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Mass drug administration (MDA) with ivermectin is the cornerstone of efforts to eliminate human onchocerciasis by 2020 or 2025. The feasibility of elimination crucially depends on the effects of multiple ivermectin doses on Onchocerca volvulus. A single ivermectin (standard) dose clears the skin-dwelling microfilarial progeny of adult worms (macrofilariae) and temporarily impedes the release of such progeny by female macrofilariae, but a macrofilaricidal effect has been deemed minimal. Multiple doses of ivermectin may cumulatively and permanently reduce the fertility and shorten the lifespan of adult females. However, rigorous quantification of these effects necessitates interrogating longitudinal data on macrofilariae with suitably powerful analytical techniques. Using a novel mathematical modeling approach, we analyzed, at an individual participant level, longitudinal data on viability and fertility of female worms from the single most comprehensive multiple-dose clinical trial of ivermectin, comparing 3-monthly with annual treatments administered for 3 years in Cameroon. Multiple doses of ivermectin have a partial macrofilaricidal and a modest permanent sterilizing effect after 4 or more consecutive treatments, even at routine MDA doses (150 µg/kg) and frequencies (annual). The life expectancy of adult O. volvulus is reduced by approximately 50% and 70% after 3 years of annual or 3-monthly (quarterly) exposures to ivermectin. Our quantification of macrofilaricidal and sterilizing effects of ivermectin should be incorporated into transmission models to inform onchocerciasis elimination efforts in Africa and residual foci in Latin America. It also provides a framework to assess macrofilaricidal candidate drugs currently under development.

Progress has been catalysed, in part, by partnerships including the Onchocerciasis Elimination Program for the Americas, the Onchocerciasis Control Program in West Africa, the African Program for Onchocerciasis Control, and the Expanded Special Project for Elimination of Neglected Tropical Diseases. [...]the Mectizan Donation Program, established in 1987 by MSD (Merck and Co. Inc), has supported the delivery of donated antiparasitics to endemic settings, reaching more than 400 million people annually, and delivering over four billion Mectizan (ivermectin) tablets since its inception. In a statement to The Lancet Infectious Diseases, Ibrahima Socé Fall, Director of the Department of Control of Neglected Tropical Diseases, WHO, said “The Global Onchocerciasis Network for Elimination provides a platform for endemic countries, civil society organisations and individuals to share experiences and challenges, identify gaps and best practices, and strengthen cross-sectoral partnerships and integration along the path to achieving the targets set out in the global 2030 NTD road map. The network will serve as an advocacy body, at both the national and international levels, to support the so-called ‘last mile’ of elimination, while also providing a platform to improve communication, support the integration and mainstreaming of interventions, and to ensure cross-cutting, inter- and multidisciplinary approaches with other NTDs, ultimately ensuring that members are accountable, focused and motivated to provide concrete, measurable and continuing support to endemic countries as they seek to meet the 2030 NTD road map targets for onchocerciasis.

At present, control of onchocerciasis depends almost entirely on yearly treatments with 150 μg/kg ivermectin. We aimed to compare the effect of higher doses, more frequent doses, or both with the standard regimen on adult Onchocerca volvulus. We randomly allocated 657 patients who had onchocerciasis to 150 μg/kg ivermectin yearly (reference group), 150 μg/kg every 3 months, 400 then 800 μg/kg yearly, or 400 then 800 μg/kg every 3 months. We took skin snip samples from every patient before, and 3 years and 4 years after the first dose, and, at the same time excised one subcutaneous O volvulus nodule, which was examined histologically. The primary outcome was the vital status of the female worms. Analysis was done per protocol. We obtained nodules from 511 patients. After 3 years of treatment, more female worms had died in the groups treated every 3 months than in the reference group (odds ratio=1·84 [95% CI 1·23–2·75], p=0·003 for 150 μg/kg; and 2·17 [1·42–3·31], p<0·001 for high doses). Female worms were also less fertile in these groups than in the reference group (0·24 [0·14–0·43], p<0·0001; and 0·14 [0·06–0·29], p<0·0001, respectively). No difference was recorded between groups treated yearly (p=0·83 for the proportion of dead females). Unexpected side-effects consisted of mild, temporary, subjective visual changes in patients on high-dose regimens. Treatment with 3-monthly ivermectin could greatly reduce the number of female worms and acute itching and skin lesions; lower transmission of O volvulus; and change the duration of control programmes.

