Abstract
Malaria is a significant public health problem and impediment to socioeconomic development in countries of the Greater Mekong Subregion (GMS), which comprises Cambodia, China’s Yunnan Province, Lao People’s Democratic Republic, Myanmar, Thailand, and Vietnam. Over the past decade, intensified malaria control has greatly reduced the regional malaria burden. Driven by increasing political commitment, motivated by recent achievements in malaria control, and urged by the imminent threat of emerging artemisinin resistance, the GMS countries have endorsed a regional malaria elimination plan with a goal of eliminating malaria by 2030. However, this ambitious, but laudable, goal faces a daunting array of challenges and requires integrated strategies tailored to the region, which should be based on a mechanistic understanding of the human, parasite, and vector factors sustaining continued malaria transmission along international borders. Malaria epidemiology in the GMS is complex and rapidly evolving. Spatial heterogeneity requires targeted use of the limited resources. Border malaria accounts for continued malaria transmission and represents sources of parasite introduction through porous borders by highly mobile human populations. Asymptomatic infections constitute huge parasite reservoir requiring interventions in time and place to pave the way for malaria elimination. Of the two most predominant malaria parasites, Plasmodium falciparum and P. vivax, the prevalence of the latter is increasing in most member GMS countries. This parasite requires the use of 8-aminoquinoline drugs to prevent relapses from liver hypnozoites, but high prevalence of glucose-6-phosphate dehydrogenase deficiency in the endemic human populations makes it difficult to adopt this treatment regimen. The recent emergence of resistance to artemisinins and partner drugs in P. falciparum has raised both regional and global concerns, and elimination efforts are invariably prioritized against this parasite to avert spread. Moreover, the effectiveness of the two core vector control interventions—insecticide-treated nets and indoor residual spraying—has been declining due to insecticide resistance and increased outdoor biting activity of mosquito vectors. These technical challenges, though varying from country to country, require integrated approaches and better understanding of the malaria epidemiology enabling targeted control of the parasites and vectors. Understanding the mechanism and distribution of drug-resistant parasites will allow effective drug treatment and prevent, or slow down, the spread of drug resistance. Coordination among the GMS countries is essential to prevent parasite reintroduction across the international borders to achieve regional malaria elimination.
Keywords
- malaria elimination
- Greater Mekong Subregion
- epidemiology
- drug resistance
- migration
- insecticide resistance
1. Introduction
With steady gains in the fight against malaria over the past decade, the international malaria community once again is embracing the global goal of malaria eradication. Meanwhile, the World Health Organization (WHO) has launched a new Global Technical Strategy for Malaria (http://www.who.int/malaria/areas/global_technical_strategy/en/) as the operational framework guiding malarious nations and regions in their pursuit of malaria elimination. In the Greater Mekong Subregion (GMS) of Southeast Asia (SEA), which comprises Cambodia, China’s Yunnan Province, Lao People’s Democratic Republic (Laos), Myanmar, Thailand, and Vietnam, malaria has been a significant public health problem and impediment to socioeconomic development [1, 2]. Intensified malaria control in recent years, fueled by increased international funding and local bustling economic development, has greatly reduced the regional malaria burden. Compared with confirmed malaria cases in 2010, the number of malaria cases in the GMS was reduced by ~50% in 2014. Driven by increasing political will and financial support and motivated by recent achievements in malaria control, the six GMS nations have endorsed a regional malaria elimination plan with an ultimate goal of eliminating
2. Border malaria
Malaria epidemiology in the GMS is complex and rapidly evolving. There is immense spatial heterogeneity in both regional and countrywide disease distribution (Figure 1 and Table 1). Within the GMS, Myanmar has the heaviest malaria burden and accounts for more than 53% of regionally confirmed malaria cases. Within each country, the pattern of malaria distribution remains similar, but transmission is still concentrated along international borders—the so-called border malaria. In border areas, there is poor accessibility to healthcare services, and surveillance for malaria is far less than optimal [8]. Given that these border regions represent probable malaria reservoirs and that importation and dispersal by migratory human populations are extremely difficult to monitor, border malaria constitutes one of the biggest obstacles for malaria elimination. Highly mobile populations crossing porous borders are a major contributor to parasite introduction and continued transmission [9]. Border areas also are home to ethnic minorities, hill tribes, temporary and seasonal migrants, refugees, and internally displaced people; many have poor educational level, limited access to healthcare services, and reduced legal rights. Geographical and cultural isolation leaves these groups at a high risk for infection and poor access to treatment [1, 2, 10, 11]. In Thailand, malaria makes up ~31% of communicable diseases diagnosed in migrants, as compared to 3% in Thai natives [12]. Heavy population flow along the extremely porous borders makes neighboring countries very vulnerable to malaria introduction and reintroduction [13, 14]. As a result, malaria prevalence on both sides of the border is often highly correlated [15]. In Yunnan Province of China, although autochthonous

Figure 1.
