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Assessment of the impact of implementation research on the Visceral Leishmaniasis (VL) elimination efforts in Nepal [1]

['Anand Ballabh Joshi', 'Public Health', 'Infectious Disease Research Center', 'Phidrec', 'Kathmandu', 'Megha Raj Banjara', 'Central Department Of Microbiology', 'Tribhuvan University', 'Kirtipur', 'Unicef Undp World Bank Who Special Programme For Research']

Date: 2023-12

Nepal, Bangladesh, and India signed a Memorandum of Understanding (MoU) in 2005 to eliminate visceral leishmaniasis (VL) as a public health problem from the Indian subcontinent by 2015. By 2021, the number of reported VL cases in these countries had declined by over 95% compared to 2007. This dramatic success was achieved through an elimination programme that implemented early case detection and effective treatment, vector control, disease surveillance, community participation, and operational research that underpinned these strategies. The experience offered an opportunity to assess the contribution of implementation research (IR) to VL elimination in Nepal. Desk review and a stakeholder workshop was conducted to analyse the relationship between key research outputs, major strategic decisions in the national VL elimination programme, and annual number of reported new cases over time between 2005 and 2023. The results indicated that the key decisions across the strategic elements, throughout the course of the elimination programme (such as on the most appropriate tools for diganostics and treatment, and on best strategies for case finding and vector management), were IR informed. IR itself responded dynamically to changes that resulted from interventions, addressing new questions that emerged from the field. Close collaboration between researchers, programme managers, and implementers in priority setting, design, conduct, and review of studies facilitated uptake of evidence into policy and programmatic activities. VL case numbers in Nepal are now reduced by 90% compared to 2005. Although direct attribution of disease decline to research outputs is difficult to establish, the Nepal experience demonstrates that IR can be a critical enabler for disease elimination. The lessons can potentially inform IR strategies in other countries with diseases targeted for elimination.

Investigators supported by TDR, WHO, and other partners engaged with national stakeholders (policy makers, implementers, clinicians, public health workers, and others) in the development and validation of strategies for elimination of visceral leishmaniasis (VL) in Nepal in the context of the regional Kala Azar Elimination Programme. Linkage and regular consultations with the national programme guided the research focus and facilitated continued uptake of results into policy and implementation of evidence-based interventions. Knowledge from implementation research led to public health programme decisions that facilitated VL elimination in Nepal.

Competing interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Abraham Aseffa and John C. Reeder are employees of The UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR).

Funding: This work was supported by The UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR). ABJ received the grant. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright: © 2023 Joshi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

The UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR), World Health Organization (WHO), and several other partners have coordinated and financed implementation research (IR) in support of the VL elimination initiative in the Indian subcontinent before and throughout the course of the regional elimination programme. Available data on IR in the Indian subcontinent with a particular focus on Nepal, which covered all strategic elements and sustained throughout the course of the programme, may provide useful insight from the national perspective on the contribution of IR to achieving disease elimination targets.

Nepal signed a Memorandum of Understanding (MoU) with Bangladesh and India in 2005 to eliminate VL as a public health problem from the region by 2015 [ 12 ]. By 2021, the number of reported VL cases in these countries had declined by over 95% compared to 2007 [ 13 ]. The target of the MoU was to achieve disease elimination (new case rate < 1/10,000 population at the district level) by 2015, through 3 phases of preparatory (2005 to 2008), attack (2008 to 2015), and consolidation (2015 onwards). The 5 strategic elements for elimination were early case diagnosis and complete treatment, integrated vector management (IVM), effective disease surveillance, social mobilization and partnership, and operational research.

Visceral leishmaniasis (VL), also known as kala-azar (KA), is a fatal parasitic disease, if untreated. It is transmitted by sandflies, with anthroponotic transmission (in the Indian subcontinent), mostly affecting socially deprived populations [ 1 – 4 ]. Worldwide, an estimated 50,000 to 90,000 new VL cases occur annually with more than 90% of cases reported from just 10 countries, including Bangladesh, India, and Nepal [ 5 – 11 ].

Methodology

A desk review of relevant VL publications, documents on VL elimination, and strategies and operational plans of Nepal or relevant to Nepal (from internal and external sources) was conducted.

