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          J O H N   J A M E S  writes  on  A I D S
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AIDS TREATMENT NEWS Issue # 200, June 3, 1994
   phone 800/TREAT-1-2, or 415/255-0588

CONTENTS:

Antivirals and Immune Recovery: Interview with Michael S. 
        Saag, M.D.
D4T (Stavudine): Approval Recommended
Government AIDS Research: the ACTG. Interview with Michael S.
        Saag, M.D.

***** Antivirals and Immune Recovery: Interview with Michael
S. Saag, M.D.

by John S. James

Michael S. Saag, M.D., is Associate Professor in the Division 
of Infectious Diseases at the University of Alabama at 
Birmingham. He is both a laboratory scientist and a physician 
who treats patients. "I combine my laboratory experience and 
my clinical experience, and participate as a member of a 
dynamic scientific group here at the University of Alabama at 
Birmingham, where I help translate what's happening in the 
lab and what's happening in the clinic, so the clinical and 
laboratory groups can communicate efficiently. We are trying 
to coordinate new developments in the laboratory with 
clinical care and apply the developments to patients as soon 
as possible."

Dr. Saag's group has done some of the earliest work with L-
524, the Merck & Co. protease inhibitor, a new anti-HIV drug 
which is now in small-scale clinical trials. He is finding 
evidence that the immune system can recover on its own to a 
surprising degree, even from late-stage AIDS -- if the virus 
can be suppressed enough, as measured by experimental blood 
tests.

AIDS Treatment News: In a time of widespread pessimism, you 
have said that there are important grounds for hope.

Dr. Saag: Much of the pessimism among HIV patients and their 
physicians accelerated a little over a year ago, as the 
Concorde data [questioning early use of AZT] started to be 
discussed. I saw people get hung up on the details of a 
single study, and lose sight of the big picture.

In the big picture, this is a viral disease. The virus 
constantly wants to replicate, and the immune system tries to 
suppress replication. The use of antiretrovirals helps 
suppress the virus, but to date, the available agents are 
effective for a limited time. The good news is that we have 
learned a lot about HIV in less than a decade. We can target 
specific elements of its life cycle to attack with antiviral 
therapy. We can test new approaches [for example, protease 
inhibitors] in the laboratory and find that they work; now we 
are beginning to test them in people and find that they work 
quite well, at least so far. The fact that we can figure 
these things out is quite a testimony to basic sciences being 
applied to clinical medicine. This is unprecedented in the 
history of treating infectious diseases, where discoveries 
are usually made by lucky accident, rather than by a reasoned 
approach to drug development.

And now we have newer techniques to measure how well these 
drugs work; we can follow the viral burden, as measured by 
circulating RNA levels of the virus. We need more research to 
be sure that tests not only tell us that the drugs are 
active, but also translate into clinical benefit. Then we can 
use the tests to tell us which drugs are working best in a 
specific individual. If we can achieve that, it will be a 
real step forward, and we will be great shape in the next two 
or three years.

ATN: Is the P24 antigen test not very effective?

Saag: It could be OK if someone has a level that is 
measurable. But for the majority who are not p24 positive, or 
for those who are marginally positive and convert to 
negative, you cannot tell how well the drugs are working and 
how long their effect lasts. I think the HIV RNA is a much 
more direct marker in people; I believe that ultimately it 
will be proven to be useful in day-to-day practice.

ATN: What needs to be done to get more certainty, and to make 
these tests more widely available?

Saag: We need to show that the tests correlate to clinical 
outcome. That is easy to say and hard to do.

One approach would be a retrospective study -- a case-
controlled evaluation of a known cohort. We could use stored 
specimens from previously conducted trials, and select 
specifically those individuals who had disease progression, 
and compare them with those who did well on the study. This 
might require several hundred patients over many time points. 
Then we will see if these tests can indeed predict who is 
going to do well. Other studies may prospectively evaluate 
the marker, allowing those with a poor prognosis to keep 
trying different treatments until the tests show that the 
prognosis has improved.

