Modelling spatiotemporal patterns of visceral leishmaniasis incidence in two endemic states in India using environment, bioclimatic and demographic data, 2013-2022.

BACKGROUND: As of 2021, the National Kala-azar Elimination Programme (NKAEP) in India has achieved visceral leishmaniasis (VL) elimination (<1 case / 10,000 population/year per block) in 625 of the 633 endemic blocks (subdistricts) in four states. The programme needs to sustain this achievement and target interventions in the remaining blocks to achieve the WHO 2030 target of VL elimination as a public health problem. An effective tool to analyse programme data and predict/ forecast the spatial and temporal trends of VL incidence, elimination threshold, and risk of resurgence will be of use to the programme management at this juncture. METHODOLOGY/PRINCIPAL FINDINGS: We employed spatiotemporal models incorporating environment, climatic and demographic factors as covariates to describe monthly VL cases for 8-years (2013-2020) in 491 and 27 endemic and non-endemic blocks of Bihar and Jharkhand states. We fitted 37 models of spatial, temporal, and spatiotemporal interaction random effects with covariates to monthly VL cases for 6-years (2013-2018, training data) using Bayesian inference via Integrated Nested Laplace Approximation (INLA) approach. The best-fitting model was selected based on deviance information criterion (DIC) and Watanabe-Akaike Information Criterion (WAIC) and was validated with monthly cases for 2019-2020 (test data). The model could describe observed spatial and temporal patterns of VL incidence in the two states having widely differing incidence trajectories, with >93% and 99% coverage probability (proportion of observations falling inside 95% Bayesian credible interval for the predicted number of VL cases per month) during the training and testing periods. PIT (probability integral transform) histograms confirmed consistency between prediction and observation for the test period. Forecasting for 2021-2023 showed that the annual VL incidence is likely to exceed elimination threshold in 16-18 blocks in 4 districts of Jharkhand and 33-38 blocks in 10 districts of Bihar. The risk of VL in non-endemic neighbouring blocks of both Bihar and Jharkhand are less than 0.5 during the training and test periods, and for 2021-2023, the probability that the risk greater than 1 is negligible (P<0.1). Fitted model showed that VL occurrence was positively associated with mean temperature, minimum temperature, enhanced vegetation index, precipitation, and isothermality, and negatively with maximum temperature, land surface temperature, soil moisture and population density. CONCLUSIONS/SIGNIFICANCE: The spatiotemporal model incorporating environmental, bioclimatic, and demographic factors demonstrated that the KAMIS database of the national programmme can be used for block level predictions of long-term spatial and temporal trends in VL incidence and risk of outbreak / resurgence in endemic and non-endemic settings. The database integrated with the modelling framework and a dashboard facility can facilitate such analysis and predictions. This could aid the programme to monitor progress of VL elimination at least one-year ahead, assess risk of resurgence or outbreak in post-elimination settings, and implement timely and targeted interventions or preventive measures so that the NKAEP meet the target of achieving elimination by 2030.

The lymphatic filariasis treatment study landscape: A systematic review of study characteristics and the case for an individual participant data platform.

