Abstract
Depletion of Wolbachia endosymbionts of human pathogenic filariae using 4–6 weeks of doxycycline treatment can lead to permanent sterilization and adult filarial death. We investigated the anti-Wolbachia drug candidate ABBV-4083 in the Litomosoides sigmodontis rodent model to determine Wolbachia depletion kinetics with different regimens. Wolbachia reduction occurred in mice as early as 3 days after the initiation of ABBV-4083 treatment and continued throughout a 10-day treatment period. Importantly, Wolbachia levels continued to decline after a 5-day-treatment from 91.5% to 99.9% during a 3-week washout period. In jirds, two weeks of ABBV-4083 treatment (100mg/kg once-per-day) caused a >99.9% Wolbachia depletion in female adult worms, and the kinetics of Wolbachia depletion were recapitulated in peripheral blood microfilariae. Similar to Wolbachia depletion, inhibition of embryogenesis was time-dependent in ABBV-4083-treated jirds, leading to a complete lack of late embryonic stages (stretched microfilariae) and lack of peripheral microfilariae in 5/6 ABBV-4083-treated jirds by 14 weeks after treatment. Twice daily treatment in comparison to once daily treatment with ABBV-4083 did not significantly improve Wolbachia depletion. Moreover, up to 4 nonconsecutive daily treatments within a 14-dose regimen did not significantly erode Wolbachia depletion. Within the limitations of an animal model that does not fully recapitulate human filarial disease, our studies suggest that Wolbachia depletion should be assessed clinically no earlier than 3–4 weeks after the end of treatment, and that Wolbachia depletion in microfilariae may be a viable surrogate marker for the depletion within adult worms. Furthermore, strict daily adherence to the dosing regimen with anti-Wolbachia candidates may not be required, provided that the full regimen is subsequently completed.
Highlights
Onchocerciasis and lymphatic filariasis are neglected tropical diseases that are caused by the filarial nematodes Onchocerca volvulus and Wuchereria bancrofti, Brugia malayi and Brugia timori, respectively [1]
Onchocerciasis and lymphatic filariasis represent debilitating neglected tropical diseases that are caused by parasitic filarial nematodes
The present studies addressed several points that are important for subsequent phase 2 clinical trials, namely the comparison of once vs. twiceper-day treatments, the impact of missed treatments, and a comparison of the kinetics of Wolbachia depletion in adult worms and microfilariae, the latter of which has the potential to be a surrogate indicator to avoid the necessity of surgically removing nodules with adult worms at repeated time points
Summary
Onchocerciasis and lymphatic filariasis are neglected tropical diseases that are caused by the filarial nematodes Onchocerca volvulus and Wuchereria bancrofti, Brugia malayi and Brugia timori, respectively [1]. Mass drug administrations have been performed over the last decades with ivermectin for onchocerciasis in sub-Saharan Africa, ivermectin plus albendazole for lymphatic filariasis in sub-Saharan Africa, and diethylcarbamazine (DEC) plus albendazole for lymphatic filariasis outside of Africa [2, 3] These regimens are mainly microfilaricidal, leading to the loss of the filarial offspring, the microfilariae. Administration of a triple therapy consisting of ivermectin, DEC and albendazole was introduced for lymphatic filariasis, and it is recommended by the WHO in areas non-endemic for onchocerciasis [5], as it leads to a prolonged depletion of the microfilariae and may provide macrofilaricidal efficacy [6, 7]. New macrofilaricidal drugs are needed for case management and for clearance of residual foci in order to eliminate onchocerciasis and lymphatic filariasis
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