New hope for a cure for chronic hepatitis C

New hope for a cure for chronic hepatitis C



Henk W. ReesinkCorresponding Author Informationemail address, Christine J. Weegink



published online 21 July 2009.

Corrected Proof



Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection.
McHutchison JG, Everson GT, Gordon SC, Jacobson IM, Sulkowski M, Kauffman R, McNair L, Alam J, Muir AJ; PROVE1 Study Team.



Background: Current therapy for chronic hepatitis C virus (HCV) infection is effective in less than 50% of patients infected with HCV genotype 1. Telaprevir, a protease inhibitor specific to the HCV nonstructural 3/4A serine protease, rapidly reduced HCV RNA levels in early studies.

Methods: We randomly assigned patients infected with HCV genotype 1 to one of three telaprevir groups or to the control group. The control group (called the PR48 group) received peginterferon alfa-2a (180microg per week) and ribavirin (1000 or 1200mg per day, according to body weight) for 48weeks, plus telaprevir-matched placebo for the first 12weeks (75 patients). The telaprevir groups received telaprevir (1250mg on day 1 and 750mg every 8hours thereafter) for 12weeks, as well as peginterferon alfa-2a and ribavirin (at the same doses as in the PR48 group) for the same 12weeks (the T12PR12 group, 17 patients) or for a total of 24weeks (the T12PR24 group, 79 patients) or 48weeks (the T12PR48 group, 79 patients). The primary outcome was a sustained virologic response (an undetectable HCV RNA level 24weeks after the end of therapy).

Results: The rate of sustained virologic response was 41% (31 of 75 patients) in the PR48 group, as compared with 61% (48 of 79 patients) in the T12PR24 group (P=0.02), 67% (53 of 79 patients) in the T12PR48 group (P=0.002), and 35% (6 of 17 patients) in the T12PR12 group (this group was exploratory and not compared with the control group). Viral breakthrough occurred in 7% of patients receiving telaprevir. The rate of discontinuation because of adverse events was higher in the three telaprevir-based groups (21%, vs. 11% in the PR48 group), with rash the most common reason for discontinuation.

Conclusions: Treatment with a telaprevir-based regimen significantly improved sustained virologic response rates in patients with genotype 1 HCV, albeit with higher rates of discontinuation because of adverse events. (ClinicalTrials.gov number, NCT00336479.)



[Abstract reproduced by permission of N Engl J Med 2009;360:1827–1838]



Telaprevir and peginterferon with or without ribavirin for chronic HCV infection.

Hézode C, Forestier N, Dusheiko G, Ferenci P, Pol S, Goeser T, Bronowicki JP, Bourlière M, Gharakhanian S, Bengtsson L, McNair L, George S, Kieffer T, Kwong A, Kauffman RS, Alam J, Pawlotsky JM, Zeuzem S, PROVE2 Study Team.



Background: In patients with chronic infection with hepatitis C virus (HCV) genotype 1, treatment with peginterferon alfa and ribavirin for 48weeks results in rates of sustained virologic response of 40 to 50%. Telaprevir is a specific inhibitor of the HCV serine protease and could be of value in HCV treatment.

Methods: A total of 334 patients who had chronic infection with HCV genotype 1 and had not been treated previously were randomly assigned to receive one of four treatments involving various combinations of telaprevir (1250mg on day 1, then 750mg every 8hours), peginterferon alfa-2a (180microg weekly), and ribavirin (dose according to body weight). The T12PR24 group (81 patients) received telaprevir, peginterferon alfa-2a, and ribavirin for 12weeks, followed by peginterferon alfa-2a and ribavirin for 12 more weeks. The T12PR12 group (82 patients) received telaprevir, peginterferon alfa-2a, and ribavirin for 12weeks. The T12P12 group (78 patients) received telaprevir and peginterferon alfa-2a without ribavirin for 12weeks. The PR48 (control) group (82 patients) received peginterferon alfa-2a and ribavirin for 48weeks. The primary end point, a sustained virologic response (an undetectable HCV RNA level 24weeks after the end of therapy), was compared between the control group and the combined T12P12 and T12PR12 groups.

Results: The rate of sustained virologic response for the T12PR12 and T12P12 groups combined was 48% (77 of 160 patients), as compared with 46% (38 of 82) in the PR48 (control) group (P=0.89). The rate was 60% (49 of 82 patients) in the T12PR12 group (P=0.12 for the comparison with the PR48 group), as compared with 36% (28 of 78 patients) in the T12P12 group (P=0.003; P=0.20 for the comparison with the PR48 group). The rate was significantly higher in the T12PR24 group (69% [56 of 81 patients]) than in the PR48 group (P=0.004). The adverse events with increased frequency in the telaprevir-based groups were pruritus, rash, and anemia.

