Management of Chronic Hepatitis C in 2013 John M. Vierling, M.D., F.A.C.P. Professor of Medicine and Surgery Chief of Hepatology Director of Advanced Liver Therapies Baylor College of Medicine St. Luke’s Medical Center Houston, Texas HCC, hepatocellular carcinoma; SVR, sustained virologic response.

Management of Chronic Hepatitis C in 2013 I would rather donate all of my organs right now than hear another talk about currently approved therapies for chronic hepatitis C. True False HCC, hepatocellular carcinoma; SVR, sustained virologic response.

HCV Infection a Global Problem: 170 M Persons Hepatitis C Death Rates Per 100,000 www.worldlifeexpectancy.com

Chronic Hepatitis C: A Treatable Disease HCV infection Chronic in 70-85% and progressive in substantial proportion Complications increasingly common[1,2] Decompensated cirrhosis Hepatic failure HCC 3-7% per year in cirrhotics Treatment resulting in SVR Eradication of HCV infection (cure) Results in histologic improvement and regression of fibrosis[3] Reduces risk of hepatic failure and HCC Improves survival[4,5] HCC, hepatocellular carcinoma; SVR, sustained virologic response. 1. Kanwal F, et al. Gastroenterology. 2011;140:1182-1188. 2. Shaw JJ, et al. Expert Rev Gastroenterol Hepatol. 2011;5:365-370. 3. Poynard T, et al. Gastroenterology. 2002;122:1303-1313. 4. Craxi A, et al. Clin Liver Dis. 2005;9:329-346. 5. Shiratori Y, et al. Ann Intern Med. 2005;142:105-114.

Cirrhosis: Treat Before Decompensation! Survival Probability Compensated 100 After first major complication 80 60 Patients (%) 40 20 HCV, hepatitis C virus.   12 24 36 48 60 72 84 96 108 120 Mos 384 65 376 39 342 21 288 11 236 7 165 4 126 4 79 3 52 3 39 2 25 1 Pts at Risk, n Fattovich G, et al. Gastroenterology. 1997;112:463-472.

Patients With Liver Complications (%) Liver-Related Complications Decrease Following SVR in Cirrhotic Patients No SVR 100 SVR 80 60 Patients With Liver Complications (%) 40 20 SVR, sustained virologic response. 24 48 72 96 120 144 168 Mos 759 124 702 119 634 116 527 108 345 70 207 41 34 12 Pts at Risk, n Bruno S, et al. Hepatology. 2007;45:579-587.

Probability of decompensation Compensated Cirrhosis: HVPG  10 mmHg is the strongest predictor of decompensation 0.2 0.4 0.6 0.8 1.0 Probability of decompensation (ascites, VH, HE) 80 20 100 40 60 Months Baseline HVPG ≥10mmHg Baseline HVPG <10mmHg Log rank test: p<0.01 HR 3.95 (2.29–6.83) Ripoll et al (Timolol Study Group). Gastroenterology 2007; 133:481-488.

* Almost immediately after completing AVT HCV Antiviral Therapy Decreases HVPG in Patients with Advanced Fibrosis or Cirrhosis with Portal Hypertension (n=20) 9/11 patients with HVPG ≥ 12 mmHg had a reduction >20% or to <12 mmHg HVPG reduction superior in virological and biochemical responders at EOT * * Almost immediately after completing AVT Rincon et al. Am J Gastroenterol 2006;101:2269–2274.

Compensated Cirrhosis: Reduction in HVPG >10% at one-year prevents development of varices 12 60 24 72  HVPG > 10%  HVPG  10% % Free of varices Months 100 80 40 20 36 48 p=0.014 Groszmann, Garcia-Tsao, Bosch et al. N Engl J Med 2005, 353:2254-2261.

SVR is Meaningful Clinical Endpoint SVR= endpoint of successful HCV treatment Defined as undetectable serum HCV RNA levels 24 wks after end of treatment Represents a cure SVR associated with significant reductions of HCV-associated complications and mortality[1,2] SVR better No SVR better Genotype 1 P < .0001 Genotype 2 P = .004 Genotype 3 P < .0001 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 All-Cause Mortality HR (95% CI) Morgan TR, et al. Hepatology. 2010;52:833-844. 2. Backus L, et al. 2010 AASLD. Abstract 213.

