Primary Prophylaxis with Pyrimethamine for Toxoplasmic Encephalitis in Patients with Advanced Human Immunodeficiency Virus Disease: Results of a Randomized Trial

Jacobson, Mark A.; Besch, C. Lynn; Child, Carroll; Hafner, Richard; Matts, John P.; Muth, K; Wentworth, Deborah; Neaton, James D.; Abrams, Donald I.; Rimland, David; Perez, George; Grant, I.; Saravolatz, Louis D.; Brown, Lawrence S.; Deyton, Lawrence; Aids, Terry Beirn Community Programs for Clinical on

doi:10.1093/infdis/169.2.384

Cited by 54 publications

(23 citation statements)

References 21 publications

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“…Because the development of anemia is proportional to both concentration and time of exposure to dapsone hydroxylamine [55], slightly lower toxicity might have occurred with smaller doses of dapsone given more frequently. As the mortality rate was identical for both prophylaxis groups, data suggesting higher mortality among patients receiving prophylaxis with either dapsone [48] or pyrimethamine [56] are not supported by our study.…”

Section: Discussioncontrasting

confidence: 76%

Once-Weekly Administration of Dapsone/Pyrimethamine vs. Aerosolized Pentamidine as Combined Prophylaxis for Pneumocystis carinii Pneumonia and Toxoplasmic Encephalitis in Human Immunodeficiency Virus-Infected Patients

Opravil

Hirschel

Lazzarin

et al. 1995

Clinical Infectious Diseases

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To evaluate combined prophylaxis for Pneumocystis carinii pneumonia (PCP) and toxoplasmic encephalitis, 533 patients with symptomatic human immunodeficiency virus infection and/ or CD4 lymphocyte counts of <200/AL were randomized to receive dapsone/pyrimethamine (200/75 mg once weekly) or aerosolized pentamidine (300 mg every 4 weeks). The median CD4 lymphocyte count was 110/AL; 47.5% were seropositive for toxoplasma antibodies. The median duration of follow-up was 483 days. In the intent-to-treat analysis, 12 cases of PCP and 14 of toxoplasmic encephalitis occurred in the dapsone/pyrimethamine group and 13 and 20 cases, respectively, in the aerosolized pentamidine group (adjusted relative risk for toxoplasmosis, 0.56; P = .10). However, only two of the 14 cases of toxoplasmic encephalitis in the dapsone/ pyrimethamine group developed during actual treatment. The mortality among the two groups was similar. Dapsone/pyrimethamine was not tolerated by 30% of participants. A subanalysis of 240 matched, tolerant patients yielded a relative risk for toxoplasmosis of 0.21 (P = .014), a result favoring the use of dapsone/pyrimethamine. Dapsone/pyrimethamine was as effective as aerosolized pentamidine as prophylaxis for PCP and significantly reduced the incidence of toxoplasmic encephalitis among those participants who tolerated it.Prophylaxis for opportunistic infections has had a strong impact on the management of immunosuppressed human immunodeficiency virus (HIV)-infected patients in recent years, and epidemiological data indicate that Pneumocystis carinii pneumonia (PCP) has become less frequent as a consequence of prevention [1]. Aerosolized pentamidine became available in Switzerland in 1987 and was subsequently proven effective for both primary and secondary prophylaxis for PCP in controlled trials [2,3]. Among systemic prophylactic agents, trimethoprim-sulfamethoxazole became widely used [4] and was later shown to be more effective but also more toxic than aerosolized pentamidine [5,6] nations, such as dapsone and trimethoprim [7] or pyrimethamine and sulfadiazine [8], have been used for treatment of PCP before, but sparse data exist concerning their prophylactic efficacy [9]. Only recently, the prophylactic efficacy of the combination of dapsone and pyrimethamine against PCP and toxoplasmosis was demonstrated [ 10].Since in >95% of all AIDS patients with toxoplasmic encephalitis there is serological evidence of previous infection with Toxoplasma gondii [10][11][12][13], reactivation of a latent infection is the principal pathogenetic step in the development of toxoplasmic encephalitis during immunodeficiency. Considering the increasing frequency of toxoplasmic encephalitis among AIDS-defining opportunistic infections [ 1] and the 50% seroprevalence of toxoplasma antibodies in Switzerland [14], primary prophylaxis for toxoplasmic encephalitis seems desirable and clinically important, at least for seropositive patients.The sequential inhibition of dihydrofolate reductase by pyrimethamine and of dihydropteroate sy...

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Section: Discussioncontrasting

confidence: 76%

Once-Weekly Administration of Dapsone/Pyrimethamine vs. Aerosolized Pentamidine as Combined Prophylaxis for Pneumocystis carinii Pneumonia and Toxoplasmic Encephalitis in Human Immunodeficiency Virus-Infected Patients

Opravil

Hirschel

Lazzarin

et al. 1995

Clinical Infectious Diseases

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“…After reintroduction, all patients were administered 1 open-label, singlestrength TMP-SMZ tablet daily for 6 months (maintenance phase). Patients missing 11 week of consecutive doses or 130 doses during the maintenance phase were declared to have treatment failure. The use of antihistamines, nonsteroidal agents, or corticosteroids was encouraged during both the reintroduction and the maintenance phases, as needed for any adverse reactions.…”

