Subject: Ribavirin; Peptide T, Toxoplasmosis, AZT
Date: Feb  6 1989 944 lines

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 TREATMENT ISSUES -- The GMHC Newsletter
     of Experimental AIDS Therapies
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Volume 3 Number 1 February 6, 1989


[Footnotes are enclosed in triple quotation marks:  ((()))]

In this issue:

Ribaririn
Peptide T
Toxoplasmosis
AZT Update
New Studies
In Brief


Ribavirin

by Don Shewey

     Ribavirin is a relatively new antiviral that has significant,
reproducible activity against a wide variety of DNA and RNA viruses
((( Huffman JH et al.  In vitro effect of 1-B-D- Ribofuranosyl-1,2,4-
Tirazole-3-Carboxamide (Virazole ICN 1229) on deoxyribonucleic acid
and ribonecleic acid viruses.  Antimicrob Ag Chemother 3:235, 1973.)))
It was developed in 1972 at the Nucleic Acid Research Institute in
Costa Mesa, CA, which is jointly owned by Eastman Kodak and the ICN
Pharmaceuticals, a subsidiary of Viratek Inc. Ribavarin has been
approved by the FDA for treatment of respiratory syncytial virus
disease in infants.  It has been approved for use in much of the Third
World as a treatment for Hepatitis A, herpes, and influenza; in Cen-
tral Africa, it has been used successfully to treat Lassa fever.  It is
sold over the counter in Mexico and is available in pill form in 17
countries.  ((( CDC AIDS Weekly, Feb. 9, 1987, p.4.)))  As a treatment
for AIDS, ribavirin has been studied for several years with incon-
clusive results.  Several studies are ongoing.

How it Works

     Ribavirin was one of the first synthetic broad-spectrum antiviral
agents ever created.  Antiviral drugs are much more difficult to find
than antibacterial drugs because of the difference between bacteria
and viruses.  A bacterium is a living cell capable of surviving and
repoducing on its own.  It is relatively easy to find a drug that
interferes with the workings of a bacterium without greatly affecting
the working of cells in the human body.  A virus, however, to repro-
duce itself, must first infect a living cell and use that cell's
biochemical machinery.  Any drug, therefore, that interferes with the
working of a virus runs the danger of interfering with the normal
workings of the host cell.  Ribavarin, however, can be given in large
doses with few side effects.

     Early research on ribavirin revealed that the range of its
antiviral activity is wide.  Unlike other antivirals, development of
ribavirin-resistant virus strains has not been demonstrated.  Cell
cultures treated iwth ribavirin show a decreased yield of infectious
virus and contain less viral antigen, suggesting that ribavirin inhi-
bits replication of the virus at an early stage, before the accumula-
tion of viral antigens within cells.  ((( Jahrling PB et al.  Lassa
virus infection in rhesus monkeys:  pathogenesis and treatment with
ribavirin.  J Infect Dis 141:580-589.)))  It was originally thought
that ribavirin didn't concentrate adequately in the central nervous
system to combat viruses causing encephalitis, which led to the search
for derivatives more likely to penetrate the blood-brain barrier.  
((( Canonico PG. Ribavirin, a review of efficacy , toxicity and mechan-
isms of antiviral activity.  In Hahn FE, ed.  Antibiotics Vol VI:  Modes
and Mechanisms of Microbial Growth Inhibitors.  Berlin:  Springer-
Verlag, 1983.)))  The senelium analogue, called selenazole, is excep-
tionally active against a broad range of viruses, seems to be syn-
ergistic with ribarivin, and crosses the blood-brain barrier, raising
the possibility that it might be successful in treating encephalitic
viral illnesses.  ((( Canonico PG, et al.  In-vivo activity of
antivirals against exotic RNA viral infections.  J Antimicrob
Chemother 14:  Suppl. A, 27-41, 1984.)))  However, more recent studies
assert that ribavirin does cross the blood-brain barrier, and that
significant concentrations of the drug are found in cerebrospinal
fluid after prolonged administration.  ((( Crumpacker C et al.
Ribavirin treatment of the acquired immunodeciency syndrome (AIDS) and
the acquired-immunodeficiency-syndrome-related complex (ARC).  Ann
Intern Med 107:664, 1987.)))

     It appears that ribavirin also has immunoregulatory functions.  At
lower concentrations, it seems to stimulate immune reponses.  When the
concentration of the drug is increased, it appears to inhibit immune
response, depending upon the time the agent is administered relative
to the appearance of foreign substances in the blood and the dose
used.  ((( Jolley WB et al.  Effects of ribavirin on the immune system
(Second Report).  In Smith RA, et al., eds,.  Clinical applications of
ribavirin, Orland:  Academic Press, 1984.)))

Experimental History

     When ribavirin was first developed, it was shown to inhibit the
viral effects of herpes (types 1 and 2) and CMV (cytomegalovirus) in
vitro.  The drug was effective when applied topically to herpes and
vaccinia virus-induced eye infections in rabbits locally, and it has
also been reported to inhibit various forms of cancer in mice.  The
greatest efficacy was seen when therapy was begun early in the infec-
tion.  ((( Sidwell RW et al.  Effect of 1-B [beta]-D-Ribofuranosyl-
1,2,4- Triazole-3-Carboxamide (Ribavirin) on Friend leukemia virus
infections in mice (38647).  Proc Soc Exp Biol Med #854, 1975.)))  In
the search for effective chemotherapy against a number of exotic
viruses threatening to become epidemic in Africa, Latin America,
Europe, and Northern Asia -- such as Rift Vally Fever virus, Hantaan
virus, and Lassa fever -- several hundred compounds have been tested,
and none has been more efficacious than ribavirin.

     Administered by aerosol mist, ribavirin was shown to be effective
in treatment of respiratory virus infections as well as influenza A
and B. ((( Canonico PG, et al.  Hematological and bone marrow effects
of ribavirin in rhesus monkeys.  Tox Appl Pharmacol 74:163, 1984.)))

