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

plos medicine

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