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Background: Moxidectin is a macrocyclic lactone registered for the treatment of human onchocerciasis. The drug has a good safety profile, large volume of distribution and a long elimination half-life. This paper reports tolerability data from the first use of moxidectin in persons with Wuchereria bancrofti infection. Methods: In this randomized, open-label, masked-observer superiority trial, adults with Wuchereria bancrofti microfilaremia in Côte d'Ivoire were randomized to 1 of 4 treatment arms: ivermectin + albendazole (IA), moxidectin + albendazole (MoxA), ivermectin + diethylcarbamazine (DEC) + albendazole (IDA), or moxidectin + DEC + albendazole (MoxDA). As part of a larger efficacy trial, all participants were closely monitored for 7 days after treatment. Results: One hundred sixty-four individuals were treated, and monitored for treatment emergent adverse events (TEAE). Eighty-seven participants (53%) experienced one or more mild (grade 1) or moderate (grade 2) TEAE. Four participants had transient Grade 3 hematuria after treatment (3 after IDA and 1 after IA). There were no serious adverse events. There were no significant differences in frequency or types of TEAE between treatment groups (IA = 22/41 (53%), MoxA = 24/40 (60%), IDA = 18/41 (44%), MoxDA = 15/42 (36%), p = 0.530). Fifty-nine participants (36%) had multiple TEAE, and 8.5% had a one or more grade 2 (moderate) TEAE. Grade 2 TEAE were more frequent after triple drug treatments (IDA, 14.6%; MoxDA, 9.5%) than after two-drug treatments (IA, 7.3%; MoxA, 2.5%). There was no difference in TEAEs based on baseline Mf counts (OR 0.69 (0.33, 1.43), p-value 0.319). Conclusion: All treatment regimens were well tolerated. We observed no difference in safety parameters between regimens that contained ivermectin or moxidectin. Trial registration: Clinicaltrials.gov, NCT04410406. Author summary: Lymphatic Filariasis (LF) is a mosquito-borne parasitic infection caused predominantly by Wuchereria bancrofti. Infection can lead to significant lymphatic dysfunction, including hydroceles and lymphedema, which can progress to elephantiasis. The World Health Organization's Global Programme to Eliminate LF (GPELF) recommends mass drug administration (MDA) in endemic populations to eliminate the disease. GPELF recommendations for MDA include ivermectin (IVM) plus albendazole (IA) in sub-Saharan Africa where onchocerciasis is present. In 2018 the US Food and Drug Administration approved use of moxidectin for treatment of onchocerciasis. Moxidectin is a macrocytic lactone, similar to IVM, but more lipophilic, with a larger volume of distribution and longer half-life. Onchocerciasis studies found moxidectin to be superior to IVM for clearance of microfiladermia in people with onchocerciasis, with a treatment emergent adverse event (TEAE) profile similar to that of ivermectin. Moxidectin has not yet been studied, alone or in combination with other antihelminthic drugs. This is a safety evaluation of the first trial of moxidectin combination therapy for LF, which shows that moxidectin combination regimens are well tolerated in Wuchereria bancrofti-infected patients, with a TEAE profile comparable to standard ivermectin containing regimens. [ABSTRACT FROM AUTHOR]

Moxidectin (MOX) is a milbemycin endectocide recently approved by the U.S. FDA for the treatment of onchocerciasis in persons at least 12 years of age. MOX has been shown to have a good safety profile in recent clinical trials. The efficacy of MOX for the treatment of lymphatic filariasis (LF) and its potential use in mass drug administration protocols for the elimination of LF is currently under evaluation. In the context of a clinical trial, we investigated the pharmacokinetics and drug interactions of a combination of MOX plus albendazole (ALB) with or without diethylcarbamazine (DEC) compared to ivermectin (IVM) plus ALB with or without DEC in the following four different treatment arms: (I) IVM (0.2mg/kg) plus DEC (6 mg/kg) and ALB (400mg); (II) IVM plus ALB; (III) MOX (8 mg) plus DEC and ALB; and (IV) MOX plus ALB. Drug concentrations were determined using validated liquid chromatography-mass spectrometric methods. Pharmacokinetic parameters were determined using standard non-compartmental analysis methods. Statistical analysis was performed using JMP software. Fifty-eight of 164 study participants (53 men and five women) were included with ages ranging from 18 to 63 yrs (mean = 37). MOX apparent oral clearance (Cl/F) ranged from 0.7 to 10.8 L/hr with Cmax values ranging from 20.8 to 314.5 ng/mL. The mean (range) area under the curve (AUC)0-∞ for MOX, 3405 ng*hr/mL (742–11376), and IVM 1906 ng*hr/mL (692–5900), varied over a ~15.3 and ~8.5-fold range, respectively. The geometric mean ratio for Cmax, AUC0–t, and AUC0–∞ were within the no-drug interaction range of 80–125% for all drugs. This indicates that the addition of MOX to ALB alone or ALB plus DEC for LF therapy did not alter the drug exposure of co-administered drugs compared to IVM combinations. Clinical Trial Registration: NCT04410406, https://clinicaltrials.gov/. Author summary: Mass Drug administration (MDA) with multiple drugs is common for the treatment and control of lymphatic filariasis (LF). This study aimed to determine whether the incorporation of moxidectin (MOX) into MDA regimens for LF will alter the pharmacokinetics (PK) of co-administered drugs. In the context of a clinical trial, we investigated the PK and drug interactions of a combination of moxidectin (MOX) plus albendazole (ALB) with or without diethylcarbamazine (DEC) compared to ivermectin (IVM) plus ALB with or without DEC. The study was conducted in adult patients located in Côte d'Ivoire. The addition of MOX did not alter the exposure (AUC0-t) or maximum concentration (Cmax) of co-administered drugs. These results suggest the incorporation of MOX into current MDA LF treatment programs will not result in clinically significant alterations in drug exposure. [ABSTRACT FROM AUTHOR]