Side Effects

     By 1980, ribavirin has been administered to over 1000 human sub-
jects in various clinical trials.  Early studies evaluating the drug
for treatment of cancer and other malignancies indicated that it was
well tolerated by adult patients at dosages approaching 3300 mg/day
for 7 days.  At a very high dosage (3900 - 12,600 mg/day) a decline in
blood hemoglobin levels was seen by days 7-13 of treatment.  ((( Fer-
nandez H. Ribavirin:  a summary of clinical trials - herpes genitalis
and measles.  In Smith RA and Kirkpatrick W, eds., Ribavirin:  A Broad
Spectrum Antiviral Agent, Nw York:  Academic Press, 1980.)))
     The cancer studies were among the first human trials.  All subse-
quent studies have used lower doses of the drug -- 400 to 800 mg/day
for 10 days or 1000 mg/day for 5 days.  Data indicated that ribavirin
can be administered at 600 mg/day for 28 days without significant
adverse effects.  It was shown to cause a mild dose-related decrease
in circulating red blood cell mass, which is reversible when treatment
is discontinued.  Even at the highest doses, the total RBC lost is so
small that there is no symptomatology attributable to anemia.

History with AIDS

     In December 1984, a federal government announcement that ribavi-
rin was effective against HIV in vitro attracted considerable atten-
tion.  ((( McCormick JB et al.   Ribavirin suppresses replication of
lymphadenopathy-associated virus in cultures of human adult T-
lymphocytes.  Lancet, Dec. 15, 1984, p. 1367.)))  By early 1985,
flyers were circulating in the AIDS treatment underground describing a
combination treatment of 1800 mg/day of ribavirin and 1500 mg/day of
isoprinisine (an immune system booster), five days on and five days
off.  The concept of combining antiviral and immune-boosting drugs was
credited to Dr. John Hadden, an immunopharmacologist from Tampa,
Florida, whose unpublished paper proposing the use of two (unspeci-
fied) drugs to treat AIDS was widely circulated.

     Physicians seemed to have hit upon ribavirin and isoprinisine as
the drugs to use because they were the oldest, safest, and most
thoroughly studied drugs of their kind; their only side effects were
temporary and mild.  Sensational reports abounded, such as that of a
59-year-old PWA, thought to be on his deathbed, who was able to leave
intensive care after two days on this regimen; on the fifth day he
went home and eventually returned to work.  ((( Burke P. Doctors hope-
ful of AIDS "Cure."  New York Native, Sept. 9, 1985, p. 10.  Reprinted
from Update, August 21 1985.)))

     In a study conducted at four medical centers during eight months
of 1986, 163 patients with lymphadenopathy syndrome (LAS) received
either 800 mg, 500 mg, or a placebo each day.  Of the 52 who received
800 mg, none developed AIDS; of 55 who received 500 mg, 6 contracted
AIDS; 10 of those on the placebo contracted AIDS.  Around the same
time, Dr. Luc Montagnier in Paris reported using ribavirin to treat
adults and children with AIDS, with good results.  Another study in
Boston around the same time, led by Dr. Clyde Crumpacker, treated AIDS
and ARC patients with ribavirin.  Of the 14 people with AIDS who com-
pleted the trial, three had a return of some skin-test reactivity (a
measurement of immune function) after previously having been anergic
(non- reactive).  Many of them were anemic at initiation of treatment
but were nevertheless able to complete eight weeks of treatment with
ribavirin.  (These findings were in contrast to those of AZT, in which
anemia and neutropenia were commonly noted side effects.)  The three
ARC patients who survived after six months reported no opportunistic
infections; all gained weight and had fewer skin eruptions, and one
had complete resolution of oral candidiasis (thrush).  In further tri-
als, some required monthly transfusions.

     Meanwhile, in the active AIDS treatment underground, there were
anecdotal reports of ribavirin use, as people with AIDS traveled to
Mexico to acquire semi-llegal supplies of the drug not yet approved by
the FDA for use in treating AIDS.  People were reportedly taking ini-
tial doses of 1200 to 2400 mg/day for 3 to 7 days, followed by mainte-
nance dose of 600 to 1800 mg/day for extended periods.  (FDA trials
were using an initial dose of 2400 mg/day for 5 days and then 600 to
800 mg/day thereafter.)  Some reported converting to "negative" on
viral culture at 1200 mg/day, with mild anemia; significant anemia was
reported in dosages between 1200 and 2400 mg/day.  There were patients
who reported no significant side effects while taking 1800 mg/day,
though a few reported problems at dosages as low as 600 mg/day.

     After the manufacturer made its much-publicized announcement
about ribavirin as a promising treatment for AIDS in January 1987,
however, the drug's reputation took a dive.  The New York Times
reported that the company's claims were being greeted with some skep-
ticism because of a history of unsupported statements.  In 1986, the
FDA had ordered Viratek to change publicity material about the value
of ribavirin in treating a lung ailment in infants because it con-
tained "false and misleading" information that "grossly exaggerated"
the drug's effectiveness.  Initial reports of a follow-up study indi-
cated that ribavirin had done poorly; another trial involving ARC
patients suggested that the drug had little or no beneficial effect.
Two Congressional committees were investigating whether the company
had failed in the past to report adverse reactions to ribavirin.  
((( Boffey PM. Experts find lag on testing drugs in AIDS patients.  
New York Times, April 12, 1987, p.1.)))

What Now?  

     In the two years since then, very little has come out about
ribavirin.  It was tested in combination with other nucleoside analogs
and shown to be synergistic with two (including DDA) but antagonistic
with four (including DDC).  ((( Ribavirin enhances DDA inhibition of
HIV, in vitro study shows.  CDC AIDS Weekly, Nov. 30, 1987, p.4.)))
Ribavirin had previously been shown to be antagonistic with AZT and
synergistic with foscarnet.  At the moment there are two Phase I tri-
als underway, one run by Dr. Juan Lertora at Tulane University in New
Orleans and a multicenter trial headed by Dr. Clyde Crumpacker at Har-
vard.  In addition, the NIAID is running a phase I/II trial on ribavi-
rin and isprinosine in asymptomatic HIV patients at George Washington
University.  In the meanwhile, Ribavirin is still available in Mexico,
and thanks to new FDA regulations need not be smuggled.

