**1. Introduction**

Considerable global and domestic investments have averted millions of malaria-attributable deaths since 2000 [1, 2]. Nevertheless, one person (usually a child) still dies every 1.2 minutes from this disease, with no reduction in mortality between 2015 and 2016 [1]. Progress is further threatened by failure to contain artemisinin resistance, as confirmed by the Regional Artemisinin Initiative (RAI) mid-term review [3]. In Cambodia, between mid-2014 and mid-2015, *Plasmodium falciparum* (Pf) malaria increased by 65%, with further substantial rise in 2017, especially along the border with Vietnam [4]. High rates of clinical treatment failures to nearly all antimalarial drugs—including artemisinin derivatives—are now widespread in the country [3] and there is evidence of its spread into southern Vietnam (from western Cambodia) [5]. Multidrug-resistant malaria parasites could cause a global health catastrophe if they were to spread to other countries, particularly malaria-endemic nations in Africa [4, 6–9]. Spread may be facilitated by international peacekeeping missions and migration for work [10–13]. Given available evidence of this current threat, urgent and decisive action is essential.

rapid spread of resistance across the endemic areas of the world. Despite being an obvious conduit for the spread of multidrug-resistant (MDR) malaria, the use of standard malaria prevention measures has not yet been put into practice by most militaries in SEA. This is due,

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The spread of disease by peacekeepers is well documented. For example, following the 2010 earthquake in Haiti, United Nations troops from Nepal were the source of a cholera epidemic with over 730,000 cases and 8700 deaths, and an estimated economic cost of US\$2.2 billion [10]. A single infected peacekeeper could potentially serve as the source for the next malaria pandemic [10].

A similar threat is posed by migration of workers from SEA to sub-Saharan Africa. For example, nearly 20,000 Vietnamese are legally working in Angola [23], and an unknown number are there illegally. These migrants are importing malaria from Angola into Vietnam [13]; the converse could also happen. Chinese workers are employed in mining and construction industries in the forests of Cambodia. They are hard to access, and malaria prevention and treatment practices are of uncertain quality (CO, personal communications). It is quite probable that some workers will move on to the African continent, where there is huge Chinese investment in these industries. Due to the high burden of malaria in Africa, it is likely that malaria strains

With immediate decisive action, we believe the transmission of the MDR strains can be interrupted approaching the 2020 target (see box, **Table 1**) [24]. The World Health Organization (WHO)'s declaration of a Public health emergency of international concern (PHEIC) led to impressive increases in resources for both Ebola and Zika epidemics, and may be essential to address the current MDR malaria threat. Together, Ebola and Zika claimed fewer than 12,000 lives [25]. Yet, with MDR malaria, millions of lives are at stake. In 2015, WHO published a document warning that MDR malaria "…*has reached alarming levels in several areas of the GMS"* and that malaria "…*could become untreatable with currently available drugs within a few years*" [24]. In 2014, Bill Gates commented: "*There's the potential for a real nightmare scenario here. If a strain of malaria that's resistant to artemisinin were to spread to Africa*"… "*it would be the worst ever disaster in malaria control*" [7]. Chris Plowe, former president of American Society of Tropical Medicine and Hygiene, argues that, "*The danger of untreatable malaria is real and* 

The world needs to focus efforts to eliminate incurable malaria strains by 2020. The critical remaining actions are: **1.**Commitment and real sense of urgency through declaration of multidrug-resistant malaria as a "Public health

**4.**Utilize surveillance as a core intervention with result-based funding to drive the targeting malaria transmission foci

**2.**Establish response leadership with sufficient authority, respect, expertise and operational funding; **3.**Engage affected security forces to stop disease transmission and support elimination operations;

in part, to the fact that they are a neglected population receiving little aid [22].

originating from Asia would go undetected until the next pandemic is underway.

**Recommendations for rapid elimination of emerging incurable malaria**

emergency of international concern" or similar set of directives;

**Table 1.** Critical actions to eliminate emerging incurable malaria strains.

with rapid, localized and effective action.