The geographical proximity of countries and reported malaria cases for data based on 2016 in the Greater Mekong Subregion (GMS).
Country/drug policy* | Year | No. of malaria cases | % of confirmed cases° | No. of death cases | ||
---|---|---|---|---|---|---|
Pf | Pv | Others | ||||
Uncomplicated Pf: ART + NQ; AS + AQ; D-P Severe malaria: AM; AS; pyronaridine | 2011 | 3000 | 41.9 | 56.6 | 1.5 | ≤100 |
2012 | 240 | 8.2 | 91.8 | — | 0 | |
2013 | ≤100 | 64.1 | 35.9 | — | 0 | |
2014 | ≤100 | 10.7 | 89.3 | — | 0 | |
2015 | ≤100 | 3.0 | 78.8 | 18.2 | 0 | |
2016 | ≤10 | 0.0 | 100.0 | — | 0 | |
Uncomplicated Pf: AS + MQ, D-P Severe malaria: AM; AS; QN | 2011 | 203,600 | 62.6 | 37.4 | — | 400 |
2012 | 146,000 | 50.4 | 49.6 | — | 220 | |
2013 | 76,500 | 45.8 | 54.2 | — | 110 | |
2014 | 89,700 | 58.8 | 41.2 | — | 150 | |
2015 | 120,300 | 61.3 | 38.7 | — | 210 | |
2016 | 83,300 | 58.2 | 41.8 | — | 140 | |
Uncomplicated Pf: AL Severe malaria: AS + AL | 2011 | 42,800 | 92.7 | 7.1 | 0.2 | ≤100 |
2012 | 112,700 | 83.4 | 16.6 | — | 250 | |
2013 | 93,500 | 67.0 | 33.0 | — | 170 | |
2014 | 117,300 | 52.9 | 47.1 | — | 180 | |
2015 | 87,900 | 42.3 | 57.7 | — | 120 | |
2016 | 27,390 | 39.5 | 60.5 | — | ≤100 | |
Uncomplicated Pf: AL; AM; AS + MQ; D-P; PQ Severe malaria: AM; AS; QN | 2011 | 1,506,000 | 68.4 | 31.6 | — | 2800 |
2012 | 1,974,000 | 71.8 | 28.2 | — | 4000 | |
2013 | 585,000 | 70.4 | 29.6 | — | 1100 | |
2014 | 360,000 | 69.9 | 30.1 | — | 700 | |
2015 | 236,500 | 64.1 | 35.9 | — | 400 | |
2016 | 142,600 | 60.3 | 39.7 | — | 240 | |
Uncomplicated Pf: D-P Severe malaria: QN + doxycycline | 2011 | 24,900 | 40.5 | 59.5 | 0.1 | ≤100 |
2012 | 32,600 | 39.8 | 60.2 | — | ≤100 | |
2013 | 33,300 | 44.0 | 46.8 | 9.3 | ≤100 | |
2014 | 37,900 | 37.8 | 54.1 | 8.1 | ≤100 | |
2015 | 8000 | 41.7 | 58.0 | 0.2 | ≤100 | |
2016 | 11,520 | 32.5 | 46.1 | 21.5 | ≤100 | |
Uncomplicated Pf: D-P Severe malaria: AS; QN | 2011 | 22,630 | 64.3 | 35.7 | — | ≤100 |
2012 | 26,610 | 61.3 | 38.7 | — | ≤100 | |
2013 | 23,140 | 58.0 | 42.0 | — | ≤100 | |
2014 | 21,200 | 54.2 | 45.8 | — | ≤100 | |
2015 | 12,560 | 48.9 | 51.0 | 0.2 | ≤100 | |
2016 | 6000 | 57.6 | 42.1 | 0.4 | ≤10 |
Table 1.
Antimalarial drug policy and malaria transmission trends in the Greater Mekong Subregion (GMS) countries during 2011–2016 [7].
