Strategies for Understanding and Reducing the Plasmodium vivax and Plasmodium ovale Hypnozoite Reservoir in Papua New Guinean Children: A Randomised Placebo-Controlled Trial and Mathematical Model

• DOI: 10.1371/journal.pmed.1001891
• Publication Date: 2015-10-27T18:41:03Z
• Authors: Leanne J. Robinson; Rahel Wampfler; Inoni Betuela; Stephan Karl; Michael T. White; Connie S. N. Li W...; Natalie E. Hofmann; Benson Kinboro; Andreea Waltmann; Jessica Brewster; Lina Lorry; Nandao Tarongka; Lornah Samol; Mariabeth Silkey; Quique Bassat; Peter M. Siba; Louis Schofield; Ingrid Felger; Ivo Mueller
• Keywords: Primaquine; Artemether/lumefantrine; Plasmodium ovale; Mass drug administration; Tropical Medicine

Background The undetectable hypnozoite reservoir for relapsing Plasmodium vivax and P. ovale malarias presents a major challenge malaria control elimination in endemic countries. This study aims to directly determine the contribution of relapses burden infection, illness, transmission Papua New Guinean children. Methods Findings From 17 August 2009 20 May 2010, 524 children aged 5–10 y from East Sepik Province Guinea (PNG) participated randomised double-blind placebo-controlled trial blood- plus liver-stage drugs (chloroquine [CQ], 3 d; artemether-lumefantrine [AL], primaquine [PQ], d, 10 mg/kg total dose) (261 children) or blood-stage only (CQ, AL, placebo [PL], d) (263 children). Participants, staff, investigators were blinded treatment allocation. Twenty excluded during phase (PQ arm: 14, PL 6), 504 followed actively 9 mo. During follow-up time, 18 7, 11) lost follow-up. Main primary secondary outcome measures time first infection (by qPCR), clinical episode, force gametocyte positivity, PCR). A basic stochastic model was developed estimate potential effect mass drug administration (MDA) prevention recurrent infections. Targeting hypnozoites through PQ reduced risk having at least one qPCR-detectable 8 mo (P. vivax: arm 0.63/y versus 2.62/y, HR = 0.18 [95% CI 0.14, 0.25], p < 0.001; ovale: 0.06 0.31 0.13, 0.77], 0.011) episode (HR 0.25 0.11, 0.61], 0.002). also molecular 1.90/y 7.75/y, incidence rate ratio [IRR] 0.21 0.15, 0.28], 0.001). Children who received less likely carry gametocytes (IRR 0.27 0.19, 0.38], had comparable irrespective presence (p 0.14). Modelling revealed that screening with highly sensitive quantitative real-time PCR, MDA alone, would have transient on levels, while includes is predicted be effective strategy elimination. inclusion observed 20-d regime maximises efficiency clearance but limits generalisability results real-world programmes. Conclusions These suggest cause approximately four every five infections three PNG are important sustaining transmission. campaigns combining efficacious intervention reducing Trial registration ClinicalTrials.gov NCT02143934