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Statement from Mectizan Donation Program

Posted by gyamey on 31 Oct 2007 at 20:47 GMT

The Mectizan Donation Program's statement in response to this new study in PLoS Neglected Tropical Diseases [1], and to a related study in The Lancet [2], can be found at:

1. Bourguinat C, Pion SDS, Kamgno J, Gardon J, Duke BOL, et al. (2007) Genetic Selection of Low Fertile Onchocerca volvulus by Ivermectin Treatment. PLoS Negl Trop Dis 1(1): e72.
2. Osei-Atweneboana MY, Eng JK, Boakye DA, Gyapong JO, Prichard RK. Prevalence and intensity of Onchocerca volvulus infection and efficacy of ivermectin in endemic communities in Ghana: a two-phase epidemiological study. Lancet, 2007;369:2021-2029.

RE: Statement from Mectizan Donation Program

rogerprichard replied to gyamey on 30 Nov 2007 at 23:47 GMT

Response to the Mectizan Expert Committee (MEC) and APOC's Technical Consultative Committee (TCC) Statements on recent studies on resistance to ivermectin in onchocerciasis (river blindness) control programs

Ivermectin has brought huge benefits to people in onchocerciasis endemic areas and the emergence of parasites in some communities which appear not to be fully responding to ivermectin as expected [1] is of grave concern and warrants further urgent investigation and the implementation of drug response surveillance.

We concur with the recommendations that, at this time, treatment with ivermectin for onchocerciasis control should continue in all endemic areas. However, in those areas where responses indicate that ivermectin is not suppressing the repopulation of the skin of treated people with microfilariae as expected, further investigations are urgently required with a view to determining whether the control strategies might need to be modified to reduce the possible spread of resistant parasites.

The finding that ivermectin is selecting on the beta-tubulin gene in Onchocerca volvulus, the nematode which causes onchocerciasis, and that the extent of this selection is correlated with the number of rounds of ivermectin treatment [2] is of concern because of recent evidence that selection on the same gene is found in ivermectin resistant Haemonchus contortus, a nematode found in farm animals [3,4]. There are now multiple studies which show that ivermectin is selecting on O. volvulus genes whose homologs are associated with ivermectin resistance in veterinary nematodes. This genetic evidence, together with modification in the phenotypic expression of response to ivermectin in O. volvulus, suggests that strains of the parasite are being selected which respond differently to IVM treatment.

The TCC/APOC statement that “other explanations exist that are not related to Ivermectin resistance” requires that those “other explanations” be set out and subjected to scientific review in the light of the available data. Without scientific elaboration as to what those other explanations might be, and review of such explanations, one must suspend judgement of a statement of this nature. We await scientific publication of any alternative explanations as to the cause of the rapid skin microfilarial repopulation in the concerned communities.

In response to the TCC statement that “after careful review, (the TCC) concluded that the study findings are not conclusive and that possibility of other explanations exist that are not related to Ivermectin resistance”, we recognize that findings such as we have reported do warrant further investigations. However, the data that is available suggests that ivermectin resistance appears to be developing and being expressed as a failure to suppress reproduction in the adult female worms to the extent expected. It has been suggested that the rapid repopulation of the skin with microfilariae could be due to newly maturing adult parasites which had established in the 6–8 months when ivermectin might not fully suppress parasite reproduction [5,6]. This explanation seems unlikely for several reasons [7]. The infective larvae take at least 1 year to become reproductively active adults. At 30 days after treatment, virtually all microfilariae were removed from the skin. Yet by day 90 after treatment there were already significant differences between the communities that responded suboptimally and the ivermectin-naive community or the previously treated communities that responded as expected. This would leave only a 60- day window for newly maturing adult parasites to begin microfilaria production, while not being affected at the time of treatment.

