A glimpse of future hepatitis C virus treatment paradigms

A glimpse of future hepatitis C virus treatment paradigms

Hepatology Jan 2010

Norah Terrault, MD MPH, Mandana Khalili, MD, MAS

University of California, San Francisco

Potential conflict of interest: Dr. Terrault received grant support from Vertex Pharmaceuticals and Roche Pharmaceuticals; Dr. Khalili has nothing to disclose.


Editor(s) for this article:

Kris Kowdley 1, Geoffrey McCaughan 2, Christian Trautwein 3

1Seattle, WA

2Newtown, Australia

3Aachen, Germany



Article Text


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. Collaborators (28) L Benhamou Y, Bourlière M, Bronowicki JP, Couzigou P, Grangé JD, Marcellin P, Mathurin P, Pawlotsky JM, Pol S, Serfaty L, Tran A, Trépo C, Zarski JP, Berg T, Buggisch P, Diepolder H, Erhardt A, Gerken G, Goeser T, Günther R, Rasenack J, Schmidt W, Spengler U, Wedemeyer H, Zeuzem S, Dusheiko G, Mutimer D, Ferenci P. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med 2009 Apr 30;360(18):1839-50. Reprinted with permission.


Abstract


Background: In patients with chronic infection with hepatitis C virus (HCV) genotype 1, treatment with peginterferon alfa and ribavirin for 48 weeks 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 (1250 mg on day 1, then 750 mg every 8 hours), peginterferon alfa-2a (180 microg weekly), and ribavirin (dose according to body weight). The T12PR24 group (81 patients) received telaprevir, peginterferon alfa-2a, and ribavirin for 12 weeks, followed by peginterferon alfa-2a and ribavirin for 12 more weeks. The T12PR12 group (82 patients) received telaprevir, peginterferon alfa-2a, and ribavirin for 12 weeks. The T12P12 group (78 patients) received telaprevir and peginterferon alfa-2a without ribavirin for 12 weeks. The PR48 (control) group (82 patients) received peginterferon alfa-2a and ribavirin for 48 weeks. The primary end point, a sustained virologic response (an undetectable HCV RNA level 24 weeks 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.) 2009 Massachusetts Medical Society.


McHutchison JG, Everson GT, Gordon SC, Jacobson IM, Sulkowski M, Kauffman R, McNair L, Alam J, Muir AJ; PROVE1 Study Team. Collaborators (38): Afdhal N, Arora S, Balan V, Vargas H, Bernstein D, Black M, Brown R, Bzowej N, Davis G, Di Bisceglie A, Dienstag J, Everson G, Faruqui S, Franco J, Fried M, Ghalib R, Gordon SC, Gross J, Jacobson IM, Jensen D, Kugelmas M, Kwo P, Lawitz E, Lee W, Martin P, Nelson D, Northup P, Patel K, Poordad F, Reddy RK, Rodriguez-Torres M, Rustgi V, Schiff E, Sherman K, Shiffman M, Sulkowski M, Szabol G, Younossi Z. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med 2009 Apr 30;360(18):1827-38. Reprinted with permission.


Abstract


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 (180 microg per week) and ribavirin (1000 or 1200 mg per day, according to body weight) for 48 weeks, plus telaprevir-matched placebo for the first 12 weeks (75 patients). The telaprevir groups received telaprevir (1250 mg on day 1 and 750 mg every 8 hours thereafter) for 12 weeks, as well as peginterferon alfa-2a and ribavirin (at the same doses as in the PR48 group) for the same 12 weeks (the T12PR12 group, 17 patients) or for a total of 24 weeks (the T12PR24 group, 79 patients) or 48 weeks (the T12PR48 group, 79 patients). The primary outcome was a sustained virologic response (an undetectable HCV RNA level 24 weeks 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.) 2009 Massachusetts Medical Society


