Realize the advance in HCV treatment, but remain cautious
Authors: Tarik Asselah
Journal: Journal of Hepatology (2011)

COMMENTARY ON Telaprevir for previously untreated chronic hepatitis C virus infection. Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, Bzowej NH, Marcellin P, Muir AJ, Ferenci P, Flisiak R, George J, Rizzetto M, Shouval D, Sola R, Terg RA, Yoshida EM, Adda N, Bengtsson L, Sankoh AJ, Kieffer TL, George S, Kauffman RS, Zeuzem S; ADVANCE Study Team. N Engl J Med. 2011 Jun 23;364(25):2405–2416. Copyright (2011). Abstract reprinted with permission of the Massachusetts Medical Society. http://www.ncbi.nlm.nih.gov/pubmed/21696307 Abstract. Background: In phase 2 trials, telaprevir, a hepatitis C virus (HCV) genotype 1 protease inhibitor, in combination with peginterferon-ribavirin, as compared with peginterferon-ribavirin alone, has shown improved efficacy, with potential for shortening the duration of treatment in a majority of patients. Methods: In this international, phase 3, randomized, double-blind, placebo-controlled trial, we assigned 1088 patients with HCV genotype 1 infection who had not received previous treatment for the infection to one of three groups: a group receiving telaprevir combined with peginterferon alfa-2a and ribavirin for 12weeks (T12PR group), followed by peginterferon-ribavirin alone for 12weeks if HCV RNA was undetectable at weeks 4 and 12 or for 36weeks if HCV RNA was detectable at either time point; a group receiving telaprevir with peginterferon-ribavirin for 8weeks and placebo with peginterferon-ribavirin for 4weeks (T8PR group), followed by 12 or 36weeks of peginterferon-ribavirin on the basis of the same HCV RNA criteria; or a group receiving placebo with peginterferon-ribavirin for 12weeks, followed by 36weeks of peginterferon-ribavirin (PR group). The primary end point was the proportion of patients who had undetectable plasma HCV RNA 24weeks after the last planned dose of study treatment (sustained virologic response). Results: Significantly more patients in the T12PR or T8PR group than in the PR group had a sustained virologic response (75% and 69%, respectively, vs. 44%; p<0.001 for the comparison of the T12PR or T8PR group with the PR group). A total of 58% of the patients treated with telaprevir were eligible to receive 24weeks of total treatment. Anemia, gastrointestinal side effects, and skin rashes occurred at a higher incidence among patients receiving telaprevir than among those receiving peginterferon-ribavirin alone. The overall rate of discontinuation of the treatment regimen owing to adverse events was 10% in the T12PR and T8PR groups and 7% in the PR group. Conclusions: Telaprevir with peginterferon-ribavirin, as compared with peginterferon-ribavirin alone, was associated with significantly improved rates of sustained virologic response in patients with HCV genotype 1 infection who had not received previous treatment, with only 24weeks of therapy administered in the majority of patients. (Funded by Vertex Pharmaceuticals and Tibotec; ADVANCE ClinicalTrials.gov number, NCT00627926) AND Telaprevir for retreatment of HCV infection. Zeuzem S, Andreone P, Pol S, Lawitz E, Diago M, Roberts S, Focaccia R, Younossi Z, Foster GR, Horban A, Ferenci P, Nevens F, Müllhaupt B, Pockros P, Terg R, Shouval D, van Hoek B, Weiland O, Van Heeswijk R, De Meyer S, Luo D, Boogaerts G, Polo R, Picchio G, Beumont M; REALIZE Study Team. N Engl J Med. 2011 Jun 23;364(25):2417–28. Copyright (2011). Abstract reprinted with permission of the Massachusetts Medical Society. http://www.ncbi.nlm.nih.gov/pubmed/21696308 Abstract. Background: Up to 60% of patients with hepatitis C virus (HCV) genotype 1 infection do not have a sustained virologic response to therapy with peginterferon alfa plus ribavirin. Methods: In this randomized, phase 3 trial, we evaluated the addition of telaprevir to peginterferon alfa-2a plus