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Title: Atovaquone-Proguanil in Combination with Artesunate to Treat Multidrug-Resistant P. falciparum Malaria in Cambodia: An Open-Label Randomized Trial
Authors: Mariusz Wojnarski
Chanthap Lon
Pattaraporn Vanachayangkul
Panita Gosi
Somethy Sok
Agus Rachmat
Dustin Harrison
Catherine M. Berjohn
Michele Spring
Suwanna Chaoratanakawee
Mali Ittiverakul
Nillawan Buathong
Soklyda Chann
Saowaluk Wongarunkochakorn
Andreea Waltmann
Worachet Kuntawunginn
Mark M. Fukuda
Hana Burkly
Vireak Heang
Thay Keang Heng
Nareth Kong
Threechada Boonchan
Bolin Chum
Philip Smith
Andrew Vaughn
Satharath Prom
Jessica Lin
Dysoley Lek
David Saunders
The University of North Carolina at Chapel Hill
Armed Forces Research Institute of Medical Sciences, Thailand
Mahidol University
Ministry of National Defense
Naval Medical Research Unit-2
US Army Medical Materiel Development Activity
National Center for Parasitology, Entomology and Malaria Control
Keywords: Medicine
Issue Date: 5-Oct-2019
Citation: Open Forum Infectious Diseases. Vol.6, No.9 (2019)
Abstract: © 2019 Published by Oxford University Press on behalf of Infectious Diseases Society of America 2019. Background: Recent artemisinin-combination therapy failures in Cambodia prompted a search for alternatives. Atovaquone-proguanil (AP), a safe, effective treatment for multidrug-resistant Plasmodium falciparum (P.f.), previously demonstrated additive effects in combination with artesunate (AS). Methods: Patients with P.f. or mixed-species infection (n = 205) in Anlong Veng (AV; n = 157) and Kratie (KT; n = 48), Cambodia, were randomized open-label 1:1 to a fixed-dose 3-day AP regimen +/-3 days of co-administered artesunate (ASAP). Single low-dose primaquine (PQ, 15 mg) was given on day 1 to prevent gametocyte-mediated transmission. Results: Polymerase chain reaction-adjusted adequate clinical and parasitological response at 42 days was 90% for AP (95% confidence interval [CI], 82%-95%) and 92% for ASAP (95% CI, 83%-96%; P =. 73). The median parasite clearance time was 72 hours for ASAP in AV vs 56 hours in KT (P <. 001) and was no different than AP alone. At 1 week postprimaquine, 7% of the ASAP group carried microscopic gametocytes vs 29% for AP alone (P =. 0001). Nearly all P.f. isolates had C580Y K13 propeller artemisinin resistance mutations (AV 99%; KT 88%). Only 1 of 14 treatment failures carried the cytochrome bc1 (Pfcytb) atovaquone resistance mutation, which was not present at baseline. P.f. isolates remained atovaquone sensitive in vitro but cycloguanil resistant, with a triple P.f. dihydrofolate reductase mutation. Conclusions: Atovaquone-proguanil remained marginally effective in Cambodia (≥90%) with minimal Pfcytb mutations observed. Treatment failures in the presence of ex vivo atovaquone sensitivity and adequate plasma levels may be attributable to cycloguanil and/or artemisinin resistance. Artesunate co-administration provided little additional blood-stage efficacy but reduced post-treatment gametocyte carriage in combination with AP beyond single low-dose primaquine.
ISSN: 23288957
Appears in Collections:Scopus 2019

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