Macrofilaricidal Efficacy of Repeated Doses of Ivermectin for the Treatment of River Blindness.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Plasma-derived parasitic microRNAs have insufficient concentrations to be used as diagnostic biomarker for detection of Onchocerca volvulus infection or treatment monitoring using LNA-based RT-qPCR.

River blindness, caused by infection with the filarial nematode Onchocerca volvulus, is a neglected tropical disease affecting millions of people. There is a clear need for diagnostic tools capable of identifying infected patients, but that can also be used for monitoring disease progression and treatment efficacy. Plasma-derived parasitic microRNAs have been suggested as potential candidates for such diagnostic tools. We have investigated whether these parasitic microRNAs are present in sufficient quantity in plasma of Onchocerca-infected patients to be used as a diagnostic biomarker for detection of O. volvulus infection or treatment monitoring. Plasma samples were collected from different sources (23 nodule-positive individuals and 20 microfilaridermic individuals), microRNAs (miRNAs) were extracted using Qiagen miRNeasy kit, and a set of 17 parasitic miRNAs was evaluated on these miRNA extracts using miRCURY Locked Nucleic Acid (LNA) Universal RT microRNA PCR system. Of the 17 miRNAs evaluated, only 7 miRNAs were found to show detectable signal in a number of samples: bma-miR-236-1, bma-miR-71, ov-miR71-22nt, ov-miR-71-23nt, ov-miR-100d, ov-bantam-a, and ov-miR-87-3p. Subsequent melting curve analysis, however, indicated that the signals observed for ov-miR-71 variants and ov-miR-87-3p are non-specific. The other miRNAs only showed positive signal in one or few samples with Cq values just below the cutoff. Our data indicate that parasitic miRNAs are not present in circulation at a sufficiently high level to be used as biomarker for O. volvulus infection or treatment monitoring using LNA-based RT-qPCR analysis.

Canine ocular onchocerciasis: a retrospective review of the diagnosis, treatment, and outcome of 16 cases in New Mexico (2011-2015).

OBJECTIVE: To describe the clinical exam findings, treatment and outcomes of 16 dogs diagnosed with ocular onchocerciasis in New Mexico. MATERIALS AND METHODS: Records of dogs diagnosed by the primary author were reviewed (2011-2015). Records that were accessible and included a diagnosis of Onchocerca lupi by histopathologic or molecular identification of the nematode were included. RESULTS: Sixteen cases were included. 3/16 dogs were treated with year-round heartworm prophylaxis prior to infection. Clinical exam findings included conjunctival hyperemia and/or episcleral injection (16/16), focal subconjunctival mass(es) (14/16), retinal detachment (7/16), corneal edema (4/16), chemosis (3/16), corneal opacity (2/16), exophthalmia (1/16), glaucoma (1/16), strabismus (1/16), blepharospasm (1/16), and vitreal degeneration (1/16). Ocular involvement was unilateral in 7/16 dogs and bilateral in 9/16 dogs. The diagnosis was confirmed via histologic identification of the nematodes and/or PCR. Treatment consisted of medical management or a combination medical and surgical management. Known or suspected recurrence of disease was documented in 10 dogs. CONCLUSIONS: Canine ocular onchocerciasis is endemic in New Mexico. Histopathology and molecular identification are useful diagnostic tools. Medical management alone was successful in many cases.

Does Increasing Treatment Frequency Address Suboptimal Responses to Ivermectin for the Control and Elimination of River Blindness?

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.

Doing well while fighting river blindness: the alignment of a corporate drug donation programme with responsibilities to shareholders.

