**2. Epidemiological drivers of malaria in APMEN countries**

Malaria elimination in APMEN countries faces many challenges. The challenges include large numbers of people living in malaria risk areas; presence of all forms of human malaria: *Plasmodium falciparum*, *P. vivax*, *P. ovale, P. malariae*, and *P. knowlesi*; the high incidence of *P. vivax* malaria, which is particularly difficult to control due to the dormant stages of its life cycle within the human host, and zoonotic malaria caused by *P. knowlesi*, which has animal reservoirs; antimalarial drug resistance in *P. falciparum* and *P. vivax* parasites; diverse vectors with different feeding behaviour and insecticide resistance; forest malaria; human migration across porous international borders and cross-border malaria; and inadequacies in health systems in the region.

#### **2.1.** *Plasmodium vivax* **Malaria**

*Plasmodium vivax* is an important but relatively neglected malaria parasite globally [17]. This form of malaria is more widespread than *P. falciparum* malaria with 2.9 billion people at risk of infection, of which 90% live in the Asia Pacific region [18–22]. *P. vivax* is more difficult to treat than *P. falciparum* due to dormant liver stages (hypnozoites) [23–25], and the development of transmissible blood stages (gametocytes) before clinical symptoms [26]. These characteristics enable the parasite to adapt to environmental challenges and evade control interventions in place and time.

In many countries embarking on malaria elimination, *P. falciparum* incidence declines more rapidly than *P. vivax* incidence, due to the greater effectiveness of interventions for the former. Treating all stages of the parasite (radical cure) is a critical strategy for the successful control and ultimate elimination of *P. vivax*. In order to achieve radical cure of *P. vivax*, blood stage parasites, as well as the hypnozoites, need to be cleared. The only current widely available drug against hypnozoites is the 8-aminoquinoline compound, primaquine [27]. Unfortunately, individuals who have a genetic deficiency for glucose-6-phosphate dehydrogenase (G6PD) enzyme are at risk of severe haemolysis when treated with the drug [28–30]. In addition, primaquine requires prolonged daily administration over seven to 14 days. The complexities of prescribing reliable, safe and effective radical cure of *P. vivax* highlights the urgent need for innovative new approaches to assure schizonticidal and hypnozoiticidal treatment; without which, *P. vivax* elimination is unlikely in most settings.

#### **2.2. Zoonotic malaria**

Democratic People's Republic of Korea (DPR Korea), Indonesia, Malaysia, the Philippines, Republic of Korea, Solomon Islands, Sri Lanka, and Vanuatu) that now have expanded to 18 countries (adding Bangladesh, Cambodia, Lao People's Democratic Republic (Lao PDR), India, Nepal, Papua New Guinea, Thailand, and Vietnam) [11] (**Figure 1**). APMEN countries encompass the largest malaria reporting area outside the African region. APMEN serves the country partners and together with regional partners from the academic, development, nongovernmental and private sectors, and global agencies including the WHO, collaboratively address the unique challenges of malaria elimination in the region through leadership, advocacy, capacity building, knowledge exchange and building evidence to support more effec-

Each member State has defined elimination goals based on malaria transmission trends (**Table 1**). Countries with low incidence of malaria are targeting elimination at the national level, while countries with higher incidence are planning to eliminate malaria at the subnational level before pursuing elimination at the national level. However, all countries are committed to eliminating malaria in the Asia Pacific region by 2030 [13]. Sri Lanka eliminated malaria in 2012 and WHO certified Sri Lanka malaria free nation in 2016 [14]. Bhutan and the Republic of Korea have targeted to eliminate malaria in 2018 and 2019 respectively [15, 16]. Bangladesh, China, Malaysia, Philippines, and Vanuatu plan to eliminate malaria by 2020; DPR Korea, Cambodia, Lao People's Demographic Republic (Lao PDR), and Papua New Guinea (PNG) are planning to eliminate by 2025, and Nepal by 2026; finally India, Indonesia, Thailand, and Vietnam plan to eliminate malaria by 2030 [15]. The success of malaria elimination in APMEN States will greatly enhance the global drive towards malaria elimination. Therefore, the aim of this review is to present a compilation of available evidence on the challenges and way forward for malaria elimination in APMEN countries.

