Reply to Rasmussen and Ringwald, “Continued Low Efficacy of Artemether-Lumefantrine in Angola?” (2024)

REPLY

We thank Rasmussen and Ringwald for further highlighting the importance of routine monitoring of antimalarial drug efficacy in sub-Saharan Africa, including Angola (1). Longitudinal monitoring is critical to identify potential new, persistent, and/or expanding foci of parasite resistance to available drugs. In 3 of the last 4 rounds, artemether-lumefantrine (AL) was estimated to have an efficacy of <90% at one of the three sentinel sites in Angola. To our knowledge, in sub-Saharan Africa, only Angola and Burkina Faso (2) have shown AL efficacy of <90% across multiple therapeutic efficacy study (TES) rounds. Thus, we chose a title to highlight this persistent concern.

We concur that the significance of the high rates of day 2 slide positivity in Lunda Sul Province is not fully known, and as pointed out, there may be various explanations for this finding. Measuring drug levels is resource intensive and not feasible every year, but this could help rule out underdosing in future studies. However, we believe our study procedures, as described in this and previous studies, are robust and thus make systematic underdosing unlikely. We have always strictly adhered to WHO guidelines, including hemoglobin criteria and analysis of day 1 severe cases, to inform our classifications.

While we agree that the 86 codon in pfmdr1 is not currently regarded as a definitive marker for lumefantrine or amodiaquine resistance, it is under consideration, and we present the information here to note the high prevalence of the N86 allele as another possible line of evidence.

There is currently no WHO-endorsed method for molecular correction using microsatellites. Similar to our colleagues in the Democratic Republic of the Congo, we used the only validated and publicly available tool for analysis of microsatellite data (3). A description of how to use the Bayesian posterior probabilities to calculate efficacy measures is provided in the original report of the algorithm (3), and our R script to apply this to the Kaplan-Meier estimator is publicly available (4). Updating the 2007 WHO genotyping guidance would be highly useful given the advances of the last 13 years (5).

Global antimalarial resistance monitoring efforts should focus on identifying foci of parasite drug resistance to emphasize early detection and timely containment of resistance. A recent systematic review of 279 therapeutic efficacy reports in the artemisinin-based combination therapy (ACT) era in sub-Saharan Africa showed that many studies had methodological errors that largely biased results toward overestimation of treatment efficacy rates (6). Systematic overestimation of ACT efficacy rates could lead to complacency as we are now 15 years into wide-scale adoption of ACTs (7). Improved methodology that prioritizes early detection, confirmation, and careful tracking of ACT resistance is critical. TESs can serve as early warning signals, and together with development of new drugs and effective containment strategies, are key to minimizing the impact of emerging antimalarial resistance.

Footnotes

REFERENCES