ddodell@stjhmc.fidonet.org (David Dodell) (05/14/91)
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J O H N J A M E S writes on A I D S
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copyright 1991 by John S. James;
permission granted for non-commercial use.
AIDS TREATMENT NEWS Issue #125, April 19, 1991
phone 800/TREAT-12, or 415/255-0588
CONTENTS: [items are separated by "*****" for this display]
AIDS Antivirals: A New Generation
L-697,661 Phase II Trials at NIH, and in Birmingham
BI-RG-587: ACT UP Urges Faster Efficacy Trial,
Learns Dose Not Tested Yet
Hypericin Update
ddI Warning: Don't Take Dapsone at Same Time
Advocacy Program for Health Providers with HIV
HIV Immigration: New Threat, AIDS Organizations
Needed
California: State Treatment Activist Meeting
San Francisco May 4 and 5; Prison, Funding
Demonstrations Sacramento May 6 and 7
California: AIDS Budget Lobby Day, Sacramento May 6
***** AIDS Antivirals: A New Generation
by John S. James
Advances in understanding the life cycle of HIV have quietly
led to the development of many potential "designer drugs" for
treating HIV disease. Several of the new drugs are now beginning
human trials. Because of the advances they represent, we believe
there is more hope now than ever before for improvements in AIDS
treatment. But optimism should remain cautious, because there
have been many disappointments in the past.
At least five of the new drugs have already been given to
humans in early tests:
* L-697,661 and L-697,639 (sometimes called the "L-drugs"),
developed by Merck & Co. These drugs are of a class called non-
nucleoside-analog reverse-transcriptase inhibitors. (This means
that they block the viral enzyme reverse transcriptase, but --
unlike AZT, ddC, and ddI -- they are not nucleoside analogs;
hopefully they can avoid the toxicity which may be inherent in
that class of drugs.) L-697,661 is now recruiting for phase II
trials at the National Institutes of Health, near Washington, DC,
and also at the University of Alabama in Birmingham (see
announcement below).
* A Hoffmann-La Roche tat inhibitor (drug which blocks the
protein produced by the tat gene of HIV). Without the tat
protein, HIV becomes inactive. This drug is now beginning human
trials at Johns Hopkins in Baltimore; we do not have details at
this time. Later, the drug may also be tested for specific
activity against KS (Kaposi's sarcoma).
* BI-RG-587, being developed by Boehringer Ingelheim
Pharmaceuticals, Inc. There has been much interest in this drug
since publication of laboratory results in Science, December 7,
1990 (see AIDS TREATMENT NEWS #21, December 21, 1990).
Unfortunately, it has recently been learned that there is less
human experience to date than had been widely assumed (see BI-
RG-587 article, below).
* At least one and probably two companies have conducted
early human tests of protease inhibitors (which block another
enzyme which is necessary for HIV). Little information is
available at this time.
Many other new antivirals have been created by
pharmaceutical companies. Some have not reached human testing
yet; others are not being actively developed, sometimes because
they seem to have no advantage over other drugs ahead of them in
the development and regulatory pipeline.
What is notable about these antivirals is that the
researchers familiar with them are convinced that they probably
will work. Laboratory and animal testing has shown that they do
stop the virus, they do get absorbed and into cells where they
are needed, and they are nontoxic in animals. The main questions
to be answered are whether there is any unexpected toxicity or
other problem with human use; and of course doctors need to learn
the best ways to use each drug in practice -- dose, schedule,
combinations with other antivirals, possible problems with viral
resistance, etc.
None of the new drugs is expected to cure AIDS; as with AZT,
treatment will have to be continued indefinitely. And no matter
how good a drug looks in theory, no one can be sure that it will
work until it has proven effective in human use.
One reason for caution is that the last time the research
community expressed similar optimism about a new drug -- soluble
CD4 -- that drug turned out to be worthless as a treatment. The
current situation, however, is different in several ways. The
case for soluble CD4 was based largely on theory; for it to work
in the body, many things had to happen, and some of them could
not readily be tested in advance. By contrast, the mechanism of
action of the new drugs is better understood, and more suitable
to laboratory and animal tests.
In addition, many new antivirals are now being created, and
most of them are very different from each other. Any problem
found with one is unlikely to also affect the others. If even
one drug works as expected, the result will be a major
improvement in treatment for HIV, compared with the current
therapy with AZT alone.
Which of the new drugs looks best at this time? It is
impossible to tell, because most of the data is secret; even if
it were available, only rough and uncertain comparisons could be
made from the laboratory and animal results. For the AIDS
community, the most important ones now are those which are moving
fastest into human trials and (if warranted) FDA approval. By
this measure, Merck's L-697,661 is now ahead.
The current system for approval of new drugs by the FDA
(which controls how drugs are developed by pharmaceutical
companies) is grossly unsuited to the needs of the current
situation -- a fact which will increasingly become a public
issue. Some of the main problems:
* The current focus is on proving efficacy -- which is not
the central issue with the new antivirals. Unless endpoints
other than death or disease progression are accepted as good
enough for drug approval, years will be wasted arranging for
enough people in trials to sicken or die on AZT to provide
statistical proof that a new drug works better.
* Combination therapies will almost certainly be better than
single drugs for HIV treatment. But combinations are not tested
until late in the development process, because the FDA wants
proof of single-drug efficacy first, and also because
pharmaceutical companies are reluctant to cooperate in testing
their rivals' products.
* Major problems can also arise in getting the large
organizations involved -- pharmaceutical company, FDA, and often
NIH as well -- to work together effectively. There has been
little national planning and coordination to see that such
problems are worked out.
* Notorious shortages of staff, facilities, and money at the
FDA prevent that agency from doing its work efficiently. For
example, NDA (New Drug Application) documents are delivered to
the FDA in boxes, by truck, because the FDA does not have
appropriate computers -- making data analysis very costly in
staff time. Pharmaceutical companies would gladly help provide
the tools needed, but that would raise issues of control.
Apparently the FDA wants to develop the needed systems itself --
a commendable intention, but without resources, little will
happen and the current deadlocks will remain.
These are some of the practical problems that will determine
how soon the new drugs are tested and made available to those who
need them.
AIDS TREATMENT NEWS will focus increasingly on the new
generation of antivirals, including those listed above, as more
news becomes available. Meanwhile, we will continue to cover
what we believe are the most promising of the older treatments --
such as the AZT/ddC (or ddI) combination, or hypericin -- as well
as other treatment news of interest to the community.
***** L-697,661 Phase II Trials at NIH, and in Birmingham
by John S. James
A phase II trial of L-697,661 (also called L-661), an
important new antiviral developed by Merck & Co., will begin soon
at the U. S. National Institute of Allergy and Infectious
Diseases (NIAID) near Washington, D. C. ; about 75 volunteers
will be enrolled. A similar but not identical trial will be
conducted at the University of Alabama in Birmingham.
NIAID Trial (Near Washington, DC)
To be eligible for the NIAID trial, volunteers must be HIV-
positive, have a T-helper count of over 200, and have a positive
titer for plasma viremia. (The Birmingham trial may later accept
persons with lower T-helper counts.) Volunteers must be between
18 and 60 years old, and either never have taken AZT or have
taken it for no more than a total of six months; they must not
have a history of serious intolerance to AZT. They cannot take
any investigational drug, AZT, or other HIV treatment within four
weeks of beginning the study. They cannot currently have any OI,
dementia, wasting syndrome, or malignancy (other than muco-
cutaneous KS). They cannot have significant kidney or liver
disease.
The reason this particular trial excludes persons who have
taken AZT for more than six months is that viral resistance to
AZT may have developed after long-term use. Because anyone
entering this trial might be assigned to the AZT arm, such
resistance could falsely bias the results against AZT.
Once in the study, volunteers will be randomized to five
groups: 25 mg of L-661 twice a day, 100 mg three times a day,
500 mg twice a day, AZT 100 mg five times a day, or placebo.