Malaria elimination in APMEN countries faces many challenges. The challenges include large numbers of people living in malaria risk areas; presence of all forms of human malaria: *Plasmodium falciparum*, *P. vivax*, *P. ovale, P. malariae*, and *P. knowlesi*; the high incidence of *P. vivax* malaria, which is particularly difficult to control due to the dormant stages of its life cycle within the human host, and zoonotic malaria caused by *P. knowlesi*, which has animal reservoirs; antimalarial drug resistance in *P. falciparum* and *P. vivax* parasites; diverse vectors with different feeding behaviour and insecticide resistance; forest malaria; human migration across porous international borders and cross-border malaria; and inadequacies in health systems in the region.

*Plasmodium vivax* is an important but relatively neglected malaria parasite globally [17]. This form of malaria is more widespread than *P. falciparum* malaria with 2.9 billion people at risk of infection, of which 90% live in the Asia Pacific region [18–22]. *P. vivax* is more difficult to treat than *P. falciparum* due to dormant liver stages (hypnozoites) [23–25], and the development of transmissible blood stages (gametocytes) before clinical symptoms [26]. These characteristics enable the parasite to adapt to environmental challenges and evade control interventions in place and time.

tive, sustained malaria elimination programmes across the region [12].

**2. Epidemiological drivers of malaria in APMEN countries**

**2.1.** *Plasmodium vivax* **Malaria**

204 Towards Malaria Elimination - A Leap Forward

*Plasmodium knowlesi* infections have been reported in a number of Asian Pacific countries [31–34]. This zoonotic species of malaria, which also infects macaque monkeys that form the main animal reservoir, was probably present in humans but was undiagnosed until molecular detection methods were developed that could distinguish *P. knowlesi* from the morphologically similar human malaria parasite *Plasmodium malariae* [35, 36]. Recently, the first case of human infection with *Plasmodium cynomolgi* was reported in Peninsular Malaysia that resembles *P. vivax* morphologically [37]. The role of animal reservoirs of malaria transmittable to humans is an almost wholly neglected question in the elimination agenda in the Asia-Pacific region [38].

#### **2.3. Characteristics of populations at risk**

Nearly 2.1 billion people in the Asia-Pacific region live in areas where there is risk of malaria transmission of which 16.8% live in high-risk areas [2, 39] (**Figure 2**). These high-risk areas include settlements located in remote parts of endemic countries including border areas. Many of these high-risk areas are characterised by forest and forest fringe environment with high malaria transmission, poor geographical accessibility, high population mobility, and low human density. In addition, most of these areas are inhabited by ethnic minorities, refugees and displaced people who are difficult to access and often experience high degree of poverty [40, 41]. Furthermore, these areas are frequented by people engaged in activities with increased risk of malaria exposure, such as tourism and pilgrimages, forest-related work such as logging, gem-mining, latex harvesting, fishing, road construction and other industrial occupations [41–45].

## **2.4. Antimalarial drug-resistance**

Historically, countries in the Mekong Region including Cambodia and Thailand are global epicentres of emerging antimalarial drug resistance [46]. Chloroquine resistance was first reported in this area in the 1970s, followed by resistance to other anti-malarial drugs [47]. Over the past decade, artemisinin-based combination therapy (ACT) became the first-line protocol for the management of *P. falciparum* infections world over. However, parasites that

**Figure 2.** Population at risk of malaria in Asia Pacific Malaria Elimination Network (APMEN) countries for data based on 2016. (at risk- low risk + high risk). Source: World malaria report 2017 [1].

are drug-resistant to artemisinin and its derivatives have recently emerged in various parts of Southeast Asia challenging all control strategies for treatment and elimination efforts [48–51]. Presently, resistance to mefloquine continues to be a concern in Thailand and Cambodia, where artesunate-mefloquine is used as first line treatment [47]. Artemether-lumefantrine remains highly effective in most parts of the world, with the exception of Cambodia [52, 53]. There are evidences of resistance to ACT in Vietnam [2, 54]. In India, ACT is used universally across the country yet declining efficacy to artesunate plus sulphadoxine-pyrimethamine has already been reported in its northeastern region [55–57] however, there have been no reports of ACT resistance in other APMEN member States (**Figure 3**).

