MNSMITH@ECS.UMASS.EDU (Michael Smith) (06/07/89)
AIDS TREATMENT NEWS Issue #79, May 19, 1989
CONTENTS:
Persantine: Anti-Clotting Drug May Enhance AZT, DDC
Hypericin Caution
New NIH Hotline for Clinical Trials Information
Beta Interferon Trial Seeks Patients Who Had to Reduce AZT Dose
San Francisco: HIV Treatment Awareness Week, June 22-25
Needed: Compulsory Licensing of Pharmaceuticals?
PML, Toxoplasmosis, and MAI: Surveying the Options
PERSANTINE: ANTI-CLOTTING DRUG MAY ENHANCE AZT, DDC
An inexpensive prescription drug used orally to prevent
blood clots in persons with certain heart conditions has been
found to substantially increase the effectiveness of AZT in
laboratory tests, without increasing its toxicity to bone marrow
or other human cells. This finding, by a team of researchers at
the U.S. National Cancer Institute, was published this week in
the Proceedings of the National Academy of Sciences, USA (volume
86, pages 3842-3846, May 15, 1989). The drug has not yet been
tested in patients in combination with AZT, so its safety and
effectiveness for anti-HIV use are not known.
The drug, dipyridamole (abbreviated DPMQthe brand name is
Persantine) had little or no antiviral effect by itself. But in
laboratory tests, it allowed AZT concentrations to be reduced by
a factor of five to ten times and still have the same anti-HIV
activity as the larger amount of AZT without the DPM. The concen-
tration of DPM needed to achieve this effect was greater than or
equal to two micromoles; usual oral doses of 100 to 400 mg per
day produce blood levels of two to six micromoles, suggesting
that such doses would likely be effective.
These tests were done in human macrophages, which are
believed to be the major reservoir of HIV. DPM also enhanced the
anti-HIV effect of DDC, an experimental antiviral in the same
class as AZT, in macrophages.
The researchers discovered this effect of DPM by chance.
They do not know why it occurred, but suspect that the mechanism
may be one which would apply only to nucleoside analogs (such as
AZT, DDC, or DDI), not to other kinds of antivirals.
DPM is an old, well-known drug and generally considered
safe. We checked medical reference books and found no indication
of serious toxicitsient"; side effects generally disappear
with long-term use. However, as far as we know the drug has never
been tested with persons with HIV, and there may be need for spe-
cial precautions. For example, since DPM works as an anticoagu-
lant by inhibiting the action of platelets, it could be dangerous
for persons with low platelet counts; a hematologist we spoke to
was very concerned about this risk. Physicians will need to weigh
potential risks and benefits.
According to a May 15 report in the San Francisco Chronicle,
DPM has already been reviewed by a committee at the U.S. National
Institute of Allergy and Infectious Diseases (NIAID), and plans
are being developed for a clinical trial combining DPM and AZT,
although no date for the trial has yet been set. Trials are
necessary because the laboratory results do not prove that the
drug will be useful against AIDS, or even safe when combined with
AZT.
DPM should not be confused with heparin or dextran sulfate,
which are also anticoagulants. DPM is different in that it is not
an antiviral by itself.
Comment
We see these laboratory findings as especially important
because of the ease with which this potential treatment can be
tested, and if found to be useful, made widely available. Physi-
cians can legally prescribe DPM for any use, although understand-
ably they may be reluctant to do so, since as of this date the
drug may never have been tried in patients for the purpose of
enhancing AZT. DPM costs littleQabout 50 cents a day or less in
its generic versionsQso cost will seldom be an obstacle to avai-
lability.
We are concerned that trials will take too long, either
because of bureaucracy before they even start, or because of
inherently slow designs, such as having to wait for opportunistic
infections or deaths (in an AZT-plus-placebo group) to gain irre-
futable statistical proof of efficacy. Much faster trials are
possible, for example looking for clear benefit from giving DPM
to persons who are already taking AZT but not getting enough
results from it.
Since many people cannot wait for trials to be completed, it
seems inevitable that some patients and physicians will try DPM
in combination with AZT; if they get good results, more will fol-
low. Community-based or other research organizations could per-
form an important service by monitoring and documenting the
results of any such use.
The example of DPM illustrates one of the major although
largely unrecognized public policy problems in the management of
research on AIDS and other diseasesQthe lack of any institutional
advocacy for the interests of patients in getting treatment
sooner. The FDA and the NIH do not do this job; neither do drug
companies, medical associations, most physicians, universities,
foundations, or AIDS service organizations. It is tragic that in
a major emergency we have had to take the time to develop new
organizations (such as ACT UP) from scratch, because existing
institutions have refused to become involved.
