SVR Updates from the 2013 EASL

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1 Updates from the 2013 EASL By Tracy Swan, Treatment Action Group Streamlining HCV Treatment Treatment for hepatitis C virus (HCV) is becoming simpler, shorter, and more effective. All-oral combinations of direct-acting antivirals (DAAs) have pushed cure rates in HCV genotype 1 to over 90 percent. Still, we are far from having a singletablet regimen (STR) suitable for everyone. Peginterferon-free treatment is less effective against HCV genotype 3, and very little is known about treating genotypes 4, 5, and 6 with DAAs. More information is needed on the safety, efficacy and tolerability of DAAs in those likely to be prioritized for HCV treatment. Despite dozens of ongoing trials, data on DAA-based regimens in people with cirrhosis especially those who are treatmentexperienced are limited. As of May 2013, there was only one peginterferon-free trial available to people coinfected with HIV and HCV. The next direct-acting antivirals likely to be approved are simeprevir, a protease inhibitor, and, a nucleotide polymerase inhibitor. These drugs have been studied with peginterferon and ribavirin, and in various peginterferon-free regimens, with and without ribavirin. Although simeprevir and are likely to be used in different ways than those for which they were developed, both drugs were highly effective in combination with peginterferon and ribavirin, either in fixed- duration or response-guided regimens. Response-guided treatment with 12 weeks of simeprevir plus peginterferon and ribavirin (24 or 48 weeks) cured 80 percent of participants in QUEST-1 and QUEST-2, trials in treatment-naive people with HCV genotype 1; most were treated for only 24 weeks. HCV Genotype 1, Treatment-Naive Peginterferon-free and peginterferon-sparing combinations have been highly effective against HCV genotype 1, regardless of viral subtype, IL28B genotype, and hepatitis C viral load. With these regimens, treatment duration is fixed (rather than response-guided); most are taken for 12 weeks. Extending treatment to 24 weeks does not appear to increase cure rates. After 12 weeks of treatment, 56 percent to 100 percent of participants in clinical trials were cured; most regimens yielded cure rates of at least 80 percent. (See table 1, in HCV Genotype 1, Treatment- Naive: Interferon-Free Regimens.) Although has become a backbone for many peginterferon-free regimens, the initial indication in genotype 1 (and genotype 4) is for 12 weeks in combination with peginterferon and ribavirin. With this regimen, cure rates reached 1

2 89 percent (and 80 percent in people with cirrhosis). (See table 2, in HCV Genotype 1, Treatment-Naive: Interferon-Sparing Regimens.) Table 1. in HCV Genotype 1, Treatment-Naive: Interferon-Free Regimens Study/Drug Population/ Treatment Arms Overall HCV Subtype: 1a vs. 1b IL28B: CC vs. non-cc AVIATOR ABT-450/r +/- ABT-267 +/- ABT-333 +/- RBV AbbVie AI daclatasvir + +/- RBV BMS/ AI daclatasvir + asunaprevir + BMS BMS ELECTRON ELECTRON FDC: / ledpiasvir (N=571) (N=126) (N=32) (N=25) (N=25) 8-week, 4-drug, 3-drug (no ABT-267), 3-drug (no ABT-333), 3-drug -24: 88% 83% 89% 87%, 4-drug 96% 24-week, 4 drug 90% 24-week, 2-drug (7-day lead-in, no RBV) 24-week, 2-drug -24: 93% 24-week, 3-drug, 2-drug -12:, 3-drug -12: -24: 94% 24-week 88% -24: 84% -12: Overall: 91% vs. 98% Overall: 95% vs. 89% 2

