Pegylated interferon based therapy with second-wave direct-acting antivirals in genotype 1 chronic hepatitis C

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1 Liver International ISSN REVIEW ARTICLE Pegylated interferon based therapy with second-wave direct-acting antivirals in genotype 1 chronic hepatitis C Nicole M. Welch and Donald M. Jensen University of Chicago Medical Center, Chicago, IL, USA Keywords direct-acting antiviral agents genotype 1 HCV hepatitis C hepatitis C therapy pegylated interferon based therapies Abbreviations CHC, chronic hepatitis C; DAAs, direct-acting antivirals; HCV-1,2,3,4, (genotypes 1,2,3,4) HCV infection; HCV, hepatitis C virus; PEG- IFN, pegylated interferon; PI, protease inhibitors; RBV, ribavirin; SOC, standard of care. Correspondence Nicole M. Welch, University of Chicago Medical Center, Chicago, IL, USA Tel: Fax: nicolemajoraswelch@gmail.com DOI: /liv Abstract Within the last few years, treatment of chronic hepatitis C infection has progressed beyond regimens containing the first-wave direct-acting antiviral agents (DAAs) boceprevir and telaprevir, which had high pill burdens as well as low efficacy and safety in treatment-experienced patients. Triple therapy regimens with newer second-wave DAAs combined with pegylated interferon (PEG-IFN) and ribavirin (RBV), have shown rates of sustained virological response never before achieved with previous regimens in treatment-na ıve genotype 1 (HCV-1) patients. Additionally, increased response rates have been found with quadruple agent therapy in prior non-responders, partialresponders, and relapsers, including those with cirrhosis. This review will focus on the second-wave DAAs including protease inhibitors (PI), nucleotide inhibitors, and NS5B inhibitors combined with PEG-IFN and RBV for both treatment-na ıve and treatment-experienced genotype 1 hepatitis C virus (HCV-1) infected patients. The current standard of care for treatment-na ıve HCV-1 is the second-wave PI, sofosbuvir, plus PEG-IFN/RBV and sofosbuvir plus the second-wave nucleotide inhibitor simeprevir with or without RBV in treatment-experienced HCV-1 patients. These recommendations could change, especially for treatment-experienced patients based on the positive results obtained with the newest quadruple therapy studies. Key points Second-wave DAAs have improved efficacy, dosing schedules, and safety profiles compared to firstwave DAAs boceprevir and telaprevir. Second-wave DAA sofosbuvir, plus PEG-IFN/ RBV, for 12 weeks is the current standard of care for treatment-na ıve HCV-1 infected patients. Quadruple therapy with two second-wave DAAs plus PEG-IFN have shown SVR rates >90% in treatment-experienced patients with genotype 1 HCV. Over 180 million people worldwide currently live with chronic hepatitis C virus (HCV) infection, with 4 million of those affected in the United States (1). There are 6 main genotypes of HCV with different responses to treatment. Genotype 1 (HCV-1) is the most common genotype in the world, as well as in the United States, making up 60% of all cases worldwide (2). Interferon (IFN) alone was the first available treatment for HCV, starting in 1986, providing sustained virological response (SVR) rates of only 6 16%. Ribavirin (RBV) was added to IFN as a treatment regimen in 1996, which resulted in an SVR of approximately 40%. After pegylated interferon (PEG- IFN) and RBV trials began, the SVR increased to 54 65% between 2000 and However, this SVR rate was closer to 50% in HCV-1 patients (3 5). HCV protease inhibitors (PI) telaprevir and boceprevir were approved in 2011, and became the standard of care (SOC) for HCV-1 treatment-na ıve patients in combination with PEG-IFN/RBV. With this new triple therapy, an SVR was obtained in approximately 70% (6, 7). These first-generation direct-acting antivirals (DAAs) were limited by their side effects, lengthy treatment duration, cost and high daily pill burden. Additionally, SVR rates with first-wave DAAs plus PEG-IFN/RBV were poor in patients with cirrhosis and prior PEG-IFN/RBV non-responders, and the side effects in these groups were frequent and often severe, including liver failure, anaemia, rash, severe infections and thrombocytopenia (8 10). In the last few years, triple therapy regimens with newer second-wave DAAs combined with PEG-IFN and RBV have obtained SVR rates never before 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 11