Background: Ivermectin (IVM) is a broad–spectrum anthelmintic drug used to treat diseases caused by filarial worms, such as onchocerciasis and lymphatic filariasis (LF). IVM is part of a triple–drug therapy used by the Mass Drug Administration (MDA) as a preventive strategy to eradicate LF in sub–Saharan Africa. The drug shows high variability in drug exposure in previous pharmacokinetic studies. This study aims to build a population pharmacokinetic (PopPK) model to identify and quantify the possible sources of the variability of IVM exposure after a single–oral dose in LF–infected subjects and healthy individuals. Methodology / Principal findings: In this analysis, 724 samples were collected from treatment–naïve Wuchereria bancrofti–infected (n = 32) and uninfected (n = 24) adults living in Côte d'Ivoire who had received one dose of IVM as a part of triple–drug therapy. PopPK analysis was conducted using Phoenix NLME 8.3 software. The Monte Carlo simulation based on the final model was performed to simulate drug exposure among different dosing groups (200 μg/kg, 18 mg, and 36 mg). A two–compartment model with zero–order dose input into the absorption compartment with a lag time function followed by first–order absorption and linear elimination best described the IVM's pharmacokinetic (PK) parameters. The final model identifies that the PK parameters of IVM are not affected by LF infection. Sex was a significant covariate on the peripheral volume of distribution (Vp/F, 53% lower in men than in women). IVM drug exposure shows linear pharmacokinetic behavior among the simulated dosing groups with similar drug exposure based on sex. Conclusion/Significance: We have developed a PopPk model to describe and identify possible sources of the variability of IVM exposure. To our knowledge, this is the first PopPK study of IVM in patients with LF. Trial registration: NCT02845713; NCT03664063 Author summary: Ivermectin has been shown to be a valuable tool in mass drug administration campaigns against lymphatic filariasis. The drug shows high variability in drug exposure in previous pharmacokinetic studies. Variability in drug exposure can lead to either a higher exposure with the potential for toxic effects or a lower exposure that may result in treatment failure. Identifying and quantifying the source of high variability using non–linear mixed effects modeling is crucial for future dosing recommendations that seek to maximize therapeutic benefit while minimizing toxicity risks. In this study, the variability of IVM exposure after a single oral dose was investigated with a population pharmacokinetic model using data from Lymphatic filariasis infected subjects and healthy individuals. [ABSTRACT FROM AUTHOR]

Background: Mass drug administration (MDA) is the main strategy towards lymphatic filariasis (LF) elimination. Progress is monitored by assessing microfilaraemia (Mf) or circulating filarial antigenaemia (CFA) prevalence, the latter being more practical for field surveys. The current criterion for stopping MDA requires <2% CFA prevalence in 6- to 7-year olds, but this criterion is not evidence-based. We used mathematical modelling to investigate the validity of different thresholds regarding testing method and age group for African MDA programmes using ivermectin plus albendazole. Methodolgy/Principal findings: We verified that our model captures observed patterns in Mf and CFA prevalence during annual MDA, assuming that CFA tests are positive if at least one adult worm is present. We then assessed how well elimination can be predicted from CFA prevalence in 6-7-year-old children or from Mf or CFA prevalence in the 5+ or 15+ population, and determined safe (>95% positive predictive value) thresholds for stopping MDA. The model captured trends in Mf and CFA prevalences reasonably well. Elimination cannot be predicted with sufficient certainty from CFA prevalence in 6-7-year olds. Resurgence may still occur if all children are antigen-negative, irrespective of the number tested. Mf-based criteria also show unfavourable results (PPV <95% or unpractically low threshold). CFA prevalences in the 5+ or 15+ population are the best predictors, and post-MDA threshold values for stopping MDA can be as high as 10% for 15+. These thresholds are robust for various alternative assumptions regarding baseline endemicity, biological parameters and sampling strategies. Conclusions/Significance: For African areas with moderate to high pre-treatment Mf prevalence that have had 6 or more rounds of annual ivermectin/albendazole MDA with adequate coverage, we recommend to adopt a CFA threshold prevalence of 10% in adults (15+) for stopping MDA. This could be combined with Mf testing of CFA positives to ensure absence of a significant Mf reservoir for transmission. Author summary: Mass drug administration (MDA) of antifilarial drugs is the main strategy towards the elimination of lymphatic filariasis (LF), but defining when MDA can safely be stopped is challenging. Current stopping guidelines require that the prevalence of microfilaraemia (Mf) in the population falls below 1% or the prevalence of circulating filarial antigenaemia (CFA) in 6-and-7-year-old children falls below 2%. The evidence base underlying this threshold is limited. The accuracy of this threshold is hard to assess in field studies due to the long timespan between stopping MDA and the occurrence of either elimination or resurgence. We used mathematical modelling to assess how well elimination can be predicted at community-level from the Mf or CFA prevalence observed 1-year after the last MDA round and we determined safe stopping thresholds (>95% certainty that elimination is achieved). We found that the currently used CFA prevalence in 6–7 year-old children is a poor indicator for stopping decisions in LF elimination programmes implementing MDA with ivermectin plus albendazole, and that CFA prevalence among people aged 5 or 15 years and older is a much more reliable and practical indicator of elimination outcomes. Lymphatic filariasis elimination programmes should reconsider guidelines for stopping MDA. [ABSTRACT FROM AUTHOR]

