Description
Background: India is on track to eliminate malaria by 2030 but emerging resistance to the first-line antimalarials is a recognized threat. Two instances of rapid development, spread, and natural selection of drug-resistant mutant parasites (chloroquine in entire India and Artesunate+Sulfadoxine-Pyrimethamine (AS+SP) in India’s north-eastern states) translated into drug policy changes for P. falciparum malaria in 2010 and 2013, respectively. Looking at these rapid changes in SP drug resistance-conferring mutation profile of P. falciparum, it becomes evident to systematically monitor the validated mutations in Pfdhfr and Pfdhps genes across India along with the AS+SP therapeutic efficacy studies. No systematic and robust countrywide surveillance has been reported for these parameters in India thereby leading us to undertake this study.
Methods: We included studies that reported data on WHO-validated SP-resistance markers in P. falciparum across India from 2008 to date. Five major databases PubMed®, Web of ScienceTM, Scopus®, Embase®, and Google Scholar were exhaustively searched. Individual and pooled prevalence estimates of mutations were obtained through random- and fixed-effect models. Data is depicted using forest plots created with a 95 % confidence interval. The study is registered with PROSPERO (CRD42021236012).
Results: A total of 37 publications, 533 Pfdhfr and 134 Pfdhps NCBI DNA sequences were included from >4000 samples. The study included information from 80 districts, 21 states and 3 Union Territories (UTs) from India. The two PfDHFR mutations, C59R (62%) and S108N (74%), are the most prevalent mutations (pooled estimates 61% and 71%, respectively) and appear to be stabilized/fixed. Although rarest overall, the prevalence of I164L was observed to be as high as 32%. The PfDHFR double mutants were the most prevalent (51%; pooled 42%) overall. The prevalence of triple and quadruple mutations was 6% and 5%, respectively which is also an area of immediate concern for some states. For PfDHPS mutations, the most prevalent mutation was A437G (39%), followed by K540E (25%) and A581G (12%). For PfDHFR/PfDHPS quintuple and sextuple mutations, it was observed that despite a low overall prevalence of these mutations, some areas are critical for surveillance.
Conclusion: The analyses span the two critical policy changes, highlight the areas of concern and guide the policymakers in strategizing and refining the antimalarial drug policy further for malaria elimination. It brings forward the SP-resistance hot spots and emphasizes critical gaps, and challenges, and suggests focal and local malaria genetic surveillance (including drug-resistance markers) till malaria is successfully eliminated.
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