rock@uunet.UU.NET (02/25/90)
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EDUCATION - Table of Contents January 1990 - Vol 1, No 4
Portrait of AIDS in the 1990s: Lecture by Dr. Anthony Fauci
Medical Update: New treatment of HIV-infected individuals
The saga of ddI
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PORTRAIT OF AIDS IN THE 1990S: LECTURE BY DR. ANTHONY FAUCI
by W. Howard Cyr, Ph.D.
On December 6, 1989, Dr. Anthony Fauci, Director of the National Institute
of Allergy and Infectious Diseases (NIAID), spoke at the Clinical Center of
NIH on the changes and progress that he foresees now that AIDS is moving
into its second decade. He recently removed himself from consideration as a
candidate for becoming the new Director of NIH, and decided to remain as
head of the AIDS effort. Dr. Fauci's speech was one of a series of seminars
given to the medical personnel at the Clinical Center. In other briefings,
Dr. Robert Gallo, co-discoverer of HIV, spoke on his work to characterize
the structure and function of HIV and its genes, and Dr. Samuel Broder, best
known for his work on AZT and ddI, also addressed this group about the many
clinical trials that are ongoing at the Center. These briefings are
certainly valuable to the medical personnel at NIH, and I thought that this
summary by Dr. Fauci would be of interest to the readers of the Washington
HIV News, particularly since his presentation was comprehensive, covering
budgetary concerns, the changing pattern of HIV disease among various risk
groups, new advances in biomedical research, new treatment methodologies,
and the future prospects for a vaccine.
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BUDGET CHANGES
The expenditures on AIDS have increased yearly, with the AIDS budget at NIH
progressing from about three million dollars in 1982 to over 750 million
dollars projected for 1990. However, Dr. Fauci suspects that the rate of
increase may taper off somewhat. There has been some concern (criticism)
expressed that AIDS is getting too much of the health budget. A recent
article in the New England Journal of Medicine pointed out that the total
AIDS budget is now over a billion dollars with the number of AIDS deaths
this year at about 35,000. This is in contrast to the budgets for cancer
and heart disease, each of which is about the same as for AIDS, but with
cancer deaths nearly a half million per year and over three-quarters of a
million deaths each year from heart disease. Dr. Fauci stressed that this
comparison is somewhat unfair, and that the more proper comparison may be
cancer and heart disease patients to the total number of people infected
with HIV. The "number of deaths" comparison misleads people when there is a
long time period (perhaps a decade) between infection and overt disease, as
there is for AIDS. Dr. Fauci states that he prefers to think that the AIDS
budget is not too large, but that the budgets for cancer and heart disease
are too little.
------------------------------
FEWER SEROCONVERSIONS AMONG GAY MEN, MORE AMONG IV DRUG USERS
Dr. Fauci believes that we should think of two epidemics: the epidemic of
the disease itself with overt symptoms and illness (AIDS), and the epidemic
of mostly-hidden infection. The face of HIV infection is changing, with
data from San Francisco showing the number of new seroconversions among gay
men decreasing to about one percent last year, compared to a yearly rate of
seroconversion of nearly 20 percent for the years 1982 and 1983. Dr. Fauci
mentioned that the statistical changes are difficult to see if one only
looks at yearly summaries. Gay men as a percentage of total AIDS cases has
remained approximately the same at about 60 percent for several years in a
row, but if one looks at more recent data, and at data in the last year on a
month-by-month basis, the changes are more apparent. Gay men in 1987
comprised 65 percent of all AIDS cases. In 1988, they comprised 57 percent.
In contrast, IV drug users have increased from 17 percent of all cases to 24
percent of all cases in those same two years.
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AIDS SPREADS RAPIDLY IN ASIA, AND IN U.S. INNER CITIES
Dr. Fauci noted important changes in the spread of AIDS, which is increasing
at a substantial rate in Asia. In Bangkok, Thailand, where there is a
thriving sex industry, over half of some 3,000 prostitutes are HIV-positive,
a very substantial change in the last two years. In addition, there are an
estimated 175,000 IV drug users in Bangkok alone.
The second change is the rapid spread of AIDS in the inner cities of the
U.S. In New York City, over two percent of the babies born in the Bronx are
HIV-positive. Manhattan (nearly two percent), Brooklyn (1.74 percent),
Queens (0.81 percent), and Staten Island (0.76 percent) follow. The
seropositive rate outside the city is 0.13 percent, substantially less than
the city. Some 81 percent of the pediatric AIDS cases can, in one way or
another, be linked to IV drug use.