2 IFN based therapy with second-wave DAAs Welch and Jensen Table 1. Second-wave DAAs plus PEG-IFN/RBV SVR results for genotype 1 HCV Class Drug Study Treatment length Dosing Patient type SVR (%) Protease Simeprevir QUEST 1, weeks QD Na ıve inhibitors ASPIRE 48 weeks QD PR PART Null CONCERTO weeks QD PR 100 Na ıve 92 Null 39 MK weeks various Na ıve Asunaprevir weeks BID Na ıve 64 Faldaprevir SILEN-C1, C3 12 weeks * QD Na ıve weeks * SILEN-C weeks QD; BID PART 32 50; 42 Null 21 35; 29 STARTVerso 1,2, weeks QD Na ıve PR 70 PART Null 33 NS5A inhibitor Daclatasvir COMMAND-1 24 weeks HCV-1a QD Na ıve weeks HCV-1b 87 Nucleotide Sofosbuvir ATOMIC weeks QD Na ıve polymerase NEUTRINO 12 weeks HCV-1a QD Na ıve 92 inhibitors 12 weeks 82 HCV-1b Mericitabine JUMP-C weeks BID Na ıve 57 PROPEL weeks BID Na ıve QUAD Mericitabine/ MATTERHORN 24 weeks BID PART 86 Danoprevir Null 84 Daclatasvir/ Asunaprevir VX-222/ Telaprevir GS-0451/ Tegobuvir QUAD B1 24 weeks BID Null 90 QUAD B2 QD 95 HALLMARK-QUAD 24 weeks QD-BID Null 93 PART ZENITH weeks BID Na ıve weeks QD-BID Na ıve 77 *12 24 weeks of faldaprevir plus weeks of PEG-IFN/RBV. Included both HCV-1 and 4 patients. Asunaprevir given once-daily, daclatasvir given twice-daily. GS-9451 given once-daily, tegobuvir given twice-daily. Na ıve, treatment-na ıve; PART, prior partial-responder; PR, prior relapse; Null, prior null-responder; QD, daily; BID, twice-daily. achieved with previous regimens in treatment-na ıve HCV-1 infected patients. Additionally, increased response rates have been shown with quadruple agent therapy in prior non-responders, partial-responders, and relapsers, including those with cirrhosis. Given the high rate of serious adverse events with existing regimens, these cases had previously been a cause to defer treatment (11). This review will describe current IFN-based therapies with second-wave DAAs in HCV-1 CHC infection (see Table 1). Trials with second-wave DAAs have changed the face of hepatitis C treatment, in some cases obtaining SVR rates above 95%, creating a reality in which hepatitis C could be completely eradicated in the decades to come (12, 13). Protease inhibitors Simeprevir added to PEG-IFN/RBV: increases SVR from 50 to 80% Simeprevir is a single pill, once-daily, oral NS3/4A PI with activity against HCV-1 and 4, with some activity against 2, 5 and 6. QUEST 1 was a phase III, double-blind, randomized control trial in 13 countries that studied the efficacy and safety of simeprevir (150 mg once-daily) plus PEG-IFN/RBV for 12 weeks vs. placebo plus PEG-IFN/RBV in 394 treatmentna ıve, HCV-1 infected patients. Both 12-week arms were followed by an additional weeks of response guided PEG-IFN/RBV, however, most patients in the treatment arm met criteria to John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

3 Welch and Jensen IFN based therapy with second-wave DAAs complete only 24 weeks of treatment. The primary endpoint, SVR12, was achieved in 80% of patients in the simeprevir arm compared to 50% with PEG-IFN/ RBV alone. When analysed by subgroup, response rates in genotype 1a (HCV-1a) were inferior to those in to genotype 1b (HCV-1b), with SVR rates of 78 and 90% respectively. However, both rates were still higher in the treatment arm than in the placebo arm. The presence of the Q80K mutation in HCV-1a, the absence of the CC-IL28B genotype, and advanced fibrosis were all associated with a significantly decreased rate of response to treatment