How to optimize HCV therapy in genotype 1 patients with cirrhosis

Transcription

1 Liver International ISSN REVIEW ARTICLE How to optimize HCV therapy in genotype 1 patients with cirrhosis Marc Bourliere 1, Astrid Wendt 1,Helene Fontaine 2, Christophe Hezode 3, Stanislas Pol 2 and Jean Pierre Bronowicki 4 1 Department of Hepato-Gastroenterology Hospital Saint Joseph, Marseille, France 2 Universite Paris Descartes, APHP Unite d Hepatologie, H^opital Cochin, INSERM U-1016, Institut Cochin, Paris, France 3H^opital Henri Mondor, Universite Paris-Est, INSERM U955, Creteil, Paris, France 4 INSERM U954, Universite de Lorraine, Centre Hospitalier Universitaire de Nancy, Vandoeuvre Les Nancy, France Keywords alisporivir asunaprevir boceprevir cirrhosis daclatasvir decompensated cirrhosis extended rapid virologic response faldaprevir genotype 1 hepatitis C virus rapid virological response simeprevir sustained virological response telaprevir Abbreviations DAA direct-acting antivirals; EVR early virological response; ervr extended rapid virologic response; FDT fixed duration therapy; French ATU temporary authorization for use; HCV hepatitis C virus; HCC hepatocellular carcinoma; PEG-IFN pegylated interferon; PR pegylated interferon and ribavirin; RVR rapid virological response; RGT response-guided therapy; RBV ribavirin; SOC standard of care; SVR sustained virological response. Correspondence: Marc Bourliere, MD, Service d Hepato- Gastroenterologie, H^opital Saint-Joseph, 26, boulevard de Louvain, Marseille Cedex 08, France mbourliere@hopital-saint-joseph.fr DOI: /liv Abstract Of all hepatitis C virus patients, those with cirrhosis are most in need of treatment owing to increased morbidity and mortality. Treatment with pegylated interferon and ribavirin (PEG-IFN/RBV) has clearly shown the benefits of successful treatment by improving fibrosis, causing the regression of cirrhosis and reducing and preventing cirrhosis-related complications. However, the sustained virological response (SVR) is lower in patients with cirrhosis. First generation protease inhibitors (boceprevir and telaprevir) in combination with PEG-IFN/RBV are a major advancement in the treatment of both na ıve and treatment-experienced genotype 1 patients. In na ıve patients, the SVR rate with the triple regimen with boceprevir increased by 14% in patients with severe fibrosis or cirrhosis compared to PEG-IFN/RBV compared by 30% in patients with mild or moderate fibrosis. The SVR rate of the triple regimen with telaprevir increased by 10 30% compared to PEG-IFN/RBV in patients with severe fibrosis or cirrhosis and by nearly 30% in patients with mild or moderate fibrosis. The greatest benefits seem to be found in patients with cirrhosis who have relapsed, and is limited in prior non-responder patients. Thus, the choice of triple therapy in the latter should be considered in relation to the increase in side effects. There are no data on the efficacy of the triple regimen in patients with decompensated cirrhosis. Results in real-life settings show that patients with cirrhosis need to be carefully followed-up during treatment due to the increase in side effects that are greater than in clinical studies. Next generation DAAs and PEG-IFN/ RBV appear to be more effective and have fewer side effects in patients with cirrhosis. Ultimately, an interferon-free regimen of DAAs combinations will probably provide a SVR in patients with cirrhosis and will probably be proposed in patients with more advanced or decompensated cirrhosis. The prognosis of hepatitis C virus (HCV) infection is mainly linked to the progression of fibrosis. Cirrhosis increases the risk of premature liver-related deaths owing to complications such as hepatic decompensation and hepatocellular carcinoma (HCC). Thus, the patients most in need of HCV treatment are those with cirrhosis in whom HCV eradication could prevent liver related complications and improve survival (1). Long-term study have demonstrated that sustained virological response (SVR) 6 months after the end of treatment may be considered to show eradication of HCV infection in nearly all patients (2). Over the past decade, knowledge of the HCV lifecycle shows that potentially each step of the viral cycle could be a target for drug development. Understanding of the structures of HCV protease and HCV polymerase has allowed structure-based drug design to develop inhibitors of these enzymes. Two first generation protease inhibitors (boceprevir and telaprevir) were marketed in 2011for HCV genotype 1 patients, and several new direct-acting antiviral agents (DAAs) and host-targeting agents (HTA) are currently in development (3). The aim of this article is to review the most recent literature on the treatment John Wiley & Sons A/S

2 Bourliere et al. Optimal triple therapy for genotype 1 of genotype 1 HCV cirrhosis in the era of these new DAAs. HCV cirrhosis treatment-response with first generation protease inhibitors (PI) in association with pegylated interferon and ribavirin The two first protease inhibitors, boceprevir (Victrelis ) and telaprevir (Incivo or Incivek ) were launched in 2011 and triple therapy with PI plus PEG-IFN/RBV has become the new standard of care (SOC) for genotype 1- infected patients. The SVR rate was increased by nearly 30% with triple therapy compared to PEG-IFN/RBV in na ıve genotype 1 patients and by 25 60%, according to previous treatment response in treatment-experienced genotype 1 patients (4 7). However, this progress is associated with an increased rate of adverse events with a two-fold increase in anaemia and new side effects such as