Mini-TAS as a confirmatory mapping tool for remapping areas with uncertain filarial endemicity to exclude/ include for mass drug administration: A report from field validation in India.

India has targeted elimination of lymphatic filariasis (LF) through mass drug administration (MDA) by 2027. Mapping of LF endemic areas is a priority for implementation of MDA. Current national LF remapping tool for unsurveyed/uncertain districts, have many limitations. The WHO has recommended a sensitive and rapid remapping protocol (Mini-TAS), that needs validation in Indian setting. Hence, in the present study a comparative assessment of these two protocols (national protocol vs Mini-TAS) was undertaken in two non-MDA districts of Odisha, with unknown filarial endemicity but reporting chronic cases. Purposive sampling was done in five top sites based on filarial case count as per the national protocol. Random 30 cluster survey was done by conducting school based Mini-TAS, Microfilariae (Mf) survey among adults (>10 years) in villages/wards with schools and Molecular Xenomonitoring (MX) of infection in vectors. Costing by activity and items of the surveys was acomplished using itemized cost menu. In Kalahandi, one of the five purposive sampling sites showed Mf prevalence above threshold (> 1%). But except Mini-TAS neither MX nor house-hold Mf survey among adults could detect the infection above the threshold. While in Balangir, Mf prevalence in all purposive sampling sites,Mini-TAS, Mf prevalence among adult and MX were above the respective thresholds confirming endemicity of LF in the district. The per sample cost of purposive sampling for Mf was the lowest INR 41, followed by adult Mf sampling INR 93. Mini-TAS and MX were expensive with INR 659 and 812 respectively. The study demonstrates that though all the sampling methods could detect filarial infection above the threshold in high-risk areas, Mini-TAS could only detect infection in low-risk areas. Therefore, in the national programme Mini-TAS can be used as a decision-making tool to determine whether to exclude/ include a district having uncertain endemicity for MDA.

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.

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 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.

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.

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.

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.

Detection of Chikungunya virus in wild populations of Aedes albopictus in Kerala State, India.

We detected Chikungunya virus (CHIKV) infection among wild populations of Aedes albopictus female specimens during the CHIKV outbreaks of 2009 and 2006 collected in different localities in Kerala State, India. The envelope 1 gene (E1) sequences of the virus isolate 2009 from the mosquito species showed close genetic relatedness (Kimura 2 Parameter genetic distance=0.0013) to CHIKV-positive isolates from human serum samples from the same area. E1 gene sequences from Ae. albopictus, as well as from human isolates, had the crucial non-synonymous C/T mutation at position 10670, leading to the A226V amino acid change. This natural inclination indicated the role of this mosquito species in the transmission of CHIKV during its recent outbreaks in Kerala State.

Diurnal pattern of human-biting activity and transmission of subperiodic Wuchereria bancrofti (Filariidea: Dipetalonematidae) by Ochlerotatus niveus (Diptera: Culicidae) on the Andaman and Nicobar islands of India.

We monitored diel-landing periodicity (biting activity/cycle) of Ochlerotatus niveus and the infection/infectivity pattern through human-landing collections on Teressa Island, which is remotely located in the Nicobar district of the Andaman and Nicobar group of Islands of India, for a period of one year. The biting activity was seen throughout the day, exhibiting a bimodal peak, the first at dawn (4:00-6:00 AM) and the other towards dusk (5:00-6:00 PM). This pattern was similar during all the seasons of the year. Peak biting hours of Oc. niveus coincides with the peak appearance of microfilariae. Overall infection and infectivity rates were 2.65% and 0.5%, respectively. Perennial transmission is evident from the records of vectors with parasites (infection), including infective larvae in all months of the year, although no infective mosquitoes were recorded at a few points. The risk of transmission of filariasis based on parity status of Oc. niveus was maximal at dusk (5:00-6:00 PM) in this region. The issue of control with respect to reducing human-vector contact is discussed.