MNSMITH%UMAECS.BITNET@oac.ucla.edu (02/04/90)
AIDS TREATMENT NEWS Issue # 93, December 15, 1989
CONTENTS:
1989/1990: Where Are We Now?
The Wrong Nightmare: The Worst Delay of Clinical Trials
NAC: "No Miracles"
San Francisco: Oral Thrush Study
San Francisco: Chinese Herbal Program Deadline January 5
New BETA (Bulletin of Experimental Treatments for AIDS)
Lymphoma Treatments Reviewed
Chronic Fatigue Organizations Seek Coalition with AIDS Efforts
Community Research Alliance Hypericin Funding
Caution: Malicious "AIDS" Computer Disk
Sulfadiazine Temporary Supply Problem
Reminder: AZT Questionnaires
Next Issue January 5
1989/1990: WHERE ARE WE NOW?
by John S. James
1990 begins at a time of confusion about research and new-
treatment issues. Much is happening, and the year ahead could
develop in any of a number of different ways. Here is one area
we believe will be important next year.
>From Access to Oversight?
Last January we predicted that access would be the major
treatment issue of 1989. At that time it was already clear that
no major treatment advance would be approved in 1989; one could
know that by looking at the drugs in the clinical-trials pipe-
line. Therefore, the issue would be whether people could use
promising treatments while they were still experimental -- treat-
ments like ddI which probably work but will take years to acquire
statistical proof that they do.
Great progress on access was made last year, thanks largely
to two key events: Fauci's proposal for a parallel track, and
the ddI program developed by Bristol-Myers in cooperation with
the FDA, AIDS activists, front-line physicians, and others.
Major problems remain, and questions, issues, and conflicts
around access will be very much with us in 1990. But we think
that another issue may become central next year -- the need for
better definition, design and management of the clinical trials,
so that they can respond better to the needs of the public-
health emergency.
We see resources as the most important single issue of
1990 -- money for prevention, research, treatment, and other care.
Since we are not experienced in financing issues, we will follow
the lead of service organizations and others. We are familiar
with research, however, and here we believe that effective scien-
tific and administrative oversight of the trials will become a
critical issue. It has been the most important issue all along,
but until now little has been said about it. Pressures are
building to end the silence:
* No major approvals in 1990. It is already clear that no
important HIV treatment will be approved in 1990 under current
procedures. ddI and ddC are now farthest ahead, but approval for
each must wait for (among other things) trials which will prob-
ably take two years. And neither of these clocks has started
yet, because each only starts when the last patient called for by
the respective protocol has been recruited and entered into the
study.
As we will show below, this problem does not arise from any
law of nature, but from unexamined assumptions in an overlooked
meeting place between scientific study design and public policy.
Critical options have been ignored because policy makers lack the
scientific background to develop them, scientists lack the
authority, and institutions lack the incentive. The growing AIDS
case load and continually worsening emergency are increasing the
pressures to bring the light of public examination and debate
into some previously dark corners.
* Parallel track limitations. A pivotal event of 1989 was
the proposal by Anthony Fauci, M. D., Director of the National
Institute of Allergy and Infectious Diseases (NIAID), for "paral-
lel track" access to promising treatments while they are still
being tested in clinical trials. Until Fauci's proposal, the
dominant idea had been that no early or compassionate access
should be allowed for AIDS treatments, because otherwise people
would not volunteer for clinical trials. Much of this thinking
had been based on a misreading of the case of the drug ganciclo-
vir, made available for compassionate use to thousands of people
over a several-year period to prevent blindness from AIDS-related
cytomegalovirus (CMV). The pharmaceutical industry wrongly
assumed that ganciclovir's developer, Syntex Corporation of Palo
Alto, CA, was being punished by the FDA for making an AIDS drug
available through compassionate use.
Since an analysis of the new drugs in the pipeline showed
that no important HIV treatment would be fully approved for
several years, this prevailing mindset was a death sentence for
tens of thousands of people. Fauci's parallel track proposal
broke this mental logjam and opened a door for new thinking
throughout government and industry. The head of the world's
largest AIDS trials program had proposed that some early access
could be allowed without damaging the trials. The new openness
allowed the development of the system for early access to ddI -- a
development unprecedented both in its speed, and in its bringing
together of many different interests, getting some of the people
involved talking to each other for the first time, to produce
results.
Parallel track is urgently necessary. But it will not solve
all the problems:
(1) Parallel track requires the good will of the company
which has the exclusive rights to each new drug. The company
must spend money to save lives, with no certainty of reward.
Many will be unwilling to do so.
(2) Individuals receive the drug without charge but pay for
required physician time and laboratory tests. Third-party payers
will probably learn to identify these expenses and refuse them as
"experimental," meaning that parallel track may be even more lim-
ited by social class than standard medical care. It will be dif-
ficult to define standards of care if crucial parts of care come
to be delivered on an optional, "experimental" basis.
(3) The most important question is what drugs to use and how
to use them. Clinical trials are supposed to help answer these
questions. t there are no trs designed to address the needs of
parallel track. Parallel track lives only on the crumbs of
knowledge which happen to fall out of trials designed for some-
thing else. (This isn't as bad as it sounds, however; clinical-
trial design has so lost its way that standard medical practice
lives largely on such crumbs, also.)
Despite these reservations, we totally support the parallel
track. It is a life and death issue and there is no alternative
ready to go. Sometimes a second-best solution is infinitely
better than no solution at all. Parallel track is an emergency
stop-gap until the entire system of clinical trials can be
rethought and redesigned.
* The clinical-trials logjam. Those who run the major
Federal system of AIDS clinical trials, the AIDS Clinical Trials
Group (ACTG) system in NIAID, are quick to admit that the system
is overloaded and cannot keep up with the important new drugs
coming out of the laboratory. People are tired from overwork due
to inadequate staff; tasks which everyone agrees are important
are postponed or eliminated. The problems only look worse in the
future as there will be more people with AIDS, more new drugs to
try, but no more and maybe even less support from Congress.
Behind this problem is the fact that new-drug approval in
the United States has become so elaborate and inefficient that it
costs an average of $120 million for each new drug approved. The
ACTG system, started from scratch to provide grants for testing
AIDS drugs, cannot be expected to test dozens of new drugs under
these rules with the limited resources available.
* Serious administrative problems. At a closed ACTG meeting
on November 6-8, 1989, it was announced that no major new trials
could start for six to nine months -- an estimate which may be
optimistic. The reason is that the statistical and data-
processing center for the ACTG system was being moved from Trian-
gle Research Institute to Harvard University, and the new center
would not be ready until then. This delay most seriously impacts
trials for opportunistic infections, since other trials were not
ready to go anyway.
In any system adequate to meet the needs of the emergency,
no such delay would be tolerated.
* Questions about lack of results. A December 12 memo from
ACT UP/New York to Federal agencies and others begins with the
sentence, "After three years supported by hundreds of millions of
public funds, the AIDS Clinical Trials Group (ACTG) has yet to
develop data leading to a single new treatment for any HIV
related condition."
We are not close enough to the ACTG to evaluate its perfor-
mance independently. But ACT UP's Treatment and Data Committee
is very well informed about the ACTG system and its problems.
Needed: Effective Oversight
It seems clear that some capable and independent oversight
body needs to examine and analyze the record, point out problems
or improvements needed, and see that the changes are made.
The National Commission on AIDS will not do this job. It is
working in other areas and has no interest in oversight of
research.
The well-regarded Institute of Medicine of the National
Academy of Sciences has a committee to investigate the ACTG sys-
tem. It remains to be seen whether this group will be effective.
The entire area of clinical research needs a thorough exami-
nation by top scientists and top administrators, with the staff,
resources, authority, and independence to do the job.
THE WRONG NIGHTMARE: THE WORST DELAY OF CLINICAL TRIALS
by John S. James
The clinical trials of ddI and ddC both illustrate what we
believe is the worst bottleneck delaying AIDS treatment research.
