                   AIDS INFORMATION NEWSLETTER
                   Michael Howe, MSLS, Editor
                     AIDS Information Center
                VA Medical Center, San Francisco
                     (415) 221-4810 ext 3305
                        January 12, 1996

                Opportunistic Infections (Part XVII)

                          Toxoplasmosis

[Opportunistic Infections and Related Disorders; From AmFAR's
AIDS/HIV Treatment Directory, Vol. 7, No. 4 (January 1995)]

     PATHOGEN: Toxoplasma gondii, a protozoan which is among the
most prevalent causes of latent infection of the central nervous
system throughout the world. Infection occurs primarily via the
oral route through ingestion of raw or undercooked meat.

     SITES OF INFECTION: Most commonly the brain (cerebral
toxoplasmosis), although other organs can be infected. T. gondii
is the most common cause of focal intracerebral lesions in AIDS
(Wong and Remington).

     SYMPTOMS: Most frequent symptoms include headache, confusion,
and fever. Focal neurologic deficits occur in most patients.

     DIAGNOSIS: Since T. gondii is the most common opportunistic
pathogen of the brain in AIDS patients, the practice of presumptive
therapy for patients with a characteristic finding on CT/MRI (e.g.,
one or more   focal lesions) and positive Toxoplasma serology is
widely accepted. Porter and Sande report that the absence of
detectable antitoxoplasma IgG antibodies does not exclude the
diagnosis. In their retrospectively reviewed series, 4/18 patients
with pathologically proven toxoplasmosis did not have detectable
antitoxoplasma antibodies.
     The risk of developing cerebral toxoplasmosis is greatly
increased in HIV-infected people with CD4 counts below 50/mm3 (Luft
et al.).
     In patients who are treated empirically, a clear clinical
response should be evident within 14 days and there should be a
clear radiographic response of all lesions within 3 weeks. In
patients who fail to respond to therapy, brain biopsy should be
considered relatively early in the course of treatment (7-10 days),
with or without change in treatment.

