REVIEW URRENT C OPINION
Hepatitis C genotype 1 Graham R. Foster and Sampath De Silva
Purpose of review To assess advances in the treatment of genotype 1 (G1 hepatitis C virus), in particular, the development of new interferon (and ribavirin)-free treatment regimes. Recent findings The treatment of hepatitis C has advanced rapidly over the last 24 months. Newer interferon-containing regimes have been developed with improved tolerability, and interferon-free regimes with outstanding efficacy and improved tolerability have been developed. Summary New treatment regimes for hepatitis C virus have significantly altered the outlook for patients with hepatitis C. New interferon-containing treatment regimes with simeprevir and sofosbuvir, which have improved response rates, have shorter treatment durations and fewer side-effects are becoming available, and interferon-free regimes have been developed. The interferon-free regimes involve multidrug combinations or two-drug combinations and offer the possibility of shorter treatment duration with 8 or 12 weeks. The efficacy of the interferon-free regimes is striking with response rates of well over 90% reported in a wide range of different patient populations. The rapid progress in the treatment of hepatitis C will hopefully result in a cure for most patients, thereby significantly decreasing the morbidity and mortality associated with hepatitis C virus infection. Keywords direct-acting antiviral agents, genotype 1, hepatitis C, interferon-free
INTRODUCTION The hepatitis C virus (HCV) was first identified in 1989 [1], and is a significant cause of chronic liver disease worldwide. Up to 170 million people may be affected (approximately 2–3% of the global population) [2]. Most patients (85%) who develop hepatitis C have chronic infection, and 20% of these individuals will develop liver cirrhosis after 20 years of infection, leading in many to significant morbidity and mortality, with hepatic decompensation, hepatocellular carcinoma, and the need for liver transplantation. Six major genotypes of hepatitis C have been identified [3], and they differ in their response to therapy. Genotype 1 is the commonest type in the USA, Europe and the east Asia and will be the focus of this review. Treatment for genotype 1 HCV infection has for many years focussed on 48-week treatment with pegylated interferon (PegIFN) and ribavirin, with response rates [defined as the proportion of patients with undetectable HCV RNA 24 weeks after treatment cessation – sustained virological response (SVR24)] approaching 50% [4]. A number of factors influence the response to interferon and ribavirin treatment and these include viral subtype (G1a), interleukin-28 genotype (non CC
genotype), ethnicity (black), advanced fibrosis or cirrhosis, and previous unsuccessful treatment all adversely affecting the response [5,6]. Over the last few years, therapy for genotype 1 HCV has been transformed by the development of direct-acting antiviral agents that synergize with interferon and ribavirin. The first drugs to be launched were the protease inhibitors (telaprevir and boceprevir), but these drugs have a relatively high side-effect burden and are now being superseded by newer protease inhibitors (simeprevir) and the nucleotide inhibitor (sofosbuvir). The development of drugs acting on different viral enzymes has allowed combination therapy to be developed that avoids the need for interferon, and the use of all-oral combination therapies has transformed the outlook for patients with genotype 1 HCV infection.
Barts and The London School of Medicine, London, United Kingdom Correspondence to Professor Graham R. Foster, The Blizard Institute, 4 Newark Street, Whitechapel, London E1 2AT, United Kingdom. Tel: +44 20 7882 2483; e-mail: [email protected],[email protected] Curr Opin Infect Dis 2014, 27:535–539 DOI:10.1097/QCO.0000000000000112
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KEY POINTS Several all-oral treatment therapies will be available for hepatitis C (genotype 1). All oral treatment has a high SVR rate even in prior treatment null responders and cirrhotic patients. The duration of HCV treatment may be shortened to 6 or 8 weeks in some patient populations.
FIRST-GENERATION PROTEASE INHIBITORS Telaprevir was assessed in three trials: ADVANCE, ILLUMINATE and REALIZE [7–9], which evaluated 12 weeks of telaprevir combined with 24 or 48 weeks of PegIFN and ribavirin. The SVR24 rates were 69 and 75% in treatment-naı¨ve patients with 24 or 48 weeks in the ADVANCE study compared to 44% with placebo, PegIFN and ribavirin. The ILLUMINATE trial showed the noninferiority of 24 weeks of treatment for patients who had an early virological response, and the REALIZE trial studied treatment-experienced patients and showed that response rates were influenced by previous treatment response, with higher SVR24 rates in previous relapsers (83–88%) compared with null responders (29–33%). The commonest side-effects with telaprevir were skin rashes, pruritus, gastrointestinal side-effects (nausea or diarrhoea) and anaemia. Subsequent studies in patients with more advanced cirrhosis have shown that over half of patients (53.8%) experienced serious adverse events [including severe infections (9.7%), hepatic decompensation (4.7%) and death (2.7%) with 29.4% stopping treatment early] [10]. Boceprevir was assessed in the SPRINT-2 and RESPOND-2 studies [11,12]. In SPRINT-2, a 4-week lead-in of PegIFN and ribavirin was followed by response-guided 24 weeks of boceprevir, PegIFN and ribavirin; or 44 weeks of all three medications for patients who did not show an early response. The SVR24 rates were 67 and 68% in these groups compared with 40% in the placebo arm. RESPOND-2 involved treatment-experienced patients and the SVR rates were 59 and 66%. Prior relapsers had better SVR rates of 69 and 75%, respectively compared with null responders, 40 and 52%, respectively. As with telaprevir, patients with advanced fibrosis had worse SVR rates (50% for treatmentnaı¨ve patients with METAVIR F3–4), as did black patients (SVR 42–53%). The commonest side-effects encountered with boceprevir were anaemia, dysgeusia, followed by nausea, diarrhoea and neutropenia. As with telaprevir, later studies showed that patients 536
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with advanced cirrhosis developed significant sideeffects at a much higher rate than seen in the pivotal trials (with 44% developing serious adverse events, including hepatic decompensation (4.2%), severe infection 3.8% and death (1.4%) [10]. The first-generation protease inhibitors transformed the management of patients with genotype 1 HCV, allowing a majority of patients to achieve an SVR. However, the treatment regimes are cumbersome (the early response to therapy needs to be assessed and the treatment duration modified to either 6 or 12 months), the drugs need to be administered three times a day and side-effects and drug interactions are problematic. Studies with telaprevir show that the dosing regime may be modified to twice daily, improving compliance [13], and the first-generation protease inhibitors remain the standard of care in many parts of the world.
