|
|
Go to the Protozoal Infections Menu
Go to the Opportunistic Infections Menu
Go to the HIVpositive.us Main Menu
13-306
Return to the Toxoplasmosis Menu
Pathogen:
Return to the Toxoplasmosis Menu
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).
Return to the Toxoplasmosis Menu
Symptoms:
Return to the Toxoplasmosis Menu
Diagnosis:
The risk of developing cerebral toxoplasmosis is greatly increased in toxo seropositive 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.
Return to the Toxoplasmosis Menu
Treatment Results:
Tenant-Flowers et al. enrolled 16 AIDS patients with cerebral toxoplasmosis and known allergies to sulfonamides in a sulfadiazine desensitization 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 µg.
Success, defined as tolerance of sulfadiazine 2 to 4g/day, was achieved in 10/16 patients. It is not known whether results are better than re-challenge without desensitization.
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 at. studied pyrimethamine (200 mg loading dose, then 75 mg/day) and folinic acid in combination with clindamycin (1,200 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 it 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.
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 (1,000 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; 619 had favorable responses. Toxicities included rash (n =5), abnormal liver function (n = 2), vomiting (n = 3)-and hypoacusia (n = 1).
A total of 42/45 patients have enrolled in ACTG, 156, a dose-escalation trial of the combination of pyrimethamine and azithromycin for toxoplasmic encephalitis. Although the optimal dosages have not been determined, azithromycin when used alone has been associated with early relapse.
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 (750 mg qid PO) for 6 weeks. 26/32 were evaluable. 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 µg/mL, between 7 and 13 µg/mL, and <7 µg/mL, respectively. Median survival was 426,424, and 116 days for patients with atovaquone plasma concentrations >13 mg/mL, >7<13 µg/mL, and <7 µg/mL, respectively.
ACTG 237 is comparing the combination of atovaquone/pyrimethamine with atovaquone/sulfadiazine in patients with acute toxoplasmosis; the trial is still underway with 45/100 patients enrolled. 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. 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 toxoplasmic encephalitis. Bockmon et al. treated seven patients with either doxycycline 4 mg/kg/day, minocycline 4 mg/kg/day, or minocychne 4 mglkg/day in combination with pyrimethamine. All patients responded to therapy.
Return to the Toxoplasmosis Menu
Maintenance:
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 pafients were included in the study; 12/22 had received atovaquone as therapy for acute toxoplasmosis, while the other 10 had received older therapies. Relapses occurred in 5/22 patients. All five relapses occured in patients who had received atovaquone for acute therapy. No side effects requiring drug discontinuation occurred.
Return to the Toxoplasmosis Menu
Prophylaxis:
A cooperative French/American study (ANRS 005/ACTG-U 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 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, since leucovorin was not used routinely.
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 has been completed by AmFAR's Community Based Clinical Trials Network (CBCTN). Data are under analysis.
A French trial (ANRS 003) compared aerosolized 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 es were cutaneous and hematological.
Opravil et al. presented interim results from an ongoing multi-center Swiss study comparing aerosolized pentamidine (300 mg/month) with dapsone/pyrimethamine (75/200 mg/week) as primary prophylaxis for toxoplasmosis and PCP. 533 HIV-infected patients who are symptomatic or have 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 (P = NS). 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 aerosol 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. Podzamczer et al. randomized 230 HIV-positive patients with CD4+ < 200 cells/mm3 to receive thrice-weekly double strength TMP/SMX (800 mg PO bid) or dapsone/pyrimethamine (50 mg twice-weekly) as prophylaxis against Pneumocystis carinii pneumonia and toxoplasmosis. The median cell count was 140 cells/mm3 . During a median follow-up of 14 months, rates of toxoplasmosis did not differ significantly between the two groups; 4% of those receiving TMP/SMX and 7% of those receiving dapsone/pyrimethamine developed toxoplasmosis.
One small randoniized 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 pyrimethamin e also receive aerosol pentamidine 300 mg monthly.) 49 patients withth CD4 counts <200/mm3 with T. gondii andbodies 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 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/pyrimethamime (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 actualal 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 an episode 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 andbodies to T. gondii. No patient who received TMP/SMX and 12/36 seropositive patients who received pentaniidine developed toxoplasmosis (P = 0.008).
REFERENCES:
Centers for Disease Control. USPHS/IDSA Guidelines for the Prevention of Opportunistic Infections in Persons Infected with Human Immunodeficiency Virus. MMWR 44: 1-24, 1995.
Canessa A et al. Cotrimoxazole treatment of Toxoplasma encephalitis in AIDS patients. VI Intl Conf AIDS San Francisco, 1: 241(TILB.477), 1990.
Carr A et al. Low-dose trimethoprim-sulfamethoxazole prophylaxis for toxoplasmic encephalitis. Ann Int Med 117: 106-11,1 992.
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 toxoplasniic encephalitis in patients with AIDS. Ann Int Med, 116: 33-43, 1991.
Girard PM et al. Dapsone-pyrimethamine compared with acrosolized pentamidine as primary prophylaxis against Pneumocystis carinii and toxoplasmosis in HIV infection. NEJM 239: 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 pyrimdiandne-sulfadiazine in AIDS toxoplasmic enoephalitis. 32nd ICAAC, Abstract #1215, 1992.
Katlama C et al. Efficacy of pyrimethamine-clindamycin for the long term suppressive therapy of toxoplasmosis encephalitis in AIDS patients (ENTA 04 study). Abstract 043, 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 in13 AIDS patients. 30th ICAAC, Abstract #1158, 1990.
Lipmm 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, lst 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 infectˇ par le VIH: resultats d'un essai randomisˇ en double insu, pyrimethamine versus placebo. Rev med inteme 14: 1002, 1993.
Mouthon B et al. Atovaquone as long-term suppressive therapy in toxoplasmiosis. Abstract 026, Fourth European Conference on Clinical Aspects and Treatment of HIV Infection, Milan, 1994.
Opravil M et al. Dapsone/prymimethamine vs. aerosolized pentamidine for combined prophylaxis of PCP and toxoplasmic encephalitis. Abstract PO-BIO-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.
Podzamczer D et al. Intemiittent trimethoprim-sulfamethoxazole compared with dapsone-pyrimethamine for the simultaneuos primary prophylaxis of Pneumocystis pneumonia and toxoplasmosis in patients with HIV. Ann Intem Men 122: 755-61, 1995.
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.
Stelfini R et al. Effectiveness of trimethoprim/sulfamethoxazole in AIDS patients with toxoplasmic encephahtis. Abstract #P76, Third European Conference on Clinical Aspects and Treatment of HIV Infection. Paris, 1992.
Tenant-Flowers M et al. Sulphadiazine 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 Pb-B1O-1453, IX Intl Conf AIDS, Berlin, 1993.
Torres RA et al. Randomized trial of dapsone and aerosolized pentamdine 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.
Luft BJ ct al. ToxoPlasmic encphalitis in patients with the acquired immunodeficiency syndrome. NEJM 329: 995-1000,1993.
Return to the Toxoplasmosis Menu
Bockmon K et al. Utility of tetracychne derivatives in treatment Of CNS toxoplasmosis. Ninth Intl Conf AIDS, Abstract PO B10-1427, 1993.
OTHER REPORTS:
Beaman MH et al. Prophylaxis for toxoplasmosis in AIDS. Ann IntMed 117:1634,1992.
Go to the Protozoal Infections Menu
Go to the Opportunistic Infections Menu
Go to the HIVpositive.us Main Menu
13-306
74