dysgeusia, observed in nearly one third of patients on the boceprevir regimen as well as cutaneous rash observed in 55% of the patients on the telaprevir regimen. There was a slight increase in severe adverse events compared to PEG-IFN/RBV (7% vs 3% with boceprevir and 11 14% vs 5 9% with telaprevir) as well as in treatment withdrawal owing to adverse events (8 16% vs 2 16% with boceprevir and 8 14% vs 4% with telaprevir) in phase III studies. Treatment response with boceprevir in genotype 1 patients with severe fibrosis or cirrhosis in phase III studies The absence of cirrhosis is one of the baseline predictive factors of response to triple therapy with boceprevir with an odds ratio for SVR of 2.5 (95% CI ) (P = 0.003) in na ıve genotype 1 patients (4). In a phase III trial in na ıve genotype 1 patients, only 100 of 1097 patients had either severe fibrosis (47) or cirrhosis (53) (4). The baseline characteristics of patients with severe fibrosis or cirrhosis were identical to those with milder fibrosis except for age (mean 52 ± 8vs49 ± 9 years respectively). Patients were randomized into three treatment groups. PR was administered in all groups for 4 weeks (lead-in phase). Group 1 then received PR for 44 weeks (SOC), group 2 received boceprevir plus PR for 24 weeks, those with detectable HCV RNA between weeks 8 and 24 received PR for an additional 20 weeks [response-guided therapy (RGT)], and group 3 received boceprevir and PR for 44 weeks [fixed duration therapy (FDT)]. The SVR rates in patients with advanced fibrosis were 52% in the triple regimen FDT arm, 41% in the triple regimen with RGT arm and 38% with SOC, whereas SVR rates were 67% with the triple regimen and 38% with SOC in patients with milder fibrosis stage (Fig. 1) (8). rates were increased by 14% compared to SOC in patients with F3/ F4 compared to nearly 30% in patients with mild or moderate fibrosis. The relapse rate was also more frequent in patients with severe fibrosis or cirrhosis compared to patients with less advanced fibrosis (12 18% vs 9% respectively) (8). A rapid virological response (RVR) during triple therapy with boceprevir (treatment week 8) was frequent (46%) and allowed the duration of treatment to be shortened in patients with no or low stage fibrosis(8). Rapid virological response was less frequent in patients with severe fibrosis or cirrhosis, (25%) and the SVR rate was higher in patients achieving RVR who received 48 weeks of treatment (92%) compared to those who received response-guided therapy (RGT) (75%), which is not the case in patients with milder fibrosis (98 and 96% respectively). Overall, na ıve genotype 1 patients with severe fibrosis or cirrhosis benefit from the triple regimen, but should receive fixed duration of treatment (FDT). In a phase III trial in treatment-experienced patients (relapsers or partial responders), 78 of 403 patients had either severe fibrosis (29) or cirrhosis (49) (6). Patients were randomized into three treatment groups. PEG- IFN/RBV was administered for 4 weeks (lead-in phase). Group 1 then received PEG-IFN/RBV for 44 weeks, group 2 received boceprevir plus PEG-IFN/RBV for 32 weeks, patients with detectable HCV RNA at week 8 received PEG-IFN/RBV for an additional 12 weeks (RGT) and group 3 received boceprevir plus PEG-IFN/ RBV for 44 weeks (FDT). The SVR rates in patients with advanced disease were 68% with the FDT triple regimen (48 weeks), 44% with the triple regimen RGT and 13% with PEG-IFN/RBV, while SVR rates were 67% with the triple regimen and 23% with PEG-IFN/RBV in patients with milder stage fibrosis (Fig. 2) (8). Sustained virological response rates were increased by 42% compared to PEG-IFN/RBV in patients with F3/F4 and nearly 44% in patients with no, mild or moderate fibrosis. According to previous treatment response, SVR rates were increased in all boceprevir regimen patients compared to PEG-IFN/RBV in both prior relapsers and partial responders irrespective of the stage of fibrosis (Fig. 3). The relapse rate was more frequent in patients with severe fibrosis or cirrhosis than in those with less N = Fig. 1. SVR with boceprevir regimen in na ıve genotype 1 patients according to fibrosis stage John Wiley & Sons A/S 47

3 Optimal triple therapy for genotype 1 Bourliere et al. advanced fibrosis (21 vs 11%). The week 4 lead-in response was predictive of SVR. During triple therapy with boceprevir (treatment week 8) a RVR occurred in 53% of the patients and a shorter duration of treatment was possible in patients with no or low stage fibrosis. An RVR was achieved in 25% of the patients with severe fibrosis or cirrhosis, and SVR rates were higher in those receiving 48 weeks of treatment (90%) than in those receiving RGT (80%). This was not the case in patients with milder fibrosis (88 and 86% respectively). Overall, treatment-experienced genotype 1 patients with severe fibrosis or cirrhosis benefit from a triple regimen, but should receive a 48 weeks FDT. The safety of and tolerance to the triple regimen with boceprevir in na ıve or treatment-experienced patients with severe fibrosis and cirrhosis, did not significantly differ from that in patients with mild or moderate fibrosis in phase III trials (8). Serious adverse events were reported in 15 and 11% respectively, and discontinuation of treatment owing to adverse events was reported in 12 and 13% respectively. However, dose modifications owing to adverse events appear to be more frequent in N = Fig. 2. with boceprevir regimen in treatment-experienced genotype 1 patients according to fibrosis stage. F 0/1/2 F 3/4 patients with advanced fibrosis than in those