Evaluating malaria elimination strategies among military forces in Cambodia: a multi-arm clinical trial comparing monthly prophylaxis and focused screening and treatment

Abstract

Background: Identifying effective malaria elimination strategies for remote regions and highly mobile populations in Southeast Asia is challenging given limited resources. In this clinical trial, two malaria elimination strategies were evaluated in partnership with the Royal Cambodian Armed Forces - monthly malaria prophylaxis (MMP) and focused screening and treatment (FSAT).

Methods: Eight military cohorts (1,050 volunteers total) along the Cambodian-Thai border were randomly assigned to three months of either MMP or FSAT (four cohorts in each treatment arm) with monthly malaria testing for six months. Cohorts were further randomly assigned to receive either permethrin treated (ITU) or sham-treated clothing (sITU). Volunteers in MMP cohort were given three monthly three-day doses dihydroartemisinin-piperaquine (DP) along with a ‘universal’ low-dose weekly regimen of 22.5 mg primaquine for 12 weeks, intended for use regardless of body weight or G6PD status. Volunteers in FSAT cohort were treated with appropriate first-line antimalarials if they tested positive for malaria.

Results: Plasmodium falciparum (Pf) positivity in MMP cohorts was reduced by 90% (10% at enrollment to 1% at six months; absolute risk reduction (ARR) 9%) at 6 months. However, 32% of Pf cases treated with DP as MMP at baseline recrudesced, requiring rescue treatment at 1 month with artesunate-mefloquine. Pf positivity in FSAT cohorts declined 66% over six months (7.6% to 2.7%; ARR 4.9%). MMP reduced P. vivax (Pv) positivity from 9% to 0% at three months, but Pv rebounded to 6.7% at six months. FSAT failed to significantly reduce Pv positivity during the study. The 22.5 mg weekly primaquine MMP regimen was safe, even for the 15% of volunteers with G6PD-deficiency. Those wearing ITU had additional Pv parasitemia reductions compared to sITU in the FSAT but not MMP cohorts.

Conclusions: MMP was safe, and superior to FSAT, suggesting greater utility to achieve malaria elimination in Cambodia. Low dose (22.5 mg) weekly primaquine was a safe adjunct in this setting, even for those with G6PD-deficiency. Permethrin-treated clothing further reduced Pv parasitemia for FSAT but not MMP. We observed that MMP may be more easily scaled to eliminate malaria and that the military may provide substantial support for regional elimination efforts.

Trial registration: The study was registered on https://clinicaltrials.gov/ on 13-01-2016 prior to enrollment (NCT02653898).

Supplementary Information: The online version contains supplementary material available at 10.1186/s12879-025-12207-4.

Keywords: Elimination; G6PD; Malaria; Mass drug administration; Prophylaxis.

Fig. 1

Study design and timeline. All volunteers were screened for malaria with monthly malaria RDT, microscopy and PCR testing. During the three-month intervention phase, volunteers in the MMP treatment arm received regularly scheduled treatment with a full monthly DP treatment course and a weekly dose of 22.5 mg primaquine regardless of malaria positivity for a total dose of 270 mg. Volunteers in the FSAT arm only received treatment if found to be malaria-positive by microscopy or PCR. The treatment arms were further subdivided into those that received insecticide-treated uniforms (ITUs) and sham-treated uniforms (sITUs). All volunteers in the study were screened monthly for three additional months or when symptomatic with RDT, PCR and microscopy and treated for malaria if positive. Treatment with standard-of-care medications was given if positive by microscopy or PCR within 24–48 h. Standard doses of PQ were used per national treatment guidelines in the FSAT arm

Fig. 2

CONSORT Flow Diagram. Volunteers were randomized to one of 8 geographically isolated unit-based cohorts. There were a total of four cohorts for MMP (green) and another four cohorts for FSAT (orange) treatment interventions. Half of the volunteers assigned to MMP and FSAT were also treated with insecticide treated uniforms (ITUs). Total follow-up was 180 days after enrollment. Most volunteer withdrawals and losses to follow-up were due to movement outside the study areas

Fig. 3

PCR-adjusted malaria prevalence on the monthly follow up in MMP and FSAT. Rapid and sustained reductions in the number of Pf malaria cases were observed in MMP (green) and FSAT (orange) (Panel A-B). A high rate of Pv malaria was detected for both interventions arms (Panel C-D) despite 270 mg total PQ dose in MMP arm (G6PD normal and G6PD deficient volunteers), over a 12 week period, and conventional doses of PQ in FSAT arm (i.e., 15 mg x 14 days in G6PD normal volunteers and 45 mg weekly x 8 weeks in G6PD deficient volunteers). Results are stratified between subjects that were positive at enrollment and tested positive at a follow-up time point and subjects that were negative at enrollment but tested positive at a follow-up time point. Error bars reflect the 95% confidence interval

Fig. 4

Diagnostic detection of malaria. Prevalence of all malaria species at each monthly follow up is shown based on the three diagnostic methods (RDT, microscopy, and PCR) performed on each individual at each visit. Participants were followed with parasitemia assessed monthly by rapid diagnostic test (RDT), microscopy (Micro) and plasmodium species-specific polymerase chain reaction (PCR) for 180 days. All RDT and Micro-positive cases were also PCR positive. Panels (A) and (B) compare detection rates between the (A) FSAT and (B) MMP arms. Panels C. and D. compare detection rates for all volunteers for (C) P. falciparum and (D) P. vivax

Fig. 5

Cumulative Pf and Pv positivity with respect to drug intervention, uniform treatment, and endemicity. Cumulative positivity from Day 0 to 180 is shown for Pf (A) and Pv (B); MMP (green bars) and FSAT (orange bars) treatment conditions, stratified by cohort endemicity (high vs. low) and uniform (sITU vs. ITU). 95% confidence interval error bars and statistical significance (* p < 0.05, ** p < 0.01, *** p < 0.001) are shown

Fig. 6

Survival curve to first Pf or Pv infection stratified by treatment. Survival curves are shown for Pf infection for FSAT (red) and MMP (blue) treatment conditions for in high endemicity cohorts (A). Survival curves for Pv infection in high and low endemicity cohorts (B and C) are shown for FSAT + ITU (red), FSAT + sITU (green), MMP + ITU (blue), and MMP + sITU (purple) conditions. 95% confidence intervals are shown as shaded colors corresponding to each condition. There was only 1 low endemicity Pf case which is not graphically displayed