CHEMOTHERAPY OF AIDS CONFERENCE
By David Rasnick
14-18 March 1999
This year 105 people attended the 1999 Chemotherapy of AIDS Conference,
with 40% coming from industry. Compared to the 1997 conference, this one
was more subdued.
In 1997, virtually every presenter of new nucleoside analog inhibitors of
reverse transcriptase characterized the compounds as DNA-chain terminators.
This year not a single presenter mentioned the phrase DNA-chain
terminators. Experimental controls were as absent as they were two years
From my perspective the 4.5 day conference was largely a protracted yawn.
However, William Cameron's talk Thursday morning made the entire trip worth
Cameron is on the faculty of the University of Ottawa. He is clearly an
expert in designing and evaluating clinical trials. He told me that he
consults for Canada's FDA.
While it was evident that Cameron fully accepts the HIV hypothesis of AIDS,
nevertheless, he completely demolished the viral load surrogate marker as a
substitute for morbidity and mortality end points in clinical trials. He
said that people don't die of HIV viremia. He also stressed that viral load
is ASSUMED to reflect quantitative effects. There was no basis for this
assumption. I should point out that over the previous four days virtually
every talk and poster (excluding mine of course) relied exclusively on
viral load measurements to determine the effectiveness or failure of
anti-HIV drug therapies.
Cameron illustrated with specific examples how easy it is to "engineer" a
desired outcome in clinical trials using viral load surrogate endpoints. In
order to guarantee a therapeutic effect one needs only to recruit
relatively healthy patients and observe them only for a short period of
time. This method works even for drugs that have no therapeutic benefit and
are actually harmful to the patients. The explanation he gave (I couldn't
have said it better myself) was that healthy people tolerate toxic drugs
better than sick people.
He gave as a specific example the DDI clinical trial disaster. Over a short
12-week study, DDI showed efficacy based on viral load. But after 12 weeks,
patients on DDI experienced severe toxicity. Robert Yarchoan of the
National Cancer Institute had discussed the severe toxicity of DDI just
before Cameron's talk, which only emphasized the point.
Cameron also showed that the placebo arm of a surrogate marker clinical
trial can also show a pronounced clinical benefit, indistinguishable from
drug therapy, if only the studies were allowed to go longer. The end result
is that there would be no difference between drug and placebo as long as
the drug was not toxic.
It should be pointed out that to date all protease inhibitor clinical
trials were terminated prematurely before it could be determined that
people taking the drugs actually lived longer and better lives than those
not taking the drugs.
Cameron suggested that any therapeutic benefits due to the HIV protease
inhibitors may result from their anti-microbial activities since many
pathogens have essential aspartyl proteases. (HIV protease inhibitors
inhibit other aspartyl proteases.) However, he told me later that the
people he'd seen on HAART looked like hell. They were wasting away to
nothing among other problems. He was clearly not impressed with the drugs.
I was sitting at the back of the room during Cameron's talk. I had a good
view of how he was being received. A number of people were noticeably
uncomfortable, for example Martin Markowitz of David Ho's Aaron Diamond
AIDS Research Center. About halfway through Cameron's talk, Markowitz
grabbed a newspaper, turned toward the wall and pretended to read it.
Cameron lecture received only short, polite applause. It was the only time
I applauded the whole week.
On to other topics. By and large the week was pretty boring. Nevertheless,
there were a few scraps of information that some may find useful.
On Sunday, Angela McLean of the UK defined what is meant by acute HIV
infection or acute illness. A person is acutely ill with HIV if he or she
has a detectable viral load, i.e. the presence of HIV RNA, and does not
have antibodies to HIV as determined by the ELISA antibody test.
This definition, of course, does not take into consideration those people
who are false positive for the viral load and antibody tests or people who
go back and forth.
McLean said that at the peak of acute illness with HIV that 6 new cells are
infected with HIV by each previous HIV infected cell. (Peter Duesberg told
me that in the laboratory one retroviral-infected cell will produce enough
virions to infect 100 new cells.) She said that cytotoxic lymphocytes (CTL)
kill wild-type HIV-infected cells in about 2 days. She went on to speculate
that CTLs do not kill mutant HIV-infected cells, implying that this was the
reason for the drug failures. McLean admitted during questioning that no
other infectious agent had been put through her analysis. That means there
is no way to judge the physiological significance of McLean's studies.