HYPERICIN CAUTION
While we are continuing to hear many good reports on hyperi-
cin, an antiviral available in St. JohnUs wort extracts (see AIDS
TREATMENT NEWS issues # 77, 75, 74, and 63), we have also heard
of two more patients taken off the treatment by their physicians
because of abnormally high values on liver- function tests.
Both patients had been using tablets containing St. JohnUs
wort extracts for four or five weeks (we do not know what kind of
tablets, or what doses), when transaminase levels were found to
be about five times normal. In both cases the levels returned to
normal after the patients stopped using the tablets. Neither was
using any other treatment likely to cause the high levels. Both
were asymptomatic, and neither had baseline tests run before they
started using the herbal extracts.
We talked to Dr. David Payne in Mesa, Arizona, who has
several dozen patients who are using hypericin extracts (many
from St. JohnUs wort tablets), and he has not seen any problem of
abnormal liver-function tests. He has seen many HIV-positive
patients with elevated liver-function values without any treat-
ment. In those using hypericin, the values often go down.
At this point we do not know whether St. JohnUs wort
extracts are causing abnormal liver-function tests in some peo-
ple, or whether those patients would have had high values anyway.
The tests have returned to normal after the treatment was
stopped, and there is no evidence of any lasting harm. But it
would be dangerous to ignore a potential problem by not getting
the tests (which are usually given as part of a blood- chemistry
panel). Anyone using St. JohnUs wort should tell their physician,
and should have a blood-chemistry panel including liver functions
probably within the first few weeks of starting, if they plan to
continue using the herb, so that the treatment can be discontin-
ued if necessary.
NEW NIH HOTLINE FOR CLINICAL TRIALS INFORMATION
The National Institutes of Health (NIH) has set up a new
toll- free hotline to provide information about all NIH clinical
trials of experimental AIDS treatments. Persons considering
volunteering for a trial can call 800/TRIALS-A between 9:00 AM
and 7:00 PM Eastern time, Monday through Friday. Three health
workers (including one who speaks Spanish) will provide the
information from a computer database which is updated weekly.
At this time the hotline has information about NIH tri-
alsQabout a third of all AIDS trials in the United States. Within
the next few months, the system plans to expand to include the
other trials also, by incorporating a database of non-NIH trials
currently being developed by the FDA. There are also plans to
make this information directly accessible to the public by per-
sonal computer, through database services already provided by the
National Library of Medicine.
NIH trials are currently being conducted at over 100 hospi-
tals and medical centers throughout the United States, and at the
NIH Clinical Center in Bethesda, MD. There are trials for adults
and for children, and for persons at all stages of HIV infection,
including those who are asymptomatic.
The hotline is sponsored by the National Institute of
Allergy and Infectious Diseases (NIAID), in cooperation with the
Centers for Disease Control (CDC).
Comment
It has long been difficult for those who want to volunteer
for trials to find out what trials are available. At the same
time, many trials have been greatly delayed because they cannot
find volunteers. The new NIH hotline service should help with
these problems. We need to see how well it works in practice, and
would appreciate hearing from our readers about their experiences
in using it.
Persons considering volunteering for trials should also
obtain A Practical Guide to Clinical Research, published by the
American Foundation for AIDS Research (AmFAR), with support from
NIAID. It was published as a special issue of AmFARUs AIDS/HIV
Experimental Treatment Directory, February, 1989. It can be
obtained for $10. (free for persons with HIV who cannot afford
it) from AmFAR, 212/719-0033; or by mail, send a check to AmFAR,
1515 Broadway, Suite 3601, New York, NY 10036.
BETA INTERFERON TRIAL SEEKS PATIENTS WHO HAD TO REDUCE AZT DOSE
A clinical trial of beta interferon and low-dose AZT is
recruiting patients who could not tolerate full-dose AZT and had
to reduce the dose. Beta interferon is an antiviral which may
work like alpha interferon but have fewer side effects.
In the laboratory, beta interferon reduced the amount of AZT
needed to stop HIV replication by up to two-hundredfold, accord-
ing to a physiciansU fact sheet prepared by the developer.
Patients using the drug have had a much lower than expected
incidence of opportunistic infections, although it is still too
early to be sure that this effect was not due to chance.
The trial is taking place at 20 sites in 12 cities in the
U.S.: Baltimore, Boston, Chicago, Cleveland, Galveston/Houston,
Irvine (CA), Los Angeles, New York City, Philadelphia, San Fran-
cisco, Tampa Bay Area, and Washington, DC. One third of the
patients will receive high-dose beta interferon (45 million
units), one third low dose (9 million units), and one third pla-
cebo; all patients will also be using AZT. The interferon is
self- administered once per day by subcutaneous injection.
