       Gay Men's Health Crisis "Treatment Issues"
       Vol. 8, No. 11 - December 1994
       ******************************************

       Implants for CMV Retinitis Show Promise
       by Kevin Robert Frost

       On December 14, the National Eye Institute (NEI), a division of
the National Institutes of Health, announced the results of a study of
intraocular implants for the treatment of CMV retinitis in people with
AIDS. The announcement coincided with publication of the results in
the Archives of Ophthalmology and an editorial appearing in the
Journal of the American Medical Association (JAMA).

       CMV retinitis is a sight-threatening condition that occurs in
approximately twenty percent of people with AIDS. The standard
regimen, involving daily infusions of either ganciclovir or foscarnet,
is difficult for patients and has limited benefit in treating CMV
retinitis. The data from the NEI study offer the hope that the Chiron
implant will significantly improve the ability to treat CMV retinitis.

       What are Intraocular Implants?

       The implant consists of a tiny device (about half the size of a
peppercorn) surgically placed directly into the eye and designed to
deliver a steady dose of ganciclovir over an extended period of time.
The implants, which are manufactured by Chiron Vision of Irvine,
California, provide a higher concentration of drug to the area of the
eye that is affected by CMV.

       The Study

       The small phase II study randomized 26 patients to receive
either the implant or deferred therapy. Patients with newly diagnosed
untreated CMV retinitis were entered into the study, provided that the
retinitis was considered peripheral and non-sight-threatening. Studies
in which patients are randomized to an "observational" arm have long
been controversial in CMV retinitis trials since those patients not
receiving treatment will suffer some tissue damage, though usually not
an actual loss of vision. Most ophthalmologists believe that deferred
therapy trials are ethical since they place the least number of
patients at risk.

       Trial participants assigned to the immediate treatment arm were
given the implant. If a patient entered the study with disease in both
eyes, then one eye served as the control (and received no treatment)
while the other eye was immediately treated with the implant. All
patients were examined on a biweekly schedule, and fundus photographs
(the "gold standard" for CMV retinitis) were taken at each visit.
Patients with clinical signs of CMV disease outside the eyes
(extraocular CMV) were excluded. However, if a patient on the study
developed extraocular CMV, systemic IV therapy with either ganciclovir
or foscarnet was given.

       Results

       The median time to progression of retinitis was fifteen days in
the delayed treatment arm compared to 226 days in the implant group
(statistically a highly significant difference). While it is difficult
to compare results from different studies, the Studies of Ocular
Complications of AIDS (SOCA) study, which compared the standard CMV
drugs intravenous ganciclovir and foscarnet, showed that the median
time to progression on these drugs was 47 and 53 days,
respectively.[1]

       Possible Toxicities

       Seven of the eyes in the trial developed a complication known
as retinal detachment, a condition in which the retinal tissue becomes
separated from the inner wall of the eye. Retinal detachment can
rapidly lead to vision loss, but is treatable with silicone oil
injections. It is unclear whether the detachments seen in the trial
were attributable to the implant since the overall rate of detachments
was only eighteen percent, when all 39 eyes that received an implant
at some point in the study (including those originally randomized to
deferred therapy) are included. This overall rate appears similar to
the incidence of retinal detachments typically found in patients with
CMV retinitis who have not been given implants. One study, by Jabs, et
al, found that approximately twenty percent of individuals with CMV
retinitis developed retinal detachments.[2]

       Spread of CMV

       The rate of CMV disease outside the eyes was 31 percent (eight
of 26 patients) and the median time to this extraocular disease was
248 days. The estimated risk of developing disease in the unaffected
eye was 50 percent at six months. Taken together, these findings
suggest that physicians may consider using some systemic therapy with
the implants. Reduced dosing and frequency of standard intravenous
therapy is one possibility.

       Looking Beyond The Study

       Some researchers believe that achieving control of CMV
retinitis would make the need for daily infusions obsolete. Currently,
Syntex, of Palo Alto, California, is conducting a study comparing oral
ganciclovir combined with the Chiron implant to both intravenous
ganciclovir alone and the implant alone.

       As of August 1994, fifteen of the 26 patients in the NEI study
had died (median survival time of 295 days). The need is paramount to
understand how this survival time differs from that obtained with the
current standard of care. The Syntex study, as well as the still
unreleased results from a phase III study of the implants by Chiron,
may provide that information.

       Access to the Implants

       Currently, the Chiron implant is an experimental therapy,
although the company plans to seek FDA approval in 1995. The Syntex
study of the implant plus oral ganciclovir is now enrolling patients
with CMV retinitis. For more information, call Lynda Thomas of Syntex
at 415/855-6021. In addition, Chiron is making the implant available
to patients that have failed or are intolerant to both ganciclovir and
foscarnet. For more information on centers able to provide the
implants, call 800/CHIRON-8.

       References

              1. SOCA-ACTG Study. Ophthalmology. Jul 1994;
       101(7):1250-61.

              2. Jabs DA et al. Archives of Ophthalmology. Jun 1991;
       109(6): 794-9.

       -------------------------------------
       3TC: Intriguing Reports, Limited Data
       by Dave Gilden

       3TC, an anti-HIV compound that has had trouble making an
impression finally got some favorable news last month. Reports at the
Second International Congress on Drug Therapy in HIV Infection (held
in Glasgow, Scotland from November 18 to 22) gave the first hint --
and it is only a hint despite a deluge of publicity -- that 3TC may
represent some real advance in HIV therapy.

       What is 3TC?

