Abstract
.Plasmodium vivax and Plasmodium ovale form dormant liver hypnozoites that can reactivate weeks to months following initial infection. Malaria recurrences caused by relapses are an important cause of morbidity and source of transmission. To estimate the proportions of P. vivax malaria recurrences caused by relapses in different geographical locations, we systematically reviewed clinical efficacy studies of uncomplicated P. vivax malaria, in which patients were randomized to treatment with or without radical cure primaquine regimens and were followed up for 1 year. The minimum proportion of recurrences caused by relapses was estimated for each study site by assuming primaquine prevented all relapses and did not augment blood-stage efficacy. Of the 261 studies identified, six were eligible enrolling 4,092 patients from 14 treatment arm comparisons across seven countries. Of the 2,735 patients treated with primaquine, 24.3% received low dose (2.5 to < 5.0 mg/kg total) and 75.7% received high-dose primaquine (≥ 5.0 mg/kg total). The overall pooled incidence rate ratio of P. vivax relapses for patients treated with primaquine versus no primaquine was 0.15 (95% CI: 0.10–0.21; I2 = 83.3%), equating to a minimum of 79% of recurrences attributable to relapse. Country-specific incidence rate ratios ranged from 0.05 (95% CI: 0.01–0.34; one estimate) in Pakistan to 0.34 in Nepal (95% CI: 0.12–0.83; one estimate) and Afghanistan (95% CI: 0.22–0.51; three estimates). Relapses account for a very high proportion of recurrent infections following schizontocidal treatment of acute P. vivax malaria across diverse geographic locations. This emphasizes the importance of implementing hypnozoitocidal treatment.
Highlights
Plasmodium vivax malaria caused an estimated 14.3 million infections in 2017.1 Unlike Plasmodium falciparum, successful treatment of blood-stage infection does not necessarily prevent recurrence
Studies published before August 6, 2019 in any language were included if they included patients with P. vivax malaria treated with and without primaquine, provided that a minimum total dose of primaquine of 2.5 mg base/kg was commenced within 3 days of enrollment and administered daily thereafter in one treatment arm and that there was active follow-up for 365 days through multiple episodes of P. vivax parasitemia should they occur
Of the remaining six studies, 224 patients from one study were excluded from an artesunate treatment arm for which there was no comparative arm with primaquine[13] and 55 patients from one study were excluded from a treatment arm because of treatment with weekly primaquine.[14]
Summary
Plasmodium vivax malaria caused an estimated 14.3 million infections in 2017.1 Unlike Plasmodium falciparum, successful treatment of blood-stage infection does not necessarily prevent recurrence. Dormant liver hypnozoites can reactivate weeks to months after the initial infection and cause recurrent parasitemia (relapse) and further episodes of clinical malaria. Primaquine is the only widely available antimalarial for the treatment of dormant liver-stage parasites, which reduces the risk of relapse by over 90%, with higher doses having greater anti-relapse efficacy.[3,4] Because relapsing infections are important drivers of transmission of P. vivax malaria,[5] quantification of the proportion of recurrences caused by relapse is critical to our understanding of the potential benefits of radical cure in different endemic locations
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