We are currently watching history repeat itself. In the late 1950s, resistance to the antimalarial chloroquine emerged in Cambodia. It eventually spread to and throughout Africa during the 1980s [14, 15], resulting in a two- to six-fold increase in malaria-related mortality [14]. Subsequent waves of resistance to two other antimalarial drugs followed the same pattern of spread [6]. It was not until the early 2000s, when international bodies finally took affirmed action against malaria, that mortality rates began to decrease globally. But as the World Malaria Report 2017 states: "*although malaria case incidence has fallen globally since 2010, the rate of decline has stalled and even reversed in some regions since 2014; mortality rates have followed a similar pattern*" [1].

Today, a two-fold increase in mortality [14] would cause in the order of 7 million malaria deaths over a decade. The threat will also be magnified by widespread resistance to insecticides already reported in Africa [16] (again history is repeating itself, in the "malaria eradication" era of 1955–1972, it was DDT resistance [17]). The concomitant threat of insecticide resistance, particularly as it affects the efficacy of insecticide-treated bed nets (ITNs) and household spraying, is widely recognized.

Drug-resistant strains of malaria will likely spread to Africa much faster in the current era. Some security forces in Southeast Asia (SEA) are a reservoir of multidrug-resistant (MDR) malaria parasites due to their occupational risk. In 2010, 5% of Cambodian army personnel, screened for research purposes, tested positive for Pf [18] using DNA (PCR) screening. Additional testing revealed failure to the latest artemisinin-based combination therapy (ACT) used at that time [18]. Despite investment by the Bill and Melinda Gates (BMGF) to stop malaria transmission in these troops, the positive cases for Pf malaria had doubled to 10% by 2016 [19, 20]. During this same time frame, more than 3300 Cambodian soldiers were deployed on UN peacekeeping missions—without prior adequate (PCR) screening for malaria—to eight countries, including five in sub-Saharan Africa [10, 21]. Such missions could lead to rapid spread of resistance across the endemic areas of the world. Despite being an obvious conduit for the spread of multidrug-resistant (MDR) malaria, the use of standard malaria prevention measures has not yet been put into practice by most militaries in SEA. This is due, in part, to the fact that they are a neglected population receiving little aid [22].

**1. Introduction**

42 Towards Malaria Elimination - A Leap Forward

essential.

*similar pattern*" [1].

household spraying, is widely recognized.

Considerable global and domestic investments have averted millions of malaria-attributable deaths since 2000 [1, 2]. Nevertheless, one person (usually a child) still dies every 1.2 minutes from this disease, with no reduction in mortality between 2015 and 2016 [1]. Progress is further threatened by failure to contain artemisinin resistance, as confirmed by the Regional Artemisinin Initiative (RAI) mid-term review [3]. In Cambodia, between mid-2014 and mid-2015, *Plasmodium falciparum* (Pf) malaria increased by 65%, with further substantial rise in 2017, especially along the border with Vietnam [4]. High rates of clinical treatment failures to nearly all antimalarial drugs—including artemisinin derivatives—are now widespread in the country [3] and there is evidence of its spread into southern Vietnam (from western Cambodia) [5]. Multidrug-resistant malaria parasites could cause a global health catastrophe if they were to spread to other countries, particularly malaria-endemic nations in Africa [4, 6–9]. Spread may be facilitated by international peacekeeping missions and migration for work [10–13]. Given available evidence of this current threat, urgent and decisive action is

We are currently watching history repeat itself. In the late 1950s, resistance to the antimalarial chloroquine emerged in Cambodia. It eventually spread to and throughout Africa during the 1980s [14, 15], resulting in a two- to six-fold increase in malaria-related mortality [14]. Subsequent waves of resistance to two other antimalarial drugs followed the same pattern of spread [6]. It was not until the early 2000s, when international bodies finally took affirmed action against malaria, that mortality rates began to decrease globally. But as the World Malaria Report 2017 states: "*although malaria case incidence has fallen globally since 2010, the rate of decline has stalled and even reversed in some regions since 2014; mortality rates have followed a* 