       Like AZT, 3TC is a nucleoside analog, a faulty DNA building
block. It stops the HIV enzyme reverse transcriptase from producing a
complete DNA copy of HIV's genes within a newly infected cell. This
step is necessary to insert those genes into the cell's own genetic
machinery within the nucleus. 3TC has a particularly low number of
side-effects (principally nausea, vomiting and headaches, with little
of the bone marrow suppression seen with AZT). Its major problem has
been that it does not seem to work as a single agent: resistance to
3TC arises a few weeks after therapy begins as a result of a single
mutation in HIV's genes.

       This resistance is not absolute. There seems to be some
continuing reduction in virus levels in people taking 3TC. More
significantly, resistance to 3TC in laboratory tests seems to
resensitize HIV to AZT.

       The observation that resistance to one drug negates resistance
to another has occurred before, with ddI and AZT, but has not been
confirmed outside the test-tube. In humans, new mutations occur that
can confer co-resistance to both AZT and ddI. Nonetheless, research
into 3TC combined with AZT was begun, and Burroughs Wellcome, AZT's
manufacturer, signed an option agreement to obtain rights to HIV
therapy applications from Glaxo, 3TC's developer.

       European Data

       The data on 3TC plus AZT presented in Glasgow received a lot of
notice, and Glaxo considered them encouraging enough to cancel its
agreement with Burroughs Wellcome. With the help of trials now being
conducted in North America, Glaxo expects to apply for marketing
approval of the combination therapy during the first half of next
year. The figures do look intriguing, but at second glance, they lack
the power to be convincing.

       Reports on two European studies were presented in Glasgow, one
for people with little prior history on AZT (AZT-naive) and the other
involving people with an average of two years on AZT. At this point,
the first study has been much more extensively analyzed than the
second.

       The AZT-naive study started out with 129 people. The median CD4
cell counts in the first study was 251. This number rose in the
combination arm of the study by 80 points after 24 weeks of therapy.
At the end of 48 weeks, the median CD4 count was still 45 above
baseline, and the month-to-month graph of CD4 count changes indicated
hardly any downward trend. The decrease in blood-borne HIV
corresponded to the increase in CD4 cells. As measured by the RNA PCR
test (see Treatment Issues, November 1994, page 4), virus levels were
down 86 percent at week 24 and 91 percent at week 48.

       An interesting aspect to this study was that it included an
AZT-only comparative arm for the first 24 weeks. This group then
switched onto open-label AZT plus 3TC for the next 24 weeks. From the
very beginning, the AZT-only people fared more poorly than the people
on combination therapy although they too had little or no prior
exposure to AZT and presumably the HIV in their bodies was not
resistant to the drug. At week 24, the AZT-only people were down a
median of seven points in their CD4 counts (at week four they had CD4
counts a median of 34 points above baseline). Their HIV levels were
only 36 percent below baseline (the peak decrease, at week two, was 76
percent).

       After the second 24 weeks, with the AZT monotherapy group now
also on 3TC, CD4 counts were a median of 40 points above their initial
values and virus load was down 92 percent from the start of the study.
In terms of lab values, the original monotherapy group had caught up
with the combination arm through adding 3TC to its regimen.

       The concept that 3TC reinforces and even rejuvenates the effect
of AZT after the first few months was reinforced by the second study
presented at the Glasgow conference. This one involved 223
AZT-experienced volunteers with an average CD4 count of about 250.
Participants either remained on AZT alone or followed a regimen of AZT
and 3TC at one of two doses (150 mg twice daily or 300 mg twice
daily). After 24 weeks, those on either of the combination therapies
saw their CD4 cell counts rise by an average of 33 (the peak value was
47 above baseline), while those remaining on AZT lost an average of 21
cells. Data on HIV levels or on CD4 cells past 24 weeks have not yet
been released.

       The Shrinking Sample Size

       Though not extraordinary, the response to AZT/3TC therapy does
seem comparatively robust given the results with most other
anti-reverse transcriptase combinations and, especially, seems more
sustained. But the soundness of the numbers is open to question. This
is particularly the case for the data after 24 weeks, which
substantiate the "sustained" nature of the response.

       In the first study, HIV levels were measured by RNA PCR in only
one of the study sites -- for a total of only 36 people at baseline,
31 persons at 24 weeks and just sixteen at 48 weeks. Initial CD4
counts were for 129 trial participants, but the 48-week values
represented 72 individuals. In both studies, twelve percent of the
participants dropped out in the first 24 weeks, and in the first
study, many of the participants had not reached 48 weeks of therapy
when the data was analyzed. (These figures were all supplied by Glaxo;
the dropout rate in the second 24 weeks of the first study was
unavailable at Treatment Issues' press time.)

       The actual sizes of the subsets involved in the data analysis
were not mentioned in any of the written accounts of the Glasgow
reports (including Glaxo and Burroughs Wellcome's press releases) nor
were they pointed out in the oral presentations themselves. It is
unclear at present whether any bias was introduced by these declining
numbers. (To give two examples of how the study findings could have
been skewed: the site used for measuring HIV levels might not be
representative of the study as a whole or the final results might be
biased because the best responders tended to remain in the study while
others dropped out.)