with mild or moderate fibrosis (41 and 35% respectively). Anaemia also appears to be slightly more frequent (53% vs 47%). However, the conclusions on safety and tolerance remain limited by the small number of patients with cirrhosis included in the phase III programme. Treatment response with telaprevir in genotype 1 patients with severe fibrosis and cirrhosis In the two phase III trials with telaprevir (5, 9) 380 na ıve genotype 1 patients of 1628 had either severe fibrosis (251) or cirrhosis (129). In the ADVANCE study 1088 patients were randomized into three treatment groups (5). Group1 received telaprevir plus PEG-IFN/RBV for 12 weeks (T12PR) followed by PEG-IFN/RBV alone for 12 weeks if HCV RNA was undetectable at weeks 4 and 12, or for 36 weeks if HCV RNA was detectable at either time point. Group 2 received telaprevir and PEG-IFN/RBV for 8 weeks and placebo plus PEG-IFN/RBV for 4 weeks (T8PR) followed by 12 or 36 weeks of PR on the basis of the same HCV RNA criteria. Group 3 received PEG- IFN/RBV for 48 weeks. The SVR rates in patients with advanced fibrosis were 62% with the triple regimen T12PR, 53% with the triple regimen T8PR and 33% with PEG-IFN/RBV while the SVR was 76% with the triple regimen and 47% with PEG-IFN/RBV in patients with milder stage fibrosis (Fig. 4). The SVR rate in patients with F3/F4 was increased by 10 30% compared to PEG-IFN/RBV and by nearly 30% in patients with no, mild or moderate fibrosis. In the ILLUMINATE study 540 patients received telaprevir plus PEG-IFN/RBV for 12 weeks followed by PEG-IFN/RBV (9). Patients who had an extended RVR (ervr) (undetectable HCV RNA at week 4 and 12) were randomly assigned to receive PEG-IFN/RBV after week 20 for 4 more weeks (T12PR24) or 28 more weeks (T12PR48). Patients without an ervr were assigned to T12PR48. The SVR rate was 63% in patients with N = N = Fig. 3. with boceprevir regimen in treatment-experienced genotype 1 patients according to fibrosis stage and previous treatment response. Fig. 4. with telaprevir regimen in na ıve genotype 1 patients according to fibrosis stage John Wiley & Sons A/S

4 Bourliere et al. Optimal triple therapy for genotype 1 N = N = Relapsers Partial responders Null responders Fig. 5. with telaprevir regimen in na ıve genotype 1 patients according to fibrosis stage and extended rapid virological response. Fig. 6. with telaprevir regimen in treatment-experienced genotype 1 patients according to fibrosis stage and previous treatment response. advanced fibrosis vs 75% in patients with mild or moderate fibrosis. An ervr was frequent under triple therapy with telaprevir: 58% with the T12PR regimen in the ADVANCE study and 60% in the ILLUMINATE study. However, an ervr was less frequent in patients with severe fibrosis or cirrhosis (46 and 49% respectively). Moreover, the SVR rates were higher in patients who achieved an ervr and received 48 weeks of treatment 88% than in those who received 24 weeks of treatment 82%, which was not the case in patients with milder fibrosis (87 and 95% respectively) (Fig. 5). Overall, na ıve genotype 1 patients with severe fibrosis or cirrhosis benefit from the triple regimen with telapevir, but should receive the T12PR48 regimen, especially patients with cirrhosis. In the phase III trial in treatment-experienced genotype 1 patients (relapsers, partial responders or nonresponders), 316 (48%) of 663 patients had either severe fibrosis (147, 23%) or cirrhosis (169, 25%) (7). Patients with cirrhosis were slightly older (54 vs 50 years) and more likely to be prior non-responders (36% vs 25%) (10). Patients were randomly assigned to three groups. Group 1 (T12PR48) received telaprevir for 12 weeks and PEG-IFN/RBV for a total of 48 weeks, group 2 (lead-in T12PR48) PR for 4 weeks followed by 12 weeks of telaprevir and PR for a total of 48 weeks, and group 3 PEG-IFN/RBV for 48 weeks. SVR rates were identical for all telaprevir regimens. SVR rates were increased in the telaprevir regimen compared to PEG-IFN/RBV whatever the stage of fibrosis, 75% vs 22% in patients with minimal or moderate fibrosis, 67% vs 7% in patients with bridging fibrosis and 47% vs 10% in patients with cirrhosis. SVR rates were increased with the telaprevir regimen compared to PEG-IFN/RBV in previous relapsers irrespective of fibrosis stage (7). SVR rates were higher with the telaprevir regimen compared to PR for previous partial responders and non-responders. However, the benefit decreased in those with advanced fibrosis (Fig. 6). The SVR rates were lower in patients with cirrhosis than in those without, except for previous relapsers, in whom the effect of telaprevir treatment was maintained compared to PEG-IFN/RBV. The relapse rate was higher in patients with cirrhosis and a previous partial or non-response than in those without cirrhosis (10% vs 4%). A high baseline ALT or AST and prior PEG-IFN/RBV response was predictive of an SVR in multivariate analysis in patients with cirrhosis. There was no association between the presence or level of telaprevir resistance and the stage of fibrosis in patients who failed the telaprevir regimen. Rash, pruritus and anaemia were more frequent in patients with cirrhosis who received telaprevir (67, 59 and 42% respectively) than both patients without cirrhosis who received telaprevir (53, 52 and 34% respectively) and patients who received PR (27, 35 and 27% respectively). Adverse events led to telaprevir discontinuation in 15% of patients with cirrhosis and in 11% of those without (10). HCV cirrhosis treatment with boceprevir and telaprevir in the real-life setting The French ATU (temporary authorization