Genetic selection of low fertile Onchocerca volvulus by ivermectin treatment.
BACKGROUND
Onchocerca volvulus is the causative agent of onchocerciasis, or "river blindness". Ivermectin has been used for mass treatment of onchocerciasis for up to 18 years, and recently there have been reports of poor parasitological responses to the drug. Should ivermectin resistance be developing, it would have a genetic basis. We monitored genetic changes in parasites obtained from the same patients before use of ivermectin and following different levels of ivermectin exposure.


RESULTS
O. volvulus adult worms were obtained from 73 patients before exposure to ivermectin and in the same patients following three years of annual or three-monthly treatment at 150 microg/kg or 800 microg/kg. Genotype frequencies were determined in beta-tubulin, a gene previously found to be linked to ivermectin selection and resistance in parasitic nematodes. Such frequencies were also determined in two other genes, heat shock protein 60 and acidic ribosomal protein, not known to be linked to ivermectin effects. In addition, we investigated the relationship between beta-tubulin genotype and female parasite fertility. We found a significant selection for beta-tubulin heterozygotes in female worms. There was no significant selection for the two other genes. Quarterly ivermectin treatment over three years reduced the frequency of the beta-tubulin "aa" homozygotes from 68.6% to 25.6%, while the "ab" heterozygotes increased from 20.9% to 69.2% in the female parasites. The female worms that were homozygous at the beta-tubulin locus were more fertile than the heterozygous female worms before treatment (67% versus 37%; p = 0.003) and twelve months after the last dose of ivermectin in the groups treated annually (60% versus 17%; p<0.001). Differences in fertility between heterozygous and homozygous worms were less apparent three months after the last treatment in the groups treated three-monthly.


CONCLUSIONS
The results indicate that ivermectin is causing genetic selection on O. volvulus. This genetic selection is associated with a lower reproductive rate in the female parasites. We hypothesize that this genetic selection indicates that a population of O. volvulus, which is more tolerant to ivermectin, is being selected. This selection could have implications for the development of ivermectin resistance in O. volvulus and for the ongoing onchocerciasis control programmes.
Bourguinat
Catherine
C
Institute of Parasitology, McGill University, Sainte Anne-de-Bellevue, Quebec, Canada.
Pion
Sébastien D S
SD
Kamgno
Joseph
J
Gardon
Jacques
J
Duke
Brian O L
BO
Boussinesq
Michel
M
Prichard
Roger K
RK
D000818:Animals; D000871:Anthelmintics / Q000627:therapeutic use*; D000977:Antiparasitic Agents / Q000627:therapeutic use*; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D006580:Genetic Carrier Screening; D005838:Genotype; D015801:Helminth Proteins / Q000235:genetics; D006801:Humans; D007559:Ivermectin / Q000627:therapeutic use*; D017181:Onchocerca volvulus / Q000187:drug effects / Q000235:genetics* / Q000302:isolation & purification; D009855:Onchocerciasis / Q000188:drug therapy* / Q000469:parasitology; D012641:Selection, Genetic; D014404:Tubulin / Q000235:genetics
D000871:Anthelmintics; D000977:Antiparasitic Agents; D015801:Helminth Proteins; D014404:Tubulin; D007559:Ivermectin