       In any case, it is hard to draw any definite conclusions on the
basis of viral load measurements of sixteen people. The CD4 count data
also become weaker as the number of people behind the data shrinks.
Any firmer conclusion on the value of the 3TC/AZT combination must
await the data from the North American trials, which will be reported
at the end of January in a conference in Washington, D.C. These two
trials have enrolled a total of about 600 people, with HIV levels
measured in 500 of them. They supposedly compare 3TC plus AZT to 3TC
plus ddC, AZT alone and 3TC alone. But this data will only be
available for the first 24 weeks on therapy. Whatever the new data
says, none of the 3TC trials to date have proved large enough to
detect any significant improvement in physical symptoms due to
therapy. Larger trials intended to collect clinical results will
commence early next year. At the same time, Glaxo intends to ready its
current analyses for an application for FDA approval of the 3TC/AZT
combination.

       Whether the modest 30 to 80 CD4 cell count rise observed will
translate into clinical improvement is an unresolved question. In
trials of other nucleoside analogs, improvements in this range did not
help patients in the long run, but these increases did not last for as
long as they seem to do with 3TC plus AZT.

       Hepatitis B

       Of note, 3TC is also being studied as a treatment for chronic
hepatitis B. Two small trials, one in the U.S. and one in China, have
been completed. In the 100 mg and 300 mg per day arms of the North
American trials, 3TC reduced virus levels below detectable amounts
after three months of treatment. These results involved 22 people. In
eleven of the 22, reduced levels of hepatitis B continued through six
months of post-treatment follow-up. Additional studies of 3TC alone
and in combination with alpha interferon are now in the planning
stages.

       3TC Expanded Access

       Glaxo operates a large expanded access program that provides
3TC to HIV-positive individuals who have CD4 counts below 300 and are
failing or cannot tolerate approved therapies. Those who are
coinfected with HIV and hepatitis B might be particularly interested
in this program. Glaxo is trying to flag coinfected enrollees for
special follow-up. Concomitant use of other drugs such as AZT has been
discouraged in the expanded access program but not absolutely
prohibited. This policy is undergoing review in light of the 3TC/AZT
combination therapy results. People who are interested in 3TC expanded
access should have their physicians call Glaxo at 800/248-9757.

       -----------------------------
       Screening for Cervical Cancer
       by Amy Fusselman

       Defining the best way to screen HIV-positive women for cervical
cancer has long been a matter of debate. Medical reports through the
years have documented that women with HIV have a greater risk of
cervical cancer and that such cancer progresses more rapidly and tends
to recur after treatment. The standard method for detecting
abnormalities that might develop into cervical cancer is the Pap
smear, a simple procedure consisting of swabbing the cervix to obtain
a sample of cells which are then examined under a microscope.
Unfortunately, the accuracy of Pap smears has been called into
question, particularly in the case of women with HIV. These women
frequently have lower genital tract infections that may obscure Pap
results. One 1991 report1 from the State University of New York Health
Science Center in Brooklyn found not only that the incidence of
cervical tissue abnormalities increased with worsening
immunosuppression but that Pap smears detected these abnormalities in
only three of the 32 women in the study. Colposcopy, a more
discriminating procedure, detected cervical problems ranging from
inflammation to precancerous lesions in another 22 of the women.

       In colposcopy, a low-power microscope (colposcope) is used to
examine the cervix, and if suspect tissue is observed, small pieces
are removed (biopsied) for further evaluation. Although colposcopy
traditionally serves only as a corroborative test in women with
abnormal Pap smears, the authors in 1991 urged that "cervical
colposcopy be part of the routine management of HIV-seropositive
women" regardless of the findings of previous Pap smears.

       Colposcopy versus Pap Smear

       When the Centers for Disease Control and Prevention (CDC) began
drafting gynecological guidelines for HIV-positive women last year,
the CDC's advisory group had to choose between a schedule of regular
Pap smears and/or colposcopy. The agency settled on recommending
repeat Pap smears as a way of countering false-negative individual
Paps. The CDC said that care providers should perform a baseline Pap
smear as part of the initial gynecological exam for women with HIV. If
the results are normal, another Pap smear should be performed in six
months, and after that, annually. If the results of the baseline Pap
are abnormal, the CDC still recommended that women wait another six
months for another Pap. If a woman's second Pap smear also is
abnormal, providers should refer the woman to a trained clinician for
colposcopy.

       Upon hearing the guidelines, many AIDS activists feared that
HIV-positive women who had to wait six months or more for testing of
abnormal Paps would risk contracting life- threatening cervical cancer
-- now regarded as a totally preventable disease. In the effort to
ensure prompter, more effective care, many activists insisted on
colposcopy examination for all HIV-positive women.

       Three medical studies published this year, though, have found
that Pap smears in HIV-positive women are just as accurate as those in
HIV-negative women. When properly conducted, Pap smears furthermore
seemed almost as accurate as colposcopy in detecting the early signs
of potential cervical cancer, even in women with HIV. The largest of
these recent studies2 was reported in October. It involved 398 women
with HIV and 357 without. Twenty percent (70) of the HIV-positive
women had precancerous cervical lesions compared to five percent
(fifteen) of the HIV-negative women. Fifteen of the women with HIV had
lesions detectable only by colposcopy and biopsy. The other two
smaller studies found similar results.[3,4]

       Strategy over Technique

       But the issue is deeper than just one tool versus another. In
the Abner Korn study cited above, twelve of 38 HIV-positive women with
scheduled appointments for further gynecological care never showed up
and were lost to follow-up. Such poor relations between doctors and
their patients cast doubt on the practicality of the repeat Pap smear
approach.

       Howard Minkoff, M.D., a gynecologist at State University of New
York's Brooklyn center commented "I don't think the case is proven
that regular pap smears are less effective than colposcopy Any
surveillance system will work as long as it is rigorous and regular."