After 12 weeks, those receiving either the placebo or AZT will be
re-randomized to one of the three L-661 groups. The study will
be evaluated every six weeks, and continued for another six-week
period as long as results warrant. It will look for changes in
"surrogate markers" (such as T-helper count, plasma viremia,
etc.) .
All drugs are taken orally. No hospitalization is required,
but weekly visits are necessary during the first part of the
trial. To obtain the best possible data, volunteers will keep
diaries and work closely with a case manager.
L-661 has been given in single-dose or short-term studies to
several dozen people so far, with no significant adverse effects.
For more information, or to volunteer for this study, call
Donna O'Neill, R. N., at 800/772-5464 ext. 312 or 301/402-0980
ext. 312, or Susan Haneiwich at the same phone numbers, ext.
403.
Birmingham, Alabama Trial
The trial at the University of Alabama is similar; however,
there will be no placebo. Three doses of L-661 will be compared
against the usual dose of AZT. This trial has just begun; it is
seeking 60 volunteers with T-helper counts between 200 and 500.
Later, a similar trial in Birmingham will need 60 additional
volunteers with T-helper counts under 200.
The trial for persons with lower T-helper counts is planned
to start in about a month. The reason for starting first with
T-helper counts from 200 to 500 is to get good information
quickly about any toxicity of the drug. Such side effects could
be masked by AIDS symptoms in persons who are more seriously ill.
Weekly visits are required during the first six weeks of
these trials. Because of the safety precautions needed during
early experience with a new drug, it is strongly preferred that
volunteers stay in Birmingham during the first six weeks they are
on the study.
For more information, or to volunteer for the Birmingham
trial, call 800/822-8816, or 205/934-9999, and ask for
information about the new L-661 study.
L-Drug Support Group
An "L-drug" support group for persons in any trial of L-
661 (or of the related drug, L-697,639), or who are considering
volunteering, has been organized by AIDS activist Bill Bahlman.
He can be reached at 212/929-4952, or by mail at 496-A Hudson
St., Suite J-11, New York, NY 10014.
Comment
L-661 is one of the most important AIDS treatments now being
tested. The NIAID and Birmingham trials are very well designed
to obtain information quickly without undue risks to
participants:
* A placebo is often necessary to obtain definitive data
quickly -- which is especially important with this drug. The
NIAID placebo arm will last for only 12 weeks (a limited risk)
and then those in that arm will be given the active drug. Since
there are five arms to the study, there is only one chance in
five of getting the placebo. By contrast, previous studies often
asked persons with serious HIV disease to take placebos for much
longer, sometimes for two years.
* These studies are designed to look for improvement in
bloodwork or in clinical condition of patients, instead of
looking for disease progression or death, as phase II studies
have often done. With "surrogate markers" instead of death or
serious disease, statistically reliable results can be obtained
much faster, and with fewer volunteers (which avoids additional
delays in organizing and conducting the trials).
* These study will produce drug-drug and (in the NIAID
study) drug-placebo comparisons, as well as dose-response
information. The doses, based on earlier laboratory, animal, and
human studies, vary over a wide range, which is appropriate with
this drug, since the range between effective and toxic doses may
be very large. Dosage information will be obtained quickly,
early in the clinical-trials process; then it will be available
to guide all later trials or other uses of the drug.
* This trial will produce data continuously, because of the
six-week evaluations; it will not be necessary to wait for a
year, two years, or more to know whether the drug is working.
And there is no arbitrary endpoint; the study will continue as
long as warranted. The same trial which produces short-term
results rapidly will go on to produce long-term results as well,
instead of wasting this opportunity, as most studies in the past
have done. This design also provides the drug to volunteers,
instead of cutting them off at the "end" of the study.
***** BI-RG-587: ACT UP Urges Faster Efficacy Trial, Learns
Doses Not Tested Yet
by John S. James
On April 11, ACT UP/Golden Gate in San Francisco wrote to
the Primary Infection Committee of the ACTG (AIDS Clinical Trials
Group, funded by the U. S. National Institute of Allergy and
Infectious Diseases) urging an immediate trial to test BI-RG-587
in comparison with AZT, and with the combination of those two
drugs. Jesse Dobson of ACT UP had heard that such a study might
be delayed until BI-RG-587 could be tested with ddI, so that a
number of combinations could then be tested together -- the
cleanest way scientifically to run a study. The point of the
letter, and of separate demands by ACT UP/Golden Gate, was to
urge that the testing of BI-RG-587 with AZT go forward now, and
not wait for dosage data on combining the drug with ddI.
After the letter was sent, activists learned from sources
within Boehringer-Ingelheim, the drug's developer, that no more
than twelve people have yet received BI-RG-587 -- and none of
them has received more than a single dose. The comparison with
AZT could not be started yet, because, under the current drug-
development system, a dosage safety trial of BI-RG-587 needs to
be done first. Activists are surprised and disappointed that a
dosage trial has not been conducted yet.
Laboratory and animal data on BI-RG-587 was published last
December 7 in Science. However, the drug to be tested in
clinical trials is apparently not the same as the one published
there, but a chemical variant of it. The delay in trials might
have been caused by changing the drug to a new one presumably
believed to work better. On the other hand, it is common for
pharmaceutical companies to present or publish data on their
second-best drugs, keeping the best ones secret. If that
happened here, the delay would be unlikely to be due to a late
change in drugs.
Activists suspect that the delay in trials may be caused by
coordination difficulties within one or more of the government
agencies involved with this drug. This example suggests that
even for the most promising treatments, the system cannot be
trusted to work by itself, without consistent oversight.
***** Hypericin Update
by John S. James
Hypericin is an antiviral found in a common plant, St.
John's wort, a medicinal herb. Unfortunately, there is very
little of the chemical in the plant, and laboratory and animal
studies suggest that the dose available in common herbal
preparations is too small to be effective. People with AIDS or
HIV have used these herbal preparations for about two years, with
mixed reports but no clear evidence of benefit. [For more
background on hypericin, see coverage in AIDS TREATMENT NEWS,
especially issues #63 (August 26, 1988), #91 (November 17, 1989),
#96 (February 2, 1990), and #117 (December 21, 1990)].
A clinical trial using chemically synthesized hypericin
could start as early as May at New York University Medical
Center/Bellevue Hospital, the University of Minnesota at
Minneapolis, and Boston Beth Israel Hospital. This trial was
scheduled to start in the summer or fall of 1990, but was delayed
by difficulties in preparing sufficient drug. Enough hypericin
is now available.
We received the following summary from Fred Valentine, M.
D., the principal investigator:
"The study is designed for HIV-infected individuals with
less than 300 CD4 cells (i.e., T-helper count under 300), with or
without symptoms, who have not taken any antiretroviral drug for
one month prior to starting hypericin. Increasing doses of
hypericin will be administered intravenously twice a week to
successive groups of individuals to determine the maximum
tolerated dose. Plasma viremia, p24, cellular viremia, and
change in CD4 T-cells will be measured to determine what doses
may be effective. It is important that individuals entering this
trial of hypericin do not take AZT, ddI, ddC, or other
antiretroviral agents, because these agents might have increased
toxicity when taken with hypericin, and because the effects of
the drugs would interfere with the ability of the trial to
measure the effect of hypericin on viremia, p24, and CD4 cells."
It is important to study this potential treatment because:
* In one animal study, hypericin worked much better than AZT
against a mouse retrovirus which is used to screen possible
anti-retroviral compounds. (HIV itself could not be used in
these tests, because ordinary mice cannot be infected with the
human virus.)
* Animals can tolerate large amounts of hypericin with
little toxicity. The levels which are expected to be antiviral
can easily be reached.
* Hypericin's mode of action against HIV in the laboratory
is entirely different than that of AZT, suggesting that hypericin
might provide an important therapeutic alternative, either alone
or in combination with AZT.
* In laboratory tests, hypericin also reduced viral activity
in whole human blood freshly drawn from HIV-positive patients.
Data suggests that it can work in both lymphocytes (e.g. T-helper
cells) and monocytes (e.g. macrophages). The test with whole
blood is important because it shows activity against the "wild"
virus strains found in patients, not only against the strains
which have been bred for years in laboratories.
