How Does the Proportion of Never Treatment Influence the Success of Mass Drug Administration Programs for the Elimination of Lymphatic Filariasis?

BACKGROUND: Mass drug administration (MDA) is the cornerstone for the elimination of lymphatic filariasis (LF). The proportion of the population that is never treated (NT) is a crucial determinant of whether this goal is achieved within reasonable time frames. METHODS: Using 2 individual-based stochastic LF transmission models, we assess the maximum permissible level of NT for which the 1% microfilaremia (mf) prevalence threshold can be achieved (with 90% probability) within 10 years under different scenarios of annual MDA coverage, drug combination and transmission setting. RESULTS: For Anopheles-transmission settings, we find that treating 80% of the eligible population annually with ivermectin + albendazole (IA) can achieve the 1% mf prevalence threshold within 10 years of annual treatment when baseline mf prevalence is 10%, as long as NT <10%. Higher proportions of NT are acceptable when more efficacious treatment regimens are used. For Culex-transmission settings with a low (5%) baseline mf prevalence and diethylcarbamazine + albendazole (DA) or ivermectin + diethylcarbamazine + albendazole (IDA) treatment, elimination can be reached if treatment coverage among eligibles is 80% or higher. For 10% baseline mf prevalence, the target can be achieved when the annual coverage is 80% and NT ≤15%. Higher infection prevalence or levels of NT would make achieving the target more difficult. CONCLUSIONS: The proportion of people never treated in MDA programmes for LF can strongly influence the achievement of elimination and the impact of NT is greater in high transmission areas. This study provides a starting point for further development of criteria for the evaluation of NT.

A Landscape on Lymphatic Filariasis with its Effects and Recent Advanced Treatments.

Lymphatic filariasis is an infection caused by parasites that poses a significant health, social, and economic burden, affecting a vast population that exceeds 120 million individuals globally. The Etiology of the infection is attributed to three nematode parasites, namely Wuchereria bancrofti, B. timori, and Brugia malayi, as well as which are phylogenetically related. These parasites are transmitted to humans via mosquitoes belonging to the Anopheles, Aedes genera, and Culex. As per the estimation provided by the WHO, the current number of individuals infected with filariasis stands at approximately 120 million across 81 countries. Furthermore, it is estimated that around 1.34 billion individuals reside in regions that are endemic to filariasis, thereby putting them at risk of contracting the disease. Different synthetic drugs such as Ivermectin, Doxycycline, Albendazole, and Suramin are used in the treatment. Some natural plants are Azadirachta indica, Tinospora cordifolia, Zingiber officinal, as well as, some marine sources are also included for better treatment. We also touch briefly on a few additional filarial diseases. Although there are only a few medications available to treat filariasis, their frequent usage may result in drug resistance. Furthermore, there is no effective vaccination for the treatment of filariasis. Due to these restrictions, it has been crucial to create new anti-filarial medications, which motivates researchers to find novel pharmaceuticals with anti-filarial action. In this article, we examine the latest achievements in the anti-filarial area, including the many forms of filariasis and their historical contexts, elimination programmes, various therapeutic classes (both synthetic and natural), investigated product-derived targets as well as clinical investigations.

Safety and efficacy of mass drug administration with a single-dose triple-drug regimen of albendazole + diethylcarbamazine + ivermectin for lymphatic filariasis in Papua New Guinea: An open-label, cluster-randomised trial.