Background: Schistosomiasis is a parasitic disease caused by trematode worms of the genus Schistosoma and belongs to the neglected tropical diseases. The disease has been reported in 78 countries, with around 290.8 million people in need of treatment in 2018. Schistosomiasis is predominantly considered a rural disease with a subsequent focus of research and control activities in rural settings. Over the past decades, occurrence and even expansion of schistosomiasis foci in peri-urban and urban settings have increasingly been observed. Rural–urban migration in low- and middle-income countries and subsequent rapid and unplanned urbanization are thought to explain these observations. Fifty-five percent (55%) of the world population is already estimated to live in urban areas, with a projected increase to 68% by 2050. In light of rapid urbanization and the efforts to control morbidity and ultimately achieve elimination of schistosomiasis, it is important to deepen our understanding of the occurrence, prevalence, and transmission of schistosomiasis in urban and peri-urban settings. A systematic literature review looking at urban and peri-urban schistosomiasis was therefore carried out as a first step to address the research and mapping gap. Methodology: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic computer-aided literature review was carried out using PubMed, ScienceDirect, and the World Health Organization Database in November 2019, which was updated in March 2020. Only papers for which at least the abstract was available in English were used. Relevant publications were screened, duplicates were removed, guidelines for eligibility were applied, and eligible studies were reviewed. Studies looking at human Schistosoma infections, prevalence, and intensity of infection in urban and peri-urban settings were included as well as those focusing on the intermediate host snails. Principal findings: A total of 248 publications met the inclusion criteria. The selected studies confirm that schistosomiasis is prevalent in peri-urban and urban areas in the countries assessed. Earlier studies report higher prevalence levels in urban settings compared to data extracted from more recent publications, yet the challenge of migration, rapid uncontrolled urbanization, and resulting poor living conditions highlight the potential for continuous or even newly established transmission to take place. Conclusions: The review indicates that schistosomiasis has long existed in urban and peri-urban areas and remains a public health problem. There is, however, a challenge of comparability of settings due to the lack of a clear definition of what constitutes urban and peri-urban. There is a pressing need for improved monitoring of schistosomiasis in urban communities and consideration of treatment strategies. Author summary: Schistosomiasis is an infectious parasitic disease and one of the 20 diseases considered by the World Health Organization as a neglected tropical disease. It is typically associated with poor environmental and sanitary conditions, primarily affecting rural communities. However, with the currently observed rapid urbanization and predicted two-thirds of the world population living in urban areas by 2050, concerns are raised about a spread of schistosomiasis to urban and peri-urban areas. At the same time, there seems to be little knowledge of the extent of schistososomiasis in urban areas. In light of the efforts to control morbidity and ultimately achieve elimination of schistosomiasis as well as reaching Sustainable Development Goals 3 "achieve health for all" and 11 "make human settlements inclusive, safe, resilient, and sustainable," this systematic literature review was conducted to address the existing research and mapping gaps and to contribute to the understanding of the burden of schistosomiasis in areas that have not, as yet, been the focus of control efforts and mass drug administration programs. The review suggests that rapid and unorganized urbanization and resulting poor living conditions in urban and peri-urban areas may lead to new disease foci and thereby increase the overall disease burden. Research and policy implications are discussed. [ABSTRACT FROM AUTHOR]

Background: Côte d'Ivoire has had 45 years of intervention for onchocerciasis by vector control (from 1975 to 1991), ivermectin mass drug administration (MDA) (from 1992 to 1994) and community directed treatment with ivermectin (CDTi) from 1995 to the present. We modeled onchocerciasis endemicity during two time periods that correspond to the scale up of vector control and ivermectin distribution, respectively. This analysis illustrates progress towards elimination during these periods, and it has identified potential hotspots areas that are at risk for ongoing transmission. Methods and findings: The analysis used Ministry of Health skin snip microfilaria (MF) prevalence and intensity data collected between 1975 and 2016. Socio-demographic and environmental factors were incorporated into a predictive, machine learning algorithm to create continuous maps of onchocerciasis endemicity. Overall predicted mean MF prevalence decreased from 51.8% circa 1991 to 3.9% circa 2016. The model predicted infection foci with higher prevalence in the southern region of the country. Predicted mean community MF load (CMFL) decreased from 10.1MF/snip circa 1991 to 0.1MF/snip circa 2016. Again, the model predicts foci with higher Mf densities in the southern region. For assessing model performance, the root mean squared error and R2 values were 1.14 and 0.62 respectively for a model trained with data collected prior to 1991, and 1.28 and 0.57 for the model trained with infection survey data collected later, after the introduction of ivermectin. Finally, our models show that proximity to permanent inland bodies of water and altitude were the most informative variables that correlated with onchocerciasis endemicity. Conclusion/Significance: This study further documents the significant reduction of onchocerciasis infection following widespread use of ivermectin for onchocerciasis control in Côte d'Ivoire. Maps produced predict areas at risk for ongoing infection and transmission. Onchocerciasis might be eliminated in Côte d'Ivoire in the future with a combination of sustained CDTi with high coverage, active surveillance, and close monitoring for persistent infection in previously hyper-endemic areas. Author summary: Côte d'Ivoire is endemic for onchocerciasis (also known as "river blindness"). This neglected tropical disease is transmitted by biting black flies that breed in fast flowing rivers. From 1975 to 1991, onchocerciasis control was based on weekly aerial spraying of the insecticide temephos, on black fly breeding sites. Vector control, however, was mostly focused on the northern and central parts of the country. From 1992 to present, mass treatment with ivermectin was implemented in all endemic areas, including forested regions in the south. Here we present the first geospatial estimates of onchocerciasis endemicity over time. Using the machine learning algorithm quantile regression forest, we implemented models to: identify important socio-demographic and environmental factors that correlate with onchocerciasis infection; predict the prevalence and density of infection in areas without ground-truth data; delineate remaining infection hotspots. Our results show that Côte d'Ivoire has made very significant progress in reducing infection parameters over time, and they may help to inform future interventions to achieve the goal of onchocerciasis elimination in Côte d'Ivoire. [ABSTRACT FROM AUTHOR]

