SUMMARY: Chronic hepatitis C patients who achieve sustained virological response after treatment with the HCV protease inhibitor telaprevir plus pegylated interferon and ribavirin continue to have undetectable viral load with long-term follow-up, according to findings from the EXTEND study presented at the recent American Association for the Study of Liver Diseases "Liver Meeting" (AASLD 2010) in Boston. Among non-responders, telaprevir resistance mutations disappeared over time, suggesting that the drug could be used again for re-treatment.

By Liz Highleyman

Current standard therapy for genotype 1 chronic hepatitis C virus (HCV) infection consists of pegylated interferon plus ribavirin for 48 weeks. Interferon-based therapy can cause difficult side effects, however, and only about half of people with this hard-to-treat genotype achieve a cure.

New drugs that directly target steps of the viral lifecycle -- such as HCV protease and polymerase inhibitors -- are in the final stages of development. While these agents are likely to initially be used in combination with pegylated interferon/ribavirin, they should shorten treatment duration and improve the likelihood of sustained response.

Sustained virological response (SVR) to hepatitis C treatment is defined as continued undetectable HCV RNA 24 weeks after completion of therapy. Studies have shown that SVR is effectively a cure in people treated with a full course of pegylated interferon/ribavirin -- with very few individuals experiencing subsequent relapse -- but this has not been well studied for new antiviral agents.

Stefan Zeuzem from J.W. Goethe University Medical Center in Frankfurt and fellow investigators with the EXTEND study conducted long-term follow-up of participants in Phase 2 clinical trials of the HCV protease inhibitor telaprevir in combination with pegylated interferon alfa-2a (Pegasys) and ribavirin.

The study is scheduled to last for 3 years. At the Liver Meeting, researchers presented data from an interim analysis of virological response durability among patients who achieved SVR, as well as changes in HCV mutations among people who did not achieve SVR.

The analysis included 202 patients selected from among the nearly 900 participants who received at least 1 dose of telaprevir in the Phase 2 trials PROVE1 and PROVE2 (treatment-naive patients), PROVE3 (prior non-responders), or Study 107 (rollover from the PROVE trials). EXTEND will also enroll participants from the Phase 3 ADVANCE, ILLUMINATE, and REALIZE trials.

Patients who achieved SVR (n = 123) were observed for a median follow-up period of 22 months (range 5-35 months) after determination of sustained response at 24 weeks. Participants who did not achieve SVR (n = 79) were followed for a median of 25 months (range 7-36 months) after the end of their initial trial.

Investigators measured HCV RNA levels and used RT-PCR testing to sequence the HCV NS3 protease, looking for amino acid changes at positions 36, 54, 155, and 156 that have been linked to decreased telaprevir susceptibility.

Results

	All but 1 patient with SVR (122 out of 123, or 99%) maintained undetectable HCV viral load during follow-up.
	1 individual from PROVE2 -- who had discontinued therapy prior to the scheduled end of treatment -- experienced late relapse at 47 weeks.
	89% of non-SVR patients (50 out of 56) who had viral variants with reduced telaprevir susceptibility at the end of the earlier studies no longer showed evidence of resistance by the end of follow-up.
	There was no evidence to suggest that time to loss of resistant HCV variants varied according to treatment arm, duration of telaprevir, or type of non-response (e.g., viral breakthrough on treatment vs post-treatment relapse).
	Analysis of a subset of non-responders found that viral populations from every patient returned to their pre-treatment state.

"In this interim analysis, SVR after telaprevir-based therapy was durable, with 122 of 123 subjects maintaining HCV RNA undetectable during a median 22 months follow-up," the investigators concluded. "Amongst patients who did not achieve SVR after telaprevir-based therapy, variants associated with decreased sensitivity to telaprevir were no longer detectable in 89% of patients within the study period."

The replacement of resistant HCV variants by wild-type (non-mutated) virus over time suggests that telaprevir may be effective if used later as part of an attempt at re-treatment. Therefore, people who did not achieve sustained response with telaprevir plus pegylated interferon/ribavirin may still be eligible for future re-treatment with all-oral combinations of direct-acting agents including telaprevir.

Some degree of telaprevir resistance may remain, however, as the PCR test used in this analysis only detected variants that made up about 20% of an individual's total virus population.

Investigator affiliations: Johann Wolfgang Goethe University Medical Center, Frankfurt am Main, Germany; Johns Hopkins University School of Medicine, Baltimore, MD; INSERM Unit 871, Lyon, France; University of Cincinnati College of Medicine, Cincinnati, OH; University of Padova, Padova, Italy; Harvard School of Public Health, Boston, MA; Tibotec BVBA, Mechelen, Belgium; Vertex Pharmaceuticals Incorporated, Cambridge, MA; Tibotec Inc., Titusville, NJ; Duke University Medical Center, Durham, NC.

11/23/10

Reference
S Zeuzem, MS Sulkowski, F Zoulim, and others. Long-term Follow-up of Patients with Chronic Hepatitis C Treated with Telaprevir in Combination with Peginterferon Alfa-2a and Ribavirin: Interim Analysis of the EXTEND Study. 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2010). Boston, October 29-November 2, 2010. Abstract 227.