Management of Chronic Hepatitis C in 2013 SVR after antiviral therapy for HCV infection: Represents a cure Reduces liver-related mortality Reduces all-cause mortality Needs to be better understood by Dr. Goss All of the above HCC, hepatocellular carcinoma; SVR, sustained virologic response.

For HCV Genotype 2 or 3, PegIFN/RBV Current Standard of Care Higher SVR rates than genotype 1 24 wks of therapy recommended[1,2] Patients with RVR and low baseline HCV RNA can be treated for 16 wks Relapse rates may be higher[2] Future regimens may offer further improvements, such as Shorter durations All-oral therapy Fewer adverse events PegIFN, peginterferon; RBV, ribavirin; RVR, rapid virologic response. 1. Ghany MG, et al. Hepatology. 2011;54:1433-1444. 2. EASL. J Hepatol. 2011;55:245-264.

Addition of BOC or TVR to Peg-IFN/RBV Improved SVR in Genotype 1 Patients BOC and TVR each indicated in combination with pegIFN/RBV for genotype 1 HCV patients who are previously untreated or who have failed previous therapy 100 PegIFN + RBV 69-83 80 BOC/TVR + pegIFN* + RBV 63-75 40-59 60 SVR (%) 38-44 29-40 40 24-29 BOC, boceprevir; pegIFN, peginterferon; RBV, ribavirin; SVR, sustained virologic response; TVR, telaprevir. 20 7-15 5 Treatment Naive[1,2] Relapsers[3,4] Partial Responders[3,4] Null Responders[4,5] *BOC was administered with pegIFN-α2b; TVR was administered with pegIFN-α2a in these trials. 1. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 2. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 3. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. 4. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428. 5. Bronowicki JP, et al. EASL 2012. Abstract 11.

BOC and TVR Potential for Multiple Drug–Drug Interactions Strong inhibitor of CYP3A4/5 Partly metabolized by CYP3A4/5 Potential inhibitor of and substrate for P-gp Most drug–drug interactions can be overcome by careful survey of the patient’s medications and judicious substitutions during HCV therapy (or just during the period of PI-based triple therapy) TVR Substrate of CYP3A Inhibitor of CYP3A Substrate and inhibitor of P-gp BOC, boceprevir; P-gp, P-glycoprotein; PI, protease inhibitor; TVR, telaprevir.

SPRINT-2: Influence of Baseline Patient and Virus Factors on SVR With BOC/PR BOC + pegIFN-α2b/RBV RGT BOC + pegIFN-α2b/RBV 48 wks 93/ 133 89/ 134 100 50 1b 1a Genotype[1] 70 66 ≤ 800,000 > 800,000 HCV RNA (IU/mL)[1] 85 76 F0-2 F3/F4 Fibrosis[1] 67 SVR (%) 75 25 41/ 54 45/ 53 213/ 319 211/ 313 n/ N = 63 59 61 41 52 118/ 187 106/ 179 14/ 34 22/ 42 192/ 314 197/ 313 44/ 55 82/ 115 26/ 44 CC CT TT 80 71 IL28B[2] BOC, boceprevir; HCV, hepatitis C virus; pegIFN, peginterferon; RBV, ribavirin; RGT, response-guided therapy; SVR, sustained virologic response. 1. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 2. Poordad F, et al. Gastroenterology. 2012;143:608-618.

ADVANCE: Influence of Baseline Patient and Virus Factors on SVR With TVR Data from TVR12 + pegIFN-α2a/RBV arm only 100 90 79 78 78 74 73 71 71 75 62 SVR (%) 50 25 HCV, hepatitis C virus; pegIFN, peginterferon; RBV, ribavirin; SVR, sustained virologic response; TVR, telaprevir. n/ N = 118/ 149 152/ 213 64/ 82 207/ 281 226/ 290 45/ 73 45/ 50 48/ 68 16/ 22 1b 1a Genotype[1] < 800,000 ≥ 800,000 HCV RNA (IU/mL)[1] F0-2 F3/F4 Fibrosis[1] CC CT TT IL28B*[2] *IL28B testing was in whites only. 1. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 2. Jacobson IM, et al. EASL 2011. Abstract 1369.