The problem, which affects any HIV treatment but is usually less
severe with other diseases, is largely responsible for the fact
that hundreds of millions of dollars have gone into AIDS trials
and produced few useful results. This lack of productivity is
not due to any law of nature, but to a widespread misjudgment.
Physicians, scientists, and regulators have marched into a morass
because they have chosen the wrong nightmare.
The clinical trials of ddI need hundreds of volunteers and
will probably have to run for two years after the last subject is
recruited. The same delay applies to all HIV treatments, and
therefore becomes a death sentence for tens of thousands of
people -- although some of them will be saved by the parallel
track. (The public does not realize that the faster approval of
AZT cannot be repeated, because today it would be unethical to
give research subjects only a placebo when an approved treatment
is available, and it is much harder to get definitive results
when comparing a new treatment to an active control than to a
placebo.)
In the design of the ddI trials, statisticians computed the
numbers of subjects needed, assuming a two-year study. The fact
that the numbers came from mathematical computations gave them an
aura of infallibility, unchallengeable by ordinary mortals. But
we can and must examine what these trials are trying to do, and
why.
The trial design -- including the two years, the hundreds of
subjects, and the consequent need for time-consuming and expen-
sive coordination of many widely distant medical centers -- was
created to produce a single bit of information, one yes-or-no
answer. The question to be answered is whether, if the drug
really does nothing at all, the chance of the trial falsely con-
cluding that the drug does work (just by chance alone) is less
than a given probability (usually five percent).
Is this the question that most needs answering? Should this
question be allowed to add two years or more delay to every new
HIV drug? Should this question serve as a gatekeeper which
prevents other research from starting until it is answered?
Should it be allowed to make research so costly in money, facili-
ties, and (most importantly) qualified personnel, that it limits
the trials to a handful of new drugs, when there will soon be
dozens that clearly deserve followup?
The real issue with ddI is not whether it works. A growing
working consensus holds that it probably does. And drugs do not
begin multimillion dollar clinical trials unless pharmaceutical
companies, which are in the business of evaluating drugs, believe
in them. The most important questions now are long-term toxi-
city, and when and how to use ddI most effectively in various
groups of patients.
Some of this information will come out of the ddI trials --
but only by accident. Because the trials will take so much time,
long-term toxicity data will be produced. And restrictive entry
criteria will assure us much information about using ddI in cer-
tain groups of patients, and none about using it in other groups.
The whole structure of the trials is built around the need to get
that one statistical bit of information, to be able to walk away
with that single yes-or-no answer -- not to answer the questions
which are most important now to patients and physicians.
Trials which studied long-term toxicity by design instead of
by accident could be started much sooner, probably as a continua-
tion of phase I, and could use many fewer patients. The time and
money saved could be used to test several other drugs which oth-
erwise will be neglected.
The medical world today is obsessed with one nightmare --
that a worthless drug will come into widespread use. This danger
is real, as such cases have occurred many times in the past. The
problems come from using this nightmare as the sole gatekeeper
which controls everything else, regardless of all other elements
in the real-world situation.
A Better Way
A rational program for clinical testing and early use of new
drugs would probably involve an expanding circle of research and
treatment, starting with dose and toxicity studies and, depending
on results obtained, moving continuously into wider use in
appropriate groups of patients. The research aspect would be
most intensive at first; then gradually the treatment aspect
would predominate.
This expanding circle of use, with research most intensive
at first, is what already occurs with conventional phase I, II,
III, and IV studies. But today's process is not rational or
planned as a whole. It is full of arbitrary discontinuities,
prohibitively burdensome requirements derived from theories, and
deliberate,ied blindness to th actual questions, issues,
knowledge base, and opportunities of the specific drug, in its
social and public-health context.
Note that we are not suggesting dropping the legal require-
ment that drugs show efficacy before they are marketed. That is
a different issue. We are saying instead that narrow efficacy
testing should not completely dominate clinical trials, should
not be applied blindly and rigidly in ways that straightjacket
and paralyze the entire research enterprise.
A coherent, rational design for an integrated research and
treatment process, using to advantage the specifics of each
situation and addressing the actual questions at issue, could get
the most important answers far faster than the present system,
and at a fraction of the cost. It could bring many more drugs
into trials than the present system, which is seriously over-
loaded with unnecessarily costly trials. It could bring us years
closer to better treatments for AIDS, thereby saving most of the
lives which otherwise would be lost.
This is one of the central research issues we intend to
address in 1990.
NAC: "NO MIRACLES"
In our issues of December 1 and October 6, AIDS TREATMENT
NEWS reported on indications that NAC (N-acetylcysteine), a drug
widely used in Europe to treat bronchitis, might be useful in
treating AIDS or HIV infection.
Since publishing those articles we have talked with Barbara
Starrett, M. D., who sees many AIDS patients in New York. About
ten of her patients have used the European form of the drug, some
starting as early as December 1988.
Dr. Starrett is confident that the drug has not hurt any-
body, and thinks that it may work as a stabilizer or mild immune
modulator. Her patients have remained stable. But she has seen
no great improvements, and has no definitive proof that the drug
helped. Most of her patients had chosen to stop taking the drug,
because it did not seem worth the expense. (Prices vary greatly,
and her patients had been using one of the most expensive brands,
from Switzerland.)
Dr. Starrett is concerned that people may have expectations
which are too high. But she says there is no question that the
drug should be available.
NAC Survey
In New York, the PWA Health Group, in association with ACT
UP's Treatment and Data Committee, will conduct a survey of peo-
ple using NAC, to ask about short-term subjective benefits and
risks. They hope "to gain some practical information about tri-
als yield results."
Registration forms and baseline questionnaires will be
available at the PWA Health Group; followup surveys will be
mailed for at least three months. Buyers clubs in other cities
might also join this study.
SAN FRANCISCO: ORAL THRUSH STUDY
Persons with oral thrush are needed to help test a new anti-
fungal at San Francisco General Hospital. The study, conducted
by Merle Sande, M. D., and others at the Department of Medicine,
lasts only 10 days.
The drug, from Schering Corp., is known as SCH 39304.
Patients will randomly be assigned to one of three groups: keto-
conazole 200 mg daily, SCH 39304 25 mg daily, or SCH 39304 50 mg
daily. Blood samples will be drawn on days 1, 3, 7, and 10,
requiring a visit to the clinic on those days.
Although the drug does not yet have a name, this is a phase
III study; SCH 39304 has already been given to dozens of people,
and only occasional minor side effects have occurred.
To volunteer or to learn more about this study, call Dr.
Belle Lee, Pharm. D., at 415/821-8450.
SAN FRANCISCO: CHINESE HERBAL PROGRAM DEADLINE JANUARY 5
The Quan Yin Healing Arts Center in San Francisco continues
to sponsor HIV treatment and research studies for seropositive
people, whether symptomatic or not, through its Chinese Herbal
Treatment Program. The next deadline for enrollment is Januthe program is $190
for the 12 weeks. Defeat of the AIDS Epidemic," by Subhuti Dharmananda, Ph.D.,
pub-
lished by his Institute for Traditional Medicine and Preventive
Health Care, Portland, Oregon. Two groups of patients were
reported. In the first, with 93 participants completing the
study, "40 felt more healthy at the end of the program, 47 felt
about the same, and only 6 reported feeling less healthy. White
blood cell counts increased by an average of 2.85 percent and
hematocrit increased by an average of 1.08 percent. T-cells were
measured in 26 participants. Fifteen showed an increase, 10
showed a decrease, and one had no change. Individuals who were
categorized as HIV+ indicated better response overall, and by
blood tests, than those with ARC or AIDS...Of the 93, six changed
diagnosis from HIV to ARC and two from ARC to AIDS.
Besides the 93 who completed that study, 54 dropped out
(including two who died); a total of 147 had started. Many were
listed as dropping out only because they failed to provide the
last report at the end of the three months.