       Marion Banzhaf executive director of the New Jersey Women in
AIDS Network, had a suggestion for how "rigorous and regular
surveillance" could be better assured. "I don't want to abandon the
fight for colposcopies," she said, "but at the same time, we're still
at square one in dealing with access. The women I work with have a
hard enough time getting gynecological care in the first place." The
first item Banzhaf would address is "incorporating GYN into HIV
primary care -- basically giving a more realistic approach to the
body."

       Risa Denenberg, a family nurse practitioner in the AIDS Clinic
at New York's Bronx Lebanon Hospital, extended Banzhaf's remarks:
"Cervix cancer, like PCP, is a preventable disease. And like PCP, a
case of cervix cancer represents not an individual failure, not a
medical failure, but a system failure. We need to work towards a
consensus that all women should receive their gynecological care in
the context of receiving their primary care. And for HIV-positive
women, we must agree that the appropriate standard of care is having a
Pap smear every six months, and that all HIV-positive women with
abnormal Pap smears need to receive colposcopy immediately. That is,
within six weeks. We are no way near achieving this standard."

       Denenberg continued, "If we now demand that all HIV-positive
women receive a colposcopy as a screening test for cervix cancer, we
fail women in two very important ways: one is that we are letting
primary care providers who don't want to do Pap smears anyway off the
hook; and, two, we will make HIV- positive women -- who are at the
greatest risk of cervix cancer -- wait even longer for an evaluation."

       Colposcopy requires specialized training as practitioners must
attain the skill to visually recognize diseased tissue through the
colposcope lens. There are not enough expert colposcopists at present
to regularly examine every women with HIV, and this exam will always
have to take place separately from other medical procedures. As a
practical matter, it may be more effective to educate women to demand
and create the best conditions for successful use of the low- tech Pap
smear than to pour resources into the more sophisticated colposcopy
technique. (See box, page 5.)

       References

              1. Maiman M et al. Obstetrics and gynecology. Jul 1991;
       78(1):84-8.

              2. Wright TC et al. Obstetrics and gynecology. Oct 1994;
       84 (4 part 1):591-7.

              3. Korn AP et al. Obstetrics and gynecology. Mar 1994;
       83(3):401-4.

              4. Brosgart C et al. Tenth International Conference on
       AIDS. Aug 1994; I(abstract 079B):26

       -----------------------------------------
       Obtaining Optimal Results from Pap Smears

       The accuracy of Pap smears varies greatly from one clinical
setting to another. Risa Denenberg, who performs hundreds of the tests
per year, says patients and clinicians should remember the following:

       * The best smears are obtained mid-cycle.

       * Smears taken during a period or when bleeding for any other
         reason are unacceptable.

       * Patients should not douche, use tampons or have sexual
         intercourse for 48 hours before a Pap smear.

       * Pap smears require two tissue samples. First, clinicians
         should trace out the squamocolumnar junction (where the
         inner, more tender and outer, plate-like cervical linings
         meet) and sample it with a cervical spatula.

       * Clinicians also need to obtain an endocervical (inner cervix)
         sample with a cotton swab or narrow "cytobrush."

       * Lubricants interfere with obtaining proper tissue samples.

       * As a preservative measure, it is necessary to apply fixative
         within ten seconds after spreading samples on microscope
         slides.

       * Proper labeling of slides is the clinician's responsibility.

       * Patients and clinicians should only accept Pap smear results
         from a lab that uses the standardized Bethesda system to
         report results.

       ------------------------------------------------------------
       Inside Roche: An Interview with Jrgen Drews and Whaijen Soo

       The Roche Group, based in Basel, Switzerland is the corporate
parent of Hoffmann-La Roche. Roche, which recently purchased Syntex
and, before that, a controlling interest in Genentech, is one of the
largest pharmaceutical companies in the world. In terms of value of
outstanding stock, Roche approaches industry leader Merck & Co in size
($46 billion versus $38 billion). While the company is a major player
in AIDS drug development, its relationship with AIDS activists has
often been strained and bitter.

       In an effort to examine AIDS drug development and research
issues and gain a better understanding of Roche itself, David Gold and
Dave Gilden of Treatment Issues interviewed Jrgen Drews, President of
International Research and Development for Roche and Whaijen Soo,
Hoffmann-La Roche Vice-President of Virology at the headquarters of
Hoffmann-La Roche in Nutley, NJ.

       Jrgen Drews
       Treatment Issues

       (TI): Can you give us an overview of Roche's HIV research
program?

       Jrgen Drews: We have HIVID [ddC] on the market and we are
developing saquinavir [a protease inhibitor], which is likely to be
the first approved protease inhibitor. We also worked on tat
inhibition which we gave up because of disappointing clinical results.
After these, we do not have other anti-HIV drugs. But we have a broad
antiviral program and a program on immuno-enhancing drugs. Our
anti-viral program, which we are enlarging, focuses on herpes,
hepatitis and papilloma viruses. In about one to two years, they will
start entering new compounds into the development pipeline. And we
also have an immunology program which is very broad. One immune
product, IL-12, is presently slotted for oncology [cancer] studies.
That may be an area where we decide to reenter the AIDS arena.

       We are also studying agents for some of the opportunistic
infections, like mycobacteria and pneumocystis carinii to see whether
we can find a drug that inhibits several of these infections.

       TI: But essentially, after saquinavir, is Roche out of the AIDS
field?