Conclusions: In this phase 2 study of patients infected with HCV genotype 1 who had not been treated previously, one of the three telaprevir groups had a significantly higher rate of sustained virologic response than that with standard therapy. Response rates were lowest with the regimen that did not include ribavirin. (ClinicalTrials.gov number, NCT00372385.)



[Abstract reproduced by permission of N Engl J Med 2009;360:1839–1850]



Special Section Editors: Peter R. Galle, Peter L.M. Jansen, Francesco Negro



Article Outline





For many years the standard of care (SOC) for difficult-to-treat patients with chronic hepatitis C, such as genotype 1, has been pegylated interferon alfa-2a/2b (Peg-IFN) combined with ribavirin (RBV), for 48weeks. However, only 40–50% of the patients will achieve sustained viral response (SVR), which is equivalent to eradication of the HCV infection. This treatment is associated with many adverse events, which decrease the quality of life and provoke a high rate of non-compliance and treatment discontinuation. Therefore, the development of specifically targeted antiviral therapy compounds for hepatitis C (STAT-C), which attack the lifecycle of the virus, gives new hope for better treatment of these patients.



The first STAT-C compound which reached clinical evaluation was BILN2061, an inhibitor of the HCV NS3 protease. When administered for 2days to HCV genotype 1 patients a rapid decline of 2–3 log10 in serum HCV-RNA was observed in all patients, both treatment-naïve and treatment-experienced to prior (Peg) IFN and RBV [1]. In other genotypes BILN2061 gave a variable response [2]. Unfortunately, due to cardio toxicity in apes and SCID mice [3] further development of BILN2061 was stopped.



The next STAT-C in development was VX-950 (telaprevir), an inhibitor of the NS3.4A HCV protease. In a phase 1 study the best dose group of telaprevir (750mg q8h), which had the highest trough drug concentration, a median reduction of HCV-RNA of 4.4 log10 was observed after 14days of treatment [4]. In the second phase 1 study, the combination of telaprevir 750mg q8h with Peg-IFN for 14days resulted in a median reduction of HCV-RNA of 5.5 log10 [5]. In the telaprevir monotherapy groups of both studies low- and high-level resistant HCV isolates were selected, due to a sharp reduction of wild-type virus, which uncovered pre-existing telaprevir-resistant variants. This viral rebound was the result of the selection of variants with greater fitness [6], [7] during telaprevir dosing. The combination of telaprevir and Peg-IFN inhibited both wild-type and resistant variants. After 14 or 28days of telaprevir treatment, subsequent treatment with Peg-IFN and RBV for 24–48weeks resulted in SVR in a considerable number of patients [8], [9].



Based on the promising results of these phase 1 studies, two phase 2 studies were initiated in the USA (PROVE1) and in Europe (PROVE2); the results of these studies have recently been published.



McHutchison et al. [10] and Hezode et al. [11] showed that in treatment-naïve chronic hepatitis C patients with genotype 1, the combination of telaprevir with Peg-IFN and RBV resulted in the achievement of an SVR of 67% and 69% in the PROVE1 and PROVE2 studies respectively, in the best treatment arms (telaprevir for 12weeks, with peg-IFN-2a and RBV for 24weeks). In the SOC control groups (which received telaprevir-matching placebo), SVR rates of 41% and 46% were observed. The difference between the 24-week telaprevir-based arms and the control arms was highly significant. The PROVE2 study also showed that when RBV was omitted in the telaprevir/Peg-IFN combination, both viral breakthrough due to selection of resistant variants and relapse significantly increased, resulting in an SVR rate of only 36%. Both studies indicated that triple combination treatment (telaprevir, Peg-IFN and RBV) of 12weeks total duration was apparently too short and 24weeks total duration is probably as efficacious as 48weeks of treatment. Development of a rapid viral response (i.e. HCV-RNA undetectable at week 4 of treatment) is probably one of the best predictors of SVR and a total treatment duration of 24weeks should be sufficient for these patients. Ongoing phase 3 studies with telaprevir and Peg-IFN/RBV will provide an answer to these questions.



The rate of discontinuation due to adverse events was higher in the telaprevir-based groups of both studies than in the control groups, with rash being the most common reason for discontinuation.



At present many STAT-C compounds are under clinical development, including HCV polymerase inhibitors, receptor entry blockers, and NS.5A inhibitors. Many other compounds are in pre-clinical development. Combination of two or more STAT-C compounds in the future may hopefully replace Peg-IFN and RBV, although at present this combination is essential for preventing clinical resistance.



The results from the two PROVE studies are an important step forward in the cure of chronic hepatitis C.



References






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[11]. [11]Hezode C, Forestier N, Dusheiko G, Ferenci P, Pol S, Goeser T, et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med. 2009;360:1839–1850. CrossRef