Estimating the Impact of Alternative Programmatic Cotrimoxazole Strategies on Mortality Among Children Born to Mothers with HIV: A Modelling Study

BACKGROUND World Health Organization guidelines recommend cotrimoxazole prophylaxis for children who are HIV-exposed until infection is excluded and vertical transmission risk has ended. While cotrimoxazole has benefits for children with HIV, there is no mortality benefit for children who are HIV-exposed but uninfected, prompting a review of global guidelines. Here, we model the potential impact of alternative cotrimoxazole strategies on mortality in children who are HIV-exposed. METHODS AND FINDINGS Using a deterministic compartmental model, we estimated mortality in children who are HIV-exposed from 6 weeks to 2 years of age in four high-burden countries: Côte d’Ivoire, Mozambique, Uganda, and Zimbabwe. Vertical transmission rates, testing rates, and antiretroviral therapy uptake were derived from UNAIDS data, trial evidence, and meta-analyses. We explored six programmatic strategies: maintaining current recommendations; shorter cotrimoxazole provision for three, six, nine or twelve months; and starting cotrimoxazole only for children diagnosed with HIV. Modelled alternatives to the current strategy increased mortality to varying degrees; countries with high vertical transmission had the greatest mortality. Compared to current recommendations, starting cotrimoxazole only after a positive HIV test had the greatest predicted increase in mortality: Mozambique (961 excess annual deaths; excess mortality 339 per 100,000 HIV-exposed children; risk ratio (RR) 1.06), Uganda (491; 221; RR 1.04), Zimbabwe (352; 260; RR 1.05), Côte d’Ivoire (125; 322; RR 1.06). Similar effects were observed for three, six, nine, and twelve-month strategies. Increased mortality persisted but was attenuated when modelling lower cotrimoxazole uptake, smaller mortality benefits, higher testing coverage, and lower vertical transmission rates. The study is limited by uncertain estimates of cotrimoxazole coverage in programmatic settings; an inability to model increases in mortality arising from antimicrobial resistance due to limited surveillance data in sub-Saharan Africa; and lack of a formal health economic analysis. CONCLUSIONS Changing current guidelines from universal cotrimoxazole provision for children who are HIV-exposed increased predicted mortality across the four modelled high-burden countries, depending on test-to-treat cascade coverage and vertical transmission rates. These findings can help inform policymaker deliberations on cotrimoxazole strategies, recognising that the risks and benefits differ across settings. Author Summary Why Was This Study Done? Cotrimoxazole prophylaxis is recommended in World Health Organization (WHO) guidelines for all children born to mothers with HIV until HIV infection has been excluded by an age-appropriate HIV test to establish the final diagnosis after complete cessation of breastfeeding. Though there is a proven mortality benefit for children who acquire HIV, recent trial evidence has shown that cotrimoxazole does not reduce mortality for majority of children who are HIV-exposed uninfected (HEU), which has led to countries considering changing their guidelines. In many resource-limited settings, however, it is difficult to reliably distinguish children with HIV from children who are HEU, due to incomplete coverage of early infant diagnosis (EID) of HIV. There is a need to model to what extent alternative cotrimoxazole strategies, which either do not provide universal cotrimoxazole for all infants who are HIV-exposed, or provide it for a shorter duration, would be predicted to increase mortality in different settings among infants who acquire HIV but are undiagnosed. What Did the Researchers Do and Find? This study uses mathematical modelling based on epidemiological data from four high-burden settings (Côte d’Ivoire, Mozambique, Uganda, and Zimbabwe) to estimate the effect on mortality of alternative programmatic cotrimoxazole strategies. The model incorporates the HIV status of the infant, perinatal and postnatal transmission rates, testing rates, and mortality benefits from trial evidence for cotrimoxazole and antiretroviral therapy (ART) across six different programmatic strategies: maintaining current recommendations; reducing the duration of cotrimoxazole provision to three, six, nine or twelve months; or starting cotrimoxazole only once a child tests positive for HIV. We demonstrate that changing the current strategy is predicted to increase mortality in all four settings, with the greatest increase in mortality in countries with the highest vertical transmission rates. Increased predicted mortality persisted in sensitivity analyses considering conservative model estimates, although cotrimoxazole had fewer predicted benefits when vertical transmission rates were lowered, testing coverage improved or uptake of cotrimoxazole was reduced. What Do These Findings Mean? Changing the current strategy of cotrimoxazole provision for all children born to mothers with HIV is estimated to increase mortality in these four high-burden settings to varying degrees as countries continue to scale up Prevention of Mother to Child Transmission of HIV (PMTCT) and EID coverage. Cotrimoxazole continues to provide important protection to children who acquire HIV and are missed by gaps in the test-to-treatment cascade, but does not replace the importance of timely testing and treatment. Our study is limited by lack of cost-effectiveness analysis, lack of data on cotrimoxazole uptake, and limited antimicrobial resistance surveillance data in sub-Saharan Africa. Policymakers need to weigh the risks and benefits of cotrimoxazole prophylaxis through any change to current recommendations, noting that these differ across settings: where lower vertical transmission rates and improved testing and treatment uptake occurs, the estimated mortality benefits of cotrimoxazole are attenuated.