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.

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.

Country Reports on Practical Aspects of Conducting Large-Scale Community Studies of the Tolerability of Mass Drug Administration with Ivermectin/Diethylcarbamazine/Albendazole for Lymphatic Filariasis.

This article is a compilation of summaries prepared by lead investigators for large-scale safety and efficacy studies on mass drug administration of IDA (ivermectin, diethylcarbamazine, and albendazole) for lymphatic filariasis. The summaries highlight the experiences of study teams that assessed the safety and efficacy of IDA in five countries: India, Indonesia, Haiti, Papua New Guinea, and Fiji. They also highlight significant challenges encountered during these community studies and responses to those challenges that contributed to success.

Multi-centric evaluation of a stage-specific reverse transcriptase-polymerase chain reaction assay as a xenomonitoring tool for the detection of infective (L3) stage Wuchereria bancrofti in vectors.

Background & objectives: An infective stage specific reverse transcriptase-polymerase chain reaction (RT-PCR) assay utilizing the abundant larval transcript-3 (Alt-3) gene of Wuchereria bancrofti was developed at ICMR-VCRC, Puducherry and found to be stage specific, and sensitive upon validation in the laboratory. This study was aimed at independently evaluating this assay for its utility as a monitoring/surveillance tool in the operational programme for elimination of lymphatic filariasis (LF) by four national research laboratories. Methods: Evaluation of the assay was carried out in a multi-centric mode in three phases. In phase I, a workshop was conducted to impart hands-on training to the scientists from the collaborating centres on the RT-PCR assay and in Phase II the assay was evaluated for specificity and sensitivity in detecting the infective (L3) stage larvae of W. bancrofti in its vector, Culex quinquefasciatus, using 50 coded pooled samples. Phase III evaluation was done on wild-caught mosquito vectors from selected endemic areas of Assam and Bhubaneswar States and Andaman Nicobar islands. Results: Phase I data indicated that the assay was able to detect all the pools of mosquito samples contaning L3 stage larvae of W. bancrofti as positive, even in the presence of other vector stages of the parasite indicating its stage specificity (100%). The assay was found highly sensitive (100%), detecting all the infected pools as positive and specific detecting all uninfected pools as negative. The results of phase II showed inter-laboratory variation. Phase III evaluation from all the centres suggested that the infectivity rate determined for pooled mosquitoes by the RT-PCR assay (0.5%) was comparable to that by dissection method (1.2%) (95% confidence interval overlaps). Interpretation & conclusions: Overall, the results from three of the four participating centres indicated that the assay is at least as sensitive and stage specific as the conventional mosquito dissection technique, and hence, may be useful as a xenomonitoring tool for Transmission Assessment Survey in Mass Drug Administration programmes for LF.

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).

Heterogeneous response of Wuchereria bancrofti-infected persons to diethylcarbamazine (DEC) and its implications for the Global Programme to Eliminate Lymphatic Filariasis (GPELF).

DEC or ivermectin (IVM) in combination with albendazole (ALB) has been the recommended strategy of the Global Programme to Eliminate Lymphatic Filariasis (GPELF) since 2000. Despite effective population coverage (> 65%) with several rounds of MDA with DEC or combination of DEC plus ALB, microfilariae persist in few individuals and they continue to be the source of infection for transmitting LF. We report an individual's variability in response to DEC by defining the response as complete absence of microfilaria (mf) (post-treatment mf count = 0) and non-response as presence of mf (post-treatment mf count ≥ 1). We analyzed follow-up data on individual's response to treatment from two randomized clinical trials in which 46 microfilaremic individuals were treated with single-dose DEC (6 mg/kg body weight). They were classified into low, medium, and high mf density categories based on their pre-treatment mf counts. Of the 46 individuals, 65.2% have not responded throughout the 12-month post-treatment period. Application of a logistic regression model with fixed (age, gender, mf density, post-treatment time, and their interactions) and random (individual's response over time) effects indicated that treatment response is independent of age, gender, and time. The overall treatment response increases in low and decreases in high mf density categories. Furthermore, the estimates for the random coefficients model showed that there is a greater variability in response between individuals over post-treatment time. The results substantiate that individual variation in response to DEC exists which indicate the importance of studying the parasite as well as host genetic factors associated with DEC action.