which were nevertheless still significantly better than in the placebo group. The incidence of side effects of anaemia and rash were similar in the treatment and placebo groups treated with PEG-IFN/RBV alone, with the most common adverse events in both arms being fatigue and headache (14). QUEST 2 was a randomized phase III trial that evaluated whether the type of IFN, PEG IFN-a-2a or PEG IFN-a-2b, influenced response rates. The trial showed that the type of IFN did not significantly affect response rates with again an 81% SVR rate in treatment-na ıve patients with HCV-1 infection treated with simeprevir and PEG-IFN/RBV. Unlike QUEST 1, the HCV subtype was not found to be a predictor of SVR in this study (80% SVR in HCV-1a and 82% SVR in HCV-1b) (15). Although SVR rates were clearly higher in treatmentna ıve patients who received simeprevir with PEG-IFN/ RBV compared to the SOC regimen, studies in previous non-responders are lacking. The ASPIRE study was a phase IIb randomized control trial including prior nonresponders to PEG-IFN/RBV therapy who were treated with simeprevir plus PEG-IFN/RBV for 12, 24, or 48 weeks. This was compared to placebo plus PEG-IFN/ RBV. SVR rates were significantly higher in the simeprevir arm than in the control group (38 59% in prior non-responders compared to 19% in the control group; 48 86% in prior partial-responders compared to 9% in the control group; and 77 89% in those with prior relapse compared to 37% in the control group). Rash and neutropenia were more common in the simeprevir group than in the placebo group, however, there was no difference in the incidence of serious adverse events between the groups (16). CONCERTO-4 was a study of non-cirrhotic, prior non-responders, relapsers and treatment-na ıve HCV-1 infected patients treated with 12 weeks of simeprevir plus either 24 or 48 weeks of PEG-IFN/RBV. An SVR was achieved in over 90% of treatment-na ıve or prior relapse patients. The SVR rate in non-responders was 39%, which was consistent with the results of the ASPIRE study (17). Overall, simeprevir was well tolerated, decreased the pill burden compared to the threetimes a day SOC with boceprevir and telaprevir, and had high rates of SVR in treatment-na ıve and prior relapsers (6, 7). MK-5172: better than boceprevir MK-5172 is a second generation macrocyclic NS3/4A PI shown to have in vitro antiviral activity against HCV-1, 2 and 3a (18). In a phase II trial, non-cirrhotic HCV-1 patients received either MK-5172 plus PEG-IFN/RBV for 12 weeks or boceprevir plus PEG-IFN/RBV for 12 weeks. SVR rates were 86 92% in the MK-5172 cohort compared to only 54% in the boceprevir cohort. HCV-1a had lower response rates (81% HCV-1a vs. 96% non-1a), but no resistant variants were found. MK5172 was also better tolerated than boceprevir with lower rates of rash, anaemia and treatment discontinuation secondary to an adverse event (19). Asunaprevir Asunaprevir is a second-wave, first-generation macrocyclic, selective NS3 PI with in vitro activity against HCV-1 as well as HCV-4, 5 and 6. It is taken twice a day. In a phase II study, treatment-na ıve adults with HCV-1 were treated with either asunaprevir plus PEG-IFN/RBV or placebo plus PEG-IFN/RBV. SVR rates were 64%, which is less than that those in trials with simeprevir (14, 15). While the rates of rash and haematological events were similar between treatment arms in the asunaprevir study, 2% discontinued asunaprevir secondary to grade 4 alanine aminotransferase elevations (20). Faldaprevir: 70 80% with SVR Faldaprevir is a second-wave, first-generation NS3/4A PI with a long half-life allowing daily dosing. In the SI- LEN-C1 study, a phase IIb trial, treatment-na ıve HCV-1 patients without cirrhosis were treated with faldaprevir plus PEG-IFN/RBV with varying doses and lead-ins, resulting in SVR rates of 72 84% (21). Similar results were found in the phase 3 STARTVerso 1 and 2 trials, in which HCV-1 treatment-na