The inner city of Baltimore also has similar high percentages of
seropositive individuals. Dr. Thomas Quinn of NIAID and Johns Hopkins
University reports that over five percent of men and over three percent of
women visiting a Sexually Transmitted Diseases clinic in Baltimore are
positive for HIV. Among young women who were seropositive, many (over 70
percent) did not know how they could have contracted HIV. They were not
members of one of the identified "high risk" groups, nor did they know if
their sex partners belonged in the high risk categories.
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RISK OF CONTRACTING HIV AMONG HEALTH CARE WORKERS
A study was conducted on some 800 health care workers who were exposed to
blood from AIDS patients, and who had no other identifiable risk factors.
Only three of these individuals seroconverted following this exposure. Dr.
Fauci concluded that there is a real, but small, risk from parenteral or
mucous membrane exposure to HIV-positive blood. The very sensitive
detection technique of polymerase chain reaction (PCR) has been done on
several of these individuals in Bethesda and San Francisco. The PCR
technique did not detect any presence of virus, other than those that could
be detected by antibody reaction (ELISA). This means that there were no
"hidden" cases, waiting in a latent state.
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PROGRESSION TO AIDS AND AIDS TREATMENT PROTOCOLS
The average time from exposure to HIV to expression of frank AIDS is about
seven to 10 years. In those individuals who have been followed for seven
years after seroconversion, some 36 percent have progressed to AIDS, about
40 percent have some detectable deterioration in clinical signs, and about
20 percent remain asymptomatic. These numbers could change dramatically
with the widespread introduction of AZT and other drug treatments at a much
earlier time.
There are at least 32 drugs being used in treatment protocols. A good many
of these are used in combinations. Three important studies were reported
recently. One indicated that AZT (Zidovudine or Retrovir) therapy slowed
disease progression when given to patients with early symptoms. A second
study showed that AZT delayed development of symptoms when given to
asymptomatic HIV-infected persons. Preliminary results of a third study
showed that a significantly lower dosage of AZT produced the same results in
extending lifespan, with much less deleterious side effects. The FDA
recently approved a major expansion of AZT use, and many more thousands of
people will be open to using this drug. Dr. Fauci (with agreement from Dr.
Broder, who was present in the audience) strongly supported clinical trials.
He described the "parallel track," in which clinical trials would be
conducted to study the safety and efficacy of drugs, and at the same time
compassionate distribution of drugs would be provided to those who could not
be on a clinical trial. Dr. Broder was optimistic that a combination of
drugs would eventually make AIDS a manageable disease, much like the present
situation with some forms of leukemia.
There was considerable discussion about an article in The Washington Post
which described research showing that AZT is carcinogenic. Dr. Fauci was
not surprised by this finding. AZT is a strong drug and many other strong
anti-tumor and anti-viral drugs have been shown to be carcinogenic. But
several things should be kept in mind about this finding. One, the dose
level was quite high, about 175 times the dose taken by AIDS patients. In
addition, the benefits from taking AZT far outweigh any risk, even
carcinogenic risk, from AZT. [EDITOR'S NOTE: A later report by Dr.
Silverman of the American Foundation for AIDS Research (AMFAR) stated that
this was actually a good piece of news, in that AZT was far less
carcinogenic than other similar drugs.]
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BASIC BIOMEDICAL RESEARCH
Dr. Fauci did not spend much time on this subject. He mentioned that Dr.
Gallo had recently addressed the same audience, and he felt that what he
(Fauci) had to say would probably be repetitive. He did mention some
interesting work with several different agents which could trigger the rapid
series of events which lead to replication of HIV. Many of the things which
"activate" HIV are the same agents which activate the immune system in
general, such as mitogens, antigens, cytokines, transfected viral genes, and
Tumor Necrosis Factor (being studied by Dr. Fauci and others).
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VACCINES
Dr. Fauci reported that there was some good news about vaccines (which was
later reported in the press). A study at Tulane University showed that a
vaccine could work in monkeys against Simian Immunodeficiency Virus (SIV),
an AIDS-like virus. This is the first report of a vaccine which works
against a virus very similar to HIV, and in a species very similar to
humans.