Onchocerciasis, also known as \"river blindness\", is caused by the bite of infected female blackflies (genus Simuliidae) that transmit the parasite Onchocerca volvulus. A high onchocerciasis microfarial load increases the risk to develop epilepsy in children between the ages of 3 and 18 years. In resource-limited settings in Africa where onchocerciasis has been poorly controlled, high numbers of onchocerciasis-associated epilepsy (OAE) are reported. We use mathematical modeling to predict the impact of onchocerciasis control strategies on the incidence and prevalence of OAE. We developed an OAE model within the well-established mathematical modelling framework ONCHOSIM. Using Latin-Hypercube Sampling (LHS), and grid search technique, we quantified transmission and disease parameters using OAE data from Maridi County, an onchocerciasis endemic area, in southern Republic of South Sudan. Using ONCHOSIM, we predicted the impact of ivermectin mass drug administration (MDA) and vector control on the epidemiology of OAE in Maridi. The model estimated an OAE prevalence of 4.1% in Maridi County, close to the 3.7% OAE prevalence reported in field studies. The OAE incidence is expected to rapidly decrease by >50% within the first five years of implementing annual MDA with good coverage (≥70%). With vector control at a high efficacy level (around 80% reduction of blackfly biting rates) as the sole strategy, the reduction is slower, requiring about 10 years to halve the OAE incidence. Increasing the efficacy levels of vector control, and implementing vector control simultaneously with MDA, yielded better results in preventing new cases of OAE. Our modeling study demonstrates that intensifying onchocerciasis eradication efforts could substantially reduce OAE incidence and prevalence in endemic foci. Our model may be useful for optimizing OAE control strategies.

[...]intervention programmes targeting elimination of onchocerciasis as a public health problem do not take into account OAE. [...]OAE may increase onchocerciasis-related mortality among children and adolescents. [...]NS incidence in Uganda has been brought down to zero [4]. The household clustering of PWE has led communities and local healthcare workers to wrongly believe that epilepsy is contagious and transmissible by direct contact, hence increasing stigma. [...]educating communities and health professionals about OAE will reduce stigma and motivate people to take ivermectin [23].

Background. Several African countries have adopted a biannual ivermectin distribution strategy in some foci to control and eliminate onchocerciasis. In 2010, the Ghana Health Service started biannual distribution to combat transmission hotspots and suboptimal responses to treatment. We assessed the epidemiological impact of the first 3 years of this strategy and quantified responses to ivermectin over 2 consecutive rounds of treatment in 10 sentinel communities. Methods. We evaluated Onchocerca volvulus community microfilarial intensity and prevalence in persons aged ≥20 years before the first, second, and fifth (or sixth) biannual treatment rounds using skin snip data from 956 participants. We used longitudinal regression modeling to estimate rates of microfilarial repopulation of the skin in a cohort of 217 participants who were followed up over the first 2 rounds of biannual treatment. Results. Biannual treatment has had a positive impact, with substantial reductions in infection intensity after 4 or 5 rounds in most communities. We identified 3 communities—all having been previously recognized as responding suboptimally to ivermectin—with statistically significantly high microfilarial repopulation rates. We did not find any clear association between microfilarial repopulation rate and the number of years of prior intervention, coverage, or the community level of infection. Conclusions. The strategy of biannual ivermectin treatment in Ghana has reduced O. volvulus microfilarial intensity and prevalence, but suboptimal responses to treatment remain evident in a number of previously and consistently implicated communities. Whether increasing the frequency of treatment will be sufficient to meet the World Health Organization's 2020 elimination goals remains uncertain.

River blindness (onchocerciasis) causes severe itching, skin lesions, and vision impairment including blindness. More than 99% of all current cases are found in sub-Saharan Africa. Fortunately, vector control and community-directed treatment with ivermectin have significantly reduced morbidity. Studies in Mali and Senegal proved the feasibility of elimination with ivermectin administration. The treatment goal is shifting from control to elimination in endemic African regions. Given limited resources, national and global policymakers need a rigorous analysis comparing investment options. For this, we developed scenarios for alternative treatment goals and compared treatment timelines and drug needs between the scenarios. Control, elimination, and eradication scenarios were developed with reference to current standard practices, large-scale studies, and historical data. For each scenario, the timeline when treatment is expected to stop at country level was predicted using a dynamical transmission model, and ivermectin treatment needs were predicted based on population in endemic areas, treatment coverage data, and the frequency of community-directed treatment. The control scenario requires community-directed treatment with ivermectin beyond 2045 with around 2.63 billion treatments over 2013-2045; the elimination scenario, until 2028 in areas where feasible, but beyond 2045 in countries with operational challenges, around 1.48 [corrected] billion treatments; and the eradication scenario, lasting until 2040, around 1.30 billion treatments. The eradication scenario is the most favorable in terms of the timeline of the intervention phase and treatment needs. For its realization, strong health systems and political will are required to overcome epidemiological and political challenges.

