An update on the treatment of genotype-1 chronic hepatitis C infection: lessons from recent clinical trials

Abstract

The launch of first-generation protease inhibitors (PIs) was a major step forward in hepatitis C virus (HCV) treatment. However, this major advance is, up to now, restricted to genotype-1 (GT-1) patients. However, the ongoing development of new direct-acting antiviral agents (DAAs) allows new hope for the future. The development of second-wave and second-generation PIs yields higher antiviral potency through plurigenotypic activity, more convenient daily administration, fewer side effects and, for the second-generation PIs, potential activity against resistance-associated variants. NS5B inhibitors (NS5B.I) include nucleoside/nucleotide inhibitors (NIs) and nonnucleotide inhibitors (NNIs). NIs have high efficacy across all genotypes. Sofosbuvir has highly potent antiviral activity across all genotypes in association with pegylated interferon (IFN) and ribavirin (PR), thus allowing shortened treatment duration. NS5A inhibitors (NS5A.I) have highly potent antiviral activity. It has recently been shown for the first time that NS5A.I in combination with PI can cure GT-1b null-responder patients in an IFN-free regimen. In addition, several studies demonstrate that IFN-free regimens with DAA combinations are able to cure a large number of either naïve or treatment-experienced GT-1 patients. Moreover, a quadruple regimen with PR is able to cure almost all GT-1 null-responders. The development of pan-genotypic DAAs (NIs or NS5A.I) allows new combinations with or without PR that increase the rate of sustained virological response (SVR) for all patients, even for those with cirrhosis and independently of the genotype. Therefore, the near future of HCV treatment looks promising. The purpose of this article is to provide an overview of the clinical results recently reported for HCV treatment in GT-1 patients.

Keywords

Hepatitis C treatment genotype 1 cirrhosis decompensated cirrhosis eRVR SVR

Introduction

Approximately 170–200 million people worldwide (3% of the world's population) are chronically infected with the hepatitis C virus (HCV). HCV prevalence and genotype distribution vary around the world. Among the six identified HCV genotypes, genotype 1 (GT-1) is the most prevalent worldwide. It is the most difficult to cure with the standard-of-care treatment: the combination of pegylated interferon (PEG-IFN) alpha and ribavirin (RBV).

Chronic hepatitis C can lead to cirrhosis and its subsequent complications such as hepatocellular carcinoma (HCC). Every year, more than 350,000 people die from hepatitis-C-related liver diseases. The goal of HCV treatment is to achieve a sustained virological response (SVR), which is defined as undetectable HCV RNA 6 months after cessation of therapy, leading to HCV clearance. SVR is associated with an improved histological outcome, and a reduction of morbidity and mortality.

In 2011, the launch of the two first-generation protease inhibitors (PIs), boceprevir and telaprevir, was a major step forward for the treatment of GT-1-infected patients. Associated with PEG-IFN/RBV therapy (PR), these two drugs increase the chance of a cure for naïve patients by 30% [Jacobson et al. 2011; Poordad et al. 2011; Sherman et al. 2011]. The benefit is even greater in treatment-experienced patients: the chance of a cure increases by 50–60% for relapsers, 40–45% for partial responders and 25% for null-responders [Bacon et al. 2011; Zeuzem et al. 2011a]. However, only GT-1 patients benefit from this major advance [Wartelle-Bladou et al. 2012].

Different potential therapeutic targets in the HCV lifecycle have been identified, which has led to the development of both direct antiviral agents (DAAs) and agents targeting the host functions that are essential for viral replication. In addition to the first-generation PIs, boceprevir and telaprevir, DAAs comprise second-wave and second-generation PIs, nucleoside/nucleotide inhibitors (NIs) and nonnucleoside inhibitors (NNIs) of the NS5B complex and NS5A inhibitors (NS5A.I). Host-targeting agents (HTAs) are, e.g., cyclophilin inhibitors and silibinin. Next-generation DAAs appear to be promising; they may enable an interferon (IFN)-free regimen for cirrhotic patients and even for patients with more advanced or decompensated cirrhosis.

The purpose of this article is to provide an overview of the recent clinical results concerning future HCV treatment of GT-1 patients.

Treatment of GT-1 patients with boceprevir or telaprevir beyond initial clinical trials

Triple therapy including boceprevir or telaprevir in combination with PR increases the SVR rates by 30% for naïve patients and by even more for treatment-experienced patients. However, this benefit is associated with the increase of side effects such as anaemia and with the onset of new side effects: dysgeusia (nearly one-third of the patients treated with boceprevir) and cutaneous rash (55% of the patients treated with telaprevir) [Cacoub et al. 2012]. Moreover, the triple regimen results in the increase of treatment withdrawals due to adverse events. Concerning anaemia management, these new treatments have led to a new paradigm: for noncirrhotic patients, the ribavirin dose can be reduced without impairing SVR, even at early stages of treatment when HCV RNA is still detectable [Sulkowski et al. 2012c; Poordad et al. 2012d; Lawitz et al. 2012d]. Substantial renal impairment can occur under triple therapy. Among a large cohort of more than 1000 patients treated with triple therapy that completed 12 weeks of treatment, glomerular filtration rate (GFR) was reduced below 60 ml/min in 4.7% of boceprevir-treated and 6.6% of telaprevir-treated patients compared with 0.9% in PR-treated patients (p < 0.05). Asymptomatic renal impairment appears to be a new safety signal that must lead to GFR monitoring during treatment and ribavirin dose reduction may be considered in case of GFR decrease [Mauss et al. 2013].

Simplification of the mode of administration of the drug is highly desirable, in particular with telaprevir, which needs to be taken with a high-fat content regimen. The OPTIMIZE phase III trial demonstrated that a simplified BID dosing regimen of telaprevir achieves similar SVR and adverse event rates as the q8h current regimen leading to a new label for telaprevir [Buti et al. 2012].

Cirrhotic patients require HCV treatment most urgently: HCV clearance allows both a significant decrease of fibrosis and potential cirrhosis reversal and a significant decrease of cirrhosis-related complications and improve overall survival [Van Der Meer et al. 2013]. GT-1 patients with severe fibrosis or compensated cirrhosis benefit from adequate triple therapy with first-generation PIs even if the increase of the SVR rate is less significant than for noncirrhotic patients [Poordad et al. 2011; Jacobson et al. 2011; Sherman et al. 2011; Bacon et al. 2011; Zeuzem et al. 2011a]. Pooled analysis of phase III trials data demonstrated that the SVR rate in cirrhotic patients is overall 55% compared with 17% in those cirrhotic patients treated with PR. SVR rate is higher in treatment-experienced cirrhotic (60%) than in naïve cirrhotic patients (48%) [Vierling et al. 2013].

With telaprevir, the SVR rate increases by 10–30% for cirrhotic patients compared with 30% for noncirrhotic patients [Jacobson et al. 2011; Sherman et al. 2011]. Treatment-experienced patients benefit from triple therapy with either boceprevir or telaprevir more if they are previous relapsers than if they are partial responders [Bacon et al. 2011; Zeuzem et al. 2011a]. For null-responders, the benefit is limited and needs to be weighted against the increase in side effects.

Cirrhosis is one of the negative predictive factors of response to triple therapy. In phase III studies with boceprevir and telaprevir, cirrhotic patients have lower RVR rates, more frequent relapses and always require long fixed-duration therapy (4 weeks of PR lead-in followed by 44 weeks of triple regimen with boceprevir; 12 weeks of triple regimen with telaprevir followed by 36 weeks of PR).