3 Study/Drug Population/ Treatment Arms ELECTRON + GS-9669 (N=25) Overall 12- week -12: 92% HCV Subtype: 1a vs. 1b IL28B: CC vs. non-cc LONESTAR + ledipasvir +/- RBV SPARE + weight-based (WB) or low-dose (LD) RBV National Institutes of Health/ QUANTUM (N=60) (N=10) All stages fibrosis (N=50); advanced fibrosis/ compensated cirrhosis (13/50) (N=50); 6% cirrhotic 8-week, 2-drug 8-week, 3-drug, 2-drug 24-week, WB RBV 24-week, WB RBV 24-week, LD RBV -8: 95% -8: -4: -24: 90% -12: 68% -12: 48% (most participants were HCV genotype 1a, non-cc IL28B, high baseline HCV RNA, and African American) -12: vs. 42% 56% 24-week 52% 67% vs. 47% Sources: Everson GT, Simms KD, Rodriguez-Torres M, et al. An interferon-free, ribavirin-free, regimen of daclatasvir (DCV), asunaprevir (ASV) and BMS yielded -4 of 94% in treatment-naive patients with genotype (GT) 1 chronic hepatitis C virus (HCV) infection (abstract LB-3). Paper presented at: 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD); 2012 November 9-13; Boston, Massachusetts. Everson GT, Simms KD, Rodriguez-Torres M, et al. Interim analysis of an interferon (IFN)-and ribavirin-(rbv) free regimen of daclatasvir (DCV), asunaprevir (ASV) and BMS in treatment-naive, hepatitis C virus genotype 1-infected patients (abstract 1423). Paper presented at: 48 th Annual Meeting of the European Association for the Study of the Liver (EASL); April 24-28; Amsterdam, the Netherlands. Gane EJ, Stedman CA, Hyland RH, et al. Nucleotide polymerase inhibitor plus ribavirin for hepatitis C. N Engl J Med Jan 3;368(1): doi: /NEJMoa

4 Gane EJ, Stedman CA, Hyland RH, Ding X, Pang PS, Symmonds WT. ELECTRON: rates for once-daily plus ledipasvir plus ribavirin given for 12 weeks in treatment-naive and previously treated patients with HCV genotype 1 (abstract 41 LB). Paper presented at: 20 th Conference on Retroviruses and Opportunistic Infections (CROI); March 3 rd 6 th ; Atlanta, Georgia. Abstract available from: (Accessed on April 15, 2013). Gane EJ, Stedman CA, Hyland RH, et al. All-oral -based regimens for the treatment of chronic HCV GT1 infection: the ELECTRON study (abstract 14). Paper presented at: 48 th Annual Meeting of the European Association for the Study of the Liver (EASL); April 24-28; Amsterdam, the Netherlands. Sciences (Press release). reports interim data from phase 2 LONESTAR study. May 2, Available from: on May 2, 2013). King M, Xie W, Larsen L, Cohen D, Podsadecki, T, Bernstein B. Risk of virologic relapse in hepatitis C virus GT1-infected subjects after 8, 12, and 24 weeks of ABT-450/r+ABT-267+ABT- 333+ribavirin: identifying optimal treatment duration (abstract 39). Paper presented at: 20 th Conference on Retroviruses and Opportunistic Infections (CROI); March 3-6; Atlanta, Georgia. Abstract available from: (Accessed on April 15, 2013) Kowdley KV, Lawitz E, Poordad F, et al. A interferon-free treatment regimen with ABT- 450/r, ABT-267, ABT-333 and ribavirin achieves -12 rates of 99% in treatment-naive patients and 93% in prior null responders with HCV genotype 1 infection (abstract LB-1). Paper presented at: 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD); November 9-13; Boston, Massachusetts. Kowdley KV, Lawitz E, Poordad F, et al. Safety and efficacy of interferon-free regimens of ABT-450/r, ABT-267, ABT-333 +/- ribavirin in patients with chronic HCV genotype 1: results from the AVAITOR study (abstract 3). Paper presented at: 48 th Annual Meeting of the European Association for the Study of the Liver (EASL); April 24-28; Amsterdam, the Netherlands. Lalazeri JP, Nelson DR, Hyland RH, et al. Once-daily plus ribavirin given for 12 or 24 weeks in treatment-naïve patients with HCV: the QUANTUM study (abstract 845). Paper presented at: 48 th Annual Meeting of the European Association for the Study of the Liver (EASL); April 24-28; Amsterdam, the Netherlands. Osinusi A, Meissner EG, Bon D, et al; NIAID SPARE Study Team. High efficacy of in combination with weight-based ribavirin for 24 weeks in difficult to treat HCV infected genotype-1 patients (abstract 157-LB) Paper presented at: 20 th Conference on Retroviruses and Opportunistic Infections (CROI); March 3-6; Atlanta,Georgia. Available from: retroconference.org/abstractsearch/default2.aspx?conf=22. (Accessed on May 2, Sulkowski MS, Gardnier DF, Rodriguez-Torres M, et al; for the AI Study Group. High rate of sustained virologic response with the all-oral combination of daclatasvir (NS5A inhibitor) plus (nucleotide NS5B inhibitor), with or without ribavirin, in treatment-naive patients chronically infected with HCV GT 1, 2, or 3 (abstract LB-2) Paper presented at: 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD); 2012 November 9-13; Boston, Massachusetts. 4