Today, a two-fold increase in mortality [14] would cause in the order of 7 million malaria deaths over a decade. The threat will also be magnified by widespread resistance to insecticides already reported in Africa [16] (again history is repeating itself, in the "malaria eradication" era of 1955–1972, it was DDT resistance [17]). The concomitant threat of insecticide resistance, particularly as it affects the efficacy of insecticide-treated bed nets (ITNs) and

Drug-resistant strains of malaria will likely spread to Africa much faster in the current era. Some security forces in Southeast Asia (SEA) are a reservoir of multidrug-resistant (MDR) malaria parasites due to their occupational risk. In 2010, 5% of Cambodian army personnel, screened for research purposes, tested positive for Pf [18] using DNA (PCR) screening. Additional testing revealed failure to the latest artemisinin-based combination therapy (ACT) used at that time [18]. Despite investment by the Bill and Melinda Gates (BMGF) to stop malaria transmission in these troops, the positive cases for Pf malaria had doubled to 10% by 2016 [19, 20]. During this same time frame, more than 3300 Cambodian soldiers were deployed on UN peacekeeping missions—without prior adequate (PCR) screening for malaria—to eight countries, including five in sub-Saharan Africa [10, 21]. Such missions could lead to The spread of disease by peacekeepers is well documented. For example, following the 2010 earthquake in Haiti, United Nations troops from Nepal were the source of a cholera epidemic with over 730,000 cases and 8700 deaths, and an estimated economic cost of US\$2.2 billion [10]. A single infected peacekeeper could potentially serve as the source for the next malaria pandemic [10].

A similar threat is posed by migration of workers from SEA to sub-Saharan Africa. For example, nearly 20,000 Vietnamese are legally working in Angola [23], and an unknown number are there illegally. These migrants are importing malaria from Angola into Vietnam [13]; the converse could also happen. Chinese workers are employed in mining and construction industries in the forests of Cambodia. They are hard to access, and malaria prevention and treatment practices are of uncertain quality (CO, personal communications). It is quite probable that some workers will move on to the African continent, where there is huge Chinese investment in these industries. Due to the high burden of malaria in Africa, it is likely that malaria strains originating from Asia would go undetected until the next pandemic is underway.

With immediate decisive action, we believe the transmission of the MDR strains can be interrupted approaching the 2020 target (see box, **Table 1**) [24]. The World Health Organization (WHO)'s declaration of a Public health emergency of international concern (PHEIC) led to impressive increases in resources for both Ebola and Zika epidemics, and may be essential to address the current MDR malaria threat. Together, Ebola and Zika claimed fewer than 12,000 lives [25]. Yet, with MDR malaria, millions of lives are at stake. In 2015, WHO published a document warning that MDR malaria "…*has reached alarming levels in several areas of the GMS"* and that malaria "…*could become untreatable with currently available drugs within a few years*" [24]. In 2014, Bill Gates commented: "*There's the potential for a real nightmare scenario here. If a strain of malaria that's resistant to artemisinin were to spread to Africa*"… "*it would be the worst ever disaster in malaria control*" [7]. Chris Plowe, former president of American Society of Tropical Medicine and Hygiene, argues that, "*The danger of untreatable malaria is real and* 

#### **Recommendations for rapid elimination of emerging incurable malaria**

The world needs to focus efforts to eliminate incurable malaria strains by 2020. The critical remaining actions are:


