Co-trimoxazole prophylaxis for children who are HIV-exposed and uninfected: a systematic review

Abstract

Introduction: Co-trimoxazole prophylaxis is recommended for children born to women with HIV to protect those who acquire HIV from opportunistic infections, severe bacterial infections and malaria. With scale-up of maternal antiretroviral therapy, most children remain HIV-exposed uninfected (HEU) and the benefits of universal co-trimoxazole are uncertain. We assessed the effect of co-trimoxazole on mortality and morbidity of children who are HEU.

Methods: We performed a systematic review (PROSPERO number: CRD42021215059). We systematically searched MEDLINE, Embase, Cochrane CENTRAL, Global Health, CINAHL Plus, Africa-Wide Information, SciELO and WHO Global Index Medicus for peer-reviewed articles from inception to 4th January 2022 without limits. Ongoing randomized controlled trials (RCTs) were identified through registries. We included RCTs reporting mortality or morbidity in children who are HEU receiving co-trimoxazole versus no prophylaxis/placebo. The risk of bias was assessed using the Cochrane 2.0 tool. Data were summarized using narrative synthesis and findings were stratified by malaria endemicity.

Results: We screened 1257 records and included seven reports from four RCTs. Two trials from Botswana and South Africa of 4067 children who are HEU found no difference in mortality or infectious morbidity in children randomized to co-trimoxazole prophylaxis started at 2-6 weeks of age compared to those randomized to placebo or no treatment, although event rates were low. Sub-studies found that antimicrobial resistance was higher in infants receiving co-trimoxazole. Two trials in Uganda investigating prolonged co-trimoxazole after breastfeeding cessation showed protection against malaria but no other morbidity or mortality differences. All trials had some concerns or a high risk of bias, which limited the certainty of evidence.

Discussion: Studies show no clinical benefit of co-trimoxazole prophylaxis in children who are HEU, except to prevent malaria. Potential harms were identified for co-trimoxazole prophylaxis leading to antimicrobial resistance. The trials in non-malarial regions were conducted in populations with low mortality potentially reducing generalizability to other settings.

Conclusions: In low-mortality settings with few HIV transmissions and well-performing early infant diagnosis and treatment programmes, universal co-trimoxazole may not be required.

Keywords: HIV exposure; co-trimoxazole; infants; morbidity; mortality; public health.

Figure 1

PRISMA flow diagram. PRISMA 2020 flow diagram for new systematic reviews which included searches of databases and registers only. Template accessed from: www.prisma‐statement.org. Adapted from: Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372:n71. https://doi.org/10.1136/bmj.n71. *Reasons for exclusion were primarily population criteria (children living with HIV instead of children who were HIV‐exposed and uninfected) or design criteria (studies were not randomized controlled trials). **For all conference abstracts, we found and checked the equivalent full‐text article.

Figure 2

Synthesis of included studies. Abbreviations: BF, breastfeeding; CTX, co‐trimoxazole prophylaxis. Notes: Daniels et al.: Duration of breastfeeding over 12 months: 50% with co‐trimoxazole; 47% with no co‐trimoxazole breastfed; median duration not reported. Sandison et al.: Median age at randomization 9.6 months (IQR 8.3–12.4) in co‐trimoxazole continued group versus 10.0 months (8.9–13.5) in the co‐trimoxazole stopped group. Kamya et al.: Median age at randomization 11.6 months (6.2–18.7) in the co‐trimoxazole group versus 10.0 months (6.0–18.0) in the no co‐trimoxazole group.

Figure 3

GRADE assessment including studies examining the primary research question. The goal of this GRADE table was to assess the primary question of whether co‐trimoxazole prophylaxis started in infancy impacts morbidity and mortality of children who are HIV‐exposed and uninfected. Therefore, due to indirectness, we did not include the Ugandan studies here. ^aRisk of bias: some concerns to high risk; ^bIndirectness: low mortality and unclear generalizability to other LMIC settings. ^cImprecision: both trials did not reach their calculated sample size due to stopping early. Figure created using GRADEPRO software (https://gradepro.org/).