Background
The Greater Mekong Subregion (GMS) is the global epicentre of anti-malarial drug resistance. High failure rates for artemisinin-based combination therapy (ACT) against
Plasmodium falciparum have been reported throughout the region, associated with resistance to both artemisinins and their partner drugs [
1]. In 2008, through the Containment Project, the World Health Organization (WHO) and its partners, with extra funding from the Bill & Melinda Gates Foundation, promoted a policy of containment and eventual elimination of artemisinin-resistant
P. falciparum in the Thailand–Cambodia border area [
2]. This strategy was subsequently expanded to target malaria elimination across the GMS for
P. falciparum by 2025 and all malaria by 2030 [
3]. The National Malaria Elimination Strategy for Thailand 2017–2026 envisions the elimination of malaria by 2024 [
4,
5].
Thailand is situated between two discrete malaria transmission regions, with the north-east provinces in a zone comprising Cambodia, southern Vietnam, and southern Laos; and the western provinces in a zone with eastern Myanmar and northern Malaysia. Although
P. falciparum and
Plasmodium vivax are the dominant parasites, malaria cases caused by
Plasmodium malariae,
Plasmodium ovale, and
Plasmodium knowlesi also occur, as do mixed infections. Malaria transmission in Thailand is concentrated in forested areas along these international borders, with forest workers, displaced people, refugees, migrants, and police and military personnel most exposed to risk [
6]. High population mobility in these areas can cause malaria to re-establish in villages where the disease has been eliminated, and civil unrest in the south of the country has hampered malaria control activities [
7]. Despite these challenges, malaria incidence has declined overall since 2000, though more rapidly for
P. falciparum compared with
P. vivax [
8]
.
Targeting malaria elimination has required repositioning of the health system in Thailand. At a national level, the Department of Disease Control is responsible for malaria policy and strategy, whereas the Division of Vector Borne Diseases (DVBD) undertakes capacity building and provides technical support, including managing the Malaria Information System (MIS)—a national database for malaria surveillance and monitoring [
9]. The electronic MIS was initially designed to track artemisinin resistance while also modernizing Thailand’s existing paper-based reporting system [
2]. In addition to malaria diagnosis and treatment, case investigation is conducted to determine the origin of the infection, thereby enabling identification, classification, and elimination of transmission foci [
10]. In areas deemed to be at risk, active case detection is employed and vector control measures enhanced, with the aim of interrupting transmission [
4]. This case-based malaria surveillance is captured in the MIS, providing near real-time information, which the DVBD uses to stratify malaria risk down to the village level. These detailed and timely data allow local authorities to understand the potential for malaria outbreaks, and to respond quickly should they occur [
4].
Given the constant threat of drug-resistant
P. falciparum, a gap in surveillance would be unacceptable. Ineffective anti-malarial therapy drives the spread of resistant parasites, so it is critical to detect changes in
P. falciparum susceptibility to deployed artemisinin-based combinations and switch regimens promptly where necessary to maintain momentum towards malaria elimination [
11]. Therapeutic efficacy studies (TES) have been the primary tool deployed to track anti-malarial efficacy and develop responses to
P. falciparum drug resistance across the GMS. Since 2000, the DVBD monitored drug efficacy from in vivo TES conducted in Thailand with mefloquine-artesunate combination therapy for
P. falciparum malaria [
12]. The aims of the subsequent multipronged Containment Project included increasing surveillance to provide information for the containment of artemisinin-resistant parasites [
2]. By 2011, the Containment Project had supported surveillance of patients who tested positive after 3 days of treatment, and it had developed systematic processes for cross-border investigation and follow-up [
12]. However, the decline in malaria incidence in Thailand means that it is more difficult to recruit the minimum patient sample size for TES—in low transmission settings, at least 50 patients are required, ideally recruited within a single malaria season [
13].
Plasmodium vivax control is complicated by the persistence of hypnozoites that remain dormant in the host’s liver before activation [
14]. Radical cure consists of chloroquine to address the blood-stage infection plus primaquine to target hypnozoites. It is not operationally possible to determine whether
P. vivax recurrences are recrudescence (chloroquine failure), relapse (primaquine failure), or re-infection. However, chloroquine should suppress asexual parasitaemia from relapse for approximately one month [
15], so recurrence on or before day 28 can be considered chloroquine treatment failure. Failures after day 28 are conservatively regarded as primaquine failures but could be caused by re-infection. Follow-up of 3 months is both sufficient to assess primaquine efficacy and operationally feasible in Thailand. By preventing relapses, radical cure both reduces malaria incidence and interrupts transmission, so ensuring effective therapy is a key component of malaria elimination.
