Ex vivo susceptibility to antimalarial drugs and polymorphisms in drug resistance genes of African Plasmodium falciparum, 2016-2023: a genotype-phenotype association study

TL;DR

This study tracks drug resistance in malaria parasites from Africa, finding reduced effectiveness of key drugs and links to genetic mutations.

Contribution

The study provides new genotype-phenotype associations for antimalarial drug resistance in African Plasmodium falciparum isolates.

Findings

Susceptibility to lumefantrine and monodesethylamodiaquine significantly decreased between 2016-2018 and 2019-2023.

Mutations in pfcrt and pfmdr1 genes were significantly associated with altered drug susceptibility.

Wild-type haplotype (pfcrt K76-pfmdr1 N86) showed the least susceptibility to lumefantrine.

Abstract

Background:
Given the altered responses to both artemisinins and lumefantrine in Eastern Africa, monitoring antimalarial drug resistance in all African countries is paramount.
Methods:
We measured the susceptibility to six antimalarials using
ex vivo
growth inhibition assays (IC
50
) for a total of 805
Plasmodium falciparum
isolates obtained from travelers returning to France (2016-2023), mainly from West and Central Africa. Isolates were sequenced using molecular inversion probes (MIPs) targeting fourteen drug resistance genes across the parasite genome.
Findings:
Ex vivo
susceptibility to several drugs has significantly decreased in 2019-2023 versus 2016-2018 parasite samples: lumefantrine (median IC
50
: 23·0 nM [IQR: 14·4-35·1] in 2019-2023 versus 13·9 nM [8·42-21·7] in 2016-2018, p<0·0001), monodesethylamodiaquine (35·4 [21·2-51·1] versus 20·3 nM [15·4-33·1], p<0·0001), and marginally piperaquine (20·5 [16·5-26·2] versus 18.0 [14·2-22·4] nM, p<0·0001). Only four isolates carried a validated
pfkelch13
mutation. Multiple mutations in
pfcrt
and one in
pfmdr1
(N86Y) were significantly associated with altered susceptibility to multiple drugs. The susceptibility to lumefantrine was altered by
pfcrt
and
pfmdr1
mutations in an additive manner, with the wild-type haplotype (
pfcrt
K76-
pfmdr1
N86) exhibiting the least susceptibility.
Interpretation:
Our study on
P. falciparum
isolates from West and Central Africa indicates a low prevalence of molecular markers of artemisinin resistance but a significant decrease in susceptibility to the partner drugs that have been the most widely used since a decade -lumefantrine and amodiaquine. These phenotypic changes likely mark parasite adaptation to sustained drug pressure and call for intensifying the monitoring of antimalarial drug resistance in Africa.