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Background. Infections with Strongyloides stercoralis are of considerable public health relevance. Moxidectin, a well-established drug in veterinary medicine under consideration for regulatory submission for the treatment of onchocerciasis, might serve as an alternative to the widely used ivermectin. Methods. We conducted an exploratory, randomized, single-blind trial to evaluate the efficacy and safety of moxidectin (8 mg) vs ivermectin (200 μg/kg) against S. stercoralis infections. Cure rate (CR) against S. stercoralis was the primary outcome. Safety and efficacy against coinfections with soil-transmitted helminths and Opisthorchis viverrini were secondary outcomes. Noninferiority required the lower limit of the 95% confidence interval (CI) of the differences in CRs not exceed 7 percentage points. Results. A total of 127 participants were enrolled and randomly assigned to the 2 treatments whereby 1 participant per arm was lost to follow-up. We observed a CR of 93.7% (59/63) for moxidectin compared to 95.2% (59/62) for ivermectin. Differences between CRs were estimated as − percentage points (95% CI, −9.6 to 6.5), thus the lower limit of the CI exceeds the noninferiority margin of 7 percentage points. No side effects were observed. CRs against hookworm infection were 57% (moxidectin) and 56% (ivermectin). Low efficacy for both drugs against O. viverrini was observed. Conclusions. Moxidectin might be a safe and efficacious alternative to ivermectin for the treatment of S. stercoralis infection, given that only slight differences in CRs were observed. However, noninferiority could not be demonstrated. Larger clinical trials should be conducted once the drug is marketed. Clinical Trials Registration. Current Controlled Trials: ISRCTN11983645

Recent findings from onchocerciasis-endemic foci uphold that increasing ivermectin coverage reduces the epilepsy incidence, and anecdotal evidence suggests seizure frequency reduction in persons with onchocerciasis-associated epilepsy, when treated with ivermectin. We conducted a randomized clinical trial to assess whether ivermectin treatment decreases seizure frequency. A proof-of-concept randomized clinical trial was conducted in the Logo health zone in the Ituri province, Democratic Republic of Congo, to compare seizure frequencies in onchocerciasis-infected persons with epilepsy (PWE) randomized to one of two treatment arms: the anti-epileptic drug phenobarbital supplemented with ivermectin, versus phenobarbital alone. The primary endpoint was defined as the probability of being seizure-free at month 4. A secondary endpoint was defined as >50% reduction in seizure frequency at month 4, compared to baseline. Both endpoints were analyzed using multiple logistic regression. In longitudinal analysis, the probability of seizure freedom during the follow-up period was assessed for both treatment arms by fitting a logistic regression model using generalized estimating equations (GEE). Ninety PWE enrolled between October and November 2017 were eligible for analysis. A multiple logistic regression analysis showed a borderline association between ivermectin treatment and being seizure-free at month 4 (OR: 1.652, 95% CI 0.975-2.799; p = 0.062). There was no significant difference in the probability of experiencing >50% reduction of the seizure frequency at month 4 between the two treatment arms. Also, treatment with ivermectin did not significantly increase the odds of being seizure-free during the individual follow-up visits. Whether ivermectin has an added value in reducing the frequency of seizures in PWE treated with AED remains to be determined. A larger study in persons with OAE on a stable AED regimen and in persons with recent epilepsy onset should be considered to further investigate the potential beneficial effect of ivermectin treatment in persons with OAE. Registration: www.clinicaltrials.gov; NCT03052998.

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.

