Short-course primaquine for the radical cure of Plasmodium vivax malaria: a multicentre, randomised, placebo-controlled non-inferiority trial

Abstract

SummaryBackgroundPrimaquine is the only widely used drug that prevents Plasmodium vivax malaria relapses, but adherence to the standard 14-day regimen is poor. We aimed to assess the efficacy of a shorter course (7 days) of primaquine for radical cure of vivax malaria.MethodsWe did a randomised, double-blind, placebo-controlled, non-inferiority trial in eight health-care clinics (two each in Afghanistan, Ethiopia, Indonesia, and Vietnam). Patients (aged ≥6 months) with normal glucose-6-phosphate dehydrogenase (G6PD) and presenting with uncomplicated vivax malaria were enrolled. Patients were given standard blood schizontocidal treatment and randomly assigned (2:2:1) to receive 7 days of supervised primaquine (1·0 mg/kg per day), 14 days of supervised primaquine (0·5 mg/kg per day), or placebo. The primary endpoint was the incidence rate of symptomatic P vivax parasitaemia during the 12-month follow-up period, assessed in the intention-to-treat population. A margin of 0·07 recurrences per person-year was used to establish non-inferiority of the 7-day regimen compared with the 14-day regimen. This trial is registered at ClinicalTrials.gov (NCT01814683).FindingsBetween July 20, 2014, and Nov 25, 2017, 2336 patients were enrolled. The incidence rate of symptomatic recurrent P vivax malaria was 0·18 (95% CI 0·15 to 0·21) recurrences per person-year for 935 patients in the 7-day primaquine group and 0·16 (0·13 to 0·18) for 937 patients in the 14-day primaquine group, a difference of 0·02 (−0·02 to 0·05, p=0·3405). The incidence rate for 464 patients in the placebo group was 0·96 (95% CI 0·83 to 1·08) recurrences per person-year. Potentially drug-related serious adverse events within 42 days of starting treatment were reported in nine (1·0%) of 935 patients in the 7-day group, one (0·1%) of 937 in the 14-day group and none of 464 in the control arm. Four of the serious adverse events were significant haemolysis (three in the 7-day group and one in the 14-day group).InterpretationIn patients with normal G6PD, 7-day primaquine was well tolerated and non-inferior to 14-day primaquine. The short-course regimen might improve adherence and therefore the effectiveness of primaquine for radical cure of P vivax malaria.FundingUK Department for International Development, UK Medical Research Council, UK National Institute for Health Research, and the Wellcome Trust through the Joint Global Health Trials Scheme (MR/K007424/1) and the Bill & Melinda Gates Foundation (OPP1054404).

Trend of malaria prevalence in Wolkite health center: an implication towards the elimination of malaria in Ethiopia by 2030

“…Plasmodium vivax seemed to be overlooked even though there were hardly any known drug resistance has been reported in the study area for P. vivax [23]. In addition, a recent randomized trial has reported the effectiveness and safety of short-course usage of Primaquine for a radical cure in P. vivax endemic areas of Ethiopia [34]. Therefore, malaria prevention and control strategy should be reinforced particularly targeting adults and rural areas and also enhancing the capacity of laboratory personnel in malaria identification is very essential to reduce the prevalence of malaria in the study area.…”

Implementing Radical Cure Diagnostics for Malaria: User Perspectives on G6PD Testing in Bangladesh

“…The WHO recommends that all patients should be tested for G6PD de ciency (G6PDd) prior to administration of PQ or TQ, and de cient patients offered alternative treatment regimens (5). Shorter treatment regimens, including TQ or a 7 day high daily dose PQ regimens, are e cacious (6,7), but increase the risk of drug-induced hemolysis and thus the need for prior screening for G6PD de ciency.…”

Cost-Effectiveness Analysis of Sex-Stratified Plasmodium vivax Treatment Strategies Using Available G6PD Diagnostics to Accelerate Access to Radical Cure

“…19 In some locations, the risk of P. vivax infection differs between males and females; accordingly, the proportion of males in the model population was derived from the proportion in adults enrolled into the clinical trial. 5 Usual care for P. vivax malaria is chloroquine plus PQ14 in Afghanistan and Vietnam, DHA-piperaquine plus PQ14 in Indonesia, and chloroquine alone in Ethiopia. Glucose-6phosphate dehydrogenase testing is not part of routine care in any of these countries.…”

“…Two recent studies have shown that a 7-day high-dose primaquine regimen (PQ7, total dose 7 mg/kg) was well tolerated with a similar efficacy to the same total dose administered more than 14 days. 5,6 Although a high-dose short-course 7-day regimen may improve adherence, it has yet to be implemented into policy. For the purpose of this study, PQ14 corresponds to the low-dose regimen and PQ7 to the high-dose regimen.…”