**5. Prospects of elimination**

With the declining transmission of malaria, the geographic clustering of both clinical and asymptomatic infections has become more apparent. Asymptomatic carriers represent a "reservoir" of parasites that are difficult to detect because the density of parasites is often below the sensitivity threshold of conventional diagnostic tools (Rapid Diagnostic Tests and microscopy). The size of these reservoirs of sub-microscopic infections (also called "hot-spots") can vary from a few households to large geographical areas. Clustering of these hotspots becomes more pronounced as transmission declines [111]. While considering malaria elimination, radical depletion of parasite reservoir (asymptomatic carriers with sub-microscopic parasitaemia) and gametocytes is a necessity. This can be achieved by two functional components: (1) early diagnosis with treatment (EDT) of the symptomatic patients (preferably within 48 hour of symptoms before the development of gametocytaemia) and (2) early detection and treatment targeting the reservoirs of sub-microscopic infections through Mass Drug Administration (MDA) [112, 113].

As a stopgap measure, two triple ACTs (mefloquine plus DP and amodiaquine plus AL) are under multicentre trial, using the inverse correlation between susceptibility to amodiaquine and lumefantrine as well as between piperaquine and mefloquine. The trial has completed the patient recruitment and the results are promising with high cure rates. However, recent increasing prevalence of parasite isolates with potential resistance to both mefloquine and

The Artemisinin Resistance in Southeast Asia: An Imminent Global Threat to Malaria Elimination

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For the *P. vivax*, chloroquine remains the first line of treatment in majority of the endemic countries. However, after the first report from Papua New Guinea in 1989, chloroquine resistance has reached northern Papua and Indonesia. Later on, data with recurrences (by day-28 of chloroquine treatment) greater than 10% have also been reported from Myanmar, Thailand, Cambodia, India, Vietnam, Turkey, South America, Ethiopia and Madagascar [119]. Resistance in *P. vivax* is more difficult to document than for *P. falciparum* because of the relapses from liver stages. The most robust proof of resistance is given when a circulating parasite is detected in the peripheral blood in the presence of therapeutic chloroquine concentrations (i.e. >100 ng/ml). The absence of long-term parasite culture for *P. vivax* further complicates the efficacy testing in the laboratory, but short-term assays have been developed

The six countries of the Greater Mekong Subregion (GMS), Thailand, Myanmar, Cambodia, Laos, Vietnam and China (Yunnan Province), are part of a larger community, the Association of Southeast Asian Nations (ASEAN). Despite political pledges to fight artemisinin resistance and eliminate malaria, coordination remains hampered by deep political, economic and geographical gaps. The WHO strategic plans to counter artemisinin resistance failed to prevent its spread to the entire sub-region. In 2013, the Global Fund launched the Regional Artemisininresistance Initiative to provide financial support to the five countries affected by this new treat. This initiative came in addition to the contributions of the Global Fund to the Malaria National Program and contributed to the decrease in malaria-related mortality and morbidity in the region. However, these efforts have been compromised by the fragmentation in the public health policies, the disparities in the infrastructures and human resources as well as corruption. In terms of treatment policies, all GMS countries had already adopted ACTs long before the emergence of resistance, but poor monitoring in some countries meant that monotherapies and sub-standard or counterfeit drugs continued to circulate until recently. The relative absence of entomological data in some parts of SEA explains that there is no coherent strategy for containment of local disease vectors. Large budgets continue to be spent on long-lasting impregnated nets (LLINs) despite the absence of evidence of their effectiveness.

piperaquine has questioned the longevity of the triple ACT [20].

**8. Regional artemisinin resistance initiative (RAI)**

**7. Drug resistance in** *P. vivax*

in recent years.

The intervention for the first element is to set up or reinforce and sustain malaria control program hence reducing the number of clinical episodes as much as possible through increased access to EDT where the use of efficacious antimalarial regimen is critical [114]. As the drug resistance worsen, the rising number of clinical cases due to increasing gametocyte carriage in the community will be inevitable. MDA or mass screening and treatment (MSAT) is only accelerating the malaria elimination alongside EDT, by eliminating the sub-microscopic reservoir [115]. The effectiveness of MDA or MSAT significantly relies on the therapeutic efficacy of the drug in use, the coverage and the total number of rounds of MDA. In turn, this means that a careful and well-conducted community engagement is primordial for enhanced coverage [115, 116].