NEW INTERFERON-CONTAINING REGIMES Simeprevir is a second-wave protease inhibitor, with an improved dosing schedule (once a day), reduced drug interactions and reduced side-effects compared with the first-generation protease inhibitors. It has been evaluated in a series of trials involving 12 weeks of simeprevir and 24 or 48 weeks of PegIFN and ribavirin, depending upon early response to treatment [14–17]. QUEST 1 and 2 involved treatment-naı¨ve patients, and 80–81% responded to simeprevir-based therapy compared with 50% in the control arm of PegIFN and ribavirin. High proportions of patients in both studies (85 and 91%) were eligible for 24 weeks of treatment in total and such patients had excellent response rates – SVR12 91% and 86%. In treatment-experienced patients [relapsers and null responders (ASPIRE)], two doses of simeprevir were evaluated for 12, 24 or 48 weeks along with 48 weeks of PegIFN and ribavirin, with an overall SVR24 of 65.5% for 100 mg of simeprevir and 72.9% for 150 mg of simeprevir, with no marked difference between 24 and 48 weeks of simeprevir (68.2–70.2%). The PROMISE trial involved previous relapsers with 12 weeks of simeprevir and 24 or 48 weeks of PegIFN and ribavirin. The overall SVR12 rate was 79.2% with no marked difference in those receiving abbreviated therapy. Of note, an analysis of factors associated with treatment failure identified a natural viral variant in patients with genotype 1a HCV (Q80K) associated with a reduced response to simeprevir, and it is now suggested that such patients should not receive this drug. Given the high proportion of patients who responded with 12 weeks of simeprevir (given with 24 weeks of PegIFN and ribavirin), most treatment guidelines recommend that for Volume 27 Number 6 December 2014
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Hepatitis C genotype 1 Foster and De Silva
treatment-naive patients, therapy be discontinued after 4 weeks in patients who do not respond and only patients who show an early virological response should be treated for a total of 24 weeks. As the ASPIRE trial only included a fixed 48-week regime of PegIFN and ribavirin, partial and null responders will still need a total of 48 weeks of treatment. The nucleotide NS5B inhibitor, sofosbuvir, is a highly potent anti-HCV agent, with an excellent safety profile and a very high barrier to resistance. Two studies involving sofosbuvir with PegIFN and ribavirin have been presented (ATOMIC [18] and NEUTRINO [19]). In ATOMIC, all patients received 12 weeks of sofosbuvir with PegIFN and ribavirin and some received a further 12 weeks of PegIFN with sofosbuvir with or without ribavirin. All subgroups had similar SVR12 rate (87–89%). In the phase 3 NEUTRINO trial, involving 12 weeks of sofosbuvir with PegIFN and ribavirin, an overall SVR of 89.4% (91.6% in G1a and 81.8% in G1b) was achieved. A number of other interferon-containing regimes have been evaluated, including the use of the NS5A inhibitor, daclatasvir, and the novel protease inhibitor, MK-5172, but these regimes seem unlikely to be developed further.
INTERFERON-FREE REGIMES The potency of new direct-acting antiviral agents has led to trials of combinations of different agents given for varying lengths of time to a wide range of different patient cohorts. A large number of different agents have been tried and many trials are ongoing. Here, we will focus on the combinations that have completed phase 3 studies.
ABT450/r, ombitasvir, dasabuvir and ribavirin The PEARL, SAPPHIRE and TURQUOISE studies [20 ,21,22 ,23 ] evaluated a combination of a protease inhibitor administered with ritonavir (ABT 450/r), in addition to an NS5A inhibitor (ombitasvir) and an NS5B nonnucleotide inhibitor (dasabuvir) and ribavirin. The SAPPHIRE study involved genotype 1 treatment-naı¨ve noncirrhotic patients who received 12 weeks of treatment and achieved an SVR12 of 95.3% in G1a, and 98% in G1b. The SVR rates were above 90% in all subgroups analysed (including difficult to cure cohorts with unfavourable host and virological factors). The SAPPHIRE II studied noncirrhotic treatment-experienced patients and 96.3% achieved an SVR12 with 12-week treatment. Previous response had no effect on treatment outcomes. The TURQUOISE-II evaluated patients with Child Pugh stage A cirrhosis, who were treatment naı¨ve or treatment experienced, and 12 &
&
&
and 24 weeks therapy was evaluated. The SVR12 rates were 91.8% for 12 weeks of treatment, and 95.9% for 24 weeks of treatment. Within this trial, patients with a previous null response to treatment, who received 12 weeks of treatment, had a comparatively lower SVR12 (80%) compared to those who received 24 weeks of treatment (92.9%). The treatment was well tolerated with the commonest sideeffects, including fatigue, headache, nausea and anaemia. In patients, who had virological failure or relapse, viral resistance-associated variants were detected most frequently at the D168 (NS3) and Q30 (NS5A) sites in patients with G1a HCV.