In the next group, 164 participants began the protocol and
127 completed it. "Fifty nine of the individuals completing the
study reported feeling more healthy and 58 reported feeling about
the same, while only 10 individuals considered themselves to be
less healthy at the end of the three-month period. White blood
cell counts increased by an average of 5.8 percent and hematocrit
increased by an average of 2.1 percent. T-cell counts were avail-
able for 12 participants; of these, six showed an increase, one
stayed about the same, and five experienced a decrease...Four
individuals changed diagnosis from HIV+ to ARC and one from HIV+
to AIDS during the course of the study."
Another group began in September, 1989, but results are not
yet available.
New BULLETIN OF EXPERIMENTAL TREATMENTS FOR AIDS
The San Francisco AIDS Foundation has published the Fall,
1989 issue of BETA (Bulletin of Experimental Treatments for
AIDS), a useful publication available free to San Francisco
residents and by subscription to others. The current issue
(dated November, 1989) includes articles on ddI, compound Q,
parallel track and treatment IND, different options for preven-
tion of PCP, blood tests for HIV progression, and an update on
AZT. There is also a complete copy of the directory of open HIV
trials in the San Francisco area, published by the County Commun-
ity Consortium.
To subscribe to BETA, call 800/327-9893, or 415/549-4300.
For non-residents, the cost is $25.00 per year for individuals,
$50.00 per year for organizations.
[It is on display here, in Therapies/Beta. -- sysop]
LYMPHOMA: A CURRENT LOOK AT THERAPIES
by Denny Smith
Lymphoma is a diagnosis facing at least 5% of people with
AIDS. The term lymphoma refers to a number of malignancies in
which various cells of the body's lymph system have proliferated
out of control; those most commonly seen in the presence of HIV
are of B-cell origin, and are classified as high and intermediate
grade, large cell immunoblastic or small non-cleaved Non-
Hodgkin's lymphomas (NHL). They may develop in lymph nodes, but
are more commonly found at extra-nodal sites such as the central
nervous system (CNS), bone marrow, the bowel, liver, or lungs.
The other major malignancy identified with AIDS is Kaposi's sar-
coma (KS -- see AIDS TREATMENT NEWS #73, 75, & 87), which has prob-
ably gathered more attention than lymphoma from the treatment
establishment. Fortunately the rate of new KS diagnoses has
slowed since early epidemic years; however, the incidence of lym-
phoma appears to be on the rise.
Like KS, lymphoma occurring as a consequence of HIV infec-
tion is considered an opportunistic neoplasm, or cancer, rather
than an infection caused by organisms. In spite of that distinc-
tion, however, the development of some lymphomas has been linked
to infections of a herpes-family virus, Epstein-Barr (EBV). This
virus can cause infectious nucleosis, and implicated in the
development of lymphomas in people who must take immunosuppress-
ing transplant medications. For similar reasons, an HIV-impaired
immune response may allow a latent EBV infection to reactivate,
and theoretically provoke lymphoproliferations. EBV is already
known to be implicated in hairy leukoplakia, and has been much
discussed as a possible cofactor in HIV immune deterioration --
each virus has been observed in vitro to activate the other.
However, EBV is not always present in people with HIV, nor uni-
formly evident in AIDS-associated lymphoma tissue. In data col-
lected at San Francisco General Hospital, EBV was identified in
only about a third of lymphoma biopsies, suggesting that EBV
could be a passenger virus which coincides with but is not the
cause of AIDS lymphoma.
Diagnosing lymphoma can involve several complications. The
symptoms of CNS lymphoma in adults might resemble other, more
common AIDS-related neurological problems such as toxoplasmic
encephalitis. By contrast, CNS lesions in children with AIDS
will much more likely prove to be lymphoma than otherwise. The
non-invasive tests for diagnostic purposes, CT or MRI scans, are
not usually dependable for distinguishing infections from lym-
phoma in the brain. A conclusive diagnosis can be made by
biopsy, but antibiotic therapy may be tried first in adults to
rule out infections, and if the symptoms fail to respond then
presumptive treatment can begin for lymphoma. For children that
approach could represent a dangerous delay in appropriate treat-
ment, given the probability of finding lymphoma behind these
symptoms.
Symptoms of lymphoma in the rest of the body may resemble
lymphadenopathy but are easily verified with a biopsy. Obtaining
a sample of tissue through a fine-needle aspiration is less
invasive than a surgical biopsy, although needle aspirations pro-
duce a somewhat higher rate of false-negative results.
Standard treatments for lymphoma have involved radiation or
chemotherapy, or both. These and a few experimental therapies
are briefly discussed below. The occurance of AIDS-related lym-
phoma, like any consequence of HIV, warrants the start or con-
tinuation of an anti-HIV agent such as AZT to address the under-
lying problem. A review of patients treated for CNS lymphoma at
three Los Angeles medical centers pointed to concurrent oppor-
tunistic infections as a factor diminishing the rate of survival
following otherwise successful lymphoma treatments. The report
suggests that an HIV therapy would affect positively a course of
treating lymphoma. Ironically, the underlying problem can be
exacerbated by treatments for secondary infections. Radiation
and chemotherapy, for example, each suppress bone marrow produc-
tion of blood cells (myelosuppression) independently of HIV or
AZT. We spoke to several AIDS-experienced physicians about
refinements in lymphoma therapy which, like new approaches to KS,
attempt to minimize this danger.
CNS lymphoma usually develops as small, individual lesions
on the brain, and can be treated with a series of localized, low-
volume doses of radiation over a period of 5 to 7 weeks. If the
lymphoma is disseminated, present at multiple sites within the
central nervous system, radiation treatment alone is not advised
and is augmented with a chemotherapy agent, such as methotrexate,
administered intrathecally (injected into the cerebrospinal
fluid) since many drugs given intravenously fail to penetrate the
blood-brain barrier. William Wara, M. D., of the Department of
Radiation Oncology at the University of California in San Fran-
cisco, described his modification of the treatment for AIDS-
related CNS lymphoma. By irradiating lesions with larger dose
volumes and shortening the duration of the total therapy to 3
weeks, Dr. Wara obtains an optimum tumor response while minimiz-
ing the trauma of a longer course of therapy. He found this more
intensive regimen improved on previous practice without increas-
ing immunosuppression, because the field of radiation remains
very small and specific.
Treatments of peripheral lymphomas, those diagnosed at sites
outside the CNS, are relieved of the challenge of crossing the
blood-brain barrier; therefore the diseases can be addressed with
a wider spectrum of treatments. The first line of options con-
sists of various chemotherapy combinations, both with and without
radiation.
A list of chemotherapeutic agents tried against lymphoma, in
addition to methotrexate already mentioned, includes bleomycin,
cyclophosphamide, daunorubicin, dexamethasone, doxorubicin, eto-
poside, ifosfomide, prednisone, procarbazine, and vincristine.
Apparently no consensus regarding the choice of agents or degree
of treatment aggressiveness has been established. Physicians at
San Francisco General Hospital noted shortened survival rates
among patients who were treated with high-dose cyclophosphamide,
and they suggest that lymphoma regimens be designed to control
toxicity or to include agents for reducing bone marrow and immune
suppression. Another report at the Montreal Conference described
a decision by clinicians at the Los Angeles Oncologic Institute
and Baylor University Medical Center in Dallas to decrease the
aggressiveness of lymphoma chemotherapy. They then obtained
excellent results in five patients with cautious use of bleomy-
cin, vincristine, and prednisone combined with acyclovir and low-
dose AZT (abstract B. 588).
The investigational agent called granulocyte macrophage-
colony stimulating factor (GM-CSF) may prove useful for protect-
ing the bone marrow from damage associated with chemotherapy, and
permit the addition of other valuable but potentially suppressive
therapies, such as AZT and interferon. esearchers at thentro di
Riferimento Oncologico in Aviano, Italy, presented a report at
the International Conference on AIDS last June finding GM-CSF
effective for reversing myelosuppression due to chemotherapy and
AZT in some people with KS or lymphoma (abstract M. C. P. 103).
GM-CSF is available in the U. S. only through clinical trials.
Refractory lymphomas, those which resist other treatment
attempts, have been affected by mitoxantrone with cytarabine.