In phase III studies, serious adverse events (SAEs) occur in approximately 10% of the patients with both drugs. SAEs are higher for cirrhotic patients. However, the number of cirrhotic patients enrolled in these studies was limited. In the real-life setting of the French CUPIC cohort, which includes more than 600 treatment-experienced cirrhotic patients, it has been demonstrated in an interim analysis for safety done in 497 patients who received 16 weeks of therapy that the rate of SAEs increases dramatically: by 38% with boceprevir and 49% with telaprevir [Hezode et al. 2013]. Six patients died, mainly related to infection or hepatic decompensation. In multivariate analysis, two baseline factors are predictive for death infection or hepatic decompensation: platelets count < 100,000/mm³ and serum albumin level <35 g/l. As expected, anaemia is frequent and severe for cirrhotic patients treated with PIs in the CUPIC cohort. Despite the use of erythropoietin for nearly half of the patients, the blood transfusion rate is high (6.3% with boceprevir and 16% with telaprevir after 16 weeks of treatment). This can partly be explained by the relatively small number of patients for whom the RBV dose was reduced (10% with boceprevir and 13% with telaprevir). In a second interim analysis of the same cohort, assessing safety and efficacy 12 weeks after cessation of therapy in 485 TE cirrhotic patients, SAEs were observed in 54% of patients treated with telaprevir and 51% of those treated with boceprevir [Fontaine et al. 2013]. Ten patients (2%) died, mainly related to infection or hepatic decompensation. SVR12 rate was 40% in patients treated with telaprevir and 41% in those treated with boceprevir. SVR rate was higher in previous relapsers (53% with telaprevir and 51% with boceprevir) compared with partial responders (32% with telaprevir and 40% with boceprevir) and to null responders (29% with telaprevir and 11% with boceprevir). These results are in line with those of phase III trials except in relapsers in whom SVR is lower than expected. However, overall these results are good for these difficult-to-treat patients and we clearly identified a subgroup of patients with more advanced cirrhosis based on albumin level <35 g/l and platelets count <100,000/mm³ in which treatment should not be initiated.

Few data are available concerning the use of triple regimens in the post-transplant setting [Coilly et al. 2013; Verna et al. 2013]. End-of-treatment response rate was 82% in the boceprevir group and 38% in the telaprevir group in the French cohort. In contrast, in the USA cohort in which 88% of patients were treated with telaprevir, end-of-treatment response rate was 67% and SVR4 rate was 65% (93% in those who had an extended rapid virological response (eRVR) and 19% in those without eRVR. However, treatment is difficult due to very frequent haematological side effects. Drug–drug interactions with calcineurin inhibitors appear to be manageable by a sizeable dose reduction of the calcineurin inhibitors.

A small randomized, controlled study has recently been performed in dialysis patients and demonstrated that triple therapy with telaprevir is feasible, associated with low-dose ribavirin 200 mg/J. SVR rate was 63% for a 24-week treatment (12 + 12) versus 25% in patients treated with PR [Basu et al. 2013].

Two small, randomized controlled studies have been performed in HIV/GT-1 HCV co-infected naïve patients. They demonstrated a higher SVR rate compared with patients treated with PR with an SVR rate of 74% with telaprevir and 62.5% with boceprevir, comparable with those observed in mono-infected HCV patients [Sulkowski et al. 2013d, 2013e]. Interim results from an ongoing trial in co-infected treatment-experienced patients also demonstrated a similar on-treatment virological response compared with mono-infected patients.

Treatment of GT-1 patients beyond boceprevir or telaprevir

Second-wave and second-generation PIs

The main weaknesses of the first-generation PIs are their low genetic barrier to resistance and the fact that their effectiveness is limited to GT-1 patients. Second-wave PIs have a higher barrier to resistance, better activity against multiple genotypes except GT-3, more convenient dosing schedules and improved safety and tolerance [Ciesek et al. 2011; Fusco et al. 2011; Asselah et al. 2011]. Second-generation PIs are compounds that are broadly active against all genotypes and against viral isolates that carry resistance mutations for first-generation PIs [Jacobson et al. 2013; Manns et al. 2013a; Zeuzem et al. 2012a; Ferenci et al. 2013; Sulkowski et al. 2013a, 2013b; Everson et al. 2012a; Feld et al. 2012; Manns et al. 2012; Lawitz et al. 2011b, 2012b; Poordad et al. 2012a; Bronowicki et al. 2012; Lok et al. 2012b]. In combination with PR, the new PIs appear to achieve greater SVR rates than the first-generation PIs. These new treatments allow for more convenient administration schedules (one or two administrations per day); this could result in improved pharmacokinetics and better patient compliance. In addition, the safety profile seems to be good. The pan-genotypic activity of these new treatments provides new therapeutic options for a greater number of patients, in particular for those infected with GT-4 [Moreno et al. 2010; Bronowicki et al. 2012; Hezode et al. 2012b].

Table 1 gives an overview of the efficacy and tolerance of the second-wave PIs that are currently developed. Few data are available concerning second-wave PIs for cirrhotic patients [Bourliere et al. 2013]. In a phase IIb study, 83 GT-1 treatment-experienced cirrhotic patients were treated with simeprevir 100 or 150 mg QD and PR for 12, 24 or 48 weeks followed by PR alone up to week 48. The SVR rates were 73% for previous relapsers, 82% for partial responders and 31% for null responders (for those treated with 150 mg QD); in all cases the SVR rates were higher than in the PR arms [Zeuzem et al. 2012a].

Table 1.

Overview of clinical efficacy of second-wave protease inhibitors (PIs).

Second-generation PIs are in the early stage of development. MK-5172 in monotherapy demonstrates pan-genotypic activity [Brainard et al. 2010]. In a phase II, dose-ranging study, MK-5172 in association with PR for 12 weeks followed by PR for 12 or 36 weeks demonstrated very high SVR rates of over 90% [Manns et al. 2013b]. Other molecules such as ACH-2684, AVL-181 and AVL-192 show promising results in vitro [Bourliere et al. 2011].

NS5B polymerase inhibitors (NS5B.I)

NS5B NIs

NIs mimic natural polymerase substrates and bind to NS5B active sites, thereby causing chain termination and increasing the number of errors when incorporated into a growing RNA chain. As these NS5B sites are well conserved among genotypes, NIs tend to have activity across all genotypes [Membreno et al. 2011]. They also have the highest barrier to resistance of all DAAs so far.

The first NI developed was the nucleoside analogue mericitabine. In triple regimen with PR, mericitabine shows less antiviral activity for GT-1 patients compared to the triple regimen with PIs [Wedemeyer et al. 2012; Pockros et al. 2012]. However, it has high antiviral activity for GT-2 and −3 treatment-experienced patients and for GT-4 patients [Gane et al. 2010b] (Table 2). If included in an IFN-free regimen with ritonavir-boosted danoprevir and ribavirin for treatment-experienced GT-1b patients or in quadruple therapy with boosted danoprevir and PR for treatment-experienced GT-1 patients, mericitabine leads to promising SVR rates [Feld et al. 2012] (Table 3). Few data for mericitabine in cirrhotic patients are available. For 23 GT-1/4 naïve cirrhotic patients treated with mericitabine 1000 mg BID and PR for 24 or 48 weeks, the SVR rate was 38% versus 22% in PR arms [Wedemeyer et al. 2012; Pockros et al. 2012]. However, dose or duration reduction of mericitabine impairs treatment response for cirrhotic patients. An ongoing study with GT-1 cirrhotic patients receiving a quadruple regimen (mericitabine, ritonavir-boosted danoprevir and PR) is currently being conducted.

Table 2.

Overview of clinical efficacy of NS5B nucleoside/nucleotide inhibitors (NIs) or nonnucleoside inhibitors (NNIs) polymerase inhibitors (PIs).

Table 3.

