Artemisinin-based combination therapy (ACT) offers highly successful treatment of malaria. Emergence and spread of Plasmodium falciparum (Pf) parasites with decreased susceptibility to ACT in South-East Asia has caused concern worldwide. The current accepted criteria to assess artemisinin (ART) resistance relies upon data on treatment failure, delayed parasite clearance at day 3 (DPC3), parasite clearance half-life (PCHL) and in-vitro/ex-vivo ring stage survival assays (RSAs). Interestingly, some studies suggest that DPC3 does not provide a distinct separation between ART sensitive/resistant strains, and RSA differences may also be inconclusive. More recently, recrudescence of ART treated Pf, independent of the presence of Kelch 13 (K13) mutation (C580Y), has been reported in the monkey malaria model suggesting that genes other than K13 like coronin, dhps, dhfr, crt, mdr1 and plasmepsin1 may contribute towards ACT failure. Here we have collated the distribution of K13 mutants from Pf strains in South Asia. A total of fifty Pf-K13 mutations have been studied for ART resistance in South Asia of which nine have been validated while eleven are potentials for ART resistance. The remaining thirty K13 mutations have been reported from various locations in South Asia but lack corroborative clinical data on ART resistance/ACT failure. Of the fifty, fourteen K13 mutations have been identified in India including four novel mutations (S549Y, G625R, N657H, D702N). Structural mapping of these K13 mutations does not offer any coherent explanation for their contribution towards ART resistance as they are scattered in the K13 structure. Thus, K13 mutations likely provide only a partial synopsis, and we propose that all suspect cases of ACT failure be assessed by: 1) DPC3, 2) PCHL, 3) in-vitro/ex-vivo RSAs and 4) GWAS data in an effort to annotate the resistance status of the parasites. These efforts may help in surveillance and containment of ART resistance/ACT failure in South Asia.

中文翻译：

---

南亚地区恶性疟原虫 Kelch 突变概况及其对追踪耐药性的影响。

基于青蒿素的联合疗法（ACT）对疟疾的治疗非常成功。对 ACT 敏感性降低的恶性疟原虫 (Pf) 寄生虫在东南亚的出现和传播引起了全世界的关注。目前评估青蒿素 (ART) 耐药性的公认标准依赖于治疗失败、第 3 天寄生虫清除延迟 (DPC3)、寄生虫清除半衰期 (PCHL) 和体外/离体环期生存测定 (RSA) 等数据）。有趣的是，一些研究表明 DPC3 不能区分 ART 敏感/耐药菌株，并且 RSA 差异也可能不确定。最近，在猴疟疾模型中报道了 ART 治疗的 Pf 复发，与 Kelch 13 (K13) 突变 (C580Y) 的存在无关，这表明 K13 以外的基因，如 Coronin、dhps、dhfr、crt、mdr1 和 plasmepsin1可能会导致 ACT 失败。在这里，我们整理了 Pf 菌株 K13 突变体在南亚的分布。南亚共研究了 50 种 Pf-K13 突变的 ART 耐药性，其中 9 种已得到验证，而 11 种可能具有 ART 耐药性。南亚各地已报道了其余 30 种 K13 突变，但缺乏 ART 耐药/ACT 失败确凿的临床数据。在这 50 种 K13 突变中，印度已发现 14 种 K13 突变，其中包括 4 种新突变（S549Y、G625R、N657H、D702N）。这些 K13 突变的结构图谱并未对它们对 ART 耐药性的贡献提供任何连贯的解释，因为它们分散在 K13 结构中。因此，K13 突变可能仅提供部分概要，我们建议通过以下方式评估所有 ACT 失败的可疑病例：1) DPC3、2) PCHL、3) 体外/离体 RSA 和 4) GWAS 数据努力注释寄生虫的抵抗状态。这些努力可能有助于监测和遏制南亚 ART 耐药/ACT 失败的情况。