Researchers at the Johns-Hopkins University describe a man suc-
cessfully treated for AIDS-associated NHL with a bone marrow
transplant from his sister (Montreal abstract W. B. P. 319).
Anti-idiotype antibody therapy and chlorodeoxyadenosine (CDA) are
both currently pursued in clinical trials in the U. S.
We spoke to Lawrence Kaplan, M. D., an oncologist at San
Francisco General Hospital and principle investigator for five
trials there involving some of the potential treatments mentioned
above. These trials are all still in progress, and we hope to
report any conclusive results in the future. Dr. Kaplan was wil-
ling to share some early positive impressions:
CDA, a novel drug used with success in treating another
diagnosis, has been helpful for some patients with NHL which was
unresponsive to previous treatments.
Anti-idiotype antibody therapy, also for relapsed lymphoma,
is a strategy which borrows functions ordinarily employed by
natural immune defenses. This treatment appears useful in about
25 percent of certain lymphomas.
In a randomized study, GM-CSF is being administered to two
of every three participants, all of whom receive chemotherapy for
NHL. Dr. Kaplan is optimistic for the potential of GM-CSF to
reduce the neutropenia following chemotherapy, and shorten asso-
ciated hospitalizations. For this trial and two others at San
Francisco General Hospital which include chemotherapy, the par-
ticular agents used are cyclophosphamide, doxorubicin, vincris-
tine, and prednisone. These trials are open for recruitment, and
persons interested in participating in any of them should call
415/821-5531.
REFERENCES
Epstein, L G and others,"Primary Lymphoma of the Central Nervous
System in Children With Acquired Immunodeficiency Syndrome,"
Pediatrics volume 82, number 3, September, 1989.
Formenti, S C and others, "Primary Central Nervous System Lym-
phoma in AIDS-Results of Radiation Therapy," Cancer, volume 63,
number 6, pages 1101-1107, March 15, 1989.
Ho, A D and others, "Mitoxantrone and High-Dose Cytarabine as
Salvage Therapy for Refractory Non-Hodgkin's Lymphoma," Cancer,
volume 64, number 7, pages 1388-1392, October 1, 1989.
Kaplan, L D and others, "AIDS-Associated Non-Hodgkin's Lymphoma
in San Francisco," Journal of the American Medical Association,
volume 261, number 5, pages 719-724, February 3, 1989.
Lang, D J and others, "Seroepidemiologic Studies of Cytomegalo-
virus and Epstein-Barr Virus Infection in Relation to Human Immu-
nodeficiency Virus Type 1 Infection in Selected Recipient Popula-
tions," Journal of Acquired Immune Deficiency Syndromes, volume
2, number 6, pages 540-549, 1989.
Rahman, M A and others, "Enhanced Antibody Responses to Epstein-
Barr Virus in HIV-Infected Homosexual Men," The Journal of Infec-
tious Diseases, volume 159, number 3, pages 472-479, March 1989.
CHRONIC FATIGUE ORGANIZATIONS SEEK COALITION WITH AIDS EFFORTS
A major advocacy group for persons with Chronic Fatigue
Immune Dysfunction Syndrome (CFIDS) wants to contact AIDS
activists and organizations to discuss coordination of our
efforts to advance prevention, research, and patient care.
CFIDS, like AIDS, is an infectious disease that causes seri-
ous immune-system malfunction. In 1984-1985, a major ourbreak
among residents at Incline Village, Nevada, affected 300 people;
since then the disease has become a widespread epidemic, with
thousands of cases.
While few people die from CFIDS, about a third become seri-
ously disabled, often for months or years. CFIDS, like AIDS, can
also cause neurological symptoms, or lead to lymphomas. CFIDS is
more contagious than AIDS, although most people exposed do not
become ill. The illness appears not to be sexually transmitted.
It affects women two to three times as often as men. Treatments,
including acyclovir, ketoconazole, and gamma globulin, may be
helpful in some cases.
As with AIDS (although for different reasons) government
agencies and medical professionals have been slow to respond to
CFIDS. Recently, however, important progress has been made. Mile-
stones include publication by the U. S. Centers for Disease Con-
trol of official criteria for diagnosis, and a major scientific
conference in San Francisco in April 1989.
The best single information source on CFIDS (also called
CFS, for Chronic Fatigue Syndrome) is The CFIDS Chronicle, pub-
lished by Community Health Services, P. O. Box 220398, Charlotte,
NC 28222-0398, phone 704/362-CFID.
Contact for AIDS Organizers
Persons interested in developing working relationships
between CFIDS and AIDS organizations should contact Jan
Montgomery, at the Chronic Fatigue Immune Dysfunction Syndrome
Foundation, 3543 Eighteenth St. #20, San Francisco, CA 94110,
415/525-6415.
COMMUNITY RESEARCH ALLIANCE HYPERICIN FUNDING
Our issue number 90 (November 3, 1989) included an appeal to
help San Francisco's Community Research Alliance finish its
hypericin observational study. Readers contributed $3049. in
response to this appeal. In addition, the Community Research
Alliance received two other contributions of $5,000. each.
The total is more than enough to complete the study. Data
collection is being finished this week, and there is also a
budget for a statistical consultant to help in interpreting the
results.
While the hypericin study is proceeding well, we do not have
funds to continue the operation of the organization itself beyond
the end of January. The Community Research Alliance was started
primarily by persons with AIDS. It represents the patient's per-
spective and interests, but has always been weak on fundraising.
Anyone who could help in developing an ongoing fundraising pro-
gram could contact John James at AIDS TREATMENT NEWS, or call the
Community Research Alliance at 415/626-2145.
CAUTION: MALICIOUS "AIDS" COMPUTER DISK
Widespread news reports have warned that an "AIDS Informa-
tion Diskette" mailed to thousands of computer users actually
contains a malicious program to destroy other data in the com-
puter. The disk is for IBM PC-compatible personal computers.
The disk was mailed from "PC Cyborg Corp.," a company which
may not exist. A Panama City address included with the program
was fictitious.
The malicious program is not technically a computer virus,
because it does not spread from computer to computer. The pro-
gram appears to involve no great technical sophistication. What
is unusual about this case is that someone appears to have spent
over a hundred thousand dollars to package and promote a destruc-
tive program, with no apparent motive. The disk was sent pri-
marily to mailing lists of computer users, and to health profes-
sionals.
Anyone who receives a copy of the disk should destroy it, so
that it is not accidentally installed in any computer.
SULFADIAZINE TEMPORARY SUPPLY PROBLEM
A temporary interruption in the supply of sulfadiazine, one
of the most common drugs used to treat toxoplasmosis, occurred
last week when Eli Lilly Co. discontinued manufacturing it. Phy-
sicians learned about the supply problem only after patients
could not get their prescriptions filled.
At least two other companies are now manufacturing sulfadi-
azine. Pharmacies should be able to get the drug through their
regular wholesalers. Wholesalers can buy sulfadiazine from
either Consolidated Midland, in Brewster, NY, or from Lannett, in
Philadelphia. Pharmacies can also order directly from Lannett.
REMINDER: AZT QUESTIONNAIRES
If you have used AZT for at least a year, you could help
others by returning the one-page questionnaire attached to our
last issue. We are interested in what treatments people are
using to supplement or replace AZT after long-term use, ann how
successful these treatments have been. The deadline for return-
ing the questionnaires is January 15.
NEXT ISSUE JANUARY 5
As announced in our Nov. 3 issue, AIDS TREATMENT NEWS will
now publish on the first and third Friday of each month, instead
of every other Friday -- a total of 24 issues per year instead of
26. Our next issue will be dated January 5.
STATEMENT OF PURPOSE
AIDS TREATMENT NEWS reports on experimental and complementary
treatments, especially those available now. It collects informa-
tion from medical journals, and from interviews with scientists,
physicians, and other health practitioners, and persons with AIDS
or ARC.
Long-term survivors have usually tried many different treatments,
and found combinations which work for them. AIDS Treatment News
does not recommend particular therapies, but seeks to increase
the options available.
We also examine the ethical and public-policy issues around AIDS
treatment research and treatment access.