BACKGROUND: Papua New Guinea (PNG) has a high burden of lymphatic filariasis (LF) caused by Wuchereria bancrofti, with an estimated 4.2 million people at risk of infection. A single co-administered dose of ivermectin, diethylcarbamazine and albendazole (IDA) has been shown to have superior efficacy in sustained clearance of microfilariae compared to diethylcarbamazine and albendazole (DA) in small clinical trials. A community-based cluster-randomised trial of DA versus IDA was conducted to compare the safety and efficacy of IDA and DA for LF in a moderately endemic, treatment-naive area in PNG. METHODOLOGY: All consenting, eligible residents of 24 villages in Bogia district, Madang Province, PNG were enrolled, screened for W. bancrofti antigenemia and microfilaria (Mf) and randomised to receive IDA (N = 2382) or DA (N = 2181) according to their village of residence. Adverse events (AE) were assessed by active follow-up for 2 days and passive follow-up for an additional 5 days. Antigen-positive participants were re-tested one year after MDA to assess treatment efficacy. PRINCIPAL FINDINGS: Of the 4,563 participants enrolled, 96% were assessed for AEs within 2 days after treatment. The overall frequency of AEs were similar after either DA (18%) or IDA (20%) treatment. For those individuals with AEs, 87% were mild (Grade 1), 13% were moderate (Grade 2) and there were no Grade 3, Grade 4, or serious AEs (SAEs). The frequency of AEs was greater in Mf-positive than Mf-negative individuals receiving IDA (39% vs 20% p<0.001) and in Mf-positive participants treated with IDA (39%), compared to those treated with DA (24%, p = 0.023). One year after treatment, 64% (645/1013) of participants who were antigen-positive at baseline were re-screened and 74% of these participants (475/645) remained antigen positive. Clearance of Mf was achieved in 96% (52/54) of infected individuals in the IDA arm versus 84% (56/67) of infected individuals in the DA arm (relative risk (RR) 1.15; 95% CI, 1.02 to 1.30; p = 0.019). Participants receiving DA treatment had a 4-fold higher likelihood of failing to clear Mf (RR 4.67 (95% CI: 1.05 to 20.67; p = 0.043). In the DA arm, a significant predictor of failure to clear was baseline Mf density (RR 1.54; 95% CI, 1.09 to 2.88; p = 0.007). CONCLUSION: IDA was well tolerated and more effective than DA for clearing Mf. Widespread use of this regimen could accelerate LF elimination in PNG. TRIAL REGISTRATION: Registration number NCT02899936; https://clinicaltrials.gov/ct2/show/NCT02899936.

Lymphatic filariasis, infection status in Culex quinquefasciatus and Anopheles species after six rounds of mass drug administration in Masasi District, Tanzania.

BACKGROUND: Lymphatic filariasis (LF) elimination program in Tanzania started in 2000 in response to the Global program for the elimination of LF by 2020. Evidence shows a persistent LF transmission despite more than a decade of mass drug administration (MDA). It is advocated that, regular monitoring should be conducted in endemic areas to evaluate the progress towards elimination and detect resurgence of the disease timely. This study was therefore designed to assess the status of Wuchereria bancrofti infection in Culex quinqefasciatus and Anopheles species after six rounds of MDA in Masasi District, South Eastern Tanzania. METHODS: Mosquitoes were collected between June and July 2019 using Center for Diseases Control (CDC) light traps and gravid traps for indoor and outdoor respectively. The collected mosquitoes were morphologically identified into respective species. Dissections and PCR were carried out to detect W. bancrofti infection. Questionnaire survey and checklist were used to assess vector control interventions and household environment respectively. A Poisson regression model was run to determine the effects of household environment on filarial vector density. RESULTS: Overall, 12 452 mosquitoes were collected of which 10 545 (84.7%) were filarial vectors. Of these, Anopheles gambiae complex, An. funestus group and Cx. quinquefasciatus accounted for 0.1%, 0.7% and 99.2% respectively. A total of 365 pools of Cx. quinquefasciatus (each with 20 mosquitoes) and 46 individual samples of Anopheles species were analyzed by PCR. For Cx. quinquefasciatus pools, 33 were positive for W. bancrofti, giving an infection rate of 0.5%, while the 46 samples of Anopheles species were all negative. All 1859 dissected mosquitoes analyzed by microscopy were also negative. Households with modern latrines had less mosquitoes than those with pit latrines [odds ratio (OR) = 0.407, P < 0.05]. Houses with unscreened windows had more mosquitoes as compared to those with screened windows (OR = 2.125, P < 0.05). More than 80% of the participants own bednets while 16.5% had no protection. CONCLUSIONS: LF low transmission is still ongoing in Masasi District after six rounds of MDA and vector control interventions. The findings also suggest that molecular tools may be essential for xenomonitoring LF transmission during elimination phase.