It has been shown that CD4 counts (T-helper counts) can show 
indirectly whether or not an antiviral drug is working. But 
they are not good at telling us precisely what is going to 
happen to an individual clinically. That has always been a 
problem in comparing drugs; first, because existing drugs 
were not powerful enough to make profound changes in T-helper 
counts and immune system restoration, and secondly, because 
there is much variability in the measurement of the counts. 
T-helper counts are still useful, but not as good as they 
need to be. These new blood tests (for levels of HIV RNA) may 
fine-tune the measurement so we can predict how someone is 
going to do clinically.

ATN: Has early experience with the protease inhibitor L-524 
shown that, if you can suppress the viral load, there is 
evidence of immunological and clinical improvement?

Saag: AZT seems to do this as well, but to a smaller degree. 
If you reduce viral burden by ten fold, with AZT, you'll see 
an increase in T-helper counts, but not a profound increase. 
They may go up from 50 to 100, for example, or 100 to 200. 
But it seldom does much better than that, and the durability 
of the increase is about six to 12 months, if you start later 
in the course of the disease. If you start earlier, for 
example with baseline counts of 400 to 500, the durability 
may be 18 to 36 months.

With the protease inhibitor L-524, we have seen some examples 
of viral burden dropping around 100 fold. When we achieve 
that, we can see at least temporarily a substantial increase 
in T-helper counts -- in some cases from below ten, to around 
the 200 range, lasting for several weeks or months. This is 
important because it is proof of concept that the protease 
inhibitors indeed can work, and that they mirror what we 
hoped to see from the test-tube experience. Also, it shows 
that if you can suppress viral replication to a more profound 
degree than with AZT, then the immune system has some ability 
to reconstitute itself, at least as measured by the T-helper 
count. To a degree we knew that from AZT; now, with new 
agents which may be more potent than AZT, we are seeing more 
immune system reconstitution as a natural consequence of 
reduced viral replication. [So far the effect is temporary, 
however, since HIV develops resistance to the drug, and then 
the viral load increases.]

The recent experience with L-524 and other antiviral drugs 
has been telling us a lot about viral pathogenesis. The virus 
is becoming easier to understand in terms of what it is 
trying to do -- to survive and replicate. It is constantly 
trying to infect new cells, and to turn itself over [replace 
the current virus with new generations]. This suggests that 
ideally we should be treating patients as early as possible. 
Whether people believe that AZT is good enough to begin 
therapy when T-helper counts are above 500 remains to be seen 
in clinical trials. But if we could imagine drugs that are 
two, three, or ten times better than AZT, then I don't think 
there would be much of a debate. If they are relatively 
nontoxic, we will be using the drugs as early as possible. 

ATN: We heard about one person who started L-524 with a T-
helper count of 600, and had a large increase which continued 
even after the drug was stopped.

Saag: One patient was in our earlier studies, when we just 
treated patients for 12 days. He had a T-helper count in the 
600 range, and it did go up to over 1000. He only had 12 days 
of therapy, and he stayed around 1000; he is still there at 
this time (12 months later). I can't say that this was due to 
the L-524, but it is a possibility. If we consider that this 
is a virus that is constantly trying to replicate, when you 
give antiviral therapy, you're adding air support for the 
infantry; perhaps using a drug with that much activity early 
in the course of disease may have allowed his immune system 
to get a better handle on the viral infection, and gain 
better control -- having effects even long after the drug was 
present.

The other possibility is that the T-helper increase would 
have happened anyway, due to variability in the expression of 
the disease. But usually one would expect that T-cell counts, 
left to their own devices, would continue to drift downward, 
not bounce up by 400 cells per cubic millimeter.

ATN: It would make a lot of sense to try this treatment with 
a few more patients, and see if it happened again.

Saag: I think so. We should do it in a controlled way, 
following people with that goal in mind. Remember that in the 
early studies with this compound, all we were really looking 
for was safety and the pharmacokinetic profile; what happened 
to the patients clinically was more of an incidental 
observation; we were certainly interested in it, but that was 
not an objective of the study.

We need more research on earlier infection. Indeed there are 
some trials in development right now, not so much with 
protease inhibitors just yet, but with some of the nucleoside 
analogs [e.g. AZT, ddI] and non-nucleoside reverse 
transcriptase inhibitors [e.g. nevirapine, or delavirdine], 
looking at earlier interventions to see what antiviral 
effects we get in people with higher T-helper counts. 