Efficacy evaluation of Veeralin LN, a PBO-incorporated alpha-cypermethrin long-lasting insecticidal net against Anopheles culicifacies in experimental huts in Odisha State.

BACKGROUND: The success of malaria control using long-lasting insecticidal nets (LLINs) is threatened by pyrethroid resistance developed by the malaria vectors, worldwide. To combat the resistance, synergist piperonyl butoxide (PBO) incorporated LLINs is one of the available options. In the current phase II hut trial, the efficacy of Veeralin®LN (an alpha-cypermethrin and PBO-incorporated net) was evaluated against Anopheles culicifacies, a pyrethroid resistant malaria vector. METHODS: The performance of Veeralin®LN was compared with MAGNet®LN and untreated net in reducing the entry, induced exit, mortality and blood feeding inhibition of target vector species. RESULTS: The performance of Veeralin was equal to MAGNet in terms of reducing hut entry, inhibiting blood feeding and inducing exophily, and with regard to causing mortality Veeralin was better than MAGNet. When compared to untreated net, a significant reduction in hut entry and blood feeding and an increase in exophily and mortality were observed with Veeralin. In cone bioassays, unwashed Veeralin caused > 80% mortality of An. culicifacies. CONCLUSIONS: Veeralin performed equal to (entry, exit, feeding) or better than (mortality in huts and cone bioassays) MAGNet and could be an effective tool against pyrethroid resistant malaria vectors.

Molecular xenomonitoring of diurnally subperiodic Wuchereria bancrofti infection in Aedes (Downsiomyia) niveus (Ludlow, 1903) after nine rounds of Mass Drug Administration in Nancowry Islands, Andaman and Nicobar Islands, India.

A group of four human inhabited Nancowry Islands in Nicobar district in the Andaman and Nicobar Islands, India having a population of 7674 is the lone focus of diurnally sub-periodic Wuchereria bancrofti (DspWB) that is transmitted by Aedes niveus (Ludlow). Microfilaria (Mf) prevalence was above 1% even after nine rounds of Mass Drug Administration (MDA) with DEC and albendazole. Molecular xenomonitoring (MX) was conducted to identify appropriate vector sampling method and assess the impact. BioGents Sentinel traps, gravid traps and human baited double bed nettraps were used in three locations in each village to collect Aedes niveus female mosquitoes. Subsequently daytime man landing collections (MLC) were carried out in all the 25 villages in the islands. Collections were compared in terms of the number of vector mosquitoes captured per trap collection. Females of Ae. niveus were pooled, dried and processed for detecting filarial parasite DNA using RT-PCR assay. Vector infection rate was estimated using PoolScreen software. Only 393 female mosquitoes including 44 Ae. niveus (11.2%) were collected from 459 trap collections using three trapping devices. From 151 MLCs, 2170 Ae. niveus female mosquitoes were collected. The average prevalence of W. bancrofti DNA was 0.43%. Estimated upper 95% CI exceeded the provisional prevalence threshold of 0.1% in all the villages, indicating continued transmission as observed in Mf survey. MLCs could be the choice, for now, to sample Ae. niveus mosquitoes. The PCR assay used in MX for nocturnally periodic bancroftian filariasis could be adopted for DspWB. The vector-parasite MX, can be used to evaluate interventions in this area after further standardization of the protocol.

A spatio-temporal approach to short-term prediction of visceral leishmaniasis diagnoses in India.