OBJECTIVE: Using the example of Merck's donations of ivermectin, to show how tax incentives and non-profit collaborators can make corporate largesse consistent with obligations to maximise returns to shareholders. METHODS: We obtained information from publicly available data and estimated Merck's tax deductions according to the US Internal Revenue Code. Reviews of Merck-Kitasato contracts and personal interviews provided additional information regarding key lessons from this collaboration. RESULTS: Our best estimate of the direct cost to Merck of the ivermectin tablets donated during 2005-2011 is around US$ 600 million, well below the stated value of US$ 3.8 billion. Our calculation of tax write-offs reduces the net cost to around US$ 180 million in that period. Indirect market benefits and effects on goodwill further enhanced the compatibility of Merck's donation programme with the company's profit-maximising objective. The case offers lessons for effective management of collaborations with public and non-profit organisations. CONCLUSION: Merck's role in the donation of ivermectin for the treatment of onchocerciasis is widely and justly acknowledged as a prime example of corporate largesse in the public interest. It is nevertheless important to note that several public and non-profit collaborators, and United States taxpayers, played significant roles in increasing Merck's incentives, and indeed ability, to conduct the donation programme that changed so many lives in poor countries, while meeting its responsibilities to shareholders. Overall, the record indicates responsible corporate management of Merck's ivermectin programme and demonstrates the feasibility of socially responsible policies in a manner compatible with obligations to shareholders.

Doxycycline plus ivermectin versus ivermectin alone for treatment of patients with onchocerciasis.

BACKGROUND: Onchocerciasis, also known as "river blindness," is a parasitic disease that is caused by infection from the filarial nematode (roundworm), Onchocerca volvulus. Nematodes are transmitted from person to person by blackflies of the Simulium genus, which usually breed in fast flowing streams and rivers. The disease is the second leading infectious cause of blindness in endemic areas.Ivermectin (a microfilaricide) is widely distributed to endemic populations for prevention and treatment of onchocerciasis. Doxycycline, an antibiotic, targets Wolbachia organisms that are crucial to the survival of adult onchocerca (macrofilaricide). Combined treatment with both drugs is believed to cause direct microfilarial death by ivermectin and indirect macrofilarial death by doxycycline. Long-term reduction in the numbers of microfilaria in the skin and eyes and in the numbers of adult worms in the body has the potential to reduce the transmission and occurrence of onchocercal eye disease. OBJECTIVES: The primary aim of this review was to assess the effectiveness of doxycycline plus ivermectin versus ivermectin alone for prevention and treatment of onchocerciasis. The secondary aim was to assess the effectiveness of doxycycline plus ivermectin versus ivermectin alone for prevention and treatment of onchocercal ocular lesions in communities co-endemic for onchocerciasis and Loa loa (loiasis) infection. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (Issue 7, 2015), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to July 2015), EMBASE (January 1980 to July 2015), PubMed (1948 to July 2015), Latin American and Caribbean Health Sciences Literature Database (LILACS) (1982 to July 2015), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com) (last searched 1 July 2014), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic search for trials. We last searched the electronic databases on 15 July 2015. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that had compared doxycycline plus ivermectin versus ivermectin alone. Participants with or without one or more characteristic signs of ocular onchocerciasis resided in communities where onchocerciasis was endemic. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility and extracted data. We used standard methodological procedures as expected by Cochrane. MAIN RESULTS: We identified three RCTs including a total of 466 participants with a diagnosis of onchocerciasis. All trials compared doxycycline plus ivermectin versus ivermectin alone. One study investigated improvement in visual impairment at six-month follow-up; the other two studies measured microfilarial loads in skin snips to assess sustained effects of treatment at follow-up of 21 months or longer. The studies were conducted at various centers across three countries (Cameroon, Ghana, and Liberia). We judged all studies to be at overall high risk of bias because of inadequate randomization and lack of masking (one study), missing data (two studies), and selective outcome reporting (three studies).Only one study measured visual outcomes. This study reported uncertainty about the difference in the proportion of participants with improvement in visual impairment at six-month follow-up for doxycycline plus ivermectin compared with ivermectin alone (risk ratio (RR) 1.06, 95% confidence interval (95% CI) 0.80 to 1.39; 240 participants; very low-quality evidence). No participant in either group showed improvement in optic atrophy, chorioretinitis, or sclerosing keratitis at six-month follow-up. More participants in the doxycycline plus ivermectin group than in the ivermectin alone group showed improvement in iridocyclitis (RR 1.24, 95% CI 0.69 to 2.22) and punctate keratitis (RR 1.43, 95% CI 1.02 to 2.00) at six-month follow-up; however, we graded these results as very low quality.Two studies reported that a six-week course of doxycycline may result in Wolbachia depletion and macrofilaricidal and sterilizing activities in female Onchocerca worms; however, no analysis was possible because data were missing and incomplete (graded evidence as very low quality). Adverse events were reported in 16 of 135 (12%) participants in one of these studies and included itching, headaches, body pains, and vertigo; no difference between treatment groups was reported for any adverse event. The second study reported that one (1.3%) participant in the doxycycline plus ivermectin group had bloody diarrhea after treatment was initiated. AUTHORS' CONCLUSIONS: Available evidence on the effectiveness of doxycycline plus ivermectin compared with ivermectin alone in preventing and treating onchocerciasis is unclear. Limited evidence of very low quality from two studies indicates that a six-week course of doxycycline followed by ivermectin may result in more frequent macrofilaricidal and microfilaricidal activity and sterilization of female adult Onchocerca compared with ivermectin alone; however, effects on vision-related outcomes are uncertain. Future studies should consider the effectiveness of treatments in preventing visual acuity and visual field loss and their effects on anterior and posterior segment lesions, particularly chorioretinitis. These studies should report outcomes in a uniform and consistent manner at follow-up of three years or longer to allow detection of meaningful changes in vision-related outcomes.

