Autor/a:
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Robinson, Leanne J.; Wampfler, Rahel; Betuela, Inoni; Karl, Stephan; White, Michael T.; Li Wai Suen, Connie S. N.; Hofmann, Natalie E.; Kinboro, Benson; Waltmann, Andreea; Brewster, Jessica; Lorry, Lina; Tarongka, Nandao; Samol, Loenah; Silkey, Maribeth; Bassat Orellana, Quique; Siba, Peter; Schofield, Louis; Felger, Ingrid; Mueller, Ivo
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Abstract:
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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. |