5 Table 2. in HCV Genotype 1, Treatment-Naive: Interferon-Sparing Regimens Study/Drug ATOMIC + PEG-IFN/ RBV NEUTRINO + PEG-IFN/ RBV I Population/ (N=316) N=291; 17% cirrhotic Treatment Arms, 3-drug Overall -24: 89% 24-week 89%, 3-drug, + SOF or SOF/RBV 87% -12: Cirrhotic: 80% Noncirrhotic: 92% HCV Subtype: 1a vs. 1b IL28B: CC vs. non-cc Not reported; 10/11 relapsers had non-cc genotype 92% vs. 82% 98% vs. 87% Sources: 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 Mar 14. Available from: com/journals/lancet/article/piis (13) /fulltext. (Accessed on April 20, 2013). Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for Previously Untreated Chronic Hepatitis C Infection. N Engl J Med Apr 23. Available from: NEJMoa (Accessed on May 2, 2013). HCV Genotype 1, Treatment-Experienced Trials of quad two DAAs plus peginterferon and ribavirin, or response-guided therapy are gradually being supplanted by peginterferon-free regimens in treatment-experienced people. Proof-of-concept can be quickly demonstrated in prior null responders, since what cures a null responder especially one with cirrhosis is likely to be even more effective for treatment-naive people. Re-treatment with a 12-or 24-week regimen of two, three, four, or five drugs is being explored in treatment-experienced people with HCV genotype 1. Most trials have been conducted in people who were unsuccessfully treated with peginterferon and ribavirin, but two regimens ( and an NS5a inhibitor [either daclatasvir or ledipasvir], with or without ribavirin) have been studied in people who were unsuccessfully treated with peginterferon, ribavirin, and an HCV protease inhibitor. 5

6 Cure rates have ranged from a dismal 11 percent to 100 percent; most regimens have cured around 90 percent of treatment-experienced trial participants (the majority with poor prognostic factors: IL28B CT or TT genotype, HCV genotype 1a, and high hepatitis C viral loads). (See table 3, in HCV Genotype 1, Treatment- Experienced: Interferon-Free Regimens.) Table 3. in HCV Genotype 1, Treatment-Experienced: Interferon-Free Regimens Study/Drug Population/ Treatment Arms Overall HCV Subtype: 1a vs. 1b IL28B: CC vs. non-cc AVIATOR ABT-450/r + ABT-267 +/- ABT-333, null responders (N=133), 3-drug (no ABT-333) -24: 89%, 4-drug 93% 24-week, 4 drug 95% 93% vs. 97% 94% vs. AbbVie AI daclatasvir + +/- RBV, prior boceprevir or telaprevir use (N=41) 24-week, 2-drug -12: 24-week, 3-drug BMS/ COSMOS (Interim data) simeprevir + ± RBV, null responders (N=80) non-cc genotype 12 weeks, 2 drugs 12 weeks, 3 drugs -8: 92.9% (13/14) 96.3% (26/27) N/A Janssen/ 24 weeks, 2 drugs 24 weeks, 3 drugs (5/5) 66.7% (4/6) ELECTRON, null responders (N=10) -24: 11% ELECTRON FDC: / ledipasvir, null responders (N=10) -4: 6

