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Lessons learned from deployment of primaquine (PQ) in G6PD normal and deficient volunteers in pilot malaria elimination study in the military cohort in Cambodia

Mariusz Wojnarski ; Chanthap Lon 1 ; Somethy Sok 2 ; Rathvicheth Bun 1 ; Soklyda Chann 1 ; Threechada Boonchan 1 ; Michele Spring 1 ; Panita Gosi 1 ; Kin Soveasna 2 ; Nillawan Buathong 1 ; Mali Ittiverakul 1 ; Sabaithip Sriwichai 1 ; Worachet Kuntawunginn 1 ; Huy Rekol 3 ; Muth Sinoun 3 ; Khengheng Thay 3 ; Mary So 2 ; Jessica Lin 4 ; Prom Satharath 2 ; Kong Saly 2 ; David Saunders 5 ; Philip Smith 1 ; Mark Fukuda 1
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Background: Global Technical Strategy for Malaria 2016-2030 has set the ambitious target of eliminating malaria from at least 35 countries by 2030, but elimination strategies for P. vivaxand its hidden hypnozoite reservoir remain elusive. Materials and methods: We conducted a two-arm, controlled, cluster-randomized, open-label malaria elimination study, to determine the effectiveness of monthly malaria prophylaxis (MMP), using dihydroartemisinin-piperaquine (DP) and weekly primaquine, against PCR-based monthly screening and treatment (FSAT), on malaria incidence over 6 months of follow up. G6PD deficient volunteers were monitored for adverse effects from weekly PQ of 22.5 mg for 12 weeks (270 mg total dose). Results: 1,050 volunteers were enrolled. In the monthly prophylaxis arm (n=534), PCR-based P.vivax detection rates at enrollment and month 1 through 6 follow-up were 8.8%, 0.2%, 0.00%, 0.0%, 1.6%, 2.7% and 5.0%, respectively. In the screening and treatment arm (n=516), the PCR detection rates for P.vivax were 2.7% on enrollment, and 1.8%, 1.6%, 4.5%, 2.2%, 3.6%, 1.4% on monthly follow-ups. P.vivax was undetectable for nearly 3 months during prophylaxis with DP and PQ, as compared to the monthly cases in the FSAT arm. The rise of P.vivax cases in the MMP arm in months 4-6 of follow-up might represent relapses with failure risk of 30% (95% CI 17, 43%) and 7.1% (95% CI 4.9, 10%) in patients with and without P.vivax on enrollment, respectively. Volunteers with additional insecticide-treated uniforms had lower risk of P.vivax recurrence only in the FSAT arm (ARR: 11.3%, 95%CI 4.5%, 18.1%), with greatest effect for high endemic areas, and no benefit in the monthly prophylaxis arm. Weekly PQ resulted in large variation in post-treatment hematological profiles in G6PD deficient volunteers (n=87), with 31% of deficient volunteers having no reductions in Hgb. Conclusions: High rates of P.vivax recurrence occurred despite PCR-guided treatment in the FSAT arm targeting submicroscopic P.vivax infections, and despite 270 mg of PQ treatment in the MMP arm. Reduction of P.vivax cases to zero for nearly 3 months via monthly prophylaxis has potential to break the transmission cycle but assuring radical cure will be important for elimination.