Origin and Spread of Evolving Artemisinin-Resistant Plasmodium falciparum Malarial Parasites in Southeast Asia

Abstract

In this review, we provide an epidemiological history of the emergence and ongoing spread of evolving Plasmodium falciparum artemisinin resistance (ARTR). Southeast Asia has been the focal point for emergence and spread of multiple antimalarial drug resistance phenomena, and is once again for evolving ARTR, also known as the "delayed clearance phenotype" (DCP). The five countries most impacted, Cambodia, Thailand, Myanmar, Laos, and Vietnam, each have complex histories of antimalarial drug use over many decades, which have in part molded the use of various artemisinin combination therapies (ACTs) within each country. We catalog the use of ACTs, evolving loss of ACT efficacy, and the frequency of pfk13 mutations (mutations associated with ARTR) in the Greater Mekong Subregion and map the historical spread of ARTR/DCP parasites. These data should assist improved surveillance and deployment of next-generation ACTs.

Figure 1.

(A) Artemisinin-based drugs. Dihydroartemisinin, artemether, and artesunate are the most commonly used artemisinin combination therapy (ACT) “parent” drugs. (B) Partner drugs commonly used in current ACTs.

Figure 2.

Year of artemisinin combination therapy (ACT) use introduction vs. Greater Mekong Subregion countries. If multiple ACTs are listed for a particular year, they were all recommended country-wide. Current treatment regimens are artesunate/mefloquine (AS/MQ) (square), dihydroartemisinin/piperaquine (DHA/PPQ) (triangle), or artemether/lumefantrine (ATM/LF) (circle) in Myanmar; DHA/PPQ in Thailand; DHA/PPQ or ATM/LF in Laos; AS/MQ in Cambodia; and DHA/PPQ or AS/MQ in Vietnam.

Figure 3.

Temporal spread of ARTR/DCP within the Greater Mekong Subregion (GMS). Delayed clearance phenotype originated in 2001–2002 in western Cambodia (solid white) and subsequently spread or emerged in different areas of the GMS. Delayed clearance was identified in Thailand and the Myanmar–China border in 2006–2007 (dashed white); Myanmar in 2009 (dotted white); northwest Thailand and Binh Phuoc, Vietnam, in 2010–2011 (double white); Preah Vihear, Cambodia, in 2011–2013 (dashed gray); North Tra My, Vietnam, and Chey Saen, Cambodia, in 2012–2013 (dotted gray); Thuan Bac, Vietnam, in 2012–2016 (dashed double white); central Myanmar in 2013–2014 (double gray); Gia Lai, Vietnam, and Campasak, Laos, in 2014 (solid gray); and the Savannakhet, Salavan, Sekong, and Attapeu provinces in Laos in 2015–2016 (dotted double white).