Dr. Fauci reported that there are now nine ongoing clinical studies with
vaccines against HIV. Some studies use killed whole virus, and some use
virus parts such as the outer protein (gp-120 or gp-160). Several of these
studies have used proteins such as gp-120 that have been produced by
recombinant DNA techniques.
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MANDATORY TESTING
A somewhat heated discussion followed the presentation. One member of the
audience asked Dr. Fauci if it wasn't about time that mandatory testing of
all people be implemented in order to bring the spread of AIDS under
control. Dr. Fauci, Dr. Broder, and others strongly disagreed with the
questioner, stating that mandatory testing requirements would drive the very
people away from testing who most needed it. They felt it would be a misuse
of precious resources, which could be better spent on biomedical research
and treatment. They pointed out that a one-time test would be meaningless,
if non-monogamous sex behavior continued. Dr. Fauci said that widespread
voluntary testing, counseling, and behavioral changes can stop the spread of
AIDS.
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CONCLUSION
Dr. Fauci described the 1980s as the decade of AIDS. The 1990s will
unfortunately be the second decade of AIDS. But there are signs of
progress. More has been found out about HIV faster than any other virus in
history. AIDS research will benefit cancer research and give us a much
clearer picture of the immune system.
This brief summary touched on many aspects of AIDS and HIV. If you would
like more details on any of these areas, please feel free to contact the
Washington HIV News or the Whitman-Walker Clinic.
------------------------------
W. Howard Cyr has a Ph.D. in biophysics, is a commissioned officer of the
Public Health Service, and is the AIDS Coordinator for the Office of Science
and Technology of the Center for Devices and Radiological Health of the Food
and Drug Administration.
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MEDICAL UPDATE
NEW TREATMENT OF HIV-INFECTED INDIVIDUALS
by Basil Vareldzis, M.D.
August, 1989 will be remembered as a major turning point in the treatment of
HIV disease and AIDS. This was the time when three major studies provided
data to show that a radically different treatment philosophy should be used
for this disease. The conclusion is that all HIV-infected people with CD4
counts below 500/mm^3 should be treated with AZT (Retrovir) 500 mg per day.
This includes persons with AIDS, ARC, and those who are asymptomatic.
These new recommendations radically alter the previous premise that infected
persons should only be treated when they are ill (i.e. ARC or AIDS) or when
their immune system is so compromised as to put them at very high risk for
illness (CD4 below 200/mm^3). The change in the recommendations is due to
two factors: the proof that a lower dose of AZT is effective, and the proof
that people treated with AZT progress more slowly to AIDS than those who
receive a placebo. The studies that yielded these results were the
following:
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ACTG 002
ACTG 002 (AIDS Clinical Trials Group Protocol number 002, sponsored by the
National Institute of Allergy and Infectious Diseases) -- This study of some
580 persons with AIDS was begun in 1987 in order to compare the efficacy
(effectiveness) of two doses of AZT (Retrovir). Half the patients received
1200 mg of AZT per day while the rest received 600 mg per day. The two
groups were followed over a two-year period. The endpoint for the study was
cumulative survival. The results showed that survival of patients on 600 mg
per day was the same (no statistical difference) as those on the 1200 mg
regimen. Side effects (or toxicities), on the other hand, were much lower
in the low-dose group.
The conclusion: 600 MG OF AZT PER DAY WAS EQUALLY EFFECTIVE IN TERMS OF
OVERALL SURVIVAL as 1200 mg per day in AIDS patients WITH FEWER SIDE EFFECTS
NOTED in the lower dose group. This study was presented to the meeting of
AIDS researchers at the ACTG meeting July 12-14, 1989 and was leaked to the
press thereafter. This has not yet been published in the medical
literature.
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ACTG 016
ACTG 016 (protocol number 016 was a multi-center trial sponsored by NIAID) -
- This protocol was started in July, 1987 with some 740 ARC patients
involved. Patients were randomized to either AZT (Retrovir) 1200 mg per day
or placebo. Patients also had CD4 counts measured at entry and were grouped
into either 200-500 CD4 cells/mm^3 or 501-800 CD4 cells at entry. This
study was reviewed by a Data and Safety Monitoring Board (DSMB) on August 6,
1989. The DSMB stopped the study because they found AZT treatment made a
significant difference in progression to AIDS for those persons with CD4
counts below 500. Of the approximately 350 persons with ARC and CD4 counts
below 500, half were on AZT and half on placebo. Thirty-six of the placebo
patients went on to develop AIDS while only 14 of the AZT-treated group did
so. Mean time of follow-up in the study was nine months. The DSMB felt it
to be unethical to continue the study based on this result. All AZT vs.
placebo trials in ARC patients with CD4 counts below 500 were also stopped
the next day with placebo patients being started on AZT. This study also
showed that ARC patients had far fewer side effects from high dose AZT (1200
mg per day) than AIDS patients. Only five percent of patients on AZT
experienced side effects.