Onchocerca volvulus-neurotransmitter tyramine is a biomarker for river blindness.

Onchocerciasis, also known as "river blindness", is a neglected tropical disease infecting millions of people mainly in Africa and the Middle East but also in South America and Central America. Disease infectivity initiates from the filarial parasitic nematode Onchocerca volvulus, which is transmitted by the blackfly vector Simulium sp. carrying infectious third-stage larvae. Ivermectin has controlled transmission of microfilariae, with an African Program elimination target date of 2025. However, there is currently no point-of-care diagnostic that can distinguish the burden of infection--including active and/or past infection--and enable the elimination program to be effectively monitored. Here, we describe how liquid chromatography-MS-based urine metabolome analysis can be exploited for the identification of a unique biomarker, N-acetyltyramine-O,ß-glucuronide (NATOG), a neurotransmitter-derived secretion metabolite from O. volvulus. The regulation of this tyramine neurotransmitter was found to be linked to patient disease infection, including the controversial antibiotic doxycycline treatment that has been shown to both sterilize and kill adult female worms. Further clues to its regulation have been elucidated through biosynthetic pathway determination within the nematode and its human host. Our results demonstrate that NATOG tracks O. volvulus metabolism in both worms and humans, and thus can be considered a host-specific biomarker for onchocerciasis progression. Liquid chromatography-MS-based urine metabolome analysis discovery of NATOG not only has broad implications for a noninvasive host-specific onchocerciasis diagnostic but provides a basis for the metabolome mining of other neglected tropical diseases for the discovery of distinct biomarkers and monitoring of disease progression.

Therapeutic efficacy and macrofilaricidal activity of doxycycline for the treatment of river blindness.

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.

Human case of Onchocerca lupi infection, Germany, August 2014.

Onchocerca lupi, a nematode parasite infecting dogs and cats with a hitherto unknown arthropod vector, is also being recognised as a parasite also responsible for human eye infections. Here we describe a case of human eye infection diagnosed molecularly by nematode 12S rDNA PCR in a German patient who had travelled to Tunisia and Turkey. The patient recovered after treatment with antibiotic and anti-inflammatory therapy.

Do Residents Believe that Onchocerciasis Transmission Was Eliminated? Results of A Post-Treatment Surveillance Knowledge, Attitude, and Practices Survey in Three Foci of Uganda.