BACKGROUND: The elimination programme for visceral leishmaniasis (VL) in India has seen great progress, with total cases decreasing by over 80% since 2010 and many blocks now reporting zero cases from year to year. Prompt diagnosis and treatment is critical to continue progress and avoid epidemics in the increasingly susceptible population. Short-term forecasts could be used to highlight anomalies in incidence and support health service logistics. The model which best fits the data is not necessarily most useful for prediction, yet little empirical work has been done to investigate the balance between fit and predictive performance. METHODOLOGY/PRINCIPAL FINDINGS: We developed statistical models of monthly VL case counts at block level. By evaluating a set of randomly-generated models, we found that fit and one-month-ahead prediction were strongly correlated and that rolling updates to model parameters as data accrued were not crucial for accurate prediction. The final model incorporated auto-regression over four months, spatial correlation between neighbouring blocks, and seasonality. Ninety-four percent of 10-90% prediction intervals from this model captured the observed count during a 24-month test period. Comparison of one-, three- and four-month-ahead predictions from the final model fit demonstrated that a longer time horizon yielded only a small sacrifice in predictive power for the vast majority of blocks. CONCLUSIONS/SIGNIFICANCE: The model developed is informed by routinely-collected surveillance data as it accumulates, and predictions are sufficiently accurate and precise to be useful. Such forecasts could, for example, be used to guide stock requirements for rapid diagnostic tests and drugs. More comprehensive data on factors thought to influence geographic variation in VL burden could be incorporated, and might better explain the heterogeneity between blocks and improve uniformity of predictive performance. Integration of the approach in the management of the VL programme would be an important step to ensuring continued successful control.

Evaluation of DawaPlus 3.0 and DawaPlus 4.0, deltamethrin-PBO combination nets against pyrethroid-resistant Anopheles culicifacies in experimental huts in India.

BACKGROUND: The development of resistance in vectors is one of the major impediments for malaria control. Adding synergists to insecticides has proven to be an alternative choice for controlling resistant mosquitoes. DawaPlus 3.0 and DawaPlus 4.0 are new long-lasting insecticidal nets (LLINs) in which deltamethrin and a synergist, piperonyl butoxide (PBO) are added into filaments and their efficacy was tested against resistant malaria vector, Anopheles culicifacies in experimental huts in India. METHODS: The performance of two trial nets in terms of deterrence induced exiting, blood-feeding inhibition and mortality of An. culicifacies was compared with DawaPlus 2.0 and untreated net. RESULTS: There was a significant reduction in entry, blood feeding and mortality (p < 0.05) and increase in exit rates of An. culicifacies in the treatment arms compared to untreated arm. But, both candidate LNs washed 20 times could not perform better than the washed reference net (DawaPlus 2.0). Cone bioassay results showed that all the treatment arms (both washed and unwashed) produced < 80% mortality of An. culicifacies before and after hut evaluation. CONCLUSIONS: DawaPlus 3.0 and DawaPlus 4.0 with their current specification may not be as effective as required to control the resistant vector, An. culicifacies, in east-central India.

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.

Dosing pole recommendations for lymphatic filariasis elimination: A height-weight quantile regression modeling approach.

BACKGROUND: The World Health Organization (WHO) currently recommends height or age-based dosing as alternatives to weight-based dosing for mass drug administration lymphatic filariasis (LF) elimination programs. The goals of our study were to compare these alternative dosing strategies to weight-based dosing and to develop and evaluate new height-based dosing pole scenarios. METHODOLOGY/PRINCIPAL FINDINGS: Age, height and weight data were collected from >26,000 individuals in five countries during a cluster randomized LF clinical trial. Weight-based dosing for diethylcarbamazine (DEC; 6 mg/kg) and ivermectin (IVM; 200 ug/kg) with tablet numbers derived from a table of weight intervals was treated as the "gold standard" for this study. Following WHO recommended age-based dosing of DEC and height-based dosing of IVM would have resulted in 32% and 27% of individuals receiving treatment doses below those recommended by weight-based dosing for DEC and IVM, respectively. Underdosing would have been especially common in adult males, who tend to have the highest LF prevalence in many endemic areas. We used a 3-step modeling approach to develop and evaluate new dosing pole cutoffs. First, we analyzed the clinical trial data using quantile regression to predict weight from height. We then used weight predictions to develop new dosing pole cutoff values. Finally, we compared different dosing pole cutoffs and age and height-based WHO dosing recommendations to weight-based dosing. We considered hundreds of scenarios including country- and sex-specific dosing poles. A simple dosing pole with a 6-tablet maximum for both DEC and IVM reduced the underdosing rate by 30% and 21%, respectively, and was nearly as effective as more complex pole combinations for reducing underdosing. CONCLUSIONS/SIGNIFICANCE: Using a novel modeling approach, we developed a simple dosing pole that would markedly reduce underdosing for DEC and IVM in MDA programs compared to current WHO recommended height or age-based dosing.

