Protective efficacy of co-trimoxazole prophylaxis against malaria in HIV exposed children in rural Uganda: a randomised clinical trial

Abstract

Objective To evaluate the protective efficacy of co-trimoxazole prophylaxis against malaria in HIV exposed children (uninfected children born to HIV infected mothers) in Africa.Design Non-blinded randomised control trialSetting Tororo district, rural Uganda, an area of high malaria transmission intensityParticipants 203 breastfeeding HIV exposed infants enrolled between 6 weeks and 9 months of ageIntervention Co-trimoxazole prophylaxis from enrolment until cessation of breast feeding and confirmation of negative HIV status. All children who remained HIV uninfected (n=185) were then randomised to stop co-trimoxazole prophylaxis immediately or continue co-trimoxazole until 2 years old.Main outcome measure Incidence of malaria, calculated as the number of antimalarial treatments per person year.Results The incidence of malaria and prevalence of genotypic mutations associated with antifolate resistance were high throughout the study. Among the 98 infants randomised to continue co-trimoxazole, 299 malaria cases occurred in 92.28 person years (incidence 3.24 cases/person year). Among the 87 infants randomised to stop co-trimoxazole, 400 malaria cases occurred in 71.81 person years (5.57 cases/person year). Co-trimoxazole prophylaxis yielded a 39% reduction in malaria incidence, after adjustment for age at randomisation (incidence rate ratio 0.61 (95% CI 0.46 to 0.81), P=0.001). There were no significant differences in the incidence of complicated malaria, diarrhoea, pneumonia, hospitalisations, or deaths between the two treatment arms.Conclusions Co-trimoxazole prophylaxis was moderately protective against malaria in HIV exposed infants when continued beyond the period of HIV exposure despite the high prevalence of Plasmodium genotypes associated with antifolate resistance.Trial registration Clinical Trials NCT00527800

Temporal Changes in Prevalence of Molecular Markers Mediating Antimalarial Drug Resistance in a High Malaria Transmission Setting in Uganda

“…Other reports have noted a fairly high prevalence of SNPs that mediate high-level antifolate resistance in some settings, including a pfdhfr 164L prevalence of 14% in P. falciparum from an area of Uganda with low malaria transmission intensity 29 and modest prevalence of both the pfdhfr 164L and pfdhps 581G mutations in human immunodeficiency virus (HIV)-infected Ugandan children receiving regular trimethoprim-sulfamethoxazole prophylaxis. 49,50 In other recent studies from East Africa, the prevalence of pfdhps 581G was 50% in samples from eastern Kenya and Tanzania. 27,28 In our results from Tororo, the pfdhfr 164L and pfdhps 581G mutations were very uncommon, except for increased prevalence from 2008 to 2011.…”

The epidemiological impact of HIV antiretroviral therapy on malaria in children

“…Because we only measured the benefit of protease inhibitors, our model’s predicted annual malaria incidence per person for HIV-infected children was above the incidence levels from the Ugandan clinical study [5]. This is due, in part, to compounding protective factors in the Ugandan clinical study, such as the significant antimalarial benefit that all HIV infected children received from the antimicrobial, trimethoprim-sulfamethoxazole [39]. In addition, the clinical study on the effect of protease inhibitors on malaria incidence determined that HIV-infected children treated with protease inhibitor-based HAARTendure 0.93 less annual malaria incidence per person [5] in comparison to their NNRTI-based HAART counterparts.…”

In Vitro and In Vivo Antimalarial Efficacies of Optimized Tetracyclines

“…In the developing world, antimalarial drugs are increasingly considered components of malaria control. In particular, the use of intermittent preventive therapy and seasonal malaria chemoprevention in high-risk groups has offered benefits to children and pregnant women (7,28,29), and regular use of trimethoprim-sulfamethoxazole in patients with HIV infection has led to dramatic reductions in malaria incidence (30). However, to date these approaches are highly dependent on antifolates, which are losing efficacy because of parasite resistance.…”