Asia-Pacific region (19 different species) poses unique challenges for elimination [70, 71] (**Table 2**). There is considerable variation in bionomical characteristics of mosquito vectors making control efforts difficult. The commonest malaria vector species in the region, including *Anopheles dirus, An. baimaii,* and *An. minimus* [72, 73], are able to avoid indoor sprayed surfaces because of their exophilic and exophagic characteristics [70, 74, 75] rendering most domicile-based interventions, like long-lasting insecticidal nets (LLIN) and indoor residual spraying (IRS), less effective [74, 76]. Other challenges include insecticide resistance [77] and absence of local vector surveillance [78]. To address these challenges, APMEN instituted the APMEN Vector Control Working Group (VcWG) in 2010 [79]. The working group fosters information exchange between vector control experts and national programme managers of APMEN countries to formulate strategies to counter the challenges faced in the region. The Working Group has supported a range of activities to build vector control capacity in the region, including providing training fellowships to vector control officers in priority areas, supporting community efficacy studies of interventions, and

**Figure 3.** Distribution of malarial multidrug resistance for data based on 2016. ACT- artemisinin-based combination therapy; 1 ACT- resistance to one ACT; 2 ACT- resistance to two ACTs; 3 ACTs- resistance to three ACTs; 4 ACTs-

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Forest malaria constitutes bulk of transmission in APMEN countries [42, 43, 80–83]. Many species of *Anopheles* mosquitoes that transmit malaria agents are abundant in natural forests

consolidating information on vector management practices in the region [78].

resistance to four ACTs. Source: World malaria report 2017 [1].

**2.6. Forest malaria**

Chloroquine has remained the main choice of treatment for *P. vivax* blood stage infections, however, this policy is under threat from emerging drug resistant *P. vivax* strains [58]. A number of APMEN countries have reported *P. vivax* resistance to chloroquine. There are reports of resistance in some States of India [59–62], central Vietnam [63], and Thai-Myanmar border [64]. However, *P. vivax* is still sensitive to chloroquine in Cambodia [65], border area of Yunnan Province of China and Myanmar [66], central China [67], and Nepal [68, 69].

#### **2.5. Vector control**

Vector control remains one of the main preventive strategies of containing malaria transmission in APMEN countries. However, a lack of technical capacity in entomology and vector control represents a key gap in elimination programmes. In addition, the diversity of malaria vectors in the Ending Malaria Transmission in the Asia Pacific Malaria Elimination Network (APMEN) Countries… http://dx.doi.org/10.5772/intechopen.75405 207

**Figure 3.** Distribution of malarial multidrug resistance for data based on 2016. ACT- artemisinin-based combination therapy; 1 ACT- resistance to one ACT; 2 ACT- resistance to two ACTs; 3 ACTs- resistance to three ACTs; 4 ACTsresistance to four ACTs. Source: World malaria report 2017 [1].

Asia-Pacific region (19 different species) poses unique challenges for elimination [70, 71] (**Table 2**). There is considerable variation in bionomical characteristics of mosquito vectors making control efforts difficult. The commonest malaria vector species in the region, including *Anopheles dirus, An. baimaii,* and *An. minimus* [72, 73], are able to avoid indoor sprayed surfaces because of their exophilic and exophagic characteristics [70, 74, 75] rendering most domicile-based interventions, like long-lasting insecticidal nets (LLIN) and indoor residual spraying (IRS), less effective [74, 76]. Other challenges include insecticide resistance [77] and absence of local vector surveillance [78]. To address these challenges, APMEN instituted the APMEN Vector Control Working Group (VcWG) in 2010 [79]. The working group fosters information exchange between vector control experts and national programme managers of APMEN countries to formulate strategies to counter the challenges faced in the region. The Working Group has supported a range of activities to build vector control capacity in the region, including providing training fellowships to vector control officers in priority areas, supporting community efficacy studies of interventions, and consolidating information on vector management practices in the region [78].