     TREATMENT RESULTS: The combination of pyrimethamine and
sulfadiazine is standard treatment for toxoplasmic encephalitis.
This treatment is limited by a high incidence of adverse reactions,
and alternative regimens are under investigation. Due to a domestic
shortage sulfadiazine, the CDC is providing access to the drug on
a case-by-case basis for AIDS patients with acute toxoplasmosis.
Call the Sulfadiazine Enrollment Service at 404-488-4928.
     Tenant-Flowers et al. enrolled 16 AIDS patients with cerebral
toxoplasmosis and known allergies to sulfonamides in a sulfadiazine
dose de-sensitization protocol. Patients received pyrimethamine 25
mg bid and folinic acid 7.5 mg/day. 8 patients received concomitant
steroids. Sulfadiazine was administered every three hours over five
days in doses gradually escalating from 10 mcg. Success, defined
as tolerance of sulfadiazine 2 to 4 g/day, was achieved in 10/16
patients. It is unclear if these results are better than 
re-challenge without de-sensitization.
     Katlama et al. compared the combination of pyrimethamine (50
mg/day) and clindamycin (2.4 g/day) (P/C) to the combination of
pyrimethamine (50 mg/day) and sulfadiazine (4 g/day) (P/S) in AIDS
patients with first-episode toxoplasmic encephalitis. 342 patients
were randomly assigned to receive open-label P/C (n = 175) or P/S
(n = 167) for six weeks. In the P/C group, 47% had a complete
response, 21% had a partial response, and 18% died during acute
therapy. In the P/S group, 55% had a complete response, 22% had a
partial response, and 14% died during acute therapy. These
differences were not statistically significant. Significantly more
patients had to discontinue therapy due to side effects in the
pyrimethamine/sulfadiazine compared with the pyrimethamine/
clindamycin group (44 v. 17, P = 0.0001)(DeWit et al.). Skin rash
and fever occurred in more patients in the pyrimethamine/
sulfadiazine group (58 v. 44, P = 0.073), while diarrhea occurred
in more patients on pyrimethamine/clindamycin (29 v. 8, P =
0.0007).
     Dannemann et al. studied pyrimethamine (200 mg loading dose,
then 75 mg/day) and folinic acid in combination with clindamycin
(1200 mg IV four times daily for 3 weeks, then 300-450 mg PO four
times daily) or sulfadiazine (100 mg/kg PO four times daily) in a
study that assessed only the first 6 weeks of therapy. 59 patients
with AIDS and a definitive diagnosis of toxoplasmic encephalitis
were randomized between the two regimens. After three weeks, 20/26
(77%) of patients randomized to pyrimethamine/clindamycin (P/C) and
26/33 (79%) of patients randomized to pyrimethamine/sulfadiazine
(P/S) had a complete or partial clinical response. After six weeks,
17/26 (65%) of patients randomized to P/C and 23/33 (70%) of
patients randomized to P/S showed a partial or complete clinical
response. No patient on either regimen who exhibited a complete
response after three weeks had deteriorated at six weeks. The
investigators concluded that P/C is an acceptable alternative
regimen for patients unable to tolerate P/S. P/S showed enhanced
efficacy based on some parameters. After six weeks, 5/26 (19%)
patients randomized to P/C and 2/33 (6%) patients randomized to P/S
had died. This difference was not significant. Frequency of adverse
reactions was equivalent in the two groups.
     Leport et al. studied 13 AIDS patients with cerebral
toxoplasmosis; after 3 weeks' treatment with pyrimethamine (200 mg
PO x 1 w; then 75 mg PO) plus clarithromycin (1000 mg PO bid) plus
folinic acid (20 mg PO qd), complete clinical remission was seen
in 6/13 (46%). Side effects noted include anemia, thrombocytopenia,
nausea, elevated LFTs, rash and hypoacusis.
     Saba et al. enrolled 14 AIDS patients with toxoplasmic
encephalitis in an open-label study of the combination of
pyrimethamine (200 mg loading dose, then 75 mg/day) and
azithromycin (1000 mg loading dose, then 500 mg/day). 8/14 patients
with cerebral toxoplasmosis were treated for more than 21 days and
were evaluated for efficacy; 5/8 had a favorable clinical response.
(A favorable response was defined as >50% improvement.) Nine
patients were evaluable for a radiologic response; 6/9 had
favorable responses. Toxicities included rash (n = 5), abnormal
liver function (n = 2), vomiting (n = 3) and hypoacusia (n = 1).
     41 patients (out of an anticipated 45) have enrolled in ACTG
156, a phase I/II dose-escalation trial of the combination of
pyrimethamine and azithromycin for toxoplasmic encephalitis.
Although the optimal dosages of drugs have not been determined,
azithromycin when used alone has been associated with early
relapse.
     Two case reports describe the use of azithromycin as a salvage
therapy for toxoplasmosis. Godofsky described a patient intolerant
to sulfa drugs who developed a rash while receiving clindamycin/
pyrimethamine/folinic acid. The patient was switched to
azithromycin 1000 mg daily (after a 1500 mg loading dose);
cerebellar lesions had almost completely resolved by six weeks, and
significant clinical improvement was observed. Kovacs et al.
treated two patients intolerant to pyrimethamine/sulfadiazine with
azithromycin 1,200 mg/day alone; both patients showed radiologic
evidence of progression at two weeks.
     Azithromycin is available on a compassionate-use basis for
patients who have failed or are intolerant of pyrimethamine,
sulfadiazine, or clindamycin.
     Clumeck et al. enrolled 32 AIDS patients with toxoplasmosis
in a pilot study of atovaquone (566). Patients received atovaquone
(750 mg qid PO) for 6 weeks. 26/32 were evaluable (patients were
excluded if they did not have toxoplasmosis, had concomitant OI,
or were non-compliant). At day fourteen, 12 patients had a complete
and 10 had a partial clinical response; 3 had a complete and 17 had
a partial radiologic response. Adverse reactions included elevated
LFTs (13 patients), rash (6), and GI disturbances (3).
     Torres et al. treated 93 AIDS patients with toxoplasmosis with
atovaquone 750 mg qid as salvage treatment. Response to treatment
and median survival were correlated with the plasma concentration
of atovaquone. After six weeks of therapy, clinical improvement or 
stability was noted in 22/25 (88%), 15/24 (63%), and 7/13 (54%) of
patients with atovaquone plasma concentrations >13 mcg/ml, between
7 and 13 mcg/ml, and <7 mcg/ml, respectively. Median survival was
426, 424, and 116 days for patients with atovaquone plasma
concentrations >13 mcg/ml, >7<13 mcg/ml, and <7 mcg/ml,
respectively.
     ACTG 237 is comparing the combination of atovaquone/
pyrimethamine with atovaquone/sulfadiazine in patients with acute
toxoplasmosis. Additionally, an open-label study of atovaquone/
pyrimethamine is under way at NIH.
     Canessa et al. treated 25 patients with toxoplasmosis with
TMP/SMX 40-50 mg/kg qd IV. Radiological and clinical improvements
were seen in 18/25 patients. Mean survival time for responders was
8.8 months vs 2.1 months for non-responders. Stellini et al.
retrospectively analyzed 37 AIDS patients with toxoplasmosis
treated with TMP/SMX (8-10 mg/40-50 mg/kg qd IV and PO) for 4-6
weeks. 33/37 had both clinical and radiological improvement. Rashes 
requiring drug discontinuation occurred in 7 patients.
     The results of a small open-label study suggest that
trimetrexate is not adequate as a single-agent therapy for
toxoplasmosis. Masur et al. enrolled nine sulfonamide-intolerant
AIDS patients with toxoplasmosis in the study. Patients received
trimetrexate IV at doses ranging from 30 - 280 mg/m2 daily with
leucovorin calcium 20 mg/m2 IV or PO every 6 hours. Partial
clinical and/or radiologic responses were observed in 8/9 patients; 
however, these responses were transient, and all eight patients
deteriorated within 13 - 109 days of their initial responses.
Trimetrexate was well tolerated in this group.
     One report suggests that tetracycline derivatives (doxycycline
and minocycline) may be effective for toxplasmic encephalitis.
Bockmon et al. treated seven patients with either doxycycline 4
mg/kg/day, minocycline 4 mg/kg/day, or minocycline 4 mg/kg/day in
combination with pyrimethamine. All patients responded to therapy.

