Plasmodium falciparum Resistance to Artemisinin Derivatives and Piperaquine: A Major Challenge for Malaria Elimination in Cambodia

Abstract

Abstract. Artemisinin-based combination therapies (ACTs) are the cornerstone of current strategies for fighting malaria. Over the last decade, ACTs have played a major role in decreasing malaria burden. However, this progress is being jeopardized by the emergence of artemisinin-resistant Plasmodium falciparum parasites. Artemisinin resistance was first detected in western Cambodia in 2008 and has since been observed in neighboring countries in southeast Asia. The problem of antimalarial drug resistance has recently worsened in Cambodia, with reports of parasites resistant to piperaquine, the latest generation of partner drug used in combination with dihydroartemisinin, leading to worrying rates of clinical treatment failure. The monitoring and the comprehension of both types of resistance are crucial to prevent the spread of multidrug-resistant parasites outside southeast Asia, and particularly to Africa, where the public health consequences would be catastrophic. To this end, new tools are required for studying the biological and molecular mechanisms underlying resistance to antimalarial drugs and for monitoring the geographic distribution of the resistant parasites. In this review, we detail the major advances in our understanding of resistance to artemisinin and piperaquine and define the challenges that the malaria community will have to face in the coming years. BACKGROUND

Sequence Analysis of the K13-Propeller Gene in Artemisinin Challenging Plasmodium falciparum Isolates from Malaria Endemic Areas of Odisha, India: A Molecular Surveillance Study

“…Further continuous reuse of this single ACT resulting in P. falciparum-resistant alleles to Artemisinin or its derivatives has been reported for the first time in Western Cambodia and Thailand border [2,3]; more interestingly, these resistant isolates might be carried by the parasites distributed rapidly across all SE Asian countries and also some parts of Africa [4,5]. Both Artemisinin Combination Therapies (ACTs) and its derivatives along with partner drug resis-tance to P. falciparum isolates have threatened the current efforts for the reduction of the burden of infectious malaria all over the world [6,7] As per the WHO guidelines, the definition of the emerged resistant alleles across Thai and Cambodia border has been characterized by [8,9] not only with reduced parasite clearance rate and increasing parasite clearance halflife or survived young ring stage parasites but also with the continuation of parasites on the third day of ACTs [1,[10][11][12][13][14][15][16][17][18]. These worldwide problems give rise to several approaches for the intense surveillance and detection of Artemisinin-resistant falciparum parasites including molecular marker evaluation [7,19].…”

Cyclical Regression Covariates remove the major confounding effect of cyclical developmental gene expression with strain-specific drug response in the malaria parasitePlasmodium falciparum

“…The P. falciparum parasite causes the most lethal form of malaria, a vector-borne disease that killed an estimated 405,000 people in 2018, 272,000 of them children under the age of five [1]. Although malaria prevention strategies and early treatment efforts have reduced the worldwide incidence of malaria 18% since 2010, the persistence of malaria is due in part to the rapid emergence and spread of parasites resistant to antimalarial drugs, including artemisinin-based combination therapies, the last line of defense in regions where multiple drug resistance has arisen [2-4].…”

Biochemical characterization of Plasmodium falciparum parasite specific helicase 1 (PfPSH1)

“…The failure of old conventional antimalarial therapy and the loss of effectiveness of the artemisinin-based combination therapy (ACT) have resulted in emergence of multiple drug-resistant parasites. It is evident from the reports of ACT-resistant parasite from western Cambodia, Thailand, Myanmar, Vietnam, and China that drug-resistant parasites are major threats for the effort to contain malaria [4][5][6][7][8][9][10][11]. Therefore, new class of antimalarials is required to reduce the effect of malaria on world population.…”