Overview of clinical efficacy of direct-acting antiviral agents (DAAs) combination studies.

The pyrimidine nucleotide analogue sofosbuvir has highly potent pan-genotypic antiviral activity and a high genetic barrier to resistance. A triple regimen with PR for 12 weeks in GT-1, −2, −3, −4 and −6 naïve patients achieves SVR rates from 88% to 100% [Lawitz et al. 2012a, 2013b, 2013c; Kowdley et al. 2013a; Rodriguez-Torres et al. 2013] in phase II trials (Table 2). Those studies demonstrate no additional benefit of extending treatment beyond 12 weeks in this population [Kowdley et al. 2013a]. Phase III trials recently demonstrated an SVR rate of 89% among 292 GT-1 naïve patients with a SVR rate of 80% among the 54 cirrhotic patients [Lawitz et al. 2013c].

In combination with ribavirin in an IFN-free regimen for 12 weeks, sofosbuvir (400 mg/day) achieved an SVR rate of 84% for GT-1 naïve patients in phase II studies [Gane et al. 2013a]. For treatment-experienced GT-1 patients, SVR rates are lower (11%); almost all patients relapse after treatment discontinuation [Gane et al. 2013a].

NNIs

NNIs have a restricted spectrum of activity against the various genotypes and a low barrier to resistance. They are active against GT-1 with less antiviral activity for GT- 1a-infected patients than for GT-1b-infected patients. Table 2 gives an overview of the clinical efficacy of NNIs in combination with PR [Larrey et al. 2012; Jacobson et al. 2010; Rodriguez-Torres et al. 2010; Lawitz et al. 2010, 2011a; Poordad et al. 2012b]. They appear to have less antiviral activity compared with the triple regimen with PIs or NS5A.I. Nevertheless, the fact that they target five different sites of the NS5B-polyprotein suggests that combinations with other NNIs or with different DAAs (PIs or NS5A.I) could be effective.

NS5A.I

HCV NS5A is a phosphoprotein that does not possess any enzymatic function but has a crucial role in HCV replication. NS5A is composed of three structural domains as well as an amphipathic alpha helix that functions in membrane localisation. Domain I is essential for viral RNA replication. Domain II is involved in the binding to cyclophilin A. It has been postulated to play a role in antagonising the innate immune response to HCV. Domain III seems to be important for the assembly of infectious viral particles [Lok, 2013]. The first-in-class NS5A.I daclatasvir shows potent pan-genotypic antiviral activity, and has a low barrier to resistance. In particular, GT-1a patients can select resistance-associated variants (RAVs) after a single administration.

In triple therapy with PR, daclatasvir demonstrates high antiviral potency for GT-1 and −4 naïve patients [Hezode et al. 2012a] (Table 4). Studies with treatment-experienced GT-1 patients and with GT-2/3 are still ongoing [Ratziu et al. 2012; Dore et al. 2012]. Daclatasvir 20 or 60 mg QD in association with PR for 24 weeks reached a SVR rate of between 57% and 62% in 20 GT-1 naïve cirrhotic patients [Hezode et al. 2012a].

Table 4.

Overview of clinical efficacy of NS5A inhibitors.

Quadruple therapy with daclatasvir in association with the PI asunaprevir and PR for 24 weeks resulted in SVR rates of more than 90% for GT-1 null-responders (who are the most difficult to treat) [Lok et al. 2012a, 2012b]. However, this approach is feasible only for patients who can tolerate PEG-IFN and ribavirin. For cirrhotic patients, response rates are likely to be lower while adverse event rates are probably higher.

Several IFN-free regimens with daclatasvir have been studied. Dual therapy with daclatasvir and asunaprevir for 24 weeks achieved SVR for 65–78% of GT-1b patients who were previous null-responders [Lok et al. 2012a]. Dual or triple therapy with daclatasvir and sofosbuvir (with or without ribavirin) for 24 weeks achieved SVR for 93–100% of naïve GT-1 patients [Sulkowski et al. 2012a].

Other NS5A.I are currently in development. In association with PR, ABT-267 shows promising on-treatment results [Sullivan et al. 2012]. GS-5885 (ledipasvir) has been studied either in triple regimen with PR or in quadruple regimen with PI and PR or in an IFN-free regimen with PI, NNI and ribavirin [Marcellin et al. 2013; Sulkowski et al. 2012d; Thompson et al. 2013]. Patients treated with ledipasvir and PR for 24 or 48 weeks according to RVR reach a SVR rate of 60% in naïve GT-1 patients [Marcellin et al. 2013]. Second-generation NS5A.I including MK-8742 and ACH-3102 have been developed, but clinical results are pending.

HTAs and other antiviral treatments

Cyclophilins are a highly conserved family of human enzymes involved in cellular processes associated with protein folding, transport and secretion, as well as mitochondrial function and immune response [Flisiak et al. 2008]. HCV can co-opt cyclophilins as cofactors for viral replication. In the hepatocyte, cyclophilin A and B bind with the viral proteins NS5A, NS5B and NS52 to form a replication complex mediating the correct folding and trafficking of HCV proteins. Thus, they are functioning as a positive modulator for HCV replication [Membreno et al. 2013]. Alisporivir (Debio 025) (ALV) is a nonimmunosuppressive form of cyclophilin inhibitor that shows a potent antiviral activity for many HCV genotypes and low resistance rates without cross-resistance to PI, NS5B.I and NS5A.I. Phase II studies show increased SVR rates compared with PR for naïve GT-1 patients receiving a combination of ALV and PR for at least 24 weeks. For GT-1 treatment-experienced patients, ALV + PR demonstrated higher cEVR compared to PR in relapsers, partial responders and null-responders [Alberti et al. 2012]. Moreover, for GT-2/3 naïve patients, the possibility of an IFN-free regimen has been studied and the results demonstrate the ability of such a regimen to cure almost one-quarter of GT-2/3 naïve patients [Pawlostky et al. 2012]. In the phase II program ALV appears to have a good safety profile with rare cases of hyperbilirubinaemia. However, during the phase III program in April 2012, US FDA placed the ALV program on a full clinical hold and all patients discontinued therapy. This was due to a cluster of three cases of acute pancreatitis with one of them fatal in the treatment group receiving ALV and PR. Two other cyclophilin inhibitors are currently in development (SCY-635, NIM-811). Cyclophilin inhibitors could be an important addition to DAAs in treatment combinations and may be able to shorten and simplify therapy. They have the potential to be a cornerstone drug for an IFN-free regimen in combination with DAAs, because they have a high barrier to resistance, no cross-resistance with DAAs and a pan-genotypic activity. ALV development is likely to move forward but will not be used in association with PEG-IFN because of the potential risk of acute pancreatitis.

Therapeutic vaccines fail to show any significant positive results yet. GI-5005 is not able to increase SVR compared with PR alone except in a subgroup of difficult-to-treat patients. Other vaccines such as ChronVac-C, IC41 and TG-4040 demonstrate limited antiviral activity [Bourliere et al. 2011; Wedemeyer et al. 2012]. Polyclonal and monoclonal antibodies do not reach any endpoint in trials evaluating recurrence after liver transplantation. Toll-like receptors may enhance the host immune system against HCV; they are currently in the early development phase.

Silibinin is a flavonoid compound targeting the host cell. It is a direct inhibitor of HCV RNA-dependent RNA polymerase and a blocker of virus entry and transmission. It was recently proved to be successful in the treatment of previous PR non-responders [Biermer et al. 2012].

PEG-IFNλ has the same antiviral efficacy as PEG-IFNα but significantly reduces side effects for GT-1 and −4 patients (even if they are cirrhotic) [Muir et al. 2012]. It may become a new alternative in combination with DAAs.