ıve patients from Europe, Asia, and North America were treated with either 120 mg or 240 mg of faldaprevir or placebo plus PEG- IFN/RBV. The SVR12 rate was similar between the two treatment arms (72 73%) compared to a significantly lower SVR12 rate of 50% in the placebo group (22). Discontinuation rates in the treatment arms were 5 8% secondary to adverse events including rash, jaundice and gastrointestinal upset. This was comparable to discontinuation rates with placebo plus PEG-IFN/RBV. In the high-dose faldaprevir group, 43% had bilirubin elevations greater than 2.5 times the upper limit of normal compared to only 0.4% in the placebo group. Otherwise, adverse event rates were similar in the three arms. The increases in bilirubin were predominately indirect bilirubin and were because of transporter inhibition. It reversed when faldaprevir was discontinued. SILEN-C3 was a parallel group study comparing weeks of once-daily faldaprevir with PEG-IFN/RBV 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 13

4 IFN based therapy with second-wave DAAs Welch and Jensen in 160 treatment-na ıve HCV-1 patients. The SVR rate was 67% in the 12-week arm, and although it reached 74% in the 24-week arm, the difference was not statistically significant (P = 0.51). A total of 35% (7/20) of patients with cirrhosis, achieved an SVR in all arms. Adverse events occurred in 12% of patients in the 12-week group and 9% in the 24-week group including anaemia, neutropenia, rash and depression. Treatment was discontinued in 6% secondary to adverse events (23). In the SILEN-C2 trial, 290 prior partial-responders and non-responders to PEG-IFN/RBV without cirrhosis were treated with faldaprevir (240 mg daily or twicedaily) plus PEG-IFN/RBV for weeks. SVR rates for partial-responders and non-responders reached 32 50% and 21 35% respectively (24). There was no placebo group. STARTVerso 3 was a phase III trial that evaluated prior non-responders, partial-responders and relapsers treated with the same regimen, with SVR results similar to those in the SILEN-C2 trial (25). NS5A inhibitor Daclatasvir: more than 80% with SVR among HCV-1b patients Daclatasvir is a highly selective NS5A replication complex inhibitor with broad genotypic coverage in vitro and once-daily dosing. In the COMMAND-1 trial, daclatasvir was combined with PEG-IFN/RBV and found to have SVR rates of 65% in all treatment-na ıve HCV-1 infected patients, while HCV-1b patients achieved SVR rates as high as 87%. Treatment was generally well tolerated with a rate of adverse events that was comparable to those with placebo (26). Nucleotide polymerase inhibitors Sofosbuvir: more than 90% with SVR Sofosbuvir is a direct-acting nucleotide PI of the HCVspecific NS5B polymerase with pan-genotypic activity. It was approved for the treatment of chronic HCV infection in ATOMIC was a phase II trial in which previously untreated, non-cirrhotic HCV-1 infected patients received weeks of sofosbuvir plus PEG- IFN/RBV. The SVR in the 12-week cohort was 90% (CI 79 97), while it was 93% (CI 86 97) in the 24 week cohort. A third cohort received 12 weeks of sofosbuvir/ PEG-IFN/RBV followed by 12 weeks of either sofosbuvir monotherapy or sofosbuvir/rbv, also resulting in statistically similar SVR rates compared to the other groups. The most common adverse events leading to discontinuation of a study drug were anaemia and neutropenia. There was a trend towards more anaemia resulting in dose reductions or interruption in the cohorts with longer treatment regimens. The ATOMIC study concluded that there was no benefit to extending treatment in the sofosbuvir regimens from 12 to 24 weeks (27). The NEUTRINO study was a phase III, single-group, open-label study including treatment-na ıve HCV-1 patients. The treatment arm included 12 weeks of sofosbuvir plus PEG-IFN/RBV with a primary endpoint of SVR12. The SVR was 89% (CI 85 93) in HCV-1 patients. Patients with HCV-1a had an