Comments


Chronic HCV infection represents a major public health problem. Eradication of HCV with treatment is the most effective means of preventing liver-related complications. The current standard of care is combined peginterferon (peg-IFN) and ribavirin, which achieves sustained virologic responses (SVR) in only 55% of patients overall,[1][2] but with disappointing response rates in patients with HCV genotype 1.[1][2] HCV genotype 1 infection has been a primary focus of several new drugs that specifically target the virus (STAT-C drugs) including protease inhibitors, nucleoside and non-nucleoside NS5B polymerase inhibitors, and non-nucleoside NS5A inhibitors. The serine protease inhibitors telaprevir and boceprevir are most advanced in clinical study; both have recently completed enrollment of phase-3 studies. NS3/4A is responsible for cleavage of the NS4A/4B, NS4B/5A, and NS5A/B junctions of the large HCV polyprotein that in turn are critical in forming the replicative complex from which viral RNA synthesis occurs.[3] Additionally, NS3 has inhibitory effects on interferon signaling pathways[4] and inhibition of NS3 may help to restore interferon responsiveness. In phase 1 studies, telaprevir produced a 4.4-log10IU/mL reduction in HCV RNA levels over 14 days in subjects infected with HCV genotype 1.[5] Also seen in this early study, was the rapidity with which drug-resistant mutants emerged during treatment with virologic breakthrough evident after only 7-14 days of treatment.[5] Subsequently, it was shown that adding peg-IFN decreased the rate of virologic breakthrough due to drug-resistance and achieved a 5.5-log10IU/mL reduction in HCV RNA with 14 days therapy.[6] Thereafter, peg-IFN became an integral part of evolving treatment algorithms.


The U.S. and European multicenter phase 2b studies of telaprevir in combination with peg-IFN and ribavirin, termed PROVE 1[7] and PROVE 2,[8] respectively, were recently reported. Both studies share certain common aspects of study design, patient populations, and study endpoints. The studies were randomized, double-blind or partially blinded studies of treatment-naïve patients with genotype 1 HCV who were without cirrhosis and predominantly White (over 90% in PROVE 2, and 77% in PROVE 1). The studies differed in the duration and specific drug combinations tested as well as the stopping rules used for suboptimal responders. In PROVE 2, shorter duration therapy was used (12-24 weeks) and telaprevir plus peg-IFN without ribavirin examined. In PROVE 1, all 3 telaprevir-containing regimens utilized triple therapy (telaprevir, peg-IFN, ribavirin) for the initial 12 weeks but the duration of subsequent treatment with peg-IFN and ribavirin differed (0, 12 and 36 weeks). Both PROVE 1 and 2 studies confirmed the benefit of adding telaprevir for 12 weeks to standard combination therapy and concluded that the optimal duration of total therapy appeared to be 24 weeks (i.e., 12 weeks of triple therapy followed by 12 weeks of peg-IFN and ribavirin). This 24-week treatment course increased significantly the SVR rates to 61% and 69% (in PROVE 1 and 2, respectively) compared with 41% and 46% with peg-IFN and ribavirin for 48 weeks.[7][8] Moreover, the PROVE 2 study from Europe clearly showed that the use of ribavirin was critical in achieving superior SVR rates.[8] Thus, the emerging treatment paradigm for telaprevir is one of more intensive therapy (peg-IFN, ribavirin and telaprevir) given for a shorter duration.