       Drews: We are not out. We are really putting a lot of energy in
saquinavir and ddC and trying out all kinds of combinations. But for
the time being, we haven't done much in AIDS because we don't see any
compelling ideas that seem particularly rewarding. If the scientific
or technical feasibility is not there, we would rather do something
that is more compelling at this point.

       TI: Last summer, TAG [Treatment Action Group, the New York-
based advocacy organization] proposed a "large simple trial" to
evaluate saquinavir and other protease inhibitors. How does the
company view such proposals?

       Drews: The controlled trials with several thousand patients
that we have now in the works will give us better information than
these large simple trials, the way they were envisaged. They really
wanted to use the protease inhibitors against the background of
anything that might be taken in a very, very large population. Now,
that's not impossible. But you need many, many patients in order to
power the study to be able to say something. This is particularly
impractical in the case of protease because it is so difficult and
expensive to make. You may be willing to think about it with a drug
that you can provide in large amounts at reasonable cost, but with
these particular compounds it is not feasible.

       TI: But look at ddC: the data is controversial and ambiguous at
best. People don't have much confidence in the drug. Drews: It depends
really on which parameters you use. If you use certain surrogate
parameters, there is clearly an effect. If you use
mortality/morbidity, we know very little. We are moving away from
using such drugs as single agents. The combination studies are most
likely to be able to show some benefit in terms of improving morbidity
over the long range.

       TI: What should be the standard for measuring whether a drug
like saquinavir is ready for accelerated approval?

       Drews: We all have become a little less optimistic about the
meaning of CD4 cells. Of course, morbidity and mortality are what
really matters, but I have confidence in viral loads. If I can reduce
PCR-detectable virus by one or two orders of magnitude, I would feel
pretty confident that that will eventually have an effect on the
course of the disease.

       TI: When does Roche plan to apply for approval of saquinavir?

       Drews: We don't really have a time schedule. We now have two
large studies ongoing. One started accruing patients this year, the
other in 1993. The original plans were to seek approval in 1995, but
we may have to postpone that somewhat depending on the availability of
drug. We don't want to apply for approval and not have the material to
launch it broadly.

       TI: If the compound is so expensive to produce, is it a
feasible drug to develop?

       Drews: I think it can be done. There have been improvements in
the manufacturing and the number of steps required. We now think we
can produce the drug in sufficient quantities and at a price that is
feasible.

       TI: How do we encourage greater investment in HIV research by
the private sector?

       Drews: It's difficult to say. HIV is perceived as a technically
difficult area of study. Scientifically, there are not yet many
obvious and very promising targets of intervention. It is a bit like
oncology looked ten to fifteen years ago, [when] the investment wasn't
all that overwhelming either. Today, oncology looks much different,
with new mechanisms and an understanding of how it is caused. New
targets are evolving at a rather rapid pace, and companies are
reentering the field.

       The other thing is that people perceive HIV as a highly
politicized field where you risk not being able to judge your programs
and developmental compounds on the basis of medical, scientific and
economic feasibility. You have to take into account many other
factors. That is perceived by many people -- quite frankly -- as a
negative. This is to some extent due to the activity of groups like
yours. On the other hand, the same groups have done quite a few good
things such as pushing accelerated approval.

       Whether the interference was positive or negative, it is
perceived as putting a constraint on those who invest resources, money
and time in finding something. In terms of encouraging more
investment, the community advocates have become more constructively
involved instead of simply protesting the inability of science or of
the industrial community to come up with something that makes a big
therapeutic difference. So there has been a change which is slowly
being perceived as helpful. But we need a little more time and perhaps
some stronger signals.

       TI: The last time I was at Roche's offices was during an ACT UP
demonstration. Why do you think there was such tension between Roche
and activists?

       Drews: First, I think there is a tremendous tension in the
community about treatment issues. That is understandable and everybody
will respect that. Secondly, the relationship between Roche and the
community may not always have been handled very well, on both sides. I
think that Roche has not been terribly open and communicative.
Sometimes too guarded, and perhaps too cautious in dealing with the
community. That is my impression coming in as an outsider with an
international perspective and seeing the situation as it is. When I
came to Nutley, I thought the organization here was more guarded,
cautious and secretive than at Basel. But to me, improvement along
these lines with more open communication is possible.

       TI: One of the things that struck me about Roche was that the
people in Nutley did not seem capable of making decisions. Everything
had to go through headquarters in Basel.

       Drews: But, you see, your negative impressions may have come
from a time when Roche was really in transition. We started a new
organization in pharmaceuticals in 1990, and my coming over here was
part of that reorganization. Until that time, decision-making was
really not so clear. Basel and Nutley were kind of acting like almost
autonomous centers. For someone from the outside, it must indeed have
been very confusing, and very difficult to really trace decisions.
Now, the decision-making mechanisms are very clear.

       TI: Roche also owns the rights to PCR technologies. How do you
see the impact of these tests in HIV?

       Drews: They're going to have a very large impact. PCR allows
for a quick and convenient way to quantify viral loads. I am quite
optimistic that it would be possible to extend the present ways of
measuring viral RNA to make separate assessments for intracellular
virus, for virus in plasma, and for virus in several cell compartments
-- and thereby gaining a picture of what is really happening in HIV
infection. I really see a tremendous increase in understanding of what
actually is going on and how you can modify that by various treatment
regimens.

       TI: Do you anticipate the price of the HIV PCR test going down?

       Drews: It's very difficult to say. Since the technology is
going to come up with even better ways of doing this, you can charge
the higher prices for the newer generation tests. And the older
technologies will probably become cheaper. But you should really
discuss it with our diagnostic people.

