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 - 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 - https://www.scopus.com/pages/publications/85073510745
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 -