High versus low dose of 14 days treatment of primaquine in Plasmodium vivax infected patients in Cambodia: a randomised open-label efficacy study

BackgroundThe WHO malaria treatment guidelines recommend a total dose in the range of 3{middle dot}5 to 7{middle dot}0 mg/kg of primaquine to eliminate Plasmodium vivax (P. vivax) hypnozoites and prevent relapses. There are however indications that for tropical P. vivax isolates, notably from Southeast Asia, the lower dose of 3{middle dot}5 mg/kg is insufficient. Determining the most effective regimen to eliminate P. vivax hypnozoites is needed to achieve elimination of this malaria parasite. MethodsWe conducted an open-label randomised controlled trial in Kampong Speu province, Western Cambodia. P. vivax infected patients with uncomplicated malaria, diagnosed at the community level or in health centres of the province, were offered to participate. Patients aged less than 15 years old, and pregnant or breastfeeding women were excluded. Enrolled patients were treated with a blood schizonticidal artesunate regimen of 2 mg/kg/day for 7 days. Upon enrolment, patients glucose-6-phosphate dehydrogenase (G6PD) activity was determined. G6PD normal patients were randomly assigned (2:2:1) to receive either (i) 3{middle dot}5 mg/kg (low dose as 0{middle dot}25 mg/kg/day) or (ii) 7{middle dot}0 mg/kg (high dose as 0{middle dot}5 mg/kg/day) of primaquine over 14 days or (iii) no primaquine as comparator arm. G6PD deficient patients were assigned to the no-primaquine comparator arm. Randomisation was done by blocks of 5 using sealed envelopes. Upon enrolment, patients were relocated to the study site in Aoral town where no malaria transmission occurs to ensure that they were not reinfected during their 90-day follow-up. After 90 days of relocation, G6PD normal patients in the no-primaquine arm were provided 3{middle dot}5 mg/kg for 14 days of primaquine to be taken unsupervised. At day 90, all the patients returned home and they were further followed monthly for three months until day 180. The primary outcome was the treatment failure rate defined as the proportion of patients with at least one P. vivax recurrence within 90 days of relocated follow-up. All patients that completed treatment and complied with relocation without interruption before any recurrence was detected were included in the primary efficacy analysis. All patients enrolled and assigned to an intervention arm were included in the safety analysis. The study is registered on ClinicalTrials.gov (NCT04706130). FindingsBetween Nov 10, 2021, and Feb 10, 2024, a total of 160 patients were enrolled and 156 were allocated to one of the three study arms. Of these, 37 G6PD deficient patients were assigned to the no primaquine arm and 119 G6PD normal patients were randomised: 24 in the no primaquine arm, 49 in the primaquine 3{middle dot}5 mg/kg arm, and 46 in the primaquine 7{middle dot}0 mg/kg arm. The proportion of participants with at least one P. vivax recurrence within 90 days in the no primaquine arm was 81{middle dot}4% (95% CI 69{middle dot}6-89{middle dot}2). The proportion of participants with recurrence was higher in the low dose primaquine arm (24{middle dot}4%, 95% CI 14{middle dot}2-38{middle dot}7) compared to the high primaquine arm (4{middle dot}7%, 95% CI 0{middle dot}8-15{middle dot}5, p=0{middle dot}0141) resulting in a hazard ratio of high dose primaquine compared to low dose of 0{middle dot}17 (95% CI 0{middle dot}04-0{middle dot}79, p=0{middle dot}0229). Both primaquine arms were well tolerated. InterpretationNot providing primaquine to patients led to a considerable rate of P. vivax recurrence. The risk of P. vivax recurrence was 5{middle dot}9 times lower for the 7{middle dot}0 mg/kg of primaquine treatment compared to 3{middle dot}5 mg/kg. Tolerability and safety of both primaquine regimens in G6PD normal individuals was comparable. Policy makers in Cambodia and most likely in other Southeast Asian countries should endorse the 7{middle dot}0 mg/kg of primaquine regimen to reduce the risk of P. vivax relapses. FundingNational Institutes of Health (R01AI146590) Research in contextO_ST_ABSEvidence before this studyC_ST_ABSThe WHO treatment guidelines for preventing Plasmodium vivax relapses using primaquine recommend a range of 3{middle dot}5-7{middle dot}0 mg/kg. These guidelines mention that for P. vivax infections acquired in Southeast Asia and Oceania, 7{middle dot}0 mg/kg should be preferred. We searched Pubmed for randomized controlled trials studies containing the terms "vivax" and "primaquine" published between 1990 and November 2024, with no language restrictions, to identify studies comparing primaquine regimen to treat P. vivax infections. Our search retrieved only two studies comparing head-to-head the efficacy of 3{middle dot}5mg/kg with 7{middle dot}0 mg/kg primaquine administered over a same duration of 14 days but were both conducted in South Asia and both showed similar efficacy of high dose compared to low dose primaquine. No studies compared 3{middle dot}5 and 7{middle dot}0 mg/kg of primaquine administered over 14 days in South East Asian countries. Added value of this studyThis randomised controlled trial compared the efficacy of a total dose of 3{middle dot}5 mg/kg and 7{middle dot}0 mg/kg of primaquine over 14 days to prevent relapses of P. vivax in Cambodia. Our study design minimized confounding factors affecting therapeutic efficacy evaluation. This study confirms that 7{middle dot}0 mg/kg has greater efficacy to prevent recurrences than the low 3{middle dot}5mg/kg regimen, with comparable safety and tolerability in G6PD normal patients from Cambodia. Implications of all the available evidenceOur results confirm that 7{middle dot}0 mg/kg of primaquine should be recommended to prevent relapses in P. vivax infections acquired in Cambodia and most likely in South East Asia. National treatment guidelines in those countries should be changed to endorse this regimen rather than the 3{middle dot}5 mg/kg.