--------------------------------------------------------------------MNSMITH@umaecs.BITNET (Michael Smith) (02/04/90)
AIDS TREATMENT NEWS Issue # 93, December 15, 1989
CONTENTS:
1989/1990: Where Are We Now?
The Wrong Nightmare: The Worst Delay of Clinical Trials
NAC: "No Miracles"
San Francisco: Oral Thrush Study
San Francisco: Chinese Herbal Program Deadline January 5
New BETA (Bulletin of Experimental Treatments for AIDS)
Lymphoma Treatments Reviewed
Chronic Fatigue Organizations Seek Coalition with AIDS Efforts
Community Research Alliance Hypericin Funding
Caution: Malicious "AIDS" Computer Disk
Sulfadiazine Temporary Supply Problem
Reminder: AZT Questionnaires
Next Issue January 5
1989/1990: WHERE ARE WE NOW?
by John S. James
1990 begins at a time of confusion about research and new-
treatment issues. Much is happening, and the year ahead could
develop in any of a number of different ways. Here is one area
we believe will be important next year.
>From Access to Oversight?
Last January we predicted that access would be the major
treatment issue of 1989. At that time it was already clear that
no major treatment advance would be approved in 1989; one could
know that by looking at the drugs in the clinical-trials pipe-
line. Therefore, the issue would be whether people could use
promising treatments while they were still experimental -- treat-
ments like ddI which probably work but will take years to acquire
statistical proof that they do.
Great progress on access was made last year, thanks largely
to two key events: Fauci's proposal for a parallel track, and
the ddI program developed by Bristol-Myers in cooperation with
the FDA, AIDS activists, front-line physicians, and others.
Major problems remain, and questions, issues, and conflicts
around access will be very much with us in 1990. But we think
that another issue may become central next year -- the need for
better definition, design and management of the clinical trials,
so that they can respond better to the needs of the public-
health emergency.
We see resources as the most important single issue of
1990 -- money for prevention, research, treatment, and other care.
Since we are not experienced in financing issues, we will follow
the lead of service organizations and others. We are familiar
with research, however, and here we believe that effective scien-
tific and administrative oversight of the trials will become a
critical issue. It has been the most important issue all along,
but until now little has been said about it. Pressures are
building to end the silence:
* No major approvals in 1990. It is already clear that no
important HIV treatment will be approved in 1990 under current
procedures. ddI and ddC are now farthest ahead, but approval for
each must wait for (among other things) trials which will prob-
ably take two years. And neither of these clocks has started
yet, because each only starts when the last patient called for by
the respective protocol has been recruited and entered into the
study.
As we will show below, this problem does not arise from any
law of nature, but from unexamined assumptions in an overlooked
meeting place between scientific study design and public policy.
Critical options have been ignored because policy makers lack the
scientific background to develop them, scientists lack the
authority, and institutions lack the incentive. The growing AIDS
case load and continually worsening emergency are increasing the
pressures to bring the light of public examination and debate
into some previously dark corners.
* Parallel track limitations. A pivotal event of 1989 was
the proposal by Anthony Fauci, M. D., Director of the National
Institute of Allergy and Infectious Diseases (NIAID), for "paral-
lel track" access to promising treatments while they are still
being tested in clinical trials. Until Fauci's proposal, the
dominant idea had been that no early or compassionate access
should be allowed for AIDS treatments, because otherwise people
would not volunteer for clinical trials. Much of this thinking
had been based on a misreading of the case of the drug ganciclo-
vir, made available for compassionate use to thousands of people
over a several-year period to prevent blindness from AIDS-related
cytomegalovirus (CMV). The pharmaceutical industry wrongly
assumed that ganciclovir's developer, Syntex Corporation of Palo
Alto, CA, was being punished by the FDA for making an AIDS drug
available through compassionate use.
Since an analysis of the new drugs in the pipeline showed
that no important HIV treatment would be fully approved for
several years, this prevailing mindset was a death sentence for
tens of thousands of people. Fauci's parallel track proposal
broke this mental logjam and opened a door for new thinking
throughout government and industry. The head of the world's
largest AIDS trials program had proposed that some early access
could be allowed without damaging the trials. The new openness
allowed the development of the system for early access to ddI -- a
development unprecedented both in its speed, and in its bringing
together of many different interests, getting some of the people
involved talking to each other for the first time, to produce
results.
Parallel track is urgently necessary. But it will not solve
all the problems:
(1) Parallel track requires the good will of the company
which has the exclusive rights to each new drug. The company
must spend money to save lives, with no certainty of reward.
Many will be unwilling to do so.
(2) Individuals receive the drug without charge but pay for
required physician time and laboratory tests. Third-party payers
will probably learn to identify these expenses and refuse them as
"experimental," meaning that parallel track may be even more lim-
ited by social class than standard medical care. It will be dif-
ficult to define standards of care if crucial parts of care come
to be delivered on an optional, "experimental" basis.
(3) The most important question is what drugs to use and how
to use them. Clinical trials are supposed to help answer these
questions. t there are no trs designed to address the needs of
parallel track. Parallel track lives only on the crumbs of
knowledge which happen to fall out of trials designed for some-
thing else. (This isn't as bad as it sounds, however; clinical-
trial design has so lost its way that standard medical practice
lives largely on such crumbs, also.)
Despite these reservations, we totally support the parallel
track. It is a life and death issue and there is no alternative
ready to go. Sometimes a second-best solution is infinitely
better than no solution at all. Parallel track is an emergency
stop-gap until the entire system of clinical trials can be
rethought and redesigned.
* The clinical-trials logjam. Those who run the major
Federal system of AIDS clinical trials, the AIDS Clinical Trials
Group (ACTG) system in NIAID, are quick to admit that the system
is overloaded and cannot keep up with the important new drugs
coming out of the laboratory. People are tired from overwork due
to inadequate staff; tasks which everyone agrees are important
are postponed or eliminated. The problems only look worse in the
future as there will be more people with AIDS, more new drugs to
try, but no more and maybe even less support from Congress.
Behind this problem is the fact that new-drug approval in
the United States has become so elaborate and inefficient that it
costs an average of $120 million for each new drug approved. The
ACTG system, started from scratch to provide grants for testing
AIDS drugs, cannot be expected to test dozens of new drugs under
these rules with the limited resources available.
* Serious administrative problems. At a closed ACTG meeting
on November 6-8, 1989, it was announced that no major new trials
could start for six to nine months -- an estimate which may be
optimistic. The reason is that the statistical and data-
processing center for the ACTG system was being moved from Trian-
gle Research Institute to Harvard University, and the new center
would not be ready until then. This delay most seriously impacts
trials for opportunistic infections, since other trials were not
ready to go anyway.
In any system adequate to meet the needs of the emergency,
no such delay would be tolerated.
* Questions about lack of results. A December 12 memo from
ACT UP/New York to Federal agencies and others begins with the
sentence, "After three years supported by hundreds of millions of
public funds, the AIDS Clinical Trials Group (ACTG) has yet to
develop data leading to a single new treatment for any HIV
related condition."
We are not close enough to the ACTG to evaluate its perfor-
mance independently. But ACT UP's Treatment and Data Committee
is very well informed about the ACTG system and its problems.
Needed: Effective Oversight
It seems clear that some capable and independent oversight
body needs to examine and analyze the record, point out problems
or improvements needed, and see that the changes are made.
The National Commission on AIDS will not do this job. It is
working in other areas and has no interest in oversight of
research.
The well-regarded Institute of Medicine of the National
Academy of Sciences has a committee to investigate the ACTG sys-
tem. It remains to be seen whether this group will be effective.
The entire area of clinical research needs a thorough exami-
nation by top scientists and top administrators, with the staff,
resources, authority, and independence to do the job.
THE WRONG NIGHTMARE: THE WORST DELAY OF CLINICAL TRIALS
by John S. James
The clinical trials of ddI and ddC both illustrate what we
believe is the worst bottleneck delaying AIDS treatment research.
