Telaprevir Monotherapy Is Potent against HCV Genotype 2 but Not 3; Best Results when Combined with Interferon/ribavirin

		SUMMARY: The investigational protease inhibitor telaprevir strongly inhibited replication of hepatitis C virus (HCV) genotype 2 when used alone for 2 weeks before adding pegylated interferon and ribavirin. However, it had only a minimal effect on HCV genotype 3, according to a presentation at the 45th Annual Meeting of the European Association for the Study of the Liver (EASL 2010) last month in Vienna. Researchers also presented data about telaprevir for treatment-naive and treatment-experienced genotype 1 patients.

By Liz Highleyman

Given the side effects and sub-optimal effectiveness of standard hepatitis C treatment using pegylated interferon plus ribavirin, researchers have evaluated direct-acting anti-HCV agents used without interferon. The virus can develop resistance to single drugs, however, so it is only safe to test them as monotherapy for short periods.

In the Phase 2a Study C209, 49 previously untreated participants with genotype 2 or 3 chronic hepatitis C were randomly assigned to receive telaprevir alone (750 mg every 8 hours), telaprevir with pegylated interferon alfa-2a (Pegasys) plus 800 mg ribavirin, or pegylated interferon/ribavirin with placebo for 2 weeks. All participants then received pegylated interferon/ribavirin through week 24 (the standard duration of treatment for these genotypes).

Results

	Among genotype 2 patients, HCV viral load decreased dramatically in the telaprevir monotherapy, triple therapy, and standard therapy arms:
	G2 telaprevir alone: -3.27 log by day 3 and -3.66 log by day 15; G2 telaprevir/pegylated interferon/ribavirin: -4.03 log and -5.51 log, respectively; G2 pegylated interferon/ribavirin: -2.04 log and -4.83 log, respectively.
	However, fewer people in the telaprevir monotherapy arm went on to achieve sustained virological response (SVR) by 24 weeks after completing treatment:
	G2 telaprevir alone: SVR 56%; G2 telaprevir/pegylated interferon/ribavirin: SVR 100%; G2 pegylated interferon/ribavirin: SVR 89%.
	Among genotype 3 patients, HCV viral load decreased much less in the telaprevir monotherapy arm:
	G3 telaprevir alone: -0.54 log by day 3 and -0.54 log by day 15; G3 telaprevir/pegylated interferon/ribavirin: -3.05 log and -4.85 log, respectively; G3 pegylated interferon/ribavirin: -2.38 log and -4.72 log, respectively.
	Looking at genotype 3 patients, SVR rates were lower overall and did not diverge so much across the treatment arms:
	G3 telaprevir alone: SVR 50%; G3 telaprevir/pegylated interferon/ribavirin: SVR 67%; G3 pegylated interferon/ribavirin: SVR 44%.
	6 genotype 2 patients and 3 genotype 3 patients developed viral break-though by day 15 in the telaprevir monotherapy arm, compared with none in the arms that included pegylated interferon/ribavirin.
	Nevertheless, 3 genotype 2 patients and 1 genotype 3 patient who continued treatment with pegylated interferon/ribavirin went on to achieve SVR.
	Telaprevir was generally well tolerated.
	Overall incidence of adverse events was similar across treatment arms.
	The most common adverse events in the telaprevir arms were skin-related events, nausea, flu-like symptoms, and weakness.
	One genotype 2 patient who received tipranavir monotherapy discontinued treatment due to skin rash.

Based on these findings, the study investigators concluded, "The monotherapy arms demonstrated that telaprevir alone has substantial antiviral activity against HCV genotype 2 while its activity against genotype 3 is limited."

"The highest SVR rates were observed when telaprevir was combined with [pegylated interferon/ribavirin]," they continued. "Some patients harboring variants with decreased susceptibility to telaprevir achieved a SVR with continued [pegylated interferon/ribavirin] treatment."

Queen Marys University of London, Institute of Cellular and Molecular Sciences, London, UK; Hôpital Henri-Mondor, AP-HP, Université Paris XII, Créteil, France; Centre Hospitalier Universitaire de Nancy, Vandoeuvre-lès-Nancy, France; Clinic of Infectious and Tropical Diseases, University of Brescia, Brescia, Italy; Karolinska University Hospital Huddinge, Stockholm, Swede; Tibotec BVBA, Mechelen, Belgium; Tibotec, Inc, Yardley, PA.

5/14/10

Reference
GR Foster, C Hezode, J-P Bronowicki, and others. Activity of telaprevir alone or in combination with peginterferon alfa-2a and ribavirin in treatment-naive genotype 2 and 3 hepatitis-C patients: final results of Study C209. 45th Annual Meeting of the European Association for the Study of the Liver (EASL 2010). Vienna, Austria. April 14-18, 2010. (Abstract).