for use) provides patients who are the most in need with a medicinal product before marketing authorization (MA). The major objective of the ATU was to make first generation PIs available and evaluate their safety. In the telaprevir and boceprevir ATUs, genotype 1, treatment-experienced patients (either relapsers or partial responders to prior PEG-IFN/RBV therapy) with compensated cirrhosis were eligible to receive a 48 weeks of treatment with triple therapy. Between January 2011 and July 2011 for boceprevir and September 2011 for telaprevir, 558 patients were treated with 12 weeks of triple therapy followed by 32 weeks of PR, and 373 patients were treated by a 4 week PEG-IFN/RBV lead-in phase followed by 44 weeks of triple therapy with boceprevir. Moreover, 63 patients were also treated during the same period 2012 John Wiley & Sons A/S 49

5 Optimal triple therapy for genotype 1 Bourliere et al. with a nominative ATU. These patients were mostly (42) responders. The ATU was not a clinical trial. Only limited data could be collected by the pharmaceutical companies involved and only safety data should be reported by clinicians and could not be monitored by either French health authorities or pharmaceutical companies. Clinicians had no obligation to report any efficacy data. Recently data from telaprevir ATU have been reported after a median follow-up of 18.6 weeks ( weeks) (11). Seventy one per cent of the patients were men with a median age of 56 years (range 22 89), 56% were genotype 1b and the median viral load at baseline was 6.05 log 10 IU/ml; 54% of patients were partial responders and 43% were relapsers. Ninety-eight per cent of the patients began with 180 lg/week of PEG-IFNalfa-2a and a weight-based dose of RBV with a median dose of 14.3 mg/kg/days. Eighty-nine per cent of the patients had adverse events and 40% experienced serious adverse events, leading to discontinuation of telaprevir in 14%. Three patients died during the treatment period. Haematological disorders were frequent during treatment. Anaemia below 10 g/dl was observed in 36% of the patients despite the use of erythropoietin in 49% of the patients. Transfusions were given to 11% of the patients and a RBV dose reduction was used to manage anaemia in 6.6% of the patients. Grade 4 neutropenia (<500 cells/mm 3 ) was observed in 2% of the patients and grade 4 thrombopenia (< cells/mm 3 ) was observed in 3% of the patients. Only one severe telaprevir-related rash was reported. A RVR was observed in 70% (157 of 223) of patients, 66% in partial responders, 77% in relapsers, 62% in genotype 1a and 82% in genotype 1b patients. An ervr was observed in 69% (84 of 122) of the patients, 66% in partial responders, 72% in relapsers, 63% in genotype 1a and 83% in genotype 1b patients. Overall no new adverse events were observed, the safety profile of telaprevir regimen appeared to be compatible with use in clinical practice but close monitoring of haematological parameters is recommended in those with cirrhosis. Preliminary ontreatment virological response appeared to be promising in this population. However, the main drawback of the ATU is the absence of systematic data collection and the absence of data monitoring. Therefore, the data provide by ATU are relatively scarce and may be significantly biased. To collect reliable data from patients with cirrhosis, we set up a prospective cohort on the use of protease inhibitors in these patients (CUPIC cohort) on behalf of the French national agency for AIDS and viral hepatitis (ANRS). The aim of this cohort was to collect data on the efficacy, safety, resistance, pharmaco-kinetics (PK) and quality of life. All data were monitored as in clinical trials. From February 2011 to April 2012, 674 genotype 1 patients with cirrhosis were included in 55 sites. Recently an interim analysis in 455 patients who had received at least 16 weeks of treatment was reported (12). Most patients had compensated cirrhosis, had not responded to prior PEG-IFN/RBV and were treated in the French ATU. Although non-responders were theoretically excluded, after the end of ATU the protocol was amended and these patients were included. All patients were treated with a regimen of 48 weeks of treatment recommended by the ATU. The choice of PIs (telaprevir or boceprevir) was left to the physicians and therefore no head-to-head comparison could be obtained from the cohort. Baseline patient s characteristics are given in Table 1. They were similar to patient characteristics in the ATU cohort. Most of the patients were Child Pugh A cirrhosis, however, at least 15% of the patients had oesophageal varices and 26% of the patients in the boceprevir regimen and 34% in the telaprevir regimen had exclusion criteria for phase III trials. Therefore, this cirrhotic population was different from that included in clinical trials and reflected a more reallife population with cirrhosis. Preliminary safety findings for the telaprevir regimen are provided in Table 2. Serious adverse events were more frequent in the CUPIC cohort (48.6%) than in phase 3 trials, leading to premature discontinuation of treatment in 14.5% of the population treated so far. Six deaths (2%) occurred during the early course of treatment, half of them from infection. Grade 3/4 infection occurred in 8.8% of the population and hepatic decompensation (ascites, encephalopathy or variceal bleeding) occurred in 13 patients (4.4%) leading to death in two patients. Severe rash was rare and occurred in two patients. Preliminary safety findings for the boceprevir regimen are given in Table 3. Serious adverse events were more frequent in the CUPIC cohort (38.4%) than in phase 3 trials, leading to premature discontinuation in 7.4% of the population treated so far. Two deaths (1.3%) owing to Table 1. Patient characteristics of the CUPIC cohort at baseline Telaprevir (N = 296) Boceprevir (N = 159) Men (%) Mean age (years) Median follow-up duration (days) Median PIs duration (days) Mean neutrophils (10 3 cells/mm 3 ) Mean haemoglobin (g/dl) Mean platelets (cells/mm 3 ) Genotype 1b/1a (%) 61/39 60/40 Mean baseline HCV RNA (Log 10 IU/ml) Mean prothrombin time (ratio) 88% 88% Mean total bilirubin (lmol/l) Mean Albumin (g/dl) Oesophageal varices (%) Previous treatment response (%) Partial responders Relapsers Null responders 8 3 Patients with exclusion criteria for phase III trials (%) John Wiley & Sons A/S