There is no charge for participating in the trial; however,
the study will not pay for the AZT. If beta interferon proves
effective, patients who complete the study or are dropped through
no fault of their own will be able to receive the interferon free
indefinitely.
To qualify for the study, patients must have AIDS or T-cell
counts under 200, must not currently have poorly controlled
opportunistic infections, extensive KS, or HIV wasting syndrome,
and must have hematologic toxicity which required AZT dose reduc-
tion but allows 500-600 mg per day to be used. There are several
other requirements in addition, such as acceptable liver and kid-
ney function. Full information on eligibility requirements can be
obtained from the number below.
The trial is sponsored by Triton Biosciences (a subsidiary
of Shell Oil Company), of Alameda, CA. For more information,
patients or physicians can call 800/432-2828.
SAN FRANCISCO: HIV TREATMENT AWARENESS WEEK, JUNE 22-25, 1989
A series of events sponsored by several San Francisco AIDS
and health agencies will discuss treatment-related issues includ-
ing medical strategies for AIDS/HIV treatment, immune system mon-
itoring for asymptomatics, access to insurance, HIV discrimina-
tion and the law, and political action for access to treatment.
Sponsoring organizations are Project Inform, AIDS Service Provid-
ers Association of the Bay Area, Bayview HunterUs Point Founda-
tion, Latino AIDS Project of Instituto Familiar de La Raza,
Mobilization Against AIDS, San Francisco AIDS Foundation, and the
San Francisco Department of Public Health.
A public-policy symposium on Thursday, June 22, from 9 AM to
5 PM, will focus on economic issues and access to treatment,
especially for the disadvantaged. Rev. Jesse Jackson will give
the closing address.
A medical symposium on the following day, Friday June 23,
includes an opening address by Anthony Fauci, M.D., Director,
National Institute of Allergies and Infectious Diseases, and con-
current sessions on psychosocial/medical issues, clinical roundt-
able on case management, and adjunctive therapies, including
nutrition and Eastern medicine.
On Saturday, June 24, there will be an all-day health fair,
with roundtables and exhibits. The program will close with a tea
dance fundraiser party, Sunday June 25, 4:00 PM to 9:00 PM at The
Arena, Civic Auditorium
For persons with AIDS or ARC, registration for both symposi-
ums is $10. ($5. for one). For others, registration for both is
$40. before June 10, $100. after that date ($25. before June 10
or $50. after for a single symposium). The Saturday events are
free and open to the public. All activities will take place at
the Civic Auditorium, 99 Grove Street, San Francisco.
To register, make check to "Project Inform HIV Treatment
Awareness Week", and send it to HIV Treatment Awareness Week,
Suite 500, 44 Montgomery Street, San Francisco, CA 94104. For
more information, contact Mr. Michael S. Cullen at the Montgomery
St. address, or by phone at 415/955-2666.
NEEDED: COMPULSORY LICENSING OF PHARMACEUTICALS?
by John S. James
Compulsory licensing, a concept used in the copyright law in
the United States and many other countries, is also applied to
patented pharmaceuticals in Canada. Under this part of Canadian
patent law, a company can in certain circumstances market a drug
patented by another company. It pays a royalty to the patent
holder; the royalty percentage is set by a government agency.
This system is called compulsory licensing because the patent
holder cannot stop the other company from using its drug (and
paying it a royalty for doing so).
In the United States, it would probably be impossible to
pass such a law over the opposition of the pharmaceutical indus-
try; too many lawmakers are more influenced by campaign contribu-
tions than by the public interest. We suggest the concept because
a limited kind of compulsory licensing might be in the interest
of pharmaceutical companies (and therefore politically possible),
as well as in the interest of persons with serious or life-
threatening illnesses. Compulsory licensing could overcome the
liability problems which otherwise block the treatment use of new
drugs even when government agencies ask for their release. It
could place responsibility for emergency access to drugs clearly
in the hands of the government, which has public accountability,
as private companies do not. It would not open the door to quack-
ery, because compulsory licensing would only be used for drugs
requested by government bodies for emergency treatment use. And
it might be acceptable to the industry, because whenever it was
used it would turn an unmarketable drug which was only a loss to
the company which held the patent into a risk-free, trouble-free
source of profit instead.
In Canada, compulsory licensing of pharmaceutical patents
has been the law since 1923. Its main purpose is to keep drug
prices low by encouraging generic pharmaceuticals. Compulsory
licensing was not used very often until 1969, however, because
until that year the generic drug had to be manufactured in Canada
in order to qualify for such a license. In 1969, an amendment
allowed imported drugs to qualify also, and compulsory licensing
became more widely used.