DAA combinations: the challenge of IFN-free regimens

Most DAAs currently being developed for HCV treatment have been initially tested in combination with PR. The rationale of combination therapy is to increase viral potency, to decrease viral resistance and to avoid the use of PEG-IFN.

IFN-related side effects remain a major problem in clinical routine. They often affect the patient’s compliance and hinder treatment in cirrhotic patients or in those with HCV-recurrence after liver transplantation. DAA combinations may permit association of molecules with different mechanisms of action, different resistance profiles and high antiviral activity.

An overview of the efficacy and tolerability of DAA combination treatments with or without PEG-IFN is outlined in Table 3 [Gane et al. 2010a, 2012; Feld et al. 2012; Zeuzem et al. 2010, 2011, 2012b, 2012c; Di Bisceglie et al. 2011; Jacobson et al. 2012; Poordad et al. 2012c; Lawitz et al. 2012c; Lok et al. 2012a, 2012b; Chayama et al. 2012; Kowdley et al. 2013b; Sulkowski et al. 2012a, 2012b; Everson et al. 2012, 2013].

Quadruple therapy with PEG-IFN

Six studies have been reported so far. The first study (quadruple regimen, associating asunaprevir (PI), daclatasvir (NS5A.I) and PR for 24 weeks for previous GT-1 null-responders) reports SVR rates of over 90% [Lok et al. 2012, 2012]. Three studies associating GS-9451 (PI) plus ledipasvir (NS5A.I) and PR have been reported. In naïve, non-cirrhotic IL28B CC, GT-1 patients, this quadruple regimen for 6 or 12 weeks versus PR for 24 weeks leads, in patients with RVR, to a SVR rate of 98% in patients treated for 12 weeks versus 79% in those treated for 6 weeks and 73% in those treated by PR [Thompson et al. 2013]. In naïve GT-1 patients, the same regimen for 12 or 24 weeks reaches a SVR rate of 84% (94% GT-1b, 79% GT-1a) [Marcellin et al. 2013]. In treatment-experienced GT-1 patients, this regimen for 24 or 48 weeks according to RVR led to a SVR rate of 70% (47% in prior GT-1a null-responders) [Everson et al. 2013].

Two studies combining a PI, an NS5B.I and PR for GT-1 patients have been reported. Telaprevir (PI) plus VX-222 (NNI) and PR for 12 weeks followed by 12 weeks of PR leads to SVR rates of 83–90% for GT-1 naïve patients [Nelson et al. 2011]. Ritonavir-boosted danoprevir (PI/r) in combination with mericitabine (NI) and PR for 24 weeks leads to SVR rates of 75–96% for GT-1 previous partial responders and to SVR rates of 73-100% for GT-1 previous null-responders. Overall the results of quadruple therapy with PEG-IFN show SVR rates of over 90% for the most difficult to cure patients and a reasonable safety profile [Feld et al. 2012].

Two DAAs in IFN-free regimens

The first proof of concept of IFN-free regimens was given by the INFORM-1 study, which demonstrated that 13 days of dual therapy with danoprevir (PI) and mericitabine (NI) is able to induce a 5.1 log₁₀IU/ml decline from baseline for naïve GT-1 patients and a 4.9 log₁₀IU/ml decline from baseline for treatment-experienced null-responders [Gane et al. 2010a]. A full dual-therapy with asunaprevir (PI) and daclatasvir (NS5A.I) without IFN for GT-1b treatment-experienced null-responders for 24 weeks shows SVR12 rates from 65–78% up to 91% (depending on the asunaprevir dosage) [Lok et al. 2012, 2012; Chayama et al. 2012]. Similarly, a phase II study with simeprevir (PI) and sofosbuvir (NI) for 12 or 24 weeks in GT-1 null-responders reached a SVR rate of 93% in those treated for 12 weeks [Lawitz et al. 2013a]. The combination of NS5A.I and NI has been studied in two phase II trials. A dual therapy with daclatasvir (NS5A.I) and sofosbuvir (NI) for 24 weeks demonstrated SVR rates from 93% to 100% in GT-1 naïve patients [Sulkowski et al. 2012b]. A dual therapy with daclatasvir (NS5A.I) and sofosbuvir (NI) for 24 weeks in 21 patients who failed triple therapy with either boceprevir or telaprevir demonstrated SVR in all patients [Sulkowski et al. 2013c] (Table 3).

Two DAAs and RBV in IFN-free regimens

Four studies combined PIs, NNIs and RBV (Table 3). The largest trial involves 362 GT-1 naïve patients. They are treated with faldaprevir (PI), deleobuvir (NNI) and RBV for 16–48 weeks. SVR rates range from 55% to 84% for GT-1b patients and from 38% to 47% in GT-1a patients. In this study, 33 naïve GT-1 cirrhotic patients were treated. The SVR rates were 43–50% for GT-1a patients and 57–80% for GT-1b patients [Soriano et al. 2012]. These rates are close to those observed for the noncirrhotic population. A second-wave ritonavir-boosted PI (ABT-450) in association with NNIs and RBV for 12 weeks can achieve SVR rates of over 90% for GT-1 naïve patients (regardless of the HCV subtype 1a or 1b). However, the SVR rate was lower in GT-1 null-responders. This suggests that such a combination is not optimal for this difficult-to-treat population.

The combination of ritonavir-boosted ABT-450 (PI), ABT-267 (NS5A.I) and RBV for 12 weeks increases SVR rates up to 89% for null-responders.

The combination of sofosbuvir (NI), ledipasvir (NS5A.I) and RBV for 12 weeks reached a SVR in all GT-1 patients, whether naïve or treatment experienced [Gane et al. 2013b].

The addition of RBV to the combination of daclatasvir (NS5A.I) and sofosbuvir (NI) for 24 weeks did not increase the SVR rate compared with dual therapy for GT-1 patients either naïve or failure to triple PI regimen.

Three DAAs with or without RBV in IFN-free regimens

Three studies combined a second-wave PI, an NS5B.I and an NS5A.I with or without RBV. The first study by Gilead associates GS-9451 (second-wave PI) and ledipasvir (NS5A.I) and tegobuvir (NNI) with or without RBV for 12 or 24 weeks for GT-1 naïve patients; the SVR rate was 97%, However, tegobuvir development has been stopped by FDA. The second phase-II study associates asunaprevir (PI), daclatasvir (NS5A.I) and BMS-790052 (NNI) for 12 or 24 weeks for GT-1 naïve patients; the SVR rate is 94%. The third study associates a second-wave ritonavir-boosted PI (ABT-450/r), ABT-333 (NNI), ABT-267 (NS5A.I) and RBV for 12 weeks for GT-1 naïve or treatment-experienced patients; the SVR rate is 96% for GT-1 naïve patients and 93% for GT-1 null-responders [Kowdley et al. 2013b]. The safety profiles of these regimens appear to be good.

Recommendations for treatment in 2013

According to the treatment landscape and the availability of the first-generation PIs, it appears reasonable to treat all GT-1 patients with advanced fibrosis, those with extra-hepatic manifestations of HCV such as symptomatic cryoglobulinaemia and those who want to be treated. Patients with more advanced cirrhosis should be treated on a case-by-case basis evaluating the risk/benefit ratio. Real-life studies have shown that patients with both platelets <100,000/mm³ and albumin 35 g/l should not be treated with triple therapy with first-generation PIs.

