A Randomized, Double-Blind Clinical Trial of a 3-Week Course of Doxycycline plus Albendazole and Ivermectin for the Treatment of Wuchereria bancrofti Infection

Abstract

Treatment with doxycycline for 3 weeks is more effective in inducing a long-term amicrofilaremia than is standard treatment alone, but it is ineffective at inducing curative effects. Inflammatory reactions to antifilarial treatment are associated with levels of microfilariae and Wolbachia endosymbionts released into plasma.

Macrofilaricidal Activity and Amelioration of Lymphatic Pathology in Bancroftian Filariasis after 3 Weeks of Doxycycline Followed by Single-Dose Diethylcarbamazine

“…8 Compared with these studies, the 21-day course of doxycycline reported here resulted in an equivalent macrofilaricidal activity (93.3%). In the study in Ghana by Turner and others, 10 doxycycline given for 21 days did not reduce Wolbachia as much as it did in this study, and no macrofilaricidal effect was observed. Whether the macrofilaricidal effect in the 21-day doxycycline group seen in this trial resulted from the combination with DEC, which also has macrofilaricidal activity whereas ivermectin does not, or from the stronger Wolbachia reduction seen before the administration of DEC cannot be decided at present.…”

“…A 3-week course of doxycycline treatment followed by a single dose of ivermectin plus albendazole showed a reduction in Wolbachia single gene copies/Mf of ~80% and led to a sustained absence of microfilaremia for > 1 year 10 ; however, no macrofilaricidal activity was observed with this regimen. Because most LF pathologies are induced by adult worms rather than Mf, it is important to determine the threshold, or minimum treatment duration of doxycycline in combination with one of the classically used drugs that retains macrofilaricidal activity and improves lymphatic pathology.…”

“…Before the initiation of doxycycline treatment, the Mf load was assessed by microscopic examination of finger prick night blood samples as published. 10 Subsequently, eligible patients donated 10 mL of venous blood for accurate Mf quantification using the Whatman Nucleopore filter method as described previously. 11 Afterward, using a microscope and fine glass pipette, 100 Mf were picked from the remaining blood and lyophilized for later DNA extraction.…”

“…8,9 In the placebo group, no significant change of Wolbachia per Mf could be observed. Interestingly, in our earlier study in Ghana 10 where doxycycline was also administered for 3 weeks, Wolbachia copy numbers were only reduced by 80% after 4 months (i.e., before any other combination drug was administered). The reasons for this lower performance of doxycycline in Africa is not clear, but reasons like different nourishment are likely because it is known from systematic studies in animals that these factors result in better pharmacokinetics and bioavailability of doxycycline.…”

Innate Immune Responses to Endosymbiotic Wolbachia Bacteria in Brugia malayi and Onchocerca volvulus Are Dependent on TLR2, TLR6, MyD88, and Mal, but Not TLR4, TRIF, or TRAM

“…In filarial worms, Wolbachia bacteria are concentrated in intracytoplasmic vacuoles of hypodermal lateral cords and female reproductive organs and are also detectable in oocytes and microfilaria, reflecting matrilinear inheritance (16). Nematode reproduction, molting, and survival dependent on the endosymbiont as prolonged exposure to antibiotics targeting Wolbachia result in decreased fecundity, impaired molting, and even worm death in vitro as well as in animal and human infections (17)(18)(19)(20). Results of studies of filaria-infected individuals are consistent with the hypothesis that Wolbachia contribute to the pathogenesis of filarial disease.…”