ATN: The big interest now is combination treatments, for 
delaying or avoiding resistance; this has worked for other 
diseases. Is there anything you can add from your work? What 
combinations would make sense to test with L-524?

Saag: The results so far with the Merck drug (L-524) are all 
with monotherapy [the drug alone, not in a combination]. 
Roche is finding some success with their protease inhibitor 
in combination with AZT. So the first approach would be to 
use the protease inhibitors with AZT. The rationale is that 
you're attacking two different areas of the viral life cycle; 
that is sound reasoning.

Another approach would be to combine a protease inhibitor 
with other nucleoside drugs that have different toxicity 
profiles [for example, ddI], or perhaps with non-nucleoside 
drugs, such as nevirapine.

We may also want to try combining different protease 
inhibitors. The resistance patterns for the different 
protease inhibitors are different. After growing HIV in cell 
culture in the laboratory [with low doses of a protease 
inhibitor, to deliberately produce resistant viruses], 
resistant or less susceptible viruses can be identified, and 
they have certain changes in their genetic structure that 
confer the resistance. If you do this with another drug, you 
get a virus which is less susceptible to that drug, but often 
not less susceptible to the first drug; there may be little 
or no cross resistance. The reason is that different changes 
in the genetic makeup of the virus give resistance to the 
different drugs.

So if you have the two drugs together in the same patient, 
you might have broader coverage against the two types of 
genetic changes that could occur, just using protease drugs. 
That may work well in the future. But first we must prove 
that the new drugs are safe and well tolerated, and that the 
drugs being combined do not have harmful interactions. If 
they can be safely administered together, a combination test 
will be important. 


***** Government AIDS Research: the ACTG. Interview with
      Michael S. Saag, M.D.

by John S. James

[Note: This interview was conducted as a continuation of 
"Antivirals and Immune Recovery," above.]

Michael S. Saag, M.D., a researcher at the University of 
Alabama at Birmingham, is a new member of the Executive 
Committee of the AIDS Clinical Trials Group (ACTG), the main 
U.S.-government program for clinical trials of AIDS drugs. 
Among other responsibilities, Dr. Saag directs the 
subcommittee in charge of the ACTG's interaction with outside 
groups, including the pharmaceutical industry, community 
organizations, and government medical-research teams outside 
the ACTG. 

ATN: What is most important for our readers about the ACTG?

Saag: I think the ACTG is a very valuable resource for the 
country. It has taken a lot of criticism, some of it fairly 
applied. But the success of the ACTG is not widely 
understood.

If you think about what happens in clinical practice today in 
a doctor's office, and compare it to six or seven years ago, 
you will find that much -- perhaps 70 to 80 percent of the 
activities of a physician, in terms of new approaches to 
management of their HIV patients -- was initiated through the 
results of an ACTG trial. When you go to conferences, and 
hear discussions about patient care and trial results, you 
almost always hear references to ACTG studies. There have 
been many contributions, not only in the primary infection 
area [treating HIV itself], but especially in opportunistic 
infectious diseases. What types of prophylaxis work best, 
what is the best treatment for cryptococcal meningitis or 
pneumocystis pneumonia or CMV retinitis, these results have 
usually come from ACTG trials. People should recognize that 
the ACTG has made major contributions.

Also, much that goes on behind the scenes at the ACTG helps 
pharmaceutical-industry studies. Consider the quality 
assurance program that assures that virology labs working 
with the ACTG all operate in a standardized way, and that the 
measurements of T-cell counts are standardized. All these 
spill over into industry trials. The sites that are ACTG 
funded also can do industry studies, and whenever a company 
goes to those sites, it is using the same laboratories that 
are ACTG certified. That's been a very important plus for 
studies that are not ACTG affiliated.

In the future, due to a recent reorganization, the work of 
the ACTG will be based more directly on a foundation of its 
scientific agenda. In the past, an individual researcher at 
an ACTG site would come up with an idea, propose it as a 
concept sheet, and go through the system from the bottom up. 
While that is democratic and taps into the great resources of 
a number of very talented people, it can also be inefficient. 
In the future, all these researchers with their talents and 
ideas will first come together to brainstorm and come up with 
a scientific agenda, and then develop specific protocols to 
address that agenda. This should speed protocol development 
and the conduct of trials.