The problem, which affects any HIV treatment but is usually less
severe with other diseases, is largely responsible for the fact
that hundreds of millions of dollars have gone into AIDS trials
and produced few useful results. This lack of productivity is
not due to any law of nature, but to a widespread misjudgment.
Physicians, scientists, and regulators have marched into a morass
because they have chosen the wrong nightmare.
The clinical trials of ddI need hundreds of volunteers and
will probably have to run for two years after the last subject is
recruited. The same delay applies to all HIV treatments, and
therefore becomes a death sentence for tens of thousands of
people -- although some of them will be saved by the parallel
track. (The public does not realize that the faster approval of
AZT cannot be repeated, because today it would be unethical to
give research subjects only a placebo when an approved treatment
is available, and it is much harder to get definitive results
when comparing a new treatment to an active control than to a
placebo.)
In the design of the ddI trials, statisticians computed the
numbers of subjects needed, assuming a two-year study. The fact
that the numbers came from mathematical computations gave them an
aura of infallibility, unchallengeable by ordinary mortals. But
we can and must examine what these trials are trying to do, and
why.
The trial design -- including the two years, the hundreds of
subjects, and the consequent need for time-consuming and expen-
sive coordination of many widely distant medical centers -- was
created to produce a single bit of information, one yes-or-no
answer. The question to be answered is whether, if the drug
really does nothing at all, the chance of the trial falsely con-
cluding that the drug does work (just by chance alone) is less
than a given probability (usually five percent).
Is this the question that most needs answering? Should this
question be allowed to add two years or more delay to every new
HIV drug? Should this question serve as a gatekeeper which
prevents other research from starting until it is answered?
Should it be allowed to make research so costly in money, facili-
ties, and (most importantly) qualified personnel, that it limits
the trials to a handful of new drugs, when there will soon be
dozens that clearly deserve followup?
The real issue with ddI is not whether it works. A growing
working consensus holds that it probably does. And drugs do not
begin multimillion dollar clinical trials unless pharmaceutical
companies, which are in the business of evaluating drugs, believe
in them. The most important questions now are long-term toxi-
city, and when and how to use ddI most effectively in various
groups of patients.
Some of this information will come out of the ddI trials --
but only by accident. Because the trials will take so much time,
long-term toxicity data will be produced. And restrictive entry
criteria will assure us much information about using ddI in cer-
tain groups of patients, and none about using it in other groups.
The whole structure of the trials is built around the need to get
that one statistical bit of information, to be able to walk away
with that single yes-or-no answer -- not to answer the questions
which are most important now to patients and physicians.
Trials which studied long-term toxicity by design instead of
by accident could be started much sooner, probably as a continua-
tion of phase I, and could use many fewer patients. The time and
money saved could be used to test several other drugs which oth-
erwise will be neglected.
The medical world today is obsessed with one nightmare --
that a worthless drug will come into widespread use. This danger
is real, as such cases have occurred many times in the past. The
problems come from using this nightmare as the sole gatekeeper
which controls everything else, regardless of all other elements
in the real-world situation.
A Better Way
A rational program for clinical testing and early use of new
drugs would probably involve an expanding circle of research and
treatment, starting with dose and toxicity studies and, depending
on results obtained, moving continuously into wider use in
appropriate groups of patients. The research aspect would be
most intensive at first; then gradually the treatment aspect
would predominate.
This expanding circle of use, with research most intensive
at first, is what already occurs with conventional phase I, II,
III, and IV studies. But today's process is not rational or
planned as a whole. It is full of arbitrary discontinuities,
prohibitively burdensome requirements derived from theories, and
deliberate,ied blindness to th actual questions, issues,
knowledge base, and opportunities of the specific drug, in its
social and public-health context.
Note that we are not suggesting dropping the legal require-
ment that drugs show efficacy before they are marketed. That is
a different issue. We are saying instead that narrow efficacy
testing should not completely dominate clinical trials, should
not be applied blindly and rigidly in ways that straightjacket
and paralyze the entire research enterprise.
A coherent, rational design for an integrated research and
treatment process, using to advantage the specifics of each
situation and addressing the actual questions at issue, could get
the most important answers far faster than the present system,
and at a fraction of the cost. It could bring many more drugs
into trials than the present system, which is seriously over-
loaded with unnecessarily costly trials. It could bring us years
closer to better treatments for AIDS, thereby saving most of the
lives which otherwise would be lost.
This is one of the central research issues we intend to
address in 1990.
NAC: "NO MIRACLES"
In our issues of December 1 and October 6, AIDS TREATMENT
NEWS reported on indications that NAC (N-acetylcysteine), a drug
widely used in Europe to treat bronchitis, might be useful in
treating AIDS or HIV infection.
Since publishing those articles we have talked with Barbara
Starrett, M. D., who sees many AIDS patients in New York. About
ten of her patients have used the European form of the drug, some
starting as early as December 1988.
Dr. Starrett is confident that the drug has not hurt any-
body, and thinks that it may work as a stabilizer or mild immune
modulator. Her patients have remained stable. But she has seen
no great improvements, and has no definitive proof that the drug
helped. Most of her patients had chosen to stop taking the drug,
because it did not seem worth the expense. (Prices vary greatly,
and her patients had been using one of the most expensive brands,
from Switzerland.)
Dr. Starrett is concerned that people may have expectations
which are too high. But she says there is no question that the
drug should be available.
NAC Survey
In New York, the PWA Health Group, in association with ACT
UP's Treatment and Data Committee, will conduct a survey of peo-
ple using NAC, to ask about short-term subjective benefits and
risks. They hope "to gain some practical information about tri-
als yield results."
Registration forms and baseline questionnaires will be
available at the PWA Health Group; followup surveys will be
mailed for at least three months. Buyers clubs in other cities
might also join this study.
SAN FRANCISCO: ORAL THRUSH STUDY
Persons with oral thrush are needed to help test a new anti-
fungal at San Francisco General Hospital. The study, conducted
by Merle Sande, M. D., and others at the Department of Medicine,
lasts only 10 days.
The drug, from Schering Corp., is known as SCH 39304.
Patients will randomly be assigned to one of three groups: keto-
conazole 200 mg daily, SCH 39304 25 mg daily, or SCH 39304 50 mg
daily. Blood samples will be drawn on days 1, 3, 7, and 10,
requiring a visit to the clinic on those days.
Although the drug does not yet have a name, this is a phase
III study; SCH 39304 has already been given to dozens of people,
and only occasional minor side effects have occurred.
To volunteer or to learn more about this study, call Dr.
Belle Lee, Pharm. D., at 415/821-8450.
SAN FRANCISCO: CHINESE HERBAL PROGRAM DEADLINE JANUARY 5
The Quan Yin Healing Arts Center in San Francisco continues
to sponsor HIV treatment and research studies for seropositive
people, whether symptomatic or not, through its Chinese Herbal
Treatment Program. The next deadline for enrollment is Januthe program is $190
for the 12 weeks. Defeat of the AIDS Epidemic," by Subhuti Dharmananda, Ph.D.,
pub-
lished by his Institute for Traditional Medicine and Preventive
Health Care, Portland, Oregon. Two groups of patients were
reported. In the first, with 93 participants completing the
study, "40 felt more healthy at the end of the program, 47 felt
about the same, and only 6 reported feeling less healthy. White
blood cell counts increased by an average of 2.85 percent and
hematocrit increased by an average of 1.08 percent. T-cells were
measured in 26 participants. Fifteen showed an increase, 10
showed a decrease, and one had no change. Individuals who were
categorized as HIV+ indicated better response overall, and by
blood tests, than those with ARC or AIDS...Of the 93, six changed
diagnosis from HIV to ARC and two from ARC to AIDS.
Besides the 93 who completed that study, 54 dropped out
(including two who died); a total of 147 had started. Many were
listed as dropping out only because they failed to provide the
last report at the end of the three months.