BACKGROUND: Lymphatic filariasis (LF) is a neglected tropical disease (NTD) targeted by the World Health Organization for elimination as a public health problem (EPHP). Since 2000, more than 9 billion treatments of antifilarial medicines have been distributed through mass drug administration (MDA) programmes in 72 endemic countries and 17 countries have reached EPHP. Yet in 2021, nearly 900 million people still required MDA with combinations of albendazole, diethylcarbamazine and/or ivermectin. Despite the reliance on these drugs, there remain gaps in understanding of variation in responses to treatment. As demonstrated for other infectious diseases, some urgent questions could be addressed by conducting individual participant data (IPD) meta-analyses. Here, we present the results of a systematic literature review to estimate the abundance of IPD on pre- and post-intervention indicators of infection and/or morbidity and assess the feasibility of building a global data repository. METHODOLOGY: We searched literature published between 1st January 2000 and 5th May 2023 in 15 databases to identify prospective studies assessing LF treatment and/or morbidity management and disease prevention (MMDP) approaches. We considered only studies where individual participants were diagnosed with LF infection or disease and were followed up on at least one occasion after receiving an intervention/treatment. PRINCIPAL FINDINGS: We identified 138 eligible studies from 23 countries, having followed up an estimated 29,842 participants after intervention. We estimate 14,800 (49.6%) IPD on pre- and post-intervention infection indicators including microfilaraemia, circulating filarial antigen and/or ultrasound indicators measured before and after intervention using 8 drugs administered in various combinations. We identified 33 studies on MMDP, estimating 6,102 (20.4%) IPD on pre- and post-intervention clinical morbidity indicators only. A further 8,940 IPD cover a mixture of infection and morbidity outcomes measured with other diagnostics, from participants followed for adverse event outcomes only or recruited after initial intervention. CONCLUSIONS: The LF treatment study landscape is heterogeneous, but the abundance of studies and related IPD suggest that establishing a global data repository to facilitate IPD meta-analyses would be feasible and useful to address unresolved questions on variation in treatment outcomes across geographies, demographics and in underrepresented groups. New studies using more standardized approaches should be initiated to address the scarcity and inconsistency of data on morbidity management.

Factors for hesitancy towards vaccination against COVID-19 among the adult population in Puducherry, India - a cross sectional study.

BACKGROUND: Vaccine hesitancy is a complex phenomenon that threatens global health. Present-day communication technology has paved the way for self-education but also contributed to the infodemic surrounding vaccination. This has resulted in pockets of people who are reluctant, refuse recommended vaccinations, or choose to delay being vaccinated. The present study was designed to estimate the magnitude of hesitancy towards the COVID-19 vaccination and determine its associated factors in the community. METHODS: This cross-sectional study was conducted among 776 adults aged ≥ 18 years in 15 clusters in Puducherry district, India, between March 2022 and May 2022. Face-to-face interviews were conducted using a validated, structured questionnaire. Socio-demographic variables, co-morbidities, attitudes towards vaccination, etc., were expressed as frequencies and percentages. Vaccine hesitancy was dichotomized with the median score as the cut-off and reported as a proportion with a 95% confidence interval. Univariate and multivariate analyses were carried out to determine the factors associated with vaccine hesitancy. RESULTS: The mean age of participants was 43.3 ± 14.8 years, with the majority being female (67.0%). Nearly 92.4%, 74.4%, and 0.5% of participants received their first, second, and precautionary doses, respectively, during the study period. Among the unvaccinated, 93.2% were unwilling to receive any dose of vaccination. More than half of the participants were hesitant towards vaccination, according to the vaccine hesitancy scale. Participants aged above 45 years were less hesitant, while those educated up to school level, belonging to the upper socio-economic class, never tested for COVID-19 in the past, and having a negative attitude towards vaccination were significantly associated with higher vaccine hesitancy. CONCLUSIONS: It is imperative to address vaccine hesitancy by alleviating existing fears and misconceptions in the community through efficient communication strategies to win the fight against current as well as future public health emergencies.

Coverage evaluation of mass drug administration with triple drug regimen in an evaluation unit in Nagpur district of Maharashtra, India.