GT-1 patients with mild or moderate fibrosis can expect to be treated with an IFN-free regimen with shorter duration of treatment, fewer or even no side effects and easy-to-take regimen in the next 2 or 3 years. DAA combinations of two or three DAAs directed against different HCV targets have already demonstrated a very high SVR rate in all GT-1 patients. Combination of PI plus NNI plus NS5A.I appears to be very promising either in naïve or treatment-experienced GT-1 patients. Combination of sofosbuvir (NI) and NS5A.I appears to be very promising in GT-1, −2 or −3 patients opening the way for a pan-genotypic combination. Moreover, combination of sofosbuvir (NI) and NS5A.I with or without RBV appears to be efficient in failure to first-generation PI. However, the timing for the availability of such a regimen will depend on the price and on the willingness of the payers that can vary according to country. Taking this aspect into account, keeping patients off treatment (i.e. warehousing) should be considered individually for each country according to the expected delay between agency approval and the availability of the combination; for example, it could take 2 months in Germany and France, but near 1 year in Belgium or Ireland.

Conclusion

Triple therapy with first-generation PIs was a major step forward in HCV treatment for GT-1 patients. Since 2010, more than 10 different DAAs are in phase II or III development. Approximately 10 more DAAs are either in preclinical or in early clinical development. Meanwhile, several studies demonstrate that IFN-free regimens are able to cure a large number of either naïve or treatment-experienced GT-1 patients. Moreover, for the most difficult-to-cure patients, a quadruple regimen with PR is able to cure almost all GT-1 null-responders. The development of pan-genotypic DAAs such as NIs or NS5A.Is allows new DAA combinations with or without PR; these increase the SVR rates for all patients (even for those with cirrhosis and for all genotypes). This new regimen appears, so far, to be safer and also allows shorter treatment duration. These developments appear to be another major step forward for HCV treatment. There is hope that almost all treated patients can be cured in the near future.

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement

Marc Bourliére is board member of: MSD, Roche, Vertex, Gilead, Boehringer-Ingelheim, Janssen, Abbott, BMS, GSK; and speaker for: MSD, Roche, Vertex, Gilead, Boehringer-Ingelheim, Janssen, Abbott, BMS; Astrid Wendt has no conflicts of interest.

References

Alberti

Chuang

Flisiak

Mazzalla

Horban

Goeser

(2012) Alisporivir plus PEGinterferon/ribavirin in HCV genotype 1 treatment-experienced patients achieves primary endpoint with superior efficacy at treatment week 12 compared to retreatment with PR. J Hepatol 56(Suppl. 2): S553–S553.

Asselah

Marcellin

(2011) New direct-acting antivirals' combination for the treatment of chronic hepatitis C. Liver Int 31(Suppl. 1): 68–77.

Bacon

Gordon

Lawitz

Marcellin

Vierling

Zeuzem

(2011) Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 364: 1207–1217.

Basu

Siriki

Shah

Farhat

Mittimani

Atluri

(2013) Telaprevir with adjusted dose of ribavirin in naive CHC-G1: efficacy and treatment in CHC in hemodialysis population. Target C (RCT). J Hepatol 58(Suppl. 1): S30–S31.

Biermer

Schlosser

Fulop

Van Bommel

Brodzinski

Heyne

(2012) High-dose silibinin rescue treatment for HCV-infected patients showing suboptimal virologic response to standard combination therapy. J Viral Hepat 19: 547–553.

Bourliere

Khaloun

Wartelle-Bladou

Oules

Portal

Benali

(2011) Chronic hepatitis C: treatments of the future. Clin Res Hepatol Gastroenterol 35(Suppl. 2): S84–S95.

Bourliere

Wendt

Fontaine

Hezode

Pol

Bronowicki

(2013) How to optimize HCV therapy in genotype 1 patients with cirrhosis. Liver Int 33(Suppl. 1): 46–55.

Brainard

Petry

Van Dyck

Nachbar

De Lepeleire

Caro

(2010) Safety and antiviral activity of MK-5172 a novel HCV NS3/4A protease inhibitors with potent activity against known resistance mutants in genotype 1 and 3 HCV-infected patients. Hepatology 52(Suppl): 706A–707A.

Bronowicki

Pol

Thuluvath

Larrey

Martorell

Rustgi

(2012) Asunaprevir, an NS3 Protease inhibitor in combination with PEGinterferon and ribavirin in treatment-naive patients with genotype 1 chronic hepatitis C infection. J Hepatol 56(Suppl.): S431–S432.

10.

Buti

Agarwal

Horsmans

Sievert

Janczewska

Zeuzem

(2012) Optimize trial: non inferiority of twice-daily telaprevir versus administration every 8 hours in treatment-naive genotype 1 HCV infected patients. Hepatology 56(Suppl.): LB–LB8.

11.

Cacoub

Bourliere

Lubbe

Dupin

Buggisch

Dusheiko

(2012) Dermatological side effects of hepatitis C and its treatment: patient management in the era of direct-acting antivirals. J Hepatol 56: 455–463.

12.

Chayama

Takahashi

Toyota

Karino

Ikeda

Ishikawa

(2012) Dual therapy with the nonstructural protein 5a inhibitor, daclatasvir, and the nonstructural protein 3 protease inhibitor, asunaprevir, in hepatitis C virus genotype 1b-infected null responders. Hepatology 55: 742–748.

13.

Ciesek

Von Hahn

Manns

(2011) Second-wave protease inhibitors: choosing an heir. Clin Liver Dis 15: 597–609.

14.

Coilly

Dumortier

Botta-Fridlund

Latournerie

Leroy

Pageaux

(2013) End of therapy response after protease inhibitor (PI)-based therapy for hepatitis C recurrence after liver transplantation: a multicentric European experience. J Hepatol 58(Suppl. 1): S572–S573.

15.

Di Bisceglie

Nelson

Gane

Alves

Koziel

De Souza

(2011) VX-222 with TVR alone or in combination with PEGinterferon alfa-2a and ribavirin in treatment naive patients with chronic hepatitis C: Zenith study interim results. J Hepatol 54: S540–S540.

16.

Dore

Lawitz

Hezode

Shafran

Ramji

Tatum

(2012) Twelve or 16 week treatment with daclatasvir combined with PEGinterferon alfa and ribavirin for hepatitis C virus genotype 2 or 3 infection: Command GT2/3 study. Hepatology 56(Suppl.): 558A–559A.

17.

Everson

Cooper

Hezode

Shiffman

Yoshida

Beltran-Jaramillo

(2012a) Rapid and sustained achievement of undetectable HCV RNA during treatment with ritonavir-boosted danoprevir/PEGIFN alfa-2a/RBV in HCV genotype 1 or 4 patients: Dauphine week 12 interim analysis. J Hepatol 56: S466–S466.

18.

Everson

Di Bisceglie

Vierling

Hsieh

Trenkle

Kanwar

(2013) Combination of the NS5A inhibitor GS-5885, the NS3 protease inhibitor GS-9451 and pegylated interferon plus ribavirin in treatment experienced patients with genotype 1 hepatitis C infection. J Hepatol 58(Suppl. 2): S6–S6.

19.

Everson

Sims

Rodriguez-Torres

Hezode

Lawitz

Bourliere

(2012b) An interferon-free, ribavirin-free 12-week regimen of daclatasvir, asunaprevir and BMS-791325 yielded SVR4 of 94% in treatment-naive patients with genotype 1 chronic hepatitis C virus infection. Hepatology 56(Suppl.): LB–LB3.

20.

Feld

Jacobson

Jensen

Foster

Pol

Tam

(2012) Up to 100% SVR4 rates with ritonavir-boosted danoprevir, mericitabine and ribavirin with or without PEGinterferon alfa-2a in HCV genotype 1-infected partial and null responders: results from the Matterhorn study. Hepatology 56(Suppl.): 231A–232A.

21.