SVR12 rate of 92% (CI 87 95) while those with HCV-1b had a SVR rate of 82% (CI 70 90). This study also included patients with cirrhosis, and the SVR rate in HCV-1 patients with cirrhosis was 81%. In addition to cirrhosis, a lack of genotype CC-IL28B polymorphism was also associated with a lower response rate. The most common adverse effects were fatigue, headache, and nausea. Only 2% of patients discontinued treatment because of an adverse event (28). Mericitabine: lower efficacy than sofosbuvir Mericitabine is a pan-genotypic selective nucleoside analogue inhibitor of the NS5B RNA-dependent RNA polymerase with a twice-daily dose. In the JUMP-C trial, SVR rates in treatment-na ıve patients with mericitabine plus PEG-IFN/RBV were 57% vs. 36% with placebo (29). In the PROPEL trial, treatment-na ıve HCV-1 and 4 patients were treated with either 8 or 12 weeks of mericitabine plus PEG-IFN/ RBV. Once again, response rates were lower than with sofosbuvir, the other NS5B PI, with HCV-1/4 SVR rates ranging from 33 to 50% depending on the duration of treatment (30). Mericitabine was, however, well tolerated in all trials. QUAD therapy Traditionally prior non-responders are considered a difficult group to treat and obtain an SVR, even with newer second-wave DAA triple therapy plus PEG-IFN/RBV. However, when two of the newer agents are combined with PEG-IFN/RBV in quadruple therapy, SVR rates are higher in prior non-responders with no increased side effects profiles (31 33). Mericitabine/danoprevir: hope for non- or partialresponders to PEG-IFN/RBV Although mericitabine was not as effective as other triple therapy regimens in inducing SVR in treatment-na ıve patients, it could play a role when combined with danoprevir, a NS3/4A PI, in quadruple therapy for treatment-experienced patients. In the phase IIb MATTERHORN trial, 379 patients with HCV-1 who were either non-responders or partialresponders were randomly assigned to 24 weeks of IFN-free therapy with mericitabine/danoprevir plus RBV; triple therapy with mericitabine/danoprevir plus PEG-IFN; or quadruple therapy with mericitabine, John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

5 Welch and Jensen IFN based therapy with second-wave DAAs ritonavir-boosted danoprevir and PEG-IFN/RBV. Although patients with cirrhosis were excluded from the trial, 24% of the patients had advanced liver fibrosis. The results of the trial showed that overall SVR12 rates in HCV-1 treatment-experienced patients were 84 86%, which was significantly higher than in IFN-free or triple therapy alone arms. The SVR rates in the IFN-free arm were only 33 55%, in non- and partial-responders, indicating that IFN was necessary in these hard to cure patient groups. In particular, HCV-1b patients achieved SVR12 rates of 90% or more in all treatment arms, including the IFN- free regimen. The most common side effects were gastrointestinal symptoms and flu-like symptoms. Severe adverse symptoms were reported in 4% of the patients in the quadruple therapy group compared to 9% in the IFN-free group and 2% in the triple therapy group (31). Daclatasvir/Asunaprevir In a randomized, phase 2 study evaluating non-cirrhotic HCV-1 non-responders, two arms were studied with PEG-IFN: QUAD B1 with twice-daily daclatasvir/asunaprevir plus PEG-IFN/RBV and QUAD B2 with oncedaily daclatasvir/asunaprevir plus PEG-IFN/RBV. Both arms included HCV-1a and HCV-1b patients. The SVR4 and SVR24 in the QUAD B1 were 90%, while the post-treatment SVR in QUAD B2 reached 95%. The most frequent adverse events were mild or moderate, including headache, diarrhoea, fatigue and asthenia. Increased aminotransferase levels occurred in 4% of patients. These patients were asymptomatic and there was no discontinuation of treatment. The SVR in a predominantly HCV-1a group in QUAD regimens was 95%, which was improved from prior studies with telaprevir, boceprevir, and mericitabine/danoprevir based regimens. In