Challenging Patients with Suboptimal Current Treatment Options Cirrhosis (all genotypes) Decompensated cirrhosis Null responders Pre-transplantation Post-transplantation Chronic Renal failure Impaired renal function Dialysis Renal transplantation recipients Injection-drug users Methadone substitution Thalassemics Children IFN contraindicated IFN intolerant Those with poor social support Psychiatric comorbidities HCV, hepatitis C virus; IV, intravenous; PI, protease inhibitor.

HCV Antivirals New Studies Using Current Therapies

CONCISE: Telaprevir + P/R for Patients with HCV GT 1 and IL28B CC Interim analysis of ongoing, multicenter, randomized, active-controlled, exploratory phase IIIb study Wk 12 Wk 24 T12/PR12 Stop all treatment (n = 107) Treatment-naive patients or previous relapsers with GT 1 HCV, IL28B CC genotype, and no cirrhosis (N = 239) Telaprevir + P/R 2:1 randomization* BOC, boceprevir; GT, genotype; HCV, hepatitis C virus; P/R, peginterferon/ribavirin; RVR, rapid virologic response; T, telaprevir. Stefan Zeuzem, MD: The CONCISE study is part of the phase IIIb program for telaprevir. This interim analysis of the ongoing, multicenter, randomized, active-controlled, exploratory study is evaluating whether noncirrhotic patients with the IL28B CC genotype who are infected with genotype 1 HCV can receive a shortened therapy duration of a total of 12 weeks. This trial was based on a retrospective post hoc analysis of the large phase II PROVE-2 study,[1] which showed that patients with the IL28B CC genotype had high SVR rates with telaprevir plus peginterferon/ribavirin for 12 weeks.   Reference 1. Hézode C, Forestier N, Dusheiko G, et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med. 2009;360:1839-1850. T12/PR24 Continue P/R alone (n = 52) *Patients with RVR randomly assigned 2:1 to T12/PR12 or T12/PR24. Nelson DR, et al. EASL 2013. Abstract 881.

CONCISE: Virologic Responses TVR12/PR12 vs. TVR12/PR24 after eRVR T12/PR12 T12/PR24 99 98 100 97 100 89 87 80 60 Patients (%) 40 20 105/ 106 51/ 52 93/ 104 38/ 38 74/ 85 29/ 30 n/N = eRVR, extended rapid virologic response; GT, genotype; HCV, hepatitis C virus; PR, peginterferon/ribavirin; RVR, rapid virologic response; SVR, sustained virologic response; T, telaprevir; TVR, telaprevir.   Stefan Zeuzem, MD: The interim efficacy data from CONCISE show that a 12-week regimen of telaprevir plus peginterferon/ribavirin in patients with the IL28B CC genotype resulted in an SVR rate of 87%. Among patients randomized to the standard of care—24 weeks of therapy—the SVR rate was 97%. Although the numbers are small and no statistical analysis was performed, there is a trend suggesting that although the outcome with 12 weeks of therapy was excellent, the SVR rate was even better with 24 weeks of treatment. In my experience, patients typically are very reluctant to shorten HCV therapy if it compromises SVR rates, even if it is only a numerical decline and not a statistically significant difference. If the numerical decrease of 10% is confirmed in the final analysis of this study, I have doubts that this will be fully adopted in clinical practice. Paul Y. Kwo, MD: I agree with Dr. Zeuzem and think that clinicians may use these data not to recommend shorter durations of therapy from the outset, but rather to provide reassurance to patients with favorable characteristics, such as IL28B CC, who have marked difficulty in tolerating therapy, that truncating therapy at or after 12 weeks will not sacrifice a large percentage of their opportunity to achieve SVR. To that extent, I view these data as similar to those from the ADVANCE study, with 8 vs 12 weeks of telaprevir-based triple therapy: Although SVR rates were numerically lower with 8 weeks of therapy, they still were quite good.[1] For more information on this study, review the CCO Capsule Summary at: http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/Amsterdam%202013/HCV%20Phase%20III/Capsules/881.aspx Reference 1. 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. eRVR SVR4 SVR12 Relapse in 8% of patients in TVR12/PR12 arm vs 0% in T12/PR24 arm Safety profile consistent with that observed in previous TVR studies eRVR: undetectable HCV RNA at Wks 4 and 12. Nelson DR, et al. EASL 2013. Abstract 881. Reproduced with permission.

