Global assessment of partial artemisinin resistance: multicenter trial across Kenya, Peru, and Thailand in patients with uncomplicated Plasmodium falciparum malaria

Abstract

Objectives: Artemisinin-resistant Plasmodium falciparum challenges the effectiveness of all artemisinin-based combination therapies.

Methods: We conducted a clinical study in Peru, Kenya, and Thailand between June 2013 and November 2015 in subjects treated with three standard doses of artesunate followed by two doses of mefloquine. The primary endpoint was parasite clearance half-life (PC_1/2) during the 72-hour period of treatment. Secondary endpoints included clinical outcome at 42 days, detection of kelch13 (K13) mutations, pharmacokinetics, and pharmacodynamics.

Results: The mean PC_1/2 was higher in the Thai (4.1 hours) than Peruvian (2 hours) or Kenyan cohorts (2.2 hours) (P <0.0001). Higher PC_1/2 was partially explained by K13 mutations in 13 (28%) of 46 Thai subjects, including World Health Organization (WHO) validated and candidate mutations. Twelve (26%) Thai cohort subjects had PC_1/2 ≥5 hours with parasites from nine subjects carrying K13 mutations. There was an overall 42-day cure rate of 100% across all subjects.

Conclusions: This is the first concurrent evaluation of artemisinin resistance across three continents. The presence of 11% Thai subjects who satisfied WHO criteria for drug resistance establishes this area as endemic. Longer PC_1/2 found in wild-type and candidate K13 mutant infections within the Thai cohort require further investigation to identify alternative mechanisms of resistance.

Keywords: Artemisinin; K13 mutations; Malaria; Resistance.

Figure 1.

Study locations in Peru, Kenya, and Thailand. Map in R using open data from GADM database, version 3.6. www.gadm.org and the Sf package.

Figure 2.

Median parasite clearance curves during treatment course for all three study sites. Figure shows that Kenya and Peru displayed a similar pattern of parasite clearance in contrast to Thailand.

Figure 3.

PC_1/2 across study sites. Thailand data are disaggregated by K13 wild-type (THA^WT) and K13 mutant (THA^MUT). Dots indicate the PC_1/2 of individual patient curves. Data labels indicate geometric mean PC_1/2, and shaded bands show 95% confidence interval around geometric mean. PC_1/2, parasite clearance half-life.

Figure 4.

Sensitivity of K13 mutant strains measured using RSA^0–3h. Light blue bars represent percentage of ring-stage parasite survival as measured during RSA^0–3h. Dark blue lines indicate corresponding PC_1/2 s of K13 mutant strains. Dashed red line shows 1% RSA^0–3h cut-off, and dashed black line shows PC_1/2 = 5 hours cut-off. RSA^0–3h results were not obtained for subjects 101005, 101034, 101035, 101050, and 101058. PC_1/2, parasite clearance half-life; RSA, ring-stage survival.