Daclatasvir and asunaprevir Early studies with the protease inhibitor asunaprevir combined with the NS5A inhibitor daclatasvir suggested that response rates were excellent in patients with genotype 1b HCV but suboptimal in those with genotype 1a. Future trials, therefore, focussed on genotype 1b, and the HALLMARKDUAL trial [24 ] reviewed daclatasvir and asunaprevir in G1b patients for 24 weeks. The SVR rates for the treatment-naı¨ve group were 90%, 82% for previous nonresponders and 82% (192/235) for previously treatment-intolerant/ineligible patients. The commonest side-effects experienced by patients in this trial were headache, fatigue, diarrhoea, nausea and weakness. Further studies evaluating this combination with additional drugs are in progress. &
Sofosbuvir-based regimes Initially, very small-scale pilot trials [25] assessed the efficacy of 12-week treatment with sofosbuvir and ribavirin. The SVR rate in treatment-naive patients was 84%, but in patients with previously unsuccessful treatment, this fell to 10%. Increasing the duration of therapy to 24 weeks led to response rates of 68% overall. Given the promising results with short duration of sofosbuvir-based treatment regimes, a number of pilot studies were conducted with other agents. The combination of the NS5A inhibitor daclatasvir and sofosbuvir with or without ribavirin was trialled for 12 and 24 weeks in previously untreated patients, and for 24 weeks in patients with previous virological failure, including treatment with a first-generation protease inhibitor (the A1444040 trial) [26 ]. Overall, patients with G1 HCV had an SVR12 of 98%, including 99% who received 24 weeks and 97.5% in patients with 12 weeks of treatment and the addition of ribavirin appeared to confer little benefit. These data led to studies of 12-week therapy combining sofosbuvir and the alternative NS5A inhibitor ledipasvir (see later). The COSMOS trial [27 ] was a pilot study evaluating sofosbuvir and the protease inhibitor
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simeprevir for 12 or 24 weeks with or without ribavirin in two cohorts of patients. The first cohort was previous treatment nonresponders with METAVIR F0-F2 fibrosis, and the second cohort included treatment-naı¨ve and previous treatment nonresponders with METAVIR F3–4 fibrosis. The overall SVR12 for the trial was 92%, (cohort 1 with 90% and cohort 2 with 94%). The SVR rates were similar with or without ribavirin that is 91 and 95%, and for 12 and 24 weeks of treatment the SVR rates were 94 and 91%, respectively. High SVR rates were noted in patients with previous null response to treatment, non CC IL28 genotype and advanced fibrosis. Even in patients with Q80k mutations, the SVR rate was 91% with no marked difference between 12 and 24 weeks of treatment. The success of pilot studies combining sofosbuvir with an NS5A inhibitor led to the development of a coformulated, single-tablet regimen involving the novel NS5A inhibitor ledipasvir with sofosbuvir. This single-tablet regimen was assessed in the ION studies [28 ,29 ,30]. The ION-1 trial involved treatment-naive patients with genotype 1 hepatitis C, with 12 and 24 weeks treatment with or without ribavirin and response rates were 97–99% in all treatment arms. The ION-2 trial involved previous treatment nonresponders (including previous protease inhibitor exposure) who were randomized into treatment arms of 12 or 24 weeks sofosbuvir and ledipasvir with or without ribavirin. Response rates were similar for all groups with SVR12 of 96% for 12 weeks treatment with ribavirin and 94% without ribavirin. With 24 weeks of treatment, an SVR12 was 99% with ribavirin and 99% without. Cirrhotic patients had a lower SVR12 rate in the 12-week treatment arms: 86% with ledipasvir and sofosbuvir and 82% when ribavirin was added to this combination. The ION-3 trial evaluated treatment-naive noncirrhotic patients in three treatment groups given 8 or 12 weeks of ledipasvir and sofosbuvir, and 8 weeks of ledipasvir, sofosbuvir and ribavirin. The SVR12 rates were 94% with 8 weeks of ledipasvir and sofosbuvir, 95% with 12 weeks of the same combination and 93% with 12 weeks of treatment including ribavirin. No features predisposing to lower SVR12 rates were identified in this trial. The commonest side-effects in all the ION studies were fatigue, headaches, nausea and insomnia. The ION trials showed that the single-tablet regimen of sofosbuvir and ledipasvir was very well tolerated and it is likely that for treatment-naive patients without cirrhosis, the combination will be licensed for a total treatment duration of 8 weeks. A number of exploratory studies are currently underway, evaluating different regimes based upon sofosbuvir and ledipasvir. Early studies with 6 weeks &&
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of combination therapy suggested that response rates were suboptimal [31], but the SYNERGY study is underway to evaluate a fixed dose combination (sofosbuvir and ledipasvir) with a third agent [either a nonnucleotide inhibitor (GS-9669) or protease inhibitor (GS-9451). Early results are promising, and 6 weeks of treatment may be sufficient with these triple therapy regimes (SVR12 of 95 and 100% were achieved) [32].
CONCLUSION The treatment of hepatitis C has progressed rapidly over the last 24 months. The introduction of the first-generation protease inhibitors transformed the outlook for patients with genotype 1 HCV. The introduction of better-tolerated protease inhibitors will allow more patients to benefit from therapy with interferon-based regimes. However, interferon and ribavirin are poorly tolerated drugs. The extraordinary success of all oral regimes with either triplecombination regimes or dual therapy with sofosbuvir-based regimes indicates that for the vast majority of patients, a virological cure can be obtained without the need for interferon. There has been no significant benefit of adding ribavirin to many of these treatment regimes, and so therapy without interferon and ribavirin is likely to become the standard of care in the very near future. The new drugs do not require changes to treatment duration on the basis of early virological response. The combination of side-effect-free and all-tablet therapy requiring minimal monitoring offers the very real prospect of effective therapy for almost all patients with genotype 1 HCV. The only obstacle to widespread access to these new medications is their cost and the access to therapy will be greatly influenced by affordability. It is to be hoped that the increasing options available to patients with chronic HCV will lead to a reduction in the costs of therapy, allowing more patients to benefit from these recent advances. Acknowledgements None. Conflicts of interest The authors have no conflicts of interest to declare.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Choo QL, Kuo G, Weiner AJ, et al. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 1989; 244:359– 362.
