Reduced toxicity with gradual initiation of trimethoprim-sulfamethoxazole as primary prophylaxis for Pneumocystis carinii pneumonia: AIDS Clinical Trials Group 268

Trimethoprim-sulfamethoxazole (TMP/SMX) is recognized as the superior agent for Pneumocystis carinii pneumonia (PCP) prophylaxis but a high incidence of adverse drug reactions, which may be due to toxic drug metabolites, limi ts its use. AIDS Clinical Trials Group protocol 268 was a randomized, doubl e-blind, controlled two-arm trial designed to determine whether gradual ini tiation of TMP/SMX suspension reduced the incidence of treatment-limiting a dverse drug reactions compared with routine initiation of double-strength ( DS; 160 mg/800 mg) tablets. In all, 372 HIV-1-infected study subjects with a CD4(+) cell count <250 x 10 cells/mm(3) who had not previously received T MP/SMX for PCP prophylaxis were randomized to receive either daily TMP/SMX DS tablets or a gradually increasing dose of TMP/SMX suspension. The suspen sion dose was increased to reach the equivalent of a DS tablet by study day 13. During the first 2 weeks, study subjects also received a matching plac ebo tablet/ suspension. After week 2, all study subjects received TMP/SMX t ablets for the next 10 weeks. There were significantly fewer study subjects who discontinued prophylaxis during the first 12 weeks when TMP/SMX therap y was initiated gradually (17%) than when initiated in DS tablet formulatio n (33%) (p = .0002). Gradual initiation was also associated with significan tly fewer adverse drug reactions. Gradual initiation of TMP/ SMX for primar y PCP prophylaxis reduces the incidence of its treatment-limiting adverse e ffects.