     MAINTENANCE: Maintenance therapy is required since recurrence
is nearly invariable. For maintenance, sulfadiazine (2-4 g in
divided doses) is administered with pyrimethamine (25-50 mg/day).
Other treatment regimens are also under investigation.
     Katlama et al. conducted the maintenance phase of a trial for
acute toxoplasmic encephalitis. For maintenance, 83 patients
received pyrimethamine 25 mg/day with sulfadiazine 2 g/day, and 92
patients received pyrimethamine 25 mg/day and clindamycin 1.2
g/day. After a median follow-up of 60 weeks, toxoplasmosis relapses
were proven in 6 patients receiving pyrimethamine/sulfadiazine and
26 receiving pyrimethamine/clindamycin (P = 0.0007).
     One report (Mouthon et al.) describes the open-label use of
atovaquone 750 mg four times daily as a maintenance therapy for
patients who have recovered from acute toxoplasmosis. 22 patients
were included in the study; 12/22 had received atovaquone as
therapy for acute toxoplasmosis, while the other 10 had received
other therapies. Relapses occurred in 5/22 patients. All five
relapses occurred in patients who had received atovaquone for acute
therapy. No side  effects requiring drug discontinuation occurred.

     PROPHYLAXIS: No primary prophylactic treatment has been
established as standard-of-care.
     A cooperative French/American study (ANRS 005/ACTG 154)
compared pyrimethamine 50 mg/week plus leucovorin to placebo as
prophylaxis for toxoplasmosis in patients with T. gondii antibodies
and CD4 counts under 200/mm3 (Morlat et al.). 554 patients were 
randomized (274 to pyrimethamine and 280 to placebo) and followed
for a mean of 14 months. 86% of the patients were receiving AZT and
86% received PCP prophylaxis with aerosol pentamidine. On an
intent-to-treat analysis, statistically equivalent rates of
cerebral toxoplasmosis (12% on pyrimethamine and 13% on placebo)
and survival (85% vs. 80%) were observed. Side effects requiring
the discontinuation of therapy (in particular skin rash) were
significantly more frequent in the pyrimethamine group (20% vs. 8%,
P <0.0001).
     Pyrimethamine (25 mg three times weekly) without leucovorin
was compared with placebo (CPCRA 001, Jacobson et al.). The study
began as a comparison of clindamycin (300 mg twice daily),
pyrimethamine, and placebo, but the clindamycin arm was
discontinued early due to a high toxicity rate. The trial continued
as a comparison of pyrimethamine and placebo. Patients with
hematologic toxicity received leucovorin. All patients had a CD4
count <200/mm3 or an AIDS diagnosis, and antibodies to T. gondii.
264 patients were randomized to pyrimethamine and 132 to placebo.
Toxoplasmosis occurred at lower rate than expected, preventing the
evaluation of pyrimethamine's efficacy. The study was terminated
when a significantly higher mortality rate was observed in the
pyrimethamine group (relative risk, 2.5; 95% confidence interval
1.3 - 4.8, P = 0.006). A significant difference remained after
adjustment for factors predictive of survival. Although the reason
for the mortality difference has not been determined, it was noted
that patients who entered the trial with low hemoglobin levels had
a high risk of death associated with pyrimethamine (relative risk,
7.7; 95% confidence interval, 2.0 - 29.7, P = 0.003). This result
suggests the hypothesis that pyrimethamine's anti-folate activity
accounted for the excess mortality.
     A double-blind dose-randomized trial of pyrimethamine (50 mg
once or three times weekly) as prophylaxis in HIV-infected patients
with antibodies to T. gondii is under way through the Community
Based Clinical Trials Network (CBCTN). 270 patients have enrolled. 
Participants may also take leucovorin on an optional basis.
     A French trial (ANRS 003) compared aerosol pentamidine (300
mg/month) with dapsone (50 mg/day)/pyrimethamine (50 mg/week) plus
leucovorin as primary prophylaxis for both toxoplasmosis and PCP.
75% of patients were positive for T. gondii antibodies at baseline,
and the mean entry CD4 count was 115/mm3. Girard et al. reported
that toxoplasmosis developed in 32/176 and 19/173 of patients
receiving aerosol pentamidine and dapsone/pyrimethamine
