Macrofilaricidal Activity after Doxycycline Only Treatment of Onchocerca volvulus in an Area of Loa loa Co-Endemicity: A Randomized Controlled Trial

Abstract

BackgroundThe 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.MethodsA double-blind, randomized, field trial was conducted of 6 weeks of doxycycline (200 mg/day) alone, doxycycline in combination with ivermectin (150 µg/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.ResultsOne 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.ConclusionsA 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 o...

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

“…We included three studies with a total of 466 participants with a diagnosis of onchocerciasis (Hoerauf 2008; Masud 2009; Turner 2010). We later learned from the study investigator that one study that we had initially included on the basis of the full-text report was not randomized, but rather was quasi-randomized (Masud 2009).…”

Pattern recognition receptors in microbial keratitis

“…Meanwhile the endosymbiotic nature of O. volvulus with Wolbachia bacteria has led to trials of doxycycline being used to deplete the bacteria and facilitate treatment of the worms. [212][213][214] Corneal infiltrates in non-keratitic diseases show some promise and offer another avenue of exploration: a case report of cryopyrin associated periodic fever syndrome, in which a mutation in the NLRP3 gene causes overexpression of IL-1β, demonstrated successful treatment outcomes with IL-1β monoclonal antibody kanakinumab, 215 and anakira, an IL-1 antagonist, has been used successfully in corneal infiltrates. 216 Currently, there is strong interest in the use of collagen cross-linking (CXL) using ultraviolet-A (UV-A) light and riboflavin is a treatment of infectious keratitis.…”

A lack of confirmation with alternative assays questions the validity of IL-17A expression in human neutrophils using immunohistochemistry

“…The combination of stimuli from the filarial nematode and its bacterial endosymbiont Wolbachia could promote a cytokine milieu favourable for the induction of an IL-17-mediated immune response [22], but little is currently known about the actual presence and role of such a response in filariasis [23][24][25]. We identified IL-17A expressing neutrophils in Wolbachia-positive Onchocerca volvulus nodules from infected Cameroonian patients [26] using immunohistochemistry (IHC) staining with a commercially available antibody (R&D Systems, goat polyclonal anti-IL-17A, Nodules from patients infected with O. volvulus were surgically removed, fixed in 80% ethanol and paraffin-embedded as part of the evaluation of a phase II trial of doxycycline [26]. Sections of 4 m were cut by microtome and mounted in an electrothermal bath at 45 • C on poly l-lysine slides (which were incubated overnight at 58 • C before use).…”