**2. Resistance to artemisinin and ACT: current and future approaches**

Antimalarial drug resistance is not a new biological phenomenon. In the 1970s and 1980s, *Plasmodium falciparum*—the parasite species responsible for the most common and deadliest form of malaria—developed widespread resistance to previous antimalarial medicines, such as chloroquine and sulfadoxine-pyrimethamine (SP) [8]. Artemisinin based combination therapies (ACTs), introduced in the 1990s, are currently the most effective antimalarial drugs [9] and represent the first line-treatment for uncomplicated falciparum malaria in all endemic countries.

Although artemisinin usually kills all malaria parasites, the use of a combination of drugs as opposed to monotherapy—helps ensure that any remaining parasites will be killed by the partner drug before the resistant parasites can spread. According to the World Health Organisation (WHO), clinical artemisinin (and its derivatives) resistance is defined as delayed parasite clearance and represents a partial/relative resistance that has thus far only affected ring-stage malaria parasites [10]. In Southeast Asia, however, some malaria parasites have already developed resistance to artemisinin-based drugs; a recent report of a single multidrug resistant malaria parasite lineage (PfPailin) with associated piperaquine resistance in Vietnam and its implications of subsequent transnational spread is of international concern [11]. Artemisinin resistance was first reported along the Thailand-Cambodia border in 2008 [12, 13] and has continued to spread in all Greater Mekong Subregion countries [14–18]. In addition, artemisinin resistance has been involved in selecting for resistance to ACT partner drugs, resulting in high late treatment failure rates with dihydroartemisinin-piperaquine in Cambodia [14, 19–25] and with artesunate-mefloquine on the Thai-Myanmar border [26].

There are many factors that are thought to have contributed to the emergence and spread of artemisinin resistance in the GMS. One important factor is thought to be the use of oral artemisinin monotherapy (AMT) in place of WHO-recommended ACTs (as unregulated artemisinin or artesunate monotherapy has been available since mid-1970s in the region). In Myanmar, private healthcare facilities and healthcare providers who prioritize consumers' demand instead of recommended practices were more likely to stock oral AMT [26, 27]. Malaria elimination strategies should include targeted interventions to effectively reach these outlets. Fortunately, a major achievement during the resistance containment (and more recently elimination) activities has ceased the use of artemisinin monotherapies. ACT watch methods are monitoring displacement of oral AMTs, a major objective of the resistance containment strategy [28], and data will feed into regional score cards such as the Asia Pacific Leaders Malaria Alliance Access to Quality Medicines Task Force and the World Health Organisation (WHO) Emergency Response to Artemisinin Resistance (ERAR), which are vested in supporting national programs in tracking progress towards halting the availability and use of oral AMTs [28]. In Southeast Asia, where malaria transmission is generally low and emergence of resistance has been documented in multiple independent locations [29]; containment programmes have been converted into elimination of *P. falciparum* strategies to ensure halting the spread of resistance entirely.

many endemic countries have adopted (or are adopting) this policy [36, 37]. Reverting back to quinine because of artemisinin resistance would also jeopardise all these gains achieved in

Human and Simian Malaria in the Greater Mekong Subregion and Challenges for Elimination

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The spread of ACT resistance requires constant and comprehensive monitoring across regions. Continuous monitoring of drug resistance in malaria-endemic countries along with contributing factors is a key and will enable health authorities and practitioners to prevent drug resistance from spreading. WHO issues regular reports about the status of artemisinin resistance in malaria endemic countries [38], provides updates on the status of resistance to artemisinins and ACT, and maintains a network of sentinel sites performing therapeutic effi-

Although most of malaria endemic countries in Southeast Asia have incorporated malaria elimination goals in their national strategic plans, yet this region experiences high volume of population movement (both within and between countries) causing a great hindrance in achieving their elimination targets given the increased risk of importation of infection, spread of drug resistance, and challenges in providing healthcare services to mobile populations at