ATN: We have heard of many cases where concept sheets don't 
go anywhere, probably because the leadership does not agree 
with them. This change might help to avoid that problem.

Saag: I think it will. And I think the other problem is that 
some members of the ACTG, especially in leadership positions, 
get so inundated with paper, having to keep up, that it's 
hard to give every concept sheet a clean, fresh look every 
time. You never know when one is going to be coming in.

So we will back up and say, "What are the big-picture issues 
that we should be addressing as a group?" We will define 
those questions, establish that agenda, prioritize, and then 
ask, "What kind of trials will help us answer this question?" 
I believe that the proposal I have seen will reduce protocol 
development time -- going from an idea to a protocol open for 
enrollment -- from over 230 days down to about 85 days. This 
is about to be implemented.

Also, we also should keep in mind what would happen if the 
ACTG did not exist. Suppose it had never been created; what 
would people be saying about what ought to be done? They 
would say that we should get together some of the best 
scientists and clinical investigators in the country, and 
form a network where they could work together and study new 
approaches to treat the disease. Also, you would want to 
bring those people together, at least semi-annually, to talk 
about progress, discuss current issues, decide directions 
together, and then implement those new protocols and studies 
that they come up with. That is precisely what the ACTG is. 
The problem is that it has been inefficient in its ability to 
get things done quickly; it has been too bureaucratic in the 
past. I think that with the reorganization it will become 
more streamlined, and enable us to fulfill those desperately 
needed missions of having some of the better investigators in 
the country working together on joint projects.

I'm very encouraged by what is happening. There is a dynamic 
interaction within the ACTG leadership, and a lot of 
dedication to making the organization run efficiently, and be 
as productive as possible. I'm optimistic that we can do 
that. But it will take much work to get us to that next 
level.

ATN: Recently some leading scientists have called for a 
redirection of AIDS research. [See "AIDS Research Direction: 
New Scientific Approach?," AIDS Treatment News #199, May 20, 
1994.] Some have interpreted Dr. Fields' recent paper as 
calling from a shift from clinical to basic research; but 
what he really seems to be saying is that there should be 
better communication between the laboratory studies and the 
clinical trials which test new drugs in patients. Where do 
you think we should focus now?

Saag: There has been a fairly strong emphasis on basic 
science from NIAID [the U.S. National Institute of Allergy 
and Infectious Diseases, which runs the ACTG] over the last 
five or six years. In 1987, there was a project called 
Programs for Excellence in Basic Research on AIDS (PEBRA); 
our team at the University of Alabama was one of the 
recipients of that award, and that is what started us 
coordinating the clinical side and the basic science side. 
That's the kind of initiative we should continue with.

NIAID has continued this approach, with the new SPIRATS 
grants, which encourage investigators to work together from 
the beginning of a new concept of treatment, to developing 
that approach in the laboratory, and carrying it through all 
the way to the initial clinical trials. [Note: SPIRATS stands 
for Special Program for Innovative Research on AIDS 
Treatments. The first five to eight SPIRATS grants are 
expected to be awarded in August 1994.] This is an important 
initiative that encourages creativity among investigators 
within different disciplines, having them work together.

This kind of approach is where progress in HIV will come 
from. I think we do it at the University of Alabama about as 
well as it's done anywhere; it was the U.S. National 
Institutes of Health programs that got us going. The PEBRA, 
our Center for AIDS Research, and other government programs, 
have all been used to have scientists from different 
disciplines work together. This is the critical issue that 
should be emphasized, rather than segregating out more money 
for basic science, or for clinical science. We are trying to 
get money used in a way that maximizes the interaction 
between the different disciplines and different research 
groups.


***** D4T (Stavudine): Approval Recommended

by John S. James

The experimental anti-HIV drug d4T (generic name stavudine, 
brand name Zerit), now widely available in a "parallel track" 
program for patients who cannot successfully use either of 
the approved drugs AZT or ddI, was cautiously recommended for 
early approval by the Antiviral Drugs Advisory Committee, at 
an all-day public hearing on May 20. The FDA [U.S. Food and 
Drug Administration] must make the final decision on whether 
to grant approval on the basis of the data so far available; 
it does not have to follow the recommendation of its advisory 
committee, but usually does.

