{"doi":"10.1101/2024.07.17.24310448","title":"<i>Ex vivo</i> susceptibility to antimalarial drugs and polymorphisms in drug resistance genes of African <i>Plasmodium falciparum</i> , 2016-2023: a genotype-phenotype association study","abstract":"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&lt;0·0001), monodesethylamodiaquine (35·4 [21·2-51·1] versus 20·3 nM [15·4-33·1], p&lt;0·0001), and marginally piperaquine (20·5 [16·5-26·2] versus 18.0 [14·2-22·4] nM, p&lt;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. Funding This work was supported by the French Ministry of Health (grant to the French National Malaria Reference Center) and by the Agence Nationale de la Recherche (ANR-17-CE15-0013-03 to JC). JAB was supported by NIH R01AI139520. JR postdoctoral fellowship was funded by Institut de Recherche pour le Développement. Research in context Evidence before this study Artemisinin-based combination therapies (ACTs) have been introduced since the 2000s as the first-line curative treatment of malaria. ACTs combine an artemisinin derivative, which rapidly reduces parasite load, with another antimalarial drug –known as partner drug-which eliminates the remaining parasites thanks to its longer half-life. This approach reduces the likelihood of parasites developing resistance to both drugs, thereby increasing treatment efficacy and delaying the emergence of resistance. However, resistance to artemisinins and then to some partner drugs was identified in Southeast Asia more than a decade ago and has spread throughout the region. Artemisinin partial resistance is now emerging in the East and Horn of Africa. It manifests as delayed parasite clearance from the bloodstream after treatment, increasing the parasite load in contact with the partner drug only and the likelihood of selecting resistant parasites. It is, therefore, important to monitor antimalarial drug susceptibility and drug resistance mutations in contemporary African isolates, especially in the understudied West and Central African regions, to anticipate the spread of multidrug-resistant parasites. We searched for articles on antimalarial drug resistance published between January 1, 2000, and July 1, 2024, using the PubMed search terms “antimalarial resistance”, “Africa”, and “ ex vivo ”. Of the 69 published studies, only six encompassing a total of 827 isolates across five West and Central African countries from 2016 to 2022 combined ex vivo drug assays with genotyping data. Parasites with an increased rate of ex vivo survival to artemisinins were reported in one study from Ghana (7/90 isolates in 2018) and another from The Gambia (4/41 isolates in 2017). 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Fola","orcid":"0000-0001-5392-2859","position":1,"is_corresponding":false},{"id":1327503,"name":"Sandrine Cojean","orcid":"0000-0001-6914-7957","position":2,"is_corresponding":false},{"id":1327964,"name":"Véronique Sarrasin","orcid":null,"position":3,"is_corresponding":false},{"id":818216,"name":"Romain Coppée","orcid":"0000-0002-3024-5928","position":4,"is_corresponding":false},{"id":1327965,"name":"Rizwana Zaffaroulah","orcid":null,"position":5,"is_corresponding":false},{"id":1327966,"name":"Azza Bouzayene","orcid":null,"position":6,"is_corresponding":false},{"id":1327967,"name":"Liliane Cicéron","orcid":null,"position":7,"is_corresponding":false},{"id":1032960,"name":"Ludivine Houzé","orcid":null,"position":8,"is_corresponding":false},{"id":998542,"name":"Rebecca Crudale","orcid":"0000-0002-0789-4196","position":9,"is_corresponding":false},{"id":249742,"name":"L. Musset","orcid":"0000-0003-0215-4110","position":10,"is_corresponding":false},{"id":1327504,"name":"Marc Théllier","orcid":"0000-0003-4867-2423","position":11,"is_corresponding":false},{"id":1327505,"name":"Bruno Pradines","orcid":"0000-0002-2360-3803","position":12,"is_corresponding":false},{"id":1327506,"name":"Jérôme Clain","orcid":"0000-0002-0232-5058","position":13,"is_corresponding":false},{"id":242456,"name":"Jeffrey A. Bailey","orcid":"0000-0002-6899-8204","position":14,"is_corresponding":false},{"id":1275632,"name":"Sandrine Houzé","orcid":"0000-0001-9016-3847","position":15,"is_corresponding":false},{"id":1327968,"name":"Investigation Study Group","orcid":null,"position":16,"is_corresponding":false},{"id":587270,"name":"Jason Rosado","orcid":"0000-0003-4834-2088","position":0,"is_corresponding":true}],"reference_count":41,"raw_metadata":null,"created_at":"2026-07-19T02:07:47.633574Z","pmid":"39072017","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}