TY - JOUR
T1 - Atovaquone-Proguanil in Combination with Artesunate to Treat Multidrug-Resistant P. falciparum Malaria in Cambodia
T2 - An Open-Label Randomized Trial
AU - Wojnarski, Mariusz
AU - Lon, Chanthap
AU - Vanachayangkul, Pattaraporn
AU - Gosi, Panita
AU - Sok, Somethy
AU - Rachmat, Agus
AU - Harrison, Dustin
AU - Berjohn, Catherine M.
AU - Spring, Michele
AU - Chaoratanakawee, Suwanna
AU - Ittiverakul, Mali
AU - Buathong, Nillawan
AU - Chann, Soklyda
AU - Wongarunkochakorn, Saowaluk
AU - Waltmann, Andreea
AU - Kuntawunginn, Worachet
AU - Fukuda, Mark M.
AU - Burkly, Hana
AU - Heang, Vireak
AU - Heng, Thay Keang
AU - Kong, Nareth
AU - Boonchan, Threechada
AU - Chum, Bolin
AU - Smith, Philip
AU - Vaughn, Andrew
AU - Prom, Satharath
AU - Lin, Jessica
AU - Lek, Dysoley
AU - Saunders, David
N1 - Funding Information:
Financial support. This work was supported by the Naval Advanced Medical Development Program, Washington, DC. The funding source had no role in the analysis or interpretation of data, preparation of the manuscript or the decision to publish.
Publisher Copyright:
© 2019 Published by Oxford University Press on behalf of Infectious Diseases Society of America 2019.
PY - 2019/10/5
Y1 - 2019/10/5
N2 - 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.
AB - 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.
KW - artesunate
KW - atovaquone-proguanil
KW - drug resistance
KW - malaria
KW - primaquine
UR - http://www.scopus.com/inward/record.url?scp=85073510745&partnerID=8YFLogxK
U2 - 10.1093/ofid/ofz314
DO - 10.1093/ofid/ofz314
M3 - Article
AN - SCOPUS:85073510745
SN - 2328-8957
VL - 6
JO - Open Forum Infectious Diseases
JF - Open Forum Infectious Diseases
IS - 9
M1 - ofz314
ER -