* Laboratory tests have also shown activity against certain
other viruses, including herpes and possibly CMV.
* In small doses, hypericin has already been in widespread
human use for years, both as an "alternative" HIV treatment, and
as an antidepressant in Europe.
* Hypericin should be convenient to take. Animal studies
suggest that it can be given orally -- and may only need to be
taken twice a week to maintain effective blood levels.
There are also disadvantages. Human toxicity of large doses
is not known. Possible problems to watch for are herbal extract,
although not necessarily caused by hypericin), and phototoxicity
(extreme sensitivity to sunlight or other ultraviolet light, a
problem seen in farm animals when they eat large amounts of the
plant).
Comments
The trial described above plans to test hypericin doses up
to 2 mg per kg of body weight (about 150 mg for an average
adult), providing that no serious toxicities are seen before that
level. By contrast, the herbal tablets most commonly sold in
buyers' clubs contain 250 mg of 0.14 percent hypericin, or 0.35
mg of the drug -- hundreds of times smaller than the highest dose
planned for the trial. The tablets and other herbal preparations
contain many chemicals, and taking very large doses would involve
serious risks.
We have heard that it is not very difficult to chemically
extract relatively pure hypericin from the St. John's wort plant;
the plant is common in most of the world. At this time, however,
we do not know of any source where the chemical is available.
(We have not looked for it, because of the risks of trying a new
drug; it seemed better to wait for the clinical trial, which will
test hypericin with very close monitoring for possible toxicity.)
One factor delaying this drug was the need to develop an
improved synthesis procedure which will be suitable for large-
scale commercial use. If researchers had used the plant material
first, they would have had to repeat animal and human testing
after the synthetic version became available. FDA-required
animal toxicity testing, done in specialized labs, can cost
hundreds of thousands of dollars, creating major barriers to drug
development by all but large or well-financed companies.
One problem which no one anticipated is that the synthetic
material has not proven as effective as the plant material in
antiviral tests in animals (although it is still effective). It
is not known why this is so.
Another finding which anyone researching hypericin should
know is that animal tests have found that some preparations of
the chemical are less orally available than others, for reasons
now unknown. If one hypericin extract fails to work, then blood
tests could be used to make sure the chemical is being absorbed.
A different extraction procedure might work better.
The chemical mode of action of hypericin may involve a
singlet oxygen; if so, certain antioxidants might reduce its
effectiveness.
What should have been done two years ago, and still should
be done now, is to chemically extract enough hypericin from the
plant to treat a few people and see whether or not there is a
clear, dramatic benefit. If there is, then the resources would
be found to make the treatment available quickly, by whatever
means is best. On the other hand, if the results of this early
efficacy test are negative or unclear, then the development of
the drug can proceed on its present course.
This approach, of an early, rapid test for a possible "home
run" drug, may be impossible in the current regulatory system.
It may happen instead underground.
Hypericin Technical Articles
These articles and abstracts are relevant to the development
of hypericin as a possible antiviral. Also see the previous
issues of AIDS TREATMENT NEWS cited above.
Barnard DL, Huffman JH, and Wood, SG. Characterization of the
anti human cytomegalovirus (HCMV) activity of three anthraquinone
compounds [abstract #1093]. 30th Interscience Conference on
Antimicrobial Agents and Chemotherapy, Atlanta, October 21-24,
1990.
Chu CK, Schinazi RF, and Nasr M. Anti-HIV-1 activities of
anthraquinone derivatives in vitro [abstract #M. C. P. 115]. V
International Conference on AIDS, Montreal, June 4-9, 1989.
Cooper WC and James JS. An observational study of the safety and
efficacy of hypericin in HIV+ subjects [abstract #2063]. VI
International Conference on AIDS, San Francisco, June 21-24,
1990.
Degar S, Lavie G, Levin B, and others. Inhibition of HIV
infectivity by hypericin: Evidence for a block in capsid
uncoating [abstract #I-16]. HIV Disease: Pathogenesis and
Therapy, University of Miami, March 1991.
Kraus GA, Pratt D, Tossberg J, and Carpenter S. Antiretroviral
activity of synthetic hypericin and related analogs. Biochemical
and Biophysical Research Communications. 1990; volume 172, pages
149-153.
Lavie G, and Meruelo D. Inhibition of retrovirus-induced
diseases by two naturally occurring polycyclic aromatic diones
hypericin and pseudohypericin [abstract #C. 501]. V International
Conference on AIDS, Montreal, June 4-9, 1989.
Lavie G, Valentine F, Levin B, and others. Studies of the
mechanisms of action of the antiretroviral agents hypericin and
pseudohypericin. Proceedings of the National Academy of
Sciences, USA. August 1989; volume 86, pages 5963-5967.
Lavie G, Mazur Y, Lavie D, Levin B, Ittah Y, and Meruelo D.
Hypericin as an antiretroviral agent; mode of action and related
analogues. Annals of the New York Academy of Sciences. 1990;
volume 616, pages 556-562.
Lavie G, Meruelo D, Daub M, and others. Retroviral particle
inactivation by organic polycyclic quinones: A novel mechanism
of virucidal activity characterized by diminution of virus
particle derived reverse transcriptase enzymatic activity
[abstract I-27]. HIV Disease: Pathogenesis and Therapy
conference, University of Miami, March 1991.
Meruelo D, Lavie G, and Lavie D. Therapeutic Agents with
Dramatic Antiretroviral Activity and Little Toxicity at Effective
Doses: Aromatic Polycyclic Diones Hypericin and Pseudohypericin.
Proceedings of the National Academy of Sciences, USA. July 1988;
volume 85, pages 5230-5234.
Meruelo D, Degar S, Levin B, Lavie D, Mazur Y, and Lavie G.
Inactivation of retroviral particles by hypericin: Possible role
of oxidative reactions in the antiretroviral activity [abstract
I-29]. HIV Disease: Pathogenesis and Therapy, University of
Miami, March 1991.
Schinazi RF, Chu CK, Babu JR, and others. Anthraquinones as a
new class of antiviral agents against human immunodeficiency
virus. Antiviral Research. 1990; volume 13, pages 265-272.
Takahashi I, Nakanishi S, Kobayashi E, Nakano H, Suzuki K, and
Tamaoki T. Hypericin and pseudohypericin specifically inhibit
protein kinase C: possible relation to their antiretroviral
activity. Biochemical and Biophysical Research Communications.
December 29, 1989; volume 165, number 3, pages 1207-1212.
Tang J, Colacino JM, Larsen SH, and Spitzer W. Virucidal
activity of hypericin against enveloped and non-enveloped DNA
and RNA viruses. Antiviral Research. 1990; volume 13, pages
313-326.
Valentine F, Meruelo D, Itri V, and Lavie G. yMHypericin:
efficacy of a new agent against HIV in vitro [abstract #M. C. P.
18]. V International Conference on DS, Montreal, June 4-9, 1989.
Valentine FT. Hypericin: A hexahydroxyl, dimethyl-
naphthodianthrone with activity against HIV in vitro and against
murine retroviruses in vivo [oral presentation, published
abstract]. HIV Disease: Pathogenesis and Therapy, University of
Miami, March 1991.
Weiner DB, Lavie G, Williams WV, Lavie D, Greene MI, and Meruelo
D. Hypericin mediates anti-HIV effects in vitro [abstract #C.
608]. V International Conference on AIDS, Montreal, June 4-9.
Wood S, Huffman J, Weber N, and others. Antiviral activity of
naturally occurring anthraquinones and anthraquinone derivatives.
Planta Medica; Journal of Medicinal Plant Research. 1990; volume
56, number 6, pages 651-652.
***** ddI Warning: Don't Take Dapsone at Same Time
The U. S. Division of AIDS has issued a warning to
physicians that patients using ddI and also using dapsone, a drug
for pneumocystis prophylaxis, should not take the drugs within
two hours of each other. The problem is that dapsone requires an
acid environment in order to be dissolved; but ddI cannot
tolerate an acid environment, so it is taken with a buffer to
neutralize stomach acidity. The lack of acidity causes the
dapsone not to be absorbed.
