High versus low dose of 14 days treatment of primaquine inPlasmodium vivaxinfected patients in Cambodia: a randomised open-label efficacy study
Authors: Eng Virak , Lek Dysoley , Sin Sitha , Feufack-Donfack Lionel Brice , Orban Agnes , Salvador Jeremy , Seng Dynang , Heng Sokleap , Khim Nimol , Tebben Kieran , Flamand Claude , Sommen Cecile , van der Pluijm Rob W. , White Michael , Witkowski Benoit , Serre David , Popovici Jean 
Published: January 2025

Background

The WHO malaria treatment guidelines recommend a total dose in the range of 3·5 to 7·0 mg/kg of primaquine to eliminatePlasmodium vivax(P. vivax) hypnozoites and prevent relapses. There are however indications that for tropicalP. vivaxisolates, notably from Southeast Asia, the lower dose of 3·5 mg/kg is insufficient. Determining the most effective regimen to eliminateP. vivaxhypnozoites is needed to achieve elimination of this malaria parasite.

Methods

We conducted an open-label randomised controlled trial in Kampong Speu province, Western Cambodia.P. vivaxinfected 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) 3·5 mg/kg (low dose as 0·25 mg/kg/day) or (ii) 7·0 mg/kg (high dose as 0·5 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 3·5 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 oneP. vivaxrecurrence 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 onClinicalTrials.gov(NCT04706130).

Findings

Between 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 3·5 mg/kg arm, and 46 in the primaquine 7·0 mg/kg arm. The proportion of participants with at least oneP. vivaxrecurrence within 90 days in the no primaquine arm was 81·4% (95% CI 69·6-89·2). The proportion of participants with recurrence was higher in the low dose primaquine arm (24·4%, 95% CI 14·2-38·7) compared to the high primaquine arm (4·7%, 95% CI 0·8-15·5, p=0·0141) resulting in a hazard ratio of high dose primaquine compared to low dose of 0·17 (95% CI 0·04-0·79, p=0·0229). Both primaquine arms were well tolerated.

Interpretation

Not providing primaquine to patients led to a considerable rate ofP. vivaxrecurrence. The risk ofP. vivaxrecurrence was 5·9 times lower for the 7·0 mg/kg of primaquine treatment compared to 3·5 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 7·0 mg/kg of primaquine regimen to reduce the risk ofP. vivaxrelapses.

Funding

National Institutes of Health (R01AI146590)

Research in context

Evidence before this study

The WHO treatment guidelines for preventingPlasmodium vivaxrelapses using primaquine recommend a range of 3·5-7·0 mg/kg. These guidelines mention that forP. vivaxinfections acquired in Southeast Asia and Oceania, 7·0 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 treatP. vivaxinfections. Our search retrieved only two studies comparing head-to-head the efficacy of 3·5mg/kg with 7·0 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 3·5 and 7·0 mg/kg of primaquine administered over 14 days in South East Asian countries.

Added value of this study

This randomised controlled trial compared the efficacy of a total dose of 3·5 mg/kg and 7·0 mg/kg of primaquine over 14 days to prevent relapses ofP. vivaxin Cambodia. Our study design minimized confounding factors affecting therapeutic efficacy evaluation. This study confirms that 7·0 mg/kg has greater efficacy to prevent recurrences than the low 3·5mg/kg regimen, with comparable safety and tolerability in G6PD normal patients from Cambodia.

Implications of all the available evidence

Our results confirm that 7·0 mg/kg of primaquine should be recommended to prevent relapses inP. vivaxinfections 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 3·5 mg/kg.