PEPTIDE T

     With the possible exception of AZT, no potential AIDS therapy has
generated debate as intense as that surrounding Peptide T, a drug
developed in 1986 by neuropharmacologist Candace Pert and associates
at the National Institute of Mental Health (NIMH) in Bethseda, Mary-
land.  Unfortunately for those most in need, the debate -- now nearly
two years old has had the opposite effect of speeding the process of
understanding if Peptide T is an effective treatment against HIV. On
the contrary, it highlights the potential negative consequences of
scientific competition on drug development and reveals how politics
can adversely affect the speed with which new ideas run the obstacle
course described by some as the "race" to cure AIDS.  

Background

     The discovery of Peptide T was the result of two separate
research efforts.  The first conducted several years ago by Dr. Robert
Gallo and others at the National Cancer Institute, yielded the
knowledge that AIDS, in addition to being an immune disorder, also has
a distinct neuropsychiric component including symptons such as demen-
tia, memory loss, and other cognitive deficiencies.  The second, led by
Dr. Pert, explored the complex interaction between the brain and the
immune system, and found that both share some neuropeptides (strings
of amino acides that serve as chemical signals between cells) and
receptors (proteins that receive and interpret these signals), one of
which is CD4 , the HIV receptor.  (((Dalgleish AG et al.  The CD4
antigen is an essential component of the receptor for the AIDS retro-
virus.  Nature 312:  763, 1985.;  Pert CB et al.  Octapeptides deduced
from the neuropeptide receptor-like pattern of antigen T4 in brain
potently inhibit HIV receptor binding and T-cell infectivity.  Proc
Nat Acad Sci USA 83:  9254, 1986.)))

     Pert found that the pattern of CD4 receptors in the brain coin-
cided with the receptor patterns of many naturally occuring brain pep-
tides and theorized that a peptide with an amino acid structure simi-
lar to a portion of HIV must therefore exist.  ((( Interview with Can-
dace Pert.  Science Impact, June, 1987, p.6.)))

     Pert's thinking was that flooding the body with copies of this
peptide could block HIV binding to CD4 by occupying the CD4 receptor
site that HIV required to infect cells.  Peptide T was discovered
through a computer search attempting to match know peptide sequences
and the amino acid structure required to infect cells.  It was later
found by Pert that a subset of Peptide T -- the last five amino acides
in the sequence of eight that make up the peptide -- is common to all
known HIV varieties.  ((( Ruff M et al.  CD4 receptor binding peptides
that block HIV infectivity cause human monocyte chemotaxis.  FEBS Lett.
211: 17, 1987 )))  This subset also closely resembles a portion of a
28-amino acid peptide called VIP, or vasoactive intestinal peptide,
which is active in the brain, immune system, and gut.  Pert theorizes
that HIV, VIP and Peptide T all utilize the same CD4 receptor , and
that HIV, in addition to infecting and killing human cells, interferes
with the normal biologic functions performed by VIP. Through adminis-
tration of Peptide T (which, Pert argues, mimics the effects of VIP),
HIV is unable both to bind with CD4 and to interfere with VIP func-
tioning.

Clinical Trials and Controversy

     The painfully long story of Peptide T clinical testing starts
back in 1986, when Swedish researchers tested the drug in four men for
one month.  They found that T4 lymphocyte counts increased during the
test period, that in one patient, psoriasis improved during treatment
and that certain central nervous sytem measurements also improved.  No
toxicity was observed.  ((( Wetterberg L et al.  Peptide-T in treatment
of AIDS.  Lancet, January 17, 1987, p. 159.)))  The study, while
clearly very limited, justified further investigation of Peptide T. 
By the end of 1986, Dr. Frederick Goodwin of the NIMH had applied to
the FDA to begin clinical testing in the Unitted States.  In June,
1987, FDA approval to begin clinical trials had still not been
received though approval appeared imminent.  ((( Dagnani R Controversy
surrounds new AIDS drug called Peptide T. C&EN June 20, 1987, p. 48.
)))  At this time, Dr. William Haseltine of Harvard University
announced at the Washington, D. C. AIDS conference, as well as in a
letter published in the Lancet ((( Sodroski J et al.  HIV envelope-CD4
interaction not inhibited by synthetic octapeptides.  Lancet, June 20,
1987, p. 1428.))) that he was unable to duplicate Candace Pert's in
vitro findings and that in a variety of systems he tested, Peptide T
was found to be completely ineffective against HIV. Furthermore,
several other scientists also saw no in vitro activity against HIV in
independent laboratory tests.  In fact, Pert's most basic research
observation, that a common set of core amino acids is conserved across
all HIV isolates, was challenged.  Some believe that such vocal opposi-
tion to Peptide T prevented it from being tested as part of the
National Institute of Health's AIDS Clinical Trials Group (ACTG) pro-
gram (The National Institue of Mental Health is part of the Alcohol,
Drug Abuse and Mental Health Administration and is not affiliated with
the NIH).  In a letter published by the Lancet in September, 1987,
Pert defended Peptide T's scientific basis.  ((( Ruff M et al.  Peptide
T is core HIV envelope sequence required for CD4 receptor attachment.
Lancet, Sept. 26, 1987, p. 751.)))

     Despite the stormy controversy, the FDA approved Peptide T for
clinical trials, and in November, 1987 a one-month Phase 1 toxicity
trial was conducted in six patients.  The results of this brief trial
were presented at last year's international AIDS Conference in Stock-
holm, and showed that Peptide T (which can be administered both
intravenously and intranasally) improved neurologic functioning in the
patients in which it was tested, who were all classified as minimally
or moderately cognitively impaired at the start of the study.  (((
1988 International AIDS Conference, Stockholm, Sweden, Abstracts 3103,
3105.)))  As noted in the Swedish trial, no toxicity was observed.
In August, 1988, a Phase I dose ranging trial was launched with 24
patients, and is expected to run through next summer.  ((( C. Pert,
personal communication.)))  Also in August, 1988, Bristol Myers Co. 
signed a federal license for exclusive rights to manufacture and
market Peptide T. Bristol Myers is collaborating with the NIMH in the
design of clinical trials and is expected to take over financial
responsibility for Phase II trials.  (((  Smyth D, SF Sentinel, August
26, 1988.)))  In a telephone interview, a Bristol Myers representa-
tive refused to give any indication as to when Phase II trials could
be expected to begin.