In Uganda, 15 of 17 foci have interrupted transmission of onchocerciasis (river blindness) and stopped mass drug administration (MDA) of ivermectin. This 2016 study describes the results of a knowledge, attitude, and practices survey regarding river blindness among participants (N = 1,577) 3-5 years after ivermectin MDA was halted in three foci: Imaramagambo halted in 2012, Kashoya-Kitomi in 2013, and Mt. Elgon in 2011. The study showed high levels of composite knowledge (focus-specific range: 66.8-81.2%) related to river blindness transmission, signs, symptoms, and treatment. However, 38.1% of respondents did not know that blackflies transmitted river blindness. Notably, 72.2% claimed they had not been informed why MDA was stopped, 56.3% did not believe river blindness had been eliminated, and 83.1% wanted ivermectin MDA to resume. During the 3-5 year post-treatment surveillance period, only 27.7% (438 of 1,577) reported being informed of what to do once treatments stopped, with the most knowledgeable hailing from the Mt. Elgon focus (47.9%). This study reinforces the need for programs to intensify health education and information dissemination when MDA is stopped. Programs must remind residents that although biting insects may persist, they no longer transmit river blindness. Incorporating messages about the elimination of river blindness into community health education campaigns can help improve the community's perceptions related to the disease's absence and the ending of a long-standing MDA intervention.

Elimination of transmission of onchocerciasis (river blindness) with long-term ivermectin mass drug administration with or without vector control in sub-Saharan Africa: a systematic review and meta-analysis.

BACKGROUND: WHO has proposed elimination of transmission of onchocerciasis (river blindness) by 2030. More than 99% of cases of onchocerciasis are in sub-Saharan Africa. Vector control and mass drug administration of ivermectin have been the main interventions for many years, with varying success. We aimed to identify factors associated with elimination of onchocerciasis transmission in sub-Saharan Africa. METHODS: For this systematic review and meta-analysis we searched for published articles reporting epidemiological or entomological assessments of onchocerciasis transmission status in sub-Saharan Africa, with or without vector control. We searched MEDLINE, PubMed, Web of Science, Embase, Cochrane Central Register of Controlled Trials, African Index Medicus, and Google Scholar databases for all articles published from database inception to Aug 19, 2023, without language restrictions. The search terms used were "onchocerciasis" AND "ivermectin" AND "mass drug administration". The three inclusion criteria were (1) focus or foci located in Africa, (2) reporting of elimination of transmission or at least 10 years of ivermectin mass drug administration in the focus or foci, and (3) inclusion of at least one of the following assessments: microfilarial prevalence, nodule prevalence, Ov16 antibody seroprevalence, and blackfly infectivity prevalence. Epidemiological modelling studies and reviews were excluded. Four reviewers (NM, AJ, AM, and TNK) extracted data in duplicate from the full-text articles using a data extraction tool developed in Excel with columns recording the data of interest to be extracted, and a column where important comments for each study could be highlighted. We did not request any individual-level data from authors. Foci were classified as achieving elimination of transmission, being close to elimination of transmission, or with ongoing transmission. We used mixed-effects meta-regression models to identify factors associated with transmission status. This study is registered in PROSPERO, CRD42022338986. FINDINGS: Of 1525 articles screened after the removal of duplicates, 75 provided 282 records from 238 distinct foci in 19 (70%) of the 27 onchocerciasis-endemic countries in sub-Saharan Africa. Elimination of transmission was reported in 24 (9%) records, being close to elimination of transmission in 86 (30%) records, and ongoing transmission in 172 (61%) records. I2 was 83·3% (95% CI 79·7 to 86·3). Records reporting 10 or more years of continuous mass drug administration with 80% or more therapeutic coverage of the eligible population yielded significantly higher odds of achieving elimination of transmission (log-odds 8·5 [95% CI 3·5 to 13·5]) or elimination and being close to elimination of transmission (42·4 [18·7 to 66·1]) than those with no years achieving 80% coverage or more. Reporting 15-19 years of ivermectin mass drug administration (22·7 [17·2 to 28·2]) and biannual treatment (43·3 [27·2 to 59·3]) were positively associated with elimination and being close to elimination of transmission compared with less than 15 years and no biannual mass drug administration, respectively. Having had vector control without vector elimination (-42·8 [-59·1 to -26·5]) and baseline holoendemicity (-41·97 [-60·6 to -23·2]) were associated with increased risk of ongoing transmission compared with no vector control and hypoendemicity, respectively. Blackfly disappearance due to vector control or environmental change contributed to elimination of transmission. INTERPRETATION: Mass drug administration duration, frequency, and coverage; baseline endemicity; and vector elimination or disappearance are important determinants of elimination of onchocerciasis transmission in sub-Saharan Africa. Our findings underscore the importance of improving and sustaining high therapeutic coverage and increasing treatment frequency if countries are to achieve elimination of onchocerciasis transmission. FUNDING: The Bill & Melinda Gates Foundation and Neglected Tropical Diseases Modelling Consortium, UK Medical Research Council, and Global Health EDCTP3 Joint Undertaking. TRANSLATIONS: For the Swahili, French, Spanish and Portuguese translations of the abstract see Supplementary Materials section.