ribavirin in patients with HCV genotype 1 infection who had no response or a partial response to previous therapy or who had a relapse after an initial response. A total of 663 patients were assigned to one of three groups: the T12PR48 group, which received telaprevir for 12weeks and peginterferon plus ribavirin for a total of 48weeks; the lead-in T12PR48 group, which received 4weeks of peginterferon plus ribavirin followed by 12weeks of telaprevir and peginterferon plus ribavirin for a total of 48weeks; and the control group (PR48), which received peginterferon plus ribavirin for 48weeks. The primary end point was the rate of sustained virologic response, which was defined as undetectable HCV RNA 24weeks after the last planned dose of a study drug. Results: Rates of sustained virologic response were significantly higher in the two telaprevir groups than in the control group among patients who had a previous relapse (83% in the T12PR48 group, 88% in the lead-in T12PR48 group, and 24% in the PR48 group), a partial response (59%, 54%, and 15%, respectively), and no response (29%, 33%, and 5%, respectively) (p<0.001 for all comparisons). Grade 3 adverse events (mainly anemia, neutropenia, and leukopenia) were more frequent in the telaprevir groups than in the control group (37% vs. 22%). Conclusions: Telaprevir combined with peginterferon plus ribavirin significantly improved rates of sustained virologic response in patients with previously treated HCV infection, regardless of whether there was a lead-in phase. (Funded by Tibotec and Vertex Pharmaceuticals; REALIZE ClinicalTrials.gov number, NCT00703118.) New direct acting antivirals (DAA), such as protease and polymerase inhibitors, are currently under development [[1]Asselah T. Marcellin P. New direct-acting antivirals' combination for the treatment of chronic hepatitis C.Liver Int. 2011; 31: 68-77Crossref PubMed Scopus (129) Google Scholar]. For the treatment of genotype 1 chronic hepatitis C, in both treatment-naïve and treatment-experienced patients, two NS3/4A protease inhibitors, telaprevir, and boceprevir, were approved in Europe and the United States in 2011 for use in combination with pegylated interferon and ribavirin. In a previous article, we discussed results obtained with Boceprevir (developed by the companies Merk/Schering Plough) in both treatment-naïve and treatment-experienced patients [2Asselah T. A sprint to increase response to HCV treatment: expectancies but caution.J Hepatol. 2011; 55: 1154-1158Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar, 3Poordad F. McCone Jr., J. Bacon B.R. et al.Boceprevir for untreated chronic HCV genotype 1 infection.N Engl J Med. 2011; 364: 1195-1206Crossref PubMed Scopus (2238) Google Scholar, 4Bacon B.R. Gordon S.C. Lawitz E. et al.Boceprevir for previously treated chronic HCV genotype 1 infection.N Engl J Med. 2011; 364: 1207-1217Crossref PubMed Scopus (1503) Google Scholar]. Interesting data were reported with Telaprevir (developed by the companies Vertex and Tibotec) in both treatment-naïve [5Jacobson I.M. McHutchison J.G. Dusheiko G. et al.Telaprevir for previously untreated chronic hepatitis C virus infection.N Engl J Med. 2011; 364: 2405-2416Crossref PubMed Scopus (2162) Google Scholar, 6Sherman K.E. Flamm S.L. Afdhal N.H. et al.Telaprevir in Combination with Peginterferon Alfa2a and Ribavirin for 24 or 48 weeks in Treatment-Naïve Genotype 1 HCV Patients who Achieved an Extended Rapid Viral Response.Hepatology. 