respectively. Patients assigned to aerosol pentamidine had a
significantly higher risk of developing toxoplasmosis compared to
dapsone/pyrimethamine recipients (relative risk 1.81, 95%
confidence interval, 1.12 - 2.94, P = 0.02). Survival was
statistically equivalent (41 and 45 deaths in the aerosol
pentamidine and dapsone/pyrimethamine groups, respectively). More
patients in the dapsone/pyrimethamine group than in the aerosolized
pentamidine group discontinued treatment due to toxicity (42 vs.
3, P <0.001). Most frequent toxicities were cutaneous and
hematological.
     Opravil et al. presented interim results from an ongoing
multi-center Swiss study comparing aerosol pentamidine (300
mg/month) with dapsone/pyrimethamine (75/200 mg/week) as primary
prophylaxis for toxoplasmosis and PCP. 533 HIV-infected patients
with either symptoms or a CD4 count below 200/mm3 have enrolled;
47% are positive for T. gondii antibodies. After a median follow-up
of more than a year, 14/291 (4.8%) patients receiving
dapsone/pyrimethamine and 20/242 (8.26%) patients receiving aerosol
pentamidine have developed toxoplasmosis. Intolerance to
dapsone/pyrimethamine occurred significantly more frequently than
to aerosol pentamidine.
     Torres et al. conducted a randomized comparison of dapsone
(100 mg twice weekly) and aerosolized pentamidine (100 mg every two
weeks) for the prevention of toxoplasmosis and PCP. 278 patients
with AIDS or ARC and CD4 counts <250/mm3 were randomized. The mean
follow-up time was 42 and 44 weeks in the dapsone and aerosol  
pentamidine groups, respectively, Significantly fewer cases of
toxoplasmosis occurred in the dapsone group (none vs. 6, P = 0.01).
     Some evidence suggests that TMP/SMX prevents toxoplasmosis;
however, no large, prospectively randomized trial of prophylactic
TMP/SMX for toxoplasmosis has been completed to date. One small
randomized study (Stellini et al.) is under way to compare TMP/SMX
(one double-strength tablet every other day) with pyrimethamine (50
mg twice weekly). (Patients randomized to pyrimethamine also
receive aerosol pentamidine 300 mg monthly.) 49 patients with CD4
counts <200/mm3 with T. gondii antibodies have been randomized. An
interim analysis after a mean follow-up of 20 months showed that 
toxoplasmosis had developed in 1 and 7 patients in the TMP/SMX and
pyrimethamine groups respectively (P = 0.03), and PCP developed in
0 and 2 patients (NS). Adverse reactions were observed in 7 and 4
patients (NS).
     A multi-center, randomized Italian study is under way to
compare TMP/SMX (one double-strength tablet daily) with
dapsone/pyrimethamine (50 mg daily/50 mg weekly). Patients
randomized to dapsone/pyrimethamine will also receive folinic acid
25 mg weekly. All participants have CD4 counts below 200/mm3; the
presence of T. gondii antibodies is not required. The accrual
target is 360.
     Several retrospective chart reviews also support the efficacy
of TMP/SMX. Lipman et al. conducted a chart review of all patients 
who had received TMP/SMX or aerosol pentamidine as prophylaxis for
PCP. Of 210 patients who received prophylaxis with aerosol
pentamidine, 8/210 (3.8%) developed toxoplasmosis; 1/154 (0.6%)
patients who received prophylaxis with TMP/SMX developed
toxoplasmosis. Another non-randomized retrospective chart review
was reported by Carr et al. This study included Australian AIDS
patients who received TMP/SMX or pentamidine as secondary
prophylaxis after a bout of PCP. 60 patients received TMP/SMX (two
double-strength tablets twice weekly), and 95 received pentamidine
(aerosolized in 78 and intravenous in 17). 37% of patients in each
group had antibodies to T. gondii. No patient who received TMP/SMX
and 12/36 seropositive patients who received pentamidine developed
toxoplasmosis (P = 0.008). 

REFERENCES: Bockmon K et al. Utility of tetracycline derivatives
in treatment of CNS toxoplasmosis. Ninth Intl Conf AIDS, abstract
PO B10-1427, 1993.

     Canessa A et al. Cotrimoxazole treatment of Toxoplasma
encephalitis in AIDS patients. VI Intl Conf AIDS San Francisco, 1:
241(Th.B.477), 1990.

     Carr A et al. Low-dose trimethoprim-sulfamethoxazole
prophylaxis for toxoplasmic encephalitis. Ann Int Med 117: 106-11,
1992.

