community Programs for Clinical Research on AIDS (CPCRA) that were
recently de-funded (see Treatment Issues, October 1994, page 12).
Three of the four defunded sites were in New York City. The three New
York CPCRA sites had enrolled 67 percent of all Latinos, 59 percent of
all injection drug users, 54 percent of all women and 42 percent of
all African- Americans in the CPCRA nationally. Additionally, without
these three sites it is difficult to imagine how the CPCRA plans to
initiate its new tuberculosis trials. To sign onto this consensus
statement, call or fax your organization's name, city, state and
contact phone number to: Linda Podhurst, Ph.D., Clinical Directors
Network, 212/255-3841 (telephone) or 212/255-4840 (fax).

       New CDC Treatment Call-In Service

       The CDC National AIDS Clearinghouse has started a new HIV/AIDS
Treatment Information Service. Those interested can call 800/HIV-0440.
TDD/deaf access is 800/243-7012. Hours are Monday through Friday, 9
a.m. to 7 p.m. eastern time, and all calls are completely
confidential. The service provides federally approved treatment
guidelines and information. It also can link callers to other
appropriate information resources. Please contact Paul Warren at GMHC
by fax (212/337-3656) or mail with any comments you have about using
this information service. The feedback will be directed to the CDC to
develop and improve this service.

       Reports on 3TC Data

       A number of unconfirmed reports suggest that the combination of
3TC (also known as lamivudine) and AZT is achieving impressive
antiviral effects in studies of HIV-positive patients. Results of
combination AZT/3TC studies are expected to be released this month at
the Second International on Drug Therapy and HIV Infection in Glasgow,
Scotland. 3TC is a nucleoside analog active in the test tube against
both HIV and hepatitis B (HBV). It is at present in phase II/III
trials for both HIV and HBV. Resistance to 3TC occurs rapidly when the
drug is used against HIV. But test tube studies suggest that
resistance to 3TC makes AZT-resistant strains of HIV again susceptible
to AZT. Burroughs Wellcome, the manufacturer of AZT, has purchased an
option to buy the rights to 3TC for HIV disease. An expanded access
program for 3TC is available for HIV-infected adults and children with
CD4 counts of less than 300. Eligible individuals must have failed or
be intolerant to approved anti-HIV therapies and unable to qualify for
ongoing clinical trials. Physicians can call 800/248-9757 for
information.

       Petition for Saquinavir Access

       The nation's leading AIDS organizations have petitioned the
Food and Drug Administration, the National Institutes of Health, and
Hoffmann-La Roche to implement without delay an expanded access
program for saquinavir, an HIV protease inhibitor. The petition, which
was released at the October meeting of the National AIDS Drug
Development Task Force meeting, calls for a program that grants
immediate access to individuals who are ineligible for on-going
studies or who lack other treatment options. The coalition of groups
emphasizes that expanded access remains a critical component of AIDS
drug development. Hoffmann-La Roche, the New Jersey- based drug
company that manufactures saquinavir, has announced no plans for an
expanded access program at this time. At a September 12 FDA Advisory
committee meeting, FDA Commissioner David A. Kessler said, "The FDA
would strongly welcome expanded access for saquinavir." To add your
organization's support to this petition, contact Derek Link at GMHC,
212/337-3502.

       Cryptosporidiosis Trial

       A trial of IGX for the treatment of cryptosporidiosis will
begin at New York Cornell Medical Center in New York under the
direction of Rosemary Soave, M.D. IGX is hyperimmunized chicken egg
yolk. In the open label 21-day study, patients will drink one-quarter
cup of yolk (which some patients have described as a rather tasty
"nog") five times a day. The theory behind hyperimmunized egg yolks is
that the egg antibodies will fight the crypto parasite in human
intestines. Dr. Soave notes that the egg yolks have been irradiated to
remove salmonella and other bacteria, and her experience is that the
cholesterol is not a problem for most patients. To enroll, call Dr.
Soave at 212/746-6320.

       Correction

       A wandering zero garbled one of the questions and answers in
last month's interview with David Ho. The question concerned
measurements of blood levels of HIV by PCR or bDNA. Here is the
corrected passage from the article:

       Treatment Issues: What does it really mean if you have a level
of 200,000?

       David Ho: Well, obviously, the lower the better. But let's say
that it is on the order of 10,000 to 20,000. That is, relatively
speaking, pretty low. Whereas if you begin to have levels of 100,000,
that's pretty rampant viral replication, and I would do something to
control that.

       Copyright (c) 1994 - Gay Men's Health Crisis.  Noncommercial
       reproduction encouraged.  DISTRIBUTED BY GENA/aegis *
       714.248.2836 * 8N1/Full Duplex * v.34.