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Hepatitis C genotype 1 Foster and De Silva 2. Viral Hepatitis Prevention Board. Global surveillance and control of hepatitis C. Report of a WHO Consultation organized in collaboration with the Viral Hepatitis Prevention Board, Antwerp, Belgium. J Viral Hepat 1999; 6:35–47. 3. Simmonds P, Bukh J, Combet C, et al. Consensus proposals for a unified system of nomenclature of hepatitis C virus genotypes. Hepatology 2005; 42:962–973. 4. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002; 347:975–982. 5. Poynard T, McHutchison J, Goodman Z, et al. Is an ‘a la carte’ combination interferon alfa-2b plus ribavirin regimen possible for the first line treatment in patients with chronic hepatitis C? The ALGOVIRC Project Group. Hepatology 2000; 31:211–218. 6. McHutchison JG, Poynard T, Pianko S, et al. The impact of interferon plus ribavirin on response to therapy in black patients with chronic hepatitis C. The International Hepatitis Interventional Therapy Group. Gastroenterology 2000; 119:1317–1323. 7. Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011; 364:2405– 2416. 8. Sherman KE, Flamm SL, Afdhal NH, et al. Response-guided telaprevir combination treatment for hepatitis C virus infection. N Engl J Med 2011; 365:1014–1024. 9. Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med 2011; 364:2417–2428. 10. Hezode C, Fontaine H, Dorival C, et al. Effectiveness of telaprevir or boceprevir in treatment-experienced patients with HCV genotype 1 infection and cirrhosis. Gastroenterology 2014; 147:132.e4–142.e4. 11. Poordad F, McCone J Jr, Bacon BR, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011; 364:1195–1206. 12. Bacon BR, Gordon SC, Lawitz E, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 2011; 364:1207–1217. 13. Sievert W, Buti M, Agarwal K, et al. 905 adherence with telaprevir BID vs. Q8 h dosing in treatment-naı¨ve HCV-infected patients: results from the phase III optimize study. J Hepatol 2015; 58:S373. 14. Jacobson IM, Dore GJ, Foster GR, et al. Simeprevir with pegylated interferon alfa 2a plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-1): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet 2014; 384:403–413. 15. Manns M, Marcellin P, Poordad F, et al. Simeprevir with pegylated interferon alfa 2a or 2b plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-2): a randomised, double-blind, placebocontrolled phase 3 trial. Lancet 2014; 384:414–426. 16. Zeuzem S, Berg T, Gane E, et al. Simeprevir increases rate of sustained virologic response among treatment-experienced patients with HCV genotype-1 infection: a phase IIb trial. Gastroenterology 2014; 146:430.e6–441.e6. 17. Forns X, Lawitz E, Zeuzem S, et al. Simeprevir with peginterferon and ribavirin leads to high rates of SVR in patients with HCV genotype 1 who relapsed after previous therapy: a phase 3 trial. Gastroenterology 2014; 146:1669.e3– 1679.e3. 18. Kowdley KV, Lawitz E, Crespo I, et al. 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 2013; 381:2100–2107. 19. Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013; 368:1878–1887. 20. Ferenci P, Bernstein D, Lalezari J, et al., PEARL-III Study; PEARL-IV Study. & ABT-450/r-ombitasvir and dasabuvir with or without ribavirin for HCV. N Engl J Med 2014; 370:1983–1992. Trial evaluating the all-oral combination in treatment-naı¨ve noncirrhotic genotype 1 patients for 12 weeks that identified a lower SVR in genotype 1a (90.2%) when treated without ribavirin compared to treatment with ribavirin (97.0%).
21. Feld JJ, Kowdley KV, Coakley E, et al. Treatment of HCV with ABT-450/rombitasvir and dasabuvir with ribavirin. N Engl J Med 2014; 370:1594–1603. 22. Zeuzem S, Jacobson IM, Baykal T, et al. Retreatment of HCV with ABT-450/ & r-ombitasvir and dasabuvir with ribavirin. N Engl J Med 2014; 370:1604–1614. Trial evaluating the all-oral combination in genotype 1 patients with previous treatment with pegIFN and ribavirin, achieving an overall SVR12 of 96.3% (including an SVR 12 of 95.2% in prior null responders). 23. Poordad F, Hezode C, Trinh R, et al. ABT-450/r-ombitasvir and dasabuvir with & ribavirin for hepatitis C with cirrhosis. N Engl J Med 2014; 370:1973–1982. Trial evaluating 12 or 24 weeks of treatment in Child Pugh A cirrhotic patients (with an SVR12 of 91.8% with 12 weeks, and 95.9% with 24 weeks). 24. Manns M, Pol S, Jacobson IM, et al., HALLMARK-DUAL Study Team. All-oral & daclatasvir plus asunaprevir for hepatitis C virus genotype 1b: a multinational, phase 3, multicohort study. Lancet 2014. [Epub ahead of print] Trial evaluating 12 weeks of daclatasvir and asunaprevir in genotype 1b patients. The SVR12 rates of 90% were achieved in the treatment-naı¨ve group and 82% in previous treatment failure groups. 25. Gane EJ, Stedman CA, Hyland RH, et al. Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J Med 2013; 368:34–44. 26. Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al. Daclatasvir plus && sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med 2014; 370:211–221. Trial evaluating 12 or 24 weeks of sofosbuvir and daclatasvir in treatment-naı¨ve patients (with an SVR12 of 93–100%), and 24 weeks of treatment in patient with previous treatment exposure, including those with previous treatment with firstgeneration protease inhibitors (with an SVR12 of 95 and 100% with and without ribavirin). 27. Lawitz E, Sulkowski MS, Ghalib R, et al. Simeprevir plus sofosbuvir, with or && without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in nonresponders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study. Lancet 2014. [Epub ahead of print] Trial evaluating 12 or 24 weeks of treatment with simeprevir and sofosbuvir in treatment-naı¨ve patients and pegIFN and ribavirin-experienced patients (including patients with advanced fibrosis and compensated cirrhosis). The SVR 12 rates of 90% in those with METAVIR F0-1 and 94% in those with F3-4 were achieved. The overall SVR in patients with the Q80K mutation was 91%. 28. Afdhal N, Zeuzem S, Kwo P, et al. Ledipasvir and sofosbuvir for untreated && HCV genotype 1 infection. N Engl J Med 2014; 370:1889–1898. Trial evaluating 12 or 24 weeks of sofosbuvir and ledipasvir with or without ribavirin in treatment-naı¨ve patients. An SVR12 of 97 and 99% were achieved with and without ribavirin for 12 weeks of treatment with no marked difference, with 24 weeks of treatment. 29. Afdhal N, Reddy KR, Nelson DR, et al. Ledipasvir and sofosbuvir for previously && treated HCV genotype 1 infection. N Engl J Med 2014; 370:1483–1493. Trial evaluating 12 or 24 weeks of sofosbuvir and ledipasvir with or without ribavirin in treatment-experienced patients. With 12 weeks of treatment, an SVR12 of 96 and 94% with and without ribavirin were achieved. An SVR12 was 99% with 24 weeks of treatment. An SVR12 in those with previous treatment, including firstgeneration protease inhibitors was above 93%. 30. Kowdley KV, Gordon SC, Reddy KR, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med 2014; 370:1879– 1888. 31. Gane EJ, Stedman CA, Hyland RH, et al. Efficacy of nucleotide polymerase inhibitor sofosbuvir plus the NS5A inhibitor ledipasvir or the NS5B nonnucleoside inhibitor GS-9669 against HCV genotype 1 infection. Gastroenterology 2014; 146:736.e1–743.e1. 32. Kohli A, Zayani S, Miriam M et al. Abstract 27LB combination oral, hepatitis C antiviral therapy for 6 or 12 Weeks: final results of the SYNERGY trial. 21st Conference on Retroviruses and Opportunistic Infections; 3–6 March 2014; Boston, Massachusetts.
