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

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.

98 Towards Malaria Elimination - A Leap Forward

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

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

susceptible parasites but leave resistant mutants to survive and reproduce [32].

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 higher risk of malaria [40, 41].

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

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 high-risk groups.

Therefore, although population mobility is a key factor to take into account when addressing drug resistance, it suffers from a range of challenges that limit countries' capacity to effectively engage and deliver interventions to migrant and mobile populations (MMPs). In addition, outdoor biting mosquitoes represent a major challenge for vector control for MMPs working during the night or sleeping outdoors, as well as forest-fringe communities.

importance of scaling up and expanding the reach of point of access care and dissemination of information, such as through border posts or at large development or construction areas that are likely to host high-risk malaria occupational groups. These posts can potentially be used as effective channels to target and deliver specific interventions such as Behavioral Change

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

http://dx.doi.org/10.5772/intechopen.76901

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Therefore, there is an urgent need to develop appropriate and sustainable malaria services for MMPs in different settings, in the context of the spread of artemisinin resistance and malaria elimination in the GMS. Different types of mobility require different malaria control interventions and therefore elimination strategies that should be based on an in-depth understanding of malaria risk in each group [66]. A population movement framework can assist in improved targeting of malaria (and other public health interventions) by going beyond a simple labeling of risk groups to develop a better understanding of risk behaviour and vulnerabilities. The implementation of the framework should be carefully evaluated to identify the changes in

In 2012, global malaria transmission was reported as mainly attributable to 51 *Anopheles* species, with an average of about 3 major species per country [68]. Biological factors that determine whether a species becomes a major local threat are its competence for transmitting human malaria parasites, its anthropophilic *versus* zoophilic preference, and its abundance in relation to its ability to multiply, survive, and compete for resources with other *Anopheles* species. The third of these factors is regulated by the ecosystem's carrying capacity for potent vectors depending on their ecological niches [69]. Species of several *Anopheles* complexes are either major or secondary malaria vectors depending on their geographical range of distribution [70]. The peculiarity of these sibling species within a complex is that they cannot be distinguished using morphological criteria. However, several Asian malaria vectors within the Dirus, Leucosphyrus, Minimus, Maculatus, Culicifacies, Sundaicus, Subpictus complexes or groups show similar morphological characteristics, different ecological traits and vector competencies and overlapping geographical distribution with other vectors and non-vectors [70, 85, 92]. As some of these sibling species occur sympatrically and differ in their ability to transmit malaria and in their behaviour, the use of molecular tools to differentiate the vectors from the non-vectors is essential to target the correct species in vector control programs.

Malaria vector control relies largely on Long-Lasting Insecticidal Nets (LLINs) and Indoor Residual Spraying (IRS), along with Larval Source Management (LSM) as a supplementary measure appropriate in certain settings. These core interventions are highly efficacious for control of susceptible malaria vectors when implemented at universal coverage; LLINs and IRS contributed to a 48% reduction in malaria infection prevalence and 47% reduction in mortality worldwide between 2000 and 2013 [71]. However, malaria transmission can persist even when LLINs and/or IRS are effectively implemented and malaria vectors are susceptible to the insecticides used. This may be due to a combination of vector and human behaviour and bionomical characteristics, which compromise inadequate control measures against early and/or outdoor biting mosquitoes, and human activity away from protected houses or places

Communication (BCC) materials, insecticide-treated uniforms or hammock nets.

coverage, access, and effectiveness of the programme efforts to serve MMPs [67].

**4. Residual and outdoor transmission: how much and where?**

Another challenge is the large proportion of asymptomatic infections within geographical clusters of high malaria transmission (hot-spots), where infections with low and submicroscopic parasite densities are highly prevalent in MMP and other risk groups [54]. Asymptomatic carriers can repeatedly fuel transmission to surrounding areas as the vector population expands during the wet season [55–57]. Whilst groups of homesteads consisting of asymptomatic carriers can act as stable clusters over several years [7], it is likely that the flight range of 800 m for *An. dirus* may account for increased probability of repeated mosquito feeding in the same house and clustering of cases over the dry season in Southeastern Thailand [58]. Recent clusters of malaria infection among the parasite reservoir responsible for preserving malaria over the dry season in Ratanakiri Province (northeastern Cambodia) may also explain recurrent transmission at the onset of the rainy season when the vector populations expand [59]. This reservoir is often not (completely) covered by control strategies [60] and parasite specific approaches are non-existent [61]. Programmatic interventions to interrupt transmission in "hidden" asymptomatic reservoir must focus on individuals with malaria infection at early stage, as asexual parasitemia left untreated will eventually produce gametocytes, and diagnostics for the sexual stage are limited [62].

This represents an important hindrance to malaria elimination as these infections are unlikely to be detected by passive surveillance and conventional diagnostic tools, and therefore require additional approaches to effectively reach all infections [63]. A combination of methods, or new diagnostics, may be required to detect infections in these asymptomatic parasite reservoirs. Also, a cross-sectoral response, involving non-health government agencies and the private sector addressing the links between malaria transmission, mobility and labor, will play an important role in responding to drug resistance and achieving elimination in the Southeast Asia region. Preliminary studies of the use of peer outreach workers to conduct screening of suspected cases, providing health education, and distributing nets in hot-spot areas in or near the forest, suggest that it is feasible to target high-risk populations in a culturally appropriate and evidence-based manner to reach the goal of elimination in Pursat Province, Cambodia [64]. Mobile Malaria Workers or peer outreach activities often face logistic challenges including muddy roads, river crossings, and transportation difficulties that make it hard to quickly respond to all infections. The recent President Malaria Initiative (PMI) studies show this is a potential resource that can be piloted or replicated across GMS countries (John Hustedt, personal communication).