The risk of severe adverse events following treatment of onchocerciasis with ivermectin in areas co-endemic with loiasis currently compromises the development of control programmes and the treatment of co-infected individuals. We therefore assessed whether doxycycline treatment could be used without subsequent ivermectin administration to effectively deliver sustained effects on Onchocerca volvulus microfilaridermia and adult viability. Furthermore we assessed the safety of doxycycline treatment prior to ivermectin administration in a subset of onchocerciasis individuals co-infected with low to moderate intensities of Loa loa microfilaraemia. A double-blind, randomized, field trial was conducted of 6 weeks of doxycycline (200 mg/day) alone, doxycycline in combination with ivermectin (150 microg/kg) at +4 months or placebo matching doxycycline + ivermectin at +4 months in 150 individuals infected with Onchocerca volvulus. A further 22 individuals infected with O. volvulus and low to moderate intensities of Loa loa infection were administered with a course of 6 weeks doxycycline with ivermectin at +4 months. Treatment efficacy was determined at 4, 12 and 21 months after the start of doxycycline treatment together with the frequency and severity of adverse events. One hundred and four (60.5%) participants completed all treatment allocations and follow up assessments over the 21-month trial period. At 12 months, doxycycline/ivermectin treated individuals had lower levels of microfilaridermia and higher frequency of amicrofilaridermia compared with ivermectin or doxycycline only groups. At 21 months, microfilaridermia in doxycycline/ivermectin and doxycycline only groups was significantly reduced compared to the ivermectin only group. 89% of the doxycycline/ivermectin group and 67% of the doxycycline only group were amicrofilaridermic, compared with 21% in the ivermectin only group. O. volvulus from doxycycline groups were depleted of Wolbachia and all embryonic stages in utero. Notably, the viability of female adult worms was significantly reduced in doxycycline treated groups and the macrofilaricidal and sterilising activity was unaffected by the addition of ivermectin. Treatment with doxycycline was well tolerated and the incidence of adverse event to doxycycline or ivermectin did not significantly deviate between treatment groups. A six-week course of doxycycline delivers macrofilaricidal and sterilizing activities, which is not dependent upon co-administration of ivermectin. Doxycycline is well tolerated in patients co-infected with moderate intensities of L. loa microfilariae. Therefore, further trials are warranted to assess the safety and efficacy of doxycycline-based interventions to treat onchocerciasis in individuals at risk of serious adverse reactions to standard treatments due to the co-occurrence of high intensities of L. loa parasitaemias. The development of an anti-wolbachial treatment regime compatible with MDA control programmes could offer an alternative to the control of onchocerciasis in areas of co-endemicity with loiasis and at risk of severe adverse reactions to ivermectin. Controlled-Trials.com ISRCTN48118452.

Objective Sierra Leone, a country where onchocerciasis is endemic in 14 of the 16 districts, was the focus of our investigation. Despite 17 rounds of annual ivermectin treatment since 2005, a report circulated by a local politician indicated an increase in cases of suspected onchocerciasis-related vision impairment in two villages (Mangobo and Petifu) in Tonkolili district. In response, the National Neglected Tropical Disease Program conducted a comprehensive investigation. Ophthalmological, parasitological, and serological tests were conducted using standard procedures to determine the relationship between self-reported vision loss and onchocerciasis in adults. In addition, serological tests were carried out on children aged 5 to 9 years to assess the recent status of exposure to onchocerciasis in the two villages. Results Reported vision loss in 37 patients was mainly due to cataracts (35.1%), allergic conjunctivitis (18.9%), refractive error (10.8%), and other conditions not related to onchocerciasis. There were 40.7% of all adults ( N  = 54) tested and 29.0% of 31 persons with self-reported vision loss who were positive for Ov-16 IgG4 antibodies, suggesting a history of exposure to onchocerciasis. However, otoscopic eye examinations and microscopic skin snip tests were all negative for Onchocerca volvulus microfilariae, indicating no active or low-intensity infection among adults and a low or zero risk of serious ocular morbidity in the two villages. Onchocerciasis may no longer be a major cause of blindness in these two villages. Apparently, 4.6% of 153 children aged 5 to 9 years tested positive for Ov-16 IgG4 antibodies, suggesting that onchocerciasis transmission is likely still ongoing in the two villages. The data presented here suggest that more annual rounds of mass treatment with ivermectin with high coverage are needed to eliminate onchocerciasis transmission in this area.

Lymphatic filariasis and onchocerciasis are parasitic helminth diseases that constitute a serious public health issue in tropical regions. The filarial nematodes that cause these diseases are transmitted by blood-feeding insects and produce chronic and long-term infection through suppression of host immunity. Disease pathogenesis is linked to host inflammation invoked by the death of the parasite, causing hydrocoele, lymphoedema, and elephantiasis in lymphatic filariasis, and skin disease and blindness in onchocerciasis. Most filarial species that infect people co-exist in mutualistic symbiosis with Wolbachia bacteria, which are essential for growth, development, and survival of their nematode hosts. These endosymbionts contribute to inflammatory disease pathogenesis and are a target for doxycycline therapy, which delivers macrofilaricidal activity, improves pathological outcomes, and is effective as monotherapy. Drugs to treat filariasis include diethylcarbamazine, ivermectin, and albendazole, which are used mostly in combination to reduce microfilariae in blood (lymphatic filariasis) and skin (onchocerciasis). Global programmes for control and elimination have been developed to provide sustained delivery of drugs to affected communities to interrupt transmission of disease and ultimately eliminate this burden on public health.