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.

Bio-efficacy of LifeNet, a deltamethrin incorporated long-lasting insecticidal net, as assessed in experimental huts against Anopheles fluviatilis, a major malaria vector in east-central India.

LifeNet, a deltamethrin incorporated long-lasting insecticidal (polypropylene) net (LLIN), was qualified by the World Health Organization Pesticide Evaluation Scheme (WHOPES) for Phase-II trial in India. The purpose of this trial was to assess the bio-efficacy of unwashed and 20 and 30 times washed LifeNet in comparison to the nets conventionally treated with deltamethrin against the natural population of Anopheles fluviatilis, a major malaria vector, in terms of deterring hut entry, inhibiting blood feeding, inducing exophily and causing mortality. The trial was carried out in six experimental huts constructed at Kandhaguda village in Malkangiri district, Odisha State. The efficacy of unwashed and washed (20 or 30 times) LifeNet was compared with untreated polypropylene and conventionally treated (with deltamethrin) polyester net washed to just before exhaustion or washed 20 times. The study showed a significant reduction of entry (treatment: 1.61-4.78; control: 7.61 per hut) and an increase in exit (50.7-64.4% and 39.1%) of An. fluviatilis in the treated arms compared to the control arm (untreated net) (P < 0.05). Blood feeding rates reduced in treated arms (20.7-68.0%) compared to the control (80.3%) (P < 0.05). Total mortality was significantly higher in LifeNet arms (73.8-98.3%) than the control (2.2%) (P < 0.05). After 30 washes, the active ingredient (AI) retention in LifeNet was 62%. Performance of the three LifeNet arms against the susceptible population of An. fluviatilis met the WHO efficacy criteria of Phase II evaluation for LLINs.

Validating the Association of Japanese Encephalitis Vector Abundance with Paddy Growth, Using MODIS Data.

Japanese encephalitis (JE) is one of the leading causes of viral encephalitis in Southeast Asia, particularly India. The major vector transmitting the disease, Culex tritaeniorhynchus, breeds in paddy field and its associated water bodies. The incidence of human infection usually occurs after the peak in vector abundance. Earlier, an association between JE vector abundance and paddy growth was demonstrated in Bellary district of Karnataka state, India, using radar satellite (RISAT 1) data. In this study, an attempt has been made to validate this phenomenon with the data collected from Uttar Pradesh state, using moderate resolution imaging spectroradiometer data.

Are Alternative Strategies Required to Accelerate the Global Elimination of Lymphatic Filariasis? Insights From Mathematical Models.

