A randomized trial of prolonged co-trimoxazole in HIV-infected children in Africa

Abstract

Background: Co-trimoxazole (fixed-dose trimethoprim-sulfamethoxazole) prophylaxis administered before antiretroviral therapy (ART) reduces morbidity in children infected with the human immunodeficiency virus (HIV). We investigated whether children and adolescents receiving long-term ART in sub-Saharan Africa could discontinue co-trimoxazole.

Methods: We conducted a randomized, noninferiority trial of stopping versus continuing daily open-label co-trimoxazole in children and adolescents in Uganda and Zimbabwe. Eligible participants were older than 3 years of age, had been receiving ART for more than 96 weeks, were using insecticide-treated bed nets (in malaria-endemic areas), and had not had Pneumocystis jirovecii pneumonia. Coprimary end points were hospitalization or death and adverse events of grade 3 or 4.

Results: A total of 758 participants were randomly assigned to stop or continue co-trimoxazole (382 and 376 participants, respectively), after receiving ART for a median of 2.1 years (interquartile range, 1.8 to 2.3). The median age was 7.9 years (interquartile range, 4.6 to 11.1), and the median CD4 T-cell percentage was 33% (interquartile range, 26 to 39). Participants who stopped co-trimoxazole had higher rates of hospitalization or death than those who continued (72 participants [19%] vs. 48 [13%]; hazard ratio, 1.64; 95% confidence interval [CI], 1.14 to 2.37; P = 0.007; noninferiority not shown). There was no evidence of variation across ages (P=0.93 for interaction). A total of 2 participants in the prophylaxis-stopped group (1%) died, as did 3 in the prophylaxis-continued group (1%). Most hospitalizations in the prophylaxis-stopped group were for malaria (49 events, vs. 21 in the prophylaxis-continued group) or infections other than malaria (53 vs. 25), particularly pneumonia, sepsis, and meningitis. Rates of adverse events of grade 3 or 4 were similar in the two groups (hazard ratio, 1.20; 95% CI, 0.83 to 1.72; P=0.33), but more grade 4 adverse events occurred in the prophylaxis-stopped group (hazard ratio, 2.04; 95% CI, 0.99 to 4.22; P=0.05), with anemia accounting for the largest number of events (12, vs. 2 with continued prophylaxis).

Conclusions: Continuing co-trimoxazole prophylaxis after 96 weeks of ART was beneficial, as compared with stopping prophylaxis, with fewer hospitalizations for both malaria and infection not related to malaria. (Funded by the United Kingdom Medical Research Council and others; ARROW Current Controlled Trials number, ISRCTN24791884.).

Figures

Figure 1. Study Enrollment, Randomization, and Follow-up

Among 1145 participants in the Antiretroviral Research for Watoto (ARROW) trial who had received 96 weeks of antiretroviral therapy (ART) or were at least 3 years of age, 133 were not approached to undergo randomization (e.g., because the participant attended the clinic without a caregiver who could be approached to provide informed consent). A total of 252 participants in the ARROW trial were eligible for randomization but declined, predominantly because of strong caregiver beliefs in the benefits of co-trimoxazole. A total of 2 participants (both in the stop-treatment group) were receiving dapsone prophylaxis and had undergone randomization in error; they were not included in the analysis. A total of 5 participants were ineligible for this study but were nevertheless included in the analysis: 2 participants (both in the prophylaxis-continued group) had received less than 96 weeks of ART, and 3 (2 participants in the prophylaxis-stopped group and 1 in the prophylaxis-continued group) had received a diagnosis of Pneumocystis jirovecii pneumonia; however, the diagnosis was not considered to be definitive, it occurred before enrollment, and it was not considered by the treating clinician to be plausible. In the prophylaxis-continued group, 1 participant temporarily discontinued co-trimoxazole at randomization and restarted it 1 month later. In the prophylaxis-stopped group, 3 participants continued to receive co-trimoxazole in error; 1 participant stopped prophylaxis 4 months after randomization, but the other 2 did not stop once the error was identified, owing to caregiver preference. In the prophylaxis-continued group, 3 participants stopped receiving co-trimoxazole (median duration of prophylaxis, 62 weeks [range, 42 to 78]); 2 participants stopped for approximately 6 weeks owing to clinic error, and 1 stopped intentionally when she became pregnant. In the prophylaxis-stopped group, 22 participants restarted co-trimoxazole (median duration until restarting, 30 weeks [range, 1 day to 95 weeks]).The reasons for restarting prophylaxis included caregiver concern (in the case of 14 participants) and clinician concern (in the case of 4: 1 with tuberculosis, 1 with P. jirovecii pneumonia, and 2 with low CD4 T-cell counts); prophylaxis was temporarily restarted in 2 patients owing to clinic or caregiver error, and no reason was provided for 2. The study ended on March 16, 2012; the minimum follow-up was 48 weeks in the prophylaxis-continued group and 30 weeks in the prophylaxis-stopped group.

Figure 2. First Hospitalization or Death and First Diagnostically Confirmed Episode of Malaria in Participants Who Continued or Stopped Co-trimoxazole Prophylaxis

All hazard ratios were stratified according to randomization factors, with P values calculated from the stratified log-rank test. The number of patients who would need to be treated with co-trimoxazole for 1 year to prevent a first hospitalization or death was 25 (Panel A); the number need to treat in order to prevent a first episode of malaria was 16 (Panel B).

Figure 3. Changes in Laboratory and Anthropometric Variables

The between-group differences in changes from randomization to 12 weeks (prophylaxis-stopped group minus prophylaxis-continued group) are shown. Vertical lines indicate 95% confidence intervals.