Background
The prevalence of
Plasmodium falciparum malaria in Southeast Asia is at historically low levels and the region is collectively engaging in malaria elimination strategies [
1]. Concurrently, the Greater Mekong Subregion (GMS) is meeting the challenge of resistance to artemisinin and partner drugs used in artemisinin-based combination therapy (ACT). Artemisinin-based combinations are the global first-line therapies for the treatment of uncomplicated malaria and losing them to resistance would jeopardize malaria control and elimination activities worldwide [
2].
Artemisinin and partner drug resistance and subsequent ACT failures force countries in the GMS to anticipate new treatment strategies to protect their malaria control and elimination ambitions [
3]. Countries rotate artemisinin-based combinations, when treatment failures are observed, but rotation has repeatedly proven a temporary solution before the replacement ACT also fails [
4]. Other proposed strategies include the simultaneous deployment of multiple first-line therapies, or extending ACT use from 3 to 7 days [
5,
6]. However, these solutions have been associated with significant operational challenges and limited feasibility.
Another option that is now being explored in the GMS and elsewhere is the introduction of
triple artemisinin-based combination therapy (TACT) [
7,
8]. The rationale is that combining the artemisinin derivative with two carefully selected partner drugs will extend the therapeutic lifetime of each compound because the parasite will need to develop resistance to three drugs instead of two. The potential benefits of introducing TACT would be twofold: 1) they can provide direct clinical relief in case all current artemisinin-based combinations (including newly introduced artesunate-pyronaridine) would fail, and 2) they can protect artemisinin and its partner drugs from resistance, preserving future treatment options.
Although results from current clinical trials [
7,
9] and mathematical modelling studies [
10,
11] are encouraging, the introduction of TACT in the GMS is debated [
12,
13]. Some scholars and representatives of policy institutes perceive TACT as a useful intervention towards malaria elimination in the GMS, while others prefer relying on current strategies of rotating ACT until malaria elimination is established. A recently conducted Delphi study systematically assessed expert perspectives towards the introduction of TACT in Southeast Asia [
14]. Prominent malaria experts identified major advantages, disadvantages and implementation barriers for introducing TACT and they rated the relevance of each item on a 5-point Likert scale. The insights of the Delphi study led to a first, tentative overview of major barriers and drivers towards TACT deployment in the GMS. However, these insights lack contextualization to the individual countries. More in-depth attention can—and should—be paid to the specific implementation challenges for deploying TACT in the GMS and to strategies to overcome these challenges [
15]. This study addresses this gap in literature through a qualitative study of implementation challenges and deployment strategies of TACT in three countries in the GMS: Cambodia, Vietnam and Lao PDR.
Methods
Research design
The study was conducted under the auspices of the UK Government’s Foreign, Commonwealth & Development Office funded Development of Triple Artemisinin Combination Therapies (DeTACT) project. A qualitative research approach was employed to investigate implementation challenges and deployment strategies for TACT in the Greater Mekong Subregion (GMS) of Southeast Asia. Three countries were selected for data collection: Cambodia, Vietnam, and Lao PDR. All three countries are engaging in malaria elimination strategies, have repeatedly been confronted with artemisinin and partner drug resistance, yet they all have unique health system characteristics. In-depth interviews were conducted in all three countries to obtain insight into specific implementation challenges for TACT and to explore strategies to overcome these implementation challenges. The multi-country research approach enabled investigating country-specific dynamics in relation to the deployment of TACT, while enabling the extraction of general topics that were applicable to more than one country. Data was collected through in-depth interviews with key actors in the healthcare systems in Cambodia, Vietnam and Lao PDR. The implementation challenges for introducing TACT in Southeast Asia identified in the previously conducted Delphi study [
14] was considered as a starting point for the in-depth interviews (Table
1). Furthermore, one participatory workshop was conducted in Cambodia. The goal of the workshop was to interactively discuss preliminary insights obtained during the interviews with key stakeholders and to discuss strategic solutions towards the deployment of TACT in the GMS.