#### **2.6. Forest malaria**

are drug-resistant to artemisinin and its derivatives have recently emerged in various parts of Southeast Asia challenging all control strategies for treatment and elimination efforts [48–51]. Presently, resistance to mefloquine continues to be a concern in Thailand and Cambodia, where artesunate-mefloquine is used as first line treatment [47]. Artemether-lumefantrine remains highly effective in most parts of the world, with the exception of Cambodia [52, 53]. There are evidences of resistance to ACT in Vietnam [2, 54]. In India, ACT is used universally across the country yet declining efficacy to artesunate plus sulphadoxine-pyrimethamine has already been reported in its northeastern region [55–57] however, there have been no reports

**Figure 2.** Population at risk of malaria in Asia Pacific Malaria Elimination Network (APMEN) countries for data based

Chloroquine has remained the main choice of treatment for *P. vivax* blood stage infections, however, this policy is under threat from emerging drug resistant *P. vivax* strains [58]. A number of APMEN countries have reported *P. vivax* resistance to chloroquine. There are reports of resistance in some States of India [59–62], central Vietnam [63], and Thai-Myanmar border [64]. However, *P. vivax* is still sensitive to chloroquine in Cambodia [65], border area of Yunnan

Vector control remains one of the main preventive strategies of containing malaria transmission in APMEN countries. However, a lack of technical capacity in entomology and vector control represents a key gap in elimination programmes. In addition, the diversity of malaria vectors in the

of ACT resistance in other APMEN member States (**Figure 3**).

on 2016. (at risk- low risk + high risk). Source: World malaria report 2017 [1].

206 Towards Malaria Elimination - A Leap Forward

**2.5. Vector control**

Province of China and Myanmar [66], central China [67], and Nepal [68, 69].

Forest malaria constitutes bulk of transmission in APMEN countries [42, 43, 80–83]. Many species of *Anopheles* mosquitoes that transmit malaria agents are abundant in natural forests


in the region [80, 90–93]. Deforestation increases the risk of malaria through a number of favourable conditions for the *Anopheles* mosquito by creating mosquito-breeding sites in the stumps of trees, ditches and puddles on the ground. The direct sunlight on the pools of water increases temperatures promoting mosquito breeding. Increased human activities in deforested areas such as logging, increased large-scale agricultural activities, mining, building of hydropower projects, and the collection of wood for fuel, all enhance contact with mosquitoes

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Populations in border areas are at greater risk of malaria infections because they frequently visit forests, forest fringe areas, or forested plantations at or near the border [42, 75, 97, 98]. Occupational exposures affect malarial receptivity by age group–for example, in forest fringe villages, adult infections are more prevalent due to forest-related activities such as logging, rubber tapping, bamboo cutting, charcoaling, foraging, and overnight stays in the forests [99]. Migration of the population working in the forest and forest fringe results in spread via carriers to new areas previously free from malaria transmission [100]. Despite high coverage of preventive measures such as LLIN or insecticide-treated nets (ITNs) and IRS in the member States of APMEN, populations working and staying overnight in the forest are not protected [43, 82, 101]. A lack of infrastructure such as roads and healthcare facilities hinder malaria

One of the main challenges that continues thwart malaria elimination is cross-border malaria [94, 102]. People migrate across international borders for a number of reasons including work opportunities, visiting friends and relatives, and displacement as a result of natural and manmade calamities (such as ethnic conflicts) and major development projects. Malaria control in border areas is often difficult for being heavily forested, mountainous and inaccessible terrain, and unregulated population movements across the borders [103, 104]. Open porous international borders allow unchecked movement of people [105–111]. Such cross-border migration is likely to derail the malaria control activities of the neighbouring countries and risk introduction of drugresistant parasites [112]. Mobile populations along the border areas often live in poverty and have poor access to healthcare services. Movement of people across international borders has contributed to maintaining high transmission hotspots adjacent to border points [73, 105, 113].