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.

Implementation challenges and opportunities for improved mass treatment uptake for lymphatic filariasis elimination: Perceptions and experiences of community drug distributors of coastal Kenya.

Community drug distributors (CDDs) who are volunteers have the responsibility of awareness creation, household census, drug distribution and record-keeping and are thus key stakeholders in the campaign for Lymphatic Filariasis (LF) elimination. Taking into account their experiences and perceptions is important for a successful elimination campaign. We conducted a qualitative study in 2018 to identify implementation challenges and opportunities for improved mass drug administration (MDA) uptake based on the CDDs perceptions and experiences. Within a larger study that used mixed methods quasi-experimental design, we collected qualitative data from two wards in Kaloleni Sub-County of Kilifi County which was purposively selected owing to its low, 56% and 50.5% treatment coverage in 2015 and 2016 respectively. Focus group discussions (FGDs) (n = 8) and in-depth interviews (IDIs) (n = 8) with CDDs, IDIs (n = 22) with opinion leaders and IDIs (n = 8) with health workers were conducted and the data analyzed by QSR NVIVO version 10 according to thematic areas. The results showed that based on the perceptions and experiences of the CDDs, several challenges: communities' refusal to take the drugs; absenteeism during MDA; non-adherence to CDDs selection criteria; inadequacy in number of CDDs engaged during the campaign and training provided; insufficiency of drugs issued to CDDs; lack of CDDs supervision and low motivation negatively impact on MDA uptake. Opportunities to address the challenges included: awareness creation on MDA, health education on LF and observation of hygiene during drug administration, increased duration of awareness creation and drug administration, adherence to CDDs selection criteria and putting into consideration the vastness of an area and population density while deploying CDDs. Other opportunities include: improved CDDs training and scheduling; issuing of enough drugs to CDDs to meet the communities' demand and improved supervision and motivation of CDDs. Addressing the challenges highlighted is an important step of maximizing MDA uptake. The opportunities presented need to be considered by the NTD program personnel, the county health personnel and the community while planning the implementation of MDA campaigns.

The impact of four years of semiannual treatments with albendazole alone on lymphatic filariasis and soil-transmitted helminth infections: A community-based study in the Democratic Republic of the Congo.

BACKGROUND: The World Health Organization now recommends semiannual mass drug administration (MDA) of albendazole with integrated vector management as an option for eliminating lymphatic filariasis (LF) in areas of loiasis-endemic countries where it may not be safe to use diethylcarbamazine or ivermectin in MDA programs. However, the published evidence base to support this policy is thin, and uptake by national programs has been slow. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a community trial to assess the impact of semiannual MDA on lymphatic filariasis and soil-transmitted helminth infections (STH) in two villages in the Bandundu province of the Democratic Republic of the Congo with moderately high prevalences for LF and hookworm infections. MDA with albendazole was provided every six months from June 2014 to December 2017 with treatment coverages of the eligible population (all ≥ 2 year of age) that ranged between 56% and 88%. No adverse effects were reported during the trial. Evaluation at 48 months, (i.e. 6 months after the 8th round of MDA), showed that W. bancrofti microfilaremia (Mf) prevalence in the study communities had decreased between 2014 to 2018 from 12% to 0.9% (p<0.001). The prevalence of W. bancrofti antigenemia was also significantly reduced from 31.6% to 8.5% (p<0.001). MDA with albendazole also reduced hookworm, Ascaris lumbricoides and Trichuris trichiura infection prevalences in the community from 58.6% to 21.2% (p<0.001), from 14.0% to 1.6% and 4.1% to 2.9%, respectively. Hookworm and Ascaris infection intensities were reduced by 93% (p = 0.02) and 57% (p = 0.03), respectively. In contrast, Trichuris infection intensity was not significantly reduced by MDA (p = 0.61) over this time period. CONCLUSION/SIGNIFICANCE: These results provide strong evidence that semiannual MDA with albendazole alone is a safe and effective strategy for LF elimination in Central Africa. Community MDA also had a major impact on STH infections.