particular, IFN-free therapies evaluated in this same study were not effective in HCV-1a nonresponders, because most of them experienced a virological breakthrough (32). The open-label, phase III HALLMARK-QUAD study evaluated the efficacy of daclatasvir/asunaprevir plus PEG-IFN/RBV for both prior non- and partial-responders with HCV-1 and 4 infection. It also included 23% of patients with compensated cirrhosis. The SVR12 rate in all prior HCV-1 non-responders was 93%. In partialresponders, the SVR12 rates were similar, from 87 to 98%. SVR was achieved more often in HCV-1b (99%) than 1a (87%) patients. The SVR rate was not statistically different (90% vs. 94%) between patients with cirrhosis and those without. In addition to cirrhosis, this study found that neither prior PEG-IFN/RBV response nor IL28B genotype influenced SVR rates. Moreover, an excellent response was found in patients with HCV-4, with an SVR24 of 100% with no virological failures. Adverse events included pancytopenia and aminotransferase elevations with serious adverse events in 5.5% of patients, and discontinuations in 4.5%. These results were comparable to those evaluating either DAA alone and lower than those in previous studies in nonresponders (33). VX-222/Telaprevir VX-222 is a non-nucleoside polymerase inhibitor of the HCV NS5B polymerase. ZENITH was a phase IIb study evaluating the efficacy and safety of weeks of quadruple therapy with either high-dose or low-dose VX- 222 (twice-daily), telaprevir (twice-daily), and PEG- IFN/RBV in treatment-na ıve HCV-1. The SVR for all comers in this study was 90% with the 400 mg VX-222 dose (compared to 83% with 100 mg). HCV RNA was undetectable at weeks 2 and 8 in 50% of the patients who stopped treatment at week 12. SVR12 rates in patients who were eligible to complete a total of 12 weeks of treatment were 93% with higher doses of VX-222. Mild gastrointestinal side effects and fatigue were the most common adverse effects and there were no treatment discontinuations because of these symptoms (34). There is a study underway examining this regimen in treatment-experienced patients with cirrhosis. Tegobuvir/GS-9451 Like VX-222, GS-9451 is also a non-nucleoside NS5B PI. In a phase II trial, the combination of GS-9451 (daily), tegobuvir (twice-daily) and PEG-IFN/RBV was studied in 239 treatment-na ıve HCV-1 infected patients. Treatment was stopped at 16 weeks in patients who achieved undetectable HCV RNA at week 2. Treatment was stopped at week 24 in patients who achieved undetectable HCV RNA between weeks The remaining patients received additional PEG-IFN/RBV treatment. Overall SVR12 was 77%. Results were higher in HCV- 1b than in HCV-1a, with SVR12 rates of 87% and 73% respectively. The regimen was well tolerated with statistically similar rates of haematological reductions across arms (quad therapy vs. triple therapy vs. placebo plus PEG-IFN/RBV) and serious adverse events in only 4 6% (35). Conclusion The current SOC for HCV-1 treatment-na ıve patients is 12 weeks of sofosbuvir plus PEG-IFN/RBV. Simeprevir plus PEG-IFN/RBV is an alternative regimen. In treatment-experienced or IFN intolerant patients, the current SOC is 12 weeks of sofosbuvir and simeprevir, with or without RBV (36). Because treatment for CHC began as early as the 1990s, many of those living with HCV today have already been treated and are considered nonor partial-responders. The new, all-oral combinations have been shown to be remarkably active in all these groups so that the future role of IFN-based therapies is 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 15

