Co-trimoxazole for HIV-exposed uninfected infants
Authors: Ceri Evans, Andrew J Prendergast
Journal: The Lancet Global Health (2017)

The reduction in mother-to-child transmission (MTCT) of HIV is one of the greatest success stories of the antiretroviral therapy (ART) era. However, evidence is accumulating that, despite avoiding HIV, HIV-exposed uninfected (HEU) infants have more infectious morbidity and mortality than HIV-unexposed infants.1Evans C Jones CE Prendergast AJ HIV-exposed, uninfected infants: new global challenges in the era of paediatric HIV elimination.Lancet Infect Dis. 2016; 16: e92-107Summary Full Text Full Text PDF PubMed Scopus (171) Google Scholar Because antenatal HIV prevalence is not decreasing as rapidly as reductions in MTCT,2Joint UN Programme on HIV/AIDSThe Gap Report.http://www.unaids.org/en/resources/campaigns/2014/2014gapreport/gapreportDate: 2014Google Scholar the number of HEU infants is increasing.1Evans C Jones CE Prendergast AJ HIV-exposed, uninfected infants: new global challenges in the era of paediatric HIV elimination.Lancet Infect Dis. 2016; 16: e92-107Summary Full Text Full Text PDF PubMed Scopus (171) Google Scholar Evidence-based interventions for this population are therefore important to improve child health outcomes, particularly in sub-Saharan Africa. WHO guidelines recommend co-trimoxazole prophylaxis for all infants of HIV-infected mothers, regardless of infant HIV status, from age 4–6 weeks until the end of HIV exposure (usually the end of breastfeeding). This approach was first recommended in 2000, with the aim of preventing mortality from Pneumocystis jirovecii pneumonia in infants who become infected. In HIV-infected children, co-trimoxazole also reduces invasive bacterial infections;3Mulenga V Ford D Walker AS et al.Effect of cotrimoxazole on causes of death, hospital admissions and antibiotic use in HIV-infected children.AIDS. 2007; 21: 77-84Crossref PubMed Scopus (56) Google Scholar, 4Bwakura-Dangarembizi M Kendall L Bakeera-Kitaka S et al.A randomized trial of prolonged co-trimoxazole in HIV-infected children in Africa.N Engl J Med. 2014; 370: 41-53Crossref PubMed Scopus (91) Google Scholar given the increased burden of morbidity and mortality in HEU infants, particularly from pneumonia,5Koyanagi A Humphrey JH Ntozini R et al.Morbidity among human immunodeficiency virus-exposed but uninfected, human immunodeficiency virus-infected, and human immunodeficiency virus-unexposed infants in Zimbabwe before availability of highly active antiretroviral therapy.Pediatr Infect Dis J. 2011; 30: 45-51Crossref PubMed Scopus (119) Google Scholar, 6Marinda E Humphrey JH Iliff PJ et al.Child mortality according to maternal and infant HIV status in Zimbabwe.Pediatr Infect Dis J. 2007; 26: 519-526Crossref PubMed Scopus (243) Google Scholar co-trimoxazole might have similar benefits for this population.1Evans C Jones CE Prendergast AJ HIV-exposed, uninfected infants: new global challenges in the era of paediatric HIV elimination.Lancet Infect Dis. 2016; 16: e92-107Summary Full Text Full Text PDF PubMed Scopus (171) Google Scholar, 7Church JA Fitzgerald F Walker AS Gibb DM Prendergast AJ The expanding role of co-trimoxazole in developing countries.Lancet Infect Dis. 2015; 15: 327-339Summary Full Text Full Text PDF PubMed Scopus (72) Google Scholar However, the evidence base for co-trimoxazole prophylaxis in HEU infants is weak, and current guidelines have therefore been debated.8Coutsoudis A Coovadia HM Kindra G Time for new recommendations on cotrimoxazole prophylaxis for HIV-exposed infants in developing countries?.Bull World Health Organ. 