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Hepatitis C genotype 1 Graham R. Foster and Sampath De Silva
Purpose of review To assess advances in the treatment of genotype 1 (G1 hepatitis C virus), in particular, the development of new interferon (and ribavirin)-free treatment regimes. Recent findings The treatment of hepatitis C has advanced rapidly over the last 24 months. Newer interferon-containing regimes have been developed with improved tolerability, and interferon-free regimes with outstanding efficacy and improved tolerability have been developed. Summary New treatment regimes for hepatitis C virus have significantly altered the outlook for patients with hepatitis C. New interferon-containing treatment regimes with simeprevir and sofosbuvir, which have improved response rates, have shorter treatment durations and fewer side-effects are becoming available, and interferon-free regimes have been developed. The interferon-free regimes involve multidrug combinations or two-drug combinations and offer the possibility of shorter treatment duration with 8 or 12 weeks. The efficacy of the interferon-free regimes is striking with response rates of well over 90% reported in a wide range of different patient populations. The rapid progress in the treatment of hepatitis C will hopefully result in a cure for most patients, thereby significantly decreasing the morbidity and mortality associated with hepatitis C virus infection. Keywords direct-acting antiviral agents, genotype 1, hepatitis C, interferon-free
INTRODUCTION The hepatitis C virus (HCV) was first identified in 1989 [1], and is a significant cause of chronic liver disease worldwide. Up to 170 million people may be affected (approximately 2–3% of the global population) [2]. Most patients (85%) who develop hepatitis C have chronic infection, and 20% of these individuals will develop liver cirrhosis after 20 years of infection, leading in many to significant morbidity and mortality, with hepatic decompensation, hepatocellular carcinoma, and the need for liver transplantation. Six major genotypes of hepatitis C have been identified [3], and they differ in their response to therapy. Genotype 1 is the commonest type in the USA, Europe and the east Asia and will be the focus of this review. Treatment for genotype 1 HCV infection has for many years focussed on 48-week treatment with pegylated interferon (PegIFN) and ribavirin, with response rates [defined as the proportion of patients with undetectable HCV RNA 24 weeks after treatment cessation – sustained virological response (SVR24)] approaching 50% [4]. A number of factors influence the response to interferon and ribavirin treatment and these include viral subtype (G1a), interleukin-28 genotype (non CC
genotype), ethnicity (black), advanced fibrosis or cirrhosis, and previous unsuccessful treatment all adversely affecting the response [5,6]. Over the last few years, therapy for genotype 1 HCV has been transformed by the development of direct-acting antiviral agents that synergize with interferon and ribavirin. The first drugs to be launched were the protease inhibitors (telaprevir and boceprevir), but these drugs have a relatively high side-effect burden and are now being superseded by newer protease inhibitors (simeprevir) and the nucleotide inhibitor (sofosbuvir). The development of drugs acting on different viral enzymes has allowed combination therapy to be developed that avoids the need for interferon, and the use of all-oral combination therapies has transformed the outlook for patients with genotype 1 HCV infection.
Barts and The London School of Medicine, London, United Kingdom Correspondence to Professor Graham R. Foster, The Blizard Institute, 4 Newark Street, Whitechapel, London E1 2AT, United Kingdom. Tel: +44 20 7882 2483; e-mail: [email protected],[email protected] Curr Opin Infect Dis 2014, 27:535–539 DOI:10.1097/QCO.0000000000000112
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Antimicrobials
KEY POINTS Several all-oral treatment therapies will be available for hepatitis C (genotype 1). All oral treatment has a high SVR rate even in prior treatment null responders and cirrhotic patients. The duration of HCV treatment may be shortened to 6 or 8 weeks in some patient populations.
FIRST-GENERATION PROTEASE INHIBITORS Telaprevir was assessed in three trials: ADVANCE, ILLUMINATE and REALIZE [7–9], which evaluated 12 weeks of telaprevir combined with 24 or 48 weeks of PegIFN and ribavirin. The SVR24 rates were 69 and 75% in treatment-naı¨ve patients with 24 or 48 weeks in the ADVANCE study compared to 44% with placebo, PegIFN and ribavirin. The ILLUMINATE trial showed the noninferiority of 24 weeks of treatment for patients who had an early virological response, and the REALIZE trial studied treatment-experienced patients and showed that response rates were influenced by previous treatment response, with higher SVR24 rates in previous relapsers (83–88%) compared with null responders (29–33%). The commonest side-effects with telaprevir were skin rashes, pruritus, gastrointestinal side-effects (nausea or diarrhoea) and anaemia. Subsequent studies in patients with more advanced cirrhosis have shown that over half of patients (53.8%) experienced serious adverse events [including severe infections (9.7%), hepatic decompensation (4.7%) and death (2.7%) with 29.4% stopping treatment early] [10]. Boceprevir was assessed in the SPRINT-2 and RESPOND-2 studies [11,12]. In SPRINT-2, a 4-week lead-in of PegIFN and ribavirin was followed by response-guided 24 weeks of boceprevir, PegIFN and ribavirin; or 44 weeks of all three medications for patients who did not show an early response. The SVR24 rates were 67 and 68% in these groups compared with 40% in the placebo arm. RESPOND-2 involved treatment-experienced patients and the SVR rates were 59 and 66%. Prior relapsers had better SVR rates of 69 and 75%, respectively compared with null responders, 40 and 52%, respectively. As with telaprevir, patients with advanced fibrosis had worse SVR rates (50% for treatmentnaı¨ve patients with METAVIR F3–4), as did black patients (SVR 42–53%). The commonest side-effects encountered with boceprevir were anaemia, dysgeusia, followed by nausea, diarrhoea and neutropenia. As with telaprevir, later studies showed that patients 536
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with advanced cirrhosis developed significant sideeffects at a much higher rate than seen in the pivotal trials (with 44% developing serious adverse events, including hepatic decompensation (4.2%), severe infection 3.8% and death (1.4%) [10]. The first-generation protease inhibitors transformed the management of patients with genotype 1 HCV, allowing a majority of patients to achieve an SVR. However, the treatment regimes are cumbersome (the early response to therapy needs to be assessed and the treatment duration modified to either 6 or 12 months), the drugs need to be administered three times a day and side-effects and drug interactions are problematic. Studies with telaprevir show that the dosing regime may be modified to twice daily, improving compliance [13], and the first-generation protease inhibitors remain the standard of care in many parts of the world.
