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

**5. Prospects of elimination**

24 Towards Malaria Elimination - A Leap Forward

of malaria elimination [10, 26, 87, 118].

therapies and their full development will take many years.

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]. 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].

The current malaria elimination program along the Thai-Myanmar border is using artemetherlumefantrine (AL) for treating the clinical cases at the village malaria posts or by malaria workers [114], whereas dihydroartemisinin-piperaquine (DP) is deployed in MDA activities [117]. In this area, the third ACT, mefloquine-artesunate combination, is already failing [25], and the prospect of elimination program is highly dependent on the therapeutic efficacy of AL and DP. Recent emergence of piperaquine resistance following the artemisinin resistance has depleted the available ACTs to be deployed in malaria elimination programs. High failure rates of AL in Laos PDR and DP in Vietnam and Cambodia have cast doubts on the optimism

There are very few new compounds in the development pipeline. The front runners are OZ439, a synthetic endoperoxide, structurally related to artemisinin, and KAF156 belonging to a new class of antimalarial (imidazolopiperazines) and the spiroindolone cipargamin (formerly KAE609). However, these short-acting drugs will have to be deployed in combination

**6. Choice of drug for malaria elimination: is the pipeline empty?**

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 in recent years.
