1. Introduction
With an estimated 20.9 million people infected worldwide, of whom over 99% live in sub-Saharan Africa [
1],
Onchocerca volvulus (O. volvulus) infections are an important global health problem.
O. volvulus is a filarial nematode causing onchocerciasis and is transmitted by blackflies (
Simuliidae). Clinical manifestations associated with onchocerciasis include skin and eye disease, nodding syndrome, and other forms of epilepsy (hereafter referred to as onchocerciasis-associated epilepsy (OAE)) [
2]. Adult female worms reside in subcutaneous nodules and produce larvae, called microfilariae (mf), that migrate under the skin.
Ivermectin, a broad-spectrum anti-helmintic drug, rapidly kills mf. A single dose of ivermectin leads to a decline in skin mf density of approximately 99% within the first two months [
3]. Unfortunately, ivermectin does not kill the adult worms, it only temporarily represses mf production by the adult female worms and therefore mf production resumes at a slow rate after approximately 3 to 6 months [
4,
5]. Nonetheless, mf loads are expected to remain below 20% of the pre-ivermectin levels for up to 10 months following a single dose of ivermectin [
3]. Therefore, many onchocerciasis endemic areas have adopted annual or bi-annual community-directed treatment with ivermectin (CDTI) as a strategy to decrease onchocerciasis transmission [
6,
7].
Onchocerciasis elimination programs using CDTI have significantly reduced
O. volvulus transmission and onchocerciasis-related blindness in many African countries [
7]. Nevertheless, despite a long history of CDTI, there is still active onchocerciasis transmission in many endemic areas in Ghana [
8], Cameroon [
9], Democratic Republic of Congo (DRC) [
10], and Tanzania [
11]. Moreover, such meso- and hyperendemic settings have also been noted to harbor a high burden of OAE [
10,
11,
12,
13]. In Ghana and Cameroon, an
O. volvulus phenotype with sub-optimal ivermectin response has been documented [
4,
14] which may contribute, at least partly, to the persistence of
O. volvulus transmission. To determine host factors associated with the high onchocerciasis prevalence and transmission observed in OAE hotspots, we conducted a study assessing individual mf density before and after ivermectin administration.
4. Discussions
In this study, we investigated treatment response to ivermectin in 329
O. volvulus-infected PWE living in four onchocerciasis-endemic areas in sub-Saharan Africa. The post-ivermectin mf density was >20% the pre-treatment value in 105 (31.9%) participants, suggesting that their response to ivermectin warrants further investigation [
8]. We observed the highest GM mf reduction of 89.4% three months after ivermectin treatment, as compared to 69.0% GM mf reduction five months post-treatment. Previous studies reported up to 98% reduction of GM mf density, 14 to 90 days after a single dose of ivermectin, with a recuperation of adult worm fertility starting around the third month resulting in a reduction in GM mf density of about 84%, four months post-ivermectin [
3].
In the three study sites where the second skin snip was obtained within four months, the percentage of PWE with positive skin snips after ivermectin was lower when compared with a study in Ghana, where 70% of participants had detectable mf four months post-ivermectin [
8]. This was not the case with participants from Maridi (South Sudan) whose skin snips were obtained 5 months after treatment and up to 80.4% of participants still presented with microfiladermia. The proportion of participants with positive skin snips post-treatment was higher in our study than observed in moxidectin-treated participants during a comparative trial with ivermectin in the Logo health zone. In this trial, only 8% of the participants who received moxidectin still had detectable mf six months after treatment [
24]. In addition to being more potent in reducing mf density, the microfilaricidal effects of moxidectin also last longer than ivermectin [
25]. Therefore annual moxidectin or bi-annual ivermectin treatment should be considered for mass treatment in hyperendemic settings as it results in a long-lasting suppression of mf compared to ivermectin once a year.
In our study, we observed that a high pre-ivermectin mf density was significantly associated with a lower mf reduction in the follow-up skin snip. This was previously reported by Pion et al. [
26] and in a meta-analysis by Churcher et al. [
27], possibly because of the presence of a higher adult worm burden and/or higher numbers of newly patent adult worms in individuals with higher mf density. Therefore, we assume that almost all of the post-treatment positive skin snips in our study can be explained by skin repopulation, which is in line with our observation that post-ivermectin skin snip positivity increased with increasing time between ivermectin treatment and follow-up skin snipping.
We found that in younger persons, the post-ivermectin
O. volvulus mf densities initially decreased with an increase in age as previously documented by Pion et al. [
26]. A potential explanation is that skin repopulation may be more rapid in younger individuals because the adult worms are still maturing (lifespan of about 9–11 years) and rapidly releasing huge numbers of mf in the early phase of the infection [
26,
28]. In the older participants (>38 years) however, post-ivermectin
O. volvulus mf densities increased as they got older (
Figure 1). A possible explanation for the reversal in trends observed after 38 years could be the absence of adjustments for the number of nodules in our multivariate model [
26,
29].
An increasing number of previous CDTI rounds was associated with higher probability of achieving <80% mf reduction after ivermectin treatment (
Table 5). This finding concurs with previous reports from Cameroon [
26,
29] where the embryostatic effect of ivermectin was reduced among individuals who had been treated several times with ivermectin in the past, compared to ivermectin-naïve individuals. In contrast, a longer history of CDTI tended to decrease the chances of having a positive skin snip post-ivermectin, although this trend was not statistically significant (
p = 0.079;
Table 4). This could be due to a very low pre-treatment mf density among participants who had been receiving ivermectin for several years prior to our study.
Our study has several limitations. Firstly, our study sites were very different in many aspects, including the time between ivermectin treatment and follow-up skin snipping, and the number of previous CDTI rounds. Secondly, we only evaluated mf densities at two time points and given that we did not collect adult female worms at either of the four sites, we were not able to assess the fecundity and mf density dynamics immediately after ivermectin use, which are needed to confirm sub-optimal treatment response. Moreover, the number of palpable nodules, as a proxy for the total number of adult worms, was not assessed in our study participants. Finally, PWE who take anti-epileptic drugs may experience decreased ivermectin drug levels. It is well known that phenobarbital can influence the p-glycoprotein (MDR1) transporter, which plays an important role in the elimination of ivermectin. Unfortunately, ivermectin plasma concentrations were not measured in this study.
In conclusion, our study shows that ivermectin effectively reduces mf density in our study participants, similar to what was observed in other onchocerciasis endemic areas. The fact that almost one third of our participants still had >20% of their pre-treatment mf density, as well as the high ongoing
O. volvulus transmission observed at our study sites are most likely related to elevated mf densities at baseline as a result of ineffective or inexistent onchocerciasis elimination programs. While we clearly demonstrate that post-ivermectin parasitic load depends on pre-treatment infection intensity, it is unclear whether some study participants exhibit a sub-optimal response to ivermectin. Resistance to the ivermectin treatment has been reported in several parasites in veterinary studies [
30,
31,
32]. Given the rapid rise and spread of ivermectin resistance in the veterinary field, studies should also investigate the possibility of ivermectin resistance in human medicine. In the light of the apparent decreasing effect of ivermectin as the number years of CDTI increases, studies need to investigate the number/fecundity of adult female worms that may be contributing to skin repopulation, and whether a sub-optimal response genotype is present in these areas as was the case in Ghana [
14].