Integrated drug efficacy surveillance (iDES) is a novel approach that incorporates drug resistance monitoring as part of routine case-based surveillance and response. iDES expanded the initiatives undertaken in the Containment Project, requiring that all malaria cases, symptomatic or asymptomatic, have a laboratory confirmed malaria diagnosis and receive treatment according to national guidelines, with parasitological follow-up to ensure parasite clearance. iDES aims to support evidence-based strategic policy development and operational decision making to realize malaria elimination while ensuring patient outcomes. This study examines the trends and status of malaria in Thailand, the implementation of iDES, initial measures of programme performance, and the potential for further development. The contribution of iDES data to decision making in the context of malaria elimination is also discussed.
Discussion
Thailand has made significant progress towards malaria elimination, surpassing its 2020 milestone reductions for both malaria incidence and mortality [
8]. However, many areas remain receptive to malaria, and re-establishment of transmission continues to be a significant risk across most of the country [
26].
It was clear that as malaria incidence declined in Thailand, TES would no longer be feasible in many provinces. The reorganization of the health system to target malaria elimination offered an opportunity to integrate drug efficacy surveillance. However, retroactive adaptation of the MIS to incorporate the iDES module was complex and has required continued refinement of the platform to adapt to changing epidemiology and corresponding data needs. The DVBD can examine the data in almost real time, thereby enabling limited resources to be targeted to the provinces, villages, or health facilities most in need of support to improve iDES compliance. The DVBD and its partners are working to further improve data visualizations to facilitate the data analyses most needed by subnational officers, such as health care workers interested in patient follow-up and treatment outcomes.
In order to move from TES to iDES, it was necessary for Thailand to have a strong case-based surveillance system and the capacity for universal and supervised anti-malarial treatment. For countries that have not yet reached the elimination phase, TES remains the most appropriate drug efficacy surveillance method [
18]. For iDES to have an impact on policy, other aspects of the health system need to be aligned for delivering different anti-malarial drugs to different regions. For example, purchasing and supply logistics, laboratory capacity and coordination, health financing, communication with prescribers, community outreach, and patient education. Thus, iDES cannot just be appended to an information system, but instead must be fully integrated into all health system processes.
Rapid diagnostic tests for malaria have been an invaluable tool in areas of high-to-moderate transmission to identify cases and direct appropriate therapy. However, iDES requires microscopic malaria diagnosis to confirm parasite clearance. Maintaining microscopy skills in an elimination setting is challenging as some laboratories see very few cases. With sustained support from external funding partners, Thailand has invested in a strong cadre of trained microscopists stationed throughout the country, and 33 professionals hold current expert certification from the WHO. However, other countries in the GMS and elsewhere may need to consider how to build these skills as malaria burden reduces, and as an iDES system becomes the recommended programme for case-based surveillance and follow-up.
Despite being included in the iDES protocol, the collection of dried blood spots for PCR analysis of P. falciparum has been sporadic, with difficulties in managing their storage and processing. Thus, only crude efficacy rates are reported here, but in a country aiming for elimination it is expected that all recurrences are recrudescences. The collection of samples for molecular resistance markers has also been sub-optimal while subnational officers gain new skills. The DVBD anticipates enhanced molecular surveillance and streamlined processes to triangulate clinical and laboratory data as a National Reference Laboratory database is developed and with additional training for health workers and laboratory staff.
Follow-up rates for iDES have been increasing steadily since its introduction, supported by a network of village health volunteers and through community education. High burden provinces in western Thailand (Fig.
3) have lower follow-up rates, as does the crucial Sisaket Province. Also, follow-up rates among short-term migrants have been consistently low. Maintaining contact with this population is challenging, and cross-border collaboration between countries may be required to ensure patient outcomes. There is the potential to incorporate mobile health data (mHealth) within iDES [
27], boosting follow-up rates by expanding coverage of malaria follow-up services to the household and individual levels via patients’ mobile devices. iDES could also be enhanced by complementary research to identify potential bottlenecks to patient follow-up—such as patient resistance or forgetfulness, provider lack of knowledge, poor adherence, or issues with recording and reporting. A positive sign is that in FY2020, malaria case follow-up and iDES showed resilience to disruption caused by the novel coronavirus disease (COVID-19) epidemic, given that both follow-up rates and data capture improved.
