Identification of a Novel Plasmodium falciparum Kelch13 A676T Variant and high Chloroquine and Sulfadoxine-Pyrimethamine Resistance in Cibitoke, Burundi

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ABSTRACT Antimalarial resistance, including reduced susceptibility to artemisinin-based combination therapies, is increasing in Africa. 157 P. falciparum isolates from Cibitoke, Burundi, were sequenced for ten resistance markers (including background loci associated with kelch13 -mediated artemisinin partial resistance) using Nanopore sequencing. Plasmepsin -2 and pfmdr1 copy number variations were assessed by digital PCR. No validated pfkelch13 mutations linked to artemisinin partial resistance were detected. A novel pfkelch13 mutation, A676T, was identified in one isolate, adjacent to the validated A675V mutation reported in neighboring East African countries. Mutant alleles were observed at several background loci previously implicated in artemisinin resistance in Southeast Asia, including pffd D193Y (7.0%), pfmdr2 I492V (31.8%), pfatg18 T38I (3.2%), and pfarps10 V127M/D128H (2.6%), while pfpx1 (C1484F) and pfmdr2 (T484I) remained wild type. However, their functional role in Africa remains uncertain. Sulfadoxine-pyrimethamine (SP) resistance was widespread. In single-clone infections, the quintuple pfdhfr/pfdhps haplotype predominated (59.6%). Chloroquine resistance–associated pfcrt IET triple mutant haplotypes at codons 74-76 were detected in 94.3% of isolates. pfmdr1 haplotypes defined by codons 86, 184, and 1246 were dominated by NYD (56.3%) and NFD (40.4%). No pfpm2 duplications were observed, while pfmdr1 copy number amplification was rare (1.8%). These findings reveal a high prevalence of mutations associated with SP resistance, posing a threat to the efficacy of intermittent preventive treatment in pregnancy and seasonal malaria chemoprevention in Burundi. The identification of the pfkelch13 A676T variant highlights the importance of continued genomic surveillance. However, the role of this mutation in artemisinin resistance remains to be determined.

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