No statement could be made about ARC patients with CD4 counts above 500 as
not enough endpoints were reached to be able to analyze the data. The
placebo arm has been stopped, however, and all the patients have been put on
AZT. This will now become a long-term AZT follow-up study in ARC patients.
The conclusion: ALL ARC PATIENTS WITH CD4 COUNTS BELOW 500/MM^3 SHOULD BE
TREATED WITH AZT (RETROVIR) because it will decrease their rate of
progression to AIDS in half (from 10 percent to five percent in nine
months). This data has been sent to all the physicians in the United States
by the NIAID. In addition, this has been widely publicized in the popular
press and is about to be published in the NEW ENGLAND JOURNAL OF MEDICINE.
------------------------------
ACTG 019
ACTG 019 (protocol number 019 is a multi-center trial sponsored by the
NIAID) -- This protocol also started in July, 1987 with a total of 3,200
asymptomatic HIV-infected people enrolled. Patients were randomized to one
of three areas: high dose AZT (1500 mg per day), low dose AZT (500 mg per
day) and placebo. The group was stratified by CD4 count to 200-500 and 501-
800 CD4 cells/mm^3.
The study endpoint is development of late ARC or AIDS. Some 1,400 patients
were in the 200-500 CD4 cell range at entry while the rest were above 500.
Like protocol 016, this protocol was also reviewed by a DSMB on August 16,
1989. The DSMB stopped the below 500 CD4 arm of the study because there was
a statistical difference between AZT and a placebo. What they found in
asymptomatic patients with CD4 cell counts below 500/mm^3 was that 38 people
on a placebo developed ARC/AIDS, 17 people on low dose AZT developed
ARC/AIDS, and 19 people on high dose AZT developed ARC/AIDS.
The lowest progression rate (measured in progressions per 100 person-years
of observation) was in the low dose AZT group. This group also had very few
side effects, with only three percent experiencing nausea. No severe
hematologic toxicities were noted with this dose of AZT. No statement was
made about the group with CD4 counts between 501-800. That placebo-
controlled study is continuing.
The conclusion: AZT 500 MG PER DAY IS AS EFFECTIVE AS HIGH DOSES IN
PREVENTING PROGRESSION OF DISEASE in asymptomatic patients, and slows the
rate of disease progression in half with very few side effects.
------------------------------
In brief, these results have led physicians to recommend the lower dose of
AZT (Retrovir) to ALL their HIV-infected patients with CD4 counts below 500.
This includes switching AIDS patients who have been on the 1200 mg dose to
the lower dose.
This change has had enormous impact on Burroughs Wellcome, the manufacturer
of AZT (Retrovir). Rather than aiming for a market of 20,000 to 30,000
persons with AIDS, the company can now aim to market the drug to some
600,000 people who meet the new criteria--this allows for economies of
scale. The company has applied to the FDA for a change in labeling to make
the 500 mg dose the standard regimen as well as an expansion in indication
to allow use in asymptomatic people. This change will take a few months to
be implemented through FDA.
However, since Retrovir is already FDA approved, physicians are free to
prescribe it to whoever they choose regardless of the labeled indications.
This has already begun with several thousand patients having started AZT in
the past few months nationwide.
Lately, after intense pressure, Burroughs Wellcome reduced the price of AZT
by 20 percent in mid-September. This now means that patients on the new 500
mg per day regimen can expect to pay $180.00 per month at the wholesale cost
of the drug (150 capsules at $1.20 per capsule). This is still very high,
although much more reasonable than the $700.00 per month that AIDS patients
were paying for the higher dose earlier this year.
We hope that further price reductions and dose modifications may further
reduce the cost of this lifelong therapy. Stay tuned for future updates.
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Basil Vareldzis, M.D., is the Clinical Director of the Whitman-Walker
Clinic.
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THE SAGA OF DDI
by Basil Vareldzis, M.D.
