[
Lancet,
2007]
BACKGROUND: Ivermectin has been used for onchocerciasis control since 1987. Because of the long-term use of this drug and the development of resistance in other nematodes, we have assessed Onchocerca volvulus burdens, effectiveness of ivermectin as a microfilaricide, and its effect on adult female worm reproduction. METHODS: For the first phase of the study, 2501 individuals in Ghana, from 19 endemic communities who had received six to 18 annual rounds of ivermectin and one ivermectin naive community, were assessed for microfilarial loads 7 days before the 2004 yearly ivermectin treatment, by means of skin snips, and 30 days after treatment to assess the ivermectin microfilaricidal action. For the second phase, skin snips were taken from 342 individuals from ten communities, who were microfilaria positive at pretreatment assessment, on days 90 and 180 after treatment, to identify the effects of ivermectin on female worm fertility, assessed by microfilaria repopulation. FINDINGS: 487 (19%) of the 2501 participants were microfilaria positive. The microfilaria prevalence and community microfilarial load in treated communities ranged from 2.2% to 51.8%, and 0.06 microfilariae per snip to 2.85 microfilariae per snip, respectively. Despite treatment, the prevalence rate doubled between 2000 and 2005 in two communities. Microfilaria assessment 30 days after ivermectin treatment showed 100% clearance of microfilaria in more than 99% of people. At day 90 after treatment, four of ten communities had significant microfilaria repopulation, from 7.1% to 21.1% of pretreatment counts, rising to 53.9% by day 180. INTERPRETATION: Ivermectin remains a potent microfilaricide. However, our results suggest that resistant adult parasite populations, which are not responding as expected to ivermectin, are emerging. A high rate of repopulation of skin with microfilariae will allow parasite transmission, possibly with ivermectin-resistant O volvulus, which could eventually lead to recrudescence of the disease.
[
Int J Parasitol Drugs Drug Resist,
2012]
Ivermectin (IVM) has been in operational use for the control of onchocerciasis for two decades and remains the only drug of choice. To investigate the parasitological responses and genetic profile of Onchocerca volvulus, we carried out a 21month epidemiological study to determine the response of the parasite to IVM in 10 Ghanaian endemic communities. Onchocerca nodules were surgically removed from patients in three IVM response categories (good, intermediate and poor) and one IVM naive community. DNA from adult worms was analyzed to determine any association between genotype and IVM response phenotypic. Embryogramme analysis showed significantly higher reproductive activity in worms from poor response communities, which had up to 41% of females with live stretched microfilaria (mf) in utero, despite IVM treatment, compared with good response communities, which had no intra-uterine stretched mf. -tubulin isotype 1 gene has been shown to be linked to IVM selection in O. volvulus and also known to be associated with IVM resistance in veterinary nematodes. We have genotyped the full length genomic DNA sequence of the -tubulin gene from 127 adult worms obtained from the four community categories. We found SNPs at 24 sites over the entire 3696bp. Eight of the SNPs occurred at significantly higher (p<0.05) frequencies in the poor response communities compared with the good response communities and the IVM naive community. Phenotypic and genotypic analyses show that IVM resistance has been selected and the genotype (1183GG/1188CC/1308TT/1545GG) was strongly associated with the resistance phenotype. Since the region in the -tubulin gene where these four SNPs occur is within 362bp, it is feasible to develop a genetic marker for the early detection of IVM resistance.
[
PLoS Negl Trop Dis,
2011]
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-naive 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.