Effect of higher dose primaquine for the radical cure of Plasmodium vivax in Indonesia: a systematic review and individual patient data meta-analysis

BackgroundPlasmodium vivax malaria has diverse transmission and relapse patterns in Indonesia. The optimal dose of primaquine to prevent relapses across the country is unknown. We evaluated the anti-relapse efficacy, gastrointestinal tolerability, and haematological safety (G6PD activity [&ge;]30%) of different primaquine regimens in varied endemic settings in Indonesia. MethodsWe systematically searched for studies published between 1 January 2000 and 23 July 2024 prospectively enrolling patients with acute uncomplicated P. vivax malaria where some patients were treated with primaquine. Individual patient data (IPD) from eligible studies were pooled and harmonised. We fitted one-stage IPD multivariable regression models to estimate the causal relationship between the body weight-adjusted primaquine dose with three separate primary outcomes: (i) the time to first P. vivax recurrence (days 7-180), (ii) any gastrointestinal discomfort (days 5-7), and (iii) [&ge;]25% reduction relative to baseline haemoglobin and a reduction to <7 g/dL (days 1-14). FindingsOf ten eligible studies, seven were available for inclusion. Compared with a total dose of 3{middle dot}5 mg/kg primaquine, patients treated with a total dose of 7 mg/kg had a lower rate of recurrence over 6 months (adjusted hazard ratio 0{middle dot}53; 95% confidence interval [CI] 0{middle dot}45 to 0{middle dot}63; n = 1797); the relative efficacy was consistent across regions, but the absolute benefit varied. Gastrointestinal discomfort was more frequent with higher doses (adjusted risk ratio 1{middle dot}32 per 0{middle dot}25 mg/kg daily dose; 95% CI 1{middle dot}15 to 1{middle dot}51; n = 952). In 822 patients available to be assessed for haematological safety (788 [96%] with G6PD activity [&ge;]70% and 34 [4%] with activity 30% to <70%), only one patient developed clinically relevant haemolysis. InterpretationAcross all transmission settings in Indonesia, a total dose of 7 mg/kg halved the rate of recurrent P. vivax malaria over a 6-month period compared with the low dose of 3{middle dot}5 mg/kg. However, increased daily doses slightly increased risks of gastrointestinal discomfort and haemolysis. FundingNDM Tropical Network Fund, Bill and Melinda Gates Foundation Research in contextO_ST_ABSEvidence before this studyC_ST_ABSIndonesia is a geographically vast country with heterogeneous patterns of periodicity and varying magnitudes of risk for Plasmodium vivax relapse. However, the optimal regimen for the radical cure of P. vivax is unknown. The national antimalarial guidelines continue to recommend a low-dose regimen of 3{middle dot}5 mg/kg without routine glucose-6-phosphate dehydrogenase (G6PD) testing. We systematically searched for trials conducted in Indonesia that randomly assigned patients with P. vivax malaria to primaquine dosing regimens. Articles published in any language between 1 January 2000 and 23 July 2024, using the terms "vivax" and "primaquine" in MEDLINE, Embase, Web of Science, Scopus, and the Cochrane Library were identified. No published randomised controlled trial directly comparing high-dose ([&ge;]5 mg/kg total) versus low-dose (2 to <5 mg/kg total) primaquine in Indonesia was identified. We identified two trials that randomised patients with P. vivax malaria to receive either high-dose (target total dose of 7 mg/kg over seven or 14 days) or low-dose (3{middle dot}5 mg/kg over 14 days) primaquine, compared with placebo, in combination with dihydroartemisinin-piperaquine. One multi-country trial included two study sites in Sumatra: Hanura and Tanjung Leidong. Compared with placebo, high-dose primaquine reduced relapse by 60-89%. In another trial, patients acquired infections in Papua and were followed in malaria-free East Java. Low-dose primaquine reduced relapse by 74% compared with placebo. Added value of this studyThis country-specific systematic review and individual patient data meta-analysis included 1797 patients from seven studies evaluating anti-relapse efficacy, gastrointestinal tolerability, and haematological safety. The analysis represents the most comprehensive analysis to date of different primaquine dosing regimens for P. vivax malaria in Indonesia. The results suggest that doubling the total dose from 3{middle dot}5 mg/kg to 7 mg/kg would halve the rate of P. vivax recurrence within 180 days, however, the absolute benefit of this reduction depends on the underlying risk of recurrence in different regions of Indonesia. An increase in the daily dose of primaquine resulted in a moderate increase in gastrointestinal discomfort; and only a rare occurrence of clinically relevant haemolysis, given that G6PD activity among patients was mostly [&ge;]70%. Implication of all the available evidenceFor Indonesian patients with P. vivax malaria, a high total primaquine dose of 7 mg/kg is more efficacious than the currently implemented 3{middle dot}5 mg/kg regimen. Higher daily doses of primaquine are associated with increased gastrointestinal discomfort, however, these may be mitigated by co-administration with food. Clinically relevant haemolysis is rare in patients with G6PD activity >30%.