Therapeutic Efficacy of Artemisinin-Based Combination Therapies in Democratic Republic of the Congo and Investigation of Molecular Markers of Antimalarial Resistance

Abstract

Routine assessment of the efficacy of artemisinin-based combination therapies (ACTs) is critical for the early detection of antimalarial resistance. We evaluated the efficacy of ACTs recommended for treatment of uncomplicated malaria in five sites in Democratic Republic of the Congo (DRC): artemether-lumefantrine (AL), artesunate-amodiaquine (ASAQ), and dihydroartemisinin-piperaquine (DP). Children aged 6–59 months with confirmed Plasmodium falciparum malaria were treated with one of the three ACTs and monitored. The primary endpoints were uncorrected and polymerase chain reaction (PCR)-corrected 28-day (AL and ASAQ) or 42-day (DP) cumulative efficacy. Molecular markers of resistance were investigated. Across the sites, uncorrected efficacy estimates ranged from 63% to 88% for AL, 73% to 100% for ASAQ, and 56% to 91% for DP. PCR-corrected efficacy estimates ranged from 86% to 98% for AL, 91% to 100% for ASAQ, and 84% to 100% for DP. No pfk13 mutations previously found to be associated with ACT resistance were observed. Statistically significant associations were found between certain pfmdr1 and pfcrt genotypes and treatment outcome. There is evidence of efficacy below the 90% cutoff recommended by WHO to consider a change in first-line treatment recommendations of two ACTs in one site not far from a monitoring site in Angola that has shown similar reduced efficacy for AL. Confirmation of these findings in future therapeutic efficacy monitoring in DRC is warranted.

Molecular surveillance for operationally relevant genetic polymorphisms in Plasmodium falciparum in Southern Chad, 2016–2017

“…It has mostly proven to be efficacious over the nearly 15 years since ACT was recommended as first-line treatments worldwide and across the malaria endemic world. Recent reports of reduced efficacy from Angola, Burkina Faso and the Democratic Republic of Congo however underline the need for continued surveillance of the efficacy of this drug [ 35 – 37 ]. In southern Chad, a relatively high prevalence of the combined pfmdr1 - pfcrt N F D-K haplotype was detected which remained unchanged over both rounds of sample collection (see Table 3 ).…”

Monthly sulfadoxine/pyrimethamine-amodiaquine or dihydroartemisinin-piperaquine as malaria chemoprevention in young Kenyan children with sickle cell anemia: A randomized controlled trial

“…This may merit baseline QT measurement to limit DP-induced prolongation, though this risk may be mitigated by alternate DP dosing schemes or by, as we observed, the plateauing of QT intervals after 6 months of prophylaxis (Table S9, Supplemental Figure). These clinical factors would need to be complemented before wider policy adoption by considerations of DP resistance, which was detected as declining clinical efficacy first in Southeast Asia [26]and more recently at several sites in Africa [27,28]. Though wider use of DP will necessarily increase pressure to develop resistance, this may be mitigated by a restriction of DP use to high-risk populations like pregnant women and children with SCA, and by the observation through multiple studies [29][30][31][32] that mass-drug administration with DP across diverse populations has not reliably increased molecular markers of DP resistance.…”

Monthly sulfadoxine/pyrimethamine-amodiaquine or dihydroartemisinin-piperaquine as malaria chemoprevention in young Kenyan children with sickle cell anemia: A randomized controlled trial

“…This may merit baseline QT measurement to limit DP-induced prolongation, although this risk may be mitigated by alternate DP dosing schemes or by, as we observed, the plateauing of QT intervals after 6 months of prophylaxis (Table I and Figure A in S1 Text). These clinical factors would need to be complemented before wider policy adoption by considerations of DP resistance, which was detected as declining clinical efficacy first in Southeast Asia [26] and more recently at several sites in Africa [27,28]. Although wider use of DP will necessarily increase pressure to develop resistance, this may be mitigated by a restriction of DP use to high-risk populations like pregnant women and children with SCA, and by the observation through multiple studies [29][30][31][32] that mass drug administration with DP across diverse populations has not reliably increased molecular markers of DP resistance.…”