       TI: Since many people with HIV are using vitamin supplements,
and Roche is one of the largest producers of vitamins, how can we get
real answers about whether these are useful? Drews: Again I only have
an oversight in R & D, not in this area. It is very difficult to find
industrial responses for these kinds of studies. While we are quite
interested in learning more about these products, nobody really wants
to do the studies. We support several such studies in various fields,
usually in oncology, but we don't want to do them all. They should be
done by health organizations like the NIH and by other national health
organizations.

       Whaijen Soo

       TI: How many people will you be able to provide saquinavir for
on an expanded access program?

       Whaijen Soo: We had hoped to have enough drug for up to 4,000
or 5,000 patients [starting next year]. Because of the formulation
problem, we really can't say for sure. We believe that once we commit
the drug supply to these patients, we can't just run out of drug and
leave them unable to continue.

       TI: What is the drug supply problem?

       Soo: The drug supply problem is more related to the formulation
of the drug itself, not the substance. The drug is extremely difficult
to manufacture, requiring multiple steps and a long lead time type of
synthesis.

       TI: Are you certain that you will have drug for expanded access
program?

       Soo: We are hopeful. The scientists from the United Kingdom and
Switzerland working on this say that this problem can be solved. So we
are very hopeful that we will be able to initiate an expanded access
program sometime in 1995.

       TI: Has there been any toxicity associated with saquinavir at
the dose that you are testing?

       Soo: At the doses used in the Phase I/II studies, we have not
run into any toxicities that can be directly associated with
saquinavir. However, in the study we have now been working on with Tom
Merigan at Stanford, with doses up to 7200 mg per day (which is 7.2
grams), we have now run into GI complaints. It is not clear if this is
due to the drug per se or the fact that it is such large quantity of
drug, and a material that is not well absorbed.

       TI: How far are you away from a new, more bioavailable form?

       Soo: We have a formulation that is being studied -- so far only
in single dose availability studies. And in all volunteers, we have
seen up to a three-fold increase in bioavailability. But it is still
quite early in terms of the drug development stage. We have to run a
number of studies to make sure that the formulation is the right one
to take into further clinical trials.

       TI: In the Merigan study, have you seen toxicities at 3,600 mg?

       Soo: No, we only saw the toxicity at the 7,200. We have seen a
mild elevation of liver function in both dose regimens, 3,600 and the
7,200, such as the SGOT [enzyme]. But not in bilirubin. Not any sort
of obstructive liver damage. These are mild and based on very
preliminary information. TI: Is the 1,800 mg dose used in the [large
Roche] trials a suboptimum dose?

       Soo: If we had to increase the dose during our early dose range
studies, we would have required a much larger quantity of the drug.
That was not realistically possible from a business sense. And
therefore our choice was to go in and study the 600 mg regimen based
on the early phase research data showing a biological effect,
primarily based on CD4, and some effect on HIV RNA and then
immediately go into the combination therapy. [But] we have not stopped
trying to maximize the potential of this drug. We believe that the
only way we can really go beyond the current dose regimen is to
provide a formulation with a better bioavailability.

       TI: What type of HIV reductions are you seeing at the 3,600 and
the 7,200 regimen?

       Soo: The data are very preliminary, but I think it is
comparable to what is being reported by Merck.

       TI: So it is a greater reduction than the decrease seen at
1,800 mg?

       Soo: Yes.

       TI: As a virologist, what do you believe are antiviral targets
beyond protease?

       Soo: A number of transcription-related steps in the viral
replication have been targeted in the past such as tat. People are
also looking at rev. [tat and rev are HIV proteins that regulate virus
production.] But in those cases, I don't think we have a very complete
knowledge of how the virus actually works, and it looks like the virus
might be able to bypass some of these mechanisms to replicate. So I am
less enthusiastic towards those steps. Integration will be a step that
would be virus-specific. Glycosylation [adding sugar units to HIV
protein molecules] is another step that people have targeted, and
actually, there are a couple of drugs now in development that target
the glycosylation process. But you have to be careful to target only
HIV-specific glycosylation, not cellular glycosylation processes. I
certainly hope additional basic research on viral replication can help
us lead to better targets.

       TI: Are you concerned that after the protease inhibitors, there
doesn't appear to be at this point many new antiviral classes that can
be available in the reasonable future?

       Soo: I am. That is why I agree with Bill Paul [director of the
Office of AIDS Research at the National Institute of Health] that we
have to go back and look at the virus more critically and not try to
pretend that we know enough about this virus. We have to do detailed
work on viral replication. We also need to develop a strategy to
maximize the drugs that we have right now: the nucleoside analogs,
non-nucleoside reverse transcriptase inhibitors, and protease
inhibitors. And we have some preliminary information that we might be
able to combine some protease inhibitors. So in that sense, we might
have enough agents to look for incremental gains in HIV therapy.

       TI: Some labs have volunteered to do a small study using the
combination of Roche's and Merck's protease inhibitors to see if
resistance can be delayed. Would you be able to provide a small amount
of drug to such a lab?

       Soo: Yes, we would be very happy to provide drug for such a
trial. I think such a combination certainly offers some hope.

       TI: Does Roche still have the rights to IL-2? Soo: Yes, we have
studied the drug for ten years, but we discontinued the program due to
the toxicity profile and also the fact that so far we have not seen
any significant data suggesting the activity of IL-2.

       TI: What about the increases in T-cells?