NEW INTERFERON-CONTAINING REGIMES Simeprevir is a second-wave protease inhibitor, with an improved dosing schedule (once a day), reduced drug interactions and reduced side-effects compared with the first-generation protease inhibitors. It has been evaluated in a series of trials involving 12 weeks of simeprevir and 24 or 48 weeks of PegIFN and ribavirin, depending upon early response to treatment [14–17]. QUEST 1 and 2 involved treatment-naı¨ve patients, and 80–81% responded to simeprevir-based therapy compared with 50% in the control arm of PegIFN and ribavirin. High proportions of patients in both studies (85 and 91%) were eligible for 24 weeks of treatment in total and such patients had excellent response rates – SVR12 91% and 86%. In treatment-experienced patients [relapsers and null responders (ASPIRE)], two doses of simeprevir were evaluated for 12, 24 or 48 weeks along with 48 weeks of PegIFN and ribavirin, with an overall SVR24 of 65.5% for 100 mg of simeprevir and 72.9% for 150 mg of simeprevir, with no marked difference between 24 and 48 weeks of simeprevir (68.2–70.2%). The PROMISE trial involved previous relapsers with 12 weeks of simeprevir and 24 or 48 weeks of PegIFN and ribavirin. The overall SVR12 rate was 79.2% with no marked difference in those receiving abbreviated therapy. Of note, an analysis of factors associated with treatment failure identified a natural viral variant in patients with genotype 1a HCV (Q80K) associated with a reduced response to simeprevir, and it is now suggested that such patients should not receive this drug. Given the high proportion of patients who responded with 12 weeks of simeprevir (given with 24 weeks of PegIFN and ribavirin), most treatment guidelines recommend that for Volume 27 Number 6 December 2014
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Hepatitis C genotype 1 Foster and De Silva
treatment-naive patients, therapy be discontinued after 4 weeks in patients who do not respond and only patients who show an early virological response should be treated for a total of 24 weeks. As the ASPIRE trial only included a fixed 48-week regime of PegIFN and ribavirin, partial and null responders will still need a total of 48 weeks of treatment. The nucleotide NS5B inhibitor, sofosbuvir, is a highly potent anti-HCV agent, with an excellent safety profile and a very high barrier to resistance. Two studies involving sofosbuvir with PegIFN and ribavirin have been presented (ATOMIC [18] and NEUTRINO [19]). In ATOMIC, all patients received 12 weeks of sofosbuvir with PegIFN and ribavirin and some received a further 12 weeks of PegIFN with sofosbuvir with or without ribavirin. All subgroups had similar SVR12 rate (87–89%). In the phase 3 NEUTRINO trial, involving 12 weeks of sofosbuvir with PegIFN and ribavirin, an overall SVR of 89.4% (91.6% in G1a and 81.8% in G1b) was achieved. A number of other interferon-containing regimes have been evaluated, including the use of the NS5A inhibitor, daclatasvir, and the novel protease inhibitor, MK-5172, but these regimes seem unlikely to be developed further.
INTERFERON-FREE REGIMES The potency of new direct-acting antiviral agents has led to trials of combinations of different agents given for varying lengths of time to a wide range of different patient cohorts. A large number of different agents have been tried and many trials are ongoing. Here, we will focus on the combinations that have completed phase 3 studies.
ABT450/r, ombitasvir, dasabuvir and ribavirin The PEARL, SAPPHIRE and TURQUOISE studies [20 ,21,22 ,23 ] evaluated a combination of a protease inhibitor administered with ritonavir (ABT 450/r), in addition to an NS5A inhibitor (ombitasvir) and an NS5B nonnucleotide inhibitor (dasabuvir) and ribavirin. The SAPPHIRE study involved genotype 1 treatment-naı¨ve noncirrhotic patients who received 12 weeks of treatment and achieved an SVR12 of 95.3% in G1a, and 98% in G1b. The SVR rates were above 90% in all subgroups analysed (including difficult to cure cohorts with unfavourable host and virological factors). The SAPPHIRE II studied noncirrhotic treatment-experienced patients and 96.3% achieved an SVR12 with 12-week treatment. Previous response had no effect on treatment outcomes. The TURQUOISE-II evaluated patients with Child Pugh stage A cirrhosis, who were treatment naı¨ve or treatment experienced, and 12 &
&
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and 24 weeks therapy was evaluated. The SVR12 rates were 91.8% for 12 weeks of treatment, and 95.9% for 24 weeks of treatment. Within this trial, patients with a previous null response to treatment, who received 12 weeks of treatment, had a comparatively lower SVR12 (80%) compared to those who received 24 weeks of treatment (92.9%). The treatment was well tolerated with the commonest sideeffects, including fatigue, headache, nausea and anaemia. In patients, who had virological failure or relapse, viral resistance-associated variants were detected most frequently at the D168 (NS3) and Q30 (NS5A) sites in patients with G1a HCV.