2010; 88: 949-950Crossref PubMed Scopus (17) Google Scholar Co-trimoxazole reduces the incidence of malaria in HEU infants in malaria-endemic regions,9Dow A Kayira D Hudgens M et al.Effects of cotrimoxazole prophylactic treatment on adverse health outcomes among HIV-exposed, uninfected infants.Pediatr Infect Dis J. 2012; 31: 842-847Crossref PubMed Scopus (16) Google Scholar but the benefits for HEU infants in non-malarial regions remain unclear. In areas with high antenatal HIV prevalence, such as KwaZulu-Natal, South Africa, as many as 40% of infants10UNAIDS South African National AIDS CouncilNational Department of HealthGlobal AIDS response progress report: Republic of South Africa.http://files.unaids.org/en/dataanalysis/knowyourresponse/countryprogressreports/2012countries/ce_ZA_Narrative_Report.pdfGoogle Scholar are exposed to HIV and therefore receive long-term co-trimoxazole. Such widespread use of prophylaxis drives antimicrobial resistance at a population level,7Church JA Fitzgerald F Walker AS Gibb DM Prendergast AJ The expanding role of co-trimoxazole in developing countries.Lancet Infect Dis. 2015; 15: 327-339Summary Full Text Full Text PDF PubMed Scopus (72) Google Scholar increases costs and the complexity of supply-chain logistics for health systems, and increases individual risks such as potential toxicity and adverse effects on the microbiota during a developmentally sensitive period. Given the uncertain risk–benefit ratio, further evidence is needed to guide recommendations for prophylaxis in HEU infants. The clinical trial by Shahin Lockman and colleagues11Lockman S Hughes M Powis K et al.The effect of co-trimoxazole on mortality in HIV-exposed uninfected children in Botswana (the Mpepu Study): a double-blind, randomised, placebo-controlled trial.Lancet Glob Health. 2017; 5: e491-e500Summary Full Text Full Text PDF PubMed Scopus (32) Google Scholar in The Lancet Global Health is therefore an important and timely addition to the literature. This randomised, placebo-controlled, double-blind trial in 2848 HIV-exposed infants in a non-malarial region of southern Botswana found no survival benefit of co-trimoxazole prophylaxis up to age 18 months, and recruitment was stopped early on the advice of the data safety monitoring board. This was a well conducted trial, with high retention; however, infant mortality was much lower than anticipated in the placebo group and the study was therefore only powered to detect a 50% reduction in mortality between groups. Nevertheless, results were consistent across a range of outcomes (eg, hospital admission, pneumonia, diarrhoea), and the reduction in the prespecified composite secondary endpoint of death, hospital admission, or grade 3–4 clinical diagnoses was not significant. Of note, only 20% of infants in this trial were breastfed because free formula is provided to HIV-infected mothers in Botswana; although no evidence of a difference in the efficacy of co-trimoxazole by feeding method was found, the trial was not powered to assess this interaction. A non-inferiority trial12Coutsoudis A Daniels B Moodley-Govender E et al.Randomised controlled trial testing the effect of cotrimoxazole prophylaxis on morbidity and mortality outcomes in breastfed HIV-exposed uninfected infants: study protocol.BMJ Open. 2016; 6: e010656Crossref PubMed Scopus (5) Google Scholar is currently underway in South Africa (also a non-malarial region) among breastfed HEU infants, who are being randomly assigned to receive co-trimoxazole or not; however, an even smaller benefit of co-trimoxazole in breastfed HEU infants might be expected than in Lockman and colleagues' trial, given the significant reduction in all-cause mortality associated with breastfeeding.13Lamberti LM Zakarija-Grković I Fischer Walker CL et al.Breastfeeding for reducing the risk of pneumonia morbidity and mortality in children under two: a systematic literature review and meta-analysis.BMC Public Health. 