Elimination of diurnally sub-periodic Wuchereria bancrofti in Andaman and Nicobar Islands, India, using mass DEC-fortified salt as a supplementary intervention to MDA.

Feasibility of implementing a DEC-fortified (DEC at 0.2% w/w and iodine) salt strategy to hasten elimination of diurnally sub-periodic Wuchereria bancrofti (DspWB) from the lone foci in Nancowry islands, Nicobar district, India, was assessed. This is a two-arm community-based study: one arm (12 villages, population 2936) received double fortified salt along with annual mass drug administration (MDA) of DEC plus albendazole (DEC-salt+MDA-arm), and another (14 villages; population 4840) received MDA under the National Filaria Elimination Programme. DEC salt was distributed on camp mode supplemented by door delivery. Monthly survey was carried out in fixed and random households to assess the coverage, usage of DEC salt and DEC content. The impact on prevalence of mf at community level and antigenaemia among children was assessed. A total of 21 metric tonnes of free-flow DEC salt manufactured by Tamil Nadu Salt Corporation, India, was distributed for 1 year. In the DEC-salt+MDA-arm, > 90% of the households received and used the DEC salt. DEC was within therapeutic range (0.2-0.32% w/w) in the samples collected from kitchens. Community mf prevalence reduced from 2.27 to 0.14% in the DEC-salt-arm (< 1% in all the villages) and 1.26 to 0.74% (> 1% in 4 out of 14 villages) in the MDA-arm. Ag prevalence reduced to zero from 1.0 (DEC-salt+MDA-arm) and 6.3% (MDA-arm) in 2-3 years old, 1.2 and 3.6% from 2.9 in the DEC-salt-arm and 4.5% in the MDA-arm among 6-7 years old. It was feasible to deliver DEC-fortified salt covering > 90% of the households with compliance reaching the elimination target in the islands.

Isolated Epitrochlear Filarial Lymphadenopathy: Cytomorphological Diagnosis of an Unusual Presentation.

Filariasis is a major public health problem in tropical countries like India. Despite the large number of people at risk, detection of eggs with or without larva (microfilaria) on fine-needle aspiration cytology is very unusual, especially in an uncommon site or incidentally detected in clinically unsuspected cases of filariasis with the absence of microfilariae in the peripheral blood. A 19-year-old male presented with swelling over medial aspect of left arm (just above the elbow), with no other specific signs and symptoms. Fine needle aspiration cytology revealed an adult gravid female filarial worm in a background of reactive lymphoid cells and lymphohistiocytic clusters. We report a case with elaborate fine needle aspiration cytology findings of filarial worm infestation with unusual presentation of isolated epitrochlear lymph node involvement in a clinically unsuspected case and recommend clinicians and pathologists to consider a high index of suspicion for such infections at uncommon sites especially in endemic territories, as early diagnosis and treatment prevent the more severe manifestations of disease.

Elimination of lymphatic filariasis as a public health problem from the Arab Republic of Egypt.