Jacobus Pharmaceutical Company, the manufacturer of dapsone,
brought the problem to the attention of the Division of AIDS
after several cases of pneumocystis were found in patients who
were taking both drugs. At least 11 cases of pneumocystis have
occurred within 10 to 130 days after starting therapy with the
two drugs together.
This problem could also affect other drugs which require an
acid stomach -- for example, ketoconazole.
The following recommendation is included in Safety Memo 013
of the Division of AIDS:
"Recommendation: The Division of AIDS and Jacobus
Pharmaceutical Company recommend that clinicians contact all
patients who are receiving both ddI and dapsone by telephone and
advise them to take dapsone two hours prior to ddI. "
The memo also says that if patients cannot take dapsone at
least two hours before ddI, they should wait until two hours
after. The two drugs should not be taken within two hours of
each other.
***** Advocacy Program for Health Providers with HIV
by Denny Smith
The American Association of Physicians for Human Rights
(AAPHR), a national organization of gay and lesbian physicians,
is sponsoring an effort to protect the rights and livelihoods of
doctors and other health workers from proposals requiring
disclosure of their HIV status. The "Medical Expertise Retention
Program, The National Program for Physicians With HIV Disease" is
directed by attorney Ben Schatz, who will assist and advocate on
behalf of seropositive health workers.
Recently, alarm bells have been clanging in the media and
professional organizations over allegations that patients are at
risk for contracting "the AIDS virus" when they are under the
care of a dentist or physician with HIV. Ironically, many
physicians with HIV have had to compensate for years of their
colleague's AIDS phobia by providing more than their share of the
care required by thousands of Americans with HIV.
For information about AAPHR's program, or to make a tax-
deductible contribution, interested persons can call 415/864-
0408.
Comment
This is a crucial civil rights issue for anyone involved in
the AIDS epidemic. The concern voiced for the "safety of the
patient" echoes the older "safety of the physician" campaigns
waged against seropositive patients. In both situations the
issue of safety has been finessed to serve other agendas.
Health workers should be observing "universal" blood and
body fluid precautions with all of their patients, for their own
safety and that of their patients' as well. If universal
precautions are observed, there remains no compelling reason to
compromise the privacy of health workers, or their patients, with
HIV. Hepatitis and other serious infections have amounted to a
far greater risk than HIV in the healthcare setting. But HIV has
garnered far more hysteria -- a dangerous mismatch between
perception and reality.
If alarmists achieve their goals, then physicians, dentists
and nurses will be discriminated against openly, and no other
sector of the workforce or general population would be exempt
from similar bias. Many competent care-givers could be removed
from their positions unfairly and needlessly, and the loss of
those experienced in caring for HIV would impoverish the quality
of medicine generally for everyone needing HIV care.
***** HIV Immigration: New Threat, AIDS Organizations Needed
by John S. James
As reported previously in AIDS TREATMENT NEWS, the U. S.
Department of Health and Human Services recommended that HIV --
along with all other diseases except active tuberculosis -- be
dropped as grounds for excluding visitors and immigrants from the
United States. But conservative Republicans are now pressuring
President Bush to overrule the HHS recommendation and keep HIV as
grounds for exclusion, at least for permanent immigrants.
Apparently the argument this time is avoiding medical-care
costs to the government, rather than fear of contagion. Our
understanding is that existing law already allows immigrants to
be excluded if they are likely to require government expense.
The real issue, then, is whether HIV should be singled out from
all other diseases for automatic exclusion not based on public-
health requirements.
A hundred and fifty organizations have already signed an
April 16 consensus letter supporting the recommendation of HHS
that HIV not be used to bar U. S. entry by visitors or
immigrants. Signers include the American Public Health
Association, United States Conference of Mayors, American ts and 2 children developed AIDS after receiving
blood screened for HIV antibody. One additional person received only
HIV-infected tissue.
*** "Other" refers to 3 health-care workers who seroconverted to HIV and
developed AIDS after occupational exposure to HIV-infected blood.
"Undetermined" refers to patients whose mode of exposure to HIV is
unknown. This includes patients under investigation; patients who
died, were lost to follow-up, or refused interview; and patients
whose mode of exposure to HIV remains undetermined after investigation.
Table 3. AIDS cases by age group, exposure category, and sex,
reported April 1989 through March 1990, April 1990 through
March 1991; and cumulative totals, by age group and exposure
category, through March 1991, United States (Continued)
Totals
Apr. 1989- Apr. 1990- Cumulative
ADULT/ADOLESCENT Mar. 1990 Mar. 1991 Total****
EXPOSURE CATEGORY No. (%) No. (%) No. (%)
Male homosexual/bisexual contact 21,066 (57) 23,726 (55) 99,941 (59)
Intravenous (IV) drug use
(female and heterosexual male) 8,888 (24) 10,007 (23) 37,090 (22)
Male homosexual/bisexual contact
and IV drug use 2,288 (6) 2,275 (5) 11,153 (7)
Hemophilia/coagulation disorder 288 (1) 324 (1) 1,462
(1)
Heterosexual contact: 2,182 (6) 2,867 (7) 9,191
(5)
Sex with IV drug user 1,253 1,597 4,868
Sex with bisexual male 118 142 540
Sex with person with hemophilia 26 28 86
Born in Pattern-II* country 408 413 2,143
Sex with person born in
Pattern-II country 31 50 142
Sex with transfusion recipient
with HIV infection 39 76 177
Sex with person with HIV
infection, risk not specified 307 561 1,235
Receipt of blood transfusion,
blood components, or tissue** 781 (2) 837 (2) 3,861 (2)
Other/undetermined*** 1,462 (4) 2,729 (6) 6,215
(4)
Adult/adolescent subtotal 36,955 (100) 42,765 (100) 168,913
(100)
PEDIATRIC (<13 years old)
EXPOSURE CATEGORY
Hemophilia/coagulation disorder 28 (4) 31 (4) 146 (5)
Mother with/at risk for HIV
infection: 613 (88) 672 (88) 2,490 (84)
IV drug use 280 304 1,228
Sex with IV drug user 147 137 518
Sex with bisexual male 16 8 53
Sex with person with hemophilia - 4 11
Born in Pattern-II country 51 37 221
Sex with person born
in Pattern-II country 3 5 12
Sex with transfusion recipient
with HIV infection 5 1 12
Sex with person with HIV
infection, risk not specified 29 38 110
Receipt of blood transfusion,
blood components, or tissue 12 12 49
Has HIV infection, risk not
specified 70 126 276
Receipt of blood transfusion,
blood components, or tissue 42 (6) 36 (5) 259 (9)
Other/undetermined 16 (2) 28 (4) 68
(2)
Pediatric subtotal 699 (100) 767 (100) 2,963
(100)
TOTAL 37,654 43,532 171,876
* See technical notes (available only in the printed version of this report
** Thirteen adults/adolescents and 2 children developed AIDS after
receiving
blood screened for HIV antibody. One additional person received only
HIV-infected tissue.
*** "Other" refers to 3 health-care workers who seroconverted to HIV and
developed AIDS after occupational exposure to HIV-infected blood.
"Undetermined" refers to patients whose mode of exposure to HIV is
unknown. This includes patients under investigation; patients who
died, were lost to follow-up, or refused interview; and patients
whose mode of exposure to HIV remains undetermined after investigation.
**** Includes 3 patients known to be infected with human immunodeficiency
virus type 2 (HIV-2). See MMWR 1989;38:572-580.
--
-------------------------------------------------------------------------
St. Joseph's Hospital and Medical Center, Phoenix, Arizona
uucp: {gatech, ames, rutgers}!ncar!asuvax!stjhmc!ddodell
Bitnet: ATW1H @ ASUACAD FidoNet=> 1:114/15
Internet: ddodell@stjhmc.fidonet.org FAX: +1 (602) 451-1165ddodell@stjhmc.fidonet.org (David Dodell) (05/14/91)
&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&
J O H N J A M E S writes on A I D S
&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&
copyright 1991 by John S. James;
permission granted for non-commercial use.