This summer has witnessed another interesting saga in the AIDS field--the
on-again off-again story of 2',3'-dideoxyinosine (ddI)--the wonder drug of
the last half of 1989.
The story begins in June, 1989 at the Fifth International AIDS Conference in
Montreal. Researchers there presented their latest findings on new AIDS
drugs. ddI came out as by far the most promising drug. The data that was
presented involved some nine months of follow-up from a Phase I study
undertaken by the National Cancer Institute. Some 26 patients had been
entered beginning in Fall, 1988 and were given gradually escalating doses of
ddI.
The data presented showed the drug to be equally as effective as AZT, with
very few side effects and with a viral resistance pattern that was very
different from that of AZT. That is to say, we now have a drug to give to
someone with AIDS who either cannot tolerate AZT due to side effects, or who
is failing on AZT due to viral resistance. This was a very exciting bit of
news!
July saw a flurry of activity surrounding this new proposal called the
"parallel track." This parallel track, as outlined by Dr. Anthony Fauci,
and several others, allowed for distribution of the drug concurrently with
the Phase II clinical trials. The rationale was obvious--an AIDS patient
who can no longer take AZT has extremely limited treatment options and may
have a life span of a few years at best and weeks at worst. Clearly, a drug
of this nature could not be denied to the patient in need while the world
waits for two to three years for the results of Phase II clinical trials.
August saw several reversals--first of all, a series of three Phase II
protocols were designed by Bristol Meyers (the maker of ddI), the NIAID and
the FDA. These protocols were designed on a fast track without full
consultation with the investigators in the field or patient advocates. The
result was that the protocols were not very workable in their original
format and had to go back for revisions.
One of the problems involved the fact that two of the three studies were
double-blind comparisons of ddI vs. high dose AZT. Given the new data we
have about low dose AZT, it did not seem reasonable or ethical to start a
study that exposes patients to the toxicities of high dose AZT when a low
dose is equally effective. The second problem was the narrow definition of
AZT-intolerance. This was defined in such a way that most patients who are
truly intolerant of AZT would NOT be eligible for the ddI study.
Another hitch appeared in late August, when reports began to surface about
toxicities and side effects of ddI. The once-thought-to-be-perfect drug now
had some blemishes. In particular, the side effect of greatest concern is
called peripheral neuropathy--a pain and tingling sensation in the hands and
feet that can become disabling. This toxicity did not appear until patients
had been on the drug for several weeks at the higher doses and was now
starting to appear many months later in those receiving the lower doses.
Reports on this problem have been scanty with some reports in the popular
press suggesting that this problem may be as severe as the effects caused by
2',3'-dideoxycytosine (ddC), another AIDS drug currently in Phase III
trials. ddC cannot be taken alone because of this side effect, and is given
in alternation with AZT.
In September, we heard that the release of ddI was delayed due to a
production problem. This was followed by some uncertainty as to the amount
of drug that would be available--would it be enough for 2,000 patients or
12,000 patients? The drug finally became available through what has become
known as the "parallel track" in early October. This allowed all patients
who needed to be on ddI to get the drug free of charge outside of a study
setting. At this time, we now have almost 3,000 patients on ddI through
this "parallel track" mechanism. Although good news for these patients,
this has actually become a problem, because the sites that are supposed to
be doing the clinical studies were not able to begin the phase II trials in
October because of a lack of case report forms, shortages in the
availability of ddI, and other reasons.
It is now early December, and we are finally ready to begin the clinical
trials (which will be needed in order to get the drug licensed), yet very
few patients seem to be interested in the studies at this time. One of the
major incentives to patients is getting the drug free, while the major
drawback seems to be the cost of the associated laboratory tests. The study
requires us to obtain several blood tests, chest X-rays, and other tests in
order to screen the patient prior to entry--this costs about $650.00 and is
not paid for by the NIAID. In addition, patients are charged about
$3,600.00 per year for laboratory studies (most of which are routine tests
that the patient would get anyway) which should be covered by health
insurance in most cases. There is no charge for professional services
(doctor's visits) received at the Whitman-Walker clinic.
Overall, we are very excited about participating in the phase II ddI
studies, which will hopefully lead to licensing of this very promising anti-
retroviral agent. We hope to be able to accrue the necessary number of
patients in the near future to be able to complete the trial in a timely
manner so that the drug can be made even more widely available to all who
are in need.
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Basil Vareldzis, M.D., is the Clinical Director of the Whitman-Walker
Clinic.
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