Mass Drug Administration (MDA) programs to eliminate Lymphatic Filariasis (LF) in western Africa use the anthelminthics ivermectin plus albendazole. These drugs have the potential to impact also Soil-Transmitted Helminth (STH) infections, since the drugs have a broad range of anthelminthic activity. Integration of preventive chemotherapy efforts for LF, onchocerciasis and STH is recommended by the World Health Organization (WHO) in order to avoid duplication of MDA and to reduce costs. The objective of the current study was to determine whether five semi-annual rounds of community-wide MDA to eliminate LF and onchocerciasis have a greater impact on STH than three annual rounds of MDA with similar compliance. The effects of MDA using ivermectin (IVM, 0.2 mg/kg) combined with albendazole (ALB, 400 mg) on the prevalence and intensity of hookworm infection were evaluated in the Abengourou (annual MDA) and Akoupé (semi-annual MDA) health Districts in eastern Côte d'Ivoire from 2014 to 2017. A cross-sectional approach was used together with mixed logistic regression, and mixed linear models. Subjects were tested for STH using the Kato-Katz technique before the first round of MDA and 12, 24, and 36 months after the first round of MDA. The mean self-reported MDA compliance assessed during the survey was 65%, and no difference was observed between treatment areas. These results were confirmed by an independent coverage survey as recommended by WHO. Hookworm was the most prevalent STH species in both areas (23.9% vs 12.4%) and the prevalence of other STH species was less than 1%. The crude prevalence of hookworm dropped significantly, from 23.9% to 5.5% (p <0.001, 77% reduction) in the annual MDA treatment area and from 12.4% to 1.9% (p <0.001, 85% reduction) in the semi-annual treatment area. The average intensity of hookworm infection decreased in the annual MDA area (406.2 epg to 118.3 epg), but not in the semi-annual MDA area (804.9 epg to 875.0 epg). Moderate and heavy infections (1% and 1.3% at baseline) were reduced to 0% and 0.4% in the annual and semi-annual treatment areas, respectively. Using a mixed logistic regression model, and after adjusting for baseline prevalence, only the year 2 re-examination showed a difference in prevalence between treatments (OR: 2.26 [95% CI: 1.03, 4.98], p = 0.043). Analysis of intensity of hookworm infection indicated also that treatment differences varied by follow-up visit. In conclusion twelve months after the last treatment cycle, three annual and five semi-annual rounds of community-wide MDA with the combination of IVM and ALB showed strong, but similar impact on hookworm prevalence and intensity in eastern Côte d'Ivoire. Therefore, an annual MDA regimen seems to be an efficient strategy to control hookworm infection in endemic areas with low and moderate infection prevalence. Trial registration: The study was registered at ClinicalTrial.gov under the number NTC02032043. Author summary: Community-wide MDA to eliminate LF and onchocerciasis has the beneficial effect to reduce also STH infections. The objective of the current study was to determine whether five semi-annual rounds of MDA have a greater impact on STH than three annual rounds of MDA using ivermectin combined with albendazole. In Abengourou and Akoupé health Districts in eastern Côte d'Ivoire the prevalence and intensity of hookworm infection were evaluated before and after MDA. Prior to MDA and after each annual treatment cycle, study participants were tested for STH using the Kato-Katz technique. The mean MDA compliance assessed during the survey was 65%, and no difference was observed between treatment areas. Compliance results were confirmed by an independent coverage survey as recommended by WHO. Hookworm was the most prevalent STH species in both areas and the prevalence of other STH species was less than 1%. The crude prevalence of hookworm dropped significantly, from 23.9% to 5.5% in the annual and from 12.4% to 1.9% in the semi-annual treatment areas. The intensity of hookworm infection in infected persons decreased significantly in the annual MDA area (406.2 epg to 118.3 epg, p = 0.017), but not in the semi-annual MDA area (804.9 epg to 875.0 epg, p = 0.216). Moderate and heavy infections were reduced to less than 1% in both treatment areas. Three annual and five semi-annual rounds of community-wide MDA with the combination of IVM and ALB showed strong, but similar effects on hookworm prevalence and intensity in eastern Côte d'Ivoire. Therefore, an annual MDA regimen seems to be an efficient strategy for controlling hookworm infection in endemic areas with low and moderate infection prevalence. [ABSTRACT FROM AUTHOR]