According to a 1985 Canadian report (by the Commission of
Inquiry on the Pharmaceutical Industry), the law had succeeded in
greatly reducing drug prices, at no cost to the overall profita-
bility of the Canadian pharmaceutical industry. However, that
industry has bitterly opposed compulsory licensing, and after
great controversy significant restrictions were adapted in 1987.
As far as we know, Canada is the only country with compul-
sory licensing of pharmaceuticals. In the United States, a bill
proposing such a system was introduced in the House of Represen-
tatives in 1981.
In the United States today, compulsory licensing could be
most important when patent holders have refused to allow the use
of irreplaceable drugs for treating AIDS or other serious
diseases (through compassionate use or through the "treatment
IND"), even when the FDA has pleaded with them to do so. Under
current law, there is no public recourse for access to such
drugs. And companies have no incentive to make the drugs avail-
able, since it is expensive to do so and the manufacturers are
seldom allowed to charge anything, even to reimburse their costs.
In addition, they could face product liability lawsuits in the
future, another reason to deny use of the drug, for which they
are usually the only legal source. All existing incentives are
for companies to deny access to potentially lifesaving drugs,
before completion of the years-long process of obtaining full
marketing approval. In the United States today, allowing physi-
cians to use any experimental drug is all cost and no benefit to
the company which holds the patent rights.
Under compulsory licensing, a government body (probably a
commission set up within in the Public Health Service) could
designate drugs urgently needed for treatment use (not for gen-
eral marketing), and issue a license to any qualified company
which contracted to supply the drug. The price would be set in
the contract. The commission would also set a fair royalty (prob-
ably a percentage of the contract price), which would be paid to
the patent holder. The patent holder would therefore receive a
royalty without any trouble or expenseQor any risk of liability,
since it had done nothing to provide the drug. It would also
benefit from data which could speed full marketing approval, and
also from the favorable publicity of having its drug selected by
an independent body as beneficial and indeed essential.
The cost for this system would be minimal, for several rea-
sons. The price for the drug would presumably be low, near the
generic price; this emergency access system would not have to pay
for the cost of development of the drug, since compulsory licens-
ing places no additional cost on the licensor, but only provides
pure profit. If the government paid for the drug, the total cost
would also be kept low by the fact that few drugs would be dis-
tributed this way, as this system would be used only when
urgently necessary. The cost of deciding which drugs to release
would also be low, since only a few obvious candidates would ever
be considered. (By contrast, the FDA must consider thousands of
drug applications, and apply much more thorough criteria to
approve for general marketing than would be appropriate to
approve for treatment use in an emergency.)
In the United States, the concept of compulsory licensing of
patented pharmaceuticals has been absent from public discussion.
We suggest that the idea be investigated and considered, so that
legislation to provide this access to essential treatments can be
proposed if necessary.
References
Chromecek, M. The amended Canadian patent act: general amendments
and pharmaceutical patents compulsory licensing provisions. Ford-
ham International Law Journal, volume 11 number 3, pages 504-548,
Spring 1988.
Hayhurst, WL. Food for thought: compulsory licensing of patents.
Intellectual Property Journal, volume 1 number 1, pages 73-76,
July 1984.
Shulman, SR, and Richard, BW. The 1987 Canadian patent law amend-
ments: revised pharmaceutical compulsory licensing provisions.
Food Drug Cosmetic Law Journal, volume 43 number 5, pages 745-
757, September 1988.
U.S. House of Representatives. HR 915, compulsory licensing of
prescription drug patents (12 cosponsors). House Proceedings,
97-046, page H1049, March 23, 1981.
PML, TOXOPLASMOSIS AND MAI: SURVEYING THE OPTIONS
by Denny Smith
The early years of the epidemic made clear that people who
are immunocompromised are susceptible to infections from various
bacteria, fungi, viruses and protozoa which would ordinarily be
harmless. Since these microorganisms take advantage of a disarmed
immune system, they are described as "opportunistic" infections
(OIs).
The most familiar of these is a pneumonia caused by the
organism Pneumocystis carinii (PCP). P. carinii is found every-
where in the environment and exposure to it is impossible to
avoid. But PCP has become one of the most treatable of OIs, if
diagnosed early enough. And the FDA recently acknowledged what
thousands of people with HIV and their physicians already knew:
that a decline in T-helper cells to 200 or less warrants the use
of a prophylaxis (preventive measure) such as dapsone, sulfa
trimethoprim or aerosol pentamidine to ward off even a first bout
with PCP.
