ICMR-National Institute of Malaria Research, New Delhi, India.
ICMR-National Institute of Malaria Research, New Delhi, India.
Int J Parasitol Drugs Drug Resist. 2021 Apr;15:43-56. doi: 10.1016/j.ijpddr.2020.11.006. Epub 2020 Dec 13.
Artemisinin-based combination therapies (ACT) are currently used as a first-line malaria therapy in endemic countries worldwide. This systematic review aims at presenting the current scenario of drug resistance molecular markers, either selected or involved in treatment failures (TF) during in vivo ACT efficacy studies from sub-Saharan Africa (sSA) and India. Eight electronic databases were comprehensively used to search relevant articles and finally a total of 28 studies were included in the review, 21 from sSA and seven from India. On analysis, Artemether + lumefantrine (AL) and artesunate + sulfadoxine-pyrimethamine (AS + SP) are the main ACT in African and Indian regions with a 28-day efficacy range of 54.3-100% for AL and 63-100% for AS + SP respectively. It was observed that mutations in the Pfcrt (76T), Pfdhfr (51I, 59R, 108N), Pfdhps (437G) and Pfmdr1 (86Y, 184F, 1246Y) genes were involved in TF, which varied with respect to ACTs. Based on studies that have genotyped the Pfk13 gene, the reported TF cases, were mainly linked with mutations in genes associated with resistance to ACT partner drugs; indicating that the protection of the partner drug efficacy is crucial for maintaining the efficacy of ACT. This review reveals that ACT are largely efficacious in India and sSA despite the fact that some clinical efficacy and epidemiological studies have reported some validated mutations (i.e., 476I, 539T and 561H) in circulation in these two regions. Also, the role of PfATPase6 in ART resistance is controversial still, while P. falciparum plasmepsin 2 (Pfpm2) in piperaquine (PPQ) resistance and dihydroartemisinin (DHA) + PPQ failures is well documented in Southeast Asian countries but studied less in sSA. Hence, there is a need for continuous molecular surveillance of Pfk13 mutations for emergence of artemisinin (ART) resistance in these countries.
基于青蒿素的联合疗法（ACT）目前被用作全球流行地区的一线疟疾治疗药物。本系统综述旨在介绍撒哈拉以南非洲（sSA）和印度进行的体内 ACT 疗效研究中，药物耐药性分子标志物的现状，这些标志物要么被选择，要么与治疗失败（TF）有关。综合使用了 8 个电子数据库来搜索相关文章，最终共有 28 项研究被纳入综述，其中 21 项来自 sSA，7 项来自印度。分析结果显示，青蒿琥酯+阿莫地喹（AL）和青蒿琥酯+磺胺多辛-乙胺嘧啶（AS+SP）是非洲和印度地区的主要 ACT，AL 的 28 天疗效范围为 54.3-100%，AS+SP 的疗效范围为 63-100%。研究发现，PfCRT（76T）、PfDHFR（51I、59R、108N）、PfDHPS（437G）和 Pfmdr1（86Y、184F、1246Y）基因的突变与 TF 有关，这些突变因 ACT 而异。基于对 Pfk13 基因进行基因分型的研究，报告的 TF 病例主要与与 ACT 联合用药耐药相关的基因突变有关；这表明保护联合用药的疗效对于维持 ACT 的疗效至关重要。本综述表明，ACT 在印度和 sSA 地区的疗效显著，尽管一些临床疗效和流行病学研究报告了这两个地区存在一些已验证的突变（即 476I、539T 和 561H）。此外，PfATPase6 在 ART 耐药中的作用仍存在争议，而 Plasmepsin 2（Pfpm2）在哌喹（PPQ）耐药和二氢青蒿素（DHA）+PPQ 失败中的作用在东南亚国家得到了很好的记录，但在 sSA 研究较少。因此，需要对 Pfk13 突变进行持续的分子监测，以发现这些国家青蒿素（ART）耐药的出现。