     At the time Bristol Myers signed the Peptide T license, research-
ers in Sweden were conductiong a small, double-blind, placebo con-
trolled trial of Peptide T, and reported that patients showed signifi-
cant decreases in HIV activity, improved lymphocyte counts, and
improved brain function.  ((( ditto )))  Unfortunately, the trial was
suspended pending the outcome of negotiations with Bristol Myers on
access to the drug and trial funding.  In separate conversations,
researchers at the NIMH report that recipients of Peptide T have been
experiencing significant improvements in such constitutional symptoms
as diarrhea, night sweats, and weight loss.  They have not, however,
detected improvements in T4 cell counts as a result of Peptide T
administration.  ((( C. Pert, personal communication.)))

Conclusion

     The unfortunate result of these unconnected reports is that
today, well over two years after the first PWA received Peptide T, we
are not much closer to a definitive answer as to the drug's benefits
than we were then.  For a substance that may actually have in vivo
activity against HIV, and which appears to be non-toxic, it is aston-
ishing that more Peptide T clinical testing has not been performed
earlier.  It is not surprising, based on the long delays, that we have
received unconfirmed reports of individuals acquiring "underground"
supplies of Peptide T from domestic and foreign peptide manufacturers
in order to gain access to the drug.  Given the drug's ability to
cross the blood/brain barrier, Peptide T may turn out to be useful as
an adjunctive therapy for neurological manifestations of HIV infec-
tion.  We can only hope that Bristol Myers, holding the exclusive
license to market Peptide T, will work quickly in developing Phase II
trieals, and that the merits of Peptide T itself, and not scientific
competition and politics, will be the only factors affecting the pros-
pects for this potentially valuable drug.


Toxoplasmosis

by Victoria Nott


     Toxoplasmosis is perhaps the most common opportunistic infection
of the central nervous system (CNS).  This ubiquitous but usually
unimportant parasite causes a fulminant encephalitis in immune
suppressed people that can lead rapidly to coma and death.  Available
treatments, which are toxic and often poorly tolerated, must be con-
tinued life-long.  The urgent need for safer and more effective thera-
pies is recognized by leading researchers.  ((( Luft BJ et al.  Toxo-
plasmic encephalitis.  J Infect Dis 157:1, 1988.)))

     A first step in improving treatment options is proving the effec-
tiveness of an already available antibiotic as an alternative to the
sulfa component -- itself standard therapy -- but this frequently pro-
duces an allergic response.  If early results of an ongoing trial are
borne out, clidamycin may be prescribed with equal confidence as sul-
fadiazine.  ((( Dannemann BR et al.  Treatment of toxoplasmic
encephalitis in patients with AIDS:  preliminary report of the Calli-
fornia Collaborative Treatment Group randomized trial of pyrimethamine
plus sufonamides versus pyrimethamine plus clindamyin.  Abstracts of
the 1988 ICAAC, #562.)))

Background

     Before the recognition of AIDS, toxoplasmic encephalitis was
rare, even in immune suppressed cancer patients.  Toxoplasmosis was
mainly important as a congenital infection sometimes causing blindness
or retardation in children whose mothers became infected during preg-
nancy.  ((( McCabe R et al.  Toxoplasmosis:  The time has come (Edi-
torial).  N Engl J Med 318:313, 1988.)))  Toxoplasma gondii is a pro-
tozoa that lives quietly in countless animals and hundreds of millions
of people worldwide.  Antibodies to T. gondii have been found in up to
50% of surveyed populations in the United States and up to 90% in
France.  Most infections are asymptomatic although a mild self- lim-
ited illness with swollen glands can occur.  The cysts develop within
all kinds of mammalian tissue, most commonly in the brain, eye, heart,
and skeletal muscle.  Each cyst contains and may release thousands of
larvae (tachyzoites), the invasive form responsible for tissue damage
and acute illness.  The cysts are more durable and resistant to
environmental conditions and drugs, and thus important in transmission
and persistence of latent disease.

     The organism is associated with cats because the mature oocyst
lives only in cats' intestines.  Oocysts excreted by cats undergo
sporulation 1 to 3 weeks after excretion and they become infectious at
that time.  The organism survives in the soil and goes into the food
chain.  Most human infections are believed to occur from eating under-
cooked meat.  Although new infection is possible, most toxoplasmosis
in AIDS patients represents activation of latent disease as the waning
immune system fails to repress the organism.

Clinical Presentation

     The characteristic presentation of cerbral toxoplasmosis is the
development over the course of a week or two of neurologic problems
such as weakness on one side of the bocy, difficulty walking or speak-
ing, or perhaps seizures, palsies, or vision disturbances.  Equally
common are severe headache, confusion, and lethargy that may progress
to stupor or coma if treatment is not promptly started.

     Navia and associates ((( Navia BA et al.  Cerebral Toxoplasmosis
complicating the Acquired Immune Deficiency Syndrome:  clinical and
neuropathological findings in 27 patients.  Ann Neurol 19:224, 1986.)))
found persistent fever accompanied nervous system symptoms in 15
of their series of 27 patients, and 15 had severe headaches.  Two
patients had behavioral disturbances (1 a paranoid psychosis and the
other increased anxiety).  Impairment of recent memory and slowness to
respond, indistinguishable from that seen in AIDS dementia, was noted
in 18 of the 27 at some time during their illness; in 9 patients these
developed before toxoplasmosis symptoms and in 9 they developed or
progressed after successful treatment for toxoplasmosis.

Diagnosis

     Computed tomographic (CT) scans will demonstrate at least some of
the brain abscesses in most patients.  Contrast studies (a CT scan
taken after the injection of dye) will usually show the characteristic
rings around the lesions, depicting the area of inflammation surround-
ing the abscess.  Magnetic resonance imaginmg (MRI) may detect lesions
that do not show on CT scans.  Luft and Remington advise MRI be per-
formed in HIV patients seropositive for T. gondii who have neurologic
signs and symptoms but a negative CT scan.

     Almost all patients will have antibody to toxoplasma in their
blood, showing exposure to the organism.  But they may have only low
concentrations of antibody instead of the rapidly rising levels usu-
ally seen during an acute infection.  Detection of these antibodies in
the spinal fluid may be helpful in establishing a diagnosis in puz-
zling cases without having to do a brain biopsy.

