Triple Combination Therapy and Drug Cycling-Tangential Strategies for Countering Artemisinin Resistance

Abstract

Purpose of review: This review attempts to understand the reasons for the successes and failures of the two novel strategies that have slowly begun to emerge as potential counters for anti-malarial drug resistance-"Triple Combination Therapy" and "Drug Cycling."

Recent findings: Recent reports have suggested that increasing the heterogeneity within the parasite's environment, both at an individual and the population level, may help raise the probabilistic barrier of development of resistance in the parasite. The encouraging results following the implementation of a few experimental triple combination therapies like atovaquone-proguanil-artesunate along with the re-emergence of chloroquine sensitive Plasmodium falciparum parasites in the sub-Saharan African nations have re-kindled mankind's hope of curbing anti-malarial drug resistance. The addition of a third drug with traits like a medium half-life and benign safety profile is crucial to achieving SERCAP (single encounter radical cure and preventive therapy), the principle of a triple combination therapy. Simultaneously, the plausible reasons behind the re-emergence of chloroquine sensitive Plasmodium falciparum malaria in the high transmission regions could be the re-expansion of an existing chloroquine susceptible parasite reservoir and a greater predisposition towards the development of polyclonal infections. Another potential reason for this observation could be an impaired deoxyribonucleic acid (DNA) repair mechanisms in the south-east Asian Plasmodium falciparum parasites. These strategies may potentially emerge as the key players in warding off anti-malarial drug resistance in the near future. However, their implementation would be dictated by a host of factors like the epidemiological knowledge, population pharmacokinetics, drug-resistance patterns, cost, availability, and ease of adherence.

Keywords: Chloroquine renaissance; Combination therapy; Drug resistance; Environmental heterogeneity; Malaria.