The Importance of Scientific Debate in the Identification, Containment, and Control of Artemisinin Resistance

To the Editor—The introduction to the article by Phyo and colleagues [1] contains the statement “However, the link between K13 polymorphism and treatment failure was not clearly established and some authors have contested whether use of the term artemisinin resistance is justified [16–18]. This uncertainty may have contributed to the failure to contain artemisinin resistance in the greater Mekong area.” Our article [2] was one of those cited in this statement (as [17]) and we are deeply concerned that our attempts to improve the standard of scientific debate surrounding resistance to artemisinin combination therapies (ACTs) appears to have been misinterpreted as being retrogressive and even as having “contributed to the failure to contain artemisinin resistance.” Our article [2] used pharmacological modeling to investigate the likely properties of infected red blood cell (iRBC) clearance dynamics posttreatment. Notably, we never “contested whether use of the term artemisinin resistance is justified” and explicitly stated (see page 6343 of [2]) that “K13 mutations … appear to virtually remove parasite hypersensitivity in the early ring stages, allowing its detection through increased iRBC clearance rates.” In brief, we argued in our article the following: (1) Artemisinins have been historically underdosed: 2 mg/kg was initially suggested because no increase in clearance rates occurred at higher doses [3]. Artemisinins are currently dosed at 4 mg/kg, but the lower previous doses may have contributed to resistance emergence. (2) Splitting current daily ACT regimens into twice-daily half doses was rejected on the basis that clearance rates did not increase [4]; again, we were concerned that suboptimal dosing regimens may lead to resistance [5]. (3) Substantial levels of artemisinin resistance in sequestered parasite stages would not manifest as reduced iRBC clearance rates. (4) Heritability estimates of iRBC clearance rates are methodologically compromised and should be interpreted with extreme caution (Supplementary Information of [2]); we are disappointed that Phyo et al chose not to point the journal readership to this work and blandly self-cited that clearance rate “was found to be heritable.” In summary, we showed that regarding iRBC clearance rates as sensitive or specific measures of drug efficacy and resistance could lead to a potentially highly damaging level of complacency about current dosing regimens and patterns of existing drug resistance and that an informed, evidence-based debate is required to ensure this threat is properly addressed. Finally, any implication that our work might have “contributed to the failure to contain artemisinin resistance” is easily refuted by the timing: Our article was published online in August 2015, long after the World Health Organization had finalized its plans for artemisinin containment [6, 7], and after the time period of 2003–2013 discussed by Phyo et al. In fact, the debate around “containment” centered on 3 questions: (1) Is it feasible to eliminate the “resistant” populations? (2) Is it cost effective to do so? (3) Are resistance mutations confined to these areas? The answer to all 3 questions should have been unambiguously affirmative for “containment” to proceed and, for the record, we took no part in this debate or surrounding discussions. Potential conflicts of interest. All authors: No potential conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.