**Table 1.** Critical actions to eliminate emerging incurable malaria strains.

*present*" [6]. If the WHO's call for "urgent action" is to be answered, a PHEIC or similar set of directives would be hugely important. The definition of PHEIC is "an extraordinary event which is determined to constitute a public health risk to other States through the international spread of disease and potentially require a coordinated international response" [26–28]. We argue that almost incurable malaria in Cambodia, and now Vietnam, with the threat to other countries and regions, undoubtedly fits this definition. WHO contends the regulations were designed to address acute public health conditions and the public health community has known of the emergence and spread of multidrug resistance for a number of years [29]. We claim that if a PHEIC had been declared in 2014, when WHO first learned of high ACT treatment failure rates crossing into Vietnam, malaria would be nearly eliminated now in these countries. The new "extraordinary event" is a marked increase in malaria in eight provinces of Cambodia in 2017, which is continuing in five provinces in early 2018 (CO, personal communication) despite substantial Global Fund resources in the region. Furthermore, in the province where parasites crossed into Vietnam, malaria was up 2.5 fold in 2017, with an extraordinary annual parasite index of about 55. It is not too late to call a PHEIC. If a PHEIC declaration is politically not achievable, a set of similar instructions could generate both commitment and urgency. One example would be a US Department of Defense (DoD) directive [30]—this should be achievable, as malaria is the number one infectious disease threat for US troops [31] and the US DoD continues to invest large sums of money in new antimalarial drug and vaccine development. We are currently at risk of losing all drugs for both malaria prophylaxis and treatment, which should prompt a major investment in direct support of elimination of these strains. The current Defense Malaria Elimination Program [32] was intended by the lead author to be modeled after the DoD Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome Prevention Program (DHAPP) to Support Foreign Militaries directive [30]; instead it turned out to be just more research funding (CO, unpublished observations).

proved inefficacious in initial clinical trials in Cambodia [37]. However, these are unlikely to be more than very temporarily solutions. When international leaders and policy-makers, ministries of health, donors and the philanthropic and scientific communities understand the gravity of this situation, only then can there be a concerted, effective push to finally eliminate malaria in SEA. Under the late Alan Magill's previous leadership, the BMGF made great strides in its ambitious goal to eradicate malaria; tragically, Dr. Magill passed away before his plan was fully

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In 2014, Bill & Melinda Gates, Alan Magill and a team visited the epicenter of MDR malaria in western Cambodia. In Gates' notes from that trip, they reported the threat as outlined above [7]. Recently, Mr. Gates has proposed a global strategy to prepare for "the next epidemic" [41]. We developed "Recommendations for rapid elimination of emerging incurable malaria" (**Table 1**) based on his article. A key recommendation of Mr. Gates is that it should be "*coordinated by a global institution given enough authority and funding to be effective…*". He also noted that cooperation among various nations' militaries should be a priority. In 2014, SEA military

**Figure 1.** Three potential future trajectories for malaria as per the late Alan Magill from his "Accelerate to Zero" presentation [40]. He recommended to "bend the curve." One of his specific goals was Pf elimination "East of Bangkok" by 2020. 1 and 2 in circles represent additional reduction of malaria cases in the timeframe represented (reproduced with permission from the Bill & Melinda Gates Foundation). We are currently on the resurgence curve in Cambodia and may

**Figure 2.** Mobilize for action. How to accelerate the trajectory to malaria eradication by concurrently achieving three goals: (1) identifying the human reservoir of infection in asymptomatic persons + (2) eliminating the human parasite reservoir + (3) combined with geographically and temporally targeted transmission prevention and strengthened

surveillance and response [40] (reproduced with permission from the Bill & Melinda Gates Foundation).

soon be worldwide if effective action is not taken.

implemented [38, 39]. Two of his key concepts are presented in **Figures 1** and **2**.

In the SEA context, the artemisinin-based drugs are only one of several classes of previously effective drugs. Over time, malaria parasites in Cambodia have accumulated multiple resistance mechanisms against all of these drug classes. Global health stakeholders and donors must learn from past experience, and urgently recognize the continually evolving malaria parasites in Cambodia as an emergency that must be halted.