Lymphatic filariasis (LF) has been known in Egypt since ancient times. By 1930s it was recognized to be a major public health problem in the Nile Delta, and to be caused by Wuchereria bancrofti and transmitted by Culex pipiens. Remarkably, as a result of widespread DEC treatment and intensive vector control by the Ministry of Health and Population (MoHP), the infection rate of LF declined in the 1960s. However, relaxation of these efforts resulted in resurgence of filariasis in the 1980s and 1990s. In 2000, Egypt was among the first countries to join the WHO global efforts to eliminate LF as a public health problem by initiating a national LF elimination programme (NLFEP). This article reviews the history of LF control activities and summarizes the NLFEP extensive interventions to eliminate LF in Egypt. Based on MoHP data, mass drug administration (MDA) with DEC and ALB was started in 2000 in 161 implementation units (IUs). Additional IUs were included in subsequent MDA rounds, with the last IU included in 2007. MDA stopping surveys were conducted based on WHO guidelines (2005; 2011). Information about the presence of those suffering from lymphoedema/elephantiasis and hydrocele patients was collected, and care provided to those needing care in five rural health units (RHU) by primary health care system providers who were given training on LF morbidity management and disability prevention (MMDP). The NLFEP made excellent progress due to strong collaboration between different ministries, through intensive training and supervision, and the use of advocacy for mobilization of endemic communities. The epidemiological coverage for all MDA rounds was effectively ≥80%. Antigenemia levels found in schoolchildren during transmission assessment surveys (TAS) in 166 IUs approximately 10 years after stopping MDA was 0%. In 2017, TAS conducted in additional 29 IUs indicated 0.1% antigenemia and 0% microfilaremia. In 2015, the registration of chronic LF patients was updated to 1472 lymphoedema and 18 hydrocele patients. Lymphoedema patients were trained on self-management, and hydrocele patients were referred to local General Hospitals for surgery. Thus, after over a decade of sustained effort, Egypt met the WHO criteria for successful elimination of LF as a public health problem. In December 2017, WHO validated Egypt as the first country in the Eastern Mediterranean Region to successfully achieve elimination.

Improved assessment of mass drug administration and health district management performance to eliminate lymphatic filariasis.

Lymphatic filariasis (LF) elimination as a public health problem requires the interruption of transmission by administration of preventive mass drug administration (MDA) to the eligible population living in endemic districts. Suboptimal MDA coverage leads to persistent parasite transmission with consequential infection, disease and disability, and the need for continuing MDA rounds, requiring considerable investment. Routine coverage reports must be verified in each MDA implementation unit (IU) due to incorrect denominators and numerators used to calculate coverage estimates with administrative data. IU are usually the health districts. Coverage is verified so IU teams can evaluate their outreach and take appropriate action to improve performance. Mozambique and the Democratic Republic of Congo (DRC) have conducted MDA campaigns for LF since 2009 and 2014, respectively. To verify district reports and assess the declared achievement using administrative data of the minimum 80% coverage of eligible people (or 65% of the total population), both countries conducted rapid probability surveys using Lot Quality Assurance Sampling (LQAS)(n = 1102) in 2015 and 2016 in 58 IU in 49 districts. The surveys identified IU with suboptimal coverage, reasons residents did not take the medication, place where the medication was received, information sources, and knowledge about diseases prevented by the MDA. LQAS identified four inadequately covered IU triggering district team performance reviews with provincial and national teams and district retreatment. Provincial estimates using probability samples (weighted by populations sizes) were 10 and 17 percentage points lower than reported coverage in DRC and Mozambique. The surveys identified: absence from home during annual MDA rounds as the main reason for low performance and provided valuable information about pre-campaign and campaign activities resulting in improved strategies and continued progress towards elimination of LF and co-endemic Neglected Tropical Diseases.

Assessment of treatment impact on lymphatic filariasis in 13 districts of Benin: progress toward elimination in nine districts despite persistence of transmission in some areas.

BACKGROUND: Lymphatic filariasis (LF) is still a public health burden in many developing countries. In Benin, a West African country, at least 6.6 million people are at risk for LF. With the goal of eliminating LF by 2020, mass drug administration (MDA) has been scaled-up during the last decade. Currently, 23 districts are believed to have eliminated LF as a public health problem, and 25 other districts are still under treatment. In this study we report the results of the first transmission assessment survey of LF (TAS1) in 13 districts from the second group, which have received at least six rounds of MDA with albendazole and ivermectin. METHODS: The 13 districts were grouped into six evaluation units (EU). In each EU, 30 schools randomly selected by survey sample builder (SSB) software were surveyed. Children aged six and seven were sampled in schools and for each child the Alere™ Filariasis Test Strip test was carried out using finger-prick blood to detect the circulating filarial antigen from Wuchereria bancrofti. RESULTS: Overall, 9381 children were sampled in 191 schools from the six EU with 47.6% of the children aged six years and 52.4% aged seven years. Five EU passed the assessment, with no positive cases identified. The EU of Ouinhi which grouped the districts of Ouinhi, Cove, Za-Kpota and Zagnanado failed, with 47 positive cases. These cases were clustered in the districts of Ouinhi (n = 20), Za-Kpota (n = 11) and Zagnanado (n = 16). No cases were found in the district of Cove. CONCLUSIONS: The findings of our study indicate that Benin has made important progress towards elimination in most districts evaluated. However, this study also shows that transmission of LF is ongoing in the EU of Ouinhi, part of the Zou department. The MDA strategy needs to be strengthened in order to control the human reservoir of infection in these districts.