2010; 52 ([AASLD, abstract]): LB-2Google Scholar] and treatment-experienced patients [[7]Zeuzem S. Andreone P. Pol S. et al.Telaprevir for retreatment of HCV infection.N Engl J Med. 2011; 364: 2417-2428Crossref PubMed Scopus (1433) Google Scholar]. This article is discussing the two major phase III clinical trials published recently (Advance [[5]Jacobson I.M. McHutchison J.G. Dusheiko G. et al.Telaprevir for previously untreated chronic hepatitis C virus infection.N Engl J Med. 2011; 364: 2405-2416Crossref PubMed Scopus (2162) Google Scholar] and Realize [[7]Zeuzem S. Andreone P. Pol S. et al.Telaprevir for retreatment of HCV infection.N Engl J Med. 2011; 364: 2417-2428Crossref PubMed Scopus (1433) Google Scholar]). The Advance study (Fig. 1A and B) is a 3-arm double-blind, randomized, placebo-controlled Phase 3 study assessing efficacy and safety of two telaprevir-based response-guided regimens compared with PEG-IFN alfa-2a and RBV in treatment-naïve patients with chronic genotype 1 HCV infection [[5]Jacobson I.M. McHutchison J.G. Dusheiko G. et al.Telaprevir for previously untreated chronic hepatitis C virus infection.N Engl J Med. 2011; 364: 2405-2416Crossref PubMed Scopus (2162) Google Scholar]. The trial design is presented in Fig. 1A. A significantly greater proportion of patients achieved SVR with the 12-week and 8-week telaprevir-based combination regimens (75% and 69%, respectively) compared with the PEG-IFN alfa-2a and RBV 48 weeks control arm (44%, p <0.001) (Fig. 1B). The most common (>25%) adverse events in the telaprevir arms were fatigue, pruritus, nausea, headache, anemia, rash, influenza-like illness, insomnia, pyrexia, and diarrhea. Discontinuation of treatment due to adverse events occurred in 7% and 8% in telaprevir regimens and 4% in PEG-IFN alfa-2a and RBV; it was caused by rash in 0.5%, 1.4%, and 0.0%, and it was due to anemia in 3.3%, 0.8%, and 0.6% in telaprevir 8 weeks in combination with PEG-IFN alfa-2a and RBV, telaprevir 12 weeks with PEG-IFN alfa-2a and RBV; and control arms, respectively. Finally, the telaprevir-based therapy improved SVR rates in genotype 1 treatment-naive patients. A 12-week telaprevir-based regimen demonstrated a better benefit:risk profile than an 8-week regimen. With response guided therapy, nearly two-thirds naïve patients were eligible for a 24-week treatment, and attained high rates of SVR. Discontinuation of the treatment regimen due to rash was minimized by stopping medication sequentially. The Illuminate study is a Phase 3 open-label study evaluating patients randomized to two durations of therapy among those who achieved extended rapid viral response (eRVR) [[6]Sherman K.E. Flamm S.L. Afdhal N.H. et al.Telaprevir in Combination with Peginterferon Alfa2a and Ribavirin for 24 or 48 weeks in Treatment-Naïve Genotype 1 HCV Patients who Achieved an Extended Rapid Viral Response.Hepatology. 2010; 52 ([AASLD, abstract]): LB-2Google Scholar]. Five hundred and forty HCV genotype 1 treatment-naïve patients were treated with telaprevir (12 weeks, 750 mg po q8 h) with PEG-IFN alfa2a and RBV. Patients who achieved eRVR (undetectable HCV RNA at weeks 4 and 12) were randomized at week 20 to continue receiving PEG-IFN alfa2a and RBV for 24 or 48 weeks of total treatment. Patients not achieving eRVR were assigned 48 weeks of treatment [[6]Sherman K.E. Flamm S.L. Afdhal N.H. et al.Telaprevir in Combination with Peginterferon Alfa2a and Ribavirin for 24 or 48 weeks in Treatment-Naïve Genotype 1 HCV Patients who Achieved an Extended Rapid Viral Response.Hepatology. 2010; 52 ([AASLD, abstract]): LB-2Google Scholar]. 72% (n = 389) of patients achieved RVR; 65.2% (n = 352) of patients achieved eRVR. 322 (59.6%) patients were randomized (1:1) to either a 24- or 48-weeks arm. SVR was 92% among patients randomized to 24 weeks (n = 162) and 87.5% (Δ4.5%, 2-sided 95% C.I. = −2.1% to +11.1%) among patients randomized to 48 weeks (n = 160). Overall, SVR was 71.9% (ITT analysis). SVR was 92% among patients randomized to 24 wks (n = 162). SVR was 87.5% (Δ4.5%, 2-sided 95% C.I. = −2.1% to +11.1%) among patients randomized to 48 weeks (n = 160). 36 patients (6.7%) discontinued treatment due to virologic failure. 