Other opportunistic infections have generally been handled
less successfully than PCP, particularly MAI, toxoplasmosis and
PML. But new experimental approaches to all three of these are
receiving attention, and it is possible that the risk for
developing the first two can be lessened by avoiding routine
exposure to the responsible pathogens. This article suggests some
precautions, and surveys the drugs now being tried or considered
to control active infections. Many of the drugs mentioned are FDA
approved, and a doctor can prescribe them as she or he determines
appropriate for any condition. If they are only investigational
in the U.S. we will indicate so, although new guidelines allow
the importation of drugs approved in other countries if
prescribed by a physician for personal use. As any treatments,
approved or unapproved, gain a strong consensus as effective (or
ineffective) therapies, we will report on them in depth. Until
then we want to name the possibilities we are aware of in order
to maximize the choices of people with these diagnoses and their
physicians.
PML
Progressive multifocal leukoencephalopathy (PML) is an
uncommon but devastating brain infection with an historically
bleak outlook, and many physicians have opted not to initiate
treatment, or simply rely hopefully on AZT for its antiviral and
CNS access capacity. The results of intervention in the progress
of PML have increased the possible options, however, enough to
justify an aggressive attempt to treat.
This OI probably results from reactivation of a latent papo-
vavirus to which most people gain immunity after childhood expo-
sure. Some symptoms of PML, such as headaches, confusion, visual
impairment in one or both eyes, aphasia (difficulty with verbal
comprehension or expression) or loss of muscle coordination on
one side of the body, can resemble toxoplasmosis, herpes
encephalitis or meningitis. Each of those infections, as well as
PML, can be imminently life-threatening and should be seen
immediately by an AIDS-knowledgeable physician, who may consult a
neurologist. Someone experiencing these symptoms may become too
disoriented to respond quickly to the situation, so the observant
help of friends or family could make a difference. The time from
appearance of symptoms to diagnosis to treatment is crucial for
PML or other AIDS-related neurological infections.
AIDS TREATMENT NEWS recommends to interested readers a very
comprehensive, well-researched report on experimental treatments
for PML compiled by two concerned AIDS activists in Los Angeles,
Lisa A. Muller and Peter L. Brosnan, with an introduction by
Ronald Webeck, a long-term survivor of PML. The treatments dis-
cussed in this report were drawn from current medical literature
and include beta interferon, vidarabine (adenine arabinoside, or
ARA-A), cytarabine (cytosine arabinoside, or ARA-C), alpha-2
interferon, acyclovir, clonazepam, trimethoprim with sulfamethox-
azole, and dexamethasone combined first with sulfadiazine and
then with pyrimethamine. The first three in the list appeared to
be more effective when administered intrathecally (injected into
the spinal fluid) instead of intravenously. The others were tried
only intravenously. (Clonazepam is probably useful to control
convulsions which may accompany PML, but not as a primary treat-
ment.)
Some of these drugs have side effects which people with HIV
and their doctors would usually weigh carefully, but the gravity
of an untreated PML infection may override these concerns, and
AIDS-experienced physicians often make similar compromises in
treating other OIs. None of these drugs have been proven to work
repeatedly, but accumulated attempts to treat PML have resulted
in better survival rates than nontreatment. The articles refer-
enced from the literature are included in entirety in the
reportUs appendix, making it self-contained and practical for
outpatient clinics and AIDS-care health professionals. A copy of
the report can be obtained by sending a request (with $10 dona-
tion or more to cover the cost of printing and mailing) to Lisa
Muller, 4015 Bemis, Los Angeles, CA 90039.
Toxoplasmosis
AIDS-related toxoplasmosis is a serious infection of the
central nervous system caused by the protozoan Toxoplasma gondii.
The symptoms of toxoplasmic encephalitis can be difficult to
diagnose with certainty, but as mentioned above call for urgent
attention.
Various mammals and birds can be infected with T. gondii,
but only cats appear to harbor the reproductive forms of the
organism. Resting forms called oocysts are shed by cats in their
feces, where they can survive in the soil for more than a year.
Here they are a ready source of infection for other animals and
humans. In humans the oocysts themselves are not damaging, but
when the multiplicative forms, or active parasites, break out of
the cysts they are capable of causing disease in infants and
immunosuppressed adults. Active parasite forms of T. gondii can
also be transmitted to people in undercooked meat.
The standard treatment for toxoplasmosis is pyrimethamine
with sulfadiazine. These drugs are effective against the
parasite, but they do not destroy oocysts, so a continuous
maintenance dose is necessary to squelch emerging parasites. Some
people reach toxic intolerance of these drugs, and folinic acid
(Leucovorin) is then used to diminish this toxicity. Pyrimetham-
ine is also being studied in combinations with dapsone,
trimetrexate, clindamycin and spiramycin (investigational),
instead of sulfadiazine. Clindamycin is probably substituted most
often.