Background. Onchocerca volvulus and lymphatic filariae, causing river blindness and elephantiasis, depend on endosymbiotic Wolbachia bacteria for growth, development, fertility, and survival. Clinical trials have shown that doxycycline treatment eliminates Wolbachia, causing long-term sterilization of adult female filariae and effecting potent macrofilaricidal activity. The continual reinfection by drug-naive worms that occurs in these trial settings dilutes observable anti-Wolbachia and antifilarial effects, making it difficult to estimate therapeutic efficacy and compare different doxycycline regimens, evaluated at different times after treatment. Methods. A meta-analytical modeling framework is developed to link all usable data collected from clinical trials measuring the Wolbachia status and viability of individual female adult worms collected at various times after treatment with 4, 5, or 6 weeks of daily 100 or 200 mg oral doxycycline. The framework is used to estimate efficacy parameters that are not directly measurable as trial outcomes. Results. The estimated efficacy of doxycycline (the maximum proportional reduction in the percentage of adult female O. volvulus positive for Wolbachia) is 91%–94% on average, irrespective of the treatment regimen. Efficacy is >95% in the majority of trial participants. The life span of Wolbachia-depleted worms is reduced by 70%–80%, from approximately 10 years to 2–3 years. Conclusions. The efficacy parameters are pertinent to the prospects of using doxycycline on a \"test and treat\" basis for onchocerciasis control and confirm doxycycline as a potent macrofilaricidal therapy. The modeling approach is more generally relevant to the design and evaluation of clinical trials for antifilarial drugs conducted in endemic settings.

Onchocerciasis, or river blindness, has historically been one of the most important causes of blindness worldwide, and a major cause of socio-economic disruption, particularly in sub-Saharan Africa. Its importance as a cause of morbidity and an impediment to economic development in some of the poorest countries in the world motivated the international community to implement several programs to control or eliminate this scourge. Initially, these involved reducing transmission of the causative agent Onchocerca volvulus through controlling the vector population. When ivermectin was found to be a very effective drug for treating onchocerciasis, the strategy shifted to mass drug administration (MDA) of endemic communities. In some countries, both vector control and ivermectin MDA have been used together. However, traditional vector control methods involve treating rivers in which the black fly vectors breed with insecticides, a process which is expensive, requires trained personnel to administer, and can be ecologically harmful. In this review, we discuss recent research into alternatives to riverine insecticide treatment, which are inexpensive, ecologically less harmful, and can be implemented by the affected communities themselves. These can dramatically reduce vector densities and, when combined with ivermectin MDA, can accelerate the time to elimination when compared to MDA alone.

Ivermectin has been used for onchocerciasis control since 1987. Because of the long-term use of this drug and the development of resistance in other nematodes, we have assessed Onchocerca volvulus burdens, effectiveness of ivermectin as a microfilaricide, and its effect on adult female worm reproduction. For the first phase of the study, 2501 individuals in Ghana, from 19 endemic communities who had received six to 18 annual rounds of ivermectin and one ivermectin naive community, were assessed for microfilarial loads 7 days before the 2004 yearly ivermectin treatment, by means of skin snips, and 30 days after treatment to assess the ivermectin microfilaricidal action. For the second phase, skin snips were taken from 342 individuals from ten communities, who were microfilaria positive at pretreatment assessment, on days 90 and 180 after treatment, to identify the effects of ivermectin on female worm fertility, assessed by microfilaria repopulation. 487 (19%) of the 2501 participants were microfilaria positive. The microfilaria prevalence and community microfilarial load in treated communities ranged from 2·2% to 51·8%, and 0·06 microfilariae per snip to 2·85 microfilariae per snip, respectively. Despite treatment, the prevalence rate doubled between 2000 and 2005 in two communities. Microfilaria assessment 30 days after ivermectin treatment showed 100% clearance of microfilaria in more than 99% of people. At day 90 after treatment, four of ten communities had significant microfilaria repopulation, from 7·1% to 21·1% of pretreatment counts, rising to 53·9% by day 180. Ivermectin remains a potent microfilaricide. However, our results suggest that resistant adult parasite populations, which are not responding as expected to ivermectin, are emerging. A high rate of repopulation of skin with microfilariae will allow parasite transmission, possibly with ivermectin-resistant O volvulus, which could eventually lead to recrudescence of the disease.