Successful malaria prevention for HIV-exposed children

Efficacy and safety of three regimens for the prevention of malaria in young HIV-exposed Ugandan children: a randomized controlled trial.

Kamya MR, Kapisi J, Bigira V, Clark TD, Kinara S, Mwangwa F, Muhindo MK, Kakuru A, Aweeka FT, Huang L, Jagannathan P, Achan J, Havlir DV, Rosenthal PJ, Dorsey G. AIDS. 2014 Nov 28;28(18):2701-9. doi: 10.1097/QAD.0000000000000497.

Objective: Trimethoprim-sulfamethoxazole prophylaxis is recommended for HIV-exposed infants until breastfeeding ends and HIV infection has been excluded. Extending prophylaxis with a focus on preventing malaria may be beneficial in high transmission areas. We investigated three regimens for the prevention of malaria in young HIV-exposed children.

Design: An open-label, randomized controlled trial.

Setting: Tororo, Uganda, a rural area with intense, year-round, malaria transmission.

Participants: Two hundred infants aged 4-5 months enrolled and 186 randomized after cessation of breastfeeding and confirmed to be HIV uninfected (median 10 months of age).

Intervention: No chemoprevention, monthly sulfadoxine-pyrimethamine, daily trimethoprim-sulfamethoxazole or monthly dihydroartemisinin-piperaquine given from randomization to 24 months of age.

Main outcome measures: The primary outcome was the incidence of malaria during the intervention period. Secondary outcomes included the incidence of hospitalization, diarrhoeal illness, or respiratory tract infection; prevalence of anaemia and asymptomatic parasitemia; measures of safety; and incidence of malaria over 1 year after the intervention was stopped.

Results: During the intervention, the incidence of malaria in the no chemoprevention group was 6.28 episodes per person-year at risk. Protective efficacy was 69% [95% confidence interval (95% CI) 53-80, P < 0.001] for dihydroartemisinin-piperaquine, 49% (95% CI 23-66, P = 0.001) for trimethoprim-sulfamethoxazole and 9% for sulfadoxine-pyrimethamine (95% CI -35 to 38, P = 0.65). There were no significant differences in any secondary outcomes, with the exception of a lower prevalence of asymptomatic parasitemia in the dihydroartemisinin-piperaquine arm.

Conclusion: Monthly chemoprevention with dihydroartemisinin-piperaquine was well tolerated and associated with a significant reduction in malaria in young HIV-exposed children.

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Editor’s notes: WHO recommends placing HIV-exposed but HIV-negative children on trimethoprim-sulfamethoxazole prophylaxis starting at six weeks of age, and discontinuing this prophylaxis after the period of HIV exposure. That is after breastfeeding cessation and HIV infection has been excluded.

This article reports on a four-arm randomized controlled trial examining the effect of chemoprevention beyond the period of HIV exposure. The efficacy and safety of daily trimethoprim-sulfamethoxazole, monthly sulfadoxine-pyrimethamine, and monthly dihydroartemisinin-piperaquine was compared with the current standard of care which is no chemoprevention beyond the period of HIV exposure. Children received the allocated treatment until two years of age. They were followed up for an additional year after the programme to examine whether chemoprevention would delay the acquisition of antimalarial immunity, which would lead to a rebound in the incidence of malaria after the activity, was stopped.

The trial found that continuing daily trimethoprim-sulfamethoxazole or starting monthly dihydroartemisinin-piperaquine had significant protective efficacy against malaria in comparison to the current standard of care which is the discontinuation of trimethoprim-sulfamethoxazole prophylaxis. Monthly dihydroartemisinin-piperaquine was found to be the most protective chemoprevention.

The trial found no evidence of significant protection against diarrhoeal illnesses or respiratory tract infections, and no evidence of a negative impact of chemoprevention on the development of antimalarial immunity. The authors suggest that integration of chemoprevention strategies for HIV-exposed but HIV-negative children in the era of Option B+ (initiating lifelong antiretroviral therapy among pregnant women living with HIV) needs to be further evaluated.

Interestingly the authors found a high incidence of malaria in the children who were receiving standard care, despite the use of insecticide-treated nets. They also found a discrepancy between the caregivers’ reported adherence to dihydroartemisinin-piperaquine and its blood concentrations, suggesting non-adherence to the monthly dosing schedule. 

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