Progress toward elimination of onchocerciasis in the Americas - 1993-2012.

Onchocerciasis (river blindness) is caused by the parasitic worm Onchocerca volvulus, transmitted to humans by the bite of infected black flies of the genus Simulium, and is characterized by chronic skin disease, severe itching, and eye lesions that can progress to complete blindness. Currently, among approximately 123 million persons at risk for infection in 38 endemic countries, at least 25.7 million are infected, and 1 million are blinded or have severe visual impairment. Periodic, communitywide mass drug administration (MDA) with ivermectin (Mectizan, Merck) prevents eye and skin disease and might interrupt transmission of the infection, depending on the coverage, duration, and frequency of MDA. The Onchocerciasis Elimination Program for the Americas (OEPA) was launched in response to a 1991 resolution of the Pan American Health Organization (PAHO) calling for the elimination of onchocerciasis from the Americas. By the end of 2012, transmission of the infection, judged by surveys following World Health Organization (WHO) guidelines, had been interrupted or eliminated in four of the six endemic countries in the WHO Americas Region. Thus, in 2013, only 4% (23,378) of the 560,911 persons originally at risk in the Americas will be under ivermectin MDA. Active transmission currently is limited to two foci among Yanomami indigenes in adjacent border areas of Venezuela and Brazil.

Onchocerciasis: the role of Wolbachia bacterial endosymbionts in parasite biology, disease pathogenesis, and treatment.

The discovery of Wolbachia intracellular bacteria within filarial nematodes, including Onchocerca volvulus, the causative agent of onchocerciasis or "river blindness," has delivered a paradigm shift in our understanding of the parasite's biology, to where we now know that the bacterial endosymbionts are essential for normal development of larvae and embryos and may support the long-term survival of adult worms. The apparent mutualistic dependency has also offered a novel approach to the treatment of onchocerciasis through the use of antibiotics to eliminate Wolbachia, delivering for the first time a treatment which has significant macrofilaricidal efficacy. Studies with other filarial nematode species have also highlighted a role for Wolbachia in transmission and infection of the mammalian host through a fascinating manipulation of mast cell-mediated vasodilation to enhance infectivity of vector-borne larvae. Wolbachia has also been identified as the principal driver of innate and adaptive Th1 inflammatory immunity, which can either contribute to disease pathogenesis or, with the Wolbachia-mediated recruitment of mast cells, enhance infectivity. The Wolbachia activation of innate inflammation also drives inflammatory adverse events in response to chemotherapy with either diethylcarbamazine (DEC) or ivermectin. In this review we summarize the experimental and field trial data which have uncovered the importance of Wolbachia symbiosis in onchocerciasis.

Autochthonous Onchocerca lupi infection of a domestic dog in Austria.

Onchocerca lupi is an emerging canine ocular pathogen with zoonotic potential. In Europe, known endemic areas are the Iberian Peninsula and Greece, but the parasite has also been found in Romania, Hungary, and Germany. A 5-year-old Irish Wolfhound was presented in August 2021 with ocular discharge. A subconjunctival granulomatous nodule containing several nematode fragments was removed. Molecular analysis of the mitochondrial cytochrome c oxidase subunit I gene confirmed the presence of O. lupi genotype 1. This is the first report of autochthonous O. lupi infection in a dog from Austria.

