Concerns about malaria parasite resistance to treatment with artemisinin drugs (ARTs) have grown with findings of prolonged parasite clearance t_1/2s (>5 h) and their association with mutations in Plasmodium falciparum Kelch-propeller protein K13. Here, we describe a P. falciparum laboratory cross of K13 C580Y mutant with C580 wild-type parasites to investigate ART response phenotypes in vitro and in vivo. After genotyping >400 isolated progeny, we evaluated 20 recombinants in vitro: IC₅₀ measurements of dihydroartemisinin were at similar low nanomolar levels for C580Y- and C580-type progeny (mean ratio, 1.00; 95% CI, 0.62–1.61), whereas, in a ring-stage survival assay, the C580Y-type progeny had 19.6-fold (95% CI, 9.76–39.2) higher average counts. In splenectomized Aotus monkeys treated with three daily doses of i.v. artesunate, t_1/2 calculations by three different methods yielded mean differences of 0.01 h (95% CI, −3.66 to 3.67), 0.80 h (95% CI, −0.92 to 2.53), and 2.07 h (95% CI, 0.77–3.36) between C580Y and C580 infections. Incidences of recrudescence were 57% in C580Y (4 of 7) versus 70% in C580 (7 of 10) infections (−13% difference; 95% CI, −58% to 35%). Allelic substitution of C580 in a C580Y-containing progeny clone (76H10) yielded a transformant (76H10^C580Rev) that, in an infected monkey, recrudesced regularly 13 times over 500 d. Frequent recrudescences of ART-treated P. falciparum infections occur with or without K13 mutations and emphasize the need for improved partner drugs to effectively eliminate the parasites that persist through the ART component of combination therapy.

随着疟原虫清除时间延长t _1/2 s (> 5 h) 的发现及其与恶性疟原虫Kelch 螺旋桨蛋白 K13突变的关联，人们越来越担心疟疾寄生虫对青蒿素药物 (ART) 治疗的耐药性。在这里，我们描述了K13 C580Y 突变体与 C580 野生型寄生虫的恶性疟原虫实验室杂交，以研究体外和体内 ART 反应表型。在对 >400 个分离的后代进行基因分型后，我们在体外评估了 20 个重组体：IC ₅₀对于 C580Y 和 C580 型后代，双氢青蒿素的测量值处于类似的低纳摩尔水平（平均比率，1.00；95% CI，0.62–1.61），而在环期存活分析中，C580Y 型后代有 19.6-倍 (95% CI, 9.76–39.2) 更高的平均计数。在脾切除的Aotus猴中，每天服用三剂 iv 青蒿琥酯，t _1/2通过三种不同的方法计算得出 C580Y 和C580 感染。C580Y（7 次中的 4 次）的复发率为 57%，而 C580（10 次中的 7 次）感染为 70%（-13% 差异；95% CI，-58% 至 35%）。在含有 C580Y 的后代克隆 (76H10) 中 C580 的等位基因取代产生了一个转化体 (76H10 ^C580Rev )，它在受感染的猴子中，在 500^天后有规律地复发 13 次。ART 治疗的恶性疟原虫感染频繁复发，无论是否发生 K13 突变，都强调需要改进合作药物以有效消除通过联合治疗的 ART 组成部分持续存在的寄生虫。