94 patients (17.4%) had permanent discontinuation of all study drugs for adverse events. Fatigue (n = 22) and anemia (n = 12) were the most common adverse events leading to discontinuation. Treatment discontinuation due to anemia and rash were 3 (0.6%) and 6 (1.1%) patients, respectively, during the telaprevir treatment phase. Finally, among patients who achieved eRVR, a 24-week telaprevir-based regimen was non-inferior to 48-week telaprevir-based regimen (92% SVR compared to 87.5%). Response-guided treatment led to 71.9% SVR overall and nearly two-thirds of the patients were eligible for shorter duration of treatment. Permanent discontinuation of all study drugs due to adverse events occurred in 17.4% of patients. These results support response-guided therapy for telaprevir-based regimens in treatment-naïve patients. A major information from the telaprevir studies, is that approximately two-thirds of patients achieved RVR and remain HCV RNA negative through 24 weeks and benefit from 24 weeks of treatment. Treatment-naïve patients with cirrhosis who have undetectable HCV-RNA at weeks 4 and 12 may benefit from an additional 36 weeks of peginterferon alfa and ribavirin (48 weeks total). Discontinuation of therapy is recommended in all patients with HCV-RNA levels of greater than or equal to 1000 IU/ml at treatment week 4 or 12; or confirmed detectable HCV-RNA levels at treatment Week 24. Patients may develop treatment-emergent resistance substitutions. Probably yes. In a prospective, multicenter, randomized, open-label, phase 2 clinical trial study, including 161 HCV genotype 1 patients, a high proportion (>80%) of patients achieved an SVR regardless of the telaprevir dosing frequency (q8 h or q12 h) or type of peginterferon alfa used (alfa-2a or alfa-2b) [[8]Marcellin P. Forns X. Goeser T. et al.Telaprevir Is Effective Given Every 8 or 12 Hours With Ribavirin and Peginterferon Alfa-2a or -2b to Patients With Chronic Hepatitis C.Gastroenterology. 2011; 140: 459-468Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar]. Each pegylated interferon provides approximately the same SVR (4). It might be that either interferon could be utilized with either protease inhibitor; however we need more information regarding this issue. The Realize study is a phase 3, randomized, double-blind, placebo-controlled study conducted in 662 genotype 1 chronic hepatitis C patients who did not achieve an SVR after at least one prior treatment with IFN-based therapy [[7]Zeuzem S. Andreone P. Pol S. et al.Telaprevir for retreatment of HCV infection.N Engl J Med. 2011; 364: 2417-2428Crossref PubMed Scopus (1433) Google Scholar]. Trial design is presented in Fig. 2A. There were two telaprevir-based arms (simultaneous and delayed start) and one control arm. As in all Phase 3 studies of telaprevir, patients received no more than 12 weeks of telaprevir given in combination with pegylated interferon and ribavirin. One of the telaprevir treatment arms was designed to evaluate whether there was any further improvement in viral cure rates when delaying the start of telaprevir by four weeks, during which time patients received four weeks of pegylated-interferon and ribavirin alone, compared to a simultaneous start. The SVR rates between these two arms were similar and there was no clinical benefit to the telaprevir delayed start treatment arm in any of the subgroups of patients. SVR rates for the telaprevir simultaneous start arm and the delayed start arm were 64% and 66%, respectively, overall, based on an intent-to-treat (ITT) analysis (Fig. 2B). For the primary analysis, the SVR rates for the telaprevir simultaneous start arm, delayed start arm and control arm, respectively, were 83%, 88%, and 24% in relapsers (p <0.001); 59%, 54%, and 15% in partial responders, (p <0.001); and 29%, 33%, and 5% in null responders, (p <0.001) (Fig. 2B). Prior relapsers might be treated for a duration of 24 weeks if they achieved eRVR. Among prior relapsers, 76% (218/286) achieved an eRVR and of those 95% (208/218) achieved an SVR. Partial