Background: Lymphatic filariasis (LF) is widely endemic in Côte d'Ivoire, and elimination as public health problem (EPHP) is based on annual mass drug administration (MDA) using ivermectin and albendazole. To guide EPHP efforts, we evaluated Wuchereria bancrofti infection indices among humans, and mosquito vectors after four rounds of MDA in four cross-border health districts of Côte d'Ivoire. Methodology: We monitored people and mosquitoes for W. bancrofti infections in the cross-border health districts of Aboisso, Bloléquin, Odienné and Ouangolodougou, Côte d'Ivoire. W. bancrofti circulating filarial antigen (CFA) was identified using filariasis test strips, and antigen-positive individuals were screened for microfilaremia. Moreover, filarial mosquito vectors were sampled using window exit traps and pyrethrum sprays, and identified morphologically at species level. Anopheles gambiae s.l. and Culex quinquefasciatus females were analyzed for W. bancrofti infection using polymerase chain reaction (PCR) technique. Principal findings: Overall, we found a substantial decline in W. bancrofti infection indices after four rounds of MDA compared to pre-MDA baseline data. CFA prevalence fell from 3.38–5.50% during pre-MDA to 0.00–1.53% after MDA interventions. No subjects had detectable levels of CFA in Ouangolodougou. Moreover, post-MDA CFA prevalence was very low, and below the 1% elimination threshold in Aboisso (0.19%) and Odienné (0.49%). Conversely, CFA prevalence remained above 1% in Bloléquin (1.53%). W. bancrofti microfilariae (Mf) were not found in Aboisso, Bloléquin, and Ouangolodougou, except for Odienné with low prevalence (0.16%; n = 613) and microfilaremia of 32.0 Mf/mL. No An. gambiae s.l. and Cx. quinquefasciatus pools were infected with W. bancrofti in Bloléquin and Ouangolodougou, while they exhibited low infection rates in Aboisso (1% and 0.07%), and Odienné (0.08% and 0.08%), respectively. Conclusions: In cross-border areas of Côte d'Ivoire, LF infection indices in humans and mosquito vectors substantially declined after four rounds of MDA. CFA prevalence fell under the World Health Organization (WHO)-established threshold (1%) in Aboisso, Ouangolodougou and Odienné. Moreover, W. bancrofti prevalence in mosquitoes was lower than WHO-established threshold (2%) in all areas. This might suggest the interruption of W. bancrofti transmission, and possible MDA cessation. However, a formal transmission assessment survey (TAS) and molecular xenomonitoring in mosquito vectors should be implemented before eventual MDA cessation. However, MDA should pursue in Bloléquin where W. bancrofti infection prevalence remained above 1%. Our results provided important ramifications for LF control efforts towards EPHP in Côte d'Ivoire. [ABSTRACT FROM AUTHOR]

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 . [ABSTRACT FROM AUTHOR]

Background: Onchocerciasis control in Côte d’Ivoire started with aerial insecticide spraying in 1974 and continued with community directed treatment with ivermectin (CDTi) from 1992 to the present. Onchocerciasis and lymphatic filariasis (LF) are co-endemic in 46 of the 81 health districts in the country. Fourteen and 12 districts are endemic for only LF or onchocerciasis, respectively. This paper aims to review the impact of past interventions on onchocerciasis in Côte d’Ivoire between 1975 and 2013, and review plans for disease elimination. Methods: We reviewed microfilaria (MF, skin snip) prevalence and community microfilarial load (CMFL) data from published reports from 53 health districts during two major epidemiological assessment periods. Data from 1975 through 1991 provided information on the impact of vector control, and data from 1992 through 2016 provided information on the impact of CDTi. Results: Weekly aerial insecticide spraying in 8 endemic districts between 1975 and 1991 reduced the overall MF prevalence by 68.1% from 43.5% to 13.9%. The CMFL also decreased in 7 out of 8 surveyed communities by 95.2% from 9.24 MF/snip to 0.44 MF/snip. Ivermectin distribution started in 1992. The coverage targets for control (65% of the total population) was reached in most endemic districts, and some areas achieved 80% coverage. Two sets of surveys were conducted to assess the impact of CDTi. Results from the first repeat surveys showed a significant decrease in overall MF prevalence (by 75.7%, from 41.6% to 10.1%). The second follow-up evaluation showed further improvement in most endemic districts and also documented major reductions in CMFL compared to baseline. Conclusions: Extensive data collected over many years document the very significant impact of interventions conducted by the National Onchocerciasis and other Eyes Diseases Control Programme during challenging times with periods of civil unrest. The Health Ministry has now integrated efforts to control neglected tropical diseases and adopted the goal of onchocerciasis elimination. [ABSTRACT FROM AUTHOR]

Background: Identifying priority areas for vector control is of considerable public health relevance. Arthropod-borne viruses (arboviruses) spread by Aedes mosquitoes are (re)emerging in many parts of the tropics, partially explained by changes in agricultural land-use. We explored the effects of land-use changes on the abundance, distribution, and host-seeking behavior of Aedes mosquitoes along a gradient of anthropogenic disturbance in oil palm-dominated landscapes in southeastern Côte d’Ivoire. Methodology: Between January and December 2014, eggs, larvae, pupae, and adults of Aedes mosquitoes were sampled in four types of macrohabitats (rainforest, polyculture, oil palm monoculture, and rural housing areas), using standard procedures (bamboo-ovitraps, metallic-ovitraps, larval surveys, and human-baited double-net traps). Immature stages were reared and adult mosquitoes identified at species level. Principal findings: A total of 28,276 Aedes specimens belonging to 11 species were collected. No Aedes-positive microhabitat and only four specimens of Ae. aegypti were found in oil palm monoculture. The highest abundance of Aedes mosquitoes (60.9%) was found in polyculture, while the highest species richness (11 species) was observed in rainforest. Ae. aegypti was the predominant Aedes species, and exhibited high anthropophilic behavior inflicting 93.0% of total biting to humans. The biting rate of Aedes mosquitoes was 34.6 and 7.2-fold higher in polyculture and rural housing areas, respectively, compared to rainforest. Three species (Ae. aegypti, Ae. dendrophilus, and Ae. vittatus) bit humans in polyculture and rural housing areas, with respective biting rates of 21.48 and 4.48 females/person/day. Unexpectedly, all three species were also feeding during darkness. Aedes females showed bimodal daily feeding cycles with peaks at around 08:00 a.m. and 05:00 p.m. Host-seeking activities were interrupted between 11:00 a.m. and 02:00 p.m. in rural housing areas, while no such interruption was observed in polyculture. Some rainforest-dwelling Aedes species displayed little preference to feed on humans. Conclusions: In southeastern Côte d’Ivoire, the agricultural land-use/land-cover changes due to the conversion of rainforest into oil palm monocultures influence the abundance, distribution, and host-seeking behaviors of anthropophagic and non-anthropophagic Aedes vectors. As a result, there is higher risk of humans to arbovirus transmission in polyculture and rural housing areas. There is a need for integrated vector management, including landscape epidemiology and ecotope-based vector control. [ABSTRACT FROM AUTHOR]