     The only means of definitive diagnosis for cerebral toxoplasmosis
so far is by recovering the organisms in brain tissue taken from a
successful biopsy.  Both the neurologic signs and symptoms and the
lesions seen on scans could be caused by lymphoma, Kaposi's sarcoma,
or a variety of infections.  But patients are usually subjected to
biopsy only if there is a strong reason to suspect another cause or if
a trial of medication fails to produce any improvement.

Treatment

     Standard treatment for toxoplasmosis consists of a combination of
pyrimethamine and sulfadiazine, or another sulfa drug.  Either drug
alone is not sufficient treatment.  Pyrimethamine (Daraprim, Burroughs
Wellcome) is anti-malarial.  The effective dose for toxoplasmosis is
10 to 20 times that for malaria, approaching toxic levels.  Adverse
reactions include loss of appetite and nausea, lowered white cell
count, some types of anemia, and possible central nervous system toxi-
city including convulsions.  Folinic acid (leucovorin) is usually given
to counteract the toxic effects on the blood.

     Most patients respond within 2 weeks, and often within a few
days, showing clinical improvemnt and shrinkage of brain lesions on
repeat scan.  Good response is less likely when treatment is begun
after a patient has become lethargic or unconscious.

     The initial response rate is high, but the drugs kill only the
free trphozoites, not the encysted organisms.  When medication is
stopped, the cysts grow again and release new organisms, so the medi-
cation -- usually at half-dose -- must be continued for the rest of
the patient's life.  ((( Leport C et al.  Treatment of central nervous
system toxoplasmosis with pyrimethamine/sulfadiazine combination in 35
patients with the Acquired Immunodeficiency Syndrome:  efficacy of
long-term continuous therapy.  Am J Med 84:94, 1988. )))  There is a
high incidence of side effects, mainly low white count, fever and
severe rash.

     Leport and associates noted side effects in 25 t0f 35 patients
treated but said the combination had to be discontinued in only 2
patients and sulfadiazine stopped in 8.  Toxicity was reported in 35
of 57 patients in another series.  ((( Haverkos HW. Assessment of
therapy for toxoplasma encephalitis.  Am J Med 82:907, 1987.)))

     Sulfadiazine can form crystals in the kidneys if adequate fluids
are not taken, causing blockage and kidney failure.  ((( Sahai J et
al.  Sulfadiazine-induced crystalluria in a patient with the Acquired
Immunodeficiency Syndrome:  a reminder.  Am J Med 84:791, 1988  )))
This is a consideration in treating outpatients who are in poor condi-
tion and may have little supervision.  A more soluble sulfonamide
could be substituted; however, many AIDS patients cannot tolerate sul-
fonamides at all, leaving them on the often ineffective single-drug
therapy.

     Clindamycin (Cleocin, Upjohn) has been substituted on a word-of-
mouth basis, with scattered reports of its effectiveness appearing in
the literature.  ((( Rolston KV et al.  Role of clindamycin in the
treatment of central nervous sytem toxoplasmosis.  Am J Med 83:551,
1987 )))  Dannemann collected and analyzed 15 cases and found clin-
damycin had been used successfully against toxoplasmic encephalitis in
a variety of situations.  ((( Danneman BR et al.  Treatment of toxo-
plasmic encephalitis with intravenous clindamycin.  Arch Intern Med
148:2477, 1988 )))  Patients received high dose intravenous clin-
damycin with pyrimethamine as primary or alternative therapy, usually
because of sulfa intolerance.  Oral clindamycin was also used as
suppressive thereapy.  Most patients improved after receiving clin-
damycin, including some who responded poorly to standard therapy.
Clindamycin was said to be well tolerated despite high doses and pro-
longed use.  Several instances of diarrhea and skin problems were
noted, but none were severe enough to warrant discontinuing treatment.

     Clindamycin carries a manufacturer's warning against possible
serious diarrhea dn colitis.  Slight rash is listed as the most common
side effect.  Clindamycin has been shown effective in mouse and rabbit
models of the disease, but how it works is not well understood, since
it is not active against T. gondii in the test tube and has no clear
affinity for the central nervous system.  It is currently believed
that some as yet unidentified metabolite of clindamycin may be respon-
sible for its activity against T. gondii in animals and people.  
((( Israelski DM et al.  Ex vivo activity of clindamycin against Toxo-
plasma gondii.  Abstract of the 1988 ICAAC, #1228.)))

     A controlled trial comparing pyrimethamine plus sulfonamide with
pyrimethamine plus clindamycin is now in progress.  Early results sug-
gest the two regimens are equally efficacious in the treatment of tox-
oplasmic encephalitis.  ((( B. Dannemann, personal communication )))

     German researchers reported in Stockholm that a regimen of
pyrimethamine plus clindamycin plus spiramacin was effective in about
80% of patients.  ((( Pohle HD et al.  CNS Toxoplasmosis in AIDS
patients.  Incidence and results of treatment with pyrimethamine and
macrolide antibiotics.  Abstracts of the Stockholm conference on AIDS,
June 1988, #7076.)))  Spiramycin, which is not available in the
U. S., has been used in Europe, especially in prenatal toxoplasmosis.
It is believed to be ineffective in preventing relapses.

     Slowing or halting the deterioration of the immune system is of
course preferable to treating only the symptoms of opportunistic
infections.  Most information on the survival of AIDS patients with
toxoplasmosis is pre-AZT.  But evidence now suggests that taking AZT
prolongs the lives of people who have been diagnosed with toxo-
plasmosis.

     Results of a Belgian study presented in Stockholm last June
showed that AZT was assopciated with increased survival in 25 AIDS
patients who had been diagnosed with cerebral toxoplasmosis.  ((( Her-
mans P et al.  The benefit of zidovudine in the treatment of AIDS
patients with cerebral toxoplasmosis.  Abstracts of the Stockholm
conference on AIDS, June 1988, #3667.)))  Seventeen of the 25
received only pyrimethamine and sulfadiazine.  They survived a median
of 165 days, compared to a median survival of 367 days for the 8
patients who received AZT in addition to the standard toxoplasmosis
regimen.  Only 8% of the first group survived one year, compared to
41% of the patients who also took AZT.  The authors assert the combi-
nation of toxoplasmosis drugs and AZT was "well tolerated."