7 Study/Drug LONESTAR (Interim data) + ledipasvir +/- RBV QUANTUM (Retreatment) Sciences Population/. prior boceprevir or telaprevir use (N=40) N=105; 10% cirrhotic in control or discontinued arms Treatment Arms, 2-drug, 3-drug 24-week, 2-drug retreatment Overall -4: 95% -4: 95% -12: 66% HCV Subtype: 1a vs. 1b IL28B: CC vs. non-cc 71% vs. 48% 84% vs. 63% Sources: Gane EJ, Stedman CA, Hyland RH, et al. Nucleotide polymerase inhibitor plus ribavirin for hepatitis C. N Engl J Med Jan 3;368(1): doi: /nejmoa Gane EJ, Stedman CA, Hyland RH, Ding X, Pang PS, Symmonds WT. ELECTRON: rates for once-daily plus ledipasvir plus ribavirin given for 12 weeks in treatment-naive and previously treated patients with HCV genotype 1 (abstract 41 LB). Paper presented at: 20 th Conference on Retroviruses and Opportunistic Infections (CROI); March 3 rd 6 th ; Atlanta, Georgia. Abstract available from: (Accessed on April 21, Gane EJ, Stedman CA, Hyland RH, et al. ELECTRON: all-oral -based regimens for the treatment of chronic HCV GT1 infection (abstract 14) Paper presented at: 48 th Annual Meeting of the European Association for the Study of the Liver (EASL); April 24-28; Amsterdam, the Netherlands. Sciences (Press release). reports interim data from phase 2 LONESTAR study. May 2, Available from: (Accessed on May 2, 2013). Kowdley KV, Lawitz E, Poordad F, et al. Safety and efficacy of interferon-free regimens of ABT-450/r, ABT-267, ABT-333 +/- ribavirin in patients with chronic HCV genotype 1: results from the AVIATOR study (abstract 3). Paper presented at: 48 th Annual Meeting of the European Association for the Study of the Liver (EASL); April 24-28; Amsterdam, the Netherlands. Lawitz E, Ghalib R, Rodriguez-Torres M, et al. Suppression of viral load through 4 weeks posttreatment: results of a once-daily regimen of simeprevir + with or without ribavirin in hepatitis C virus GT1 null repsonders (abstract 155 LB). Paper presented at: 20 th Conference on Retroviruses and Opportunistic Infections (CROI); March 3 rd 6 th ; Atlanta, Georgia. Abstract available from: (Accessed on April 18, 2013). 7

8 Lalazeri JP, Nelson DR, Hyland RH, et al. Once-daily plus ribavirin given for 12 or 24 weeks in treatment-naïve patients with HCV: the QUANTUM study (abstract 845). Paper presented at: 48 th Annual Meeting of the European Association for the Study of the Liver (EASL); April 24-28; Amsterdam, the Netherlands. Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al. Sustained virologic response with daclatasvir plus ± ribavirin (RBV) in chronic HCV genotype (GT) 1-infected patients who previously failed telaprevir (TVR) or boceprevir (BOC) (abstract 1417 ) Paper presented at: 48 th Annual Meeting of the European Association for the Study of the Liver (EASL); April 24-28; Amsterdam, the Netherlands. HCV Genotypes 2 and 3 Until the DAA era, genotypes 2 and 3 were considered easily cured. Indeed, it is easy to cure genotype 2, regardless of cirrhosis or prior treatment failure. But HCV genotype 3 is proving to be a challenge. Only one peginterferon-free regimen plus daclatasvir, with or without ribavirin has yielded cure rates above 65 percent, after 24 weeks of treatment. Adding peginterferon to a course of and ribavirin seems to boost cure rates. Adding peginterferon to and ribavirin for 4 or 8 weeks pushed cure rates to 100 percent in HCV genotype 3. (See table 4, in HCV Genotypes 2 and 3.) Table 4. in HCV Genotypes 2 and 3 Study/Drugs AI daclatasvir + +/ RBV BMS/ COMMAND GT 2/3 daclatasvir + PEG-IFN/RBV vs. placebo + PEG-IFN/ RBV BMS Population/ Treatment-naive, non-cirrhotic (N = 44) Treatment-naive, 20% cirrhotic (G3 only) (N = 151) Genotype Genotypes 2 & 3 Treatment Arms 24-week, 2-drug -24: 88% (7-day lead-in, no RBV) 24-week, 2-drug -24: 24-week, 3-drug -24: 93% Genotype 2-24: 88% 16-week -24: 83% placebo -24:: 63% Genotype 3-24: 69% 16-week -24: 70% placebo -24: 59% 8