HCV RNA Undetectable (%) TARGET-C: TVR With Reduced RBV + Peg-IFN in HCV-Infected Hemodialysis Patients TVR + PegIFN/RBV 200 mg Wk 12 Pts with GT 1 HCV; on hemodialysis (N = 36) PegIFN/RBV 400 mg TVR + PegIFN + Placebo Placebo + PegIFN/RBV 400 mg Wk 24 Wk 36 Wk 48 n = 12 100 PegIFN alfa-2a dosed at 135 µg/wk Increased incidence of select AEs in TVR arms vs P/R Anemia (54% vs 33%) Neutropenia (50% vs 33%) Thrombocytopenia (37% vs 25%) Rash (42% vs 17%) Anorectal dysfunction (33% vs 0%) Dysgeusia (42% vs 17%) 80 67 63 60 HCV RNA Undetectable (%) 50 50 AEs, adverse events; EOT, end of treatment; GT, genotype; HD, hemodialysis; HCV, hepatitis C virus; pegIFN/RBV, peginterferon/ribavirin; SOC, standard of care; SVR, sustained virologic response; TVR, telaprevir.   David R. Nelson, MD: The last study, TARGET-C is a very small trial exploring the safety of using telaprevir with or without ribavirin in a hemodialysis population. It is a very interesting trial design, and I think the authors deserve a lot of credit for taking this approach. Patients were randomized to either 48 weeks of peginterferon/ribavirin plus a placebo (effectively the standard of care, although ribavirin is not approved in this population) or one of 2 different arms containing telaprevir and peginterferon, with or without ribavirin. The daily ribavirin dose was 200 mg when coadministered with telaprevir or 400 mg when it was used just with peginterferon. This study design is very similar to what clinicians who treat patients with renal failure or who are on dialysis actually do: introduce very low–dose ribavirin with interferon. Because of the very small numbers, the data must be interpreted with caution. Nevertheless, I think that this is a very revealing study. First, the coadministration of telaprevir with peginterferon/ribavirin increased the rates of adverse events including anemia, neutropenia, thrombocytopenia, rash, and anorectal symptoms. However, there was a clear efficacy advantage to telaprevir-based therapy, either with or without ribavirin, in this population. Telaprevir, as well as boceprevir, was approved only in combination with peginterferon/ribavirin, and the 3 drugs together are very efficacious if patients are able to get tolerate treatment, but this study also suggests that if patients cannot receive ribavirin, telaprevir plus peginterferon alone is still better than the previous standard of peginterferon/ribavirin. Stefan Zeuzem, MD: It was quite surprising to me that these patients tolerated 400 mg/day of ribavirin. Many nephrologists report that their patients are only tolerating 200 mg/day or low doses every second day. As such, these data are quite surprising, and I am not sure whether they are explained by more aggressive use of growth factor support or simply a different experience than that in other centers. A more general observation is that the protease inhibitors are hepatically metabolized and, therefore, do not need to be dose adapted in patients with renal insufficiency. However, we lack data on the other drug classes in this setting. Experience in hepatitis B has indicated that nucleos(t)ide hepatitis B virus polymerase inhibitors require very cautious dose adaptation in this population. Therefore, clinicians need to be aware that the experience using protease inhibitors in this population cannot simply be extrapolated to other DAA classes, especially the nucleos(t)ide HCV polymerase inhibitors. I agree with this important caution. Sofosbuvir is a nucleotide polymerase inhibitor that is not hepatically metabolized but rather is primarily eliminated through renal clearance. We need additional data on new agents in renally impaired patients before using these agents in this very special population. Paul Y. Kwo, MD: The investigators of this trial deserve enormous credit for treating a special population that clearly requires attention: the hemodialysis population. Hopefully, further investigations with this and additional agents will be undertaken, so that individuals on hemodialysis will have treatment options other than just peginterferon/ribavirin. 40 25 25 20 n/ N = 8/ 12 6/ 12 3/ 12 7/ 12 6/ 12 3/ 12 EOT SVR Basu P, et al. EASL 2013. Abstract 67.