Onchocerciasis-associated epilepsy in Maridi, South Sudan: Modelling and exploring the impact of control measures against river blindness.

BACKGROUND: 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. METHODOLOGY: 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. PRINCIPAL FINDINGS: 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. CONCLUSIONS/SIGNIFICANCES: 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.

Ivermectin for onchocercal eye disease (river blindness).

BACKGROUND: It is believed that ivermectin (a microfilaricide) could prevent blindness due to onchocerciasis. However, when given to everyone in communities where onchocerciasis is common, the effects of ivermectin on lesions affecting the eye are uncertain and data on whether the drug prevents visual loss are unclear. OBJECTIVES: The aim of this review was to assess the effectiveness of ivermectin in preventing visual impairment and visual field loss in onchocercal eye disease. The secondary aim was to assess the effects of ivermectin on lesions affecting the eye in onchocerciasis. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2012, Issue 3), MEDLINE (January 1950 to April 2012), EMBASE (January 1980 to April 2012), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 2 April 2012. SELECTION CRITERIA: We included randomised controlled trials with at least one year of follow-up comparing ivermectin with placebo or no treatment. Participants in the trials were people normally resident in endemic onchocercal communities with or without one or more characteristic signs of ocular onchocerciasis. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed trial quality. We contacted study authors for additional information. As trials varied in design and setting, we were unable to perform a meta-analysis. MAIN RESULTS: The review included four trials: two small studies (n = 398) in which people with onchocercal infection were given one dose of ivermectin or placebo and followed up for one year; and two larger community-based studies (n = 4941) whereby all individuals in selected communities were treated every six or 12 months with ivermectin or placebo, whether or not they were infected, and followed for two to three years. The studies provide evidence that treating people who have onchocerciasis with ivermectin reduces the number of microfilariae in their skin and eye(s) and reduces the number of punctate opacities. There was weaker evidence that ivermectin reduced the risk of chorioretinitis. The studies were too small and of too short a duration to provide evidence for an effect on sclerosing keratitis, iridocyclitis, optic nerve disease or visual loss. One community-based study in communities mesoendemic for the savannah strain of O.volvulus provided evidence that annual mass treatment with ivermectin reduces the risk of new cases of optic nerve disease and visual field loss. The other community-based study of mass biannual treatment of ivermectin in communities affected by the forest strain of O.volvulus demonstrated reductions in microfilarial load, punctate keratitis and iridocyclitis but not sclerosing keratitis, chorioretinitis, optic atrophy or visual impairment. The study was underpowered to estimate the effect of ivermectin on visual impairment and other less frequent clinical signs. The studies included in this review reported some adverse effects, in particular an increased risk of postural hypotension in people treated with ivermectin. AUTHORS' CONCLUSIONS: The lack of evidence for prevention of visual impairment and blindness should not be interpreted to mean that ivermectin is not effective, however, clearly this is a key question that remains unanswered. The main evidence for a protective effect of mass treatment with ivermectin on visual field loss and optic nerve disease comes from communities mesoendemic for the savannah strain of O.volvulus. Whether these findings can be applied to communities with different endemicity and affected by the forest strain is unclear. Serious adverse effects were rarely reported. None of the studies, however, were conducted in areas where people are infected with Loa loa (loiasis).

Identifying sub-optimal responses to ivermectin in the treatment of River Blindness.