       Soo: We have seen the jump in CD4 cells in our earlier studies.
[But] our experience so far is that IL-2 has a lot of toxicity and its
effect is not sustained long-term. I am also concerned about the
short-term increases in HIV from IL- 2.

       On the other hand, it is not clear if interleukin-12 [IL-12]
would necessarily increase viral load. We certainly would like to have
that information. IL-12 offers the potential to be an immunomodulator
that might provide some benefit, perhaps more in earlier disease. With
a little bit more data on toxicity and HIV replication and from renal
cell carcinoma studies, we would be very enthusiastic in bringing
IL-12 into the HIV development process.

       We are also watching very carefully the antisense and gene
therapy approaches, and Roche is involved, you know, in both
technologies. So if any new approach demonstrates the opportunity to
advance HIV therapy, we can move in, you know, actually very quickly.

       TI: How do you validate that reducing viral load -- especially
to the levels that current levels of drugs achieve -- is clinically a
useful strategy?

       Soo: This is, in my mind where we are going to make some
watershed decisions between industry and the government. There might
now be a separation of responsibilities. I see the government getting
more involved in the kind of medical strategy where you have different
regimens to be used at different times, depending on when you start to
see a rebound of virus. So a drug from a particular company might only
contribute to some extent to the success of that strategy. It will be
very difficult for FDA to tease out if a drug worked in that way and
should be approved. So government now has the ability to look at all
of these drugs being developed and test if it is possible to suppress
viral replication for years. That will be the only way you can truly
validate the hypothesis that suppression of viral replication will
lead to clinical benefit.

       Right now we are looking at a four month suppression of viral
replication with individual protease inhibitors or with AZT. And
perhaps a transient effect on CD4. So it is no surprise that you end
up with very debatable surrogate marker data. You need a much
longer-term effect on the surrogate markers and viral load. And since
I am a virologist, I will bet on suppression of viral replication as
our main drive, and I think eventually we will be able to demonstrate
that a patient will benefit.

       TI: You've worked closely with the ACTG [AIDS Clinical Trials
Group of the NIH] system in some trials. How can it function more
effectively?

       Soo: Well, I actually served as the chairperson of the
pharmaceutical advisory panel to the ACTG.

       TI: So you bear part of the responsibility

       Soo: I unfortunately have to admit that I have not been able to
help them to change the process quickly enough. But I think the ACTG
leadership right now is very serious in trying to reorganize the
operation to be more useful and efficient.

       TI: Why do you think that the ACTG's primary infection effort
has been so mediocre?

       Soo: I think in general we see the ACTG group designing their
studies in the more traditional way. Perhaps it is time for the ACTG
investigators overall to be more open-minded in designing studies of
HIV drugs.

       -----------------------------------
       Promising Anti-HIV Therapy in Limbo
       by David Gold

       According to a Phase I study released at this fall's
Interscience Conference on Anti-Microbial Agents and Chemotherapy
(ICAAC), a unique therapy, Seragen's IL-2 diphtheria "fusion toxin,"
is well tolerated and shows possible anti-viral effects at higher
doses. Yet the therapy, known as DAB389 IL-2, may be dropped because
Seragen, a small biotechnology company based in Hopkinton,
Massachusetts does not have the capital to pursue additional studies
of the drug. Eli Lilly, the pharmaceutical giant that licenses the
compound from Seragen, is currently supporting phase III trials of the
drug for lymphoma, but may be unwilling to fund the HIV studies.

       The theory behind using the fusion toxin is that cell
activation, required for HIV replication, leads to the expression of
IL-2 receptors on T-cells to which the toxin can attach and target the
cells. In the test tube, DAB389 inhibited HIV replication.

       DAB389 has shown significant promise in other diseases. Phase
III trials are about to begin in cutaneous T-cell lymphoma, and it is
hoped that the drug will have activity in other cancers that express
IL-2 receptors (such as non-Hodgkin's lymphoma). DAB389 has also shown
activity in early trials in autoimmune diseases where activated
T-cells play a role, such as rheumatoid arthritis, psoriasis and early
onset type 1 diabetes.

       The study presented at ICAAC is the first study of DAB389 in
HIV. A note of caution about the drug: it is important to monitor
blood to ensure that too many immune cells (CD4s or CD8s) are not
destroyed by the drug and that serious toxicities do not result from
the diphtheria toxin.

       The Study

       In the study, 22 HIV-positive, p24-positive individuals with
CD4 cells between 300 and 600 were randomized to one of three doses.
DAB 389 was administered five times daily for three cycles three weeks
apart. A response was defined as a 50 percent decline in p24 antigen
and a hundred-fold reduction in HIV in the blood as measured in two
successive blood cultures.

       While no patient met the defined criteria for anti-HIV
response, there was a dose-dependent trend. Six individuals had a
ten-fold decline in HIV cultured in the blood cultures (PBMC
cultures), four of which were in the highest dose. One individual in
the highest dose had a ten-fold reduction in PBMC culture and a 50
percent decline in p24.

       Adverse experiences, including headache, night sweats,
fever/chills, myalgia and/or rash, occurred in approximately twenty
percent of those treated. Transient elevated liver functions (three to
five times normal) occurred in two individuals. Levels of CD4 and CD8
cells remained stable.

       Future Plans

       Investigators believe that the viral data suggest the beginning
of an anti-HIV effect at the higher doses and that adverse effects
were well tolerated and not dose-limiting. They recommend continued
study of this agent in approximately 30 HIV-infected individuals at
higher doses, with PCR tests to be used to measure viral load.