Lastly, persisting low health-care coverage and access in remote locations remains an important challenge for mobile populations and migrant workers in some Southeast Asian countries, limiting the ability of malaria programmes to effectively capture these groups through the routine surveillance system, but most importantly to adequately provide the necessary preventive measures and care needed [65]. It is encouraging, however, to see that malaria infection rates in people who had sought treatment, or blood-smear examined in a previous malaria episode, and/or who knew how to prevent malaria (e.g., sleeping under a mosquito net), tend to be lower than those that did not seek treatment or had inadequate malaria knowledge [45]. This highlights the importance of scaling up and expanding the reach of point of access care and dissemination of information, such as through border posts or at large development or construction areas that are likely to host high-risk malaria occupational groups. These posts can potentially be used as effective channels to target and deliver specific interventions such as Behavioral Change Communication (BCC) materials, insecticide-treated uniforms or hammock nets.

Therefore, although population mobility is a key factor to take into account when addressing drug resistance, it suffers from a range of challenges that limit countries' capacity to effectively engage and deliver interventions to migrant and mobile populations (MMPs). In addition, outdoor biting mosquitoes represent a major challenge for vector control for MMPs

Another challenge is the large proportion of asymptomatic infections within geographical clusters of high malaria transmission (hot-spots), where infections with low and submicroscopic parasite densities are highly prevalent in MMP and other risk groups [54]. Asymptomatic carriers can repeatedly fuel transmission to surrounding areas as the vector population expands during the wet season [55–57]. Whilst groups of homesteads consisting of asymptomatic carriers can act as stable clusters over several years [7], it is likely that the flight range of 800 m for *An. dirus* may account for increased probability of repeated mosquito feeding in the same house and clustering of cases over the dry season in Southeastern Thailand [58]. Recent clusters of malaria infection among the parasite reservoir responsible for preserving malaria over the dry season in Ratanakiri Province (northeastern Cambodia) may also explain recurrent transmission at the onset of the rainy season when the vector populations expand [59]. This reservoir is often not (completely) covered by control strategies [60] and parasite specific approaches are non-existent [61]. Programmatic interventions to interrupt transmission in "hidden" asymptomatic reservoir must focus on individuals with malaria infection at early stage, as asexual parasitemia left untreated will eventually produce

This represents an important hindrance to malaria elimination as these infections are unlikely to be detected by passive surveillance and conventional diagnostic tools, and therefore require additional approaches to effectively reach all infections [63]. A combination of methods, or new diagnostics, may be required to detect infections in these asymptomatic parasite reservoirs. Also, a cross-sectoral response, involving non-health government agencies and the private sector addressing the links between malaria transmission, mobility and labor, will play an important role in responding to drug resistance and achieving elimination in the Southeast Asia region. Preliminary studies of the use of peer outreach workers to conduct screening of suspected cases, providing health education, and distributing nets in hot-spot areas in or near the forest, suggest that it is feasible to target high-risk populations in a culturally appropriate and evidence-based manner to reach the goal of elimination in Pursat Province, Cambodia [64]. Mobile Malaria Workers or peer outreach activities often face logistic challenges including muddy roads, river crossings, and transportation difficulties that make it hard to quickly respond to all infections. The recent President Malaria Initiative (PMI) studies show this is a potential resource that can

be piloted or replicated across GMS countries (John Hustedt, personal communication).

Lastly, persisting low health-care coverage and access in remote locations remains an important challenge for mobile populations and migrant workers in some Southeast Asian countries, limiting the ability of malaria programmes to effectively capture these groups through the routine surveillance system, but most importantly to adequately provide the necessary preventive measures and care needed [65]. It is encouraging, however, to see that malaria infection rates in people who had sought treatment, or blood-smear examined in a previous malaria episode, and/or who knew how to prevent malaria (e.g., sleeping under a mosquito net), tend to be lower than those that did not seek treatment or had inadequate malaria knowledge [45]. This highlights the

working during the night or sleeping outdoors, as well as forest-fringe communities.

100 Towards Malaria Elimination - A Leap Forward

gametocytes, and diagnostics for the sexual stage are limited [62].

Therefore, there is an urgent need to develop appropriate and sustainable malaria services for MMPs in different settings, in the context of the spread of artemisinin resistance and malaria elimination in the GMS. Different types of mobility require different malaria control interventions and therefore elimination strategies that should be based on an in-depth understanding of malaria risk in each group [66]. A population movement framework can assist in improved targeting of malaria (and other public health interventions) by going beyond a simple labeling of risk groups to develop a better understanding of risk behaviour and vulnerabilities. The implementation of the framework should be carefully evaluated to identify the changes in coverage, access, and effectiveness of the programme efforts to serve MMPs [67].
