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Lymphatic filariasis caused by Wuchereria bancrofti causes hydroceles and lymphedema in millions of individuals worldwide. Annual mass drug administration of ivermectin plus albendazole (IA) temporarily clears microfilariae from the blood of infected individuals and is used in Africa to reduce W bancrofti transmission. This study aimed to investigate whether moxidectin combination therapies are superior to ivermectin combination therapies for clearance of W bancrofti microfilaremia. In this open-label, parallel assignment, masked-observer, randomised, superiority clinical trial in Côte d'Ivoire, we used gender-stratified, block randomisation to sequentially assign adults with bancroftian filariasis (1:1:1:1) to receive annual ivermectin plus albendazole (IA; standard of care) or one of three single-dose regimens: moxidectin plus albendazole (MoxA), ivermectin plus diethylcarbamazine (DEC) plus albendazole (IDA), or moxidectin plus DEC plus albendazole (MoxDA). This trial was conducted at the Filariasis Research Center in Agboville, located at the Centre Hôspitalier Regional, d'Agboville, Côte d'Ivoire. Men and non-pregnant, non-breastfeeding women aged 18–70 years in good general health and with screening microfilaria loads of at least 40 per mL (≥3 microfilariae on 60μL nocturnal thick blood smear) were eligible for enrolment; those found to have at least 40 microfilariae per mL by 1 mL blood filtration at enrolment were eligible for inclusion in the primary, modified intention-to-treat, efficacy analysis. Medicines were administered by an unmasked pharmacist; all other team members were masked to treatment assignment. Primary outcomes were complete microfilaria clearance at 12 months (MoxA vs IA) or 24 months (MoxDA vs IDA) post-treatment. This trial is registered at ClinicalTrials.gov (NCT04410406) and is complete. Enrolment occurred from Aug 20, 2020 to July 31, 2021. 190 individuals were predicted to have nocturnal blood microfilariae counts of at least 40 microfilariae per mL, of whom 26 were excluded and 164 were randomly assigned to an intervention (41 to the IA group, 40 to the MoxA group, 41 to the IDA group, and 42 to the MoxDA group). 113 participants met the pre-specified efficacy analysis criteria and completed follow-up. The proportion of participants who were amicrofilaraemic at 12 months was eight of 25 (32% [95% CI 15–54]) among IA recipients versus 18 of 19 (95% [95% CI 74–100]) among MoxA recipients (adjusted risk ratio [RR] 2·79 [95% CI 1·59–4·90]; p=0·0004). The proportion of amicrofilaraemic participants at 24 months was 20 of 22 (91% [95% CI 71–99]) for IDA versus 21 of 23 (91% [72–99]) for MoxDA (adjusted RR 0·98 [95% CI 0·83–1·15]; p=0·78). Most MoxA recipients (14 of 16 [88%; 95% CI 62–98]) remained amicrofilaraemic at 24 months. In this study, single-dose MoxA was superior to IA for W bancrofti microfilaria clearance at 12 months and provided prolonged microfilaria clearance for most participants. These results suggest that MoxA could be a powerful tool to accelerate the elimination of lymphatic filariasis in Africa. The Bill & Melinda Gates Foundation. For the French translation of the abstract see Supplementary Materials section.

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.

Background. The aim of this study was to determine whether improvement of filarial lymphedema (LE) by doxycycline is restricted to patients with ongoing infection (positive for circulating filarial antigen [CFA]), or whether the majority of CFA-negative patients with LE would also show a reduction in LE severity. Methods. One hundred sixty-two Ghanaian participants with LE stage 1–5 (Dreyer) were randomized blockwise into 2 groups (CFA positive or negative) and allocated to 3 treatment arms of 6 weeks: (1) amoxicillin (1000 mg/d), (2) doxycycline (200 mg/d), or (3) placebo matching doxycycline. All groups received standard hygiene morbidity management. The primary outcome was reduction of LE stages. Secondary outcomes included frequency of acute attacks and ultrasonographic assessment of skin thickness at the ankles. Parameters were assessed before treatment and after 3, 12, and 24 months. Results. Doxycycline-treated patients with LE stage 2–3 showed significant reductions in LE severity after 12 and 24 months, regardless of CFA status. Improvement was observed in 43.9% of doxycycline-treated patients, compared with only 3.2% and 5.6% in the amoxicillin and placebo arms, respectively. Skin thickness was correlated with LE stage improvement. Both doxycycline and amoxicillin were able to reduce acute dermatolymphangioadenitis attacks. Conclusions. Doxycycline treatment improves mild to moderate LE independent of ongoing infection. This finding expands the benefits of doxycycline to the entire population of patients suffering from LE. Patients with LE stage 1–3 should benefit from a 6-week course of doxycycline every other year or yearly, which should be considered as an improved tool to manage morbidity in filarial LE. Clinical Trials Registration. ISRCTN 90861344.