Pharmacokinetics, safety, and efficacy of a single co-administered dose of diethylcarbamazine, albendazole and ivermectin in adults with and without Wuchereria bancrofti infection in Côte d'Ivoire.

BACKGROUND: A single co-administered dose of ivermectin (IVM) plus diethylcarbamazine (DEC) plus albendazole (ALB), or triple-drug therapy, was recently found to be more effective for clearing microfilariae (Mf) than standard DEC plus ALB currently used for mass drug administration programs for lymphatic filariasis (LF) outside of sub-Saharan Africa. Triple-drug therapy has not been previously tested in LF-uninfected individuals from Africa. This study evaluated the pharmacokinetics (PK), safety, and efficacy of triple-drug therapy in people with and without Wuchereria bancrofti infection in West Africa. METHODS: In this open-label cohort study, treatment-naïve microfilaremic (>50 mf/mL, n = 32) and uninfected (circulating filarial antigen negative, n = 24) adults residing in Agboville district, Côte d'Ivoire, were treated with a single dose of IVM plus DEC plus ALB, and evaluated for adverse events (AEs) until 7 days post treatment. Drug levels were assessed by liquid chromatography and mass spectrometry. Persons responsible for assessing AEs were blinded to participants' infection status. FINDINGS: There was no difference in AUC0-inf or Cmax between LF-infected and uninfected participants (P>0.05 for all comparisons). All subjects experienced mild AEs; 28% and 25% of infected and uninfected participants experienced grade 2 AEs, respectively. There were no severe or serious adverse events. Only fever (16 of 32 versus 4 of 24, P<0.001) and scrotal pain/swelling in males (6 of 20 versus 0 of 12, P = 0.025) were more frequent in infected than uninfected participants. All LF positive participants were amicrofilaremic at 7 days post-treatment and 27 of 31 (87%) remained amicrofilaremic 12 months after treatment. CONCLUSIONS: Moderate to heavy W. bancrofti infection did not affect PK parameters for IVM, DEC or ALB following a single co-administered dose of these drugs compared to uninfected individuals. The drugs were well tolerated. This study confirmed the efficacy of the triple-drug therapy for clearing W. bancrofti Mf and has added important information to support the use of this regimen in LF elimination programs in areas of Africa without co-endemic onchocerciasis or loiasis. TRIAL REGISTRATION: ClinicalTrials.gov NCT02845713.

How Thailand eliminated lymphatic filariasis as a public health problem.

