The macrofilaricidal efficacy of repeated doses of ivermectin for the treatment of river blindness

Abstract

Background Mass drug administration (MDA) with ivermectin is the cornerstone of efforts to eliminate human onchocerciasis by 2020/2025. 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, but rigorous quantification of these effects necessitates interrogating longitudinal data on macrofilariae with suitably powerful analytical techniques. Methods Using a novel mathematical modelling approach, we analysed―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 three-monthly with annual treatments administered for three years, in Cameroon. Results Multiple doses of ivermectin have a partial macrofilaricidal and a modest permanent sterilising effect after 4 or more consecutive treatments, even at routine MDA doses (150 g/kg) and (annual) frequencies. The life expectancy of adult O. volvulus is reduced by approximately 50% and 70% after three years of annual or three-monthly (quarterly) exposures to ivermectin. Conclusions Our quantification of macrofilaricidal and sterilising effects of ivermectin should be incorporated into transmission models informing onchocerciasis elimination efforts in Africa and residual foci in Latin America. It also provides a framework to assess macrofilaricidal candidate drugs currently under development.