In Vivo Efficacy of Artemether-Lumefantrine and Chloroquine against Plasmodium vivax: A Randomized Open Label Trial in Central Ethiopia

Jimee Hwang,Jimee Hwang,Jimee Hwang,Samuel Girma Tekleyohannes,David Hoos,Joseph L Malone,Scott Filler,Scott Filler,Zenebe Melaku,Leykun Demeke,Takele Teshi Takele Teshi,Sheila Akinyi,Henry Nettey,Henry Nettey,Amanda Poe,Sintayehu Gebresillasie Birhanu,Daddi Jima,Daddi Jima,Michael Green,S Patrick Kachur,Moges Kassa,Richard Reithinger,Richard Reithinger,Bereket Hailegiorgis Alemayehu,Venkatachalam Udhayakumar

doi:10.1371/journal.pone.0063433

Abstract

Background In vivo efficacy assessments of antimalarials are essential for ensuring effective case management. In Ethiopia, chloroquine (CQ) without primaquine is the first-line treatment for Plasmodium vivax in malarious areas, but artemether-lumefantrine (AL) is also commonly used.Methods and FindingsIn 2009, we conducted a 42-day efficacy study of AL or CQ for P. vivax in Oromia Regional State, Ethiopia. Individuals with P. vivax monoinfection were enrolled. Primary endpoint was day 28 cure rate. In patients with recurrent parasitemia, drug level and genotyping using microsatellite markers were assessed. Using survival analysis, uncorrected patient cure rates at day 28 were 75.7% (95% confidence interval (CI) 66.8–82.5) for AL and 90.8% (95% CI 83.6–94.9) for CQ. During the 42 days of follow-up, 41.6% (47/113) of patients in the AL arm and 31.8% (34/107) in the CQ arm presented with recurrent P. vivax infection, with the median number of days to recurrence of 28 compared to 35 days in the AL and CQ arm, respectively. Using microsatellite markers to reclassify recurrent parasitemias with a different genotype as non-treatment failures, day 28 cure rates were genotype adjusted to 91.1% (95% CI 84.1–95.1) for AL and to 97.2% (91.6–99.1) for CQ. Three patients (2.8%) with recurrent parasitemia by day 28 in the CQ arm were noted to have drug levels above 100 ng/ml.ConclusionsIn the short term, both AL and CQ were effective and well-tolerated for P. vivax malaria, but high rates of recurrent parasitemia were noted with both drugs. CQ provided longer post-treatment prophylaxis than AL, resulting in delayed recurrence of parasitemia. Although the current policy of species-specific treatment can be maintained for Ethiopia, the co-administration of primaquine for treatment of P. vivax malaria needs to be urgently considered to prevent relapse infections.Trial RegistrationClinicalTrials.gov NCT01052584

Highlights

Plasmodium vivax transmission is more widely distributed globally than P. falciparum, with 2.85 billion people living at risk of its infection [1]
In the short term, both AL and CQ were effective and well-tolerated for P. vivax malaria, but high rates of recurrent parasitemia were noted with both drugs
The current policy of species-specific treatment can be maintained for Ethiopia, the co-administration of primaquine for treatment of P. vivax malaria needs to be urgently considered to prevent relapse infections

Summary

Introduction

Plasmodium vivax transmission is more widely distributed globally than P. falciparum, with 2.85 billion people living at risk of its infection [1]. With wide-spread P. falciparum resistance to chloroquine (CQ) [6] and sulphadoxine-pyrimethamine (SP) [7,8], in 2004, the Ethiopian Federal Ministry of Health (FMOH) adopted artemether-lumefantrine (AL) as first-line treatment of uncomplicated P. falciparum malaria and of mixed infections with both P. falciparum and P. vivax [9]. CQ remains the first-line treatment for P. vivax malaria in Ethiopia, AL is used widely for all cases of mixed infections and clinical malaria where laboratory diagnostics to determine the specific malaria species are not available or not done. In Ethiopia, chloroquine (CQ) without primaquine is the first-line treatment for Plasmodium vivax in malarious areas, but artemetherlumefantrine (AL) is commonly used

Methods

Results

Conclusion