Novel pfkelch13 Gene Polymorphism Associates With Artemisinin Resistance in Eastern India

Clin Infect Dis. 2019 Sep 13;69(7):1144-1152. doi: 10.1093/cid/ciy1038.

Abstract

Background: Artesunate-sulfadoxine-pyrimethamine (ASSP) is the frontline artemisinin combination therapy (ACT) in India. Random, irrational, subtherapeutic artemisinin doses and self-medication with ACT along with predominance of sulfadoxine-pyrimethamine resistance parasite invoked a strong possibility of emerging artemisinin-resistant malaria parasites.

Methods: This study involved 226 patients with uncomplicated Plasmodium falciparum infection who had successfully completed the 42 days follow-up after ASSP combination therapy from April 2014 to January 2016. We assessed the ASSP treatment efficacy by evaluating parasite clearance half-life, pfkelch13, and other (pfdhfr, pfdhps, pfmdr1, pfcrt) gene mutations and survival of parasites as detected by an ex vivo ring-stage survival assay (RSA).

Findings: Slow-clearing infections with longer parasite clearance half-lives (>5 hours) were observed in 12% isolates. Cure rate after ASSP treatment was declining to about 84.1%. ASSP failure was recorded in 15.9% (early treatment failure, 7.9%; late treatment failure, 7.9%) of isolates. In sum, 24 patients (10.6%) had parasite clearance half-lives greater than 5 hours with pfkelch13 polymorphism after 441 codon; in 15 of those patients (6.6%), parasites had not cleared by 72 hours after initiation of therapy. Median ex vivo ring-stage survival rate of these isolates was very high (12.2%; 95% confidence interval [CI], 10.9-13.8) from that of cured patients (0.9%; 95% CI, 0.09-1.07). Of these 15 patients, 13 patients had pfkelch13 G625R polymorphism, whereas 2 patients contained R539T polymorphism. As per the World Health Organization guideline, these 15 isolates were true artemisinin-resistant isolates.

Interpretation: Identification of artemisinin-resistant isolates in India together with new mutations and increasing combination therapy failures blow alarms for urgent malaria control.

Keywords: Kelch13 polymorphism; Plasmodium falciparum; ACT treatment failure; artemisinin resistance; delayed parasite clearance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antimalarials / pharmacology*
  • Antimalarials / therapeutic use
  • Artemisinins / pharmacology*
  • Artemisinins / therapeutic use
  • Drug Resistance*
  • Drug Therapy, Combination
  • Female
  • Follow-Up Studies
  • Genome, Protozoan
  • Genomics / methods
  • Humans
  • India / epidemiology
  • Malaria, Falciparum / drug therapy
  • Malaria, Falciparum / epidemiology*
  • Malaria, Falciparum / parasitology*
  • Male
  • Mutation
  • Parasitic Sensitivity Tests
  • Phenotype
  • Plasmodium falciparum / drug effects*
  • Plasmodium falciparum / genetics*
  • Polymorphism, Genetic*
  • Protozoan Proteins / genetics*
  • Treatment Outcome

Substances

  • Antimalarials
  • Artemisinins
  • Protozoan Proteins