AIDS TREATMENT NEWS Issue #125, April 19, 1991
phone 800/TREAT-12, or 415/255-0588
CONTENTS: [items are separated by "*****" for this display]
AIDS Antivirals: A New Generation
L-697,661 Phase II Trials at NIH, and in Birmingham
BI-RG-587: ACT UP Urges Faster Efficacy Trial,
Learns Dose Not Tested Yet
Hypericin Update
ddI Warning: Don't Take Dapsone at Same Time
Advocacy Program for Health Providers with HIV
HIV Immigration: New Threat, AIDS Organizations
Needed
California: State Treatment Activist Meeting
San Francisco May 4 and 5; Prison, Funding
Demonstrations Sacramento May 6 and 7
California: AIDS Budget Lobby Day, Sacramento May 6
***** AIDS Antivirals: A New Generation
by John S. James
Advances in understanding the life cycle of HIV have quietly
led to the development of many potential "designer drugs" for
treating HIV disease. Several of the new drugs are now beginning
human trials. Because of the advances they represent, we believe
there is more hope now than ever before for improvements in AIDS
treatment. But optimism should remain cautious, because there
have been many disappointments in the past.
At least five of the new drugs have already been given to
humans in early tests:
* L-697,661 and L-697,639 (sometimes called the "L-drugs"),
developed by Merck & Co. These drugs are of a class called non-
nucleoside-analog reverse-transcriptase inhibitors. (This means
that they block the viral enzyme reverse transcriptase, but --
unlike AZT, ddC, and ddI -- they are not nucleoside analogs;
hopefully they can avoid the toxicity which may be inherent in
that class of drugs.) L-697,661 is now recruiting for phase II
trials at the National Institutes of Health, near Washington, DC,
and also at the University of Alabama in Birmingham (see
announcement below).
* A Hoffmann-La Roche tat inhibitor (drug which blocks the
protein produced by the tat gene of HIV). Without the tat
protein, HIV becomes inactive. This drug is now beginning human
trials at Johns Hopkins in Baltimore; we do not have details at
this time. Later, the drug may also be tested for specific
activity against KS (Kaposi's sarcoma).
* BI-RG-587, being developed by Boehringer Ingelheim
Pharmaceuticals, Inc. There has been much interest in this drug
since publication of laboratory results in Science, December 7,
1990 (see AIDS TREATMENT NEWS #21, December 21, 1990).
Unfortunately, it has recently been learned that there is less
human experience to date than had been widely assumed (see BI-
RG-587 article, below).
* At least one and probably two companies have conducted
early human tests of protease inhibitors (which block another
enzyme which is necessary for HIV). Little information is
available at this time.
Many other new antivirals have been created by
pharmaceutical companies. Some have not reached human testing
yet; others are not being actively developed, sometimes because
they seem to have no advantage over other drugs ahead of them in
the development and regulatory pipeline.
What is notable about these antivirals is that the
researchers familiar with them are convinced that they probably
will work. Laboratory and animal testing has shown that they do
stop the virus, they do get absorbed and into cells where they
are needed, and they are nontoxic in animals. The main questions
to be answered are whether there is any unexpected toxicity or
other problem with human use; and of course doctors need to learn
the best ways to use each drug in practice -- dose, schedule,
combinations with other antivirals, possible problems with viral
resistance, etc.
None of the new drugs is expected to cure AIDS; as with AZT,
treatment will have to be continued indefinitely. And no matter
how good a drug looks in theory, no one can be sure that it will
work until it has proven effective in human use.
One reason for caution is that the last time the research
community expressed similar optimism about a new drug -- soluble
CD4 -- that drug turned out to be worthless as a treatment. The
current situation, however, is different in several ways. The
case for soluble CD4 was based largely on theory; for it to work
in the body, many things had to happen, and some of them could
not readily be tested in advance. By contrast, the mechanism of
action of the new drugs is better understood, and more suitable
to laboratory and animal tests.
In addition, many new antivirals are now being created, and
most of them are very different from each other. Any problem
found with one is unlikely to also affect the others. If even
one drug works as expected, the result will be a major
improvement in treatment for HIV, compared with the current
therapy with AZT alone.
Which of the new drugs looks best at this time? It is
impossible to tell, because most of the data is secret; even if
it were available, only rough and uncertain comparisons could be
made from the laboratory and animal results. For the AIDS
community, the most important ones now are those which are moving
fastest into human trials and (if warranted) FDA approval. By
this measure, Merck's L-697,661 is now ahead.
The current system for approval of new drugs by the FDA
(which controls how drugs are developed by pharmaceutical
companies) is grossly unsuited to the needs of the current
situation -- a fact which will increasingly become a public
issue. Some of the main problems:
* The current focus is on proving efficacy -- which is not
the central issue with the new antivirals. Unless endpoints
other than death or disease progression are accepted as good
enough for drug approval, years will be wasted arranging for
enough people in trials to sicken or die on AZT to provide
statistical proof that a new drug works better.
* Combination therapies will almost certainly be better than
single drugs for HIV treatment. But combinations are not tested
until late in the development process, because the FDA wants
proof of single-drug efficacy first, and also because
pharmaceutical companies are reluctant to cooperate in testing
their rivals' products.
* Major problems can also arise in getting the large
organizations involved -- pharmaceutical company, FDA, and often
NIH as well -- to work together effectively. There has been
little national planning and coordination to see that such
problems are worked out.
* Notorious shortages of staff, facilities, and money at the
FDA prevent that agency from doing its work efficiently. For
example, NDA (New Drug Application) documents are delivered to
the FDA in boxes, by truck, because the FDA does not have
appropriate computers -- making data analysis very costly in
staff time. Pharmaceutical companies would gladly help provide
the tools needed, but that would raise issues of control.
Apparently the FDA wants to develop the needed systems itself --
a commendable intention, but without resources, little will
happen and the current deadlocks will remain.
These are some of the practical problems that will determine
how soon the new drugs are tested and made available to those who
need them.
AIDS TREATMENT NEWS will focus increasingly on the new
generation of antivirals, including those listed above, as more
news becomes available. Meanwhile, we will continue to cover
what we believe are the most promising of the older treatments --
such as the AZT/ddC (or ddI) combination, or hypericin -- as well
as other treatment news of interest to the community.
***** L-697,661 Phase II Trials at NIH, and in Birmingham
by John S. James
A phase II trial of L-697,661 (also called L-661), an
important new antiviral developed by Merck & Co., will begin soon
at the U. S. National Institute of Allergy and Infectious
Diseases (NIAID) near Washington, D. C. ; about 75 volunteers
will be enrolled. A similar but not identical trial will be
conducted at the University of Alabama in Birmingham.
NIAID Trial (Near Washington, DC)
To be eligible for the NIAID trial, volunteers must be HIV-
positive, have a T-helper count of over 200, and have a positive
titer for plasma viremia. (The Birmingham trial may later accept
persons with lower T-helper counts.) Volunteers must be between
18 and 60 years old, and either never have taken AZT or have
taken it for no more than a total of six months; they must not
have a history of serious intolerance to AZT. They cannot take
any investigational drug, AZT, or other HIV treatment within four
weeks of beginning the study. They cannot currently have any OI,
dementia, wasting syndrome, or malignancy (other than muco-
cutaneous KS). They cannot have significant kidney or liver
disease.
The reason this particular trial excludes persons who have
taken AZT for more than six months is that viral resistance to
AZT may have developed after long-term use. Because anyone
entering this trial might be assigned to the AZT arm, such
resistance could falsely bias the results against AZT.
Once in the study, volunteers will be randomized to five
groups: 25 mg of L-661 twice a day, 100 mg three times a day,
500 mg twice a day, AZT 100 mg five times a day, or placebo.
After 12 weeks, those receiving either the placebo or AZT will be
re-randomized to one of the three L-661 groups. The study will
be evaluated every six weeks, and continued for another six-week
period as long as results warrant. It will look for changes in
"surrogate markers" (such as T-helper count, plasma viremia,
etc.) .