Identification of drug resistance before it becomes a public health concern requires a clear distinction between what constitutes a normal and a suboptimal treatment response. A novel method of analyzing drug efficacy studies in human helminthiases is proposed and used to investigate recent claims of atypical responses to ivermectin in the treatment of River Blindness. The variability in the rate at which Onchocerca volvulus microfilariae repopulate host's skin following ivermectin treatment is quantified using an individual-based onchocerciasis mathematical model. The model estimates a single skin repopulation rate for every host sampled, allowing reports of suboptimal responses to be statistically compared with responses from populations with no prior exposure to ivermectin. Statistically faster rates of skin repopulation were observed in 3 Ghanaian villages (treated 12-17 times), despite the wide variability in repopulation rates observed in ivermectin-naïve populations. Another village previously thought to have high rates of skin repopulation was shown to be indistinguishable from the normal treatment response. The model is used to generate testable hypotheses to identify whether atypical rates of skin repopulation by microfilariae could result from low treatment coverage alone or provide evidence of decreased ivermectin efficacy. Further work linking phenotypic poor responses to treatment with parasite molecular genetics markers will be required to confirm drug resistance. Limitations of the skin-snipping method for estimating parasite load indicates that changes in the distribution of microfilarial repopulation rates, rather than their absolute values, maybe a more sensitive indicator of emerging ivermectin resistance.

The burden of skin disease and eye disease due to onchocerciasis in countries formerly under the African Programme for Onchocerciasis Control mandate for 1990, 2020, and 2030.

BACKGROUND: Onchocerciasis ("river blindness") can cause severe morbidity, including vision loss and various skin manifestations, and is targeted for elimination using ivermectin mass drug administration (MDA). We calculated the number of people with Onchocerca volvulus infection and onchocercal skin and eye disease as well as disability-adjusted life years (DALYs) lost from 1990 through to 2030 in areas formerly covered by the African Programme for Onchocerciasis Control. METHODS: Per MDA implementation unit, we collated data on the pre-control distribution of microfilariae (mf) prevalence and the history of control. Next, we predicted trends in infection and morbidity over time using the ONCHOSIM simulation model. DALY estimates were calculated using disability weights from the Global Burden of Disease Study. RESULTS: In 1990, prior to MDA implementation, the total population at risk was 79.8 million with 26.0 million (32.5%) mf-positive individuals, of whom 17.5 million (21.9%) had some form of onchocercal skin or eye disease (2.5 million DALYs lost). By 2030, the total population was predicted to increase to 236.1 million, while the number of mf-positive cases (about 6.8 million, 2.9%), people with skin or eye morbidity (4.2 million, 1.8%), and DALYs lost (0.7 million) were predicted to decline. CONCLUSIONS: MDA has had a remarkable impact on the onchocerciasis burden in countries previously under the APOC mandate. In the few countries where we predict continued transmission between now and 2030, intensified MDA could be combined with local vector control efforts, or the introduction of new drugs for mopping up residual cases of infection and morbidity.

Model-Informed Drug Development for Anti-Infectives: State of the Art and Future.

Model-informed drug development (MIDD) has a long and rich history in infectious diseases. This review describes foundational principles of translational anti-infective pharmacology, including choice of appropriate measures of exposure and pharmacodynamic (PD) measures, patient subpopulations, and drug-drug interactions. Examples are presented for state-of-the-art, empiric, mechanistic, interdisciplinary, and real-world evidence MIDD applications in the development of antibacterials (review of minimum inhibitory concentration-based models, mechanism-based pharmacokinetic/PD (PK/PD) models, PK/PD models of resistance, and immune response), antifungals, antivirals, drugs for the treatment of global health infectious diseases, and medical countermeasures. The degree of adoption of MIDD practices across the infectious diseases field is also summarized. The future application of MIDD in infectious diseases will progress along two planes; "depth" and "breadth" of MIDD methods. "MIDD depth" refers to deeper incorporation of the specific pathogen biology and intrinsic and acquired-resistance mechanisms; host factors, such as immunologic response and infection site, to enable deeper interrogation of pharmacological impact on pathogen clearance; clinical outcome and emergence of resistance from a pathogen; and patient and population perspective. In particular, improved early assessment of the emergence of resistance potential will become a greater focus in MIDD, as this is poorly mitigated by current development approaches. "MIDD breadth" refers to greater adoption of model-centered approaches to anti-infective development. Specifically, this means how various MIDD approaches and translational tools can be integrated or connected in a systematic way that supports decision making by key stakeholders (sponsors, regulators, and payers) across the entire development pathway.