BACKGROUND: Triple drug regimen (IDA; Ivermectin, Diethylcarbamazine, Albendazole) recommended for accelerating elimination of lymphatic filariasis was launched in India in December 2018. Nagpur district in Maharashtra was one of the first five districts where this strategy was introduced. The National Vector Borne Disease Control Programme (NVBDCP) at the district reported ~85.0% treatment coverage in the first round of mass drug administration (MDA) with IDA implemented in EU-2 in Nagpur district in January 2019. As per the national guideline, a coverage evaluation survey was carried out and both quantitative and qualitative data were collected to assess the treatment coverage, the level of community preparation and identify the gaps, if any, for improvement. METHODOLOGY: A Coverage Evaluation Survey (CES) following the WHO recommended protocol was conducted in one of the two evaluation units (EU-2) in Nagpur district in March 2019. Coverage Sample Builder (CSB) V2.9 tool was used to calculate the sample size, select sites and estimate drug coverage. The CSB tool followed a two-stage cluster sampling procedure to select 30 primary sampling units (ward/village as a cluster) and a list of random numbers for selecting households (HHs) in each cluster. The results were analyzed for operational indicators. Stata ver. 14.0 software was used to construct the 95% confidence limits accounting for clustering. RESULTS: A total of 1601 individuals aged 5-85 years of both gender from 328 HHs were surveyed from the 30 randomly selected clusters in EU-2. The mean age was 33.8±17.6 years. Among the surveyed population, 78.0% received the drugs (programme reach) and 66.1% consumed the drugs (survey coverage). Survey coverage was significantly higher in rural (82.6%) than in urban (59.4%) and peri-urban (58.6%) areas (P<0.001). Directly observed treatment (DOT) among the surveyed population was 51.6%. Adverse events were reported among 6.9% respondents who reported to have consumed the drugs. CONCLUSION: The IDA based MDA strategy could achieve just the required level of treatment coverage (~65%) in EU-2, Nagpur district, which had previously undergone several rounds of DA-MDAs (Diethylcarbamazine, Albendazole). Having achieved an effective treatment coverage of >80% in rural areas, the coverage in urban and peri-urban areas need to be improved in order to attain the impact of IDA-MDA. It is imperative to strengthen drug delivery and community preparation activities along with improved DOT especially in urban and peri-urban areas to achieve the required level of treatment coverage. Addition of ivermectin did not have any additional perceived adverse events.

Probable sociobehavioural and environmental risk factors for dengue transmission in Puducherry, India - An exploratory study.

Context: Dengue is one of the most extensively spread mosquito borne disease. Puducherry has experienced outbreaks during the post monsoon season almost every year since 2003. Understanding the dynamics of disease transmission and the conducive factors favourable for its spread is necessary to plan early control measures to prevent outbreaks. Objective: To describe the sociodemographic details of the dengue recovered cases, their clinical features, management, probable sociobehavioural and environmental risk factors for acquiring infection that could favour disease spread. Methodology: An exploratory descriptive study was conducted among 23 individuals recovered from dengue during the outbreak in Puducherry in 2018. An interview guide was used to elicit details regarding the course of illness from its onset until recovery as well as the probable sociobehavioural and environmental risk factors from each participant. Descriptive statistics were reported as frequency, percentage, and mean scores. Results: All 23 were primary cases of dengue with fever and myalgia being the commonest presentation. Two of them developed dengue haemorrhagic fever, of which one completely recovered. Five were found to have dengue-chikungunya coinfection. Lack of awareness about dengue, noncompliance regarding proper solid waste management and environmental sanitation among the public was clearly evident. Conclusion: Local transmission was evident as most cases did not have any relevant travel history outside the State and from the prevailing mosquitogenic environmental conditions. Dengue being a preventable disease can be controlled only with the active participation of all stakeholders including primary care physicians and the community.

An open label, block randomized, community study of the safety and efficacy of co-administered ivermectin, diethylcarbamazine plus albendazole vs. diethylcarbamazine plus albendazole for lymphatic filariasis in India.