The studies utilized different stopping rules. In PROVE 1, patients on telaprevir were continued on their assigned duration of therapy only if they achieved a rapid virologic response with undetectable HCV RNA at 4 weeks.[7] In PROVE 2, patients on telaprevir were continued on their assigned duration of therapy only if they had an undetectable HCV RNA at the end of 10 weeks (in groups treated for total of 12 weeks) or 20 weeks (in group treated for 24 weeks).[8] Patients who did not achieve these virologic responses early in treatment, were continued on peg-IFN and ribavirin alone and considered nonresponders in the ITT analysis. This resulted in early discontinuation of telaprevir in approximately 20% of patients in the PROVE 1.[7] Since most virologic breakthroughs occurred during the first 4 weeks of therapy and about 80% of the breakthroughs occurred before the HCV RNA levels became undetectable, this strategy makes sense to minimize the risk of drug resistance. With this approach, the rate of virologic breakthroughs was low, occurring in 7% (PROVE 1) and 3% (PROVE 2) of patients receiving triple therapy for the first 12 weeks.[7][8] The rate of virologic breakthrough was substantially higher in the telaprevir plus peg-IFN group (24%), highlighting the importance of ribavirin in reducing virologic breakthrough due to drug resistance. There are several unanswered questions regarding strategies to minimize drug resistance. First, while ribavirin is clearly important, it is unknown whether combination therapy with protease inhibitors will require use of standard doses of ribavirin or whether lower doses would yield the desired benefits but with improved tolerability. Second, the appropriate time to stop treatment in suboptimal responders has not been rigorously tested. Rates of virological breakthrough early in treatment were similar in PROVE 1 and 2,[7][8] though different stopping rules were used. Understanding the risks of continued telaprevir exposure in the setting of combination therapy is important as the stopping rules used in these clinical trials may not be as rigorously adhered to when these drugs enter the clinic.


In both studies, high-level resistance was present in the majority of patients experiencing a virologic breakthrough, whereas low-level resistant variants were more frequently seen in those with virologic relapse following discontinuation of therapy. The predominant resistance mutations identified were V36M and R155K in genotype 1a and A156T in genotype 1b, with virologic breakthrough due to resistance emerging more frequently in the genotype 1a patients. Subtype differences in risk of emergent drug-resistance and whether there are sanctuaries that may allow these drug-resistant strains to persist and potentially limit future therapies with drugs of the same class, are questions to be addressed by additional, larger scale studies and by longitudinal examination of drug-exposed patients.


The improved efficacy of telaprevir, peg-IFN and ribavirin comes at a price in terms of tolerability. There were several side effects occurring at a significantly higher frequency in telaprevir-containing treatment arms including pruritus, rash, gastrointestinal symptoms (nausea, vomiting, diarrhea, hemorrhoids) and up to a median of 0.5-1.0 g/dL greater decline in hemoglobin compared to the standard peg-IFN and ribavirin therapy.[7][8] Importantly, the side effects associated with the addition of telaprevir resulted in an approximate doubling of treatment discontinuation rates (21% versus 11% with peg-IFN and ribavirin alone).[7][8] The most common adverse event leading to treatment discontinuation was rash, accounting for one-third of discontinuations. The study's authors comment on the utilization of specific management algorithms for pruritus in subsequent telaprevir studies.[8] Indeed, maximizing tolerance of future telaprevir-based regimens will be of importance to achieve optimal treatment outcomes.


In conclusion, the emerging data on the efficacy of telaprevir combined with peg-IFN and ribavirin are extremely encouraging. The phase 2b studies from McHutchison et al. (PROVE 1) and Hezode et al. (PROVE 2) in HCV genotype 1 patients show that triple therapy of telaprevir, peg-IFN and ribavirin for 12 weeks followed by 12 weeks of peg-IFN and ribavirin yields superior SVR rates with shorter duration of therapy compared to current peg-IFN and ribavirin. However, the improved efficacy comes with additional side effects and a risk of selecting drug-resistant viral variants that may limit subsequent therapeutic options. We can anticipate that the new treatment paradigms will continue to evolve as investigators seek to establish the best balance between benefits and risks. (From Jules: it is important to bear in mind that at AASLD Nov 2009 Vertex reported new data on telaprevir twice daily where the SVR rates were 83% and the rash problems appeared to be less, so by the time telaprevir comes to market management of the rash should be improved and phase 3 studies are ongoing now where we will learn more).


References


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2 Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL, Jr., et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002; 347: 975-982. Links

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5 Reesink HW, Zeuzem S, Weegink CJ, Forestier N, van Vliet A, van de Wetering de Rooij J, et al. Rapid decline of viral RNA in hepatitis C patients treated with VX-950: a phase Ib, placebo-controlled, randomized study. Gastroenterology 2006; 131: 997-1002. Links

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7 McHutchison J, Everson G, Gordon S, Jacobson I, Sulkowski M, Kauffman R, et al. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med 2009; 360: 1827-1838. Links

8 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. Links