6 Bourliere et al. Optimal triple therapy for genotype 1 Table 2. Preliminary safety findings with telaprevir regimen in the CUPIC cohort Patients, n (% patients with at least one event) Telaprevir (N = 296) Serious adverse events (SAEs)* 144 (48.6%) Premature discontinuation 77 (26%) Due to SAES 43 (14.5%) Death 6 (2%) Septicaemia, septic shock, pneumopathy, oesophageal varices bleeding, Encephalopathy, lung carcinoma Infection (grade 3/4) 26 (8.8%) Asthenia (grade 3/4) 14 (4.7%) Rash Grade 3 20 (6.8%) Grade 4 (SCAR) 2 (0.7%) Pruritus (grade 3/4) 11 (3.7%) Hepatic decompensation (grade 3/4) 13 (4.4%) *407 SAEs in 144 patients, SCAR, severe cutaneous adverse reaction. Table 3. Preliminary safety findings with boceprevir regimen in the CUPIC cohort Patients, n (% patients with at least one event) Boceprevir (N = 159) Serious adverse events (SAEs)* 61 (38.4%) Premature discontinuation 38 (23.9%) Due to SAES 12 (7.4%) Death 2 (1.3%) Bronchopulmonary infection, sepsis Infection (grade 3/4) 4 (2.5%) Asthenia (grade 3/4) 9 (5.7%) Rash Grade 3 0 Grade 4 (SCAR) 0 Pruritus (grade 3/4) 1 (0.6%) Hepatic decompensation (grade 3/4) 7 (4.4%) *158 SAEs in 61 patients, SCAR, severe cutaneous adverse reaction. infection occurred during the lead-in phase. Grade 3/4 infection occurred in 2.5% of the population and hepatic decompensation occurred in seven patients (4.4%). In addition to these findings, haematological disorders were a major issue for patient management (Table 4). Anaemia below 10 g/dl occurred in 29.7% of patients on telaprevir and in 32.7% of patients on boceprevir despite the use of erythropoietin in 56.8 and 66% of the patients respectively. The rate of blood transfusion, 15.2% with the telaprevir regimen and 10.7% with the boceprevir regimen was higher than that reported in phase 3 trials. This was probably due partly to the low frequency of RBV dose reduction in these patients (<5%) and may also be owing to the lower efficacy of erythropoietin in patients with cirrhosis. Recent data from phase III trials have shown that, in na ıve and relapse patients treated with telaprevir, a significant ( 600 mg/days) and early RBV dose reduction did not influence the SVR (13). These data modify our paradigm for the management of anaemia. However, in this Table 4. Preliminary findings for haematological disorders in the CUPIC cohort Patients, n (% patients with at least one event) Telaprevir (n = 296) Boceprevir (n = 159) Anaemia Grade 2 (8.0 <10.0 g/dl) 58 (19.6%) 36 (22.6%) Grade 3/4 (<8.0 g/dl) 30 (10.1%) 16 (10.1%) EPO use 168 (56.8%) 105 (66%) Blood transfusion 45 (15.2%) 17 (10.7%) Neutropenia Grade 3 (500 <1000/mm 3 ) 12 (4%) 7 (4.4%) Grade 4 < 500/mm 3 ) 2 (0.7%) 1 (0.6%) G-CSF use 7 (2.4%) 6 (3.8%) Thrombopenia Grade 3 ( <50 000) 35 (11.8%) 10 (6.3%) Grade 4 (<25 000) 4 (1.3%) 1 (0.6%) Thrombopo ıetin use 5 (1.7%) 3 (1.9%) EPO, erythropoietin, G-CSF, granulocyte-colony stimulating factor. difficult-to-treat population with cirrhosis, in the absence of data on SVR, it is still unknown whether significant and early RBV reductions will impair SVR. Moreover, in phase III trials, SVR rates appear to be lower in patients with advanced fibrosis and cirrhosis when RBV is reduced (19 of 33, 58%) than with the use of erythropoietin (26 of 39, 67%) (13). Grade 4 neutropenia (<500 cells/mm 3 ) is rare with both drugs and observed in less than 1% of the population while GCSF was used in less than 4% of the population. Grade 4 thrombopenia (< cells/mm 3 ) was also rare with both drugs and observed in less than 2% of the population leading to thrombopoietin use in less than 2% of the population. On-treatment virological response was high with both drugs (Figs 7 and 8) leading to undetectable viral load by week 16 in 86% of patients treated with telaprevir and 71% of patients treated with boceprevir on a per protocol analysis. Overall these data show that in this difficult-to-treat population, the triple regimen is feasible and can result in a good on-treatment virological response. However, serious adverse events are more frequent than previously observed and patients need to be carefully and frequently monitored. The preliminary analysis of the baseline characteristics of patients who died suggest that patients with either a past history of hepatic decompensation (ascites, bleeding or encephalopathy), a baseline Child Pugh score >5 and/or portal hypertension, low platelets levels and diabetes may be at a higher risk of hepatic decompensation or infection and require close follow-up and early intervention. These difficult-to-treat patients also raise the question of prophylactic antibiotics during triple therapy. In the post-transplant setting, a retrospective study from a single centre has recently been reported. Six non-responder patients to PEG-IFN/RBV after liver transplantation who had developed cirrhosis were treated with a triple regimen with telaprevir (14). Prior to 2012 John Wiley & Sons A/S 51