Infrequently, pyrimethamine fails altogether and amphoteri-
cin B has been tried next. This drug can cause severe side
effects, however, as many people who received it for cryptococcal
meningitis will verify. An investigational drug, fluconazole, has
been substituted effectively for this kind of meningitis, and
tolerated more easily. Accordingly, fluconazole has been sug-
gested for the treatment of toxoplasmosis. The FDA will probably
approve fluconazole later this year (for background, see AIDS
TREATMENT NEWS #58), but it may be accessible now with the help
of buyersU clubs in New York and San Francisco (see "Obtaining
Treatments from Abroad" in AIDS TREATMENT NEWS#78). Incidentally,
researchers at the Universite Paris VI have found a new, less
toxic derivative of amphotericin B called N-fru-AmB which demon-
strated antibiotic and immune boosting effects in mice. It is not
yet clear if it will be of use in humans, or for which infec-
tions.
Issue #75 of AIDS TREATMENT NEWS reported on two other
promising options for toxoplasmosis: roxithromycin, approved in
France, and azithromycin, approved in Yugoslavia. They may be as
effective as pyrimethamine/sulfadiazine but more easily
tolerated. However, we do not know results of human use for toxo-
plasmosis at this time. Roxithromycin might be obtainable through
buyersU clubs (see paragraph above).
The abstracts of the 1988 Interscience Conference on Antimi-
crobial Agents and Chemotherapy (ICAAC) presented results of
varying combinations of pyrimethamine, sulfadiazine and arprino-
cid (investigational) against T. gondii in mice. Arprinocid was
found to work poorly when combined with pyrimethamine, and
pyrimethamine alone was somewhat more effective that either sul-
fadiazine or arprinocid alone. But arprinocid and sulfadiazine
together worked synergistically, the best combination tried.
Additionally, a metabolite of arprinocid called arprinocid-N-
oxide was more effective alone in smaller doses than arprinocid
(Luft and Frankel, abstract number 1420). Unfortunately, another
study found that AZT made pyrimethamine much less effective in
animal tests (Israelski, Tom, and Remington, abstract number
349).
In January 1988 in The Journal of Infectious Diseases, Drs.
Benjamin L. Luft and Jack S. Remington authored a comprehensive
discussion of diagnostic procedures and potential therapies for
toxoplasmosis. In addition to many of the drugs mentioned above
they proposed the investigational agents gamma interferon and
interleukin-2 as candidates against T. gondii.
Lastly, researchers at the Robert Koch Institute in Berlin
found that monophosphoryl lipid A, or MPL (not FDA approved),
enhanced resistance in mice when administered before or at the
same time they were injected with T. gondii (Masihi and others,
1988). This raises the possibility of prophylaxis or chronic
suppressive therapy for toxoplasmosis. Also, we have heard anec-
dotally that people who are taking Septra for PCP show a reduced
incidence of toxoplasmosis. Hopefully some trends will be identi-
fied for practical use.
Most physicians we spoke with feel that AIDS-related toxo-
plasmosis is a reactivated infection from early, common exposure
to T. gondii; and indeed a large portion of the worldUs popula-
tion is chronically but asymptomatically infected. Of people with
AIDS who have the antibodies which verify this latent infection,
at least 30% develop toxoplasmic encephalitis. This incidence may
reflect the comparative virulence of different parasite strains
operating within a context of immunodeficiency. But another con-
sideration factor for the progression from latent to symptomatic
infection is inoculum threshold the amount or concentration
necessary to cause illness in someone. "Superinfection", or
repeated exposure, could be a mode of reaching this threshold. It
seems reasonably possible, especially for an immunocompromised
person, that some infections might be avoided or suppressed by
minimizing exposure to the organism.
Obviously, cat litter boxes could be kept away from food
preparation and eating areas, and the litter disposed of by some-
one who is not at risk for toxoplasmosis. Cats should not be fed
raw meat, and anyone who handles a cat or changes the litter
should wash their hands thoroughly afterward. In this regard,
toxoplasmosis is a "zoonotic" disease, one that can be transmit-
ted from animals to humans.(1) Since birds, cats, fish, reptiles
and rodents can all carry various zoonotic diseases, people with
pets should observe careful handwashing after handling pets and
before meals or food preparation.
MAI
MAI (Mycobacterium avium intracellulare) is one of a group
of mycobacteria, others of which can cause tuberculosis and Han-
senUs disease (leprosy). MAI is found widely in soil, dust,
untreated water and bird droppings. Formerly a lung infection
occurring primarily in people who have chronic lung disease or
are on steroids, MAI infection (or M. avium ComplexQMAC) in PWAs
is usually disseminated throughout the body and can cause
fatigue, fever, sweats, anemia, diarrhea and serious weight loss.