2013; 13: S18Crossref PubMed Scopus (141) Google Scholar What do these results therefore mean for policy makers? On the basis of this trial, Lockman and colleagues suggest that, in non-malarial settings with low HIV transmission and relatively low child mortality, co-trimoxazole prophylaxis might not be needed. This recommendation seems logical in view of the trial findings. Even in other settings, the only consistently reported benefit of co-trimoxazole for HEU infants is reduced malaria.9Dow A Kayira D Hudgens M et al.Effects of cotrimoxazole prophylactic treatment on adverse health outcomes among HIV-exposed, uninfected infants.Pediatr Infect Dis J. 2012; 31: 842-847Crossref PubMed Scopus (16) Google Scholar, 14Sandison TG Homsy J Arinaitwe E et al.Protective efficacy of co-trimoxazole prophylaxis against malaria in HIV exposed children in rural Uganda: a randomised clinical trial.BMJ. 2011; 342: d1617Crossref PubMed Scopus (59) Google Scholar The anti-malarial properties of co-trimoxazole would probably confer benefits even to HIV-unexposed infants, and are insufficient justification for long-term prophylaxis. However, in many regions, co-trimoxazole might continue to have important benefits for the 16% of HIV-exposed infants2Joint UN Programme on HIV/AIDSThe Gap Report.http://www.unaids.org/en/resources/campaigns/2014/2014gapreport/gapreportDate: 2014Google Scholar who still acquire HIV during pregnancy, delivery, or breastfeeding. Although the obvious solution is to improve MTCT prevention and early infant diagnosis, there is still some way to go: in 2013, only 44% of pregnant women in low-income and middle-income countries received an HIV test,2Joint UN Programme on HIV/AIDSThe Gap Report.http://www.unaids.org/en/resources/campaigns/2014/2014gapreport/gapreportDate: 2014Google Scholar and only 42% of HIV-exposed infants underwent HIV testing within 2 months of birth.2Joint UN Programme on HIV/AIDSThe Gap Report.http://www.unaids.org/en/resources/campaigns/2014/2014gapreport/gapreportDate: 2014Google Scholar Furthermore, definitive HIV testing at the end of the breastfeeding period is frequently missed.2Joint UN Programme on HIV/AIDSThe Gap Report.http://www.unaids.org/en/resources/campaigns/2014/2014gapreport/gapreportDate: 2014Google Scholar Until coverage of interventions aimed at paediatric HIV elimination is improved, co-trimoxazole prophylaxis might continue to be important in many countries. What can be done to reduce morbidity and mortality in HEU infants? Notably, a third of all mortality in the Botswana trial occurred early, before randomisation. Similarly, in a trial of more than 14 110 infants in Zimbabwe, done in the pre-MTCT-prevention era, HIV-exposed uninfected infants had 50% more hospital admissions than HIV-unexposed infants in the first 4 weeks of life.5Koyanagi A Humphrey JH Ntozini R et al.Morbidity among human immunodeficiency virus-exposed but uninfected, human immunodeficiency virus-infected, and human immunodeficiency virus-unexposed infants in Zimbabwe before availability of highly active antiretroviral therapy.Pediatr Infect Dis J. 2011; 30: 45-51Crossref PubMed Scopus (119) Google Scholar We suggest that a package of interventions might be required from birth to most effectively reduce morbidity and mortality in HEU infants. HEU infants have no specific follow-up before age 4–6 weeks, despite this being the period of highest risk, and loss to follow-up in MTCT prevention programmes is high. Future trials of alternative vaccination and prophylaxis approaches from birth might be required to improve outcomes for this growing population of infants. CE received a travel award from the European Society for Paediatric Infectious Diseases in 2016 to attend the annual conference, the money for which was funded by GlaxoSmithKline. AJP declares no competing interests. Effect of co-trimoxazole on mortality in HIV-exposed but uninfected children in Botswana (the Mpepu Study): a double-blind, randomised, placebo-controlled trialProphylactic co-trimoxazole seems to offer no survival benefit among HEU children in non-malarial, low-breastfeeding areas with a low risk of mother-to-child transmission of HIV. Full-Text PDF Open Access