McLean made the curious statement that the better the anti-HIV drugs work,
the more likely they will fail. Figure that one out. After a week of this
stuff I think I know what she was getting at. Shortly after a person begins
taking anti-HIV drugs his viral load drops. The greater the drop, the
greater the supposed therapeutic effect. However, virtually everyone on the
cocktails eventually shows a rise in viral load. This rise in viral load
was interpreted by most at the meeting to reflect drug failure. However,
there were a number of attendees who pointed out that a rise in viral load
did not mean those patients were experiencing a increase in clinical
Brendan Larder of Virco UK Limited began Monday's session on anti-HIV drug
resistance. There are now 5 HIV protease inhibitors available. The
ubiquitous viral load is the work horse of anti-HIV research and therapy. A
rise in viral load in people taking the anti-HIV drugs is interpreted as
drug failure due the appearance of drug resistant mutants. However,
responding to a questioner, Larder stated that the presence or absence of
mutations have nothing to do with "viral load resistance" seen in people.
This was echoed Tuesday by Philip Furman of Triangle Pharmaceuticals in
Durham, NC. Furman said that even a person with multiple inhibitor
resistant mutant HIVs responds to the protease inhibitor combos as
determined by a reduction in viral load in the first week. Furman did not
explain this curious observation.
Later that morning, Jaap Goudsmit of Holland continued the drug resistance
story. He began by contradicting the media reports that drug resistant
mutant strains of HIV represent a growing threat. Goudsmit said that
inhibitor resistant mutants are not transmitted from person to person. This
was due to the very poor fitness of the mutant virions. In Holland, the
appearance of mutant HIV resistant to reverse transcriptase inhibitors
peaked in 1995, he said.
Goudsmit made the obvious point that with antibiotics, the appearance of
drug resistant strains of bacteria, for example, increase with drug use. It
puzzled him that with increased drug use the appearance of drug resistant
mutants of HIV actually declined in Holland.
On Tuesday I had an interesting conversation with Che-Chung Tsai, a
pathologist at the University of Washington, Seattle. I learned that
T-cells pass through the entire lymph system, including all tissues, in 2
hours. At least 85% of T-cells reside in the gut. Because of this, he asks:
why doesn't AIDS start in the gut?
Dr. Tsai works with monkeys in his AIDS research. He said that HIV grows
2-3 times as fast in monkey lymphocytes but monkeys don't get AIDS and do
not incorporate HIV pro-viral DNA.
At the evening session on Tuesday the speakers tried to blame the metabolic
abnormalities seen in people taking the protease inhibitor combos on HIV. I
asked Kathleen Mulligan of UCSF why not treat a bunch of animals with HAART
(PI combos) and see what happens? The moderator interrupted saying that my
suggestion was irrelevant since the animals don't have HIV. That, of
course, was precisely the point: to separate the effects of the drugs from
HIV. Later a fellow in the audience told me that he was disappointed that
my question was not answered. He clearly saw the simple logic behind the
On Saint Patrick's Day our old friend Martin Markowitz of the Aaron Diamond
reported on their on-going study of 27 people still on HAART. As in 1997,
Markowitz didn't say a word about how those 27 people had been doing over
the past 2 years on the drugs. Two years ago I asked Markowitz if his
patients on HAART were doing better, the same, or worse while on the drugs.
He didn't answer after asking the question three times. He knew I was in
the audience, but this time I decided not to ask. If his patients had been
doing well I'm sure he would have let us all know, especially me.
Wednesday included a discussion of long-term non-progressors: those folks
who in spite of having either antibodies to HIV or HIV-RNA do not get sick
after 20 years and longer. Eric Rosenberg of Massachusetts General Hospital
said that viral load goes up and down in people whether they take the
anti-HIV drugs or not. In people taking the drugs, the therapy is given
credit for the reduction in viral load. In long-term non-progressors, the
immune system is given the credit for low viral loads or reductions in
viral load. Again, Rosenberg admitted without knowing it that the secret to
long-term non-progression is not taking the anti-HIV drugs.
Thursday, Anthony Japour of Abbott Laboratories cited the 1998 paper by
Palella et al. [Palella FJ, Delaney KM, Moorman AC, et al. Declining
morbidity and mortality among patients with advanced human immunodeficiency
virus infection. The New England Journal of Medicine (1998) 338(13):
853-860] as the best evidence that HAART was responsible for the decline in
AIDS deaths. After his talk I pointed out that the paper by Palella was not
a report of a clinical trial but was a retrospective survey. He
acknowledged that fact. Then I asked him didn't he think it unusual that he
used a survey and not a clinical trial as the best evidence that HAART was
extending people's lives or at least improving their quality of life? To
his credit, after the coffee break he acknowledged to the audience that his
earlier reference had been to a survey and not to clinical trial data.
