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Background: India is on track to eliminate malaria by 2030 but emerging resistance to first-line antimalarials is a recognised threat. Two instances of rapid development, spread, and natural selection of drug-resistant mutant parasites in India (chloroquine across the country and artesunate + sulfadoxine-pyrimethamine [AS+SP] in the northeastern states) translated into drug policy changes for Plasmodium falciparum malaria in 2010 and 2013, respectively. Considering these rapid changes in the SP drug resistance-conferring mutation profile of P. falciparum, there is a need to systematically monitor the validated mutations in Pfdhfr and Pfdhps genes across India alongside AS+SP therapeutic efficacy studies. There has been no robust, systematic countrywide surveillance reported for these parameters in India, hence the current study was undertaken., Methods: Studies that reported data on WHO-validated SP resistance markers in P. falciparum across India from 2008 to January 2023 were included. Five major databases, PubMed Ⓡ , Web of Science TM , Scopus Ⓡ , Embase Ⓡ , and Google Scholar, were exhaustively searched. Individual and pooled prevalence estimates of mutations were obtained through random- and fixed-effect models. Data were depicted using forest plots created with a 95% confidence interval. The study is registered with PROSPERO (CRD42021236012)., Results: A total of 37 publications, and 533 Pfdhfr and 134 Pfdhps National Centre of Biotechnology Information (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%), were the most prevalent mutations (pooled estimates 61% and 71%, respectively) and appeared to be stabilised/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 (51%; pooled 42%). The prevalence of triple and quadruple mutations was 6% and 5%, respectively, and is an immediate concern for some states. The most prevalent PfDHPS mutation was A437G (39%), followed by K540E (25%) and A581G (12%). There was a low overall prevalence of PfDHFR/PfDHPS quintuple and sextuple mutations but surveillance for these mutations is critical for some areas., Conclusion: The analyses span the two critical policy changes, highlight the areas of concern, and guide policymakers in strategising and refining the anti-malaria drug policy for malaria elimination. The results of the analyses also highlight the SP-resistance hot spots, critical gaps and challenges, and indicate that focal and local malaria genetic surveillance (including drug-resistance markers) is needed until malaria is successfully eliminated., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Plasmodium vivax malaria elimination requires radical cure with chloroquine/primaquine. However, primaquine causes hemolysis in glucose-6-phosphate dehydrogenase-deficient (G6PDd) individuals. Between February 2016 and July 2017 in Odisha State, India, a prospective, observational, active pharmacovigilance study assessed the hematologic safety of directly observed 25 mg/kg chloroquine over 3 days plus primaquine 0.25 mg/kg/day for 14 days in 100 P. vivax patients (≥ 1 year old) with hemoglobin (Hb) ≥ 7 g/dL. Pretreatment G6PDd screening was not done, but patients were advised on hemolysis signs and symptoms using a visual aid. For evaluable patients, the mean absolute change in Hb between day 0 and day 7 was -0.62 g/dL (95% confidence interval [CI]: -0.93, -0.31) for males (N = 53) versus -0.24 g/dL (95%CI: -0.59, 0.10) for females (N = 45; P = 0.034). Hemoglobin declines ≥ 3 g/dL occurred in 5/99 (5.1%) patients (three males, two females); none had concurrent clinical symptoms of hemolysis. Based on G6PD qualitative testing after study completion, three had a G6PD-normal phenotype, one female was confirmed by genotyping as G6PDd heterozygous, and one male had an unknown phenotype. A G6PDd prevalence survey was conducted between August 2017 and March 2018 in the same region using qualitative G6PD testing, confirmed by genotyping. G6PDd prevalence was 12.0% (14/117) in tribal versus 3.1% (16/509) in nontribal populations, with G6PD Orissa identified in 29/30 (96.7%) of G6PDd samples. Following chloroquine/primaquine, notable Hb declines were observed in this population that were not recognized by patients based on clinical signs and symptoms.

Background: Parenteral artesunate is the treatment of choice for severe malaria. It is safe, efficacious and well tolerated anti-malarial. However, delayed haemolysis has been reported in travellers, non-immune individuals and in African children., Methods: A prospective, observational study was carried out in admitted severe malaria patients receiving parenteral artesunate. The patients were followed up until day 28 for monitoring clinical as well as laboratory parameters for haemolytic anaemia., Results: Twenty-four patients with severe malaria receiving injection artesunate were enrolled in the study. Post-artesunate delayed haemolysis following parenteral artesunate therapy was observed in three of 24 patients (12.5%, 95% confidence interval 4.5-31.2%). Haemolysis was observed in two more patients possibly due to other reasons. The haemoglobin fall ranged from 13.6 to 38.3% from day 7 to day 28 in these patients., Conclusion: The possibility of delayed haemolysis should be considered while treating the severe malaria patients with parenteral artesunate. The study highlights the need for further studies in different epidemiological settings.

PfMDR1 single nucleotide polymorphisms (SNP) are good correlate markers for antimalarial drug resistance worldwide. Present study is a comprehensive view of screening of PfMDR1 polymorphism to antimalarials practiced with geography and time. Study sites Mizoram, Tripura, Meghalaya chosen are at multivariate drug pressure due to cross border migration and transmission. Mizoram is gateway to south east Asia through Myanmar whereas Tripura, Meghalaya share porous border with Bangladesh. Baseline finger pricked blood stained filter paper for confirmed uncomplicated Plasmodium falciparum infected patients (year 2015) were obtained from National Institute of Malaria Research, New Delhi, India. PfMDR1 polymorphism for codon N86Y, Y184F, D1246Y was determined by PCR-RFLP, further confirmed by sequencing. There observed marked predominance of Plasmodium isolates with PfMDR1 wild type alleles for all codons under study i.e. 86, 184, 1246. Spatially, Plasmodium isolates from Mizoram were most diverse with co-existence of PfMDR1 genotype with NYD, YYD, NFD haplotypes, followed by Tripura. Isolates from Meghalaya were of all NYD haplotype. Reports, referring to screening of PfMDR1 SNPs to CQ/SP/AS-SP across India, were archived. Temporal study show distinct rise in proportion of PfMDR1 wild type N86 allele since introduction of Artemether-Lumefantrine as first line antimalarial. Hence spatio-temporal screening of Plasmodium population with PfMDR1 single nucleotide polymorphism accounts for its association with antimalarial susceptibility and validate PfMDR1 SNPs as antimalarial drug resistant marker., (Copyright © 2018 Elsevier B.V. All rights reserved.)