Ferenci

Asselah

Foster

Zeuzem

Sarrazin

Moreno

(2013) Faldaprevir plus pegylated interferon alfa-2a and ribavirin in chronic HCV genotype 1 treatment-naive patients. Final results from STARTVERSO 1, a randomized double blind, placebo-controlled phase III trial. J Hepatol 58(Suppl. 1): S569–S570.

22.

Flisiak

Horban

Gallay

Bobardt

Selvarajah

Wiercinska-Drapalo

(2008) The cyclophilin inhibitor DEBIO-025 shows potent anti-hepatitis C effect in patients coinfected with hepatitis C and human immunodeficiency virus. Hepatology 47: 817–826.

23.

Fontaine

Hezode

Dorival

Larrey

Zoulim

De Ledinghen

(2013) SVR 12 rates and safety of triple therapy including telaprevir or boceprevir in 221 cirrhotic non responders treated in the French early access program (ANRS CO20-CUPIC). J Hepatol 58(Suppl. 1): S27–S27.

24.

Fusco

Chung

(2011) New protease inhibitors for HCV - help is on the way. J Hepatol 54: 1087–1089.

25.

Gane

Pockros

Zeuzem

Marcellin

Shikhman

Bernaards

(2012) Interferon-free treatment with a combination of mericitabine and danoprevir/R with or without ribavirin in treatment-naive HCV genotype 1 infected patients. J Hepatol 56(Suppl. 2): S555–S555.

26.

Gane

Roberts

Stedman

Angus

Ritchie

Elston

(2010a) Oral combination therapy with a nucleoside polymerase inhibitor (RG7128) and danoprevir for chronic hepatitis C genotype 1 infection (INFORM-1): a randomised, double-blind, placebo-controlled, dose-escalation trial. Lancet 376: 1467–1475.

27.

Gane

Rodriguez-Torres

Nelson

Jacobson

McHutchinson

Duca

(2010b) Sustained virologic response following RG7128 1500 mg BID/PEG-IFN/RBV for 28 days in HCV genotype 2/3 prior non responders. J Hepatol 52: S16–S16.

28.

Gane

Stedman

Hyland

Ding

Svarovskaia

Symonds

(2013a) Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J Med 368: 34–44.

29.

Gane

Stedman

Hyland

Pang

Ding

Symonds

(2013b) All-oral sofosbuvir-based 12 week regimen for the treatment of chronic HCV infection: the Electron study. J Hepatol 58(Suppl. 1): S6–S7.

30.

Hezode

Fontaine

Dorival

Larrey

Zoulim

Canva

(2013) Triple therapy in treatment-experienced patients with HCV-Cirrhosis in a multicentre cohort of the French Early Access Programme (ANRS CO20-CUPIC) - NCT01514890. J Hepatol 59: 434–441.

31.

Hezode

Hirschfield

Ghesquiere

Rodriguez-Torres

Shafran

Thuluvath

(2012a) Daclatasvir an NS5A replication complex inhibitor, combined with PEGinterferon alfa-2a and ribavirin in treatment naive HCV genotype 1or 4 subjects: phase 2b COMMAND-1 SVR12 results. Hepatology 56(Suppl.): 553A–553A.

32.

Hezode

Shiffman

Cooper

Everson

Marcellin

Rodriguez-Torres

(2012b) Ritonavir-boosted danoprevir plus peginterferon alfa-2a/ribavirin demonstrates up to 100% SVR24 with 12 or 24 weeks of total treatment in treatment-naive patients with genotype 4 infection in the Dauphine study. Hepatology 56(Suppl.): 557A–557A.

33.

Jacobson

Dore

Foster

Fried

Radu

Rafalskiy

(2013) Simeprevir (TMC 435) with PEGinterferon/ribavirin for chronic HCV genotype-1 infection in treatment naive patients: results from Quest-1, a phase III trial. J Hepatol 58(Suppl. 1): S574–S574.

34.

Jacobson

Pockros

Lalezari

Lawitz

Rodriguez-Torres

Dejesus

(2010) Virologic response rates following 4 weeks of filibuvir in combination with pegylated interferon alfa-2a and ribavirin in chronically-infected HCV genotype-1 patients. J Hepatol 52: S465–S465.

35.

Jacobson

Sulkowski

Gane

Koziel

De Souza

Kieffer

(2012) VX-222, telaprevir and ribavirin in treatment-naive patients with genotype 1 chronic hepatitis C: results of the Zenith study interferon-free regimen. Hepatology 56(Suppl.): 308A–308A.

36.

Jacobson

McHutchison

Dusheiko

Di Bisceglie

Reddy

Bzowej

(2011) Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 364: 2405–2416.

37.

Kowdley

Lawitz

Crespo

Hassanein

Davis

Demicco

(2013a) Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatment-naive patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomised, multicentre phase 2 trial. Lancet 381: 2100–2107.

38.

Kowdley

Lawitz

Poordad

Cohen

Nelson

Zeuzem

(2013b) Safety and efficacy of interferon-free regimen of ABT-450/R, ABT-267, ABT-333 with or without ribavirin in patients with chronic HCV GT-1 infection: results from the Aviator study. J Hepatol 58(Suppl. 2): S2–S2.

39.

Larrey

Lohse

De Ledinghen

Trepo

Gerlach

Zarski

(2012) Rapid and strong antiviral activity of the non-nucleosidic NS5B polymerase inhibitor BI 207127 in combination with PEGinterferon alfa 2a and ribavirin. J Hepatol 57: 39–46.

40.

Lawitz

Gane

Stedman

Lalezari

Hassanein

Kowdley

(2012a) PSI-7977 proton and electron: 100% concordance of SV4 with SVR24 in HCV GT1, GT2 and GT3. J Hepatol 56(Suppl. 2): S4–S4.

41.

Lawitz

Ghalib

Rodriguez-Torres

(2013a) SVR4 results of a once daily regimen of simeprevir (TMC-435) plus sofosbuvir (GS-7977) with or without ribavirin in HCV GT-1 null responders. DDW Orlando May 18–21, 2013. Gastroenterology. Abstract Sa 2073 144(suppl 1) 374–375.

42.

Lawitz

Jacobson

Godofsky

Foster

Flisiak

Bennett

(2011a) A phase 2b trial comparing 24 to 48 weeks treatment with tegobuvir (GS-9190)/PEG/RBV to 48 weeks treatment with PEG/RBV for chronic genotype 1 HCV infection [abstract]. J Hepatol 54(Suppl 1): S181–S181.

43.

Lawitz

Lalezari

Hassanein

Kowdley

Poordad

Sheikh

(2013b) Sofosbuvir in combination with peginterferon alfa-2a and ribavirin for non-cirrhotic, treatment-naive patients with genotypes 1, 2, and 3 hepatitis C infection: a randomised, double-blind, phase 2 trial. Lancet Infect Dis 13: 401–408.

44.

Lawitz

Mangia

Wyles

Rodriguez-Torres

Hassanein

Gordon

(2013c) Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med.

45.

Lawitz

Poordad

Dejesus

Kowdley

Gaultier

Cohen

(2012b) ABT-450/ritonavir combined with pegylated interferon alpha-2a and ribavirin after 3 days monotherapy in genotype 1 HCV-infected treatment-naive subjects: 12 weeks sustained virologic response and safety results. J Hepatol 56(Suppl. 2): S470–S470.

46.

Lawitz

Poordad

Kowdley

Jensen

Cohen

Siggelkow

(2012c) A 12 week interferon-free regimen of ABT-450/R, ABT-072 and ribavirin was well tolerated and achieved sustained virologic response in 91% treatment-naive HCV Il28b-Cc genotype1 infected subjects. J Hepatol 56(Suppl. 2): S7–S7.

47.