BACKGROUND: Better drug regimens for mass drug administration (MDA) could accelerate the Global Programme to Eliminate Lymphatic Filariasis (LF). This community study was designed to compare the safety and efficacy of MDA with IDA (ivermectin, diethylcarbamazine and albendazole) or DA (diethylcarbamazine and albendazole) in India. METHODOLOGY/PRINCIPAL FINDINGS: This two-armed, open-labelled, block randomised, community study was conducted in LF endemic villages in Yadgir district, Karnataka, India. Consenting participants ≥5 years of age were tested for circulating filarial antigenemia (CFA) and microfilaremia (Mf) before treatment with a single oral dose of IDA or DA. Adverse events (AEs) were monitored actively for two days and passively for five more days. Persons with positive CFA or Mf tests at baseline were retested 12-months post-treatment to assess treatment efficacy. Baseline CFA and Mf-rates were 26.4% and 6.9% in IDA and 24.5% and 6.4% in DA villages respectively. 4758 and 4160 participants received IDA and DA. Most AEs were mild after both treatments; fewer than 0.1% of participants experienced AEs with severity > grade 1. No serious AEs were observed. Fever, headache and dizziness were the most common AEs. AE rates were slightly higher after IDA than DA (8.3% vs. 6.4%, P<0.01). AEs were more frequent in females and Mf-positives after either treatment, but significantly more frequent after IDA (40.5% vs 20.2%, P < 0.001). IDA was more effective for clearing Mf than DA (84% vs. 61.8%, P < 0.001). Geometric mean Mf counts per 60µl in retested Mf-positives decreased by 96.4% from 11.8 after IDA and by 90.0% from 9.5 after DA. Neither treatment was effective for clearing CFA. CONCLUSIONS/SIGNIFICANCE: IDA had an acceptable safety profile and was more effective for clearing Mf than DA. With adequate compliance and medical support to manage AEs, IDA has the potential to accelerate LF elimination in India. TRIAL REGISTRATION: Clinical Trial Registry of India (CTRI No/2016/10/007399).

Molecular xenomonitoring as a post-MDA surveillance tool for global programme to eliminate lymphatic filariasis: Field validation in an evaluation unit in India.

BACKGROUND: Lymphatic filariasis (LF) is targeted for elimination by the year 2020. As of 2017, 67 of the 72 endemic countries have implemented annual Mass Drug Administration (MDA) for interrupting LF transmission. Transmission Assessment Survey (TAS) is the recommended protocol to evaluate the impact of MDA and to decide when to stop MDA in an Evaluation Unit (EU, population ≤2 million). As the human infection levels go down with repeated MDA rounds, it becomes a challenge to select the appropriate survey methods to assess transmission interruption. This study validates a standard protocol for molecular xenomonitoring of infection in vectors (MX) at an EU as a complementary tool for TAS to stop MDA and its utility for post-MDA or post-validation surveillance. METHODOLOGY: The study was conducted in Cuddalore district, Tamil Nadu, India, which was found eligible for TAS after 15 annual rounds of MDA (4 with DEC alone and 11 with DEC plus albendazole). The district was divided into two EUs as per the TAS protocol and one EU was randomly selected for the study. A two-stage cluster design vector sampling, developed and validated at a sub-district level, was implemented in 30 randomly selected clusters in the EU. Female Culex quinquefasciatus were collected placing gravid traps overnight (1800-0600 hrs) inside the premises of systematically selected households. Pools of 20-25 blood-fed, semi-gravid and gravid Cx. quinquefasciatus were subjected to real-time quantitative PCR (polymerase chain reaction) assay for detecting Wuchereria bancrofti DNA. Pool infection rate (% of pools positive for W. bancrofti DNA), and the estimated prevalence of W. bancrofti DNA in mosquitoes and its 95% confidence interval were calculated. Additionally, in these 30 clusters, microfilaria (Mf) survey among individuals >5 years old was carried out. School-based TAS was conducted using Immunochromatographic Card Test (ICT) in the EU. Prepared itemized cost-menu for different cost components of MX survey and TAS were estimated and compared. RESULTS: MX survey showed that only 11 (3.1%) of the 358 pools (8850 Cx.quinquefasciatus females), collected from 30 clusters, were found positive for W. bancrofti DNA. The estimated vector infection rate was 0.13% (95% CI: 0.07-0.22%), below the provisional threshold (0.25%) for transmission interruption. Of 1578 children tested in the TAS, only four (0.25%) were positive for filarial antigenemia, and it is well below the critical cut-off (18 positives) for stopping MDA. Among 9804 persons tested in the 30 clusters, only four were found positive for Mf (0.04%; 95% CI: 0.01-0.1%). The Mf-prevalence was <1% threshold for transmission interruption in humans. The estimated costs for TAS and MX per EU were $14,104 USD and $14,259 USD respectively. CONCLUSIONS: The result of MX protocol was in good agreement with that of TAS, providing evidence to recommend MX as a complementary tool to TAS to decide on stopping MDA. MX can also be a potential surveillance tool for post-MDA and post-validation phases as it could detect sites with residual infection and risk of resurgence of transmission. MX is economically feasible as its cost is slightly higher than that of TAS.

