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

Abstract

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.

Plasmodium falciparum resistance to artemisinin-based combination therapies: A sword of Damocles in the path toward malaria elimination

“…This project is the first of its kind to investigate the safety, tolerability and efficacy of triple artemisinin-based combination therapies (TACTs) in clinical trials in Southeast Asia. In TACTs, the third partner drug should have an intermediate half-life so that it can provide an associative protective effect over both the fast-acting artemisinin drug and the long-acting partner drug [ 20 , 23 , 77 ].…”

“…However, this recovered sensitivity is not systematic, as shown in Venezuela, where parasites remained resistant to chloroquine more than 15 years after the cessation of the use of chloroquine [ 16 ]. Thus, the use of drug “cycling”, based on alternative introductions of antimalarials to reduce the selective pressure on the parasite, has also been considered [ 20 ]. This raises several questions.…”

“…Should these drugs be recycled on a regular basis? [ 20 ]. It has been demonstrated that plasmepsin 2-3 gene amplification in DHA/PPQ resistant parasites is associated with pfmdr1 gene single copies, so these resistant parasites are sensitive to mefloquine [ 4 , 83 ].…”

Resistance to Artemisinin Combination Therapies (ACTs): Do Not Forget the Partner Drug!

“…Currently, there is no alternative to ACTs, even though the antimalarial drug pipeline is promising [96,97]. Strategies are needed to prolong the useful therapeutic lifespan of the current malaria medicines, including 1) extending the duration of the current 3-day regimen of ACTs [90,98,99]; 2) increasing the dose of the partner drugs [100,101]; 3) using triple combination therapies, with two partner drugs selecting in opposite directions [36,102,103]; and 4) utilizing multiple first-line treatments [36]. However, those may be solutions to preserve the efficacy of ACTs in the short- or medium-term only, as there is already some evidence of parasites developing resistance to two partner drugs and the artemisinin component at the same time [104,105].…”

Antimalarial pyronaridine resistance may be associated with elevated MDR-1 gene expression profiles but not point mutation in Plasmodium berghei ANKA isolates

“…These authors contributed equally to this work Author(s) agree that this article remain permanently open access under the terms of the Creative Commons Attribution License 4.0 International License malarial drugs presented for clinical treatment of malaria illness (Hanboonkunupakarn and White, 2015;Menard and Dondorp, 2017).This development has prompted a quest for new effective anti-malarial compounds with the least side effects (Tang et al, 2020). One such strategy for plummeting the malaria prevalence is the usage of twin-or triple-anti-malarial drug combinations, which is thought to protect each drug from the development of resistance and reduce the overall transmission of malaria (Dipanjan et al, 2017;Tse et al, 2019;Mishra et al, 2017). In the last 20 years, over 60 countries and territories have officially adopted artemisinin-based combination therapy (ACT) for the treatment of falciparum malaria (WHO, 2017).…”