All drugs are taken orally. No hospitalization is required,
but weekly visits are necessary during the first part of the
trial. To obtain the best possible data, volunteers will keep
diaries and work closely with a case manager.
L-661 has been given in single-dose or short-term studies to
several dozen people so far, with no significant adverse effects.
For more information, or to volunteer for this study, call
Donna O'Neill, R. N., at 800/772-5464 ext. 312 or 301/402-0980
ext. 312, or Susan Haneiwich at the same phone numbers, ext.
403.
Birmingham, Alabama Trial
The trial at the University of Alabama is similar; however,
there will be no placebo. Three doses of L-661 will be compared
against the usual dose of AZT. This trial has just begun; it is
seeking 60 volunteers with T-helper counts between 200 and 500.
Later, a similar trial in Birmingham will need 60 additional
volunteers with T-helper counts under 200.
The trial for persons with lower T-helper counts is planned
to start in about a month. The reason for starting first with
T-helper counts from 200 to 500 is to get good information
quickly about any toxicity of the drug. Such side effects could
be masked by AIDS symptoms in persons who are more seriously ill.
Weekly visits are required during the first six weeks of
these trials. Because of the safety precautions needed during
early experience with a new drug, it is strongly preferred that
volunteers stay in Birmingham during the first six weeks they are
on the study.
For more information, or to volunteer for the Birmingham
trial, call 800/822-8816, or 205/934-9999, and ask for
information about the new L-661 study.
L-Drug Support Group
An "L-drug" support group for persons in any trial of L-
661 (or of the related drug, L-697,639), or who are considering
volunteering, has been organized by AIDS activist Bill Bahlman.
He can be reached at 212/929-4952, or by mail at 496-A Hudson
St., Suite J-11, New York, NY 10014.
Comment
L-661 is one of the most important AIDS treatments now being
tested. The NIAID and Birmingham trials are very well designed
to obtain information quickly without undue risks to
participants:
* A placebo is often necessary to obtain definitive data
quickly -- which is especially important with this drug. The
NIAID placebo arm will last for only 12 weeks (a limited risk)
and then those in that arm will be given the active drug. Since
there are five arms to the study, there is only one chance in
five of getting the placebo. By contrast, previous studies often
asked persons with serious HIV disease to take placebos for much
longer, sometimes for two years.
* These studies are designed to look for improvement in
bloodwork or in clinical condition of patients, instead of
looking for disease progression or death, as phase II studies
have often done. With "surrogate markers" instead of death or
serious disease, statistically reliable results can be obtained
much faster, and with fewer volunteers (which avoids additional
delays in organizing and conducting the trials).
* These study will produce drug-drug and (in the NIAID
study) drug-placebo comparisons, as well as dose-response
information. The doses, based on earlier laboratory, animal, and
human studies, vary over a wide range, which is appropriate with
this drug, since the range between effective and toxic doses may
be very large. Dosage information will be obtained quickly,
early in the clinical-trials process; then it will be available
to guide all later trials or other uses of the drug.
* This trial will produce data continuously, because of the
six-week evaluations; it will not be necessary to wait for a
year, two years, or more to know whether the drug is working.
And there is no arbitrary endpoint; the study will continue as
long as warranted. The same trial which produces short-term
results rapidly will go on to produce long-term results as well,
instead of wasting this opportunity, as most studies in the past
have done. This design also provides the drug to volunteers,
instead of cutting them off at the "end" of the study.
***** BI-RG-587: ACT UP Urges Faster Efficacy Trial, Learns
Doses Not Tested Yet
by John S. James
On April 11, ACT UP/Golden Gate in San Francisco wrote to
the Primary Infection Committee of the ACTG (AIDS Clinical Trials
Group, funded by the U. S. National Institute of Allergy and
Infectious Diseases) urging an immediate trial to test BI-RG-587
in comparison with AZT, and with the combination of those two
drugs. Jesse Dobson of ACT UP had heard that such a study might
be delayed until BI-RG-587 could be tested with ddI, so that a
number of combinations could then be tested together -- the
cleanest way scientifically to run a study. The point of the
letter, and of separate demands by ACT UP/Golden Gate, was to
urge that the testing of BI-RG-587 with AZT go forward now, and
not wait for dosage data on combining the drug with ddI.
After the letter was sent, activists learned from sources
within Boehringer-Ingelheim, the drug's developer, that no more
than twelve people have yet received BI-RG-587 -- and none of
them has received more than a single dose. The comparison with
AZT could not be started yet, because, under the current drug-
development system, a dosage safety trial of BI-RG-587 needs to
be done first. Activists are surprised and disappointed that a
dosage trial has not been conducted yet.
Laboratory and animal data on BI-RG-587 was published last
December 7 in Science. However, the drug to be tested in
clinical trials is apparently not the same as the one published
there, but a chemical variant of it. The delay in trials might
have been caused by changing the drug to a new one presumably
believed to work better. On the other hand, it is common for
pharmaceutical companies to present or publish data on their
second-best drugs, keeping the best ones secret. If that
happened here, the delay would be unlikely to be due to a late
change in drugs.
Activists suspect that the delay in trials may be caused by
coordination difficulties within one or more of the government
agencies involved with this drug. This example suggests that
even for the most promising treatments, the system cannot be
trusted to work by itself, without consistent oversight.
***** Hypericin Update
by John S. James
Hypericin is an antiviral found in a common plant, St.
John's wort, a medicinal herb. Unfortunately, there is very
little of the chemical in the plant, and laboratory and animal
studies suggest that the dose available in common herbal
preparations is too small to be effective. People with AIDS or
HIV have used these herbal preparations for about two years, with
mixed reports but no clear evidence of benefit. [For more
background on hypericin, see coverage in AIDS TREATMENT NEWS,
especially issues #63 (August 26, 1988), #91 (November 17, 1989),
#96 (February 2, 1990), and #117 (December 21, 1990)].
A clinical trial using chemically synthesized hypericin
could start as early as May at New York University Medical
Center/Bellevue Hospital, the University of Minnesota at
Minneapolis, and Boston Beth Israel Hospital. This trial was
scheduled to start in the summer or fall of 1990, but was delayed
by difficulties in preparing sufficient drug. Enough hypericin
is now available.
We received the following summary from Fred Valentine, M.
D., the principal investigator:
"The study is designed for HIV-infected individuals with
less than 300 CD4 cells (i.e., T-helper count under 300), with or
without symptoms, who have not taken any antiretroviral drug for
one month prior to starting hypericin. Increasing doses of
hypericin will be administered intravenously twice a week to
successive groups of individuals to determine the maximum
tolerated dose. Plasma viremia, p24, cellular viremia, and
change in CD4 T-cells will be measured to determine what doses
may be effective. It is important that individuals entering this
trial of hypericin do not take AZT, ddI, ddC, or other
antiretroviral agents, because these agents might have increased
toxicity when taken with hypericin, and because the effects of
the drugs would interfere with the ability of the trial to
measure the effect of hypericin on viremia, p24, and CD4 cells."
It is important to study this potential treatment because:
* In one animal study, hypericin worked much better than AZT
against a mouse retrovirus which is used to screen possible
anti-retroviral compounds. (HIV itself could not be used in
these tests, because ordinary mice cannot be infected with the
human virus.)
* Animals can tolerate large amounts of hypericin with
little toxicity. The levels which are expected to be antiviral
can easily be reached.
* Hypericin's mode of action against HIV in the laboratory
is entirely different than that of AZT, suggesting that hypericin
might provide an important therapeutic alternative, either alone
or in combination with AZT.
* In laboratory tests, hypericin also reduced viral activity
in whole human blood freshly drawn from HIV-positive patients.
Data suggests that it can work in both lymphocytes (e.g. T-helper
cells) and monocytes (e.g. macrophages). The test with whole
blood is important because it shows activity against the "wild"
virus strains found in patients, not only against the strains
which have been bred for years in laboratories.