7 Optimal triple therapy for genotype 1 Bourliere et al. % of patients with undetectable HCV RNA % of pa ents with undetectable HCV RNA Per protocol ITT 53 Per protocol ITT 2/ On-treatment virological response 2/155 Week / /285 Week 4 On-treatment virological response / / /149 Week 8 Week 8 treatment, all patients were converted to administration of cyclosporin with a trough level of 100 ng/ml. After a 4-week lead-in with PEG-IFN alfa-2b (1 lg/kg/days) and RBV ( mg/days), patients received telaprevir 750 mg TID. On the first day of telaprevir, patients received 25 mg daily of cyclosporine with trough level titrated to 100 ng/ml. The virological response was promising and two of six patients had undetectable HCV RNA by week 8 and four of six by weeks 12 and 16. Only two patients experienced a breakthrough. However, safety was difficult to manage as all patients required RBV dose reduction due to severe anaemia. Nearly all patients required blood transfusions and erythropoietin. Moreover, nearly all patients required G-CSF and two patients required elthrombopag for platelet levels below cells/mm 3. Drugdrug interactions between telaprevir and cyclosporine were manageable with cyclosporin dose adjustments. Results of another multicenter study in 28 liver transplant patients including 5 patients with cirrhosis treated with either boceprevir or telaprevir were identical and 61 55/150 88/ / /281 Week 12 Week / / /151 89/126 89/146 Week 16 Fig. 8. Preliminary on-treatment efficacy data with boceprevir regimen in the CUPIC cohort. 71 Week 16 Fig. 7. Preliminary on-treatment efficacy data with telaprevir regimen in the CUPIC cohort. drug-drug interaction were manageable by major drug dose reduction in calcineurin inhibitors especially when telaprevir was used with tacrolimus(15). HCV cirrhosis treatment beyond first generation protease inhibitors The second-wave of NS3/4A serine PIs has several advantages over the first generation including a higher barrier to resistance, better efficacy with pangenotypic activity, more convenient dosing schedules, reduced pill burden and finally better safety and tolerability (16 18). All these advantages have been confirmed in phase II studies with second-wave PIs in association with PEG- IFN/RBV in a population without cirrhosis. However, data on patients with cirrhosis are still scarce. Twentyfive genotype 1 na ıve cirrhotic patients were treated with faldaprevir (BI201335) 120 mg QD in association with PEG-IFN/RBV for 12 or 24 weeks followed by PEG- IFN/RBV up to week 48 in a phase II study. SVR data were equivalent for the 12 or 24 week triple regimen, but no SVR data were obtained in patients with cirrhosis (19). In a large phase 2b study 83 treatment-experienced genotype 1 patients with cirrhosis out of 462 patients were treated with simeprevir (TMC435) 100 or 150 mg QD with PEG-IFN/RBV for 12, 24 or 48 weeks, followed by PEG-IFN/RBV until week 48 if needed, vs PEG-IFN/RBV for 48 weeks(20). SVR 24 was always higher in the simeprevir regimen than with PEG-IFN/ RBV. The SVR rate in patients with cirrhosis was 70 73% in relapse patients, 15 82% in partial responders and 31 46% in non-responders (Fig. 9). The antiviral efficacy of NS5B nucleoside inhibitors is similar for all genotypes and this treatment has the highest barrier of resistance of all DAA. In a phase 2b study, 23 genotype 1 or 4 na ıve patients with cirrhosis out of 166 enrolled patients were treated with mericitabine 1000 mg BID plus PEG-IFN/RBV for 24 or 48 weeks RGT vs PEG-IFN/RBV for 48 weeks (21). The SVR rate in patients with cirrhosis was 38.1% in the mericitabine 24 Relapsers Partial responders Null responders N = Fig. 9. with simeprevir regimen in treatment-experienced genotype 1 patients according to fibrosis stage and previous treatment response John Wiley & Sons A/S

8 Bourliere et al. Optimal triple therapy for genotype 1 regimen vs 21.7% in the PEG-IFN/RBV regimen. The 16.6% increase in SVR in patients with cirrhosis was lower than the 21.4% increase in patients without cirrhosis treated with mericitabine. Moreover, in another phase 2b study using a lower dose or shorter duration of mericitabine in association with PEG-IFN/RBV, 95 genotype 1 or 4 patients with cirrhosis were included among 408 patients enrolled (22). The SVR rate in patients with cirrhosis was lower (22 41%) than in patients with cirrhosis treated with PEG-IFN/RBV (47%). These data suggest that in genotype 1 or 4 patients with cirrhosis, a high dose (1000 mg BID) of mericitabine must be used in combination with PEG- IFN/RBV for 24 or 48 weeks. The NS5B pyrimidine nucleotide analogue, sofosbuvir (PSI or GS-7977) has highly potent antiviral activity across all HCV genotypes with a high genetic barrier to resistance. This combination with PEG-IFN/RBV induced an SVR rate of over 90% across all genotypes in na ıve patients without cirrhosis (23 25). Sofosbuvir, 400 mg QD, was administered in eight patients with Child Pugh B cirrhosis for 7 days (26). The drug was well tolerated and resulted in similar systemic exposure than in non-cirrhotic subjects. Significant declines in HCV RNA were observed in all subjects confirming the intrahepatic activity of sofosbuvir. Viral decline were less profound than those observed in less advanced patients possibly owing to modified drug absorption and modified hepatic blood flow (porto-caval shunts). Additional studies of patients with advanced cirrhosis are ongoing to determine the optimal duration of