Mapping and monitoring for a lymphatic filariasis elimination program: a systematic review.

Lymphatic filariasis (LF) is targeted for elimination by the year 2020. The Global Programme for Elimination of LF (GPELF) aims to achieve elimination by interrupting transmission through annual mass drug administration (MDA) of albendazole with ivermectin or diethylcarbamazine. The program has successfully eliminated the disease in 11 of the 72 endemic countries, putting in enormous efforts on systematic planning and implementation of the strategy. Mapping areas endemic for LF is a pre-requisite for implementing MDA, monitoring and evaluation are the components of programme implementation. This review was undertaken to assess how the mapping and impact monitoring activities have evolved to become more robust over the years and steered the LF elimination programme towards its goal. The findings showed that the WHO recommended mapping strategy aided 17 countries to delimit, plan and implement MDA in only those areas endemic for LF thereby saving resources. Availability of serological tools for detecting infection in humans (antigen/antibody assays) and molecular xenomonitoring (MX) in vectors greatly facilitated programme monitoring and evaluation in endemic countries. Results of this review are discussed on how these existing mapping and monitoring procedures can be used for re-mapping of unsurveyed and uncertain areas to ensure there is no resurgence during post-MDA surveillance. Further the appropriateness of the tests (Microfilaria (Mf)/antigenemia (Ag)/antibody(Ab) surveys in humans or MX of vectors for infection) used currently for post-MDA surveillance and their role in the development of a monitoring and evaluation strategy for the recently WHO recommended triple drug regimen in MDA for accelerated LF elimination are discussed.

The safety of double- and triple-drug community mass drug administration for lymphatic filariasis: A multicenter, open-label, cluster-randomized study.

BACKGROUND: The Global Programme to Eliminate Lymphatic Filariasis (GPELF) provides antifilarial medications to hundreds of millions of people annually to treat filarial infections and prevent elephantiasis. Recent trials have shown that a single-dose, triple-drug treatment (ivermectin with diethylcarbamazine and albendazole [IDA]) is superior to a two-drug combination (diethylcarbamazine plus albendazole [DA]) that is widely used in LF elimination programs. This study was performed to assess the safety of IDA and DA in a variety of endemic settings. METHODS AND FINDINGS: Large community studies were conducted in five countries between October 2016 and November 2017. Two studies were performed in areas with no prior mass drug administration (MDA) for filariasis (Papua New Guinea and Indonesia), and three studies were performed in areas with persistent LF despite extensive prior MDA (India, Haiti, and Fiji). Participants were treated with a single oral dose of IDA (ivermectin, 200 µg/kg; diethylcarbamazine, 6 mg/kg; plus albendazole, a fixed dose of 400 mg) or with DA alone. Treatment assignment in each study site was randomized by locality of residence. Treatment was offered to residents who were ≥5 years of age and not pregnant. Adverse events (AEs) were assessed by medical teams with active follow-up for 2 days and passive follow-up for an additional 5 days. A total of 26,836 persons were enrolled (13,535 females and 13,300 males). A total of 12,280 participants were treated with DA, and 14,556 were treated with IDA. On day 1 or 2 after treatment, 97.4% of participants were assessed for AEs. The frequency of all AEs was similar after IDA and DA treatment (12% versus 12.1%, adjusted odds ratio for IDA versus DA 1.15, 95% CI 0.87-1.52, P = 0.316); 10.9% of participants experienced mild (grade 1) AEs, 1% experienced moderate (grade 2) AEs, and 0.1% experienced severe (grade 3) AEs. Rates of serious AEs after DA and IDA treatment were 0.04% (95% CI 0.01%-0.1%) and 0.01% (95% CI 0.00%-0.04%), respectively. Severity of AEs was not significantly different after IDA or DA. Five of six serious AEs reported occurred after DA treatment. The most common AEs reported were headache, dizziness, abdominal pain, fever, nausea, and fatigue. AE frequencies varied by country and were higher in adults and in females. AEs were more common in study participants with microfilaremia (33.4% versus 11.1%, P < 0.001) and more common in microfilaremic participants after IDA than after DA (39.4% versus 25.6%, P < 0.001). However, there was no excess of severe or serious AEs after IDA in this subgroup. The main limitation of the study was that it was open-label. Also, aggregation of AE data from multiple study sites tends to obscure variability among study sites. CONCLUSIONS: In this study, we observed that IDA was well tolerated in LF-endemic populations. Posttreatment AE rates and severity did not differ significantly after IDA or DA treatment. Thus, results of this study suggest that IDA should be as safe as DA for use as a MDA regimen for LF elimination in areas that currently receive DA. TRIAL REGISTRATION: Clinicaltrials.gov registration number: NCT02899936.