A short-term solution to the challenge is the return of malaria sensitivity to the prior artemisinin combination treatment (ACT) partner drug mefloquine (Lariam®) following its reintroduction in Cambodia. One expert predicts that continued mefloquine efficacy will be short-lived [33]. When used as a monotherapy, mefloquine remained efficacious for <5 years in the Thailand– Cambodia border areas [34]; now, two years after its reintroduction in Cambodia as part of drug combinations, it fortunately appears to remain efficacious (CO, unpublished observations). It is currently being paired with artesunate, to which resistance has emerged, essentially leaving mefloquine again as monotherapy. Moreover, mefloquine is a drug greatly challenged because of both gastrointestinal and neuropsychiatric side-effects, which will undoubtedly affect compliance (adherence, or people completing the recommended three-day regimen), as effective monitoring of adherence is lacking (CO, unpublished observations in northern and eastern Cambodia). Additional solutions are currently undergoing research, including one with a combination of three drugs that are or were failing in other combinations [35]. In addition, molecular marker evidence reveals that the theory of reciprocal cross-resistance is probably not a factor [36]. Another proposed solution is to return to the use of drug combinations that previously proved inefficacious in initial clinical trials in Cambodia [37]. However, these are unlikely to be more than very temporarily solutions. When international leaders and policy-makers, ministries of health, donors and the philanthropic and scientific communities understand the gravity of this situation, only then can there be a concerted, effective push to finally eliminate malaria in SEA.

*present*" [6]. If the WHO's call for "urgent action" is to be answered, a PHEIC or similar set of directives would be hugely important. The definition of PHEIC is "an extraordinary event which is determined to constitute a public health risk to other States through the international spread of disease and potentially require a coordinated international response" [26–28]. We argue that almost incurable malaria in Cambodia, and now Vietnam, with the threat to other countries and regions, undoubtedly fits this definition. WHO contends the regulations were designed to address acute public health conditions and the public health community has known of the emergence and spread of multidrug resistance for a number of years [29]. We claim that if a PHEIC had been declared in 2014, when WHO first learned of high ACT treatment failure rates crossing into Vietnam, malaria would be nearly eliminated now in these countries. The new "extraordinary event" is a marked increase in malaria in eight provinces of Cambodia in 2017, which is continuing in five provinces in early 2018 (CO, personal communication) despite substantial Global Fund resources in the region. Furthermore, in the province where parasites crossed into Vietnam, malaria was up 2.5 fold in 2017, with an extraordinary annual parasite index of about 55. It is not too late to call a PHEIC. If a PHEIC declaration is politically not achievable, a set of similar instructions could generate both commitment and urgency. One example would be a US Department of Defense (DoD) directive [30]—this should be achievable, as malaria is the number one infectious disease threat for US troops [31] and the US DoD continues to invest large sums of money in new antimalarial drug and vaccine development. We are currently at risk of losing all drugs for both malaria prophylaxis and treatment, which should prompt a major investment in direct support of elimination of these strains. The current Defense Malaria Elimination Program [32] was intended by the lead author to be modeled after the DoD Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome Prevention Program (DHAPP) to Support Foreign Militaries directive [30]; instead it turned out to be just more research funding (CO, unpublished observations). In the SEA context, the artemisinin-based drugs are only one of several classes of previously effective drugs. Over time, malaria parasites in Cambodia have accumulated multiple resistance mechanisms against all of these drug classes. Global health stakeholders and donors must learn from past experience, and urgently recognize the continually evolving malaria

44 Towards Malaria Elimination - A Leap Forward

parasites in Cambodia as an emergency that must be halted.

A short-term solution to the challenge is the return of malaria sensitivity to the prior artemisinin combination treatment (ACT) partner drug mefloquine (Lariam®) following its reintroduction in Cambodia. One expert predicts that continued mefloquine efficacy will be short-lived [33]. When used as a monotherapy, mefloquine remained efficacious for <5 years in the Thailand– Cambodia border areas [34]; now, two years after its reintroduction in Cambodia as part of drug combinations, it fortunately appears to remain efficacious (CO, unpublished observations). It is currently being paired with artesunate, to which resistance has emerged, essentially leaving mefloquine again as monotherapy. Moreover, mefloquine is a drug greatly challenged because of both gastrointestinal and neuropsychiatric side-effects, which will undoubtedly affect compliance (adherence, or people completing the recommended three-day regimen), as effective monitoring of adherence is lacking (CO, unpublished observations in northern and eastern Cambodia). Additional solutions are currently undergoing research, including one with a combination of three drugs that are or were failing in other combinations [35]. In addition, molecular marker evidence reveals that the theory of reciprocal cross-resistance is probably not a factor [36]. Another proposed solution is to return to the use of drug combinations that previously Under the late Alan Magill's previous leadership, the BMGF made great strides in its ambitious goal to eradicate malaria; tragically, Dr. Magill passed away before his plan was fully implemented [38, 39]. Two of his key concepts are presented in **Figures 1** and **2**.