therapy in these patients. NS5A replication complex inhibitors are another class of DAA with potent antiviral and pan-genotypic activities. Daclatasvir (BMS ) 60 mg QD in combination with PEG-IFN/RBV induced an SVR of more than 80% with a good safety profile in genotype 1 patients (27). Daclatasvir in combination with the NS3/ 4A protease inhibitor asunaprevir (BMS ), administrated with or without PEG-IFN/RBV for 24 weeks in genotype 1 patients who did not respond to PEG-IFN/RBV resulted in a SVR rate of more than 90% in genotype 1b patients without PEG-IFN/RBV (28) and over 90% in all genotype 1 patients with PEG-IFN/RBV (29). Seventy-three genotype 1 treatment-experienced patients with cirrhosis are currently receiving treatment with daclatasvir plus PEG-IFN/RBV for 24 weeks (30). Alisporivir (ALV) is a host-targeting antiviral (HTA) with pan-genotypic anti-hcv activity and a high barrier to viral resistance. It is a synthetic non-immunosuppressive form of cyclosporine. In a phase 2 study, 109 genotype 1 treatment experienced patients with cirrhosis out of 461 patients were treated with alisporivir ( mg/days) and PEG-IFN/RBV for 48 weeks. Alisporivir significantly increased cevr rates in patients with or without cirrhosis and patients with cirrhosis achieved cevr rates of up to 63% with alisporivir 800 mg QD(31). However, pancreatic toxicity occurred in another alisporivir study and treatment was discontinued. HCV cirrhosis treatment with interferon-free regimen Several studies of DAAs combinations with or without RBV have been recently published demonstrating that an IFN-free regimen can cure both na ıve and treatmentexperienced genotype 1, 2 and 3 patients(16, 18). SOUND-C2 is a phase 2b study in which 362 na ıve genotype 1 patients were treated with faldaprevir (BI ) 120 mg QD and BI mg BID for 28 weeks or TID for 16, 28 or 40 weeks with RBV or 600 mg TID without RBV for 28 weeks(32). SVR rates ranged from 39% in the TID regimen without RBV (53% G1b and 1a-CC), 56 61% in the TID regimen with RBV and 68% in the BID regimen with RBV (83% for G1b and G1a-CC). Thirty-seven patients had compensated cirrhosis. SVR rates in patients with cirrhosis were 33% in the TID regimen without RBV, 57% in the TID regimen with RBV (64% for G1b and 43% G1a) and 54% in the BID regimen (71% for G1b and 33% for G1a) (33). The safety and tolerability in the BID arm was favourable in patients with cirrhosis with less than 10% of patients who discontinued owing to adverse events. Safety and tolerability were less favourable in the TID plus RBV regimen in patients with cirrhosis with 19% of patients experiencing serious AEs. Three patients had SAEs related to study medication, one severe rash and photosensitivity which resolved after discontinuation of the medication, one experienced nausea and vomiting, but remained on treatment and one patient had severe anaemia. These are the first data from an IFN-free regimen in compensated HCV cirrhosis. Further studies are needed in this population. Conclusions The first generation of protease inhibitors plus PEG- IFN/RBV treatment represents a major advancement in the treatment of both na ıve and treatment-experienced genotype 1 patients with compensated cirrhosis. The greatest benefit seems to be found with both drugs in patients with cirrhosis who are previous relapsers. There seems to be less benefit in patients with a previous nonresponse, thus the choice of this treatment should be considered in relation to the side effects. There are no data on the efficacy of the triple regimen in patients with decompensated cirrhosis. Real-life setting data show that patients with cirrhosis need to be carefully followed-up during treatment owing to increased side effects that are greater in the real-life setting than in clinical studies. Next generation DAAs in association with PEG-IFN/RBV appear to be promising in patients with cirrhosis with increased efficacy and fewer side effects. Ultimately, DAA combinations and an IFN-free regimen should result in a SVR in patients with cirrhosis 2012 John Wiley & Sons A/S 53

9 Optimal triple therapy for genotype 1 Bourliere et al. and certain DAA combinations will probably be proposed in the treatment of more advanced or decompensated cirrhosis. Disclosure Marc BOURLIERE is board members for Schering- Plough, Merck, Janssen, Gilead, Boehringer Ingelheim, BMS, Novartis, Roche, Abbott, GSK, Vertex and Speakers for Roche, Schering-Plough, Merck, Janssen, Gilead, BMS. The rest of the authors have no disclosure. References 1. Bruno S, Crosignani A, Facciotto C, et al. Sustained virologic response prevents the development of esophageal varices in compensated, Child-Pugh class A hepatitis C virus-induced cirrhosis. A 12-year prospective follow-up study. Hepatology 2010; 51: Maylin S, Martinot-Peignoux M, Moucari R, et al. Eradication of hepatitis C virus in patients successfully treated for chronic hepatitis C. Gastroenterology 2008; 135: Asselah T, Marcellin P. Direct acting antivirals for the treatment of chronic hepatitis C: one pill a day for tomorrow. Liver Int 2012; 32(Suppl. 1): Poordad F, McCone J Jr, Bacon BR, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011; 364: Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011; 364: Bacon BR, Gordon SC, Lawitz E, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 2011; 364: Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med 2011; 364: Bruno S, Vierling J, Esteban R, et al. Boceprevir in addition to standard of care enhanced SVR in hepatitis C virus genotype-1 with advanced fibrosis/cirrhosis: subgroup analysis of SPRINT-2 and RESPOND-2 studies. J Hepatol 2011; 54: S4 (abstract). 