Abstract
BackgroundAnti-malarial drug resistance remains a major threat to global malaria control efforts. In Africa, Plasmodium falciparum remains susceptible to artemisinin-based combination therapy (ACT), but the emergence of resistant parasites in multiple countries in Southeast Asia and concerns over emergence and/or spread of resistant parasites in Africa warrants continuous monitoring. The World Health Organization recommends that surveillance for molecular markers of resistance be included within therapeutic efficacy studies (TES). The current study assessed molecular markers associated with resistance to Artemether−lumefantrine (AL) and Dihydroartemisinin−piperaquine (DP) from samples collected from children aged 6–59 months enrolled in a TES conducted in Siaya County, western Kenya from 2016 to 2017.MethodsThree hundred and twenty-three samples collected pre-treatment (day-0) and 110 samples collected at the day of recurrent parasitaemia (up to day 42) were tested for the presence of drug resistance markers in the Pfk13 propeller domain, and the Pfmdr1 and Pfcrt genes by Sanger sequencing. Additionally, the Pfpm2 gene copy number was assessed by real-time polymerase chain reaction.ResultsNo mutations previously associated with artemisinin resistance were detected in the Pfk13 propeller region. However, other non-synonymous mutations in the Pfk13 propeller region were detected. The most common mutation found on day-0 and at day of recurrence in the Pfmdr1 multidrug resistance marker was at codon 184F. Very few mutations were found in the Pfcrt marker (< 5%). Within the DP arm, all recrudescent cases (8 sample pairs) that were tested for Pfpm2 gene copy number had a single gene copy. None of the associations between observed mutations and treatment outcomes were statistically significant.ConclusionThe results indicate absence of Pfk13 mutations associated with parasite resistance to artemisinin in this area and a very high proportion of wild-type parasites for Pfcrt. Although the frequency of Pfmdr1 184F mutations was high in these samples, the association with treatment failure did not reach statistical significance. As the spread of artemisinin-resistant parasites remains a possibility, continued monitoring for molecular markers of ACT resistance is needed to complement clinical data to inform treatment policy in Kenya and other malaria-endemic regions.
Highlights
Anti-malarial drug resistance remains a major threat to global malaria control efforts
Proportion of Pfk13 polymorphisms from day‐0, recurrent and recrudescent infection samples Sequencing of the Pfk13 propeller region was successful for 98.1% day-0 samples, 80.0% recurrent infections, and 95.8% recrudescent samples (Table 1)
No mutations were detected in the six codons that have been validated to correlate with artemisinin resistance
Summary
Anti-malarial drug resistance remains a major threat to global malaria control efforts. The World Health Organization recommends that surveillance for molecular markers of resistance be included within therapeutic efficacy studies (TES). Ex vivo drug testing and in vivo therapeutic efficacy studies (TES) are important for assessing the effectiveness of anti-malarial drugs [6], molecular surveillance using genetic markers associated with resistance provides a valuable tool for detecting and tracking resistance as well as providing an in-depth understanding of the development and spread of resistance. SNPs at codons 86, 184, and 1246 in the P. falciparum multidrug resistance 1 gene (Pfmdr1) have been implicated to confer parasite resistance to multiple anti-malarial drugs, with individual polymorphisms leading to opposite effects on different drugs [8].
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