Japour made it clear that clinical endpoints are no longer used in clinical
trials of anti-HIV drugs. The viral load surrogate is the sole basis for
determining clinical efficacy. Drug toxicity is apparently the only
clinical outcome that is noted. Current Phase III clinical trials are not
even blinded; they are open labeled. Both the physician and the patient
know whether they are on the drugs.
Robert Yarchoan of the NCI admitted that HAART has made the process of
clinical trial drug evaluations very difficult. He recommends that we go
back to extensive clinical trials of mono-therapy in drug naive people. The
current process is so complicated that it is virtually impossible to
conduct a clinical trial and interpret the results. In other words, we
don't know what the clinical trials are telling us. The FDA representative
in the audience said that the FDA supports mono-therapy on a case by case
In addition to relating the fiasco of the DDI clinical trials discussed
above, Yarchoan went into some detail about another tragedy: FIAU. FIAU was
supposed to treat hepatitis B and was approved after a short clinical
trial. However, after people were taking FIAU for periods just a little
longer than the clinical trials, they began dying at alarming rates before
the FDA finally pulled the drug off the market.
Yarchoan admits that the NCI is currently testing AIDS drugs that are
"likely to have severe toxicity," e.g. F-ddA.
Jeffrey Murray of the FDA gave a talk on the design of Phase III clinical
trials. By way of background, normal phase III clinical trials run from 1-4
years and cost $30-50 million. However, as of 1997, the FDA changed the
rules for anti-HIV drug clinical trials. Murray said this change was based
on a new knowledge of HIV pathogenesis. Maybe he was referring to David
Ho's viral dynamics stuff.
Accelerated Approval Protocol is as follows:
24 week double-blind study; all patient should receive standard of care (he
immediately then said this changes by the minute); report viral load
proportion below assay limit; show that CD4 cell changes are consistent
with viral load; report viral load vs proportion below 400. He said that
relying on mean changes in viral load is too limiting.
Pediatric clinical trial:
48 weeks based on last patient entered; all should receive standard of care
(i.e. AZT); report time to virologic failure (i.e. rise in viral load);
report proportion below assay limit; show consistency between CD4 and
Murray acknowledged that the FDA has not formally validated the HIV viral
load assay. Nevertheless, he said that, "the time to loss of virologic
response (i.e. how long it takes before a rise in viral load) is in a sense
a clinical endpoint." He even said that "the FDA believes in viral load."
That statement gave me the shivers. The FDA should be in the business of
evaluating evidence--not beliefs.
Murray said that failure is defined as viral load rebound. He also said
that "active drugs do not arrest symptom progression and certainly does not
return the patient to normal." This is probably why Martin Markowitz never
talks about how well his 27 patients are doing after 2 years on HAART.
Regarding safety, Murray said that toxicity studies in humans should last
48 weeks with 300-600 people evaluated over 6 months and a smaller number
over 1 year.
The FDA now asks for metabolism data for all trials. Jules Levin of NATAP
(a gay activist group in New York) told Murray that the "Community" will be
watching for the FDA to require metabolic abnormality measurements in
During the question period a guy in the audience proposed that the rise in
viral load may not represent drug failure but actually immunological
success. He based this twist of viral load interpretation on the rise in
CD4 cells is the same patients.
Following Murrary's talk, William Cameron tore to pieces the viral load
mania as I described at the beginning.
David Ho's talk was Thursday evening, following the banquet. It was much
ado about very little. He reported on 8 selected patients who had been on
HAART for some time and had no detectable viral load. They took biopsies
from a variety of tissues and examined 175 different tissue sections for
the presence of replicating HIV. They found 13 sections containing at grand
total of 19 cells replicating HIV. I repeat: 19 cells in 8 people. Even if
this were true and not an artifact, this number of cells is physiologically
irrelevant. A guy in the audience asked Ho how significant were those 19
cells? Ho answered that when HAART was stopped that the viral load
rebounded, implying that those few cells were responsible for the rebound.
Concluding, Ho said that "long-term non-progressors have something
important to tell us." They certainly do but not what he wants to hear.
Finally, I presented a poster on Tuesday by Peter Duesberg and me on the
Drugs-AIDS Hypothesis. Surprisingly, it went quite well. The 18 copies of
the AIDS Dilemma paper by Duesberg and me were all taken during the poster
session. I only took 18 because I thought hardly anyone there would want to
be seen reading it. The 20 copies of my HIV kinetics paper were all gone in
30 min. That paper was certainly less threatening and could actually be of
use to some of those folks. Some people even came up and asked questions.
What amazed me the most was that instead of avoiding me at meal times (we
all eat together at Gordon conferences) my table was almost always full
even though I made a point of being the first to sit down. It just goes to
show that things are hard to predict.
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