The response in an ivermectin naïve population may be different from that expected in a population that has been treated on more than one occasion with ivermectin. The expected response in a population that has been subjected to repeated ivermectin treatment can be assessed from [8,9]. Repopulation rates may be difficult to compare because the number of microfilariae, observed in the skin at different times after treatment, will depend on not only the rate of return to fecundity of the adult worms, but also on the number of adult parasites present. An assessment of the adult parasite population can be approximated from the pre-treatment microfilarial count. However, this relationship between pre-treatment microfilarial count and adult worm numbers will only be true if a number of factors such as the time since the last ivermectin treatment and the age structure of the adult population are similar. In this context, it is important to also assess embryograms on the adult female worms after treatment [10] and the age structure of the adult female worms. An examination of these parameters supports the conclusion that there is an ivermectin resistance problem manifested as a more rapid return to fertility than expected in O. volvulus obtained in the communities showing poor responses to ivermectin [1, Osei-Atweneboana et al, unpublished].

In conclusion, we believe that there is cause for concern about a developing drug resistance problem in O. volvulus and fully support the call for drug resistance monitoring and associated research to provide better tools for this monitoring and for the development of new drugs or vaccines to increase options for onchocerciasis control. These needs have become even more urgent as a result of the recent findings.

RK Prichard1, C. Bourguinat1, MY Osei-Atweneboana1, SDS Pion2, DA Boakye3, JO Gyapong4, M Boussinesq2

1Institute of Parasitology, McGill University, Canada
2Epidémiologie et Prévention, Département Sociétés et Santé, Institut de Recherche pour le Développement, France
3Noguchi Memorial Institute for Medical Research, University of Ghana, Ghana
4Onchocerciasis Control Programme of Ghana, Ghana

[1] Osei-Atweneboana MY, Eng JK, Boakye DA, Gyapong JO, Prichard RK (2007) Prevalence and intensity of Onchocerca volvulus infection and efficacy of ivermectin in endemic communities in Ghana: a two-phase epidemiological study. Lancet 369: 2021–2029.

[2] Bourguinat C, Pion SDS, Kamgno J, Gardon J, Duke BOL, et al. (2007) Genetic selection of low fertile Onchocerca volvulus by ivermectin treatment. PLoS Neg Trop Dis 1: 1-11.

[3] Eng JKL, Blackhall WJ, Osei-Atweneboana MY, Bourguinat C, Galazzo D, et al. (2006) Ivermectin selection on β-tubulin: Evidence in Onchocerca volvulus and Haemonchus contortus. Mol Biochem Parasitol 150: 229-235.

[4] Mottier ML, Prichard RK Genetic analysis of a relationship between macrocyclic lactone and benzimidazole anthelmintic selection on Haemonchus contortus. Pharmacogen Genomics, in press.

[5] Cupp E, Richards F, Lammie P, Eberhard M (2007) Efficacy of ivermectin against Onchocerca volvulus in Ghana. Lancet 370:1123.

[6] Remme JHF, Amazigo U, Engels D, Barryson A, Yameogo L (2007) Efficacy of ivermectin against Onchocerca volvulus in Ghana. Lancet 370:1123-1124.

[7] Osei-Atweneboana MY, Eng JKL, Boakye DA, Gyapong JO, Prichard RK (2007) Efficacy of ivermectin against Onchocerca volvulus in Ghana – Authors' reply. Lancet 370: 1124-1125.

[8] Alley ES, Plaisier AP, Boatin BA, Dadzie KY, Remme J et al. (1994) The impact of five years of annual ivermectin treatment on skin microfilarial loads in the onchocerciasis focus of Asubende, Ghana. Trans Roy Soc Trop Med Hyg 88: 581-584.

[9] Plaisier AP, Alley SE, Boatin BA, van Oortmarssen GJ, Remme H et al. (1995) Irreversible effects of ivermectin on adult parasites in onchocerciasis patients in the Onchocerciasis Control Programme in West Africa. J Inf Dis 172: 204-210.

[10] Awadzi K, Boakye DA, Edwards G, Opoku NO, Attah SK, et al. (2004) An investigation of persistent microfilaridermias despite multiple treatments with ivermectin, in two onchocerciasis-endemic foci in Ghana. Ann Trop Med Parasitol 98: 231–249.