Experimental Treatments

     Trimetrexate, an experimental drug that is used to treat PCP, was
reported to be highly effective against Toxoplasma in the test tube.
((( Kovacs JA et al.  Potent effect of trimetrexate, a lipid-soluble
antifolate, on Toxoplasma gondii.  J Infect Dis 155:1027, 1987.)))
Trimetrexate has since been tried in several patients, but has not
shown sustained effectiveness.  It is no longer activeloy being inves-
tigated as a treatment for toxoplasmosis.  At this point, there are no
new protocols for toxoplasmosis therapies through the NIH clinical
trials program.  ((( J. Kovacs, personal communication  )))

     New therapies that may hold promise are some experimental antibi-
otics and synthetic reproductions of certain substances secreted by
the immune system (gamma interferon and interleukin).  Gamma may be
especially important as a stimulant of an immune response to T. gon-
dii.  ((( Suzuki Y et al.  Interferon-gamma:  the major mediator of
resistance against Toxoplasma gondii.  Science 240:516, 1988.)))
Animal studies of these substances, alone or with experimental antibi-
otics such as roxithromycin, have had promising results.  One other
promising class of drugs mentioned by Luft and Remington in their AIDS
Commentary is the purine analogs.  Arprinocid, an antibiotic used in
veterninary medicine, should probably be tested in humans.  We will
present more informaton about toxoplasmosis treatments as it becomes
available.

AZT Update

     The largest trial of AZT to date has confiremed that this
antiviral increases survival dramatically.  More than 4000 post-PCP
patients who enrolled in the trial were evaluated; after 44 weeks of
treatment, 73% of the participants were still alive.  ((( Creagh-Kirk T
et al.  Survival experience among patients with AIDS receiving zidovi-
dine.  JAMA 260(20),3009, 1988 )))  Survival was even higher in
patients who began treatment with higher levels of hemoglobin and ini-
tiated treatment within 3 months of their PCP episode.  These findings
bolster the growing body of data that suggest that earlier interven-
tion with AZT is beneficial.  Adverse reactions largely mirrored what
has already been seen with this drug.  However, authors claim that
this is not an appropriate study from which to draw strong conclusions
about AZT's toxicity, due to the fact that adverse effects were not
uniformly reported by the large number of participating physicians.
We are told that roughly 20% of patients received transfusions, and
that 11.4% experienced "serious" anemia.  White blood cell depletion
was reported in 8.3%.  While this study leaves questions about the
long-term use of AZT unanswered, it would be irresponsible to dismiss
the significant increase in survival as compared with historical con-
trols (i.e. groups of patients who had no antiviral treatment).  This
trial is convincing proof of AZT's therapeutic value.s

     Another smaller study reported in the Lancet corroborated the
survival statistics cited in the first study, but raises some ques-
tions about sustained clinical improvement after 6 months of treat-
ment.  ((( Dournan E et al.  Effects of zidovidine in 365 consecutive
patients with AIDS or AIDS related complex.  Lancet, Dec. 12, 1988, p
1297.)))  A total of 365 patients received AZT for an average of 31
weeks.  Roughly one-third of the patients (105) were started on half
dose (600 mg/day) due to low blood counts, and the balance took full
dose.  For patients on full dose who developed hemotological toxicity
(anemia or low white counts), dosage was reduced to half.  Researchers
noted steady improvement, as measured by weight gain, T4 cell
increases and other laboratory parameters, up to the fifth month.  It
is interesting to note that patients on half dose and larger increases
in T4 counts up to the sixth month, after which most people's counts
returned to baseline (pre-treatment level).  ARC patients' T4 counts
did not settle back to baseline until the eighth month, underscoring
the advantage of early treatment.  The distressing news from this
study is that patients' clinical condition tended to deteriorate after
peaking between months 3 and 4.  Survival at 9 months was 75%; roughly
equivalent to the findings of the first study.

     Some strong evidence that AZT has a positive effect on HIV-
related neurological conditions has been published.  ((( Schmitt FA et
al.  Neuropsychological outcome of zidovidine (AZT) treatment of
patients with AIDS and AIDS-related complex.  NEJM 319(24):1573, 1988.
)))  In a paper printed in New England Journal of Medicine, research-
ers reported on neurological improvement in 134 patients who received
AZT as compared to 128 who received placebo.  Improvement was measured
by comparing patients' pre and post-treatment performance on neurop-
sychological tests examining such skills as verbal memory, visual
attention and motor abilities.  Patients were only followed for 16
weeks, so this study does not tell us much about long term use of the
drug.  However, a smaller study followed 7 patients with neurological
disease for up to 18 months.  ((( Yarchoan R et al.  Long-term
administration of AZT to patients with AIDS-related neurological
disease.  Ann Neuro supp. to vol. 23:S84, 1988.)))  AZT was found to
penetrate the cerebrospinal fluid in all 4 patients with HIV-related
dementia.  These patients improved for an average of 6 months.  Of the
remaining 3 patients, one with paraplegia stopped treatment after 3
weeks due to severe, progressive KS; another improved 4 months before
interrupting treatment due to nausea and vomiting and the last had
sustained improvement after 18 months of treatment.  This study seems
to indicate that AZT is a useful short-term treatment for HIV-related
dementia, but that prolonged courses of AZT for neurological disease
do not appear overly promising.

     Considering the blood-related toxicity that is normally associ-
ated with AZT, one small placebo-controlled, cross-over study of AZT
as  a treatment for low platelet counts (thrombocytopenia) had some
interesting findings.  ((( Hirschel et al.  Zidovudine for the treat-
ment of thrombocytopenia associated with HIV. Ann Int Med 109(9):718,
1988.)))  The 10 participants, were HIV-positive and did not have an
AIDS or ARC diagnosis.  They alternated between 8 weeks of AZT and 8
weeks on placebo.  All participants had increases in platelet counts
while on drug but not while on placebo.