     Clumeck N et al. Atovaquone (1,4-hydroxynaphthoquinone,
566C80) in the treatment of acute cerebral toxoplasmosis in AIDS
patients. 32nd ICAAC, abstract #1217, 1992.

     Dannemann B et al. Treatment of toxoplasmic encephalitis in
patients with AIDS. Ann Int Med, 116: 33-43, 1991.

     DeWit S et al. Tolerance of pyrimethamine-clindamycine and  
pyrimethamine-sulfadiazine during acute therapy of toxoplasmic
encephalitis in AIDS patients in a randomized European multicentre
study (ENTA 004). Abstract P192, Fourth European Conference on
Clinical Aspects and Treatment of HIV Infection, Milan, 1994.

     Girard PM et al. Dapsone-pyrimethamine compared with 
aerosolized pentamidine as primary prophylaxis against Pneumocystis
carinii and toxoplasmosis in HIV infection. NEJM 238: 1514-20,
1993.

     Godofsky EW. Treatment of presumed cerebral toxoplasmosis with
azithromycin (correspondence). NEJM 330:575-6, 1994.

     Jacobson M et al. Primary prophylaxis with pyrimethamine for
toxoplasmic encephalitis in patients with human immunodeficiency
virus disease: Results of a randomized trial. JID 169;384-94, 1994.

     Katlama C et al. A randomized European trial comparing
pyrimethamine-clindamycin to pyrimethamine-sulfadiazine in AIDS
toxoplasmic encephalitis. 32nd ICAAC, abstract #1215, 1992.

     Katlama C et al. Efficacy of pyrimethamine-clindamycine for
the long term suppressive therapy of toxoplasmosis encephalitis in
AIDS patients (ENTA 04 study). Abstract O43, Fourth European
Conference on Clinical Aspects and Treatment of HIV Infection,
Milan, 1994.

     Kovacs JA et al. Evaluation of azithromycin or the combination
of 566C80 and pyrimethamine in the treatment of toxoplasmosis.
Abstract PoB 3199, VIII Intl Conf AIDS, Amsterdam, 1992.

     Leport C et al. Combination of pyrimethamine-clarithromycin
for acute therapy of toxoplasmic encephalitis (TE). A pilot study
in 13 AIDS patients. 30th ICAAC, abstract #1158, 1990.

     Lipman MCI et al. Reduced incidence of toxoplasmosis in
patients taking cotrimoxazole as Pneumocystis carinii prophylaxis.
Abstract PO-B10-1443, IX Intl Conf AIDS, Berlin, 1993.

     Luft B et al. Risk factors for development of cerebral
toxoplasmosis. Abstract 474, 1st Natl Conf on Hum Retrovir, 1993.

     Masur H et al. Salvage trial of trimetrexate-leucovorin for
the treatment of toxoplasmosis in patients with AIDS. JID
167:1422-6, 1993.

     Morlat P et al. Prevention primaire de la toxoplasmose
cerebrale chez le sujet infect par le VIH: resultats d'un essai
randomis en double insu, pyrimethamine versus placebo. Rev med
interne 14:1002, 1993.

     Mouthon B et al. Atovaquone as long-term suppressive therapy
in toxoplasmosis. Abstract O26, Fourth European Conference on
Clinical Aspects and Treatment of HIV Infection, Milan, 1994.

     Opravil M et al. Dapsone/pyrimethamine vs. aerosolized
pentamidine for combined prophylaxis of PCP and toxoplasmic
encephalitis. Abstract PO-B10-1429, IX Intl Conf AIDS, Berlin,
1993.

     Opravil M et al. Combined prophylaxis of Pneumocystis carinii
pneumonia and toxoplasmosis: prospective randomized trial of
dapsone+pyrimethamine vs. aerosolized pentamidine. Abstract PoB 
3315, VIII Intl Conf AIDS, Amsterdam, 1992.

     Porter SB and Sande MA. Toxoplasmosis of the central nervous
system in the acquired immunodeficiency syndrome. NEJM 327:1643-8,
1992.

     Saba J et al. Pyrimethamine plus azithromycin for treatment
of acute toxoplasmic encephalitis in patients with AIDS. Eur J Clin
Microbiol Infect Dis 12: 853-6, 1993.

     Stellini R et al. Cotrimoxazole versus pyrimethamine in the
primary prophylaxis of toxoplasmic encephalitis in HIV infected
patients: a randomized prospective study. Abstract P193, Fourth
European Conference on Clinical Aspects and Treatment of HIV
Infection, Milan, 1994.

     Stellini R et al. Effectiveness of trimethoprim/
sulfamethoxazole in AIDS patients with toxoplasmic encephalitis.
Abstract #P76, Third European Conference on Clinical Aspects and
Treatment of HIV Infection. Paris, 1992.