Background: With the 2020 target year for elimination of lymphatic filariasis (LF) approaching, there is an urgent need to assess how long mass drug administration (MDA) programs with annual ivermectin + albendazole (IA) or diethylcarbamazine + albendazole (DA) would still have to be continued, and how elimination can be accelerated. We addressed this using mathematical modeling. Methods: We used 3 structurally different mathematical models for LF transmission (EPIFIL, LYMFASIM, TRANSFIL) to simulate trends in microfilariae (mf) prevalence for a range of endemic settings, both for the current annual MDA strategy and alternative strategies, assessing the required duration to bring mf prevalence below the critical threshold of 1%. Results: Three annual MDA rounds with IA or DA and good coverage (≥65%) are sufficient to reach the threshold in settings that are currently at mf prevalence <4%, but the required duration increases with increasing mf prevalence. Switching to biannual MDA or employing triple-drug therapy (ivermectin, diethylcarbamazine, and albendazole [IDA]) could reduce program duration by about one-third. Optimization of coverage reduces the time to elimination and is particularly important for settings with a history of poorly implemented MDA (low coverage, high systematic noncompliance). Conclusions: Modeling suggests that, in several settings, current annual MDA strategies will be insufficient to achieve the 2020 LF elimination targets, and programs could consider policy adjustment to accelerate, guided by recent monitoring and evaluation data. Biannual treatment and IDA hold promise in reducing program duration, provided that coverage is good, but their efficacy remains to be confirmed by more extensive field studies.

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.

Predicting lymphatic filariasis transmission and elimination dynamics using a multi-model ensemble framework.

Mathematical models of parasite transmission provide powerful tools for assessing the impacts of interventions. Owing to complexity and uncertainty, no single model may capture all features of transmission and elimination dynamics. Multi-model ensemble modelling offers a framework to help overcome biases of single models. We report on the development of a first multi-model ensemble of three lymphatic filariasis (LF) models (EPIFIL, LYMFASIM, and TRANSFIL), and evaluate its predictive performance in comparison with that of the constituents using calibration and validation data from three case study sites, one each from the three major LF endemic regions: Africa, Southeast Asia and Papua New Guinea (PNG). We assessed the performance of the respective models for predicting the outcomes of annual MDA strategies for various baseline scenarios thought to exemplify the current endemic conditions in the three regions. The results show that the constructed multi-model ensemble outperformed the single models when evaluated across all sites. Single models that best fitted calibration data tended to do less well in simulating the out-of-sample, or validation, intervention data. Scenario modelling results demonstrate that the multi-model ensemble is able to compensate for variance between single models in order to produce more plausible predictions of intervention impacts. Our results highlight the value of an ensemble approach to modelling parasite control dynamics. However, its optimal use will require further methodological improvements as well as consideration of the organizational mechanisms required to ensure that modelling results and data are shared effectively between all stakeholders.

Effectiveness of a triple-drug regimen for global elimination of lymphatic filariasis: a modelling study.

BACKGROUND: Lymphatic filariasis is targeted for elimination as a public health problem by 2020. The principal approach used by current programmes is annual mass drug administration with two pairs of drugs with a good safety profile. However, one dose of a triple-drug regimen (ivermectin, diethylcarbamazine, and albendazole) has been shown to clear the transmissible stage of the helminth completely in treated individuals. The aim of this study was to use modelling to assess the potential value of mass drug administration with the triple-drug regimen for accelerating elimination of lymphatic filariasis in different epidemiological settings. METHODS: We used three different transmission models to compare the number of rounds of mass drug administration needed to achieve a prevalence of microfilaraemia less than 1% with the triple-drug regimen and with current two-drug regimens. FINDINGS: In settings with a low baseline prevalence of lymphatic filariasis (5%), the triple-drug regimen reduced the number of rounds of mass drug administration needed to reach the target prevalence by one or two rounds, compared with the two-drug regimen. For areas with higher baseline prevalence (10-40%), the triple-drug regimen strikingly reduced the number of rounds of mass drug administration needed, by about four or five, but only at moderate-to-high levels of population coverage (>65%) and if systematic non-adherence to mass drug administration was low. INTERPRETATION: Simulation modelling suggests that the triple-drug regimen has potential to accelerate the elimination of lymphatic filariasis if high population coverage of mass drug administration can be achieved and if systematic non-adherence with mass drug administration is low. Future work will reassess these estimates in light of more clinical trial data and to understand the effect on an individual country's programme. FUNDING: Bill & Melinda Gates Foundation.