       However, such a study would require additional funding from
either Seragen or Lilly. Seragen is short of funds and Lilly has in
the past publicly disclosed its lack of interest in developing AIDS
therapeutics (after terminating a joint HIV protease inhibitor with
another small biotech company, Agouron).

       Activists plan to begin contacts with Lilly to obtain financing
of a phase II trial of DAB389. In a time of limited numbers of
potential anti-HIV therapies beyond nucleoside analogs (AZT, ddI,
etc.) or protease inhibitors, it is important that this unique
antiviral therapy, which has shown real promise in other conditions,
not be dropped prematurely.

       ----------------
       Treatment briefs
       by David Gold

       Large, Simple Trial for Acyclovir

       The question of whether long-term acyclovir (Zovirax) therapy
can prolong survival is one of the most enduring and unanswered
questions in HIV treatment. In an attempt to get a definitive answer,
GMHC and the Treatment Action Group (TAG) have proposed to Burroughs
Wellcome, the manufacturer of both acyclovir and AZT, a large, simple
trial (LST) of acyclovir in HIV. In a letter to David Barry, M.D.,
Director of Research and Development at Wellcome, the groups proposed
an international, double-blinded trial in which participants would be
randomized to either acyclovir or placebo and would be free to use any
other therapies. The letter suggested that valaciclovir (brand name
Valtrex), the company's new and more bioavailable form of acyclovir,
could be studied in the trial instead of acyclovir. So far no response
from Wellcome.

       Is a Sale in Wellcome's Future?

       Some analysts are speculating that Wellcome, the United
Kingdom-based parent of Burroughs Wellcome, may be sold in the
not-too-distant future. They cite recent disappointments for the
company, including the failure of valaciclovir to beat SmithKline's
famciclovir to market, the inability to obtain rights to Glaxo's 3TC,
and the mixed messages coming out about the Vertex/Wellcome protease
inhibitor program. More importantly, these analysts suggest, Wellcome
is a mid- size drug company without the "critical mass" of research
and products in the pipeline that industry giants like Merck, Roche,
Glaxo and Pfizer possess. A sale of the company could have a big
impact on AIDS research and the many community- based organizations
that rely on the company for financial support.

       Alternative Treatment Fact Sheets

       The Treatment Education Program of AIDS Project Los Angeles
publishes fact sheets on a broad range of alternative therapies for
HIV. The fact sheets are well-referenced, easy to read and available
free of charge. To obtain a set of these fact sheets call
213/993-1529.

       Report on Preventive HIV Vaccines

       Did you know that total worldwide funds spent on research and
development for a preventive HIV vaccine, in both the public and
private sectors, amount to less than $160 million? To highlight the
lack of a coordinated international effort in this area, the
Rockefeller Foundation released a report entitled "Accelerating the
Development of Preventive HIV Vaccines for the World." For a copy,
call the Rockefeller Foundation at 212/869-8500.

       Hepatitis A Vaccine Languishes at FDA

       A safe and effective vaccine for hepatitis A has languished at
the FDA for over two and one-half years. The vaccine (trade name
Havrix) is produced by SmithKline Beecham and is already approved in
over 40 countries (including the United Kingdom, France, Germany and
Australia). Hepatitis A outbreaks among gay men have been reported by
public health authorities in several cities, including New York, San
Francisco, Sydney, Houston and Copenhagen. SmithKline originally
submitted its application for FDA approval in January 1992.

       Phase III Trials for "Salk Vaccine"

       In a meeting with activists, researchers from the Immune
Response Corporation, outlined the company's plans for phase III
trials of its therapeutic vaccine, "HIV-Immunogen" (also known as the
"Salk vaccine"). HIV-Immunogen is composed of whole killed HIV with
its envelope removed. The company plans three multi-site,
placebo-controlled trials in HIV-positive individuals. The largest
trial will be a clinical endpoint trial for people with CD4 cell
counts of 300 to 500. It will enroll 3,000 patients. The two smaller
trials will look at surrogate markers (in people with over 500 CD4
cells) and at survival (in those with less than 300 CD4 cells). A
broad range of virological and immunological tests will be included.
The phase I data do not provide any clear evidence that HIV-Immunogen
provides any significant benefit as a therapy. Nevertheless, the
proposed new studies, which include patients at all stages of disease,
appear well designed. The FDA, which has requested a second meeting
with Immune Response (scheduled for January 1995), should not
unnecessarily delay the start of these trials.

       Disappointing rgp120 Results

       A large trial of rgp120, an HIV therapeutic vaccine composed of
synthetic HIV envelope protein, has been terminated early, due to
disappointing results discovered during an interim analysis of the
data. The study, which enrolled 573 asymptomatic HIV seropositives
with CD4 counts greater than 600, compared Genentech's rgp120 to
placebo vaccines. The interim results, representing fifteen months,
did not show any benefit from the vaccine therapy. No significant
difference was seen in CD4 declines, viral burden changes and minor
clinical endpoints (oral thrush, oral hairy leukoplakia, diarrhea and
weight loss). But, according to Genentech, the group given rgp120,
actually did worse in some parameters than the placebo group, without
these differences reaching statistical significance (eighteen patients
on rgp120 and seven patients on placebo had a greater than 50 percent
decline in CD4 cells). The results, although negative, once again
point out the importance of well- designed, placebo-controlled
studies.

       Copypright (c) 1994 - Gay Men's Health Crisis.  DISTRIBUTED BY
       GENA/aegis, your online global freeway to a world of people,
       information, and resources.  714.248.2836 * 8N1/Full Duplex *
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