Abstract
Relapses arising from dormant liver-stage Plasmodium vivax parasites (hypnozoites) are a major cause of vivax malaria. However, in endemic areas, a recurrent blood-stage infection following treatment can be hypnozoite-derived (relapse), a blood-stage treatment failure (recrudescence), or a newly acquired infection (reinfection). Each of these requires a different prevention strategy, but it was not previously possible to distinguish between them reliably. We show that individual vivax malaria recurrences can be characterised probabilistically by combined modelling of time-to-event and genetic data within a framework incorporating identity-by-descent. Analysis of pooled patient data on 1441 recurrent P. vivax infections in 1299 patients on the Thailand–Myanmar border observed over 1000 patient follow-up years shows that, without primaquine radical curative treatment, 3 in 4 patients relapse. In contrast, after supervised high-dose primaquine only 1 in 40 relapse. In this region of frequent relapsing P. vivax, failure rates after supervised high-dose primaquine are significantly lower (∼3%) than estimated previously.
Highlights
Relapses arising from dormant liver-stage Plasmodium vivax parasites are a major cause of vivax malaria
Individual-level data from two large clinical studies in acute vivax malaria patients presenting to clinics on the Thailand–Myanmar border were pooled (VivaX History trial: VHX18, Best Primaquine Dose trial: BPD19)
Distinguishing relapse, recrudescence, and reinfection in recurrent vivax malaria is necessary for the correct interpretation of therapeutic efficacy studies and for the optimal planning of malaria control and elimination
Summary
Relapses arising from dormant liver-stage Plasmodium vivax parasites (hypnozoites) are a major cause of vivax malaria. In endemic areas, a recurrent blood-stage infection following treatment can be hypnozoite-derived (relapse), a blood-stage treatment failure (recrudescence), or a newly acquired infection (reinfection) Each of these requires a different prevention strategy, but it was not previously possible to distinguish between them reliably. Recurrent vivax malaria can be caused by recrudescence (resulting from blood-stage treatment failure) or, within the endemic area, by reinfection (from a new mosquito inoculation). Distinguishing between these different causes of recurrent blood-stage infection is challenging, and has historically relied on the inherent periodicity of vivax relapse (time-to-event). We give recommendations for genetic marker requirements in future studies in similar settings
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