There has been considerable confusion about this hearing and 
what it means. We believe that most of the confusion does not 
involve d4T itself. Rather, it arises from the difficulty of 
fitting the particular situation of this drug into the 
existing body of approval regulations, in such a way that a 
reasonable result is achieved.

[Note: This writer did not attend the hearing. This report is 
based on discussions with people who were there.]

Background

A major clinical trial of d4T (known as the '019' study) is 
still underway in the U.S.; it is expected to finish at the 
end of 1994. After completion of this trial, it will take 
months to analyze the data and schedule another hearing of 
the Antiviral Drugs Advisory Committee; as a result, approval 
will be delayed for about a year if it is necessary to wait 
for the final data and its analysis. To avoid this delay, the 
developer of d4T, Bristol-Myers Squibb Company, asked for an 
earlier approval under the new "accelerated approval" 
regulations. These regulations allow the FDA to approve a 
drug for serious or life-threatening illnesses, when no other 
satisfactory treatment is available, on the basis of 
"surrogate markers" (for example, blood tests such as the T-
helper count, which seems to provide a crude measure of a 
drug's effectiveness). But the pharmaceutical company must 
finish its clinical trials, in order to eventually obtain 
conclusive proof that the drug is clinically beneficial to 
patients.

D4T Results

The May 20 hearing focused on partial data from two human 
studies of d4T. One is the Bristol-Myers '019' study -- the 
ongoing clinical trial mentioned above. The other is the 
parallel track program, run by Bristol-Myers with FDA 
permission primarily for compassionate purposes, to make the 
drug available before approval for persons with no other 
therapeutic option.

The '019' study includes 822 patients. All of them had been 
on AZT for at least six months (but often considerably 
longer). When they entered the study, each patient was 
randomly assigned to either continue AZT, or switch to d4T. 
The study is "blinded"; neither the patients nor their 
physicians were told who is getting which drug.

At the May 20 hearing, data was available for 359 patients. 
Data from the other 463 patients could not be used, because 
their treatment is still blinded. (Researchers are very 
reluctant to break the blind prematurely, since doing so 
could bias the study.)

About 14 percent of the patients in this study entered with a 
T-helper count under 100. About 50 percent were in the range 
of 100 to 300; and the other 36 percent were over 300. Only 
10 percent had an AIDS diagnosis at entry.

The data showed that:

* Those assigned to d4T had an average rise to a maximum of 
about 20 to 25 in their T-helper count, compared to baseline 
(just before their d4T treatment began). Counts then 
declined, however, and by week 16, the average increase from 
baseline was only about 10. For those assigned to continue on 
AZT, T-helper counts decreased. According to Bristol-Myers, a 
difference of 50 in the T-helper count between groups was 
maintained for up to 60 weeks.

* HIV titer (of PBMC-associated virus) dropped 53 percent 
from baseline, for those on d4T. For those on AZT, the titer 
increased 11 percent.

* The d4T group also showed improvement in weight gain over 
the AZT group. The weight gain on d4T was small, however, and 
there was no significant weight gain for those with T-helper 
counts under 100. But the average difference between the d4T 
and AZT groups exceeded 2 kilograms (4.4 pounds).

* In an interview with AIDS Treatment News, Lisa Dunkle, 
M.D., who presented some of the data for Bristol-Myers at the 
May 20 hearing, said that the d4T group showed hematologic 
improvements over the AZT group. She did not present the 
hematologic data at the hearing, however.

* According to Dr. Dunkle, there was also a marked difference 
in favor of d4T in reduced side effects -- with the only 
adverse event being peripheral neuropathy in 12 percent of 
the patients after one year, and in only half of those was it 
serious enough to require discontinuation of the drug. (See 
other views of side effects, below.)

The data now available from the parallel-track program was 
less clear. This program is only for patients who had already 
tried and failed both AZT and ddI. As would be expected, they 
tended to be at a more advanced stage of HIV infection; their 
median T-helper count at entry to the parallel track was 41, 
and 75 percent of these patients had a T-helper count under 
100 (compared to only 14 percent for the '019' study, as 
reported above).