In 2014, Bill & Melinda Gates, Alan Magill and a team visited the epicenter of MDR malaria in western Cambodia. In Gates' notes from that trip, they reported the threat as outlined above [7].

Recently, Mr. Gates has proposed a global strategy to prepare for "the next epidemic" [41]. We developed "Recommendations for rapid elimination of emerging incurable malaria" (**Table 1**) based on his article. A key recommendation of Mr. Gates is that it should be "*coordinated by a global institution given enough authority and funding to be effective…*". He also noted that cooperation among various nations' militaries should be a priority. In 2014, SEA military

**Figure 1.** Three potential future trajectories for malaria as per the late Alan Magill from his "Accelerate to Zero" presentation [40]. He recommended to "bend the curve." One of his specific goals was Pf elimination "East of Bangkok" by 2020. 1 and 2 in circles represent additional reduction of malaria cases in the timeframe represented (reproduced with permission from the Bill & Melinda Gates Foundation). We are currently on the resurgence curve in Cambodia and may soon be worldwide if effective action is not taken.

**Figure 2.** Mobilize for action. How to accelerate the trajectory to malaria eradication by concurrently achieving three goals: (1) identifying the human reservoir of infection in asymptomatic persons + (2) eliminating the human parasite reservoir + (3) combined with geographically and temporally targeted transmission prevention and strengthened surveillance and response [40] (reproduced with permission from the Bill & Melinda Gates Foundation).

leaders met twice and indicated their willingness to support malaria elimination efforts [42], but there has not been effective funding forthcoming to protect troops from malaria nor for them to assist with the much needed effective response. Another meeting was held in 2016, but the only available funding was for research (P. Smith, personal communication), not for an effective treatment and prevention package at scale, nor the needed direct support for malaria elimination operations that militaries can provide. A well-led military response to the MDR malaria crisis would be a large part of the solution to achieve WHO goals.

combination of both ineffective drugs and weak health infrastructure will lead to another

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In the 1980s, nearly incurable malaria parasites emerged on the Thailand-Cambodia border. Mefloquine failed four years after introduction in 1985 [34]. The only treatment option at the time was quinine-tetracycline [49]. Quinine is a very poorly tolerated drug requiring three daily doses for seven days—meaning almost no one completes it (e.g., poor adherence or compliance) unless every dose is monitored. Fortunately, artemisinin derivatives and other drugs became available all of which either did not work at the time of their introduction (e.g., lumefantrine, pyronaridine [50–52]) or have lost therapeutic efficacy (e.g., piperaquine [53]). Presently, the pipeline of new antimalarial drugs is not keeping pace with the emergence of drug resistant strains [37]. Now in Cambodia, mefloquine sensitivity has returned, but is likely to be short-lived (e.g., two more years or less), by which time we may be back to quinine-doxycycline (a tetracycline derivative). We have recently learned that the Vietnam Border Guard Forces have provided doxycycline prophylaxis to more than ½ million people over the last decade (CO, personal communication)—which means this drug might as well be rendered ineffective by now. Identification of the combination partner drugs or the new seven-day regimens must be a priority. Ineffective or incomplete treatment will result in people carrying malaria parasites, an increased transmission reservoir, cases and deaths. The US Center for Disease Control and Prevention (CDC) reported the direct costs for malaria (e.g., illness, treatment, premature death) to be at least \$12 billion per year. The cost in lost economic growth is many times more than that [54]. If key leadership does not act rapidly and effectively now, these costs will be much higher. If a PHEIC was declared, these emerging incurable parasites can be rapidly eliminated using the approaches presented here. If not, we will likely have a slight upgrade of "business as usual" with this critical window of opportunity lost. As advocated early in this chapter and by others [4, 55] (Rear Admiral C. Chinn, personal communication), we believe that the best way to handle this threat is to declare a PHEIC or similar directives. The failure of nearly all drugs in Cambodia, the crossing of these parasites into Vietnam and current increasing Pf malaria in Cambodia arguably constitute such an "extraordinary event" based on the three prongs identified by the International Health Regulations (IHRs). First, the failure of standard treatment options for deadly communicable disease constitutes a public health threat. While all forms of malaria are still currently treatable, the imminent failure of last ACT poses a public health risk, especially for sub-Saharan Africa. This situation would make the deadliest form of malaria untreatable, which would at least be comparable to the "events" that have triggered previous PHEIC declarations [56, 57]. Second, drug-resistant malaria is at risk of spreading internationally as a result of the substantial presence of security personnel from the GMS in sub-Saharan Africa such as Cambodian and military personnel and workers traveling to Africa. There is greater risk that these challenging new parasites will reach both India and Bangladesh soon. These countries have substantial