It is the movement of populations that results in importation of new infections leading to a source of local transmission [42, 43]. Cross-border movement of populations has contributed to establishment of "hot-spots" of high transmission along international borders [44, 45], and spread of drug resistance [6], because mobile populations often experience delays in receiving diagnosis and treatment, have improper health-seeking behaviour or self-medicate [88], and are subject to lower levels of surveillance [41, 46, 47]. Population mobility in the GMS is strongly associated with shifting land use, including large rural infrastructure projects and agricultural industries that attract migrant labor and influence human-vector contact. With the recent Association of Southeast Asian Nations (ASEAN) Economic Community agreement, allowing free movement of goods, services and labor between ASEAN countries [48];

In addition, the epidemiology of malaria in many parts of Southeast Asia is shifting toward migratory labor force that gets exposed to vectors in the forest, construction sites, and has variable access to healthcare services [46, 47, 49–53]. Since forested regions are concentrated along borders and much of the cross-border movement is from the migrant labor population, malaria prevalence in these pockets was hypothesized to represent foci of hotspots. Following this rationale, the increased malaria risk in these groups was recently documented in a cross-border malaria project conducted in the Thai-Cambodian, Lao-Cambodia and Vietnam-Cambodian borders. In this study [45], it was observed that the odds of infection in security/armed forces and forest-goers was 8 and 13 times higher compared to low-risk occupations (e.g., teachers, traders, salesmen, etc.). Mechanisms and risk reduction strategies should be in place to appropriately cover these special occupational

the management of severe malaria.

higher risk of malaria [40, 41].

high-risk groups.

cacy studies of first and second-line antimalarial drugs [38, 39].

**3. Targeting interventions in hard-to-reach population groups**

population movement is expected to rise even more in the coming years [6].

Other contributing factors are the use of substandard and counterfeit anti-malarial drugs and the difficulty of controlling malaria within migrant and hard-to-reach populations [30]. Given the transnational nature of this problem, the establishment of effective mechanisms for cross-country surveillance, information exchange and coordinated action is also necessary. This includes reinforcing existing institutional frameworks for regional health cooperation, particularly the Association of Southeast Asian Nations, and their potential to support enhanced capacities and cooperation to address this challenge [31]. Lastly, selection pressure—genetic mutations of wild-type genes in the parasite render them insusceptible to antimalarial drug treatment—is also thought to be important. The use of antimalarial drugs in patients with parasites containing mutations can eliminate susceptible parasites but leave resistant mutants to survive and reproduce [32].

More recently another potential contributing factor has been hypothesized. Given that there are parasite isolates that do not infect some *Anopheles* species, it is thought that artemisinin-resistant parasites are spreading so fast in Southeast Asia because they infect most or all native *Anopheles* species (e.g., *Anopheles dirus* and *An. minimus*), including African vector counterparts such as *An. coluzzii* (formerly *Anopheles gambiae* M form) [33]. The ability of artemisinin-resistant parasite clones to infect three highly genetically diverse vectors suggests that these resistant parasites have enhanced their transmission in the region and could effectively spread in sub-Saharan Africa, where most of the world's malaria mortality, morbidity, and transmission occurs [33, 34].

Since there are no equally effective alternative drugs to treat malaria, the spread of artemisinin resistance through India (Asia) to Africa and beyond could be a catastrophic setback to global efforts to control and eliminate the disease. Infection and mortality rates could dramatically increase in both regions, reversing the progress made towards malaria control and elimination efforts. The spread of artemisinin resistance would in turn expose the partner drugs in ACTs to greater selection pressure for the development of resistance and increased failure rates for the treatment of uncomplicated malaria. For severe malaria, the recent change in recommended treatment from quinine to artesunate [35] increased survival by 25%, and many endemic countries have adopted (or are adopting) this policy [36, 37]. Reverting back to quinine because of artemisinin resistance would also jeopardise all these gains achieved in the management of severe malaria.

The spread of ACT resistance requires constant and comprehensive monitoring across regions. Continuous monitoring of drug resistance in malaria-endemic countries along with contributing factors is a key and will enable health authorities and practitioners to prevent drug resistance from spreading. WHO issues regular reports about the status of artemisinin resistance in malaria endemic countries [38], provides updates on the status of resistance to artemisinins and ACT, and maintains a network of sentinel sites performing therapeutic efficacy studies of first and second-line antimalarial drugs [38, 39].
