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

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 HengNareth Kong, Threechada Boonchan, Bolin Chum, Philip Smith, Andrew Vaughn, Satharath Prom, Jessica Lin, Dysoley Lek, David Saunders*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


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.

Original languageEnglish
Article numberofz314
JournalOpen Forum Infectious Diseases
Issue number9
StatePublished - 5 Oct 2019
Externally publishedYes


  • artesunate
  • atovaquone-proguanil
  • drug resistance
  • malaria
  • primaquine


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