Background: The Global Programme to Eliminate Lymphatic Filariasis (GPELF), launched in 2000, has the target of eliminating the disease as a public health problem by the year 2020. The strategy adopted is mass drug administration (MDA) to all eligible individuals in endemic communities and the implementation of measures to reduce the morbidity of those suffering from chronic disease. Success has been recorded in many rural endemic communities in which elimination efforts have centered. However, implementation has been challenging in several urban African cities. The large cities of West Africa, exemplified in Nigeria in Kano are challenging for LF elimination program because reaching 65% therapeutic coverage during MDA is difficult. There is therefore a need to define a strategy which could complement MDA. Thus, in Kano State, Nigeria, while LF MDA had reached 33 of the 44 Local Government Areas (LGAs) there remained eleven ‘urban’ LGAs which had not been covered by MDA. Given the challenges of achieving at least 65% coverage during MDA implementation over several years in order to achieve elimination, it may be challenging to eliminate LF in such settings. In order to plan the LF control activities, this study was undertaken to confirm the LF infection prevalence in the human and mosquito populations in three urban LGAs. Methods: The prevalence of circulating filarial antigen (CFA) of Wuchereria bancrofti was assessed by an immuno-chromatography test (ICT) in 981 people in three urban LGAs of Kano state, Nigeria. Mosquitoes were collected over a period of 4 months from May to August 2015 using exit traps, gravid traps and pyrethrum knock-down spray sheet collections (PSC) in different households. A proportion of mosquitoes were analyzed for W. bancrofti, using dissection, loop-mediated isothermal amplification (LAMP) assay and conventional polymerase chain reaction (PCR). Results: The results showed that none of the 981 subjects (constituted of <21% of children 5–10 years old) tested had detectable levels of CFA in their blood. Entomological results showed that An. gambiae s.l. had W. bancrofti DNA detectable in pools in Kano; W. bancrofti DNA was detected in between 0.96% and 6.78% and to a lesser extent in Culex mosquitoes where DNA was detected at rates of between 0.19% and 0.64%. DNA analysis showed that An. coluzzii constituted 9.9% of the collected mosquitoes and the remaining 90.1% of the mosquitoes were Culex mosquitoes. Conclusion: Despite detection of W. bancrofti DNA within mosquito specimens collected in three Kano urban LGAs, we were not able to find a subject with detectable level of CFA. Together with other evidence suggesting that LF transmission in urban areas in West Africa may not be of significant importance, the Federal Ministry of Health advised that two rounds of MDA be undertaken in the urban areas of Kano. It is recommended that the prevalence of W. bancrofti infection in the human and mosquito populations be re-assessed after a couple of years. [ABSTRACT FROM AUTHOR]

Background: Failure in detecting naturally occurring breeding sites of Aedes mosquitoes can bias the conclusions drawn from field studies, and hence, negatively affect intervention outcomes. We characterized the habitats of immature Aedes mosquitoes and explored species dynamics along a rural-to-urban gradient in a West Africa setting where yellow fever and dengue co-exist. Methodology: Between January 2013 and October 2014, we collected immature Aedes mosquitoes in water containers in rural, suburban, and urban areas of south-eastern Côte d’Ivoire, using standardized sampling procedures. Immature mosquitoes were reared in the laboratory and adult specimens identified at species level. Principal findings: We collected 6,159, 14,347, and 22,974 Aedes mosquitoes belonging to 17, 8, and 3 different species in rural, suburban, and urban environments, respectively. Ae. aegypti was the predominant species throughout, with a particularly high abundance in urban areas (99.37%). Eleven Aedes larval species not previously sampled in similar settings of Côte d’Ivoire were identified: Ae. albopictus, Ae. angustus, Ae. apicoargenteus, Ae. argenteopunctatus, Ae. haworthi, Ae. lilii, Ae. longipalpis, Ae. opok, Ae. palpalis, Ae. stokesi, and Ae. unilineatus. Aedes breeding site positivity was associated with study area, container type, shade, detritus, water turbidity, geographic location, season, and the presence of predators. We found proportionally more positive breeding sites in urban (2,136/3,374, 63.3%), compared to suburban (1,428/3,069, 46.5%) and rural areas (738/2,423, 30.5%). In the urban setting, the predominant breeding sites were industrial containers (e.g., tires and discarded containers). In suburban areas, containers made of traditional materials (e.g., clay pots) were most frequently encountered. In rural areas, natural containers (e.g., tree holes and bamboos) were common and represented 22.1% (163/738) of all Aedes-positive containers, hosting 18.7% of Aedes fauna. The predatory mosquito species Culex tigripes was commonly sampled, while Toxorhynchites and Eretmapodites were mostly collected in rural areas. Conclusions/significance: In Côte d’Ivoire, urbanization is associated with high abundance of Aedes larvae and a predominance of artificial containers as breeding sites, mostly colonized by Ae. aegypti in urban areas. Natural containers are still common in rural areas harboring several Aedes species and, therefore, limiting the impact of systematic removal of discarded containers on the control of arbovirus diseases. [ABSTRACT FROM AUTHOR]