HCV Antiviral Therapy for Genotype 1 Cirrhotics

HCV-TARGET: TVR or BOC + P/R in a Diverse Patient Populations Interim analysis of longitudinal observational study of sequentially enrolled patients in academic and community medical centers in North America Patient Disposition, n (%) DAA + P/R (N = 1919) Patients in current analysis 1457 Patients with cirrhosis 550 Still on treatment, < 16 wks 139 (6) Still on treatment, > 16 wks 664 (46) Completed full course 319 (22) Patient Disposition DAA + P/R (N = 1457) Early discontinuation, n (%) 335 (23) Lack of efficacy 8 Adverse event 9 Other reasons 5 Multiple reasons 2 BOC, boceprevir; DAA, direct-acting antiviral; HCV, hepatitis C virus; P/R, peginterferon/ribavirin; TVR, telaprevir.   David R. Nelson, MD: This slide shows the first interim analysis from the HCV-TARGET database. This database encapsulates a large North American experience of DAA agents in a real-world population that includes both academic and community medical centers and very much complements the CUPIC data. Currently, there are approximately 2100 patients in the database; however, this interim analysis reported on the first 1457 patients, including a very large proportion of patients with cirrhosis. These data need to be interpreted carefully as they include on-treatment interim outcomes. However, the early results suggest that there was a virologic breakthrough rate of approximately 8% to 10%, and early discontinuation is occurring in approximately 1 in 4 patients, due to a variety of reasons including efficacy, adverse events, and lack or failure of stop rules. Fried MW, et al. EASL 2013. Abstract 818.

HCV-TARGET: Baseline Characteristics Patient Characteristic Cirrhotic (n = 550) Noncirrhotic (n = 787) 40-64 yrs of age, % 84 80 Male, % 69 55 White, % 78 70 Genotype, % 1a 1b Not otherwise specified 58 19 22 13 Treatment naive, % 41 52 Mean hemoglobin > 12 g/dL 94 Mean platelets, cells/mm3 126,000 203,000 Mean total bilirubin, mg/dL (range) 1.0 (0.2-5.0) 0.63 (0.2-2.5) Mean albumin, g/dL (range) 3.9 (1.4-5.0) 4.2 (1.9-5.4) Mean Meld score (range) 8 (6-22) N/A Presence of varices, % 33 1 BOC, boceprevir; HCV, hepatitis C virus; N/A, not applicable; NOS, not otherwise specified; P/R, peginterferon + ribavirin; TVR, telaprevir.   David R. Nelson, MD: Looking at the overall patient characteristics, the North American population is aging and is most likely to be infected with genotype 1a HCV. One concerning aspect of this database is that approximately 15% to 20% of patients with genotype 1 HCV are not further subtyped as 1a or 1b, and as we previously discussed, subtype-specific regimens and responses may be critical going forward. Consequently, at least in North America, clinicians need to be very specific about ordering an HCV genotype that provides them with the subtype as well. The database comprises approximately 50% treatment-naive and 50% treatment-experienced patients and is probably the largest cirrhotic database currently being followed. Patients with cirrhosis are carefully characterized by the presence or absence of portal hypertension and approximately one third of patients with cirrhosis has varices, with a range of model for end-stage liver disease scores that somewhat quantitate their degree of liver dysfunction. Fried MW, et al. EASL 2013. Abstract 818.

