Frequency and clinical significance of localized adverse events following mass drug administration for lymphatic filariasis in an endemic area in South India

Fear of adverse events (AEs) negatively affects compliance to mass drug administration (MDA) for lymphatic filariasis (LF) elimination program. Systemic AEs are believed to occur because of killing of microfilariae, whereas localized soft tissue reactions might be due to the death of adult worms following therapy. Most AEs are mild and self-limited. However, localized AEs are sometimes more significant and of concern to participants. Here, we describe localized AEs that were noted during a large community study that evaluated the safety of a triple-drug regimen (ivermectin, diethylcarbamazine, and albendazole) for the treatment of LF in India. We have also discussed the importance of timely detection and careful management of AEs for preserving community confidence in MDA

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

Application of a Household-Based Molecular Xenomonitoring Strategy to Evaluate the Lymphatic Filariasis Elimination Program in Tamil Nadu, India

Lymphatic filariasis (LF) is one of the world’s foremost debilitating infectious diseases with nearly 800 million people at risk of infection. Given that LF is a mosquito-borne disease, the use of molecular xenomonitoring (MX) to detect parasite DNA/RNA in mosquitoes can serve as a valuable tool for LF monitoring and evaluation, particularly in Culexvector areas. We investigated using MX in a low-level prevalence district of Tamil Nadu, India by applying a household-based sampling strategy to determine trap location sites. Two independent mosquito samples were collected in each of a higher human infection hotspot area (sites with community microfilaria prevalence �1%) and across a larger evaluation area that also encompassed the hotspots. Pooled results showed mostly reproducible outcomes in both settings and a significant higher pool positivity in the hotspot area. A follow-up survey conducted two years later reconfirmed these findings while also showing a reduction in pool positivity and estimated prevalence of infection in mosquitoes in both settings. The utilization of a household-based sampling strategy for MX proved effective and should be further validated in wider epidemiological settings

A multi-center, open-labeled, cluster-randomized study of the safety of double and triple drug community mass drug administration for lymphatic filariasis

BackgroundThe 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 findingsLarge 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 ConclusionsIn 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 registrationClinicaltrials.gov registration number: NCT02899936

Mathematical models for lymphatic filariasis transmission and control: Challenges and prospects

Abstract Background Mathematical models developed for describing the dynamics of transmission, infection, disease and control of lymphatic filariasis (LF) gained momentum following the 1997 World Health Assembly resolution and the launching of the Global Programme to Eliminate Lymphatic Filariasis (GPELF) in 2000. Model applications could provide valuable inputs for making decisions while implementing large scale programmes. However these models need to be evaluated at different epidemiological settings for optimization and fine-tuning with new knowledge and understanding on infection/disease dynamics. Discussion EPIFIL and LYMFASIM are the two mathematical simulation models currently available for lymphatic filariasis transmission and control. Both models have been used for prediction and evaluation of control programmes under research settings. Their widespread application in evaluating large-scale elimination programmes warrants validation of assumptions governing the dynamics of infection and disease in different epidemiological settings. Furthermore, the predictive power of the models for decision support can be enhanced by generating knowledge on some important issues that pose challenges and incorporating such knowledge into the models. We highlight factors related to the efficacy of the drugs of choice, their mode of action, and the possibility that drug resistance may develop; the role of vector-parasite combinations; the magnitude of transmission thresholds; host-parasite interactions and their effects on the dynamics of infection and immunity; parasite biology, and progression to LF-associated disease. Summary The two mathematical models developed offer potential decision making tools for transmission and control of LF. In view of the goals of the GPELF, the predictive power of these models needs to be enhanced for their wide-spread application in large scale programmes. Assimilation and translation of new information into the models is a continuous process for which generation of new knowledge on a number of uncertainties is required. Particularly, a better understanding of the role of immune mechanisms in regulating infection and disease, the (direct or immune mediated) mode of action of current drugs, their effect on adult worms, their efficacy after repeated treatment, and the population genetics of drug resistance are important factors that could make the models more robust in their predictions of the impact of programmes to eliminate LF. However, if these models are to be user-friendly in the hands of programme managers (and not remain as research tools), it would be necessary to identify those factors which can be considered as the minimum necessary inputs/outputs in operational settings for easy evaluation and on-site decision making.</p

Epidemiological assessment of eight rounds of mass drug administration for lymphatic filariasis in India: implications for monitoring and evaluation.

BACKGROUND: Monitoring and evaluation guidelines of the programme to eliminate lymphatic filariasis require impact assessments in at least one sentinel and one spot-check site in each implementation unit (IU). Transmission assessment surveys (TAS) that assess antigenaemia (Ag) in children in IUs that have completed at least five rounds of mass drug administration (MDA) each with >65% coverage and with microfilaria (Mf) levels 70% of 50,363 population. The corresponding values for Ag were 2.3% and 17.3 Ag-units respectively. Ag-prevalence ranged from 0.7 to 0.9%, in children (2-10 years) and 2.7 to 3.0% in adults. Although the Mf-levels in the survey and the sentinel/spot check sites were <1% and Ag-level was <2% in children, we identified 7 "residual" (Mf-prevalence ≥ 1%, irrespective of Ag-status in children) and 17 "transmission" (at least one Ag-positive child born during the MDA period) hotspots. Antigenaemic persons were clustered both at household and site levels. We identified an Ag-prevalence of ~1% in children (equivalent to 0.4% community Mf-prevalence) as a possible threshold value for stopping MDA. CONCLUSIONS/SIGNIFICANCE: Existence of 'hotspots' and spatial clustering of infections in the study area indicate the need for developing good surveillance strategies for detecting 'hotspots', adopting evidence-based sampling strategies and evaluation unit size for TAS

Detection of Wuchereria bancrofti infection in mosquitoes in areas co-endemic with Brugia malayi in Balasore district, Odisha, India

Abstract Lymphatic filariasis (LF) is a crippling and disfiguring parasitic condition. India accounts for 55% of the world’s LF burden. The filarial parasite Wuchereria bancrofti is known to cause 99.4% of the cases while, Brugia malayi accounts for 0.6% of the issue occurring mainly in some pockets of Odisha and Kerala states. The Balasore (Baleswar) district of Odisha has been a known focus of B. malayi transmission. We employed molecular xenomonitoring to detect filarial parasite DNA in vectors. In six selected villages, Gravid traps were used to collect Culex mosquitoes and hand catch method using aspirators was followed for collection of mansonioides. A total of 2903 mosquitoes comprising of Cx. quinquefasciatus (n = 2611; 89.94%), Cx. tritaeniorhynchus (n = 100; 3.44%), Mansonia annuliferea (n = 139; 4.78%) and Mansonia uniformis (n = 53; 1.82%) were collected from six endemic villages. The species wise mosquitoes were made into 118 pools, each with a maximum of 25 mosquitoes, dried and transported to the laboratory at VCRC, Puducherry. The mosquito pools were subjected to parasite DNA extraction, followed by Real-time PCR using LDR and HhaI probes to detect W. bancrofti and B. malayi infections, respectively. Seven pools (6.66%) of Cx. quinquefasciatus, showed infection with only W. bancrofti while none of the pools of other mosquito species showed infection with either W. bancrofti or B. malayi. Although the study area is endemic to B. malayi, none of the vectors of B. malayi was found with parasite infection. This study highlights the ongoing transmission of bancroftian filariasis in the study villages of Balasore district of Odisha and its implications for evaluating LF elimination programme

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