Malaria control relies heavily on pyrethroid insecticides, to which susceptibility is declining in Anopheles mosquitoes. To combat pyrethroid resistance, application of alternative insecticides is advocated for indoor residual spraying (IRS), and carbamates are increasingly important. Emergence of a very strong carbamate resistance phenotype in Anopheles gambiae from Tiassalé, Côte d'Ivoire, West Africa, is therefore a potentially major operational challenge, particularly because these malaria vectors now exhibit resistance to multiple insecticide classes. We investigated the genetic basis of resistance to the most commonly-applied carbamate, bendiocarb, in An. gambiae from Tiassalé. Geographically-replicated whole genome microarray experiments identified elevated P450 enzyme expression as associated with bendiocarb resistance, most notably genes from the CYP6 subfamily. P450s were further implicated in resistance phenotypes by induction of significantly elevated mortality to bendiocarb by the synergist piperonyl butoxide (PBO), which also enhanced the action of pyrethroids and an organophosphate. CYP6P3 and especially CYP6M2 produced bendiocarb resistance via transgenic expression in Drosophila in addition to pyrethroid resistance for both genes, and DDT resistance for CYP6M2 expression. CYP6M2 can thus cause resistance to three distinct classes of insecticide although the biochemical mechanism for carbamates is unclear because, in contrast to CYP6P3, recombinant CYP6M2 did not metabolise bendiocarb in vitro. Strongly bendiocarb resistant mosquitoes also displayed elevated expression of the acetylcholinesterase ACE-1 gene, arising at least in part from gene duplication, which confers a survival advantage to carriers of additional copies of resistant ACE-1 G119S alleles. Our results are alarming for vector-based malaria control. Extreme carbamate resistance in Tiassalé An. gambiae results from coupling of over-expressed target site allelic variants with heightened CYP6 P450 expression, which also provides resistance across contrasting insecticides. Mosquito populations displaying such a diverse basis of extreme and cross-resistance are likely to be unresponsive to standard insecticide resistance management practices. [ABSTRACT FROM AUTHOR]

Background: In West Africa, the principal vectors of lymphatic filariasis (LF) are Anopheles species with Culex species playing only a minor role in transmission, if any. Being a predominantly rural disease, the question remains whether conflict-related migration of rural populations into urban areas would be sufficient for active transmission of the parasite. Methodology/Principal Findings: We examined LF transmission in urban areas in post-conflict Sierra Leone and Liberia that experienced significant rural-urban migration. Mosquitoes from Freetown and Monrovia, were analyzed for infection with Wuchereria bancrofti. We also undertook a transmission assessment survey (TAS) in Bo and Pujehun districts in Sierra Leone. The majority of the mosquitoes collected were Culex species, while Anopheles species were present in low numbers. The mosquitoes were analyzed in pools, with a maximum of 20 mosquitoes per pool. In both countries, a total of 1731 An. gambiae and 14342 Culex were analyzed for W. bancrofti, using the PCR. Two pools of Culex mosquitoes and 1 pool of An. gambiae were found infected from one community in Freetown. Pool screening analysis indicated a maximum likelihood of infection of 0.004 (95% CI of 0.00012–0.021) and 0.015 (95% CI of 0.0018–0.052) for the An. gambiae and Culex respectively. The results indicate that An. gambiae is present in low numbers, with a microfilaria prevalence breaking threshold value not sufficient to maintain transmission. The results of the TAS in Bo and Pujehun also indicated an antigen prevalence of 0.19% and 0.67% in children, respectively. This is well below the recommended 2% level for stopping MDA in Anopheles transmission areas, according to WHO guidelines. Conclusions: We found no evidence for active transmission of LF in cities, where internally displaced persons from rural areas lived for many years during the more than 10 years conflict in Sierra Leone and Liberia. Author Summary: There have been many arguments regarding the implementation of Mass Drug Administration (MDA) activities for elephantiasis control in urban areas, and especially in countries where the disease is mostly found in rural settings. Blanket MDA in implementation units in big cities, may be costly and unnecessary, without evidence for active transmission in urban areas. Over 1 million people were treated in Freetown during the first MDA carried out in 2010. This represents hundreds of thousands dollars that may serve a better use in reducing the impact of elephantiasis in areas with established on-going transmission. This study was conducted to assess the evidence of transmission of elephantiasis in urban areas, as a result of rural to urban migration in West African countries that have experienced civil wars, and the displacement of people from rural to urban areas. The results showed that the main mosquitoes transmitting elephantiasis are in numbers not enough to support transmission. Testing of individuals also showed very few people to have infection. Together, the results show that elephantiasis infection in the urban areas, where the study was conducted, is not enough to justify the need for MDA in the national capitals. This study represents a strategy that can be adopted in many countries, to inform the decision for undertaking MDA activities in cities. [ABSTRACT FROM AUTHOR]

It was in Freetown, Sierra Leone, that the malaria mosquito Anopheles coastalis, now known as Anopheles gambiae, was first discovered as the vector of malaria, in 1899. That discovery led to a pioneering vector research in Sierra Leone and neighbouring Liberia, where mosquito species were extensively characterized. Unfortunately, the decade long civil conflicts of the 1990s, in both countries, resulted in a stagnation of the once vibrant research on disease vectors. This paper attempts to fill in some of the gaps on what is now known of the distribution of the sibling species of the An. gambiae complex, and especially the An. coluzzii and An. gambiae s.s, formerly known as the An. gambiae molecular M and S forms respectively, in the cities of Freetown and Monrovia. [ABSTRACT FROM AUTHOR]