There are quite a few drugs being tried for MAI, although it
appears to respond very slowly.
The March 30, 1989 edition of Treatment Issues, published by
the Gay MenUs Health Crisis, reports on the following drugs for
consideration in the treatment of MAI: isoniazid (INH), rifampin
(Rifadin), rifabutin (Ansamycin), ethambutol (Myambutol), amika-
cin (Amikin), imipenem (Primaxin), ethionamide (Trecator),
clofazimine (Lamprene), ciprofloxacin (Cipro), ofloxacin,
cycloserine (Seromycin), erythromycin (Robimycin) and azithromy-
cin. Usually several of these are tried in combination. The
article includes diagnostic information about MAI, as well as MTB
(Mycobacterium tuberculosis), for which PWAs are also at risk. To
obtain this article, write to GMHC, Department of Medical Infor-
mation, 129 West 20th Street, New York, NY 10011. Be sure to
specify volume 3, number 2 on mycobacterial infections. We spoke
with Shelley M. Gordon, M.D. who is an infectious disease spe-
cialist with Pacific-Presbyterian Medical Center in San Fran-
cisco. She has observed the best response so far in MAC from a
combination of rifampin, ethambutol and clofazimine, with amika-
cin included as warranted.
Researchers at Shimane Medical University in Japan have
strengthened the rifampin activity against M. avium-infected
macrophages in mice by encapsulating rifampin in liposomes. Lipo-
somal vescicles are already widely used to enhance the delivery
of other antimicrobial drugs, and the researchers suggest that
this technique is particularly suited to treat persistent infec-
tions like MAI. Of related interest, three separate studies
presented at last yearUs International Conference on AIDS in
Stockholm suggested that rifabutin in vitro demonstrated anti-HIV
activity, especially when combined with heparin. This could pro-
vide an option for many people with MAI who cannot take AZT,
although some physicians, including Dr. Gordon, feel it is nei-
ther convincingly active against HIV nor noticeably better than
rifampin for treating MAI. Despite its investigational status,
rifabutin was widely available to physicians who wished to
prescribe it; recently the manufacturer cut off compassionate
access for new patients.
Amikacin, azithromycin and roxithromycin have been examined
in various combinations with tumor necrosis factor (TNF), a
natural product of the immune system which is synthesized and
being tested for other diagnoses, particularly KaposiUs sarcoma.
M. avium-infected human macrophages were more susceptible in
vitro to each antibiotic when tried with TNF than compared to any
antibiotic alone. The mycobactericidal action was strongest when
TNF was combined with both amikacin and roxithromycin. The
researchers of that study suggest that the pairing of immunomodu-
lators with antimicrobial agents could be a useful treatment for
MAI. In addition to some of the drugs mentioned above three more
possibilities were presented at the 1988 ICAAC conference:
fusidic acid (Fusidin), which may also have anti-HIV activity and
which is approved in Canada and the U.K. but not in the U.S.,
temafloxacin, and sulfisoxazole (Gantrisin).
As a prophylactic measure to keep a latent MAI infection
inactive, San Francisco physicians working with the County Com-
munity Consortium are studying the effect of low-dose clofazimine
(50 mg daily). People taking clofazimine, however, should be
aware that in rare cases it can accumulate as crystals in various
parts of the body, including the liver, spleen and intestinal
membranes. One friend of ours who was taking clofazimine experi-
enced a mildly enlarged liver and elevated liver enzymes which
eluded diagnosis. He looked up the warnings for the drug in the
Physicians Desk Reference and brought this to his doctorUs atten-
tion. The clofazimine was discontinued but it is too early to
draw a clear connection. We hope physicians prescribing MAI
treatments carefully explain any side effects to watch for (such
as anemia, dizziness, allergic rashes, kidney impairment, emo-
tional depression, skin discoloration, etc), especially since
some drug side effects can be confused with symptoms of AIDS-
related infections.
As with toxoplasmosis, active symptoms of M. avium are often
assumed to originate from an old exposure which remained unno-
ticed as a latent, immune-controlled infection. Although MAI is
widely present in water and soil, it may be feasible and advanta-
geous to decrease exposure to it. Keith Barton, M.D., of Berkeley
recommends to all his patients with AIDS that they not eat raw
foods, especially salad and root vegetables, or unpasteurized
milk or cheese, and that the water they drink be boiled. The bac-
teria are killed at around 80 degrees centigrade, which means any
conventional cooking (oven, stove, steamer) is sufficient to neu-
tralize MAI in vegetables and meat. An alternative to cooking
vegetables or fresh fruit is to peel and rinse any surface which
could have been exposed to soil or irrigation water. Of Dr. Bar-
tonUs patients who follow this advice, only three have developed
an active MAI infection, a much lower incidence than he would
have expected otherwise. This suggests that while it is not pos-
sible to avoid exposure to MAI completely, it may be worth taking
precautions to minimize the risk.