6 IFN based therapy with second-wave DAAs Welch and Jensen in limbo in the United States, but may have a potentially significant role in resource-limited countries. The goal with the most recent second-wave DAA trials is to increase the number of patients achieving an SVR close to 100%, including both treatment-na ıve and treatment-experienced patients. Other secondary endpoints that will determine which treatments will become the future gold SOC include decreasing adverse events and side effects, decreasing pill burden, decreasing drugdrug interactions, improving dosing regimens and decreasing the length of time needed to achieve SVR. Acknowledgements We have no acknowledgements. Conflict of interest: No conflicts of interest to declare. References 1. US Department of Health and Human Services NIH. Hepatitis C. Available at hepatitis/hepatitisc/pages/default.aspx. Accessed: 12 July World Health Organization: Global Alert and Response. 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7 Welch and Jensen IFN based therapy with second-wave DAAs feron alfa-2a and ribavirin in treatment-experienced patients with chronic hepatitis C genotype-1 infection. Presented at: The 64th Annual Meeting of the American Association for the Study of Liver Diseases: The Liver Meeting October Hezode C, Hirschfield GM, Ghesquiere W, et al. Daclatasvir, an NS5A Replication Complex Inhibitor, Combined With Peginterferon Alfa-2a and Ribavirin in Treatment- Na ıve HCV-Genotype 1 or 4 Patients: Phase 2b COM- MAND-1 SVR12 Results. Presented at: Presented at: The 63rd Annual Meeting of the American Association for the Study of Liver Diseases. November 9 11, 2012; Boston, MA. 27. Kowdley KV, Lawitz E, Crespo I, et al. Sofosbuvir with pegylated interferon alfa-2a and ribavirin for treatmentnaive patients with hepatitis C genotype-1 infection (ATOMIC): an open-label, randomised, multicentre phase 2 trial. Lancet 2013; 381: Lawitz E, Lalezari JP, Hassanein T, et al. Sofosbuvir in combination with peginterferon alfa-2a and ribavirin for non-cirrhotic, treatment-na ıve patients with genotypes 1,2, and 3 hepatitis C infection: a randomized, doubleblind, phase 2 trial. Lancet Infect Dis 2013; 13: Pockros PJ, Jensen D, Tsai N, et al. JUMP-C: a randomized trial of mericitabine plus pegylated interferon alpha- 2a/ribavirin for 24 weeks in treatment-na ıve HCV genotype 1/4 patients. Hepatology 2013; 58: Wedemeyer H, Jensen D, Herring R Jr, et al. PROPEL: a randomized trial of mericitabine plus peginterferon alpha- 2a/ribavirin therapy in treatment-na ıve HCV genotype 1/4 patients. Hepatology 2013; 58: Feld JJ, Jacobson IM, Jensen DM, et al. Up to 100% SVR4 rates with ritonavir-boosted danoprevir (DNVr), mericitabine and ribavirin with or without peginterferon alfa-2a (40KD) in HCV genotype 1-infected partial and nullresponders: results from the MATTERHORN study. Presented at: The 63rd Annual Meeting of the American Association for the Study of Liver Diseases. November 9 11, 2012; Boston, MA. 32. Lok A, Gardiner D, Hezode C, et al. Randomized trial of daclatasvir and asunaprevir with or without PegIFN/RBV for hepatitis C virus genotype 1 null responders. J Hepatol 2014; 60: Jensen D, Sherman K, Hezode C, et al. Daclatasvir and Asunaprevir Plus Peginterferon Alfa and Ribavirin in HCV Genotype 1 or 4 Nonresponders. IDSA abstract. October 10, 2014; Philadelphia, PA. 34. Nelson DR, Gane E, Jacobson IM, et al. VX-222/telaprevir in combination with peginterferon-alfa-2a and ribavirin in treatment-na ıve genotype 1 HCV patients treated for 12 weeks: ZENITH study, SVR12 interim analysis. Hepatology 2011; 54: 1435A. 35. Pol S, Jablkowski M, Trenkle JD, et al. Antiviral efficacy of the NS3 protease inhibitor GS-9451, non-nucleoside NS5b inhibitor, tegobuvir, and pegylated interferon plus ribavirin in treatment-na ıve genotype 1 hepatitis C infected patients. J Hepatol 2013; 58: S American Association for the Study of Liver Diseases. Summary of Recommendations for Patients Who are Initiating Therapy for HCV Infection or Who Experienced Relapse after Prior PEG/RBV Therapy, by HCV Genotype Available at initial-treatment-box-summary-recommendations-patientswho-are-initiating-therapy-hcv. Accessed: 6 September John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 17