     The debate about AZT continues to erupt with the vehemence of
zealotry.  Skeptics point to early data and claim that the first
results were fudged.  While there may be some legitimate reasons to
criticize the original Phase II trial, the preponderance of evidence
to date is irrefutable.  Publications that claim otherwise are soing
confusion and performing a monumental disservice to the PWA community.
AZT is no magic bullet, but it clearly slows the progression of HIV-
related disease and improves the quality of life for the vast majority
of patients who take it.  We eagerly await results of trials examining
lower doses of the drug and studies that combine AZT with other drugs
that enhance its antiviral activity.

New Studies

     Two interesting studies of GMCSF, a drug that stimulates produc-
tion of certain white blood cells are opening in New York.  The Erie
County Medical Center, in Buffalo, is recruiting for a Phase 1
(safety) trial combining GMCSF with AZT, a drug that depletes white
blood cells.  Participants must be mildly neutropenic with an AIDS or
advanced ARC diagnosis.  They must have taken AZT for at least 8 weeks
prior to enrollment, and have not had any dose reduction for the pre-
vious 4 weeks.  Trial duration is 8 weeks and does not require hospi-
talization.  It is recommended that patients stay in the Buffalo area
for the course of the trial; room and board will be arranged based on
ability to pay.  The study is being sponsored by the NIH. For further
information call Maureen Maliszewski, R. N. at (716) 898-4119.

     Researchers at NYU Medical Center will begin recruiting soon for
a trial combining GMCSF with Ganciclovir, a drug that is used to treat
CMV retinitis and, like AZT, causes depletion of certain white blood
cells.  Patients must have a diagnosis of CMV retinitis and be neutro-
penic.  The study will last for four months.  While everyone will
receive Ganciclovir, patients will be randomized to GMCSF or placebo.
It is not necessary to be hospitalized, but patinets will be monitored
weekly for progression of retinal CMV lesions.  REsearchers plan to
add AZT to the protocol at a future date.  This study should provide
some information about the compatibility of AZT and maintenance Ganci-
clovir, while protecting white cell counts.  Participants will be
given access to GMCSF after the trial is completed.  For mor einforma-
tion, patients' physicians should call the NYU Cancer Center at (212)
340-6485.

     New York Hospital-Cornell Medical Center is actively recruiting
for the following studies:

     1.  Researchers will attempt to shed some light on the issue of
primary prophylaxis against PCP (i.e. preventing a first case of PCP)
in patinets at high risk for this pneumonia.  Candidates must have
fewer than 200 T4 cells.  This study will compare AZT alone and AZT in
combination with Bactrim, Dapsone (both sulfa- based drugs) or aero-
solized pentamidine.  Since some participants in this study will not
get any prophylactic treatment, all patients should carefully watch
for and immediately report any symptoms of PCP:  dry, hacking cough,
shortness of breath and fever are the most common.  This study will
run for one year.

     2.  Another study in the same vein will compare AZT in combinaton
with Bactrim, Fansidar (another sulfa-based drug) or aerosolized pen-
tamidine following a first episode of PCP.  Patients with a history of
intolerance to sulfa medications are not eligible.  Since many HIV-
infected persons are allergic to sulfa medications, it will be useful
to know how aerosolized pentamidine stacks up against them in prevent-
ing a first bout with PCP.  Everyone in this study will get some PCP
preventive treatment in addition to AZT.  The duration of the study is
one year.

     3.  A new, promising antiviral, d4T, will be available through a
Phase I study.  The purpose of this study is to see how people
tolerate the drug, in escalating doses.  This drug has been found to
be more effective than AZT in the test tube, and less toxic.  Partici-
pants must have fewer than 400 T4s, must not have taken AZT for one
month before beginning the trial, or Ribavirin for three months
before.  Any patient who has experienced serious hemotological toxi-
city to AZT is not eligible.  Candidates should be aware that this
drug has never been tested in people before.  They will have to be
hospitalized for at least one week, for close monitoring.  The study
will last for 10 weeks, and there is no guarantee of future access to
the drug.

     4.  Finally, New York Hospital will recruit patients admitted
with cases of cryptococcal meningitis into an open-label study of Flu-
conazole.  Patients who do not respont to this drug will be switched
to amphotericin B, the other, more toxic treatment available for cryp-
tococcal meningitis.  A maintenance study comparing these two drugs
will also be recruiting patients with meningitis past the acute stage.

     For more information about any of these studies at New York
Hospital-Cornell Medical Center, call (212) 746-4177.  Some of these
same studies are also recruiting at Universaty Hospital in Stony
Brook, N. Y. It may be more convenient for Long Island residents to
travel to Stony Brook to participate in a clinical trial rather than
commuting to New York City.  For more information about these and
other trials at Stony Brook, call the research nurse at (516) 444-
1659.

     The long awaited trial of CD4 will soon start recruiting in New
York.  Contrary to what we reported in Vol. 2, No. 8, only one study
will be opening up, at NYU Hospital.  This will be a Phase I-II that
will begin by examining safety, then start accumulating data on the
drug's effectiveness.  The criteria will be fairly tight; participants
must have fewer than 300 T4 cells, and must not have received prior
AZT therapy.  The largest pool of eligible patients will probably be
newly diagnosed PWAs or PWARCs.  Participants will be randomized to
one of 4 arms:  full dose AZT, half dose AZT, CD4 plus full dose AZT or
CD4 plus half dose AZT.  Anecdotal reports about the drug continue to
be positive.  Recent animal studies of CD4 against SIV, a virus simi-
lar to HIV, demonstrate the drug's ability to clear infection of that
virus from animals' blood stream.  We anxiously await more, larger
trials of this promising antiviral in New York.

In Brief

     Ganciclovir:  The war rages on concerning the new trial of Ganci-
clovir, which the FDA has demanded.  (For more information about this
drug, see our article on CMV in vol. 2 no. 8.)  Despite the fact that
over 5000 patients have been helped by the drug, and the beneficial
effects are clear, FDA wants a study that has a "placebo" group
(patients will know immediately whether they are on "placebo" because
they will receive no treatment other than AZT).  Only patients whose
eyesight is in imminent danger will be given the drug compassionately.

     There is understandably great anxiety from patients and physi-
cians alike -- and there seems to be no way of reversing this deci-
sion.  Even a top researcher at NIH has said that the trial is "ridi-
culous" and the "the FDA should go ahead and approve the drug."