Application of a household-based molecular xenomonitoring strategy to evaluate the lymphatic filariasis elimination program in Tamil Nadu, India.

BACKGROUND: The monitoring and evaluation of lymphatic filariasis (LF) has largely relied on the detection of antigenemia and antibodies in human populations. Molecular xenomonitoring (MX), the detection of parasite DNA/RNA in mosquitoes, may be an effective complementary method, particularly for detecting signals in low-level prevalence areas where Culex is the primary mosquito vector. This paper investigated the application of a household-based sampling method for MX in Tamil Nadu, India. METHODS: MX surveys were conducted in 2010 in two evaluation units (EUs): 1) a hotspot area, defined as sites with community microfilaria prevalence ≥1%, and 2) a larger area that also encompassed the hotspots. Households were systematically selected using a sampling interval proportional to the number of households in the EU. Mosquito pools were collected and analyzed by real-time polymerase chain reaction (qPCR). Two independent samples were taken in each EU to assess reproducibility of results. Follow-up surveys were conducted in 2012. RESULTS: In 2010, the proportion of positive pools in the hotspot EU was 49.3% compared to 23.4% in the overall EU. In 2012, pool positivity was significantly reduced to 24.3% and 6.5%, respectively (p<0.0001). Pool positivity based on independent samples taken from each EU in 2010 and 2012 were not significantly different except for the hotspot EU in 2012 (p = 0.009). The estimated prevalence of infection in mosquitoes, measured by PoolScreen, declined from 2.2-2.7% in 2010 to 0.6-1.2% in 2012 in the hotspot area and from 0.9-1.1% to 0.2-0.3% in the larger area. CONCLUSIONS: The household-based sampling strategy for MX led to mostly reproducible results and supported the observed LF infection trends found in humans. MX has the potential to be a cost-effective, non-invasive monitoring and evaluation tool with sensitive detection of infection signals in low prevalence settings. Further investigation and application of this sampling strategy for MX are recommended to support its adoption as a standardized method for global LF elimination programs.

Delimitation of lymphatic filariasis transmission risk areas: a geo-environmental approach.

BACKGROUND: The Global Programme to Eliminate Lymphatic Filariasis (GPELF) depends upon Mass Drug Administration (MDA) to interrupt transmission. Therefore, delimitation of transmission risk areas is an important step, and hence we attempted to define a geo-environmental risk model (GERM) for determining the areas of potential transmission of lymphatic filariasis. METHODS: A range of geo-environmental variables has been selected, and customized on GIS platform to develop GERM for identifying the areas of filariasis transmission in terms of "risk" and "non-risk". The model was validated through a 'ground truth study' following standard procedure using GIS tools for sampling and Immuno-chromotographic Test (ICT) for screening the individuals. RESULTS: A map for filariasis transmission was created and stratified into different spatial entities, "risk' and "non-risk", depending on Filariasis Transmission Risk Index (FTRI). The model estimation corroborated well with the ground (observed) data. CONCLUSION: The geo-environmental risk model developed on GIS platform is useful for spatial delimitation purpose on a macro scale.