responders and non responders will be treated for 48 weeks. Null responders may wait for future combination treatment. The mechanisms of non response to interferon are not well understood, and the addition of a protease inhibitor might partially restore IFN responsiveness [[9]Asselah T. Bièche I. Sabbagh A. Bedossa P. Moreau R. Valla D. et al.Gene expression and hepatitis C virus infection.Gut. 2009; 58: 846-858Crossref PubMed Scopus (91) Google Scholar]. Finally, a major breakthrough has been achieved with triple therapy when telaprevir is added to pegylated interferon and ribavirin. Realize the Advance in HCV treatment, but remain cautious. In genotype 1 naïve and experienced patients, standard of care is currently the triple therapy with telaprevir or boceprevir, with PEG-IFN plus ribavirin. This led to major expectancies but also caution. There will be major educational needs to achieve good clinical use of treatment. First, knowledge of treatment response predictors will include genotype 1 subtype, and also all previously known predictors (RVR, etc.). Power of IL28B polymorphisms testing to predict SVR for triple therapy is not completely evaluated currently and cannot be recommended at this time. Naïve patients who achieved eRVR benefit from a shorter duration treatment. Treatment has to be well explained and simplified. Second, it will be important to focus on compliance. In addition to PEG-IFN and ribavirin, telaprevir is administered orally at a dose of 750 mg three times daily (to be taken with food and at an interval of 7–9 h between doses) in two capsules of 375 mg each. Compliance will be an issue, since poor compliance is associated with failure and resistance. Third, management of side effects and treatment dose adaptation will be important. The main side effects observed with telaprevir are skin lesions, including rash and pruritus, and anemia. In the Advance study, rash was more frequently observed in the 12-week telaprevir arm than in the control arm (56% vs. 37%, respectively) [[5]Jacobson I.M. McHutchison J.G. Dusheiko G. et al.Telaprevir for previously untreated chronic hepatitis C virus infection.N Engl J Med. 2011; 364: 2405-2416Crossref PubMed Scopus (2162) Google Scholar]. Rash was also more frequent in the telaprevir arm in the REALIZE study (37% and 36% in the telaprevir arms vs. 19% in the control arm) [[7]Zeuzem S. Andreone P. Pol S. et al.Telaprevir for retreatment of HCV infection.N Engl J Med. 2011; 364: 2417-2428Crossref PubMed Scopus (1433) Google Scholar]. Approximately 90% of all rashes were mild or moderate (grades 1 and 2), whereas 6% of patients experienced severe (grade 3) rash, leading to telaprevir discontinuation [[5]Jacobson I.M. McHutchison J.G. Dusheiko G. et al.Telaprevir for previously untreated chronic hepatitis C virus infection.N Engl J Med. 2011; 364: 2405-2416Crossref PubMed Scopus (2162) Google Scholar]. Grade 3 to 4 cutaneous lesions require immediate treatment discontinuation and immediate consultation with experienced dermatologists. Frequent physical examinations together with laboratory testing for anemia to adapt dosing will be needed. Last but not least, measurements of HCV RNA for monitoring drug resistance will be mandatory. HCV RNA assays based on real-time PCR will have to be done frequently. A viral breakthrough in a compliant patient is very likely to be drug resistance and is a stopping rule. In the future, we do hope that once several DDAs become available, treatment strategies will include a combination of several drugs with different mechanisms of action (protease inhibitors plus polymerase inhibitors) that could hopefully result in IFN- and/or ribavirin sparing regimens leading to additive potency, lacking cross resistance and with a good safety profile. Tarik Asselah is a speaker and/or investigator for Abbott, Boehringer-Ingelheim, BMS, Gilead, Janssen, Merck, Novartis and Roche.