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.Methods and Findings
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 µg/kg or 800
µg/kg. Genotype frequencies were determined in
β-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 β-tubulin genotype and female
parasite fertility. We found a significant selection for
β-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
β-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 β-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.ConclusionsThe 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.
A randomized, double-blind, placebo-controlled trial was conducted, to determine whether the co-administration of ivermectin with albendazole is safe and more effective against Onchocerca volvulus than ivermectin alone, and whether a significant pharmacokinetic interaction occurs. Forty-two male onchocerciasis patients received ivermectin (200 mug/kg) alone, albendazole (400 mg) alone or the combination. Safety was determined from the results of detailed clinical and laboratory examinations before treatment, during hospitalization and on day 30. Microfilaricidal efficacy was estimated from the reductions in skin counts between day 0 (pretreatment) and day 30. To determine efficacy against the adult worms, two independent observers examined histology slides prepared from nodules excised on day 180; changes in the skin counts of skin microfilariae between days 30 and 365 provided additional indicators of the level of adulticidal activity. Pharmacokinetic parameters for ivermectin and albendazole sulphoxide were defined over 72 h post-treatment. The co-administration of ivermectin with albendazole did not produce more severe adverse effects than ivermectin alone. Both nodule examiners found that the combination was not macrofilaricidal and that it was not clearly superior to ivermectin alone in the effects on reproductive activity; this was supported by the similar efficacy of the two regimens in the suppression of skin microfilariae. There was no significant pharmacokinetic interaction. Although the co-administration of ivermectin with albendazole appears safe, it offers no advantage over ivermectin alone in the control of onchocerciasis. The combination does not require an alteration in the dosage of either component.
A pleomorphic neoplasm (PN) is described from sections of Onchocerca volvulus worms in nodules excised from Cameroonian patients. PN is confined to older, non-fecund, female worms, and those classed as moribund/dead. It is mainly composed of small, roundish, basophilic cells of diverse sizes, often forming a 'rosette' pattern around amorphous eosinophilic centres. The cells have a high nuclear/cytoplasmic ratio and up to 2-3 mitoses/high-power field; some become grossly enlarged, highly polymorphic and contain large, irregular blocks of chromatin. The eukaryotic PN cells first appear posteriorly in the pseudocoelom, probably from ovarian cells; they spread anteriorly, invading or compressing the uteri. Ivermectin treatment increased the prevalence PN from 3.7% of 1422 female worms in 637 patients before treatment to 17.5% of 1134 worms in 511 patients after 3 years treatment. Ivermectin at 400-800 microg/kg annually, or at 150 microg/kg or 400-800 microg/kg 3-monthly, over 3 years, did not increase the PN prevalence significantly, as compared with standard doses of 150 microg/kg annually. In other small series of African patients, PN prevalence increased in worms 2, 4, 6 and 10 months after ivermectin treatment; but there was no increase after treatment with amocarzine, albendazole or diethylcarbamazine and suramin. PN may partly account for the increased macrofilaricidal action of ivermectin on female O. volvulus in patients treated for 3 years at 3-monthly intervals.
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