HCV-TARGET: Virologic Response by Previous Treatment Category In interim analysis, on-treatment efficacy of telaprevir and boceprevir in real-world setting comparable to registration trials TVR Wk 4 TVR Wk 12 BOC Wk 8 BOC Wk 12 100 86 78 78 80 80 73 63 61 60 54 54 48 Undetectable HCV RNA (%) 43 44 45 43 BOC, boceprevir; HCV, hepatitis C virus; P/R, peginterferon/ribavirin; TVR, telaprevir. David R. Nelson, MD: This slide shows the interim on-treatment virologic response. Overall, there was very good on-treatment activity, similar to that seen in registration trials. The final SVR data are expected to be reported at the American Association for the Study of Liver Disease 2013 Liver Meeting.   40 25 20 15 n = 400 247 101 79 133 92 28 25 119 74 21 16 149 76 37 32 Treatment Naive Previous Relapser Previous Partial or Null Response Unknown Response Fried MW, et al. EASL 2013. Abstract 818. Reproduced with permission.

HCV-TARGET: Safety Assessment in Patients With Cirrhosis Event, % Cirrhotic (n = 550) Noncirrhotic (n = 787) SAE 8 Death, n 2 1 Early discontinuation Due to adverse event Due to lack of efficacy 26 44 31 21 33 38 Decompensation 11 Infection 24 Severe rash (grade 3/SCAR) Hemoglobin < 8.5 g/dL 20 14 RBV dose reduction 42 EPO 10 Transfusion 5 BOC, boceprevir; EPO, erythropoietin; HCV, hepatitis C virus; P/R, peginterferon/ribavirin; RBV, ribavirin; SCAR, severe cutaneous adverse reaction; TVR, telaprevir. David R. Nelson, MD: I think the most important insights from the TARGET study, especially in relation to the CUPIC data that we just discussed, are the overall safety data comparing cirrhotic and noncirrhotic patients. Overall, there was an increased risk of adverse events, but the profile was somewhat different than the French experience.   Deaths were relatively uncommon, occurring in only 2% of the cirrhotic population, but early discontinuation and adverse event rates were higher in the cirrhotic population. The key challenge was decompensation, which occurred in 11% of patients with cirrhosis. A multivariate analysis to assess potential predictive factors for decompensation is now under way and may shed some light on this issue. Infection was not significantly increased in the cirrhotic population, and severe rashes were fairly uncommon in North America and occurred at low level even in cirrhotics. Clearly, anemia had the biggest impact on treatment but was different from the CUPIC cohort: In the TARGET study, dose reduction was primarily used to manage anemia, limiting the development of anemia with hemoglobin levels < 8.5 g/dL—considered severe anemia—to only 20% of patients. Use of erythropoietin and transfusions was also less than that reported in the CUPIC database. This is an interesting database that is now also expanding to Europe and may help rapidly report real-world data as new drugs are approved. Paul Y. Kwo, MD: The TARGET study confirmed our own experience that clinicians using these triple-therapy regimens, particularly in patients with cirrhosis, are learning to accept lower hemoglobin levels because they are associated with better responses to therapy. Among patients who are responding to triple therapy, occasional transfusions are something that we now accept. Furthermore, it is also clear that ribavirin dose reduction does not result in lower SVR rates. Fried MW, et al. EASL 2013. Abstract 818.

CUPIC Boceprevir and Telaprevir Treatment Regimens Peg-IFN α-2a + RBV TVR + Peg-IFN α-2a + RBV Follow-up 48 4 16 12 8 Weeks 72 SVR12 BOC + Peg-IFN α-2b + RBV Peg-IFN + RBV 36 BOC: 800 mg/8h; Peg-IFNα-2b: 1.5 µg/kg/week; RBV: 800 to 1400 mg/day TVR: 750 mg/8h; Peg-IFNα-2a: 180 µg/week; RBV: 1000 to 1200 mg/day SVR24 Fontaine H, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 60 Hezode, C, et al. 63rd AASLD; Boston, MA; November 9-13, 2012. Abst. 51.