     In the near future, many patients whose eyesight is in jeopardy
will be told they will receive no treatment for CMV retinitis.  There
is only one alternative that we know of:  Ganciclovir is available by
prescription in England and probably other countries as well.  Putting
patients' eyesight on the line is a high price to pay to obtain data
which will prove the obvious.

     Nebulizers:  New York State Department of Medicaid recently
effected a policy change regarding reimbursement for nebulizers that
will cost lives.  Good nebulizers, priced between $200-400, are beyond
the financial reach of many indigent PWAs.  Referring to aerosolized
pentamidine's "experimental" status, Medicaid reversed an earlier
decision to pay for the equipment necessary for the administration of
this life-saving preventive treatment.  Aerosolized pentamidine is the
only alternative for people who are allergic to the sulfa-based treat-
ments that are also used to prevent PCP. The effectiveness of this
specific treatment, and prophylactic therapy against PCP in general
has been documented (see Treatment Issues, vol. 2 no. 6).  GMHC is
working very hard with numerous other AIDS service organizations to
convince Medicaid  to reverse this short-sighted decision.  As we go
to press, a reversal of this policy is anticipated.

     FLT:  Swedish researchers have released data on a new antiviral
that works 4-5 times better than AZT in the test tube.  Fluorinethymi-
dine (FLT) has also been tested in monkeys, and was found to inhibit
replication of SIV (a virus similar to HIV) more effectively than AZT
does.  The drug, however, is also more toxic than AZT.  Given its aug-
mented potency though, FLT could probably be administered in smaller
doses.  At this point, FLT has not been tested in people.  We will be
reporting on any developments with this antiviral as they become
available.

     Passive Immunotherapy:  This promising new treatment is one of
the only options for PWAs in advanced stages of the disease.  For more
information about this therapy, see Treatment Issues, Vol. 2, no. 8.
Doctors are having trouble making it widely available, however, due to
a lack of antibody donors.  The criteria for donors is somewhat
strict, so we strongly urge all readers who are positive and asymp-
tomatic to come forward and volunteer to help sae somebody's life.
Remeber, there is not potential harm to donors, and possibly some
benefit; one study showed that, six weeks after donating, donors had
antibody levels twice as high as before.  Those interested can call
Dr. Lou Baker at (212) 570-3248.


Other Resources

American Foundation for AIDS Research (AmFAR) has updated their
catalog of trials involving experimental drugs.  The "AIDS/HIV Experi-
mental Treatment Directory" also includes several glossaries and
information about the federal clinical trials efforts and licensing of
drugs.  Write to AMFAR at 40 West 57th St., New York, N. Y. 10019, or
call (212) 333-3118.

"AIDS Treatment News" is a short, biweekly report which chroni-
cles current developments in experimental and alternative treatments
and deals with public policy issues.  Contact John S. James at P. O. 
Box 411256, San Francisco,  CA  94141 or call (415) 282-0110.

"PWA Coalition Newsline", published "by and for people with AIDS
and AIDS Related Conditions," is a grass-roots news magazine that
appears monthly.  The publicaton reports news developments dealing
with the health crisis as well as alternative treatments.  Editorials
and literary contributions add another interesting dimension to this
excellent source of information.  Write PWA Coalition Inc., 263A West
19th Stree., Room 125, New York, N. Y. 10011, or call (212) 627-1810.
Ask about their other publication, "Surviving and Thriving with AIDS".

"ATIN" (AIDS Targeted Information Newsletter) performs a monthly
search of hundreds of medical journals worldwide.  Definitely aimed at
doctors and researchers, it is the best ongoing literature search
available.  It has an impressive cast of editors who comment on the
significance of the studies cited.  Published by Williams & Wilkins,
P. O. Box 23291, Baltimore, MD 21203 or phone 1-800-638-7422.

Body Positive is a new organization established by and for HIV-
antibody-positive people to exchange information, advocate research,
fight discrimination, and provide mutual emotional support.  They pub-
lish a monthly newsletter called "The Body Positive."  Write to:  263A
West 19th Street, New York, NY 10011 or call 212-633-1782.

Northern Lights Alternatives ("NLA") is an organization that was
created to help PWAs channel their energy in positive, healing direc-
tions.  The cornerstone of NLA is a program of weekend retreats called
AIDS Mastery Workshops.  The main goal of these workshops is to teach
NLA's central philosophy:  PWAs can improve the quality of their lives
through self-empowerment.  NLA disseminates material through the
telecommunications network of GayCom.  Anyone with a personal computer
and modem can access this service.  For more information about NLA and
the AIDS Mastery Workshops, contact Chuck Baier or Victor Phillips at
212-877-4846.

"Healing AIDS" is a monthly magazine which focuses on holostic
approaches to AIDS and ARC including diet and nutrition, relaxation
and visualization techniques, and stress reduction.  It regularly lists
other resources.  Subscriptions are $10/year for people with
AIDS/ARC/low income, and $15 for others.  Write 3835 20th Street, San
Francisco,  CA 94114 or Phone:  (415) 821- 7646.

The AIDS Health Project at the University of California San Fran-
cisco publishes a monthly newsletter called "Focus" written "to place
data and medical reports in a context that is meaningful and useful to
its readers."  It provides easy-to-understand practical information
on AIDS research.  Contact UCSF AIDS Health Project, Box 0884 San
Francisco CA 94143 or phone (415) 476-6430.

     Treatment Issues is GMHC's newsletter devoted to providing reli-
able information on experimental AIDS therapies.  Describing an exper-
imental therapy should not be construed as recommending it.  All new
treatments should be done under a physician's care.

     Treatment Issues is published ten times yearly.  Copyright 1988
Gay Men's Health Crisis, Inc.  All rights reserved.  Non-commercial
reproduction is encouraged.  Subscription lists are kept confidential.

	Editor:  Barry Gingell, M. D. 
	Managing Editor:  Kevin Armington.
GMHC, Department of Medical Information, 129 West 20th Street, New 
York, NY 10011.

We Need Your Support

     Your contribution will help GMHC to continue Treatment Issues and
is tax-deductible.  Mail to:  GMHC, Department of Medical Information,
129 West 20th Street, New York, NY 10011.

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