Many studies have suggested that onchocerciasis might be associated with epilepsy. Therefore, we did a cohort study to assess the incidence of epilepsy relative to Onchocerca volvulus skin microfilarial density (MFD) measured during childhood and to assess the possibility of a temporal relationship. During onchocerciasis surveys undertaken in 25 villages in Cameroon during 1991–93, we measured MFD in individuals aged 5 years or older. In 2017, we revisited seven of these villages. With a standardised five-item questionnaire, we collected information on the occurrence of epilepsy in 856 individuals who were aged 5–10 years in 1991–93, and had MFD determined during the original surveys. We did multivariable analyses to assess the overall incidence and incidence ratios taking into account age, sex, individual MFD in 1991–93, and onchocerciasis endemicity level in the village. In 2017, we obtained data on the history of epilepsy for 85% (729 of 856) of individuals. Among these individuals, we classified 60 as being suspected cases of epilepsy. The overall incidence of epilepsy was 350 per 100 000 person-years (95% CI 270–450). The adjusted incidence ratio for developing epilepsy was 7·07 (95% CI 0·98–51·26; p=0·0530) in individuals with initial MFD of one to five microfilariae per skin snip (mf per snip), 11·26 (2·73–46·43) in individuals with six to 20 mf per snip, 12·90 (4·40–37·83) in individuals with 21–50 mf per snip, 20·00 (3·71–108·00) in individuals with 51–100 mf per snip, 22·58 (3·21–158·56) in individuals with 101–200 mf per snip, and 28·50 (95% CI 3·84–211·27; p=0·0010) in individuals with more than 200 mf per snip, compared with that of individuals without detectable densities of skin microfilariae. Individual O volvulus MFD in childhood was associated with the risk of either seizures or epilepsy in an onchocerciasis focus in Cameroon. This temporal relationship suggests a potential causal link between onchocerciasis and epilepsy. European Research Council, NSETHIO Project.

Treatment of onchocerciasis or lymphatic filariasis has been thwarted by concerns of serious complications related to the presence of L. loa infection. This report shows that leveraging digital technology allows ivermectin to be safely administered in large communities in Cameroon.

[...]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].

Community-directed treatment with ivermectin (CDTi) is used to eliminate onchocerciasis. However, despite 25 years of annual CDTi in Mahenge, Tanzania, the prevalence of onchocerciasis and onchocerciasis-associated epilepsy remained high in certain rural villages. Therefore, in 2019, bi-annual CDTi was introduced in the area. This study assessed the impact of the programme on the incidence of epilepsy in four villages. Door-to-door epilepsy surveys were conducted prior to (2017/18) and after (2021) implementing a bi-annual CDTi program. All household members were screened for epilepsy symptoms using a validated questionnaire, and suspected cases were examined by a medical doctor to confirm/reject the diagnosis of epilepsy. The prevalence and annual incidence of epilepsy, including nodding syndrome, were calculated with 95% Wilson confidence intervals with continuity correction. The latter was also done for CDTi coverage in 2016 and 2021. Precisely 5,444 and 6,598 persons were screened for epilepsy before and after implementing the intervention. The CDTi coverage of the overall population was 82.3% (95%CI: 81.3-83.2%) in 2021 and sustained in both distribution rounds (81.5% and 76.8%). The coverage was particularly high in children and teenagers aged 6 to 18 years (93.2%, 95%CI: 92.1-94.2%). The epilepsy prevalence remained similar: 3.3% (95%CI: 2.9-3.9%) in 2017/18 versus 3.1% (95%CI: 2.7-3.5%) in 2021. However, the incidence of epilepsy declined from 177.6 (95%CI: 121.2-258.5) in 2015-2017 and 2016-2018 to 45.5 (95%CI: 22.2-89.7) in 2019-2021 per 100,000 persons-years. The incidence of probable nodding syndrome varied from 18.4 (95%CI: 4.7-58.5) to 5.1 (95%CI: 0.3-32.8). None of the nine incidence cases of epilepsy for which information on ivermectin intake was available took ivermectin in the year they developed their first seizures. A bi-annual CDTi programme should be implemented in areas with high prevalence of onchocerciasis and epilepsy. High CDTi coverage among children is particularly important to prevent onchocerciasis-associated epilepsy.