     Tenant-Flowers M et al. Sulfadiazine desensitization in
patients with AIDS and cerebral toxoplasmosis. AIDS 5:311-5, 1991.

     Torres R et al. Multicenter clinical trial of atovaquone (ATQ)
for salvage treatment and suppression of toxoplasmic encephalitis
(TE). Abstract PO-B10-1453, IX Intl Conf AIDS, Berlin, 1993.

     Torres RA et al. Randomized trial of dapsone and aerosolized
pentamidine for the prophylaxis of Pneumocystis carinii pneumonia
and toxoplasmic encephalitis. Amer J Med 95:573-83, 1993.

     Wong SY and Remington JS. Biology of Toxoplasma gondii
(Editorial review). AIDS 7:299-16, 1993.

OTHER REPORTS: Beaman MH et al. Prophylaxis for toxoplasmosis in
AIDS. Ann Int Med 117: 163-4, 1992.

     Luft BJ et al. Toxoplasmic encephalitis in patients with the
acquired immunodeficiency syndrome. NEJM 329:995-1000, 1993.

     Copyright (c) 1993 - American Foundation for AIDS Research
(AmFAR) - All Rights Reserved. Permission to reproduce for
non-profit use granted with the condition that the source and date
of the information be given, and that AmFAR be notified. Eric
Fretz, Treatment Information Services, AmFAR. DISTRIBUTED BY
GENA/aegis (714.248.2836 * 8N1/Full Duplex * v.34); taking you to
the edge of the electronic AIDS-information frontier and beyond. 

----------------------------------------------------------------

                          Toxoplasmosis
             Information Sheet for Patient Education
                          June 16, 1995

What is toxoplasmosis?

Toxoplasmosis (also known as "toxo") is the name for a treatable
infection caused by the germ (parasite) Toxoplasma gondii. 
although more than half of all adults in the United States have
been infected with the parasite, it rarely causes disease unless
there is damage to the immune system (the cells, molecules, and
processes that normally fight off or control infections).  In
persons with normal immunity, Toxoplasma organisms remain in the
body tissues as cysts which do not multiply and do not cause
disease.  In persons with impaired immunity, Toxoplasma can cause
disease in the brain and other body organs.

Toxoplasma infects many different types of farm animals that serve
as food sources.  In addition, cats transmit Toxoplasma by passing
an infectious form of the parasite called oocysts in their
excrement (feces).

How does a person get infected?

Humans can get Toxoplasma infection either by:  1) swallowing germs
from contaminated food or dirty hands; or 2) eating undercooked
meat or eggs or drinking unpasteurized milk containing tissue cysts
from infected animals.  There is no evidence that Toxoplasma
infection is transmitted from person to person by direct contact. 
However, women who become infected with the parasite during
pregnancy sometimes transmit it to their babies.

Why does toxoplasmosis occur in HIV-infected persons?

Because Toxoplasma is so common in the environment, many HIV-
infected persons have been infected previously by the parasite and
have the inactive form in their bodies.  In early HIV disease, the
infection does not cause symptoms.  When HIV disease advances to
the stage known as AIDS (T-cell count below 200), the immune system
may no longer be able to control Toxoplasma infection, and symptoms
develop.  Most toxoplasmosis in HIV-infected person is the result
of reactivation of old infection, and the brain is the most common
site of involvement.

Your doctor can perform a blood test called a Toxoplasma antibody
test to determine if you have ever been infected by the parasite. 
If the test is positive, it means you have antibodies to Toxoplasma
in your blood, and, therefore, you were infected by the parasite
sometime in the past.  While this result does not mean you have the
disease toxoplasmosis, it does mean that you may be at risk to
develop it sometime in the future.  If the test is negative, it
suggests that you are at very low risk of developing toxoplasmosis.

What are the symptoms and signs of toxoplasmosis?

Symptoms and signs of toxoplasmosis may include fever, headache,
confusion, sleepiness, weakness or numbness in one part of the
body, seizure activity, and changes in vision.  These symptoms can
get worse and progress to coma and death unless toxoplasmosis is
promptly diagnosed and treated.  Toxoplasma infection affecting
other parts of the body is rare, and symptoms vary depending on
which organs the disease affects.

How is toxoplasmosis diagnosed?

If you have some or all of the above symptoms and signs and your
T-cell count is below 200, your doctor will generally perform a
special series of x-rays of the brain called a CT or MRI scan to
determine the nature of the problem.  If the brain scan shows
abnormalities suggestive of toxoplasmosis, you will be prescribed
medications to treat the condition and followed closely to see if
it gets better over the course of two weeks.  If the condition does
not improve, another disease may be causing the problem, and
additional diagnostic tests will have to be performed.

How is toxoplasmosis treated?

