Uncertainty surrounding projections of the long-term impact of ivermectin treatment on human onchocerciasis

Abstract

Background: Recent studies in Mali, Nigeria, and Senegal have indicated that annual (or biannual) ivermectin distribution may lead to local elimination of human onchocerciasis in certain African foci. Modelling-based projections have been used to estimate the required duration of ivermectin distribution to reach elimination. A crucial assumption has been that microfilarial production by Onchocerca volvulus is reduced irreversibly by 30-35% with each (annual) ivermectin round. However, other modelling-based analyses suggest that ivermectin may not have such a cumulative effect. Uncertainty in this (biological) and other (programmatic) assumptions would affect projected outcomes of long-term ivermectin treatment.

Methodology/principal findings: We modify a deterministic age- and sex-structured onchocerciasis transmission model, parameterised for savannah O. volvulus-Simulium damnosum, to explore the impact of assumptions regarding the effect of ivermectin on worm fertility and the patterns of treatment coverage compliance, and frequency on projections of parasitological outcomes due to long-term, mass ivermectin administration in hyperendemic areas. The projected impact of ivermectin distribution on onchocerciasis and the benefits of switching from annual to biannual distribution are strongly dependent on assumptions regarding the drug's effect on worm fertility and on treatment compliance. If ivermectin does not have a cumulative impact on microfilarial production, elimination of onchocerciasis in hyperendemic areas may not be feasible with annual ivermectin distribution.

Conclusions/significance: There is substantial (biological and programmatic) uncertainty surrounding modelling projections of onchocerciasis elimination. These uncertainties need to be acknowledged for mathematical models to inform control policy reliably. Further research is needed to elucidate the effect of ivermectin on O. volvulus reproductive biology and quantify the patterns of coverage and compliance in treated communities.

Figure 1. Schematic representation of two different proposed effects of ivermectin on Onchocerca volvulus microfilarial production.

The schematic represents a closed population of adult worms (i.e., no incoming worms due to transmission or worm death). A: Ivermectin is assumed to have a cumulative effect on adult worm fertility by which the microfilarial production of ivermectin-exposed adult worms is reduced by 30% after each treatment round (red solid line). B: Ivermectin is assumed not to have a cumulative effect; ivermectin-exposed adult worms resume microfilarial production to 70% of its baseline value ten months after each treatment (blue solid line).

Figure 2. Impact on infection intensity of annual ivermectin distribution under two assumptions of ivermectin effects.

Intensity of infection is quantified as microfilarial load per mg of skin in those aged ≥20 years. The red and blue solid lines represent, respectively, model outputs assuming the operation of a cumulative impact on the fertility of O. volvulus (illustrated in Fig. 1A), or the absence of such an effect (Fig. 1B). Model calibration corresponds to an ABR of 19,000 (savannah) Simulium damnosum bites/person/year; a baseline mean microfilarial load of 44 mf/mg (in those aged ≥20 years); a 70% microfilarial prevalence (all ages); a therapeutic coverage of 80% (overall population); and a systematic non-compliance rate of 0.1%. The demography of the human population is that of northern Cameroon , , .

Figure 3. Impact on infection prevalence of annual/biannual ivermectin distribution under two assumptions of ivermectin effects.

Solid and dashed lines represent, respectively, annual and biannual treatment frequency. A: Red lines correspond to model outputs assuming that ivermectin exerts a cumulative reduction in microfilarial production by the adult female worm. B: Blue lines correspond to model outputs assuming the absence of such cumulative reduction. Calibration of the model is as in Figure 2.

Figure 4. The effect of coverage and compliance on infection intensity after 15 years of ivermectin treatment.

Intensity of infection is quantified as microfilarial load per mg of skin in those aged ≥20 years. The values presented correspond to one year after the 15^th treatment (for annual frequency, Fig. 4A), or one year after the 30^th treatment (for biannual frequency, Fig. 4B). Red and blue bars represent, respectively, a cumulative and a non-cumulative effect of ivermectin on microfilarial production by the female worm. Dotted bars: 0.1% systematic non-compliance; hashed bars: 2% systematic non-compliance; solid bars: 5% systematic non-compliance. Calibration of the model is as in Figure 2. Note the different scale on the vertical axis between 4A and 4B.