Table 1
Expert perspectives on the
implementation barriers for introducing TACTs in Southeast Asia (derived from de Haan et al. [
14])
Intensified prescriber training | Intensifying training requirements for correct TACT prescription |
Donor funder support | Obtaining support by donor funders to cover TACT implementation costs and potential price increases |
National policy support | Obtaining support from national malaria control programs and other national decision makers to engage in the deployment of TACT |
WHO and global policy support | Obtaining support from the WHO and other global decision makers to engage in the deployment of TACT |
Availability of fixed-dose combination (FDC) TACT | Ensuring timely development and production of fixed-dose combination (FDC) for TACT |
Community acceptance | Ensuring community acceptance by providing clear communication and tackling potential misconceptions about TACT |
Collecting safety and efficacy data | Collecting sufficient efficacy and safety data to support the introduction of TACT |
Supply chain logistics | Adapting import, procurement and supply routes for the introduction of TACT |
Regulatory approval | Obtaining timely regulatory approval for introducing TACT in Southeast Asia |
Set up surveillance systems | Setting up surveillance systems to monitor drug resistance rates and adherence to TACT |
Private sector engagement | Engaging the (informal) private sector in TACT deployment and creating demand beyond official programs |
Set up pharmacovigilance systems | Setting up a pharmacovigilance system for TACT |
Stockpile management | Managing stockpiles for countries that still have ACT stocks or contract deals with ACT producers |
Respondent selection
The study was conducted in Cambodia, Vietnam and Lao PDR. In each of the countries, collaborations were established with co-authoring research institutes and social scientists. The local social scientists mapped potential respondents and invited them to participate in the in-depth interviews. The aim was to include interviewees who represented a wide variety of stakeholders in anti-malarial drug transitions. Selected respondents included representatives from national malaria control programmes, regulatory authorities, academia, healthcare professionals and NGOs. Sampling of respondents in each country continued until reaching data saturation on the pre-identified implementation barriers for the deployment of TACT.
Data collection
Preparatory meetings were held between the principal investigators (FH and CA) and the social scientists in Cambodia (LO), Vietnam (VC) and Lao PDR (MV). The purpose of these meetings was to discuss the research aims, identify relevant stakeholders and prepare data collection tools. Semi-structured interview guidelines were designed using the pre-identified implementation barriers as starting questions. In line with insights gained in the ongoing DeTACT project, the study focused on the introduction of a prospective TACT that combines artemether-lumefantrine plus amodiaquine (AL + AQ). For each interview, themes that were considered most relevant to the specific background of the respondent were selected and included in a personalized interview guideline. Pilot interviews were conducted to improve mutual understanding and to reduce ambiguity. Using the semi-structured interview guides enabled exploring the same topics between the countries and respondents, while remaining flexible for newly emerging themes. Data collection was iterative: insights from previous interviews were incorporated in guidelines of later interviews.
Data analysis
Interviews were recorded with consent given by each respondent. All interviews in Cambodia, Vietnam and Lao PDR and the participatory workshop in Cambodia were transcribed verbatim and translated into English by the social scientists or by professional translators. Each transcript was then uploaded to NVivo 12 software and subjected to coding. The transcripts were coded line-by-line by FH, and codes were assigned to both the pre-defined implementation barriers and to newly emerging themes. After the process of coding, a thematic analysis was employed using deductive and inductive techniques: emerging themes were merged into overarching categories and storylines were written to present narratives of implementation challenges and deployment strategies to overcome these implementation challenges.
Study setting: introducing the three country contexts
Cambodia, Vietnam and Lao PDR have low falciparum malaria incidence and all three countries are engaging in malaria elimination strategies. In 2021, Cambodia (16.6 million inhabitants) reported 4.382 malaria cases, Lao PDR (7.4 million inhabitants) reported 3.897 malaria cases and Vietnam (97.5 million inhabitants) reported 377 malaria cases (WHO, 2022). These numbers include both
Plasmodium falciparum and other types of malaria. All three countries share goals to eliminate falciparum malaria by 2025 and all other types of malaria by 2030 [
16].
Cambodia: Cambodia has repeatedly changed its first-line ACT as a response to failures for the treatment of uncomplicated falciparum malaria. In 2017, artesunate-mefloquine (ASMQ) was re-introduced as first-line therapy in response to treatment failures with dihydroartemisinin-piperaquine (DHA-PPQ). At the time of writing, ASMQ maintained adequate treatment efficacy in Cambodia, but the national malaria control programme is preparing for the implementation of artesunate-pyronaridine (AS-PYR) as first-line therapy. The National Center for Parasitology, Entomology and Malaria Control (CNM) coordinates malaria-related activities and the Department of Drugs and Food (DDF) is responsible for drug regulation in Cambodia.