In order to collect scientific data from this program, 
patients were randomly assigned to two different doses of d4T 
-- either the standard dose of 40 mg twice a day (the dose 
used in the '019' study), or half that dose, 20 mg twice a 
day. After a median time of 40 weeks, 79 percent of the 
patients were still alive. As a check to make sure that 
patients were not left on a dose known to be inferior, a 
group called the Data Safety Monitoring Board (DSMB) secretly 
unblinded the study and compared the two doses. It found that 
there was no survival difference between the doses, but that 
those taking the larger dose had a somewhat higher risk of 
peripheral neuropathy -- 21 percent of those receiving 40 mg 
twice a day, vs. 15 percent of those receiving 20 mg twice a 
day. As a result, the DSMB asked that the 40 mg dose be 
discontinued in the parallel track, and those who had been 
receiving it were switched to 20 mg.

Since the survival rate was the same with the 40 mg and 20 mg 
doses, does this mean that the two doses both worked equally 
well -- or does it mean that the drug did not improve 
survival for those patients at all? We cannot tell from the 
parallel-track data. There was no placebo or no-treatment 
group (which would have been unethical in this situation); 
and it was also impossible to compare d4T with AZT or with 
ddI, since the patients had to fail both of those drugs as a 
condition for getting into the parallel track. (The '019' 
study is designed to look for a survival difference -- 
between switching from AZT to d4T, vs. continuing on AZT -- 
so we should have information after this study is completed.)

Patients in the parallel-track program were not required to 
obtain regular T-helper counts. Somewhat fewer than half of 
them did choose to do so; and for them, T-helper counts 
tended to be stable for over a year.

Regulatory Issues

There has been some confusion about just what the May 20 
hearing did decide, and what it means. To understand the 
current status of d4T, certain background should be kept in 
mind:

* The studies are not comparing d4T against AZT (or against 
ddI or ddC, the other approved anti-HIV drugs) as a starting 
treatment. (Early, smaller studies evaluated d4T as a 
starting treatment in some patients, and found that the T-
helper count rise appeared to last for a prolonged period -- 
but the large studies now ongoing are not designed to confirm 
this result, or to make sure that it translates into clinical 
benefit.) Also, there is no study comparing switching to d4T 
vs. switching to ddI, as a second treatment after AZT. Nor is 
there any comparison of d4T in combination with other anti-
HIV drugs. These obvious question, that doctors would like to 
have answered, will not be addressed in the approval of d4T.

* Despite the limited information, and the disappointment due 
to the small T-helper count improvement seen in the '019' 
study, there is a widespread feeling that, on balance, d4T 
should be approved -- without waiting an extra year for the 
final data from the '019' study. Everyone knows that existing 
HIV treatments are inadequate; and all the evidence suggests 
that some people do benefit from d4T. At the same time, the 
existing parallel track program restricts access to the drug, 
and limits the normal development of clinical experience by 
physicians. Bristol-Myers has provided this program as a 
public service, at a cost of millions of dollars which it may 
not be able to recover, instead of denying the treatment to 
thousands of people. (But there is increasing concern that as 
the overall process of drug development becomes more 
expensive, other companies will avoid developing potential 
AIDS drugs, and may even conceal important treatment leads.)

* The regulatory complication about approving d4T now is the 
following. The FDA's new "accelerated approval" regulations 
would need to be used, since the data so far shows 
improvement in blood tests and in weight gain, but not in 
"clinical endpoints"; there is not enough data yet to provide 
statistical proof that, in the long term, certain patients 
treated with d4T will do better than those treated otherwise. 
The accelerated approval system was designed for just this 
situation.

But the accelerated approval regulations require that no 
other treatment be available; the point is to allow the 
increased risk of approving a drug early, without clinical-
endpoint data, in situations where the need for the drug is 
very urgent. This is the case with those in the parallel 
track program, as they have already failed standard 
treatments.

The complication is that while accelerated approval does 
apply to one group of patients, the best data available are 
from another group, those with less advanced disease (who are 
in the '019' study). An additional complication is that the 
dose which generally appears best and will probably be 
approved, 40 mg twice a day, is the dose which the DSMB 
discontinued for those in the parallel-track program -- the 
patients that an accelerated approval will need to address.

