Efficacy and safety of artemisinin-based combination therapy and the implications of Pfkelch13 and Pfcoronin molecular markers in treatment failure in Senegal

Abstract

In 2006, Senegal adopted artemisinin-based combination therapy (ACT) as first-line treatment in the management of uncomplicated malaria. This study aimed to update the status of antimalarial efficacy more than ten years after their first introduction. This was a randomized, three-arm, open-label study to evaluate the efficacy and safety of artemether-lumefantrine (AL), artesunate-amodiaquine (ASAQ) and dihydroartemisinin-piperaquine (DP) in Senegal. Malaria suspected patients were screened, enrolled, treated, and followed for 28 days for AL and ASAQ arms or 42 days for DP arm. Clinical and parasitological responses were assessed following antimalarial treatment. Genotyping (msp1, msp2 and 24 SNP-based barcode) were done to differentiate recrudescence from re-infection; in case of PCR-confirmed treatment failure, Pfk13 propeller and Pfcoronin genes were sequenced. Data was entered and analyzed using the WHO Excel-based application. A total of 496 patients were enrolled. In Diourbel, PCR non-corrected/corrected adequate clinical and parasitological responses (ACPR) was 100.0% in both the AL and ASAQ arms. In Kedougou, PCR corrected ACPR values were 98.8%, 100% and 97.6% in AL, ASAQ and DP arms respectively. No Pfk13 or Pfcoronin mutations associated with artemisinin resistance were found. This study showed that AL, ASAQ and DP remain efficacious and well-tolerated in the treatment of uncomplicated P. falciparum malaria in Senegal.

Prevalence of pfk13 and pfmdr1 polymorphisms in Bounkiling, Southern Senegal

“…Our analysis revealed that all but 6 of the isolates carried wild type K13-propeller. This is in line with recent observations in Senegal, where most of the samples were also wild type for K13-propeller domain [ 17 , 32 , 38 ]. None of the 5 identified SNPs in our samples occurred in more than two samples ( Table 1 ).…”

“…falciparum malaria. In the few reported cases of recrudescence after ACT treatment, parasite samples did not carry mutations in the K13-propeller domain [ 32 ]. These observations seem to follow the regional tendency.…”

“…Although a number of studies have been published in Senegal reporting mutations in pfk13 [ 20 , 31 , 32 , 36 – 38 , 44 ], samples from those studies originate mostly from Thies and Dakar regions (near and around the capital). In one exception, a recent study reported pfk13 SNPs from Diourbel (east of Thiés) and Kedougou, in the southeast of the country ( Fig 1 ); [ 32 ]. Hence the importance of our study, which analyses samples from Bounkiling City, in the Sédhiou region in the south of Senegal ( Fig 1 ).…”

“…The haplotype YYY was not identified; however, this was not surprising since YYY is believed to be selected under the pressure of DHA-PPQ treatment from a genetic background 86Y and Y184 [ 56 , 57 ]. DHA-PPQ has not been widely used in Senegal, except to compensate for antimalarial drug shortages in 2010 and 2011 [ 32 ]. Other studies have reported absence or low prevalence of the allele 1246Y [ 35 ] or the haplotype YYY haplotype in Senegal (northern regions) [ 31 ].…”

“…Despite sustained drug pressure (accessible through public and private health facilities) and a high burden of malaria, few studies on P . falciparum molecular markers of drug resistance surveillance are available from southern regions of Senegal [ 32 ]. Most of the studies of molecular marker surveillance in Senegal have been performed in Dakar and Thiés [ 17 , 31 , 33 – 41 ] ( Fig 1 ).…”