9. Sherman KE, Flamm SL, Afdhal NH, et al. Responseguided telaprevir combination treatment for hepatitis C virus infection. N Engl J Med 2011; 365: Pol S, Roberts SK, Andreone P, et al. Efficacy and safety of telaprevir-based regimen in cirrhotic patients with HCV genotype-1 and prior peginterferon/ribavirin treatment failure: subanalysis of the REALIZE phase III study. Hepatology 2011; 54(suppl): 374A (abstract). 11. Hadacek B, Danton A, Barbe N, et al. Telaprevir French cohort authorization for temporary use in genotype 1 hepatitis C cirrhotic patients with prior partial response or relapse (Abstract). J Hepatol 2012; 56(Suppl. 2): S Hezode C, Dorival C, Zoulim F, et al. Safety of telaprevir or boceprevir in combination with peginterferon alfa/ribavirin in cirrhotic non responders. First results of the French early access program (ANRS CO20-CUPIC). J Hepatol 2012; 56(Suppl. 2): S Poordad FF, Lawitz EJ, Reddy KR, et al. A randomized trial comparing ribavirin dose reduction versus erythropoietin for anaemia management in previously untreated patients with chronic hepatitis C receiving boceprevir plus peginterferon/ribavirin (Abstract). J Hepatol 2012; 56(Suppl. 2): S Kwo P, Ghabril M, Lacerda MA, et al. Use of telaprevir plus peginterferon/ribavirin for null responders post OLT with advanced fibrosis/cholestatic hepatitis C (Abstract). J Hepatol 2012; 56(Suppl. 2): S Coilly A, Roche B, Botta-Fridlund D, et al. Efficacy and safety of protease inhibitors for severe hepatitis C recurrence after liver transplantation: a first multicentric experience (Abstract)J Hepatol 2012; 56(Suppl. 2): S Bourliere M, Khaloun A, Wartelle-Bladou C, et al. Chronic hepatitis C: treatments of the future. Clin Res Hepatol Gastroenterol 2011; 35(Suppl. 2): S Fusco DN, Chung RT. New protease inhibitors for HCV help is on the way. J Hepatol 2011; 54: Wartelle-Bladou C, Le Folgoc G, Bourliere M, Lecomte L. Hepatitis C therapy in non-genotype 1 patients: the near future. J Viral Hepat 2012; 19: Dieterich D, Asselah T, Guyader D, et al. SILEN-C3: treatment for 12 or 24 weeks with BI combinated with peginterferon alfa-2a and ribavirin in treatment naive patients with chronic genotype 1 HCV infection (Abstract). Hepatology 2011; 54(suppl): 378A. 20. Zeuzem S, Berg T, Gane E, et al. TMC435 in HCV genotype 1 patients who have failed previous pegylated interferon ribavirin treatment: Final SVR24 results of the ASPIRE trial (Abstract).J Hepatol 2012; 56(Suppl. 2): S Pockros P, Jensen D, Tsai N, et al. SVR12 among G1/4 treatement naive patients receiving mericitabine in combination with PEG-IFN alfa-2a/ribavirin; Interim analysis from the JUMP-C study (Abstract). J Hepatol 2012; 56 (suppl.2): S Wedemeyer H, Jensen D, Herring R Jr, et al. Efficacy and safety of mericitabine in combination with PEG-IFN alfa- 2a/ribavirin in genotype1/4 treatment naive HCV patients. Final analysis from the PROPEL study (Abstract).J Hepatol 2012; 56(Suppl. 2): S Kowdley KV, Lawitz E, Crespo I, et al. ATOMIC: 97% RVR for PSI PEG/RBV x 12 week regimen in HCV GT1: an end to response-guided therapy? (Abstract). J Hepatol 2012; 56(Suppl. 2): S Hassanein T, Nelson DR, Lawitz E, et al. PSI-7977 with PEG/RBV elicits rapid declines in HCV RNA in patients with HCV GT-4 and GT-6. Global Antiviral J 2011; 7(Suppl. 1 HEP DART 2011): 57 (abstract). 25. Gane EJ, Stedman C, Hyland RH, et al. Once daily PSI plus RBV: pegylated interferon alfa not required for complete rapid viral response in treatment naive patients with HCV GT2 or GT3 (Abstract)Hepatology 2011; 54: 377A. 26. Lawitz E, Rodriguez-Torres M, Cornpropst MT, Denning JMC. D., McNair L, Fang L, et al. The effect of hepatic impairment on the pharmacokinetics and antiviral activity of PSI-7977in hepatitis C infected subjects treated for seven days (Abstract). J Hepatol 2012; 56(Suppl. 2): S Pol S, Ghalib RH, Rustgi VK, et al. First report of SVR 12 for NS5A replication complex inhibitor BMS in combination with PEG-IFN and RBV: phase 2A trial in treatment naive HCV-genotype 1 subjects (Abstract). J Hepatol 2011; 54: S John Wiley & Sons A/S

10 Bourliere et al. Optimal triple therapy for genotype Suzuki F, Ikeda K, Toyota J, et al. Dual oral therapy with the NS5A inhibitor daclatasvir (BMS ) and NS3 protease inhibitor asunaprevir (BMS ) in HCV genotype 1B infected null responders or ineligible/intolerant to peginterferon/ribavirin (Abstract). J Hepatol 2012; 56(Suppl. 2): S Lok AS, Gardiner DF, Lawitz E, et al. Preliminary study of two antiviral agents for hepatitis C genotype 1. N Engl J Med 2012; 366: Ratziu V, Gadano A, Pol S, et al. Triple therapy with daclatasvir, peginterferon alfa-2a and ribavirin in HCV infected prior null and partial responders: 12 weeks results of phase s COMMAND-2 trial (Abstract). J Hepatol 2012; 56(Suppl. 2): S Alberti A, Chuang WL, Flisiak R, et al. Alisporivir plus peginterferon/ribavirin in HCV genotype 1 treatmentexperienced patients achieves primary endpoint with superior efficacy at treatment week 12 compared to retreatment with PR (Abstract). J Hepatol 2012; 56(Suppl. 2): S Zeuzem S, Soriano V, Asselah T, et al. SVR4 and SVR12 with an interferon-free regimen of BI and BI /- ribavirin in treatment naive patients with chronic genotype 1 HCV infection; interim results of SOUND-C2 (Abstract).J Hepatol 2012; 56(Suppl. 2): S Soriano V, Gane E, Angus P, et al. The efficacy and safety of the interferon-free combination of BI and BI in genotype 1 HCV patients with cirrhosis. Interim analysis from SOUND-C2 (Abstract).J Hepatol 2012; 56(Suppl. 2): S John Wiley & Sons A/S 55