Phenotypic Evidence of Emerging Ivermectin Resistance in Onchocerca volvulus

Abstract

Background

Ivermectin (IVM) has been used in Ghana for over two decades for onchocerciasis control. In recent years there have been reports of persistent microfilaridermias despite multiple treatments. This has necessitated a reexamination of its microfilaricidal and suppressive effects on reproduction in the adult female Onchocerca volvulus. In an initial study, we demonstrated the continued potent microfilaricidal effect of IVM. However, we also found communities in which the skin microfilarial repopulation rates at days 90 and 180 were much higher than expected. In this follow up study we have investigated the reproductive response of female worms to multiple treatments with IVM.

Methods and Findings

The parasitological responses to IVM in two hundred and sixty-eight microfilaridermic subjects from nine communities that had received 10 to 19 annual doses of IVM treatment and one pre-study IVM-naïve community were followed. Skin snips were taken 364 days after the initial IVM treatment during the study to determine the microfilaria (mf) recovery rate. Nodules were excised and skin snips taken 90 days following a second study IVM treatment. Nodule and worm density and the reproductive status of female worms were determined. On the basis of skin mf repopulation and skin mf recovery rates we defined three categories of response—good, intermediate and poor—and also determined that approximately 25% of subjects in the study carried adult female worms that responded suboptimally to IVM. Stratification of the female worms by morphological age and microfilarial content showed that almost 90% of the worms were older or middle aged and that most of the mf were produced by the middle aged and older worms previously exposed to multiple treatments with little contribution from young worms derived from ongoing transmission.

Conclusions

The results confirm that in some communities adult female worms were non-responsive or resistant to the anti-fecundity effects of multiple treatments with IVM. A scheme of the varied responses of the adult female worm to multiple treatments is proposed.

Author Summary

Onchocerciasis, commonly known as river blindness, is caused by the filarial nematode Onchocerca volvulus and is transmitted by a blackfly vector. Over 37 million people are thought to be infected, with over 90 million at risk. Infection predominantly occurs in sub-Saharan Africa. Foci also exist in the Arabian Peninsula and Central and South America. Ivermectin, the sole pharmaceutical available for mass chemotherapy, has been used on a community basis for annual or semi-annual treatment since 1987. Multiple treatments with ivermectin kill the microfilariae that are responsible for the pathology of onchocerciasis. More importantly, ivermectin suppresses the reproductive activity of the adult female worms, thus delaying or preventing the repopulation of the skin with new microfilariae and thereby reducing transmission. This study extends earlier reports of sub-optimal responses to ivermectin by examining repopulation levels of microfilaria one year after treatment, worm burdens per nodule, the age structure of adult female worms recovered from nodules, and the reproductive status of adult female worms 90 days after ivermectin treatment. In some communities which have shown a pattern of sub-optimal response to treatment, the data is consistent with an emergence of ivermectin non response or resistance manifested by a loss of the effect of ivermectin on the suppression of parasite reproduction.