2016 - 2023年非洲人群对抗疟药物的敏感性及耐药基因多态性：一项基因型-表型关联研究

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

作者信息

Rosado Jason, Fola Abebe A, Cojean Sandrine, Sarrasin Véronique, Coppée Romain, Zaffaroulah Rizwana, Bouzayene Azza, Cicéron Liliane, Houzé Ludivine, Crudale Rebecca, Musset Lise, Thellier Marc, Pradines Bruno, Clain Jérôme, Bailey Jeffrey A, Houzé Sandrine

机构信息

Université Paris Cité, Institut de Recherche pour le Développement, MERIT, F-75006 Paris, France.

Department of Pathology and Laboratory Medicine, Brown University, RI, USA, 02906.

出版信息

medRxiv. 2024 Jul 19:2024.07.17.24310448. doi: 10.1101/2024.07.17.24310448.

DOI:10.1101/2024.07.17.24310448

PMID:39072017

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11275679/

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 growth inhibition assays (IC) for a total of 805 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

susceptibility to several drugs has significantly decreased in 2019-2023 versus 2016-2018 parasite samples: lumefantrine (median IC: 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 mutation. Multiple mutations in and one in (N86Y) were significantly associated with altered susceptibility to multiple drugs. The susceptibility to lumefantrine was altered by and mutations in an additive manner, with the wild-type haplotype ( K76- N86) exhibiting the least susceptibility.

INTERPRETATION

Our study on 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.

摘要

背景

鉴于青蒿素和本芴醇在东非的反应发生了变化，监测所有非洲国家的抗疟药物耐药性至关重要。

方法

我们使用生长抑制试验（IC）对从返回法国（2016 - 2023年）的旅行者身上获得的总共805株分离株进行了六种抗疟药物的敏感性测定，这些旅行者主要来自西非和中非。使用分子倒置探针（MIP）对分离株进行测序，该探针靶向疟原虫基因组中的14个耐药基因。

研究结果

与2016 - 2018年的疟原虫样本相比，2019 - 2023年对几种药物的敏感性显著降低：本芴醇（2019 - 2023年的中位IC：23.0 nM [IQR：14.4 - 35.1]，而2016 - 2018年为13.9 nM [8.42 - 21.7]，p<0.0001）、单去乙基阿莫地喹（35.4 [21.2 - 51.1] 对20.3 nM [15.4 - 33.1]，p<0.0001），哌喹略有下降（20.5 [16.5 - 26.2] 对18.0 [14.2 - 22.4] nM，p<0.0001）。只有四个分离株携带经过验证的突变。中的多个突变和一个（N86Y）突变与对多种药物的敏感性改变显著相关。对本芴醇的敏感性以累加方式受到和突变的影响，野生型单倍型（ K76 - N86）表现出最低的敏感性。