Safety, tolerability, and efficacy of repeated doses of dihydroartemisinin-piperaquine for prevention and treatment of malaria: a systematic review and meta-analysis

Abstract

Background: Intermittent preventive treatment (IPT) for malaria is used in infants, children, adults, and pregnant women. Dihydroartemisinin-piperaquine (DP) is an effective, well tolerated artemisinin-based combination therapy. The long half-life of piperaquine makes it attractive for IPT. We conducted a systematic review and meta-analysis to establish the efficacy and safety of repeated treatment with DP.

Methods: Following PRISMA guidelines, we searched multiple databases on Sept 1, 2016, with the terms: "human" AND "dihydroartemisinin-piperaquine" OR "DHA-PPQ". Studies were eligible if they were randomised controlled trials (RCTs) or prospective cohort studies involving repeat exposures to standard 3-day courses of DP for either seasonal malaria chemoprevention, mass drug administration, or treatment of clinical malaria, conducted at any time and in any geographic location. Random-effects meta-analysis was used to generate pooled incidence rate ratios and relative risks, or risk differences.

Findings: 11 studies were included: two repeat treatment studies (one in children younger than 5 years and one in pregnant women), and nine IPT trials (five in children younger than 5 years, one in schoolchildren, one in adults, two in pregnant women). Comparator interventions included placebo, artemether-lumefantrine, sulfadoxine-pyrimethamine (SP), SP+amodiaquine, SP+piperaquine, SP+chloroquine, and co-trimoxazole. Of 14 628 participants, 3935 received multiple DP courses (2-18). Monthly IPT-DP was associated with an 84% reduction in the incidence of malaria parasitaemia measured by microscopy compared with placebo. Monthly IPT-DP was associated with fewer serious adverse events than placebo, daily co-trimoxazole, or monthly SP. Among 56 IPT-DP recipients (26 children, 30 pregnant women) with cardiac parameters, all QTc intervals were within normal limits, with no significant increase in QTc prolongation with increasing courses of DP.

Interpretation: Monthly DP appears well tolerated and effective for IPT. Additional data are needed in pregnancy and to further explore the cardiac safety with monthly dosing.

Funding: Bill & Melinda Gates Foundation and NIH.

Figure 1

PRISMA flow chart DP=dihydroartemisinin-piperaquine. AL=artemether-lumefantrine. A second trial reporting on the use of DP for rescue treatment among pregnant women included nine women who received at least two courses of DP (six received three courses and three received two courses), but all women had also received a preceding course of either quinine or intravenous artesunate with or without clindamycin, and there were no control women who had not received DP. *One trial comparing seasonal malaria chemoprevention (SMC) with sulphadoxine-pyrimethamine plus amodiaquine vs placebo SMC (passive case detection and case management with either DP or AL during the malaria transmissions season) was excluded because only 27 of 800 children (3·4%) in placebo SMC group (ie, the DP case management group) received two or more courses of DP and safety data by number of courses received were not available.

Figure 2

Pooled incidence rate ratio for any parasitaemia, monthly dihydroartemisinin-piperaquine vs placebo DP=dihydroartemisinin-piperaquine. PYAR=person-years at risk. IR=incidence rate. IRR=incidence rate ratio. Lwin and colleagues and Zongo and colleagues did not report PYAR, instead they reported cumulative incidence over a year. PYAR was calculated based on the incidence rate and number of events. Zongo and colleagues' numbers are based on intent to treat.

Figure 3

Pooled incidence rate ratio or relative risk for any parasitaemia, monthly dihydroartemisinin-piperaquine vs any other therapy DP=dihydroartemisinin-piperaquine. PYAR=person-years at risk. IR=incidence rate. IRR=incidence rate ratio. CTX=co-trimoxazole. SP=sulfadoxine-pyrimethamine. SP+PQ=sulfadoxine-pyrimethamine piperaquine. SP+AQ=sulfadoxine-pyrimethamine amodiaquine. AL=artemether lumefantrine. Lwin and colleagues and Zongo and colleagues did not report PYAR. PYAR was calculated based on the incidence rate and number of events. Cisse and colleagues reported cumulative incidence. Kakuru reported detection of malaria parasites by LAMP at each visit as the prevalence of positive tests during pregnancy out of all tests. Zongo and colleagues' numbers are based on intention to treat.

Figure 4

Pooled odds ratios for any serious adverse event after exposure to dihydroartemisinin-piperaquine stratified by comparator therapy DP=dihydroartemisinin-piperaquine. SAE=serious adverse event. CTX=co-trimoxazole. IPT=intermittent preventive treatment. IST=intermittent screening and treatment. SP=sulfadoxine-pyrimethamine. SP+PQ=sulfadoxine-pyrimethamine piperaquine. SP+AQ=sulfadoxine-pyrimethamine amodiaquine. SP+CQ=sulfadoxine-pyrimethamine chloroquine. AL=artemether-lumefantrine. Zongo and colleagues' numbers are based on actual drug exposures. Poespoprodjo and colleagues: only 64 of 408 DP recipients received two or more courses of DP, but information of SAEs by number of courses received was not available.

Figure 5

Pooled odds ratios for death after exposure to repeated courses of dihydroartemisinin-piperaquine stratified by comparator therapy Comparisons with zero events in both groups were excluded from the analysis of the pooled OR. OR=odds ratio. DP=dihydroartemisinin-piperaquine. CTX=co-trimoxazole. IPT=intermittent preventive treatment. IST=intermittent screening and treatment. SP=sulfadoxine-pyrimethamine. SP+PQ=sulfadoxine-pyrimethamine piperaquine. SP+AQ=sulfadoxine-pyrimethamine amodiaquine. SP+CQ=sulfadoxine-pyrimethamine chloroquine. AL=artemether-lumefantrine. Zongo and colleagues' numbers are based on actual drug exposures. Poespoprodjo and colleagues: only 64 of 408 DP recipients received two or more courses of DP.