Publication:
Atovaquone-Proguanil in Combination with Artesunate to Treat Multidrug-Resistant P. falciparum Malaria in Cambodia: An Open-Label Randomized Trial

Issued Date

2019-10-05

Resource Type

Article

ISSN

23288957

DOI

10.1093/ofid/ofz314

Other identifier(s)

2-s2.0-85073510745

Rights

Mahidol University

Rights Holder(s)

SCOPUS

Bibliographic Citation

Open Forum Infectious Diseases. Vol.6, No.9 (2019)

Suggested Citation

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 Atovaquone-Proguanil in Combination with Artesunate to Treat Multidrug-Resistant P. falciparum Malaria in Cambodia: An Open-Label Randomized Trial. Open Forum Infectious Diseases. Vol.6, No.9 (2019). doi:10.1093/ofid/ofz314 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/51368

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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

Author(s)

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

Other Contributor(s)

The University of North Carolina at Chapel Hill
 Armed Forces Research Institute of Medical Sciences, Thailand
 HJF
 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

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.

Keyword(s)

Medicine

Availability

URI

https://repository.li.mahidol.ac.th/handle/20.500.14594/51368

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Scopus 2019