There are differences in programmatic approaches among neighbouring countries in the APMEN region making the coordination of control and preventive measures challenging [114, 115]. For example, there are differences in malaria control activities across Laos-Vietnam border. In Laos, the mainstay of malaria control is distribution of LLINs but on the Vietnamese side there is a stronger focus on IRS [114, 115]. Even where the approaches are similar, the specific antimalarial drugs or insecticides used can influence effectiveness due to parasite or vector resistance. Deltamethrin (synthetic pyrethroid) is used for IRS in Bhutan, however, DDT is used in the neighbouring State of Assam in India [116–118]. Effective control

and thereby increased malaria transmission [94–96].

control activities and delayed treatment.

**2.7. Migration and cross-border malaria**

**2.8. Misalignment of programmatic approaches**

or elimination requires coordinated efforts for control interventions.

\*An., *Anopheles* names refer either to the group, complex or species when specific identifications have been done. °Corresponding references are in brackets.

**Table 2.** List of the main malaria vectors in the Asia Pacific Malaria Elimination Network (APMEN) countries.

and forested plantations. Both the forests and occurrence of deforestation impact increasing malaria risk and transmission, particularly in border areas. Forested areas provide conducive environment for vector proliferation and survival [84, 85]. Forest vectors usually prefer tree canopy coverage and are known to take shelter in tree holes [86–88]. Forest flora and sugar availability have also been shown to be crucial determinants of vectorial capacity [89]. In addition, leaves falling into larval habitats assure sustainable micro-climatic conditions for larvae of vectors like *An. dirus,* which is a dominant vector in Southeast Asia [90]. Further, there are usually abundant bodies of water including ponds, streams, and rivers in forested areas supporting vector multiplication and survival thereby sustaining malaria transmission in the region [80, 90–93]. Deforestation increases the risk of malaria through a number of favourable conditions for the *Anopheles* mosquito by creating mosquito-breeding sites in the stumps of trees, ditches and puddles on the ground. The direct sunlight on the pools of water increases temperatures promoting mosquito breeding. Increased human activities in deforested areas such as logging, increased large-scale agricultural activities, mining, building of hydropower projects, and the collection of wood for fuel, all enhance contact with mosquitoes and thereby increased malaria transmission [94–96].

Populations in border areas are at greater risk of malaria infections because they frequently visit forests, forest fringe areas, or forested plantations at or near the border [42, 75, 97, 98]. Occupational exposures affect malarial receptivity by age group–for example, in forest fringe villages, adult infections are more prevalent due to forest-related activities such as logging, rubber tapping, bamboo cutting, charcoaling, foraging, and overnight stays in the forests [99]. Migration of the population working in the forest and forest fringe results in spread via carriers to new areas previously free from malaria transmission [100]. Despite high coverage of preventive measures such as LLIN or insecticide-treated nets (ITNs) and IRS in the member States of APMEN, populations working and staying overnight in the forest are not protected [43, 82, 101]. A lack of infrastructure such as roads and healthcare facilities hinder malaria control activities and delayed treatment.

#### **2.7. Migration and cross-border malaria**

One of the main challenges that continues thwart malaria elimination is cross-border malaria [94, 102]. People migrate across international borders for a number of reasons including work opportunities, visiting friends and relatives, and displacement as a result of natural and manmade calamities (such as ethnic conflicts) and major development projects. Malaria control in border areas is often difficult for being heavily forested, mountainous and inaccessible terrain, and unregulated population movements across the borders [103, 104]. Open porous international borders allow unchecked movement of people [105–111]. Such cross-border migration is likely to derail the malaria control activities of the neighbouring countries and risk introduction of drugresistant parasites [112]. Mobile populations along the border areas often live in poverty and have poor access to healthcare services. Movement of people across international borders has contributed to maintaining high transmission hotspots adjacent to border points [73, 105, 113].

