Abstract
Artemisinin-based combination therapies (ACTs) are first-line treatments for uncomplicated Plasmodium falciparum malaria. ACT resistance is spreading in Asia but not yet in Africa. Reduced effects of ACT partner drugs have been reported but with little information regarding widely used artesunate/amodiaquine (ASAQ). We studied its efficacy in Zanzibar after 14 years as first-line treatment directly by an in vivo, single-armed trial and indirectly by prevalences of different genotypes in the P. falciparum chloroquine-resistance transporter, multidrug-resistance 1, and Kelch 13 propeller domain genes. In vivo efficacy was higher during 2017 (100%; 95% CI 97.4%–100%) than during 2002–2005 (94.7%; 95% CI 91.9%–96.7%) (p = 0.003). Molecular findings showed no artemisinin resistance–associated genotypes and major increases in genotypes associated with high sensitivity/efficacy for amodiaquine than before ASAQ was introduced. Thus, the efficacy of ASAQ is maintained and appears to be increased after long-term use in contrast to what is observed for other ACTs used in Africa.
Highlights
Artemisinin-based combination therapies (ACTs) are first-line treatments for uncomplicated Plasmodium falciparum malaria
ACT resistance represents a continuous threat in contexts such as Zanzibar, where numerous longdistance visitors represent a special risk for imported artemisinin-resistant malaria parasites
Efficacy verses resistance to ACTs is primarily assessed by the in vivo response to standard treatment in which early clearance determines the effect of the artemisinin component, and the cure rate by days 28 or 42 after treatment determines the effect of the combination, especially that of the partner drug [17]
Summary
Artemisinin-based combination therapies (ACTs) are first-line treatments for uncomplicated Plasmodium falciparum malaria. Selection of resistance/tolerance to the slowly eliminated long-acting partner drugs in ACT (e.g., amodiaquine) is expected, especially in highly malaria-endemic areas of Africa [8,9,10], which could result in relatively reduced ACT cure rates and reduced protection against artemisinin resistance [11]. Efficacy verses resistance to ACTs is primarily assessed by the in vivo response to standard treatment in which early clearance determines the effect of the artemisinin component, and the cure rate by days 28 or 42 after treatment determines the effect of the combination, especially that of the partner drug [17]. A few longitudinal studies in Africa have examined tolerance/resistance trends to ACTs, especially to artemether/lumefantrine, suggesting largely maintained treatment efficacy and higher prevalences of genotypes associated with tolerance to lumefantrine [18,19]. There is a lack of combining longitudinal in vivo cure rates and molecular findings, in relation to ASAQ, the second most widely used ACT in Africa
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