Malaria control relies heavily on pyrethroid insecticides, to which susceptibility is declining in Anopheles mosquitoes. To combat pyrethroid resistance, application of alternative insecticides is advocated for indoor residual spraying (IRS), and carbamates are increasingly important. Emergence of a very strong carbamate resistance phenotype in Anopheles gambiae from Tiassalé, Côte d'Ivoire, West Africa, is therefore a potentially major operational challenge, particularly because these malaria vectors now exhibit resistance to multiple insecticide classes. We investigated the genetic basis of resistance to the most commonly-applied carbamate, bendiocarb, in An. gambiae from Tiassalé. Geographically-replicated whole genome microarray experiments identified elevated P450 enzyme expression as associated with bendiocarb resistance, most notably genes from the CYP6 subfamily. P450s were further implicated in resistance phenotypes by induction of significantly elevated mortality to bendiocarb by the synergist piperonyl butoxide (PBO), which also enhanced the action of pyrethroids and an organophosphate. CYP6P3 and especially CYP6M2 produced bendiocarb resistance via transgenic expression in Drosophila in addition to pyrethroid resistance for both genes, and DDT resistance for CYP6M2 expression. CYP6M2 can thus cause resistance to three distinct classes of insecticide although the biochemical mechanism for carbamates is unclear because, in contrast to CYP6P3, recombinant CYP6M2 did not metabolise bendiocarb in vitro. Strongly bendiocarb resistant mosquitoes also displayed elevated expression of the acetylcholinesterase ACE-1 gene, arising at least in part from gene duplication, which confers a survival advantage to carriers of additional copies of resistant ACE-1 G119S alleles. Our results are alarming for vector-based malaria control. Extreme carbamate resistance in Tiassalé An. gambiae results from coupling of over-expressed target site allelic variants with heightened CYP6 P450 expression, which also provides resistance across contrasting insecticides. Mosquito populations displaying such a diverse basis of extreme and cross-resistance are likely to be unresponsive to standard insecticide resistance management practices. [ABSTRACT FROM AUTHOR]

Background: Onchocerciasis control in Côte d'Ivoire started with aerial insecticide spraying in 1974 and continued with community directed treatment with ivermectin (CDTi) from 1992 to the present. Onchocerciasis and lymphatic filariasis (LF) are co-endemic in 46 of the 81 health districts in the country. Fourteen and 12 districts are endemic for only LF or onchocerciasis, respectively. This paper aims to review the impact of past interventions on onchocerciasis in Côte d'Ivoire between 1975 and 2013, and review plans for disease elimination., Methods: We reviewed microfilaria (MF, skin snip) prevalence and community microfilarial load (CMFL) data from published reports from 53 health districts during two major epidemiological assessment periods. Data from 1975 through 1991 provided information on the impact of vector control, and data from 1992 through 2016 provided information on the impact of CDTi., Results: Weekly aerial insecticide spraying in 8 endemic districts between 1975 and 1991 reduced the overall MF prevalence by 68.1% from 43.5% to 13.9%. The CMFL also decreased in 7 out of 8 surveyed communities by 95.2% from 9.24 MF/snip to 0.44 MF/snip. Ivermectin distribution started in 1992. The coverage targets for control (65% of the total population) was reached in most endemic districts, and some areas achieved 80% coverage. Two sets of surveys were conducted to assess the impact of CDTi. Results from the first repeat surveys showed a significant decrease in overall MF prevalence (by 75.7%, from 41.6% to 10.1%). The second follow-up evaluation showed further improvement in most endemic districts and also documented major reductions in CMFL compared to baseline., Conclusions: Extensive data collected over many years document the very significant impact of interventions conducted by the National Onchocerciasis and other Eyes Diseases Control Programme during challenging times with periods of civil unrest. The Health Ministry has now integrated efforts to control neglected tropical diseases and adopted the goal of onchocerciasis elimination., Competing Interests: The authors have declared that no competing interests exist.

Malaria control relies heavily on pyrethroid insecticides, to which susceptibility is declining in Anopheles mosquitoes. To combat pyrethroid resistance, application of alternative insecticides is advocated for indoor residual spraying (IRS), and carbamates are increasingly important. Emergence of a very strong carbamate resistance phenotype in Anopheles gambiae from Tiassalé, Côte d'Ivoire, West Africa, is therefore a potentially major operational challenge, particularly because these malaria vectors now exhibit resistance to multiple insecticide classes. We investigated the genetic basis of resistance to the most commonly-applied carbamate, bendiocarb, in An. gambiae from Tiassalé. Geographically-replicated whole genome microarray experiments identified elevated P450 enzyme expression as associated with bendiocarb resistance, most notably genes from the CYP6 subfamily. P450s were further implicated in resistance phenotypes by induction of significantly elevated mortality to bendiocarb by the synergist piperonyl butoxide (PBO), which also enhanced the action of pyrethroids and an organophosphate. CYP6P3 and especially CYP6M2 produced bendiocarb resistance via transgenic expression in Drosophila in addition to pyrethroid resistance for both genes, and DDT resistance for CYP6M2 expression. CYP6M2 can thus cause resistance to three distinct classes of insecticide although the biochemical mechanism for carbamates is unclear because, in contrast to CYP6P3, recombinant CYP6M2 did not metabolise bendiocarb in vitro. Strongly bendiocarb resistant mosquitoes also displayed elevated expression of the acetylcholinesterase ACE-1 gene, arising at least in part from gene duplication, which confers a survival advantage to carriers of additional copies of resistant ACE-1 G119S alleles. Our results are alarming for vector-based malaria control. Extreme carbamate resistance in Tiassalé An. gambiae results from coupling of over-expressed target site allelic variants with heightened CYP6 P450 expression, which also provides resistance across contrasting insecticides. Mosquito populations displaying such a diverse basis of extreme and cross-resistance are likely to be unresponsive to standard insecticide resistance management practices.

It was in Freetown, Sierra Leone, that the malaria mosquito Anopheles coastalis, now known as Anopheles gambiae, was first discovered as the vector of malaria, in 1899. That discovery led to a pioneering vector research in Sierra Leone and neighbouring Liberia, where mosquito species were extensively characterized. Unfortunately, the decade long civil conflicts of the 1990s, in both countries, resulted in a stagnation of the once vibrant research on disease vectors. This paper attempts to fill in some of the gaps on what is now known of the distribution of the sibling species of the An. gambiae complex, and especially the An. coluzzii and An. gambiae s.s, formerly known as the An. gambiae molecular M and S forms respectively, in the cities of Freetown and Monrovia.