**2. Achieve both local and international commitment and a real sense of urgency—a "Public Health Emergency of International Concern** 

public health emergency, decisive actions must be taken immediately in Asia.

**(PHEIC) or similar set of directives"**

Gates also called for a warning and response system to enable fast decision-making. A surveillance/information system of the sort envisioned in a recent background paper [43] should be rapidly implemented across the SEA region. This is not an untested assertion, as a simple smart phone-based system has already been successfully pilot tested in central Vietnam [44]. A key 2016 finding was that each household had received an average of 4.3 treated bed nets; despite very high coverage at the household level (where there is little or no transmission), only 16% reported using a treated net when traveling to areas of elevated risk [9]. Similarly, low rates of treated net usage have been anecdotally observed by authors in four provinces in Cambodia recently and in other SEA countries [45, 46]. A smart phone-based system can provide quality monitoring including picture and video evidence to help leadership ensure that those in need of treated bed nets are actually using them and that treatments are being completed [44].

The mechanisms underlying emergence of drug resistance are not fully understood and are believed to be multifactorial [47]. A key factor leading to resistance may be incomplete treatment—effective adherence monitoring is still not in place and must be a priority. Until recently, Vietnam made standby ACT-treatment available to forest-goers, during which partial treatment may frequently occur. The same problem arises when people with symptoms of fever are provided antimalarial drugs by individuals who do not stress the need for complete treatment (e.g., private drug sellers and others). As artemisinin-derivative components have decreased efficacy in the GMS, a greater selection pressure is placed on the partner drugs. Whenever possible, all combination therapies should include a fully curative dose of each component, which, for short half-life drugs, requires seven days of therapy. Seven days of monitored treatment is feasible in the region if patients are renumerated for lost work time.

The role of mosquito vectors in the spread of drug-resistant malaria is also not fully understood. In the GMS, it is clear that malaria transmission is closely associated with the forest and forest-fringe vectors, i.e., *An. dirus* s.l. and *An. minimus* s.l. Fortunately, extensive insecticide resistance has not yet emerged to these vectors. Humans are likely the main transmission reservoir as they can infect mosquitoes for months if not cured of their malaria infection, while mosquitoes are relatively short-lived (lifespan of *Anopheles* female: three to four weeks) [48].

Lastly, no child should currently die from malaria in Africa, as all strains there are fully curable with ACT treatments. The high death rates are due to ineffective prevention and/or delayed/ inappropriate treatment as a result of weak health infrastructure. Targeted and decisive action should be taken in Africa to reduce the overall public health impact of malaria while the most commonly used antimalarial drugs remain effective. This can be done using modifications of the same approaches outlined in this chapter. Because of the threat to Africa, where the combination of both ineffective drugs and weak health infrastructure will lead to another public health emergency, decisive actions must be taken immediately in Asia.