Lymphatic filariasis is widely endemic in Myanmar. Despite the establishment of an elimination program in 2000, knowledge of the remaining burden of disease relies predominantly on programmatic information. To assist the program, we conducted an independent cross-sectional household cluster survey to determine the prevalence of filariasis infection, morbidity and mass-drug administration coverage in four townships of the Mandalay Region: Amarapura, Patheingyi, Tada-U and Wundwin. The survey included 1014 individuals from 430 randomly selected households in 24 villages. Household members one year and older were assessed for antigenaemia using immunochromatographic test cards and if positive, microfilaraemia by night-time thick blood smear. Participants 15 years and older were assessed for filariasis morbidity by ultrasound-assisted clinical examination. The overall prevalence of infection was 2.63% by antigenaemia (95% confidence interval (CI) 1.71-4.04%) and 1.03% by microfilaraemia (95%CI 0.59-1.47%). The prevalence of hydrocoele in adult males was 2.78% (95%CI 1.23-6.15%) and of lymphoedema in both genders was 0% (95%CI 0-0.45%). These results indicate the persistence of filarial infection and transmission despite six rounds of annual mass drug administration and highlight the need for further rounds as well as the implementation of morbidity management programs in the country.

There is no effective therapy for Mansonella perstans , a cause of lymphatic filariasis. In this study, patients were randomly assigned to receive treatment with doxycycline for 6 weeks, targeting the endosymbiont wolbachia, or no treatment. M. perstans microfilaremia was undetectable at 12 months in 67 of 69 treated patients (97%), as compared with 10 of 63 untreated patients (16%). Patients were randomly assigned to receive treatment with doxycycline for 6 weeks, targeting the endosymbiont wolbachia, or no treatment. M. perstans microfilaremia was undetectable at 12 months in 97% of treated patients, as compared with 16% of untreated patients. The filarial parasite Mansonella perstans is endemic in central and western Africa, with a distribution that overlaps that of Wuchereria bancrofti , Loa loa , and Onchocerca volvulus . Transmitted through the bite of an infected midge (culicoides species), infective M. perstans larvae develop over the course of months into adult worms that reside in the serous cavities and mesentery and retroperitoneal tissues. Microfilariae are carried through the bloodstream, and those of M. perstans can be distinguished from those of L. loa and W. bancrofti by their small size, lack of periodicity, and the absence of a sheath. As is . . .

In a randomized, placebo-controlled trial in Ghana, 67 onchocerciasis patients received 200-mg/day doxycycline for 4–6 weeks, followed by ivermectin (IVM) after 6 months. After 6–27 months, efficacy was evaluated by onchocercoma histology, PCR and microfilariae determination. Administration of doxycycline resulted in endobacteria depletion and female worm sterilization. The 6-week treatment was macrofilaricidal, with >60% of the female worms found dead, despite the presence of new, Wolbachia -containing worms acquired after the administration of doxycycline. Doxycycline may be developed as second-line drug for onchocerciasis, to be administered in areas without transmission, in foci with IVM resistance and in areas with Loa co-infections.

Background. The efficacy of doxycycline for treating the causal agent of human lymphatic filariasis, Brugia malayi, is unknown. Standard treatment with diethylcarbamazine-albendazole is associated with adverse reactions. We assessed whether doxycycline alone or in combination with diethylcarbamazine-albendazole would lead to sustained amicrofilaremia and reduced incidence of adverse reactions. Methods. A double-blind, randomized, placebo-controlled 6-week field trial of doxycycline treatment (100 mg/day) of 161 persons infected with B. malayi was conducted. Four months after receiving doxycycline (n=119) or placebo (n=42), participants received diethylcarbamazine (6 mg/kg) plus albendazole (400 mg) or a matching placebo. Adverse reactions were assessed 48 and 60 h after administration of diethylcarbamazine-albendazole. Treatment efficacy was evaluated at 2, 4, and 12 months after the initial doxycycline treatment. Results. Four months after beginning doxycycline treatment, Wolbachia loads were reduced by 98%. Doxycycline treatment reduced the prevalence of microfilaremia at 2, 4, and 12 months of follow-up (P<.001 for all time points). At the 1-year follow-up, prevalence was reduced by 77% and 87.5% in patients receiving doxycycline alone or doxycycline plus diethylcarbamazine-albendazole, respectively. In contrast, the reduction of microfilaremia in the group receiving placebo doxycycline plus diethylcarbamazine-albendazole was merely 26.7%. Adverse reactions were lowest in the group receiving doxycycline plus placebo diethylcarbamazine-albendazole and highest in the group receiving placebo doxycycline plus diethylcarbamazine-albendazole. The proportion of persons with high fever and severe adverse reactions was significantly reduced in the group treated with doxycycline plus diethylcarbamazine-albendazole. Conclusions. A 6-week course of doxycycline, either alone or in combination with diethylcarbamazine-albendazole, leads to a decrease in microfilaremia and reduces adverse reactions to antifilarial treatment in B. malayi—infected persons.

