Abstract
WHO recommends daily co-trimoxazole for children born to HIV-infected mothers from 6 weeks of age until breastfeeding cessation and exclusion of HIV infection. We have previously reported on the effectiveness of continuation of co-trimoxazole prophylaxis up to age 2 years in these children. We assessed the protective efficacy and safety of prolonging co-trimoxazole prophylaxis until age 4 years in HIV-exposed children. We undertook an open-label randomised controlled trial alongside two observational cohorts in eastern Uganda, an area with high HIV prevalence, malaria transmission intensity, and antifolate resistance. We enrolled HIV-exposed infants between 6 weeks and 9 months of age and prescribed them daily co-trimoxazole until breastfeeding cessation and HIV-status confirmation. At the end of breastfeeding, children who remained HIV-uninfected were randomly assigned (1:1) to discontinue co-trimoxazole or to continue taking it up to age 2 years. At age 2 years, children who continued co-trimoxazole prophylaxis were randomly assigned (1:1) to discontinue or continue prophylaxis from age 2 years to age 4 years. The primary outcome was incidence of malaria (defined as the number of treatments for new episodes of malaria diagnosed with positive thick smear) at age 4 years. For additional comparisons, we observed 48 HIV-infected children who took continuous co-trimoxazole prophylaxis and 100 HIV-unexposed uninfected children who never received prophylaxis. We measured grade 3 and 4 serious adverse events and hospital admissions. All children were followed up to age 5 years and all analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00527800. 203 HIV-exposed infants were enrolled between Aug 10, 2007, and March 28, 2008. After breastfeeding ended, 185 children were not infected with HIV and were randomly assigned to stop (n=87) or continue (n=98) co-trimoxazole up to age 2 years. At age 2 years, 91 HIV-exposed children who had remained on co-trimoxazole prophylaxis were randomly assigned to discontinue (n=46) or continue (n=45) co-trimoxazole from age 2 years to age 4 years. We recorded 243 malaria episodes (2·91 per person-years) in the 45 HIV-exposed children assigned to continue co-trimoxazole until age 4 years compared with 503 episodes (5·60 per person-years) in the 46 children assigned to stop co-trimoxazole at age 2 years (incidence rate ratio 0·53, 95% CI 0·39-0·71; p< 0·0001). There was no evidence of malaria incidence rebound in the year after discontinuation of co-trimoxazole in the HIV-exposed children who stopped co-trimoxazole at age 2 years, but incidence increased significantly in HIV-exposed children who stopped co-trimoxazole at age 4 years (odds ratio 1·78, 95% CI 1·19-2·66; p= 0·005). Incidence of grade 3 or 4 serious adverse events, hospital admissions, or deaths did not significantly differ between HIV-exposed, HIV-unexposed, and HIV-infected children.
Highlights
To reduce the risk of HIV-associated opportunistic infections, WHO recommends that infants born to HIVinfected mothers and exposed to HIV through breastfeeding (HIV-exposed children) receive cotrimoxazole prophylaxis from 6 weeks of age until breastfeeding ends and HIV infection can be excluded.[1,2]
Exclusion of HIV infection in infants younger than 12 months has to be done via the detection of HIV DNA due to the persistence of maternal antibodies in HIVexposed children’s blood until 12–18 months of age,[11,12] and HIV DNA testing can be costly and difficult to access.[13,14] www.thelancet.com/lancetgh Vol 2 December 2014
In 2011, we reported the results of a randomised controlled trial showing that prolongation of co-trimoxazole prophylaxis in HIVexposed children beyond breastfeeding cessation to age 2 years was safe and resulted in a 39% protective efficacy against malaria.[17]
Summary
HIV and malaria combined cause 2·2 million deaths worldwide.[15,16] In sub-Saharan Africa, more than 1 million deaths every year are attributed to dual infection in children.[16] In 2005, a randomised trial provided evidence that co-trimoxazole prophylaxis protected children aged 5–15 years against malaria in an area of Mali with low HIV prevalence.[6] In 2011, we reported the results of a randomised controlled trial showing that prolongation of co-trimoxazole prophylaxis in HIVexposed children beyond breastfeeding cessation to age 2 years was safe and resulted in a 39% protective efficacy against malaria.[17] We present the final results of the trial up to age 5 years. Our present hypotheses were that extending co-trimoxazole prophylaxis from age 2 to age 4 years would be associated with a reduction in the incidence of malaria and that between age 4 and age 5 years, the incidence of malaria would be higher among children who stopped co-trimoxazole at 4 years of age compared with children who stopped co-trimoxazole after cessation of breastfeeding or at 2 years of age
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