Section: Methodsmentioning

confidence: 99%

“…In addition to providing effective prophylaxis for PCP, there is evidence that TMP-SMZ is effective as prophylaxis for toxoplasmosis and also may be useful in preventing infections caused by a variety of other organisms [7][8][9][10][11][12].…”

Section: Trimethoprim-sulfamethoxazole (Tmp-smz) Is the Most Effectivementioning

confidence: 99%

Trimethoprim‐Sulfamethoxazole (TMP‐SMZ) Dose Escalation versus Direct Rechallenge forPneumocystis CariniiPneumonia Prophylaxis in Human Immunodeficiency Virus–Infected Patients with Previous Adverse Reaction to TMP‐SMZ

Leoung¹,

Stanford²,

Giordano

et al. 2001

J INFECT DIS

105

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Trimethoprim-sulfamethoxazole (TMP-SMZ) is the most effective Pneumocystis carinii pneumonia (PCP) prophylactic agent, but adverse reactions are common among human immunodeficiency virus (HIV)-infected patients and limit its use. This randomized, double-blind controlled trial compared 2 methods of TMP-SMZ reintroduction, 6-day dose escalation and direct rechallenge, for PCP prophylaxis in HIV-infected patients who had experienced previous treatment-limiting reactions. The primary end point was the ability to take single-strength TMP-SMZ daily for 6 months. Seventy-five percent of the dose-escalation group and 57% of the direct-rechallenge group continued to receive daily single-strength TMP-SMZ for 6 months (P= .014). Among premature discontinuations, 58% of the dose-escalation group and 70% of the direct-rechallenge group were due to adverse reactions. None of these reactions was serious. This study provides evidence that it is possible to successfully reintroduce TMP-SMZ to a significant proportion of HIV-infected patients who have experienced mild-to-moderate treatment-limiting adverse reactions.

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“…Therefore, treatment with pyrimethamine should be carefully considered in patients suffering from immune defects in which a worsening of clinical conditions could be determined. To this regard, it has been previously observed that human immunodeficiency virus type 1-infected patients treated with pyrimethamine as a primary prophylaxis against toxoplasmic encephalitis showed a higher mortality rate in comparison with untreated control patients (Jacobson et al, 1994).…”

Section: Mechanisms Of Pyrimethamine Apoptosis 1055mentioning

confidence: 99%

Pyrimethamine (2,4-Diamino-5-p-chlorophenyl-6-ethylpyrimidine) Induces Apoptosis of Freshly Isolated Human T Lymphocytes, Bypassing CD95/Fas Molecule but Involving Its Intrinsic Pathway

Pierdominici

Giammarioli²,

Gambardella³

et al. 2005

J Pharmacol Exp Ther

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Pyrimethamine (2,4-diamino-5-p-chlorophenyl-6-ethyl-pyrimidine), a folic acid antagonist, may exert, in addition to antiprotozoan effects, immunomodulating activities, including induction of peripheral blood lymphocyte apoptosis. However, the molecular mechanisms underlying this proapoptotic activity remain to be elucidated. Here we show that pyrimethamine, used at a pharmacologically relevant concentration, induced per se apoptosis of activated lymphocytes via the activation of the caspase-8-and caspase-10-dependent cascade and subsequent mitochondrial depolarization. Importantly, this seems to occur independently from CD95/Fas engagement. The proapoptotic activity of pyrimethamine was further confirmed in a patient with autoimmune lymphoproliferative syndrome, an immune disorder associated with a defect of Fas-induced apoptosis. In this patient, pyrimethamine treatment resulted in a "normalization" of lymphocyte apoptosis with a significant amelioration of laboratory parameters. Altogether, these results suggest a mechanism for pyrimethamine-mediated apoptosis that seems to bypass CD95/Fas engagement but fully overlaps CD95/Fas-induced subcellular pathway. On these bases, a reappraisal of the use of pyrimethamine in immune lymphoproliferative disorders characterized by defects in CD95/Fas-mediated apoptosis should be taken into account.

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Primary Prophylaxis with Pyrimethamine for Toxoplasmic Encephalitis in Patients with Advanced Human Immunodeficiency Virus Disease: Results of a Randomized Trial

Cited by 54 publications

References 21 publications

Once-Weekly Administration of Dapsone/Pyrimethamine vs. Aerosolized Pentamidine as Combined Prophylaxis for Pneumocystis carinii Pneumonia and Toxoplasmic Encephalitis in Human Immunodeficiency Virus-Infected Patients

Once-Weekly Administration of Dapsone/Pyrimethamine vs. Aerosolized Pentamidine as Combined Prophylaxis for Pneumocystis carinii Pneumonia and Toxoplasmic Encephalitis in Human Immunodeficiency Virus-Infected Patients

Trimethoprim‐Sulfamethoxazole (TMP‐SMZ) Dose Escalation versus Direct Rechallenge forPneumocystis CariniiPneumonia Prophylaxis in Human Immunodeficiency Virus–Infected Patients with Previous Adverse Reaction to TMP‐SMZ

Pyrimethamine (2,4-Diamino-5-p-chlorophenyl-6-ethylpyrimidine) Induces Apoptosis of Freshly Isolated Human T Lymphocytes, Bypassing CD95/Fas Molecule but Involving Its Intrinsic Pathway

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