Once interruption of transmission of lymphatic filariasis is achieved, morbidity prevention and management becomes more important. A study in Brugia malayi filariasis from India has shown sub-clinical lymphatic pathology with potential reversibility. We studied a Wuchereria bancrofti infected population, the major contributor to LF globally. Children aged 5-18 years from Odisha, India were screened for W. bancrofti infection and disease. 102 infected children, 50 with filarial disease and 52 without symptoms were investigated by lymphoscintigraphy and then randomized to receive a supervised single oral dose of DEC and albendazole which was repeated either annually or semi-annually. The lymphatic pathology was evaluated six monthly for two years. Baseline lymphoscintigraphy showed abnormality in lower limb lymphatics in 80% of symptomatic (40/50) and 63·5% (33/52) of asymptomatic children. Progressive improvement in baseline pathology was seen in 70·8, 87·3, 98·6, and 98·6% of cases at 6, 12, 18, and 24 months follow up, while in 4·2, 22·5, 47·9 and 64·8%, pathology reverted to normal. This was independent of age (p = 0·27), symptomatic status (p = 0·57) and semi-annual/bi-annual dosing (p = 0·46). Six of eleven cases showed clinical reduction in lymphedema of legs. A significant proportion of a young W. bancrofti infected population exhibited lymphatic pathology which was reversible with annual dosage of DEC and albendazole. This provides evidence for morbidity prevention & treatment of early lymphedema. It can also be used as a tool to improve community compliance during mass drug administration. ClinicalTrials.gov No CTRI/2013/10/004121.

Lymphatic filariasis is a disease of considerable socioeconomic burden in the tropics. Presently used antifilarial drugs are able to strongly reduce transmission and will thus ultimately lower the burden of morbidity associated with the infection, however, a chemotherapeutic principle that directly induces a halt or improvement in the progression of the morbidity in already infected individuals would constitute a major lead. In search of such a more-effective drug to complement the existing ones, in an area endemic for bancroftian filariasis in Ghana, 33 microfilaremic and 18 lymphedema patients took part in a double-blind, placebo-controlled trial of a 6-wk regimen of 200 mg/day doxycycline. Four months after doxycycline treatment, all patients received 150-200 microg/kg ivermectin and 400 mg albendazole. Patients were monitored for Wolbachia and microfilaria loads, antigenemia, filarial dance sign (FDS), dilation of supratesticular lymphatic vessels, and plasma levels of lymphangiogenic factors (vascular endothelial growth factor-C [VEGF-C] and soluble vascular endothelial growth factor receptor-3 [(s)VEGFR-3]). Lymphedema patients were additionally monitored for stage (grade) of lymphedema and the circumferences of affected legs. Wolbachia load, microfilaremia, antigenemia, and frequency of FDS were significantly reduced in microfilaremic patients up to 24 mo in the doxycycline group compared to the placebo group. The mean dilation of supratesticular lymphatic vessels in doxycycline-treated patients was reduced significantly at 24 mo, whereas there was no improvement in the placebo group. Preceding clinical improvement, at 12 mo, the mean plasma levels of VEGF-C and sVEGFR-3 decreased significantly in the doxycycline-treated patients to a level close to that of endemic normal values, whereas there was no significant reduction in the placebo patients. The extent of disease in lymphedema patients significantly improved following doxycycline, with the mean stage of lymphedema in the doxycycline-treated patients being significantly lower compared to placebo patients 12 mo after treatment. The reduction in the stages manifested as better skin texture, a reduction of deep folds, and fewer deep skin folds. In conclusion, a 6-wk regimen of antifilarial treatment with doxycycline against W. bancrofti showed a strong macrofilaricidal activity and reduction in plasma levels of VEGF-C/sVEGFR-3, the latter being associated with amelioration of supratesticular dilated lymphatic vessels and with an improvement of pathology in lymphatic filariasis patients.

In Papua New Guinea, approximately 2500 residents participated in a prospective, four-year study of the effects of a single dose of antifilarial drugs given annually for four years. The proportion of microfilariae-positive infections decreased by 86 to 98 percent, and the frequency of hydrocele declined from 15 percent to 5 percent. Annual mass treatment of a population can virtually eliminate the reservoir of microfilariae. Bancroftian filariasis causes elephantiasis, hydrocele, and economic loss throughout the tropics and subtropics. A global plan for its eradication is based on the notion that mass treatment with antifilarial drugs will reduce the reservoir of microfilariae in the blood to a level that is insufficient to sustain transmission by the mosquito vector. 1 – 3 The feasibility of the strategy is supported by observations that drugs given only once per year (diethylcarbamazine alone, diethylcarbamazine plus ivermectin, albendazole plus ivermectin, or albendazole plus diethylcarbamazine) decrease the reservoir of microfilariae. 4 – 6 The threshold below which transmission will be interrupted is not known, but mathematical . . .