Lawitz

Rodriguez-Torres

Rustgi

Hassanein

Rahimy

Crowley

(2010) Safety and antiviral activity of ANA 598 in combination with pegylated interferon alfa-2a plus ribavirin in treatment-naive genotype 1 chronic HCV patients. Hepatology 52(Suppl.): 334–335A.

48.

Lawitz

Rodriguez-Torres

Stoehr

Gane

Serfaty

Bhanja

(2011b) A phase 2b study of MK 7009 (vaniprevir) in patients with genotype 1 HCV infection who have failed previous pegylated interferon and ribavirin treatment. Hepatology 54: 1434A–1435A.

49.

Lawitz

Zeuzem

Nyberg

Nelson

Rossaro

Balart

(2012d) Boceprevir combined with PEGinterferon alfa-2b/ribavirin in treatment-naive chronic HCV genotype 1 patients with compensated cirrhosis: sustained virologic response and safety subanalyses from the Anemia Management Study. Hepatology 56(Suppl.): 216A–216A.

50.

Lok

(2013) HCV NS5A inhibitors in development. Clin Liver Dis 17: 111–121.

51.

Lok

Gardiner

Hezode

Lawitz

Bourliere

Everson

(2012a) Sustained virologic response in chronic HCV genotype 1-infected null responders with the combination of daclatasvir and asunaprevir with or without PEGinterferon alfa-2a/ribavirin. Hepatology 56(Suppl.): 230A–230A.

52.

Lok

Gardiner

Lawitz

Martorell

Everson

Ghalib

(2012b) Preliminary study of two antiviral agents for hepatitis C genotype 1. N Engl J Med 366: 216–224.

53.

Manns

Gane

Rodriguez-Torres

Stoehr

Yeh

Marcellin

(2012) Vaniprevir with pegylated interferon alpha-2a and ribavirin in treatment-naive patients with chronic hepatitis C: a randomized phase II study. Hepatology 56: 884–893.

54.

Manns

Marcellin

Poordad

De Araujo

Buti

Horsmans

(2013a) Simeprevir (TMC 435) with PEGinterferon/ribavirin for treatment of chronic HCV genotype-1 infection in treatment-naive patients: results from Quest -2. A phase III trial. J Hepatol 58(Suppl. 1): S568–S568.

55.

Manns

Vierling

Bacon

Marcellin

Caro

Gress

(2013b) High sustained viral response at 12 and 24 weeks follow-up of MK-5172 with pegylated interferon alfa-2b and ribavirin in HCV genotype 1 treatment-naive non cirrhotic patients. J Hepatol 58(Suppl. 2): S29–S29.

56.

Marcellin

Manns

Janczewska

Muir

Trenkle

(2013) 12 weeks response-guided treatment with the NS5A inhibitor, GS-5885, the NS3 protease inhibitor, GS-9451, plus pegylated interferon and ribavirin in treatment naive genotype 1 hepatitis C infected patients. J Hepatol 58(Suppl. 2): S355–S355.

57.

Mauss

Eisenbach

Moeller

Moog

Lutz

Naumann

(2013) Substantial renal impairment is not infrequent in HCV patients under triple therapy with telaprevir or boceprevir. J Hepatol 58(Suppl. 1): S358–S358.

58.

Membreno

Espinales

Lawitz

(2013) Cyclophilin inhibitors for hepatitis C therapy. Clin Liver Dis 17: 129–139.

59.

Membreno

Lawitz

(2011) The HCV NS5B nucleoside and non-nucleoside inhibitors. Clin Liver Dis 15: 611–626.

60.

Moreno

Berg

Tanwandee

Thongsawat

Van Vlierberghe

Zeuzem

(2010) A phase IIa, open label study to assess the antiviral activity of TMC435 monotherapy in patients infected with HCV genotypes 2–6. Hepatology 52(Suppl.): 749A–750A.

61.

Muir

Hillson

Gray

Ishak

Freeman

(2012) PEGinterferon lambda-1a compared to PEGinterferon alpha-2a in treatment-naive patients with HCV genotype 1 or 4. SVR24 from Emerge phase 2b. Hepatology 56(Suppl.): 299A–299A.

62.

Nelson

Gane

Jacobson

Di Bisceglie

Alves

Koziel

(2011) VX222/telaprevir in combination with PEGinterferon alfa-2a and ribavirin in treatment-naive genotype 1 HCV patients treated for 12 weeks: Zenith Study, SVR12 interim analysis. Hepatology 54(Suppl.): 1435A–1435A.

63.

Pawlostky

Sarin

Foster

Peng

Rasenack

Flisiak

(2012) Alisporivir plus ribavirin is highly effective as interferon-free or interferon-add-on regimen in previously untreated HCV-GT2 or GT3 patients: SVR12 results from VITAL-1 phase 2b study. J Hepatol 56: S553–S553.

64.

Pockros

Jensen

Tsai

Taylor

Ramji

Cooper

(2012) SVR-12 among G1/4 treatment-naive patients receiving mericitabine in combination with PEG-IFN alfa-2a/RBV: interim analysis from the JUMP-C Study. J Hepatol 56: S477–S478.

65.

Poordad

Lalezari

Lawitz

Van Vlierberghe

Shiffman

Jacobson

(2012a) Continued high virologic response rates with ACH-1625 daily dosing plus PEGIFN-alpha-2a in a 28 days and 12 week phase 2a trial. J Hepatol 56(Suppl. 2): S455–S455.

66.

Poordad

Lawitz

Dejesus

Kowdley

Gaultier

Cohen

(2012b) ABT-072 or ABT-333 combined with pegylated interferon and ribavirin after 3 days monotherapy in HCV genotype1 infected treatment-naive subjects: 12 week sustained virologic response and safety results. J Hepatol 56(Suppl. 2): S478–S478.

67.

Poordad

Lawitz

Kowdley

Everson

Freilich

Cohen

(2012c) 12 week interferon-free regimen of ABT-450/R + ABT-333 + ribavirin achieved SVR 12 in more than 90% of treatment-naive HCV genotype 1 infected subjects and 47% of previous non-responders. J Hepatol 56(Suppl. 2): S549–S549.

68.

Poordad

Lawitz

Reddy

Afdhal

Hezode

Zeuzem

(2012d) Timing and magnitude of ribavirin dose reduction do not impact sustained virologic response rates with boceprevir + PEGinterferon alfa-2b/ribavirin in the anemia management study in chronic HCV genotype 1 patients. Hepatology 56(Suppl.): 269A–270A.

69.

Poordad

McCone

Jr Bacon

Bruno

Manns

Sulkowski

(2011) Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 364: 1195–1206.

70.

Ratziu

Gadano

Pol

Hezode

Ramji

Cheng

(2012) Triple therapy with daclatasvir, peginterferon alfa-2a and ribavirin in HCV infected prior null and partial responders: 12 weeks results of phase 2b COMMAND-2 trial. J Hepatol 56(Suppl 2): S478–S479.

71.

Rodriguez-Torres

Lawitz

Conway

Kaita

Sheikh

Ghalib

(2010) Safety and antiviral activity of the HCV non-nucleoside polymerase inhibitor VX-222 in treatment-naive genotype 1 HCV infected patients. J Hepatol 52: S14–S14.

72.

Rodriguez-Torres

Lawitz

Kowdley

Nelson

Dejesus

McHutchison

(2013) Sofosbuvir (GS-7977) plus peginterferon/ribavirin in treatment-naive patients with HCV genotype 1: a randomized, 28-day, dose-ranging trial. J Hepatol 58: 663–668.

73.

Sherman

Flamm

Afdhal

Nelson

Sulkowski

Everson

(2011) Response-guided telaprevir combination treatment for hepatitis C virus infection. N Engl J Med 365: 1014–1024.