CUPIC Baseline Demographics and Disease Characteristics Telaprevir N=295 Boceprevir N=190 Child-Pugh score A/B, n (%)* 280 (95) / 6 (2) 177 (93) /1 (1) MELD score, mean (range) 8.1 (6-22) 8.1 (6-28) Prothrombin time ratio, mean % (range) 86 (27–100) 87 (23–100) Serum albumin g/L, mean (range) 40.0 (20.7–53.2) 40.7 (27.0–50.3) Total bilirubin μmol/L, mean (range) 15.5 (4.0–73.0) 15.2 (4.0–78.0) Hgb level g/dL, mean (range) 14.5 (9.0–19.7) 14.8 (10.8–18.4) Neutrophils, mean (range) (109/mm3) 3.3 (0.8-8.5) 3.2 (0.5-8.5) Platelet count, mean (range) (103/mm3) 151 (18–604) 144 (34–346) Esophageal varices, n (%) 51/145 (35.2) 37/97 (38.1) * Missing data : 21 Fontaine H, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 60

CUPIC Virological Response (ITT): SVR12 TELAPREVIR BOCEPREVIR 10 20 30 40 50 60 70 80 90 100 49% Patients with undetectable HCV RNA (Percentage) 79% 81% 56% W4 W8 W12 W24 W48 W60 W16 77 % 68 % 146 295 234 239 227 200 165 118 16% 51% 62% 65% 67% 31 190 97 124 128 108 57% 79 40% 41% Fontaine H, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 60

CUPIC SVR12 According to HCV G1 Subtype Genotype 1a 1b Undetermined genotype 1 33/98 75/162 9/33 34% 46% 27% P=0.004 10 20 30 40 50 60 70 80 90 100 SVR 12 (ITT ) (Percentage) TELAPREVIR Genotype 1a 1b Undetermined genotype 1 10 20 30 40 50 60 70 80 90 100 6/16 P=0.03 31% 51% 37% 49/96 24/77 BOCEPREVIR SVR 12 (ITT ) (Percentage) Fontaine H, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 60

CUPIC: SVR12 Safety Findings Patients, n (% patients with at least one event) Telaprevir n=295 Boceprevir n=190 Serious adverse events (SAEs)* 535 in 160 patients (54.2%) 321 in 97 patients (51.0%) Premature discontinuation / due to SAEs 139 (47.1%) / 63 (21.3%) 80 (42.1%)/ 27 (14.2%) Death 7 (2.4 %) 3 (1.6%) Infection (Grade 3/4) 27 (9.1 %) 8 (4.2%) Hepatic decompensation (Grade ¾ ) 15 (5.1 %) 9 (4.7%) Anemia (Grade ¾ : Hb < 8 g/dL) 38 (12.9 %) 19 (10%) Rash (grade 3/SCAR) 16 (5.4 %)/ 2 (0.6 %) 2 (1.0%)/ EPO use / blood transfusion 168 (57 %) / 53 (18 %) 119 (62.6%) / 26 (13.7%) GCSF use 8 (2.7 %) 13 (6.8%) TPO use 6 (2 %) Fontaine H, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 60

CUPIC Predictors of Death or Severe Complications Predictive Factors Platelets count >100,000/mm3 ≤100,000/mm3 Albumin 35 g/L 3.4 % (10/298) 4.3 % (3/69) Albumin <35 g/L 7.1 % (2/28) 44.1 % (15/34) Hezode, C, et al. 63rd AASLD; Boston, MA; November 9-13, 2012. Abst. 51.

Meta-Analysis: Five Boceprevir Phase 3 Trials Vierling JM, et al. EASL 2013. Abstract 1430. A pooled analysis of 5 BOC phase III clinical trials in patients with HCV genotype 1 infection Cirrhosis defined as METAVIR F4 score Central reading of all liver biopsies Study Patients P/R, n (%) BOC/P/R 48 weeks, BOC P/R RGT, All, Cirrhotic Patients, SPRINT-2 Previously untreated 363 (33) 366 (33) 368 (34) 1097 (100) 53 (5) Anemia Management study — 111 (16) 576 (84) 687 (100) 60 (9) RESPOND-2 Previous treatment failure 80 (20) 161 (40) 162 (40) 403 (100) 49 (12) PEG2a 67 (33) 134 (67) 201 (100) 33 (16) PROVIDE 134 (100) 17 (13) Total 510 (20) 906 (36) 1106 (44) 2522 (100) 212 (8) BOC = boceprevir; P/R = peginterferon and ribavirin; RGT = response-guided therapy