* Laboratory tests have also shown activity against certain
other viruses, including herpes and possibly CMV.
* In small doses, hypericin has already been in widespread
human use for years, both as an "alternative" HIV treatment, and
as an antidepressant in Europe.
* Hypericin should be convenient to take. Animal studies
suggest that it can be given orally -- and may only need to be
taken twice a week to maintain effective blood levels.
There are also disadvantages. Human toxicity of large doses
is not known. Possible problems to watch for are herbal extract,
although not necessarily caused by hypericin), and phototoxicity
(extreme sensitivity to sunlight or other ultraviolet light, a
problem seen in farm animals when they eat large amounts of the
plant).
Comments
The trial described above plans to test hypericin doses up
to 2 mg per kg of body weight (about 150 mg for an average
adult), providing that no serious toxicities are seen before that
level. By contrast, the herbal tablets most commonly sold in
buyers' clubs contain 250 mg of 0.14 percent hypericin, or 0.35
mg of the drug -- hundreds of times smaller than the highest dose
planned for the trial. The tablets and other herbal preparations
contain many chemicals, and taking very large doses would involve
serious risks.
We have heard that it is not very difficult to chemically
extract relatively pure hypericin from the St. John's wort plant;
the plant is common in most of the world. At this time, however,
we do not know of any source where the chemical is available.
(We have not looked for it, because of the risks of trying a new
drug; it seemed better to wait for the clinical trial, which will
test hypericin with very close monitoring for possible toxicity.)
One factor delaying this drug was the need to develop an
improved synthesis procedure which will be suitable for large-
scale commercial use. If researchers had used the plant material
first, they would have had to repeat animal and human testing
after the synthetic version became available. FDA-required
animal toxicity testing, done in specialized labs, can cost
hundreds of thousands of dollars, creating major barriers to drug
development by all but large or well-financed companies.
One problem which no one anticipated is that the synthetic
material has not proven as effective as the plant material in
antiviral tests in animals (although it is still effective). It
is not known why this is so.
Another finding which anyone researching hypericin should
know is that animal tests have found that some preparations of
the chemical are less orally available than others, for reasons
now unknown. If one hypericin extract fails to work, then blood
tests could be used to make sure the chemical is being absorbed.
A different extraction procedure might work better.
The chemical mode of action of hypericin may involve a
singlet oxygen; if so, certain antioxidants might reduce its
effectiveness.
What should have been done two years ago, and still should
be done now, is to chemically extract enough hypericin from the
plant to treat a few people and see whether or not there is a
clear, dramatic benefit. If there is, then the resources would
be found to make the treatment available quickly, by whatever
means is best. On the other hand, if the results of this early
efficacy test are negative or unclear, then the development of
the drug can proceed on its present course.
This approach, of an early, rapid test for a possible "home
run" drug, may be impossible in the current regulatory system.
It may happen instead underground.
Hypericin Technical Articles
These articles and abstracts are relevant to the development
of hypericin as a possible antiviral. Also see the previous
issues of AIDS TREATMENT NEWS cited above.
Barnard DL, Huffman JH, and Wood, SG. Characterization of the
anti human cytomegalovirus (HCMV) activity of three anthraquinone
compounds [abstract #1093]. 30th Interscience Conference on
Antimicrobial Agents and Chemotherapy, Atlanta, October 21-24,
1990.
Chu CK, Schinazi RF, and Nasr M. Anti-HIV-1 activities of
anthraquinone derivatives in vitro [abstract #M. C. P. 115]. V
International Conference on AIDS, Montreal, June 4-9, 1989.
Cooper WC and James JS. An observational study of the safety and
efficacy of hypericin in HIV+ subjects [abstract #2063]. VI
International Conference on AIDS, San Francisco, June 21-24,
1990.
Degar S, Lavie G, Levin B, and others. Inhibition of HIV
infectivity by hypericin: Evidence for a block in capsid
uncoating [abstract #I-16]. HIV Disease: Pathogenesis and
Therapy, University of Miami, March 1991.
Kraus GA, Pratt D, Tossberg J, and Carpenter S. Antiretroviral
activity of synthetic hypericin and related analogs. Biochemical
and Biophysical Research Communications. 1990; volume 172, pages
149-153.
Lavie G, and Meruelo D. Inhibition of retrovirus-induced
diseases by two naturally occurring polycyclic aromatic diones
hypericin and pseudohypericin [abstract #C. 501]. V International
Conference on AIDS, Montreal, June 4-9, 1989.
Lavie G, Valentine F, Levin B, and others. Studies of the
mechanisms of action of the antiretroviral agents hypericin and
pseudohypericin. Proceedings of the National Academy of
Sciences, USA. August 1989; volume 86, pages 5963-5967.
Lavie G, Mazur Y, Lavie D, Levin B, Ittah Y, and Meruelo D.
Hypericin as an antiretroviral agent; mode of action and related
analogues. Annals of the New York Academy of Sciences. 1990;
volume 616, pages 556-562.
Lavie G, Meruelo D, Daub M, and others. Retroviral particle
inactivation by organic polycyclic quinones: A novel mechanism
of virucidal activity characterized by diminution of virus
particle derived reverse transcriptase enzymatic activity
[abstract I-27]. HIV Disease: Pathogenesis and Therapy
conference, University of Miami, March 1991.
Meruelo D, Lavie G, and Lavie D. Therapeutic Agents with
Dramatic Antiretroviral Activity and Little Toxicity at Effective
Doses: Aromatic Polycyclic Diones Hypericin and Pseudohypericin.
Proceedings of the National Academy of Sciences, USA. July 1988;
volume 85, pages 5230-5234.
Meruelo D, Degar S, Levin B, Lavie D, Mazur Y, and Lavie G.
Inactivation of retroviral particles by hypericin: Possible role
of oxidative reactions in the antiretroviral activity [abstract
I-29]. HIV Disease: Pathogenesis and Therapy, University of
Miami, March 1991.
Schinazi RF, Chu CK, Babu JR, and others. Anthraquinones as a
new class of antiviral agents against human immunodeficiency
virus. Antiviral Research. 1990; volume 13, pages 265-272.
Takahashi I, Nakanishi S, Kobayashi E, Nakano H, Suzuki K, and
Tamaoki T. Hypericin and pseudohypericin specifically inhibit
protein kinase C: possible relation to their antiretroviral
activity. Biochemical and Biophysical Research Communications.
December 29, 1989; volume 165, number 3, pages 1207-1212.
Tang J, Colacino JM, Larsen SH, and Spitzer W. Virucidal
activity of hypericin against enveloped and non-enveloped DNA
and RNA viruses. Antiviral Research. 1990; volume 13, pages
313-326.
Valentine F, Meruelo D, Itri V, and Lavie G. yMHypericin:
efficacy of a new agent against HIV in vitro [abstract #M. C. P.
18]. V International Conference on DS, Montreal, June 4-9, 1989.
Valentine FT. Hypericin: A hexahydroxyl, dimethyl-
naphthodianthrone with activity against HIV in vitro and against
murine retroviruses in vivo [oral presentation, published
abstract]. HIV Disease: Pathogenesis and Therapy, University of
Miami, March 1991.
Weiner DB, Lavie G, Williams WV, Lavie D, Greene MI, and Meruelo
D. Hypericin mediates anti-HIV effects in vitro [abstract #C.
608]. V International Conference on AIDS, Montreal, June 4-9.
Wood S, Huffman J, Weber N, and others. Antiviral activity of
naturally occurring anthraquinones and anthraquinone derivatives.
Planta Medica; Journal of Medicinal Plant Research. 1990; volume
56, number 6, pages 651-652.
***** ddI Warning: Don't Take Dapsone at Same Time
The U. S. Division of AIDS has issued a warning to
physicians that patients using ddI and also using dapsone, a drug
for pneumocystis prophylaxis, should not take the drugs within
two hours of each other. The problem is that dapsone requires an
acid environment in order to be dissolved; but ddI cannot
tolerate an acid environment, so it is taken with a buffer to
neutralize stomach acidity. The lack of acidity causes the
dapsone not to be absorbed.