9 Study/Drugs ELECTRON + 0, 4, 8, or 12 weeks of PEG-IFN vs. monotherapy FISSION vs. PEG-IFN/RBV I Population/ Treatment-naive, non-cirrhotic (N = 60) Treatment-naive, 20% cirrhotic (N = 499) Genotype Treatment Arms Genotypes 2 & 3 8-week, 3-drug -24:, with -24: 4-week PEG-IFN, with -24: 8-week PEG-IFN, 3-drug -24:, -24: no PEG-IFN, -24: 60% only Genotype 2 Genotype 3 24-week PEG-IFN/RBV -12: 97% Cirrhotic: 91% : 98% -12: 78% Cirrhotic: 62% : 82% -12: 56% Cirrhotic: 34% : 61% FUSION I POSITRON I Treatmentexperienced, 34% cirrhotic (N = 201) Treatment naive, interferon-ineligible, -intolerant, and -unwilling; 15% cirrhotic (N = 207) 24-week PEG-IFN/RBV -12: 63% Cirrhotic: 30% : 71% Genotype 2-12: 86% Cirrhotic: 60% : 96% 16-week -12: 94% Cirrhotic: 78% : Genotype 3-12: 30% Cirrhotic: 19% : 37% 16-week -12: 62% Cirrhotic: 61% : 63% Genotype 2-12: 93% Cirrhotic: 94% : 92% Genotype 3-12: 61% Cirrhotic: 21% : 68% 9

10 Study/Drugs Population/ Treatment-naive, non-cirrhotic (N = 25) Genotype Treatment Arms -12: 92% PROTON + PEG-IFN/RBV Genotypes 2 and 3 Sources: Dore GJ, Lawitz E, Hézode C, et al. Daclatasvir combined with peginterferon alfa-2a and ribavirin for 12 or 16 weeks in patients with hepatitis C virus genotype 2 or 3 infection: COMMAND GT 2/3 study (Abstract 1418). Paper presented at: 48th Annual Meeting of the European Association for the Study of the Liver; 2013 April 24 28; Amsterdam, the Netherlands. Gane EJ, Stedman CA, Hyland RH, et al. Nucleotide polymerase inhibitor plus ribavirin for hepatitis C. N Engl J Med Jan 3;368(1): doi: /NEJMoa Jacobson IM, Gordon SC, Kowdley KV, et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. N Engl J Med Apr 23. Available from: full/ /nejmoa (Accessed 2013 May 3) Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med Apr 23. Available from: Moa (Accessed 2013 May 3). Lawitz E, Lalezari JP, Hassanein T, et al. 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 May;13(5): doi: /S (13) HCV Genotypes 4, 5, and 6 Ongoing trials are exploring different regimens in HCV genotype 4. Final data are available in HCV genotype 4 after 12 or 24 weeks of treatment with plus peginterferon and ribavirin. Only 39 people with HCV genotype 4 were treated; cure rates were 82 percent after 24 weeks and 96 percent after 12 weeks. To date,, peginterferon and ribavirin is the only regimen to have been studied in HCV genotypes 5 and 6 albeit in only 13 people, one with genotype 5. (See table 5, in HCV Genotype 4,5, and 6, Treatment-Naive: Interferon- Sparing Regimens.) 10

11 in HCV Genotype 4,5, and 6, Treatment-Naive: Interferon-Sparing Regimens Study/Drug Population HCV Genotype/ ATOMIC + PEG-IFN/RBV NEUTRINO Sofosbuvir + PEG-IFN/RBV I Genotype 4 (N=11) Genotype 6 (N=6) Liver histology not available Genotype 4 (N=28) Genotype 5 (N=1) Genotype 6 (N=6) Duration 24-week -24: 82% -24: 82% -12: 96% -12: -12: Sources: 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 Mar 14. Available from: com/journals/lancet/article/piis (13) /fulltext. (Accessed on April 20, 2013). Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for Previously Untreated Chronic Hepatitis C Infection. N Engl J Med Apr 23. Available from: NEJMoa (Accessed on May 2, 2013).

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