Meta-analysis on Plasmodium falciparum sulfadoxine-pyrimethamine resistance-conferring mutations in India identifies hot spots for genetic surveillance

Background India is on track to eliminate malaria by 2030 but emerging resistance to the first-line antimalarials is a recognized threat. As Artesunate+Sulfadoxine-Pyrimethamine (AS+SP) is the drug-of-choice for uncomplicated P. falciparum malaria in most of India, it becomes evident to systematically monitor the validated mutations in Pfdhfr and Pfdhps genes across India. No systematic and robust countrywide surveillance has been reported for these parameters in India. Methods We included studies that reported data on SP-resistance markers in P. falciparum across India from 2008. Five major databases were exhaustively searched. Individual and pooled prevalence estimates of mutations were obtained through random- and fixed-effect models. The study is registered with PROSPERO (CRD42021236012). Results A total of 37 publications with data from 80 districts, 21 states and 3 UTs were included. The two PfDHFR mutations, C59R and S108N were the most prevalent mutations 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 overall. The prevalence of triple and quadruple mutations was 6% and 5%, respectively which is an area of immediate concern. For PfDHPS, the most prevalent mutation was A437G. 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 analysis 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 eliminated. Key points This manuscript concludes that currently used first-line drugs for P. falciparum malaria, particularly sulfadoxine-pyrimethamine, have a high likelihood of failing in near future. Although currently effective, the evidence is backed by molecular meta-analyses data on drug resistance markers in India. The policy makers and program managers may use this robust data to decide whether it is time to change these currently used anti-malarials in India before it is too late. It also identifies certain hot spots for continuous genetic monitoring of the molecular markers for timely actions.