74.

Soriano

Gane

Angus

Stickel

Bronowicki

Roberts

(2012) Efficacy and safety of the interferon-free combination of BI 201335 + BI 207127 with or without ribavirin in treatment-naive patients with HCV genotype 1 infection and compensated liver cirrhosis: results from the SOUND-C2 study. Hepatology 56(Suppl.): 234A–234A.

75.

Sulkowski

Asselah

Lalezari

Ferenci

Fainboim

Leggett

(2013a) Faldaprevir combined with pegylated interferon alfa-2a and ribavirin in treatment-naive patients with chronic genotype1 HCV: SILEN-C1 trial. Hepatology 57: 2143–2154.

76.

Sulkowski

Bourliere

Bronowicki

Asselah

Pawlotsky

Shafran

(2013b) Faldaprevir combined with peginterferon alfa-2a and ribavirin in chronic hepatitis C virus genotype-1 patients with prior nonresponse: SILEN-C2 trial. Hepatology 57: 2155–2163.

77.

Sulkowski

Gardiner

Lawitz

Hinestrosa

Nelson

Thuluvath

(2012a) Potent viral suppression with the all-oral combination of daclatasvir (NS5A inhibitor) and GS-7977 (nucleotide NS5B inhibitor +/- ribavirin in treatment-naive patients with chronic HCV GT1,2, or 3. J Hepatol 56: S560–S560.

78.

Sulkowski

Gardiner

Rodriguez-Torres

Reddy

Hassanein

Jacobson

(2013c) Sustained virologic response with daclatasvir plus sofosbuvir with or without ribavirin in chronic HCV genotype 1 infected patients who previously failed telaprevir or borceprevir. J Hepatol 58(Suppl. 2): S570–S570.

79.

Sulkowski

Gardiner

Rodriguez-Torres

Reddy

Hassanein

Jacobson

(2012b) High rate of sustained virologic response with all-oral combination of daclatasvir (NS5A Inhibitor) plus sofosbuvir (nucleotide NS5B inhibitor) with or without ribavirin, in treatment-naive patients chronically infected with HCV genotype 1, 2 or 3. Hepatology 56(Suppl.): LB–LB2.

80.

Sulkowski

Pol

Mallolas

Fainboim

Cooper

Slim

(2013d) Boceprevir versus placebo with pegylated interferon alfa-2b and ribavirin for treatment of hepatitis C virus genotype 1 in patients with HIV: a randomized, double blind controlled phase 2 trial. Lancet Infect Dis 13: 597–605.

81.

Sulkowski

Roberts

Afdhal

Andreone

Diago

Pol

(2012c) Ribavirin dose modification in treatment-naive and previously treated patients who received telaprevir combination treatment: no impact on sustained virologic response in phase 3 studies. J Hepatol 56(Suppl. 2): S459–S460.

82.

Sulkowski

Rodriguez-Torres

Lawitz

Shiffman

Pol

Herring

(2012d) High sustained virologic response rate in treatment-naive HCV genotype 1a and 1b patients treated for 12 weeks with an interferon-free all-oral quad regimen: interim results. J Hepatol 56(Suppl. 2): S560–S560.

83.

Sulkowski

Sherman

Dieterich

Bsharat

Mahnke

Rockstroh

(2013e) Combination therapy with telaprevir for chronic hepatitis C virus genotype 1 infection in patients with HIV: a randomized trial. Ann Intern Med 159: 86–96.

84.

Sullivan

Rodriguez-Torres

Lawitz

Poordad

Kapoor

Campbell

(2012) ABT-267 combined with pegylated interferon alpha-2a and ribavirin in genotype 1 HCV-infected treatment-naive subject: 12 week antiviral and safety analysis. J Hepatol 56(Suppl. 2): S480–S480.

85.

Thompson

Han

Shiffman

Rossaro

Ghalib

Beavers

(2013) GS-5885 + GS-9451 + PEGinterferon and ribavirin for six or twelve weeks achieves high SVR12 rates in treatment naive genotype1 IL28B CC patients. J Hepatol 58(Suppl. 2): S29–S29.

86.

Van Der Meer

Hansen

Janssen

(2013) Sustained virological response to treatment in patients with chronic hepatitis C - reply. JAMA 309: 1457–1457.

87.

Verna

Burton

O'Leary

Lai

Saxena

Dodge

(2013) A multicenter study of protease inhibitor-triple therapy in HCV-infected liver transplant recipients: reports from the CRUSH-C group. J Hepatol 58(Suppl. 1): S10–S11.

88.

Vierling

Zeuzem

Poordad

Bronowicki

Manns

Bacon

(2013) Safety and efficacy of boceprevir/PEG-interferon/ribavirin (BOC/P/R) combination therapy for chronic HCV G1 patients with compensated cirrhosis: a meta-analysis of five phase 3 clinical trials. J Hepatol 58(Suppl. 1): S576–S577.

89.

Wartelle-Bladou

Le Folgoc

Bourliere

Lecomte

(2012) Hepatitis C therapy in non-genotype 1 patients: the near future. J Viral Hepat 19: 525–536.

90.

Wedemeyer

Janczewska

Wlodzimierz

Stanciu

Habersetzer

Carreno

(2012) Significant improvement of complete EVR in HCVAC phase II clinical trial when adding TG4040 therapeutic vaccine to PEGIFN alfa-2a and ribavirin. J Hepatol 56(Suppl. 2): S552–S552.

91.

Wedemeyer

Jensen

Herring

Jr Ferenci

Zeuzem

(2012) Efficacy and safety of mericitabinin combination with PEG-IFN alfa-2a/RBV in G1/4 treatment naive HCV patients: final analysis from the PROPEL study. J Hepatol 56: S481–S481.

92.

Zeuzem

Andreone

Pol

Lawitz

Diago

Roberts

(2011a) Telaprevir for retreatment of HCV infection. N Engl J Med 364: 2417–2428.

93.

Zeuzem

Asselah

Angus

Zarski

Larrey

Mullhaupt

(2011b) Efficacy of the protease inhibitor BI 201335, polymerase inhibitor BI 207127, and ribavirin in patients with chronic HCV infection. Gastroenterology 141: 2047–2055.

94.

Zeuzem

Berg

Gane

Ferenci

Foster

Fried

(2012a) TMC435 in HCV genotype 1 patients who have failed previous pegylated interferon ribavirin treatment: final SVR24 results of the ASPIRE trial. J Hepatol 56(Suppl. 2): S1–S1.

95.

Zeuzem

Buggisch

Agarwal

Manns

Marcellin

Foster

(2010) Dual, triple and quadruple combination treatment with a protease inhibitor (GS-9256) and a polymerase inhibitor (GS-9190) alone and in combination with ribavirin (RBV) or PEGIFN/RBV for up to 28 days in treatment naive genotype 1 HCV subjects. Hepatology 52(Suppl.): 400A–400A.

96.

Zeuzem

Soriano

Asselah

Bronowicki

Lohse

Mullhaupt

(2012b) SVR4 and SVR12 with an interferon-free regimen of BI201335 and BI207127 +/- ribavirin in treatment naive patients with chronic genotype 1 HCV infection; interim results of SOUND-C2. J Hepatol 56(Suppl. 2): S45–S45.

97.

Zeuzem

Soriano

Asselah

Bronowicki

Lohse

Mullhaupt

(2012c) Interferon-free combination treatment with HCV NS3/NS4 protease inhibitor BI201335 and the non nucleoside NS5B inhibitor BI 207127 with or without ribavirin: final results of SOUND-C2 and predictors of response. Hepatology 56(Suppl.): 308A–309A.