#### **2.8. Misalignment of programmatic approaches**

and forested plantations. Both the forests and occurrence of deforestation impact increasing malaria risk and transmission, particularly in border areas. Forested areas provide conducive environment for vector proliferation and survival [84, 85]. Forest vectors usually prefer tree canopy coverage and are known to take shelter in tree holes [86–88]. Forest flora and sugar availability have also been shown to be crucial determinants of vectorial capacity [89]. In addition, leaves falling into larval habitats assure sustainable micro-climatic conditions for larvae of vectors like *An. dirus,* which is a dominant vector in Southeast Asia [90]. Further, there are usually abundant bodies of water including ponds, streams, and rivers in forested areas supporting vector multiplication and survival thereby sustaining malaria transmission

Bangladesh [210] *An. dirus, An. minimus, An. aconitus, An. philippinensis, An. sundaicus, An. barbirostris, An. subpictus,* 

DPR Korea [210] *An. lesteri, An. sinensis, An. sineroides, An. kleini, An. yatsus hiroensis, An. lindesayi japonicas, An.* 

India [213] *An. culicifacies, An. baimaii, An. fluviatilis, An. minimus, An. stephensi, An. maculatus, An. sundaicus* Indonesia [214] *An. aconitus, An. balabacensis, An. bancrofti, An. barbirostris, An. barbumbrosus, An. farauti, An.* 

Malaysia [211] *An. balabacensis, An. campestris, An. cracens, An. donaldi, An. flavirostris, An. latens, An. letifer, An.* 

*An. kleini, An. pullus, An. belenrae, An. sineroides, An. sinensis, An. lesteri*

*An. culicifacies, An. annularis, An. subpictus, An. tessellatus, An. stephensi*

Vietnam [211] *An. dirus, An. minimus, An. maculatus, An. aconitus, An. jeyporiensis, An. subpictus, An. sinensis, An.* 

\*An., *Anopheles* names refer either to the group, complex or species when specific identifications have been done.

**Table 2.** List of the main malaria vectors in the Asia Pacific Malaria Elimination Network (APMEN) countries.

Philippines [215] *An. flavirostris, An. balabacensis, An. maculatus, An. litoralis, An. mangyanus*

PNG [216, 217] *An. farauti, An. koliensis, An. punctulatus, An. bancroftii, An. karwari*

*An. punctulatus, An. koliensis, An. farauti*

Thailand [210] *An. dirus, An. minimus, An. maculatus, An. aconitus, An. epiroticus*

*flavirostris, An. karwari, An. kochi, An. koliensis, An. leucosphyrus, An. maculatus, An. nigerrimus, An. parangensis, An. punctulatus, An. sinensis, An. subpictus, An. sundaicus, An. tessellatus, An. vagus*

*An. culicifacies, An. fluviatilis, An. maculatus*

China [73, 212] *An. sinensis, An. lesteri, An. dirus, An. minimus, An. maculatus*

Cambodia [211] *An. dirus, An. minimus, An. maculatus, An. epiroticus*

Lao PDR [211] *An. dirus, An. minimus, An. maculatus, An. jeyporiensis*

*maculatus, An. sundaicus* Nepal [210] *An. fluviatilis, An. annularis, An. maculatus*

*pampanai, An. epiroticus*

**Country° Main vectors\***

208 Towards Malaria Elimination - A Leap Forward

Bhutan [210] *An. minimus*

Republic of Korea

Solomon Islands

Sri Lanka [210,

Vanuatu [217] *An. farauti*

°Corresponding references are in brackets.

[218]

[217]

219]

*koreicus*

There are differences in programmatic approaches among neighbouring countries in the APMEN region making the coordination of control and preventive measures challenging [114, 115]. For example, there are differences in malaria control activities across Laos-Vietnam border. In Laos, the mainstay of malaria control is distribution of LLINs but on the Vietnamese side there is a stronger focus on IRS [114, 115]. Even where the approaches are similar, the specific antimalarial drugs or insecticides used can influence effectiveness due to parasite or vector resistance. Deltamethrin (synthetic pyrethroid) is used for IRS in Bhutan, however, DDT is used in the neighbouring State of Assam in India [116–118]. Effective control or elimination requires coordinated efforts for control interventions.