Expert consultations were held with key stakeholders including national VL programme managers, VL treating clinicians, entomologists, and researchers to collect information on implementation or operational research activities and alignment with the programme and IR needs to achieve sustainability of elimination. The consultations included national program officers and the WHO country office.

A 5-day workshop (23 to 27 September 2021) was organized with academic institutions, national programme managers, and development partners. The workshop discussed on the role and contributions of IR to the elimination effort so far and identified the research and programmatic priorities to achieve and maintain VL elimination going forward. The discussion points and recommendations of the workshop have been provided in findings and discussion sections below.

Findings IR on VL in Nepal covered all the strategic elements of the Kala-Azar Elimination Programme. TDR-supported country-led IR established the burden of VL, characterized population health-seeking behaviour, investigated feasibility of new interventions, identified barriers to early diagnosis and treatment, developed strategies for cost-effective active case detection (ACD), demonstrated effective and long-lasting vector control interventions, explored environmental determinants (e.g., housing as a risk factor for VL transmission), and examined the role of frontline health workers. Based on the findings from these studies and other similar research, which also fed into regional consensus, the national VL elimination program developed strategies, guidelines, and implementation plans for the attack phase of VL elimination in line with the recommendations of the WHO regional technical advisory group (RTAG), within the context of the WHO-supported regional VL elimination strategy [14,15]. Key decisions underpinned by sustained IR that directly impacted on reduced case burden in Nepal included the following: (i) rK39-based rapid test employed as a confirmatory test for VL as of 2005, following extensive field validation; (ii) miltefosine (MIL) replaced sodium stibogluconate (SSG) as a first line of treatment in 2008 to 2014; (iii) liposomal amphotericin B (L-AmB) replaced MIL in 2015 in response to increased treatment failures and relapse rates; (iv) combination therapy was introduced in Nepal’s national treatment protocol in 2014; (v) active case detection (ACD) was incorporated into the national VL elimination protocol; and (vi) integrated vector management (IVM) was recognized as an important element in the elimination efforts.

VL trends in Nepal 2002–2020 In 2003, Nepal witnessed the highest case load of VL, although there were many outbreaks of VL in the past [16]. In the same year, the rotation of synthetic pyrethroids for vector management was introduced. The overall trend of VL cases decreased significantly thereafter. The number of cases and deaths has been steadily falling since the VL elimination initiative started in 2005 (Fig 1). In 2008, MIL was introduced as oral monotherapy. The number of cases decreased further in comparison to previous years. This could be due to the convenience of the oral medication influencing patient compliance to treatment. Around the same period in 2009, long-lasting insecticide-treated nets (LLINs) were introduced in addition to indoor residual spraying (IRS), two measures that helped decrease the man–vector contact and, thus, the VL burden in the country. In addition, ACD was introduced into the VL elimination program in 2014 after a series of large intervention studies to identify the most cost-effective way of ACD. Overall, the number of VL cases has decreased by 90% in 2020 as compared to 2002, which is most likely a result of the synergistic impact of all interventions of the VL elimination program. PPT PowerPoint slide

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TIFF original image Download: Fig 1. Trend of VL cases and deaths and major interventions in Nepal, 2002–2020. https://doi.org/10.1371/journal.pntd.0011714.g001

Diagnostic tests for VL The direct agglutination test (DAT) had been in use as a diagnostic tool for VL since the early 90s following its assessment through TDR-supported research, which had confirmed it to be specific and sensitive and relatively acceptable for field laboratory settings [17,18]. In subsequent years, rK39-based rapid test was found to be more cost-effective and simpler to use in field settings [19–24]. The heterogeneity in test results of rK39 could be due to geographic region, commercial brand, disease prevalence, sample size in the study, type of reference standard, and risk of bias during testing [25]. The sensitivity of rK39 is 97% and specificity is 90.2% in Indian subcontinent, and because of ease of use [25], it was recommended for diagnosis of VL in Indian subcontinent. rK39 was introduced as a diagnostic tool in the national VL elimination program in Nepal in 2005. The key studies on VL diagnostics have been given in Table 1. PPT PowerPoint slide

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TIFF original image Download: Table 1. Research on diagnostic tests for VL. https://doi.org/10.1371/journal.pntd.0011714.t001