Vietnam: The official first-line therapy for the treatment of uncomplicated falciparum malaria in Vietnam is DHA-PPQ. However, DHA-PPQ is failing in some areas in the central-highlands and AS-PYR is being used for the treatment of uncomplicated falciparum malaria in these areas. From November 2022 onwards, AS-PYR was used throughout the entire country. Malaria control activities in Vietnam are coordinated by the National Malaria Program (NMP) and the Drug Administration of Vietnam (DAV) is responsible for drug regulation in Vietnam.
Lao PDR: The first-line therapy for the treatment of uncomplicated falciparum malaria in Lao PDR is artemether-lumefantrine (AL). Moreover, AS-PYR and ASMQ were added to national treatment guidelines as second-line therapy in 2022. In Lao PDR, malaria control efforts are coordinated by the Center of Malariology, Parasitology and Entomology (CMPE) and the Food and Drugs Department (FDD) is responsible for drug regulation.
Discussion and conclusions
Countries in Southeast Asia are experiencing a historically low malaria burden and they are increasingly dedicating resources and efforts towards the elimination of falciparum malaria [
16]. Respondents in Cambodia, Vietnam and Lao PDR indicated a general reliance on their current ACT in reaching their malaria ambitions. In particular, newly introduced artesunate-pyronaridine (AS-PYR) was mentioned as an important intervention towards malaria elimination. Although malaria elimination is without doubt the most effective way to contain drug resistance, there is a risk of over-relying on current elimination strategies while alternative scenarios are being overlooked. Resistance pathways are unpredictable and epidemiological developments can unfold rapidly [
3]. For example, the instable political situation in Myanmar and subsequent weakening of health services could result in a resurgence of falciparum malaria not only in Myanmar, but also in neighbouring countries in the GMS [
1]. Moreover, future treatment failures with AS-PYR can potentially emerge and can threaten malaria elimination ambitions when countries remain unprepared. Therefore, decision makers would benefit from an increasing number of treatment options. Triple artemisinin-based combination therapy (TACT) is currently being developed and it has the potential to ensure treatment efficacy in case ACT would fail [
7,
17], while they can also protect drug compounds from resistance, increasing future treatment options.
This qualitative study was conducted to identify implementation challenges for TACT deployment in the GMS and to explore strategies to overcome these implementation challenges. Data were collected in three GMS countries that have repeatedly been confronted with ACT failure: Cambodia, Vietnam and Lao PDR. The results were organized around four strategic themes.
The first strategic theme that emerged from the data was policy support for the deployment of TACT. This study revealed that early stakeholder engagement is essential to prevent implementation delays for new therapies such as TACT. These stakeholder engagement strategies should be encompassing and should target decision-makers, regulators and supply chain actors. Indeed, it is widely acknowledged that transitioning to new malaria therapies can be a lengthy process [
18,
19] and that early stakeholder engagement is a driving force towards accelerated uptake of malaria interventions [
20,
21]. In contrast to Vietnam and Lao PDR, Cambodia is already anticipating the potential introduction of TACT. The National Malaria Control Programme (NMCP) is considering adopting TACT as a second-line therapy in their national treatment guidelines. This will make it easier for them to rapidly switch to TACT in case artesunate-mefloquine (ASMQ) would fail again followed by AS-PYR failures. Other countries in the GMS should consider similar pro-active strategies instead of relying on reactive approaches towards drug resistance [
4,
18]. Furthermore, respondents suggested that sufficient stockpiles of effective therapies, even beyond malaria elimination, is required to prevent resurgence of the disease. Stocking challenges have indeed been widely acknowledged in literature on anti-malarial drug transitions [
22,
23], and have often been associated with expiry dates [
21,
24], or low expected demand [
25]. National malaria control programmes in the GMS should take a guiding role in ensuring adequate distribution and stocking of malaria therapies given their wealth of experience during previous drug transitions [
15]. Beyond national level policy guidance, interview respondents considered international organizations, such as the WHO, essential to guide the potential introduction of TACT through recommendations, guidelines and resource dedication. This implies the necessity of a pro-active role for these policy institutes, similar to the transition to ACT in the early 2000s [
15].
