In order to estimate compliance and a possible dose-effect relationship, pyrimethamine (Pyr.) serum levels were measured in ANRS 005-ACTG 154 trial, a double blind placebo controlled study of Pyr. as primary prophylaxis for toxoplasmic encephalitis (TE) (J. Infect. Dis. Jan 1996). Pyr. was given in 50-mg oral doses, thrice weekly. In the intent to treat analysis (n=554) the rate of TE was similar in Pyr. 12% and placebo group, 13%. Levels of Pyr. were determined by HPLC, in sera sampled at month 4, 12 and 24 in pts on study drug. For each pt, we used the mean level based on the results of all (1 to 3) determinations. Among the 554 pts, 390 had at least one determination of Pyr. level, 206/280 (74%) placebo-pts and 184/274 (67%) Pyr.-pts. Baseline characteristics of the 390 pts were not different from those of the 554 pts. In the Pyr. group, mean (+/-SD) levels of Pyr.(mg/1) were 0.63 +/- 0.51 at mth 4 (n=162) and 0.60 +/- 0.50 at mth 12 (n=l12). In the placebo group, 15/206 (6%) pts had Pyr. levels greater than 0.1 mg/l, whereas 16/184 (6%) Pyr. pts had unexplained levels less than 0.lmg/l, and were considered as non compliant. The 184 Pyr. pts were distributed into two subgroups according to Pyr.levels. In the 87 (47%) pts with Pyr. level less than 0.5 mg/l, the incidence of TE was 9.8% (95% CI : 4.9-17.6) pt-years, while it was 5.3% (2.1-10.9) pt-years, for the 97 pts with Pyr. level greater than 0.5mg/l. Median Pyr.level (mg/l) was 0.30 (0-1.10) in pts who developed TE, and 0.58(0-2.90) in patients who did not develop TE. These observations show that the proportion of non compliant pts in the trial was acceptable, and similar in the two groups. Owing to the highly variable half-life of Pyr. in HIV pts, they suggest that the dose of 50 mg thrice weekly might have been insufficient to prevent TE in some pts. Whether the dose of Pyr. should be adjusted in each individual pt to achieve serum levels greater than 0.5 mg/1 for efficient primary prophylaxis of TE is questionable.

Anti-Infective Agents/*BLOOD/THERAPEUTIC USE Chromatography, High Pressure Liquid Double-Blind Method Encephalitis/COMPLICATIONS/*PREVENTION & CONTROL/PARASITOLOGY Human Patient Compliance Placebos Pyrimethamine/*BLOOD/THERAPEUTIC USE Toxoplasmosis/COMPLICATIONS/*PREVENTION & CONTROL ABSTRACT

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