Data from: 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

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.