In the next group, 164 participants began the protocol and
127 completed it. "Fifty nine of the individuals completing the
study reported feeling more healthy and 58 reported feeling about
the same, while only 10 individuals considered themselves to be
less healthy at the end of the three-month period. White blood
cell counts increased by an average of 5.8 percent and hematocrit
increased by an average of 2.1 percent. T-cell counts were avail-
able for 12 participants; of these, six showed an increase, one
stayed about the same, and five experienced a decrease...Four
individuals changed diagnosis from HIV+ to ARC and one from HIV+
to AIDS during the course of the study."
Another group began in September, 1989, but results are not
yet available.
New BULLETIN OF EXPERIMENTAL TREATMENTS FOR AIDS
The San Francisco AIDS Foundation has published the Fall,
1989 issue of BETA (Bulletin of Experimental Treatments for
AIDS), a useful publication available free to San Francisco
residents and by subscription to others. The current issue
(dated November, 1989) includes articles on ddI, compound Q,
parallel track and treatment IND, different options for preven-
tion of PCP, blood tests for HIV progression, and an update on
AZT. There is also a complete copy of the directory of open HIV
trials in the San Francisco area, published by the County Commun-
ity Consortium.
To subscribe to BETA, call 800/327-9893, or 415/549-4300.
For non-residents, the cost is $25.00 per year for individuals,
$50.00 per year for organizations.
[It is on display here, in Therapies/Beta. -- sysop]
LYMPHOMA: A CURRENT LOOK AT THERAPIES
by Denny Smith
Lymphoma is a diagnosis facing at least 5% of people with
AIDS. The term lymphoma refers to a number of malignancies in
which various cells of the body's lymph system have proliferated
out of control; those most commonly seen in the presence of HIV
are of B-cell origin, and are classified as high and intermediate
grade, large cell immunoblastic or small non-cleaved Non-
Hodgkin's lymphomas (NHL). They may develop in lymph nodes, but
are more commonly found at extra-nodal sites such as the central
nervous system (CNS), bone marrow, the bowel, liver, or lungs.
The other major malignancy identified with AIDS is Kaposi's sar-
coma (KS -- see AIDS TREATMENT NEWS #73, 75, & 87), which has prob-
ably gathered more attention than lymphoma from the treatment
establishment. Fortunately the rate of new KS diagnoses has
slowed since early epidemic years; however, the incidence of lym-
phoma appears to be on the rise.
Like KS, lymphoma occurring as a consequence of HIV infec-
tion is considered an opportunistic neoplasm, or cancer, rather
than an infection caused by organisms. In spite of that distinc-
tion, however, the development of some lymphomas has been linked
to infections of a herpes-family virus, Epstein-Barr (EBV). This
virus can cause infectious nucleosis, and implicated in the
development of lymphomas in people who must take immunosuppress-
ing transplant medications. For similar reasons, an HIV-impaired
immune response may allow a latent EBV infection to reactivate,
and theoretically provoke lymphoproliferations. EBV is already
known to be implicated in hairy leukoplakia, and has been much
discussed as a possible cofactor in HIV immune deterioration --
each virus has been observed in vitro to activate the other.
However, EBV is not always present in people with HIV, nor uni-
formly evident in AIDS-associated lymphoma tissue. In data col-
lected at San Francisco General Hospital, EBV was identified in
only about a third of lymphoma biopsies, suggesting that EBV
could be a passenger virus which coincides with but is not the
cause of AIDS lymphoma.
Diagnosing lymphoma can involve several complications. The
symptoms of CNS lymphoma in adults might resemble other, more
common AIDS-related neurological problems such as toxoplasmic
encephalitis. By contrast, CNS lesions in children with AIDS
will much more likely prove to be lymphoma than otherwise. The
non-invasive tests for diagnostic purposes, CT or MRI scans, are
not usually dependable for distinguishing infections from lym-
phoma in the brain. A conclusive diagnosis can be made by
biopsy, but antibiotic therapy may be tried first in adults to
rule out infections, and if the symptoms fail to respond then
presumptive treatment can begin for lymphoma. For children that
approach could represent a dangerous delay in appropriate treat-
ment, given the probability of finding lymphoma behind these
symptoms.
Symptoms of lymphoma in the rest of the body may resemble
lymphadenopathy but are easily verified with a biopsy. Obtaining
a sample of tissue through a fine-needle aspiration is less
invasive than a surgical biopsy, although needle aspirations pro-
duce a somewhat higher rate of false-negative results.
Standard treatments for lymphoma have involved radiation or
chemotherapy, or both. These and a few experimental therapies
are briefly discussed below. The occurance of AIDS-related lym-
phoma, like any consequence of HIV, warrants the start or con-
tinuation of an anti-HIV agent such as AZT to address the under-
lying problem. A review of patients treated for CNS lymphoma at
three Los Angeles medical centers pointed to concurrent oppor-
tunistic infections as a factor diminishing the rate of survival
following otherwise successful lymphoma treatments. The report
suggests that an HIV therapy would affect positively a course of
treating lymphoma. Ironically, the underlying problem can be
exacerbated by treatments for secondary infections. Radiation
and chemotherapy, for example, each suppress bone marrow produc-
tion of blood cells (myelosuppression) independently of HIV or
AZT. We spoke to several AIDS-experienced physicians about
refinements in lymphoma therapy which, like new approaches to KS,
attempt to minimize this danger.
CNS lymphoma usually develops as small, individual lesions
on the brain, and can be treated with a series of localized, low-
volume doses of radiation over a period of 5 to 7 weeks. If the
lymphoma is disseminated, present at multiple sites within the
central nervous system, radiation treatment alone is not advised
and is augmented with a chemotherapy agent, such as methotrexate,
administered intrathecally (injected into the cerebrospinal
fluid) since many drugs given intravenously fail to penetrate the
blood-brain barrier. William Wara, M. D., of the Department of
Radiation Oncology at the University of California in San Fran-
cisco, described his modification of the treatment for AIDS-
related CNS lymphoma. By irradiating lesions with larger dose
volumes and shortening the duration of the total therapy to 3
weeks, Dr. Wara obtains an optimum tumor response while minimiz-
ing the trauma of a longer course of therapy. He found this more
intensive regimen improved on previous practice without increas-
ing immunosuppression, because the field of radiation remains
very small and specific.
Treatments of peripheral lymphomas, those diagnosed at sites
outside the CNS, are relieved of the challenge of crossing the
blood-brain barrier; therefore the diseases can be addressed with
a wider spectrum of treatments. The first line of options con-
sists of various chemotherapy combinations, both with and without
radiation.
A list of chemotherapeutic agents tried against lymphoma, in
addition to methotrexate already mentioned, includes bleomycin,
cyclophosphamide, daunorubicin, dexamethasone, doxorubicin, eto-
poside, ifosfomide, prednisone, procarbazine, and vincristine.
Apparently no consensus regarding the choice of agents or degree
of treatment aggressiveness has been established. Physicians at
San Francisco General Hospital noted shortened survival rates
among patients who were treated with high-dose cyclophosphamide,
and they suggest that lymphoma regimens be designed to control
toxicity or to include agents for reducing bone marrow and immune
suppression. Another report at the Montreal Conference described
a decision by clinicians at the Los Angeles Oncologic Institute
and Baylor University Medical Center in Dallas to decrease the
aggressiveness of lymphoma chemotherapy. They then obtained
excellent results in five patients with cautious use of bleomy-
cin, vincristine, and prednisone combined with acyclovir and low-
dose AZT (abstract B. 588).
The investigational agent called granulocyte macrophage-
colony stimulating factor (GM-CSF) may prove useful for protect-
ing the bone marrow from damage associated with chemotherapy, and
permit the addition of other valuable but potentially suppressive
therapies, such as AZT and interferon. esearchers at thentro di
Riferimento Oncologico in Aviano, Italy, presented a report at
the International Conference on AIDS last June finding GM-CSF
effective for reversing myelosuppression due to chemotherapy and
AZT in some people with KS or lymphoma (abstract M. C. P. 103).
GM-CSF is available in the U. S. only through clinical trials.
Refractory lymphomas, those which resist other treatment
attempts, have been affected by mitoxantrone with cytarabine.