BACKGROUND: Lymphatic filariasis is endemic in nine of the eleven Member States of the World Health Organization South East Asia Region. This article describes the intensive interventions with the National Programme for Elimination of Lymphatic Filariasis in Thailand since its launch in 2001 till the validation of its elimination in 2017. METHODS: A baseline epidemiological survey was initiated in 2001 to identify both brugian and bancroftian filarial areas and delineate its endemicity. Mass drug administration (MDA) with diethylcarbamazine citrate (DEC) and albendazole (ALB) was implemented in a total of 357 implementation units (IUs) in 11 lymphatic filariasis (LF) endemic provinces. The implementing unit (IU) was a sub-village. Stop-MDA surveys were conducted in 2006 in the 11 LF endemic provinces among population over 6 years of age and children of ≤6 years using immunochromatographic test (ICT) for Wuchereria bancrofti antigen and microfilariae (mf) detection for Brugia malayi. In Narathiwat province, Stop-MDA surveys were done in 2011 using ELISA. Transmission assessment surveys (TAS) were conducted in 2012-2013, 2015 and 2016-2017 among school students in the 6-7-year age-group. Surveillance of migrant populations through the national migrant health checkup were intensified in seven provinces over 2002-2017 for LF antigenaemia using ICT test cards. In four B. malayi endemic provinces, annual surveys to detect LF reservoir in domestic cats commenced in 1994. A 2001 survey of the chronic disease burden for LF established a register of the cumulative number of people with lymphedema/elephantiasis. RESULTS: A total of five rounds of MDA annually were implemented over 2002-2006 in all IUs. Additional annual rounds of MDA were required in 87 IUs of Narathiwat province from 2007 to 2011 due to persistent infection. The annual national drug coverage with MDA over 2002-2012 was in the range of 68.0 to 95.4%. Stop-MDA surveys in 2006 in the 11 LF endemic provinces found nine mf positive cases in seven IUs in Narathiwat province with the highest prevalence of 0.8% (range: 0.1-0.8%). In Narathiwat TAS-1, TAS-2 and TAS-3 detected below transmission threshold rates for B. malayi mf among antibody positive children (0.3, 0.2 and 0.7% respectively). Contact tracing both all mf cases in all three TAS yielded no positive cases. Through the migrant health checkup, a total of 23 477 persons were tested, showing a positive rate of 0.7% (range: 0.1-2.7%) over years 2002-2017. In Narathiwat province, annual ivermectin treatment among cats commenced in 2003 resulting in a decline of mf prevalence among cats from 8.0% in 1995 to 0.8% in 2015. As of April 2017, a total of 99 lymphoedema/elephantiasis patients were registered and followed-up under 34 health facilities. CONCLUSIONS: Thailand over the years 2002 to 2011 conducted extensive MDA with high coverage rates. Through periodic and regular monitoring surveys it delineated LF transmission areas at sub-village level and demonstrated through its evaluation surveys - the Stop-MDA surveys and TAS, below transmission threshold rates that enabled its validation of LF elimination. In September 2017, World Health Organization acknowledged the Ministry of Health Thailand had eliminated lymphatic filariasis as a public health problem.

Influence of autophagy, apoptosis and their interplay in filaricidal activity of C-cinnamoyl glycosides.

The present work aims to explore the mechanism of action of C-cinnamoyl glycoside as an antifilarial agent against the bovine filarial nematode Setaria cervi. Both apoptosis and autophagy programmed cell death pathways play a significant role in parasitic death. The generation of reactive oxygen species, alteration of the level of antioxidant components and disruption of mitochondrial membrane potential may be the causative factors that drive the parasitic death. Monitoring of autophagic flux via the formation of autophagosome and autophagolysosome was detected via CYTO ID dye. The expression profiling of both apoptotic and autophagic marker proteins strongly support the initial findings of these two cell death processes. The increased interaction of pro-autophagic protein Beclin1 with BCL-2 may promote apoptotic pathway by suppressing anti-apoptotic protein BCL-2 from its function. This in turn partially restrains the autophagic pathway by engaging Beclin1 in the complex. But overall positive increment in autophagic flux was observed. Dynamic interaction and regulative balance of these two critical cellular pathways play a decisive role in controlling disease pathogenesis. Therefore, the present experimental work may prosper the chance for C-cinnamoyl glycosides to become a potential antifilarial therapeutic in the upcoming day after detail in vivo study and proper clinical trial.

Culex species diversity, susceptibility to insecticides and role as potential vector of Lymphatic filariasis in the city of Yaoundé, Cameroon.

