Background Cotrimoxazole (CTX) prophylaxis reduces mortality among HIV-infected children, but no randomized trial has evaluated efficacy in HIV-exposed uninfected (HEU) children in a non-malarial, low-breastfeeding setting. Methods HEU children in Botswana were randomized to CTX or placebo from age 14–34 days through 15 months. Mothers chose infant feeding method. Breastfed children were randomized to breastfeeding for duration of 6 months (Botswana guidelines) or 12 months (World Health Organization guidelines). Primary analysis was modified intent-to-treat, comparing cumulative mortality for CTX versus placebo, and HIV-free survival for breastfeeding duration, from randomization to 18 months. Findings From June 2011–April 2015, 2848 HEU children were randomized (1423 CTX, 1425 placebo); the study was stopped early by the Data Safety Monitoring Board for low likelihood of showing CTX benefit. Only 5% of children were lost to follow-up, and 72% received continuous study drug through 15 months, death or study closure. Post-randomization mortality was similar between CTX/placebo arms: 30 children died in the CTX arm vs. 34 in the placebo arm; estimated mortality at 18 months was 2·4% vs. 2·6%, respectively (difference: −0·2%; 95%CI: −1·5%, 1·0%, p=0·70). At 18 months, no difference by CTX vs. placebo was noted for hospitalization (12·5% vs. 17·4%, p=0·19), grade 3/4 diagnoses (16·5% vs. 18·4%, p=0·18), or grade 3/4 anemia (8·1% vs. 8·3%, p=0·93). More infants in the CTX arm experienced grade 3/4 neutropenia (8·1% vs. 5·8%, p=0·03), and more CTX resistance was detected in commensal E. coli from stool at 3 and 6 months (p=0·001 and p=0·01, respectively). Only 572 (20%) infants breastfed; no significant difference in the composite endpoint of child HIV-infection or mortality was observed by 6 vs. 12 months randomized breastfeeding duration (3.9%% vs. 1.9%, p=0·21). Interpretation Prophylactic CTX did not improve 18-month survival among HEU children in a non-malarial area of Botswana. In non-malarial settings with very low risk for MTCT, prolonged CTX for HIV-exposed children may not be required.

Introduction Non-citizens often face barriers to HIV care and treatment. Quantifying knowledge of positive HIV status and antiretroviral therapy (ART) coverage among non-citizens in a high HIV-prevalence country like Botswana that is close to achieving UNAIDS “90-90-90” targets may expose important gaps in achieving universal HIV testing and treatment. Methods The Botswana Combination Prevention Project (BCPP) is a pair-matched cluster-randomized trial evaluating the impact of prevention interventions on HIV incidence in 30 rural or peri-urban communities. Community case finding and HIV testing were conducted in home and mobile venues in 15 intervention communities from October 2013-September 2017. In this secondary analysis, we compared HIV positivity, knowledge of positive HIV-status, and ART status among all citizens and non-citizens assessed at intake in the intervention communities. Results HIV status was assessed in 57,556 residents in the intervention communities; 4% (n = 2,463) were non-citizens. Five communities accounted for 81% of the total non-citizens assessed. A lower proportion of non-citizens were HIV-positive (15%; n = 369) compared to citizens (21%; n = 11,416) [p = 0.026]; however, a larger proportion of non-citizens did not know their HIV-positive status prior to BCPP testing (75%) as compared to citizens (15%) [p = 0.003]. Among residents with knowledge of their HIV-positive status before BCPP, 79% of the non-citizens (72/91) were on ART compared to 86% (8,267/9,652) of citizens (p = 0.137). Conclusions Although non-citizens were less likely to know their HIV-positive status compared to citizens, there were no differences in treatment uptake among non-citizens and citizens who knew their status. Designing interventions for non-citizens that provide HIV testing and treatment services commensurate to that of citizens as well as targeting communities with the largest number of non-citizens may help close a meaningful gap in the HIV care cascade and ensure ethical treatment for all HIV-positive persons. Trial registration ClinicalTrials.gov: NCT01965470 (Botswana Combination Prevention Project).

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