Daclatasvir and asunaprevir Early studies with the protease inhibitor asunaprevir combined with the NS5A inhibitor daclatasvir suggested that response rates were excellent in patients with genotype 1b HCV but suboptimal in those with genotype 1a. Future trials, therefore, focussed on genotype 1b, and the HALLMARKDUAL trial [24 ] reviewed daclatasvir and asunaprevir in G1b patients for 24 weeks. The SVR rates for the treatment-naı¨ve group were 90%, 82% for previous nonresponders and 82% (192/235) for previously treatment-intolerant/ineligible patients. The commonest side-effects experienced by patients in this trial were headache, fatigue, diarrhoea, nausea and weakness. Further studies evaluating this combination with additional drugs are in progress. &
Sofosbuvir-based regimes Initially, very small-scale pilot trials [25] assessed the efficacy of 12-week treatment with sofosbuvir and ribavirin. The SVR rate in treatment-naive patients was 84%, but in patients with previously unsuccessful treatment, this fell to 10%. Increasing the duration of therapy to 24 weeks led to response rates of 68% overall. Given the promising results with short duration of sofosbuvir-based treatment regimes, a number of pilot studies were conducted with other agents. The combination of the NS5A inhibitor daclatasvir and sofosbuvir with or without ribavirin was trialled for 12 and 24 weeks in previously untreated patients, and for 24 weeks in patients with previous virological failure, including treatment with a first-generation protease inhibitor (the A1444040 trial) [26 ]. Overall, patients with G1 HCV had an SVR12 of 98%, including 99% who received 24 weeks and 97.5% in patients with 12 weeks of treatment and the addition of ribavirin appeared to confer little benefit. These data led to studies of 12-week therapy combining sofosbuvir and the alternative NS5A inhibitor ledipasvir (see later). The COSMOS trial [27 ] was a pilot study evaluating sofosbuvir and the protease inhibitor
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Antimicrobials
simeprevir for 12 or 24 weeks with or without ribavirin in two cohorts of patients. The first cohort was previous treatment nonresponders with METAVIR F0-F2 fibrosis, and the second cohort included treatment-naı¨ve and previous treatment nonresponders with METAVIR F3–4 fibrosis. The overall SVR12 for the trial was 92%, (cohort 1 with 90% and cohort 2 with 94%). The SVR rates were similar with or without ribavirin that is 91 and 95%, and for 12 and 24 weeks of treatment the SVR rates were 94 and 91%, respectively. High SVR rates were noted in patients with previous null response to treatment, non CC IL28 genotype and advanced fibrosis. Even in patients with Q80k mutations, the SVR rate was 91% with no marked difference between 12 and 24 weeks of treatment. The success of pilot studies combining sofosbuvir with an NS5A inhibitor led to the development of a coformulated, single-tablet regimen involving the novel NS5A inhibitor ledipasvir with sofosbuvir. This single-tablet regimen was assessed in the ION studies [28 ,29 ,30]. The ION-1 trial involved treatment-naive patients with genotype 1 hepatitis C, with 12 and 24 weeks treatment with or without ribavirin and response rates were 97–99% in all treatment arms. The ION-2 trial involved previous treatment nonresponders (including previous protease inhibitor exposure) who were randomized into treatment arms of 12 or 24 weeks sofosbuvir and ledipasvir with or without ribavirin. Response rates were similar for all groups with SVR12 of 96% for 12 weeks treatment with ribavirin and 94% without ribavirin. With 24 weeks of treatment, an SVR12 was 99% with ribavirin and 99% without. Cirrhotic patients had a lower SVR12 rate in the 12-week treatment arms: 86% with ledipasvir and sofosbuvir and 82% when ribavirin was added to this combination. The ION-3 trial evaluated treatment-naive noncirrhotic patients in three treatment groups given 8 or 12 weeks of ledipasvir and sofosbuvir, and 8 weeks of ledipasvir, sofosbuvir and ribavirin. The SVR12 rates were 94% with 8 weeks of ledipasvir and sofosbuvir, 95% with 12 weeks of the same combination and 93% with 12 weeks of treatment including ribavirin. No features predisposing to lower SVR12 rates were identified in this trial. The commonest side-effects in all the ION studies were fatigue, headaches, nausea and insomnia. The ION trials showed that the single-tablet regimen of sofosbuvir and ledipasvir was very well tolerated and it is likely that for treatment-naive patients without cirrhosis, the combination will be licensed for a total treatment duration of 8 weeks. A number of exploratory studies are currently underway, evaluating different regimes based upon sofosbuvir and ledipasvir. Early studies with 6 weeks &&
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of combination therapy suggested that response rates were suboptimal [31], but the SYNERGY study is underway to evaluate a fixed dose combination (sofosbuvir and ledipasvir) with a third agent [either a nonnucleotide inhibitor (GS-9669) or protease inhibitor (GS-9451). Early results are promising, and 6 weeks of treatment may be sufficient with these triple therapy regimes (SVR12 of 95 and 100% were achieved) [32].
CONCLUSION The treatment of hepatitis C has progressed rapidly over the last 24 months. The introduction of the first-generation protease inhibitors transformed the outlook for patients with genotype 1 HCV. The introduction of better-tolerated protease inhibitors will allow more patients to benefit from therapy with interferon-based regimes. However, interferon and ribavirin are poorly tolerated drugs. The extraordinary success of all oral regimes with either triplecombination regimes or dual therapy with sofosbuvir-based regimes indicates that for the vast majority of patients, a virological cure can be obtained without the need for interferon. There has been no significant benefit of adding ribavirin to many of these treatment regimes, and so therapy without interferon and ribavirin is likely to become the standard of care in the very near future. The new drugs do not require changes to treatment duration on the basis of early virological response. The combination of side-effect-free and all-tablet therapy requiring minimal monitoring offers the very real prospect of effective therapy for almost all patients with genotype 1 HCV. The only obstacle to widespread access to these new medications is their cost and the access to therapy will be greatly influenced by affordability. It is to be hoped that the increasing options available to patients with chronic HCV will lead to a reduction in the costs of therapy, allowing more patients to benefit from these recent advances. Acknowledgements None. Conflicts of interest The authors have no conflicts of interest to declare.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Choo QL, Kuo G, Weiner AJ, et al. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 1989; 244:359– 362.
