Article Text
Abstract
Artemether–lumefantrine (AL) and artesunate–amodiaquine (AS-AQ) are the most commonly used artemisinin-based combination therapies (ACT) for treatment of Plasmodium falciparum in Africa. Both treatments remain efficacious, but single nucleotide polymorphisms (SNPs) in the Plasmodium falciparum multidrug resistance 1 (Pfmdr1) gene may compromise sensitivity. AL and AS-AQ exert opposing selective pressures: parasites with genotype 86Y, Y184 and 1246Y are partially resistant to AS-AQ treatment, while N86, 184 F and D1246 are favoured by AL treatment. Through a systematic review, we identified 397 surveys measuring the prevalence of Pfmdr1 polymorphisms at positions 86 184 or 1246 in 30 countries in Africa. Temporal trends in SNP frequencies after introduction of AL or AS-AQ as first-line treatment were analysed in 32 locations, and selection coefficients estimated. We examined associations between antimalarial policies, consumption, transmission intensity and rate of SNP selection. 1246Y frequency decreased on average more rapidly in locations where national policy recommended AL (median selection coefficient(s) of −0.083), compared with policies of AS-AQ or both AL and AS-AQ (median s=−0.035 and 0.021, p<0.001 respectively). 86Y frequency declined markedly after ACT policy introduction, with a borderline significant trend for a more rapid decline in countries with AL policies (p=0.055). However, these trends could also be explained by a difference in initial SNP frequencies at the time of ACT introduction. There were non-significant trends for faster selection of N86 and D1246 in areas with higher AL consumption and no trend with transmission intensity. Recorded consumption of AS-AQ was low in the locations and times Pfmdr1 data were collected. SNP trends in countries with AL policies suggest a broad increase in sensitivity of parasites to AS-AQ, by 7–10 years after AL introduction. Observed rates of selection have implications for planning strategies to cycle drugs or use multiple first-line therapies to maintain drug efficacy.
- malaria
- epidemiology
- parasitology
- public health
- systematic review
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Footnotes
LCO and LMR contributed equally.
Handling editor Alberto L Garcia-Basteiro
Contributors MA: conceived the study and led the design and interpretation. LMR: led the systematic review and contributed to writing the first manuscript draft. LCO: designed and conducted the analyses and wrote the first draft of the manuscript. LMR, LSE, LCO: contributed to the systematic review. VB: contributed genetic data. DB, AB, PG: contributed model projections on antimalarial coverage. OW, RV: contributed to the design and interpretation of the analysis. CR: contributed substantially to the conception, design and interpretation of the study. All authors reviewed, edited and approved the final manuscript.
Funding This study was funded by http://dx.doi.org/10.13039/100000865 Bill and Melinda Gates Foundation, http://dx.doi.org/10.13039/501100000288 Royal Society (grant number: Dorothy Hodgkin Fellowship) and http://dx.doi.org/10.13039/501100004167 Medicines for Malaria Venture.
Competing interests LCO declares grant funding from the WHO, the Bill and Melinda Gates Foundation and Medicines for Malaria Venture (MMV) and has received a consultancy contract in the past 3 years from WHO.
Patient consent Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement The systematic review Pfmdr1 data are included in the supplementary material. Coverage of ACT reported in household surveys is available from the DHS Program website. Malaria Atlas Project projections of ACT coverage are available upon reasonable request to authors Adam Bennett, Donal Bisanzio and Peter Gething.