The second strategic theme that emerged from the study was related to the collection of data and evidence on safety and efficacy. Before TACT can be deployed, evidence from clinical trials will be required to obtain market authorization in Cambodia, Vietnam and Lao PDR. Regulatory procedures have however repeatedly been suggested as delaying factors in updating malaria treatment routines [
15,
26]. They are often considered inflexible, while dealing with drug resistance requires pragmatic approaches [
27]. Established regulatory procedures entail large-scale clinical studies and approval by a stringent regulatory authority – such as WHO pre-qualification – before country-level authorization procedures can commence. Interview respondents emphasized that strategies for early dossier submission should be explored to shorten regulatory timelines [
27]. Similar procedures were suggested for reducing implementation timelines for TACT in Nigeria and Burkina Faso [
28]. One pragmatic strategy was suggested by interview respondents in Vietnam. They referred to the current off-label prescription of AS-PYR prior to its country-level registration because a new therapy was urgently needed after DHA-PPQ failures were observed.
The third strategic theme that emerged was related to logistical and operational considerations. Although malaria incidence in the GMS has significantly been reduced in the last decades, references were made to persisting general malaria management and control challenges. Malaria in the GMS is mostly prevalent amongst hard to reach populations in remote border areas, such as forest workers and labour migrants [
29,
30]. New interventions will need to reach these remote populations and they will need to be adequately adopted in order to contribute to malaria control and elimination strategies. Community-based health initiatives such as Village Malaria Worker (VMW) programmes have become a key intervention in malaria control strategies in the GMS [
31]. They are now institutionalized in public health services and are considered essential to the battle against malaria. VMWs should be actively involved in the potential introduction of TACT which will require policy attention and resource dedication [
4,
32]. Another prominent challenge that was identified by interview respondents are the limited incentives for manufacturers to engage in TACT. It was emphasized that the low case incidence of falciparum malaria in the GMS would translate to low sales volumes and that this could deter manufacturers to engage in triple artemisinin-based combination production. However, history has shown that this market dilemma can successfully be addressed, for example through corporate social responsibility programs, public–private partnerships, or external funding for research and development efforts [
15,
26,
33‐
35]. Another solution that was mentioned during the interviews was a regional pooled procurement system for the GMS. Such a pooled procurement system would enable to reach scale advantages. The GFATM could be a credible partner to rollout such a scheme, given their wealth of experience in reforming global health procurement systems [
36]. Further distribution challenges in Vietnam and Cambodia were considered limited because these countries now rely on public sector channels which are relatively compliant to national guidelines [
15]. More challenges were expected for Lao PDR where private sector distribution channels play a significant role in malaria management efforts. Lessons from earlier private sector engagement programs, such as the Public–Private Mix (PPM) [
37] and the Affordable Medicines Facility malaria (AMFm) initiative [
36,
38,
39] should therefore be evaluated and translated to the potential introduction of TACT.
The fourth and final strategic theme was downstream engagement for TACTs deployment. A recurrent question that emerged is how to engage stakeholders in TACTs while falciparum malaria incidence is receding in the GMS. Changing first-line treatment practices indeed requires substantial investments and collective actions by multiple stakeholder groups such as decision makers, regulators and prescribers [
28]. Antimalarial drug transitions are lengthy and this justifies considerations around the timing of introducing new therapies. Previous studies have emphasized that downstream engagement strategies are important to the successful introduction of new therapies [
21,
40]. Therefore, adequate training materials should be developed for TACTs. Such training modules should be clear and discuss risks of potential side-effects [
21,
41]. Moreover, respondents stressed that training programs should include education messages to address potential misconceptions about the new therapy. For the introduction of TACTs, communication strategies were also deemed necessary which should highlight advantages in terms of clinical benefits, TACTs’ potential to protect antimalarial drugs, and indirect benefits such as reduced frequency of policy changes [
14].
Four limitations should be considered when interpreting the study results. An important disclaimer is that this study does not seek to determine whether TACTs should be introduced in the GMS; we present strategic considerations for the market introduction of TACTs. Second, the generalizability of the findings is limited. Although some of the findings of this study are also relevant to other countries in the GMS, countries are heterogeneous and characterized by their own healthcare systems and epidemiological factors. We propose that similar studies should be conducted in other countries that are confronted by drug-resistant malaria. Third, although we selected respondents in close collaboration with local research institutes, it is possible that important stakeholders and perspectives were not included. Fourth, interviews were conducted in local languages and translated into English, hence translation bias could have occurred.
This paper presented a qualitative study regarding strategies to identify implementation challenges for deploying triple artemisinin-based combination therapy (TACT) and to discuss strategies to overcome these challenges in three countries in the Greater Mekong Subregion (GMS). It explored considerations for deploying TACT around four strategic themes: policy support, data and evidence, logistics and operation, and downstream engagement. The findings could benefit researchers and decision makers in strategizing effectively towards potential future deployment of TACT in the GMS.
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