In other words, there seems to be a general consensus that 
d4T should be approved; but the factual situation of this 
drug does not exactly match what the regulations were 
designed for. The FDA staff seems to have sidestepped this 
potential red-tape gridlock by asking the Advisory Committee 
to answer particular questions which have the effect of 
leaving the situation open. This gives the FDA staff more 
freedom to make the right decision on the basis of all 
available data, as it comes in, without needing to wait a 
year for the '019' study to be completed.

The FDA asked the Antiviral Drugs Advisory Committee to vote 
on the following questions:

"1. Does there exist a population for whom stavudine [d4T] 
will provide meaningful therapeutic benefit over existing 
therapies? If the answer is yes please comment on the 
characteristics of that population.

"2. Has the applicant provided evidence from adequate and 
well-controlled clinical trials establishing that stavudine 
has an effect on a surrogate endpoint that is reasonably 
likely to predict clinical benefit?"

The Advisory Committee answered yes to both questions, by 
majority vote. This is considered a recommendation in favor 
of approval.

Side Effects Controversy

Over a year ago ACT UP/Golden Gate, a San Francisco-based 
activist group, started a series of public forums for people 
in the d4T parallel-track program, independently of Bristol-
Myers or anyone else involved. ACT UP also developed a 
survey, and its own computer database to record peoples' 
reports, and was in phone contact with patients around the 
country. In July 1993 ACT UP/Golden Gate reported that more 
than half of the patients in its database had some degree of 
peripheral neuropathy or other side effect that they thought 
might be drug related. The organization presented an updated 
version of its report at the May 20, 1994 hearing on d4T. 
[Note: This writer usually attends the weekly meetings of the 
ACT UP/Golden Gate Treatment Issues Committee. We were not 
involved in the d4T study, however.]

A practical result from the ACT UP study is the suggestion 
that, if people have sleep disturbances while taking d4T, the 
problem can often be corrected by not taking the second dose 
at bedtime, but taking it earlier in the day.

In addition, the Conant Medical Group in San Francisco did a 
retrospective study of the case reports of about 100 of its 
patients who participated in the d4T parallel track program; 
it found that more than half of them reported adverse effects 
which might have been drug related. While this study has not 
yet been published, the Conant Medical Group sent a summary 
report to the FDA before the May 20 meeting.

These numbers are considerably higher than those reported by 
Bristol-Myers, and also by the DSMB. No one knows why there 
is this difference. Self-selection may have had a large 
effect on the ACT UP numbers, since those who have problems 
during a treatment may be more likely to come to a meeting 
and be recorded in the database. But self selection would not 
be expected to have affected the Conant study.

The differences might also have occurred if Bristol-Myers and 
the DSMB made more effort to screen out minor side effects or 
those which appeared not to be drug related, while the other 
reports counted everything. The major side effect of d4T is 
peripheral neuropathy, which can also be caused by HIV 
itself. This makes it hard to interpret reports of side 
effects -- especially since the patients in the parallel-
track program usually had advanced AIDS or HIV infection, 
which would have caused a number of cases of peripheral 
neuropathy that were not due to the drug.

The issue of side effects should be kept in perspective. ACT 
UP/Golden Gate, which first reported seeing a larger number 
of side effects, still supported approval of d4T at the May 
20 hearing -- but asked for neuropsychiatric studies focusing 
on possible adverse effects of the drug. And the Conant 
Medical Group is continuing to use d4T through the parallel-
track program. The issue of side effects will affect medical 
management of d4T use, but it has not changed the belief that 
the drug can be useful and should be available.

Comment

At the May 20 meeting, the FDA also asked the Advisory 
Committee to meet again, on the subject of "surrogate 
markers" in AIDS drug approval (for any drug, not focusing 
only on d4T). This concerns the ongoing controversy of 
whether we can trust blood tests such as T-helper counts, or 
clinical indications such as weight gain, as proof that an 
AIDS drug is really a benefit to patients.

On this issue, we believe it is time for AIDS community as a 
whole -- as well as the FDA, and its advisory committee -- to 
step back and take a look at the big picture. And the big 
picture, we believe, is that far too much effort is being 
spent agonizing over the details of marginal drugs which will 
never work very well. Instead, we should quickly approve the 
drugs when there is good safety data and some indication of 
benefit. Then we can re-focus research attention and 
resources on the discovery and development of fundamentally 
better treatments.


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