We want to acknowledge that many physicians and people with
HIV discount the practicality of avoiding microorganisms which
are pervasive in the environment. While the measures suggested
above may not completely eliminate exposure to pathogens like M.
avium or T. gondii, they might keep the quantity and frequency of
exposure below a disease-causing threshold. More importantly, the
search for the optimum treatments of these infections should be
intensified before they surpass the toll wrought by PCP early in
the epidemic.
For example, we have heard from some readers that their doc-
tors do not attempt to treat an MAI infection on the lethargic
assumption that there is no treatment proven conclusively to con-
trol MAI. When we called the offices of the National Institute of
Allergy and Infectious Diseases (NIAID) to clarify the status of
some promising drugs, the person we spoke with was very helpful
but repeated the same idea with nearly the same words: NIAID
does not recommend a treatment for MAI because none has been
shown to be so effective that it could win FDA approval as an MAI
treatment, even though most of them are approved for other infec-
tions and have been available to physicians for the entire epi-
demic. While waiting for the perfect treatment, disregarding
some that only might be useful, how many people with MAI (or
Kaposi's sarcoma, or plummeting T-helper cells) discovered the
consequences of waiting?
Current medical literature sometimes asks a more laissez-
faire question: "Did this patient die with MAI or from MAI?". The
question would be unnecessary if new potential treatments were
pursued aggressively and intelligently until a potent choice or
combination of choices surfaced. MAI, like HIV, is damaging
partly for its tendency to invade the disease-fighting cells
called macrophages. An unchallenged MAI infection could tip the
scales on a depleted immune system, clearing the path for other
opportunistic infections and providing another reason for treat-
ing MAI. The approach to toxoplasmosis has a similarly pessimis-
tic history but for different reasons. The drugs of choice have
been clearer than for those for MAI, but they are seriously lim-
ited by toxicity. Now the possibilities for treating toxo-
plasmosis are growing, those for MAI are being refined, and some
for PML are getting initial recognition. The pessimistic prog-
nosis surrounding these OIs appears to be changing, and the rate
of change could use a push by recognizing these infections early
and intervening with as many treatment options necessary.
References
Hawkins, CC and others. Mycobacterium avium Complex infections in
Patients with the Acquired Immunodeficiency Syndrome. Annals of
Internal Medicine, volume 105, pages 184-188, August 1986.
Bermudez, LEM and Young, LS. Activities of Amikacin, Roxithromy-
cin, and Azithromycin Alone or in Combination with Tumor Necrosis
Factor against Mycobacterium avium Complex. Antimicrobial Agents
and Chemotherapy, volume 32, number 8, pages 1149-1153, August
1988.
Henry-Toulme, N and others. Immunomodulating properties of the
N-(1-deoxy-D-fructos-lyl) derivative of amphotericin B in mice.
Immunology Letters, volume 20, pages 63-67, 1989.
Masihi, K. Noel and others. Effects of Nontoxic Lipid A and Endo-
toxin on Resistance of Mice to Toxoplasma gondii. Journal of
Biological Response Modifiers, volume 7, number 6, pages 535-539,
1988.
Suzuki, Y and others. Differences in Virulence and Development of
Encephalitis During Chronic Infection with the Strain of Toxo-
plasma gondii. The Journal of Infectious Diseases, volume 159,
number 4, pages 790-794, April 1989.
Hajime,S and Haruaki, T. Therapeutic Efficacy of Liposome-
Entrapped Rifampin against Mycobacterium avium Complex Infection
Induced in Mice. Antimicrobial Agents and Chemotherapy, volume 3,
number 4, pages 429-433, April 1989.
(1) People often derive therapeutic companionship from pets and
do not need to choose between staying healthy and having a pet. A
San Francisco organization, Pets Are Wonderful Support (PAWS),
acknowledges the value of a pet while encouraging people to
observe precautions which minimize the risk of contracting infec-
tions from an animal. To receive their Safe Pet Guidelines, write
to PAWS, P.O. Box 460489, San Francisco, CA 94146.
STATEMENT OF PURPOSE
AIDS TREATMENT NEWS reports on experimental and complementary
treatments, especially those available now. It collects informa-
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physicians, and other health practitioners, and persons with AIDS
or ARC.
Long-term survivors have usually tried many different treatments,
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does not recommend particular therapies, but seeks to increase
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zheng herbal therapy, DNCB, aerosol pentamidine, fluconazole,
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Copyright 1989 by John S. James. Permission granted for non-com-
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