Toxoplasmosis can be treated with a variety of medications, but it
usually requires at least two given at the same time.  Sulfadiazine
and pyrimethamine used together are the most common drugs for
treating toxoplasmosis.  You will need to continue to take these
medications indefinitely because the drugs only keep Toxoplasma
under control and do not kill it.  High-dose therapy is continued
for 4-6 weeks, and lower dose maintenance therapy thereafter.

Sulfadiazine may cause serious allergic reactions in some people,
including fever, rash, and sensitivity to the sun.  Pyrimethamine
can cause low blood counts in some people.  To counter the possible
effects of pyrimethamine on the bone marrow, another drug called
leucovorin (folinic acid) is given along with pyrimethamine.  If
you cannot take sulfadiazine, your doctor will usually give you
clindamycin instead.  Other drugs used less often to treat
toxoplasmosis include azithromycin, clarithromycin, dapsone, and
atovaquone.  Your doctor may consider using these medications if
standard treatment makes you sick or is not working.

Can toxoplasmosis be prevented?

If you are negative for toxoplasmosis antibody, toxoplasmosis may
be prevented by following certain precautions.  If you have a cat,
wear gloves when changing the litter and wash your hands thoroughly
afterwards, or have someone else change the litter for you.  You
should not eat undercooked meat or eggs or unwashed vegetables and
should not drink unpasteurized milk.

The combination drug trimethoprim-sulfamethoxazole (TMP-SMX,
Bactrim, Septra) that is given as a preventive treatment for
pneumocystis pneumonia also prevents toxoplasmosis much of the
time.  Some people have allergic reactions to TMP-SMX, including
fever, rash, and gastrointestinal symptoms.  An alternative agent
used is the drug dapsone alone or in combination with
pyrimethamine.


[Editor's Note:  This is one of a series of Information Sheets
prepared by the National AIDS Treatment Information Project (NATIP)
with funding from the Henry J. Kaiser Family Foundation.  The
materials are designed for self-education by HIV-infected persons
and for counseling by community advisors, case managers, social
workers, and clinicians.  For more information about NATIP, call
617-667-5520 or write:  Helen E. Woods Wogan, Project Manager,
Libby 317, Beth Israel Hospital, 330 Brookline Avenue, Boston, MA
02215.  Fax: 617-667-2885.  Internet:  hwoods@bih.harvard.edu]

----------------------------------------------------------------

                          Toxoplasmosis

Toxoplasmosis is an infection that is caused by the parasite
Toxoplasma gondii.  The parasite is carried by cats, birds, and
other animals and is found in soil contaminated by cat feces and
in meat, particularly pork.  The parasite can infect the lungs,
retina of the eye, heart, pancreas, liver, colon, and testes.  Once
T. gondii invades the body, it remains there, but the immune system
in a healthy person prevents the parasite from causing disease. 
If the immune system becomes severely damaged, as in people with
AIDS, or is suppressed by drugs, T. gondii can begin to multiply
and cause severe  disease.  The most common site of infection is
the brain. When T. gondii invades the brain, causing inflammation,
it is called toxoplasmic encephalitis.

Symptoms and Diagnosis

A severe headache that does not respond to pain relievers is often
one of the first symptoms of toxoplasmic encephalitis. Toxoplasma
infection can also cause weakness on one side of the body, fever,
seizures, visual field loss, and difficulty with speaking and
walking; later symptoms include confusion, decreased attentiveness,
and personality changes.  Nausea, dizziness, and vomiting also may
result from brain involvement.

Toxoplasma infection is difficult to diagnose, particularly since
not all patients show signs or symptoms of infection. Often, a
positive response to therapy is used to confirm the diagnosis. 
Brain scans such as computerized tomography (CT) or magnetic
resonance imaging (MRI), are sometimes used to identify brain
abnormalities and see if the treatment is working. 

Treatment

Acute.  There are two drug regimens commonly used for the treatment
of acute toxoplasmic encephalitis in people with AIDS.  The
standard therapy is a combination of pyrimethamine and
sulfadiazine; a major drawback of this regimen is the frequency of
side effects--more than 40 percent in people with AIDS.  An
alternative regimen that recently has been found to be effective
combines oral clindamycin and pyrimethamine. Folinic acid is
administered with both therapies to help prevent some of the side
effects.

Maintenance.  After treatment is completed, patients must receive
maintenance therapy for life to prevent a recurrence. Drugs used
in treatment, such as pyrimethamine plus sulfadiazine, are used at
a reduced dosage.  Some research indicates that clindamycin in
combination with pyrimethamine may be effective for maintenance
therapy in those unable to tolerate sulfadiazine.

Prevention

Many physicians recommend treatment to prevent the onset of
toxoplasmosis in individuals with a positive blood test for T.
gondii and a T-cell count under 100.  Drugs that are being
investigated for their effectiveness in preventing toxoplasmosis
include trimethoprim/sulfamethoxazole, pyrimethamine and dapsone
in various combinations.