Adherence to the national treatment guidelines is necessary to optimize patient outcomes and to support malaria elimination. Although adherence rates have been improving, further progress will require additional resources. For example, Thailand’s village health volunteers are key in accessing remote locations and engaging with patients on a personal level, and additional training of these health workers is planned in FY2021, alongside iDES capacity building. In Sisaket, iDES identified issues related to re-treatment with first-line therapy following failure, leading to subsequent treatment failure. These repeated treatment failures are programmatic and may result from stock-outs of second-line anti-malarial therapies, patients presenting at different clinics, or patient or prescriber choice. Being able to find and interrogate these cases allows interventions to be targeted at the causes of non-adherence to treatment guidelines in specific locations.
Although follow-up rates and treatment adherence are not perfect in terms of ensuring individual case outcome, data penetration has been sufficient to enable policy decisions on anti-malarial drug treatment at the provincial level, with dihydroartemisinin–piperaquine switched to pyronaridine–artesunate for two provinces. Although pyronaridine–artesunate shows high efficacy in regions in the GMS where multidrug-resistant
P. falciparum parasites are prevalent [
28‐
31], normally a TES study would be conducted to support a drug treatment policy change. Instead, pyronaridine–artesunate efficacy in Sisaket and Ubon Ratchathani will be monitored in FY2021 through ‘intensified iDES’ (Box
1), which aims to optimize data gathering, given the anticipated low number of
P. falciparum cases.
Box 1
Intensified iDES to support treatment policy change
100% adherence to the national treatment guidelines |
No stock-outs of drugs |
Additional training for treatment providers to ensure daily supervised drug intake |
Target to achieve > 90% of follow-up days |
iDES standard operating procedures are followed with increased frequency of monitoring |
Adequate patient support for follow-up visits (providing transport, etc.) |
Quality control on all microscopy slides |
Collection of all day 0 dried blood spots and at recurrence for PCR and molecular markers |
Follow-up of all treatment failures |
Integration of laboratory data and the results of molecular markers to the online system |
iDES data also underline the importance of
P. vivax malaria elimination. Although generally high efficacy rates were observed, a disparity was evident in Sisaket versus other provinces. The high day 28 failure rate in Sisaket in FY2018 suggests sub-optimal chloroquine efficacy, though efficacy was 100% in FY2020. Mutations associated with chloroquine resistance have been detected in
P. vivax isolates from Thailand [
32]. Notably, Sisaket borders Cambodia, where chloroquine was abandoned in 2012 because of parasite resistance, being replaced first by dihydroartemisinin–piperaquine, and then by mefloquine-artesunate in 2017. There is some evidence of increasing chloroquine susceptibility in Cambodian clinical isolates [
33], which could explain the improved day 28 efficacy observed in Sisaket between FY2018 and FY2020. However, day 90 efficacy has remained unacceptably low in the province, suggesting sub-optimal primaquine efficacy. Although primaquine treatment should be fully supervised, drug consumption cannot be verified and poor primaquine adherence cannot be excluded as a cause. Cytochrome 2D6 polymorphisms can affect primaquine efficacy [
34], but this was not investigated. There may also be social factors in this particular region that predispose the population to
P. vivax re-infection, despite declining case numbers. Investigations and discussions on the appropriate response to
P. vivax malaria in Sisaket are ongoing in FY2021, and the findings may also affect the management of
P. vivax malaria elsewhere in Thailand.
iDES has provided operationally relevant data on drug efficacy; however, there are some limitations. Most importantly, it is difficult to obtain a complete dataset for data collected routinely, which may introduce a bias towards patients that are more easily reached. As follow-up improves, this bias should diminish. Similarly, although health workers attempt to verify drug adherence, not all treatment is directly observed. Thus, although malaria recurrence in this report is attributed to treatment failure, it could be a result of poor adherence. From an operational perspective, it is valuable to be able to differentiate these two sources of recurrence, so health workers are receiving continued training to observe the drug pack as a proxy for consumption. A final consideration is that MIS data can be adjusted to reflect new information received or to correct records, and so should be regarded as cross-sectional.
Given the low and declining malaria incidence in Thailand, without iDES it is unlikely that a pattern of treatment failure would be detected in time to avert an outbreak of drug-resistant
P. falciparum. There is evidence that iDES can support appropriate management of imported malaria as part of a comprehensive prevention of reintroduction program [
35]. Maintaining iDES may be crucial for Thailand as neighbouring countries in the GMS strive for elimination in the coming years.
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