Jacobus Pharmaceutical Company, the manufacturer of dapsone,
brought the problem to the attention of the Division of AIDS
after several cases of pneumocystis were found in patients who
were taking both drugs. At least 11 cases of pneumocystis have
occurred within 10 to 130 days after starting therapy with the
two drugs together.
This problem could also affect other drugs which require an
acid stomach -- for example, ketoconazole.
The following recommendation is included in Safety Memo 013
of the Division of AIDS:
"Recommendation: The Division of AIDS and Jacobus
Pharmaceutical Company recommend that clinicians contact all
patients who are receiving both ddI and dapsone by telephone and
advise them to take dapsone two hours prior to ddI. "
The memo also says that if patients cannot take dapsone at
least two hours before ddI, they should wait until two hours
after. The two drugs should not be taken within two hours of
each other.
***** Advocacy Program for Health Providers with HIV
by Denny Smith
The American Association of Physicians for Human Rights
(AAPHR), a national organization of gay and lesbian physicians,
is sponsoring an effort to protect the rights and livelihoods of
doctors and other health workers from proposals requiring
disclosure of their HIV status. The "Medical Expertise Retention
Program, The National Program for Physicians With HIV Disease" is
directed by attorney Ben Schatz, who will assist and advocate on
behalf of seropositive health workers.
Recently, alarm bells have been clanging in the media and
professional organizations over allegations that patients are at
risk for contracting "the AIDS virus" when they are under the
care of a dentist or physician with HIV. Ironically, many
physicians with HIV have had to compensate for years of their
colleague's AIDS phobia by providing more than their share of the
care required by thousands of Americans with HIV.
For information about AAPHR's program, or to make a tax-
deductible contribution, interested persons can call 415/864-
0408.
Comment
This is a crucial civil rights issue for anyone involved in
the AIDS epidemic. The concern voiced for the "safety of the
patient" echoes the older "safety of the physician" campaigns
waged against seropositive patients. In both situations the
issue of safety has been finessed to serve other agendas.
Health workers should be observing "universal" blood and
body fluid precautions with all of their patients, for their own
safety and that of their patients' as well. If universal
precautions are observed, there remains no compelling reason to
compromise the privacy of health workers, or their patients, with
HIV. Hepatitis and other serious infections have amounted to a
far greater risk than HIV in the healthcare setting. But HIV has
garnered far more hysteria -- a dangerous mismatch between
perception and reality.
If alarmists achieve their goals, then physicians, dentists
and nurses will be discriminated against openly, and no other
sector of the workforce or general population would be exempt
from similar bias. Many competent care-givers could be removed
from their positions unfairly and needlessly, and the loss of
those experienced in caring for HIV would impoverish the quality
of medicine generally for everyone needing HIV care.
***** HIV Immigration: New Threat, AIDS Organizations Needed
by John S. James
As reported previously in AIDS TREATMENT NEWS, the U. S.
Department of Health and Human Services recommended that HIV --
along with all other diseases except active tuberculosis -- be
dropped as grounds for excluding visitors and immigrants from the
United States. But conservative Republicans are now pressuring
President Bush to overrule the HHS recommendation and keep HIV as
grounds for exclusion, at least for permanent immigrants.
Apparently the argument this time is avoiding medical-care
costs to the government, rather than fear of contagion. Our
understanding is that existing law already allows immigrants to
be excluded if they are likely to require government expense.
The real issue, then, is whether HIV should be singled out from
all other diseases for automatic exclusion not based on public-
health requirements.
A hundred and fifty organizations have already signed an
April 16 consensus letter supporting the recommendation of HHS
that HIV not be used to bar U. S. entry by visitors or
immigrants. Signers include the American Public Health
Association, United States Conference of Mayors, AmeRed
Cross, National Hemophilia Foundation, American Foundation for
AIDS Research, San Francisco Department of Public Health,
American Jewish Committee, AIDS Action Council, San Francisco
AIDS Foundation, and the Eighth International Conference on AIDS.
The letter has already been submitted to Health and Human
Services Secretary Louis Sullivan, but an addendum with other
signers is being prepared. If your AIDS, medical, or other
organization could sign this letter, contact Dana Van Gorder,
Harvard AIDS Institute/Eighth International Conference on AIDS,
617/495-2318, or 617/495-2863 (fax).
***** California: State Treatment Activist Meeting May 4,5;
Prison, Funding Demos Sacramento May 6 and 7
ACT UP/Golden Gate will host a statewide activist conference
in San Francisco on May 4 and 5. Demonstrations are planned for
Sacramento on the following two days, May 6 and 7. Saturday's
meeting will address treatment issues (both State and Federal),
while Sunday's will focus on California.
Issues include:
* Building coalitions with other disease activist groups.
* California's successful AIDS research program -- the only
one in the country -- and the proposal for patient advocates to
have input into this program.
* Improving California's Food and Drug Branch (FDB), which
could approve trials or even drug marketing in California.
* Faster development and approval of new antivirals, on both
Federal and State levels.
* Improving the State's AIDS Drug Program, which provides
drugs to people who could not otherwise afford them.
* Providing adequate medical care for prisoners.
The Sacramento demonstrations will focus on medical care for
prisoners with HIV (May 6), and the AIDS Drug Program (May 7).
All the issues are of course affected by the State's budget
crisis.
For more information about the conference and
demonstrations, call ACT UP/Golden Gate at 415/252-9200, or come
to the meetings in San Francisco every Tuesday evening (General
Body), Wednesday evening (Treatment Issues), or other committees
at various times throughout the week.
***** California: AIDS Budget Lobby Day, Sacramento May 6
Several AIDS service organizations will sponsor an AIDS
Budget Lobby Day, Monday, May 6, 9:00-4:00, at the State Capitol
in Sacramento. Issues include the proposal to limit AIDS funding
to last year's level despite a 25 percent growth in caseload, and
to withhold cost of living increases for persons on SSI and AFDC.
If you can go to Sacramento on that day to meet with
legislators and staff, call Regina Aragn, San Francisco AIDS
Foundation, 415/864-5855x2599, or Nancy DeStefanis, AIDS Service
Providers Association of the Bay Area, 415/241-5519.
***** Statement of Purpose
AIDS TREATMENT NEWS reports on experimental and
complementary treatments, especially those available now. It
collects information from medical journals, and from interviews
with scientists, physicians, and other health practitioners, and
persons with AIDS or HIV.
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.
***** How to Subscribe to AIDS TREATMENT NEWS by Mail
Send $100 per year for 24 issues ($100 for nonprofit
organizations, $200 for businesses and institutions), or $40
reduced rate for persons with AIDS or related conditions who
cannot afford the regular rate, to: ATN Publications, P. O. Box
411256, San Francisco, CA 94141. A six-month subscription (12
issues) is $55 for individuals or nonprofits, $110 for businesses
and institutions, or $20 reduced rate. For subscription
information and a sample issue, call 800/TREAT-12 (800/873-2812),
or 415/255-0588.
To order back issues, send $18 for issues #1 through #75,
plus the per-issue cost for each later issue you need. The per-
issue cost is $1 reduced rate, $2 individual or nonprofit rate,
and $4 for businesses and institutions (Note that issues 1
through 75 are also available through bookstores, at a retail
price of $12.95.) The back issues include articles on ddI,
compound Q, clarithromycin, azithromycin, fluconazole, AZT,
aerosol pentamidine, ganciclovir (DHPG), diclazuril, DHEA,
peptide T, passive immunotherapy, hypericin, and many other
treatments.
Outside North America, add $20 per year for airmail postage,
$6 airmail for back issues #1 through #75, and $.50 for each
additional issue. Outside U. S. A., send U. S. funds by
international postal money order, or by travelers checks, or by
drafts or checks on U. S. banks.
To protect your privacy, we mail first class without
mentioning AIDS on the envelope, and we keep our subscriber list
confidential.
Copyright 1991 by John S. James. Permission granted for
non-commercial reproduction, provided that our address and phone
number are included if more than short quotations are used.
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