People with HIV who do not show any evidence of having been exposed
to T. gondii can take preventive measures to decrease their risk
of infection:

     Wear gloves while gardening or working with soil or sand.

     Avoid eating raw or undercooked meat and wash hands after
     handling raw meat or vegetables.

     Wear gloves and a mask when cleaning cat litterboxes, or
     preferably, have someone else change the cat's litter. 
     Litterboxes should be cleaned frequently.

Research

Intensive research efforts are under way to evaluate the
effectiveness of different drug regimens, both for treatment of
acute infection and for prophylaxis of toxoplasmic encephalitis. 
Drugs under study include atovaquone with pyrimethamine or
sulfadiazine.

For information about clinical studies, call the AIDS Clinical
Trials Information Service: 1-800-TRIALS-A (1-800-874-2572)

NIAID, a component of the National Institutes of Health, supports
research on AIDS and other infectious diseases as well as allergies
and immunology.  NIH is an agency of the U.S. Public Health
Service, U.S. Department of Health and Human Services.

[Prepared by: Office of Communications, National Institute of
Allergy and Infectious Diseases, National Institutes of Health,
Bethesda, MD 20892. April 1994.]

----------------------------------------------------------------

    INFECTION FIGHTERS: PREDICTING WHO WILL GET TOXOPLASMOSIS
                         by Sein Hosein

[Treatment Update 59 - Vol 7, No. 5 (May 1995); published by
Community AIDS Treatment Information Exchange Suite 420 - 517
College Street, Toronto M6G 4A2 (416) 944-1916.

* STUDY DETAILS

     Researchers in France used data collected on 499 subjects to
try and find out which subjects would develop the life-threatening
brain infection toxo. At the time these subjects entered the study
none had toxo. The average CD4+ cell count was 70 cells. About 60%
of subjects had less than 50 CD4+ cells. Technicians tested the
blood samples from 410 subjects to find antibodies against toxo.
A total of 298 had anti-toxo antibodies. When subjects entered the
study 80 received Bactrim/Septra as preventative therapy against 
PCP/toxo; '34 received pyrimethamine'; 19 received dapsone; 11
received [Fansidar(R)]' and 1 received pyrimethamine-sulfadiazine.

* RESULT-SURVIVAL

     Researchers monitored subjects for an average of 1 year during
which 16% (83) subjects developed toxo; 75 had it as a brain
infection, 7 had the infection in their eyes and 1 developed toxo
in the lungs. Altogether, 67% of the 499 subjects died while in
this study.

* CD4+ CELL COUNTS

In this study subjects with CD4+ cell counts of less than 100 Cells
were at high risk for developing toxo. This link between low CD4+
cell counts and toxo was statistically significant; that is, not
likely due to chance alone. When subjects developed toxo they had
an average CD4+ cell count of 31 cells. About 18% of subjects who
had less than 100 CD4+ cells when they entered the study developed
toxo. By contrast, only 9% of subjects who entered the study with
CD4+ cell counts of at least 100 cells developed toxo.

* ANTIBODIES

     Subjects who had anti-toxo antibodies in their blood were very
likely to develop toxo while in the study. Over a period of 1 year
21% of these subjects developed toxo compared to none of the
subjects without these antibodies. This difference was
statistically significant.

* BACTRIM/SEPTRA REDUCES THE RISK

     "Three of 80 [subjects] receiving Bactrim/Septra and 72 of 19
subjects not receiving Bactrim/Septra developed toxo in their
brains". This was statistically significant. "One of 34 [subjects]
receiving pyrimethamine and 74 of 465 subjects who [did not use]
pyrimethamine when they entered the study developed toxo." This
difference was also statistically significant.

* CHECKING THE RISKS

     There were 149 subjects with less than 100 CD4+ cells who had
anti-toxo antibodies but did not receive antibiotics. Forty-eight
(32%) of these subjects developed toxo in their brains. Of the 74
subjects with less than 100 CD4+ cells who had antibodies against
toxo but did receive antibiotics, 5 (7%) developed toxo in their
brain. This difference was also statistically significant.

* SURVIVAL

     All subjects who developed toxo died at some point during the
study. Taking antibiotics did not seem to affect survival. When
researchers adjusted their calculations to take into account
different CD4+ cell counts, again there was no difference in
survival.

REFERENCES:

     1. Oksenhendler E, Charreau I, Tournerie C, et al. Toxoplasma
gondii infection in advanced HIV infection. AIDS 1994;8:483-487. 

     Copyright (c) 1995 - Treatment Update.  Noncommercial
reproduction encouraged.  Distributed by AEGIS, your online gateway
to a world of people, knowledge, and resources. 714.248.2836 *
8N1/Full Duplex * v.34+
