**2. Achieve both local and international commitment and a real sense of urgency—a "Public Health Emergency of International Concern (PHEIC) or similar set of directives"**

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

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

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

MDR malaria crisis would be a large part of the solution to achieve WHO goals.

completed [44].

46 Towards Malaria Elimination - A Leap Forward

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 numbers of their troops in Northeast India and Eastern Bangladesh, where these parasites will first arrive, and are currently the 2nd and 3rd largest contributors to international peacekeeping missions [58]. Third, a coordinated international response is absolutely required to manage this risk. In SEA, there are now fortunately few deaths from malaria. Leadership here has other pressing health issues to address, with malaria now becoming a low priority. Both international leadership and assistance for the countries involved, especially with security forces, is needed to ensure proper response to this peril most directly threatening Africa.
