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To date, the Pfkelch13 R561H mutation has been reported multiple times in SEA (Cambodia until 2006, Myanmar and Thailand)25, once in India35 and a few times in Africa (Democratic Republic of the Congo4, Rwanda36 and Tanzania37), but has only been associated with slow-clearing infections in SEA26. Thus, the degree to which Pfkelch13 561H mutant parasites are able to withstand exposure to ART in vivo and how Pfkelch13 561H is successfully transmitted between patients in the absence of clinical recrudescence (Table 2) requires further elucidation. It is possible that the resistance advantage afforded by the Pfkelch13 561H mutation is slight and undetectable based on day 3+ and recrudescence metrics, and thus would be evident only with ART monotherapy trials. Regarding transmission, we can offer several hypotheses. First, Pfkelch13 561H mutants could be less susceptible to ART due to an ability to enter into a dormant state38 and later produce transmissible gametocytes. Second, Pfkelch13 561H parasites may have a higher capacity to be transmitted due to an unknown genetic feature or Pfkelch13 561H gametocytes may be less susceptible to the gametocytocidal activity of artemisinin. However, it is most likely that the transmission of Pfkelch13 561H mutants in Rwanda is maintained by asymptomatic individuals or mildly symptomatic untreated patients with circulating Pfkelch13 561H mutants that have been selected by low levels of circulating drugs.
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