BACKGROUND: Culex species are widespread across Cameroon and responsible for high burden of nuisance in most urban settings. However, despite their high nuisance, they remain less studied compared to anophelines. The present study aimed to assess Culex species distribution, susceptibility to insecticide, bionomics and role in Lymphatic Filariasis (LF) transmission in the city of Yaoundé. METHODS: Mosquito collections were conducted from March to December 2017 using Centre for Disease Control light traps (CDC-LT), human landing catches (HLC) and larval collections. Mosquitoes were identified using morphological identification keys. Mosquitoes from the Culex pipiens complex were further identified using Polymerase Chain Reaction (PCR) to assess the presence of sibling species. Bioassays were conducted with 2-5 day-old unfed females to assess mosquito susceptibility to DDT, permethrin, deltamethrin and bendiocarb following WHO guidelines. Dead, control and surviving mosquitoes from bioassays were screened by PCR to detect the presence of knockdown resistance (kdr) alleles. Pools of mosquitoes were examined by PCR to detect the presence of Wuchereria bancrofti. RESULTS: A total of 197,956 mosquitoes belonging to thirteen species were collected. The density of mosquito collected varied according to the collection methods, districts and seasons. Culex quinquefasciatus emerged as the most abundant and the only species of the Culex pipiens complex in Yaoundé. Culex species were found breeding in different types of breeding sites including polluted and unpolluted sites. All Culex species including Cx antennatus, Cx duttoni, Cx perfuscus and Cx tigripes were found to be highly resistant to permethrin, deltamethrin and DDT. Culex quinquefasciatus was also found to be resistant to bendiocarb. A high frequency of the West Africa kdr allele was recorded in resistant Cx. quinquefasciatus. Out of the 247 pooled samples of 25 Culex spp. examined for the presence of Wuchereria bancrofti, none was found infected. CONCLUSION: The study confirms the high adaptation of Culex species particularly Culex quinquefasciatus to the urban environment and no implication of this species in the transmission of LF in Yaoundé Cameroon. Culex species predominance in urban settings highlight potential transmission risk of West Nile and rift valley fever in Yaoundé.

Boron-Pleuromutilins as Anti- Wolbachia Agents with Potential for Treatment of Onchocerciasis and Lymphatic Filariasis.

A series of pleuromutilins modified by introduction of a boron-containing heterocycle on C(14) of the polycyclic core are described. These analogs were found to be potent anti- Wolbachia antibiotics and, as such, may be useful in the treatment of filarial infections caused by Onchocerca volvulus, resulting in Onchocerciasis or river blindness, or Wuchereria bancrofti and Brugia malayi and related parasitic nematodes resulting in lymphatic filariasis. These two important neglected tropical diseases disproportionately impact patients in the developing world. The lead preclinical candidate compound containing 7-fluoro-6-oxybenzoxaborole (15, AN11251) was shown to have good in vitro anti- Wolbachia activity and physicochemical and pharmacokinetic properties providing high exposure in plasma. The lead was effective in reducing the Wolbachia load in filarial worms following oral administration to mice.

Elimination within reach: A cross-sectional study highlighting the factors that contribute to persistent lymphatic filariasis in eight communities in rural Ghana.

BACKGROUND: Despite the progress achieved in scaling-up mass drug administration (MDA) for lymphatic filariasis (LF) in Ghana, communities with persistent LF still exist even after 10 years of community treatment. To understand the reasons for persistence, we conducted a study to assess the status of disease elimination and understand the adherence to interventions including MDA and insecticide treated nets. METHODOLOGY AND PRINCIPAL FINDINGS: We conducted a parasitological and epidemiological cross-sectional study in adults from eight villages still under MDA in the Northern Region savannah and the coastal Western Region of the country. Prevalence of filarial antigen ranged 0 to 32.4% and in five villages the prevalence of night blood microfilaria (mf) was above 1%, ranging from 0 to 5.7%. Median mf density was 67 mf/ml (range: 10-3,560). LF antigen positivity was positively associated with male sex but negatively associated with participating in MDA the previous year. Male sex was also associated with a decreased probability of participating in MDA. A stochastic model (TRANSFIL) was used to assess the expected microfilaria prevalence under different MDA coverage scenarios using historical data on one community in the Western Region. In this example, the model simulations suggested that the slow decline in mf prevalence is what we would expect given high baseline prevalence and a high correlation between MDA adherence from year to year, despite high MDA coverage. CONCLUSIONS: There is a need for an integrated quantitative and qualitative research approach to identify the variations in prevalence, associated risk factors and intervention coverage and use levels between and within regions and districts. Such knowledge will help target resources and enhance surveillance to the communities most at risk and to reach the 2020 LF elimination goals in Ghana.