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Hepatitis C genotype 1 Foster and De Silva 2. Viral Hepatitis Prevention Board. Global surveillance and control of hepatitis C. Report of a WHO Consultation organized in collaboration with the Viral Hepatitis Prevention Board, Antwerp, Belgium. J Viral Hepat 1999; 6:35–47. 3. Simmonds P, Bukh J, Combet C, et al. Consensus proposals for a unified system of nomenclature of hepatitis C virus genotypes. Hepatology 2005; 42:962–973. 4. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002; 347:975–982. 5. Poynard T, McHutchison J, Goodman Z, et al. Is an ‘a la carte’ combination interferon alfa-2b plus ribavirin regimen possible for the first line treatment in patients with chronic hepatitis C? The ALGOVIRC Project Group. Hepatology 2000; 31:211–218. 6. McHutchison JG, Poynard T, Pianko S, et al. The impact of interferon plus ribavirin on response to therapy in black patients with chronic hepatitis C. The International Hepatitis Interventional Therapy Group. Gastroenterology 2000; 119:1317–1323. 7. Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med 2011; 364:2405– 2416. 8. Sherman KE, Flamm SL, Afdhal NH, et al. Response-guided telaprevir combination treatment for hepatitis C virus infection. N Engl J Med 2011; 365:1014–1024. 9. Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med 2011; 364:2417–2428. 10. Hezode C, Fontaine H, Dorival C, et al. Effectiveness of telaprevir or boceprevir in treatment-experienced patients with HCV genotype 1 infection and cirrhosis. Gastroenterology 2014; 147:132.e4–142.e4. 11. Poordad F, McCone J Jr, Bacon BR, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med 2011; 364:1195–1206. 12. Bacon BR, Gordon SC, Lawitz E, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med 2011; 364:1207–1217. 13. Sievert W, Buti M, Agarwal K, et al. 905 adherence with telaprevir BID vs. Q8 h dosing in treatment-naı¨ve HCV-infected patients: results from the phase III optimize study. J Hepatol 2015; 58:S373. 14. Jacobson IM, Dore GJ, Foster GR, et al. Simeprevir with pegylated interferon alfa 2a plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-1): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet 2014; 384:403–413. 15. Manns M, Marcellin P, Poordad F, et al. Simeprevir with pegylated interferon alfa 2a or 2b plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-2): a randomised, double-blind, placebocontrolled phase 3 trial. Lancet 2014; 384:414–426. 16. Zeuzem S, Berg T, Gane E, et al. Simeprevir increases rate of sustained virologic response among treatment-experienced patients with HCV genotype-1 infection: a phase IIb trial. Gastroenterology 2014; 146:430.e6–441.e6. 17. Forns X, Lawitz E, Zeuzem S, et al. Simeprevir with peginterferon and ribavirin leads to high rates of SVR in patients with HCV genotype 1 who relapsed after previous therapy: a phase 3 trial. Gastroenterology 2014; 146:1669.e3– 1679.e3. 18. Kowdley KV, Lawitz E, Crespo I, et al. 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 2013; 381:2100–2107. 19. Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013; 368:1878–1887. 20. Ferenci P, Bernstein D, Lalezari J, et al., PEARL-III Study; PEARL-IV Study. & ABT-450/r-ombitasvir and dasabuvir with or without ribavirin for HCV. N Engl J Med 2014; 370:1983–1992. Trial evaluating the all-oral combination in treatment-naı¨ve noncirrhotic genotype 1 patients for 12 weeks that identified a lower SVR in genotype 1a (90.2%) when treated without ribavirin compared to treatment with ribavirin (97.0%).
21. Feld JJ, Kowdley KV, Coakley E, et al. Treatment of HCV with ABT-450/rombitasvir and dasabuvir with ribavirin. N Engl J Med 2014; 370:1594–1603. 22. Zeuzem S, Jacobson IM, Baykal T, et al. Retreatment of HCV with ABT-450/ & r-ombitasvir and dasabuvir with ribavirin. N Engl J Med 2014; 370:1604–1614. Trial evaluating the all-oral combination in genotype 1 patients with previous treatment with pegIFN and ribavirin, achieving an overall SVR12 of 96.3% (including an SVR 12 of 95.2% in prior null responders). 23. Poordad F, Hezode C, Trinh R, et al. ABT-450/r-ombitasvir and dasabuvir with & ribavirin for hepatitis C with cirrhosis. N Engl J Med 2014; 370:1973–1982. Trial evaluating 12 or 24 weeks of treatment in Child Pugh A cirrhotic patients (with an SVR12 of 91.8% with 12 weeks, and 95.9% with 24 weeks). 24. Manns M, Pol S, Jacobson IM, et al., HALLMARK-DUAL Study Team. All-oral & daclatasvir plus asunaprevir for hepatitis C virus genotype 1b: a multinational, phase 3, multicohort study. Lancet 2014. [Epub ahead of print] Trial evaluating 12 weeks of daclatasvir and asunaprevir in genotype 1b patients. The SVR12 rates of 90% were achieved in the treatment-naı¨ve group and 82% in previous treatment failure groups. 25. Gane EJ, Stedman CA, Hyland RH, et al. Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J Med 2013; 368:34–44. 26. Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al. Daclatasvir plus && sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med 2014; 370:211–221. Trial evaluating 12 or 24 weeks of sofosbuvir and daclatasvir in treatment-naı¨ve patients (with an SVR12 of 93–100%), and 24 weeks of treatment in patient with previous treatment exposure, including those with previous treatment with firstgeneration protease inhibitors (with an SVR12 of 95 and 100% with and without ribavirin). 27. Lawitz E, Sulkowski MS, Ghalib R, et al. Simeprevir plus sofosbuvir, with or && without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in nonresponders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study. Lancet 2014. [Epub ahead of print] Trial evaluating 12 or 24 weeks of treatment with simeprevir and sofosbuvir in treatment-naı¨ve patients and pegIFN and ribavirin-experienced patients (including patients with advanced fibrosis and compensated cirrhosis). The SVR 12 rates of 90% in those with METAVIR F0-1 and 94% in those with F3-4 were achieved. The overall SVR in patients with the Q80K mutation was 91%. 28. Afdhal N, Zeuzem S, Kwo P, et al. Ledipasvir and sofosbuvir for untreated && HCV genotype 1 infection. N Engl J Med 2014; 370:1889–1898. Trial evaluating 12 or 24 weeks of sofosbuvir and ledipasvir with or without ribavirin in treatment-naı¨ve patients. An SVR12 of 97 and 99% were achieved with and without ribavirin for 12 weeks of treatment with no marked difference, with 24 weeks of treatment. 29. Afdhal N, Reddy KR, Nelson DR, et al. Ledipasvir and sofosbuvir for previously && treated HCV genotype 1 infection. N Engl J Med 2014; 370:1483–1493. Trial evaluating 12 or 24 weeks of sofosbuvir and ledipasvir with or without ribavirin in treatment-experienced patients. With 12 weeks of treatment, an SVR12 of 96 and 94% with and without ribavirin were achieved. An SVR12 was 99% with 24 weeks of treatment. An SVR12 in those with previous treatment, including firstgeneration protease inhibitors was above 93%. 30. Kowdley KV, Gordon SC, Reddy KR, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med 2014; 370:1879– 1888. 31. Gane EJ, Stedman CA, Hyland RH, et al. Efficacy of nucleotide polymerase inhibitor sofosbuvir plus the NS5A inhibitor ledipasvir or the NS5B nonnucleoside inhibitor GS-9669 against HCV genotype 1 infection. Gastroenterology 2014; 146:736.e1–743.e1. 32. Kohli A, Zayani S, Miriam M et al. Abstract 27LB combination oral, hepatitis C antiviral therapy for 6 or 12 Weeks: final results of the SYNERGY trial. 21st Conference on Retroviruses and Opportunistic Infections; 3–6 March 2014; Boston, Massachusetts.
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