Researchers at the Johns-Hopkins University describe a man suc-
cessfully treated for AIDS-associated NHL with a bone marrow
transplant from his sister (Montreal abstract W. B. P. 319).
Anti-idiotype antibody therapy and chlorodeoxyadenosine (CDA) are
both currently pursued in clinical trials in the U. S.
We spoke to Lawrence Kaplan, M. D., an oncologist at San
Francisco General Hospital and principle investigator for five
trials there involving some of the potential treatments mentioned
above. These trials are all still in progress, and we hope to
report any conclusive results in the future. Dr. Kaplan was wil-
ling to share some early positive impressions:
CDA, a novel drug used with success in treating another
diagnosis, has been helpful for some patients with NHL which was
unresponsive to previous treatments.
Anti-idiotype antibody therapy, also for relapsed lymphoma,
is a strategy which borrows functions ordinarily employed by
natural immune defenses. This treatment appears useful in about
25 percent of certain lymphomas.
In a randomized study, GM-CSF is being administered to two
of every three participants, all of whom receive chemotherapy for
NHL. Dr. Kaplan is optimistic for the potential of GM-CSF to
reduce the neutropenia following chemotherapy, and shorten asso-
ciated hospitalizations. For this trial and two others at San
Francisco General Hospital which include chemotherapy, the par-
ticular agents used are cyclophosphamide, doxorubicin, vincris-
tine, and prednisone. These trials are open for recruitment, and
persons interested in participating in any of them should call
415/821-5531.
REFERENCES
Epstein, L G and others,"Primary Lymphoma of the Central Nervous
System in Children With Acquired Immunodeficiency Syndrome,"
Pediatrics volume 82, number 3, September, 1989.
Formenti, S C and others, "Primary Central Nervous System Lym-
phoma in AIDS-Results of Radiation Therapy," Cancer, volume 63,
number 6, pages 1101-1107, March 15, 1989.
Ho, A D and others, "Mitoxantrone and High-Dose Cytarabine as
Salvage Therapy for Refractory Non-Hodgkin's Lymphoma," Cancer,
volume 64, number 7, pages 1388-1392, October 1, 1989.
Kaplan, L D and others, "AIDS-Associated Non-Hodgkin's Lymphoma
in San Francisco," Journal of the American Medical Association,
volume 261, number 5, pages 719-724, February 3, 1989.
Lang, D J and others, "Seroepidemiologic Studies of Cytomegalo-
virus and Epstein-Barr Virus Infection in Relation to Human Immu-
nodeficiency Virus Type 1 Infection in Selected Recipient Popula-
tions," Journal of Acquired Immune Deficiency Syndromes, volume
2, number 6, pages 540-549, 1989.
Rahman, M A and others, "Enhanced Antibody Responses to Epstein-
Barr Virus in HIV-Infected Homosexual Men," The Journal of Infec-
tious Diseases, volume 159, number 3, pages 472-479, March 1989.
CHRONIC FATIGUE ORGANIZATIONS SEEK COALITION WITH AIDS EFFORTS
A major advocacy group for persons with Chronic Fatigue
Immune Dysfunction Syndrome (CFIDS) wants to contact AIDS
activists and organizations to discuss coordination of our
efforts to advance prevention, research, and patient care.
CFIDS, like AIDS, is an infectious disease that causes seri-
ous immune-system malfunction. In 1984-1985, a major ourbreak
among residents at Incline Village, Nevada, affected 300 people;
since then the disease has become a widespread epidemic, with
thousands of cases.
While few people die from CFIDS, about a third become seri-
ously disabled, often for months or years. CFIDS, like AIDS, can
also cause neurological symptoms, or lead to lymphomas. CFIDS is
more contagious than AIDS, although most people exposed do not
become ill. The illness appears not to be sexually transmitted.
It affects women two to three times as often as men. Treatments,
including acyclovir, ketoconazole, and gamma globulin, may be
helpful in some cases.
As with AIDS (although for different reasons) government
agencies and medical professionals have been slow to respond to
CFIDS. Recently, however, important progress has been made. Mile-
stones include publication by the U. S. Centers for Disease Con-
trol of official criteria for diagnosis, and a major scientific
conference in San Francisco in April 1989.
The best single information source on CFIDS (also called
CFS, for Chronic Fatigue Syndrome) is The CFIDS Chronicle, pub-
lished by Community Health Services, P. O. Box 220398, Charlotte,
NC 28222-0398, phone 704/362-CFID.
Contact for AIDS Organizers
Persons interested in developing working relationships
between CFIDS and AIDS organizations should contact Jan
Montgomery, at the Chronic Fatigue Immune Dysfunction Syndrome
Foundation, 3543 Eighteenth St. #20, San Francisco, CA 94110,
415/525-6415.
COMMUNITY RESEARCH ALLIANCE HYPERICIN FUNDING
Our issue number 90 (November 3, 1989) included an appeal to
help San Francisco's Community Research Alliance finish its
hypericin observational study. Readers contributed $3049. in
response to this appeal. In addition, the Community Research
Alliance received two other contributions of $5,000. each.
The total is more than enough to complete the study. Data
collection is being finished this week, and there is also a
budget for a statistical consultant to help in interpreting the
results.
While the hypericin study is proceeding well, we do not have
funds to continue the operation of the organization itself beyond
the end of January. The Community Research Alliance was started
primarily by persons with AIDS. It represents the patient's per-
spective and interests, but has always been weak on fundraising.
Anyone who could help in developing an ongoing fundraising pro-
gram could contact John James at AIDS TREATMENT NEWS, or call the
Community Research Alliance at 415/626-2145.
CAUTION: MALICIOUS "AIDS" COMPUTER DISK
Widespread news reports have warned that an "AIDS Informa-
tion Diskette" mailed to thousands of computer users actually
contains a malicious program to destroy other data in the com-
puter. The disk is for IBM PC-compatible personal computers.
The disk was mailed from "PC Cyborg Corp.," a company which
may not exist. A Panama City address included with the program
was fictitious.
The malicious program is not technically a computer virus,
because it does not spread from computer to computer. The pro-
gram appears to involve no great technical sophistication. What
is unusual about this case is that someone appears to have spent
over a hundred thousand dollars to package and promote a destruc-
tive program, with no apparent motive. The disk was sent pri-
marily to mailing lists of computer users, and to health profes-
sionals.
Anyone who receives a copy of the disk should destroy it, so
that it is not accidentally installed in any computer.
SULFADIAZINE TEMPORARY SUPPLY PROBLEM
A temporary interruption in the supply of sulfadiazine, one
of the most common drugs used to treat toxoplasmosis, occurred
last week when Eli Lilly Co. discontinued manufacturing it. Phy-
sicians learned about the supply problem only after patients
could not get their prescriptions filled.
At least two other companies are now manufacturing sulfadi-
azine. Pharmacies should be able to get the drug through their
regular wholesalers. Wholesalers can buy sulfadiazine from
either Consolidated Midland, in Brewster, NY, or from Lannett, in
Philadelphia. Pharmacies can also order directly from Lannett.
REMINDER: AZT QUESTIONNAIRES
If you have used AZT for at least a year, you could help
others by returning the one-page questionnaire attached to our
last issue. We are interested in what treatments people are
using to supplement or replace AZT after long-term use, ann how
successful these treatments have been. The deadline for return-
ing the questionnaires is January 15.
NEXT ISSUE JANUARY 5
As announced in our Nov. 3 issue, AIDS TREATMENT NEWS will
now publish on the first and third Friday of each month, instead
of every other Friday -- a total of 24 issues per year instead of
26. Our next issue will be dated January 5.
STATEMENT OF PURPOSE
AIDS TREATMENT NEWS reports on experimental and complementary
treatments, especially those available now. It collects informa-
tion from medical journals, and from interviews with scientists,
physicians, and other health practitioners, and persons with AIDS
or ARC.
Long-term survivors have usually tried many different treatments,
and found combinations which work for them. AIDS Treatment News
does not recommend particular therapies, but seeks to increase
the options available.
We also examine the ethical and public-policy issues around AIDS
treatment research and treatment access.
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