AL, artemether + lumefantrine; AM, artemether; AQ, amodiaquine; ART, artemisinin; AS, artesunate; CQ, chloroquine; D-P, dihydroartemisinin + piperaquine; MQ, mefloquine; NQ, naphthoquine; PQ, primaquine; QN, quinine.°Pf:
3. Asymptomatic malaria as an important reservoir
It has long been held as conventional wisdom that asymptomatic infections would be much less frequent in low-endemicity settings because the level of exposure-related immunity to malaria in human populations may be low [25]. However, asymptomatic infections represent the vast majority of infections in all endemic settings [26]. The use of molecular tools is essential for identifying submicroscopic infections. For both
4. The burden of P. vivax malaria and G6PD deficiency
Another characteristic of the rapidly evolving malaria epidemiology in the GMS is that the prevalence of
In the GMS, the first-line therapy for vivax malaria remains chloroquine (CQ) and primaquine (PQ) (Table 1) [41]. Reports of clinical CQ resistance in many regions of the world and falling efficacy of PQ are of great concern for vivax malaria control [42, 43, 44, 45]. Although some studies indicated that
Studies from Papua New Guinea suggest that 80% of the vivax infections may be attributed to relapses. A modeling approach predicts that as much as 96% of clinical attacks by
The
5. Management of drug resistance in P. falciparum
ACTs have played an indispensable role in reducing global malaria-associated mortality and morbidity. However, these achievements are threatened by the recent emergence of artemisinin resistance in
The principle of ACTs is that the fast-acting artemisinins rapidly reduce the parasite biomass, leaving the slow-eliminating partner drugs to clear the residual parasites. The emergence of artemisinin resistance means that a larger parasite mass is left for the partner drugs to clear after the usual 3-day ACT course, which increases the chance of resistance development to the partner drugs. Indeed, in the short period of time since the deployment of ACTs, clinical resistance to two ACTs, first artesunate/mefloquine [106] and more recently dihydroartemisinin/piperaquine (DHA/PPQ), has emerged in the GMS. These are the two most popular ACTs deployed in the GMS countries (Table 1). Since promising new antimalarials are still in the development pipeline, possible solutions to this problem include introduction of new ACTs, rotation of different ACTs, use of longer course of ACT treatment, and introduction of triple ACTs (artemisinin derivatives with two slow-eliminating partner drugs) [112]. To mitigate the threat of spread of artemisinin-resistant
Tools for monitoring the epidemiology of antimalarial drug resistance include ex vivo or in vitro drug assays and molecular surveillance, which complement in vivo drug efficacy studies. It is noteworthy that the slow-clearance phenotype of clinical artemisinin resistance does not correspond to the 50% inhibitory concentrations of artemisinin drugs estimated from the conventional DNA replication-based in vitro assay but is better reflected in the newly developed ring-stage survival assay, which quantifies the number of early ring-stage parasites (0–3 h) that can survive the exposure to 700 nM of DHA for 6 h [114]. The discovery of mutations in the
6. Vectors
LLINs and IRS are the key vector-based malaria interventions that have been found to be highly effective in sub-Saharan Africa. However, these measures are much less efficient in the GMS [130]. The GMS has a complex vector system; most of the malaria vectors belong to species complexes or groups such as Dirus, Minimus, Maculatus, and Sundaicus, which vary significantly in terms of geographic distribution, ecology, behavior, and vectorial competence [131, 132, 133]. At least 19 species are known malaria vectors, some of which comprise cryptic species complexes [132]. In order to apply the appropriate control approaches in relation to the biology of the vector species, we first need to identify the mosquitoes to their species level and to differentiate the vector from nonvector species, which requires molecular assays [134]. These vector species display significant variations in geographical distribution and seasonal dynamics, and accordingly their roles in malaria transmission also vary in space and time [135]. In many endemic areas of the GMS, perennial malaria transmission is maintained by
7. Technological innovation for malaria elimination
The technical challenges discussed here suggest that the currently used malaria control tools (RDT, ACT, LLIN, and IRS) that were instrumental for the gains against malaria may not be sufficient for malaria elimination [144]. Additional tools are needed to achieve the final goal of malaria elimination in the GMS. First, residual transmission requires MDA to eliminate asymptomatic and submicroscopic parasite reservoirs. For the success of MDA, better knowledge of malaria epidemiology is needed so that targeted MDA can be implemented. Successful MDA programs also require strong community engagement. MDA has proved successful in eliminating malaria in Asia-Pacific regions such as Vanuatu and central China [145, 146]. In an earlier study conducted in Cambodian villages, MDA of artemisinin-PPQ at 10-day intervals for 6 months drastically reduced
8. Conclusions
Malaria elimination in the GMS carries the urgency of eliminating artemisinin-resistant
Acknowledgments
We thank the National Institute of Allergy and Infectious Diseases, NIH, for financial support (U19AI089672).