Treatment regimens for visceral leishmaniasis SSG was first introduced in Nepal in 1982 and became a first-line choice for treatment of VL in 1994. The study conducted by Karki and colleagues [32] on SSG revealed satisfactory results demonstrating better efficacy in those treated for a longer period. However, SSG showed increasing failure rates of 10% to 30% in Nepal [33] and 65% in Bihar [34] at the turn of the century. Amphotericin B was introduced for the treatment of VL in 1994. Subsequently, a TDR-supported Phase IV trial of MIL [35] showed that it was a safe and effective oral drug for treatment of VL. Oral monotherapy with MIL was introduced in 2008 as a first-line drug for VL in the absence of contraindications, until revised in 2014. Following the introduction of MIL as a first-line regimen, TDR supported another Phase IV trial conducted by Banjara and colleagues [36] in Saptari district. Although MIL was relatively safer and easier to administer than SSG [37], it is potentially teratogenic and, hence, contraindicated in pregnancy and during breastfeeding. The study by Rijal and colleagues [38] reported a 10% to 20% relapse rate after treatment with MIL. Banjara and colleagues [36] and Uranw and colleagues [39] showed that poor adherence and insufficient dose were associated with the occurrence of relapses. On the other hand, MIL is, in some case, a useful drug as a rescue treatment for patients with VL relapse [40]. TDR-supported trials conducted in the Indian subcontinent showed that combined therapies had a favourable outcome for VL treatment [41–44]. These studies revealed that combined therapy reduces the dose requirements without compromising the cure rate. The national treatment protocol of 2014 introduced combined therapy as a second-line treatment for VL. The combination regimen consists of L-AmB (5 mg/kg, single infusion) plus 7 days MIL (50 mg 2 times a day or, alternatively, L-AmB (5 mg/kg, single infusion) plus 10 days paromomycin (PM) (11 mg/kg base) or MIL plus PM for 10 days. Combined therapy has replaced amphotericin B monotherapy as a second-line treatment shifting it to third-line treatment in the national guideline of 2019. The TDR-supported dose finding studies conducted in India showed that L-AmB was safe, effective, and favorable for the treatment of VL with minimal toxicity [41,45]. In 2014, L-AmB was introduced into the treatment protocol for VL and is, since 2015, the recommended first-line drug in the national guideline for VL elimination. Table 2 presents the key studies on drugs for VL treatment. PPT PowerPoint slide

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TIFF original image Download: Table 2. Research on VL treatment (drugs). https://doi.org/10.1371/journal.pntd.0011714.t002

VL vector control Joshi and colleagues (2008), Joshi and colleagues (2009), and Das and colleagues (2010) [54,55,56] in their TDR-funded study found that integrated vector management (IVM) can play a vital role in the VL elimination program. This was subsequently introduced into the 2010 national guidelines for VL elimination. TDR-funded studies have found that indoor residual spraying (IRS), insecticide-treated nets (ITNs), and insecticidal wall painting (IWP) are effective ways to control sandflies in Nepal [57,58]. IRS with DDT, Malathion, and Lambda Cyhalothrin (ICON) had been in use from 1992 until 2002 [59,60]. From 2003 onwards, the rotational substitution of synthetic pyrethroids was introduced in order to avoid vector resistance. Alpha cypermethrin was used in 2003 and 2012, while Lambda Cyhalothrin was reintroduced in 2007. A Lambda cyhalothrin study funded by TDR showed 97% mean vector mortality and a beneficial impact of IRS for up to 4 weeks after insecticide spray [61]. However, the substandard performance and management of the spraying activity increased the risk of insecticide resistance [60,62,63]. The studies by Joshi and colleagues (2009), Picado and colleagues (2009), and Picado and colleagues (2010) [55,64,65] did not show a significant reduction of VL incidence after the use of LLINs, but the study by Das and colleagues (2010), Mondal and colleagues (2016), and Das and colleagues (2012) [56,58,66] found LLINs to be a favorable alternative to IRS. Key studies on vector control are shown in Table 3. PPT PowerPoint slide

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TIFF original image Download: Table 3. IR on VL vector control. https://doi.org/10.1371/journal.pntd.0011714.t003

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