THE TOLERANCE FOR ZIDOVUDINE PLUS THRICE WEEKLY OR DAILY TRIMETHOPRIM-SULFAMETHOXAZOLE WITH AND WITHOUT LEUCOVORIN FOR PRIMARY PROPHYLAXIS IN ADVANCED HIV DISEASE

PURPOSE: Trimethoprim-sulfamethoxazole (TMP/SMX) is the preferred agen t for prophylaxis of Pneumocystis carinii pneumonia (909) in patients with HIV infection, but frequent adverse events limit its usefulness. Intermittent dosing and supplementation with leucovorin have been trie d in attempts to improve tolerance. We evaluated these strategies in p ersons with advanced HIV disease. METHOD: One hundred seven patients w ere enrolled. All had HIV infection, <200 CD4+ lymphocytes per mm(3), and no history of PCP. Fifty-two were randomized to TMP/SMX twice dail y (BID); of these, 26 were randomized to leucovorin with each dose. Fi fty-five patients were randomized to TMP/SMX (BID) 3 times per week; o f these, 27 were randomized to leucovorin with each dose. All patients took zidovudine concurrently. RESULTS: The 24-week risk of discontinu ation due to protocol-defined limiting toxicity was 24% with thrice-we ekly TMP/SMX versus 42% with daily TMP/SMX (risk ratio 0.4; 95% CI 0.2 to 1.0). The risks of discontinuation for any reason were 41% and 59% (risk ratio 0.4; 95% CI 0.2 to 0.3). Clinical toxicity, such as heada che and gastrointestinal distress, accounted for the observed differen ce in tolerance between dosing regimens. The 24-week risk of discontin uation due to protocol-defined toxicity was 33% in both the leucovorin and non-leucovorin groups (risk ratio 1.1; 95% CI 0.5 to 2.5). The ri sks of discontinuation for any reason were 53% and 47% (risk ratio 0.8 ; 95% CI 0.3 to 1.7). CONCLUSION: Intermittent therapy with TMP/SMX BI D thrice weekly is better tolerated than daily BID therapy. Leucovorin use does not improve tolerance for chronic TMP/SMX dosing in AIDS, ev en among patients taking tablets daily.