Patient Characteristics Vierling JM, et al. EASL 2013. Abstract 1430. P/R BOC/P/R F0-2 (n = 436) F3 (n = 22) F4 (n = 32) (n = 1638) (n = 107) (n = 180) Age, mean (SD), y 49.5 (9.6) 51.6 (10.2) 54.7 (6.8) 49.7 (9.4) 52.7 (7.3) 53.2 (6.7) Male, n (%) 252 (58) 20 (91) 23 (72) 860 (53) 73 (68) 112 (62) Viral load Log10 Geometric Mean* 6.54 6.22 6.49 6.47 6.39 >800,000 IU/mL, n (%) 372 (85) 19 (86) 20 (63) 1371 (84) 91 (85) 144 (80) Genotype subtype, n (%)   1a 208 (48) 10 (45) 17 (53) 811 (50) 60 (56) 92 (51) 1b 160 (37) 11 (50) 12 (38) 622 (38) 37 (35) 65 (36) 1 (other) 68 (16) 1 (5) 3 (9) 204 (12) 10 (9) 23 (13) Missing 1 (<1) Platelets Mean (SD) × 109/L 252.9 (69.3) 188.5 (64.5) 183.1 (73.4) 249.8 (70.9)† 198.4 (64.7) 165.8 (57.4) <150 × 109 cells/L, n (%) 26 (6) 8 (36) 10 (31) 99 (6) 27 (25) 78 (43) Baseline haemoglobin (g/dL), mean (SD) 14.7 (1.3) 15.7 (1.3) 15.2 (1.1) 14.6 (1.3) 15.1 (1.4) 14.6 (1.2) Baseline serum albumin Mean (range), g/L 40.7 (32-49) 40.1 (34-46) 39.1 (34-44) 40.9 (30-51) 39.9 (30-49) 38.8 (31-49) <35 g/dL, n (%) 6 (<1) 38 (2) 5 (5) 21 (12) BOC = boceprevir; PR = peginterferon and ribavirin *Baseline viral load is the geometric mean of all virology collections during screening and before the randomization date. †Baseline platelets for 1637 patients.

Sustained Virologic Response Vierling JM, et al. EASL 2013. Abstract 1430. SVR rates were substantially higher with BOC/P/R compared with P/R alone, regardless of fibrosis score In patients receiving BOC/P/R, SVR rates were similar in patients with bridging fibrosis (F3) and cirrhosis (F4) n=1638 n=436 n=107 n=22 n=180 n=32 *Treatment-naive patients and those with previous treatment failure combined. The analyses of the pooled studies were homogeneous for the SVR rates for F0-2 and F3 patients treated with BOC/P/R, and for F3 patients treated with P/R. Therefore, the fixed-effect estimates for the SVR rates were used for these patients. The analysis of the studies for the SVR rates was heterogeneous for F4 patients treated with BOC/P/R or P/R, and for F0-2 patients treated with P/R; therefore, the random-effect estimate for the SVR rate was used for these patients BOC = boceprevir; CI = confidence interval; P/R = peginterferon and ribavirin; SVR = sustained virologic response.

SVR According to TW4 Virologic Response Vierling JM, et al. EASL 2013. Abstract 1430. Regardless of METAVIR fibrosis score, SVR rates were higher in patients with ≥1 log10 decline in HCV RNA at TW4 than those with <1 log10 decline Among patients with ≥1 log10 decline in HCV RNA, SVR rates with BOC/P/R were similar in patients with METAVIR F3 and F4 fibrosis SVR rate was 21% in cirrhotic patients receiving BOC/P/R with <1 log10 decline in HCV RNA at TW4 895/ 1155 168/415 47/70 10/35 85/128 10/48 *Treatment-naive patients and those with previous treatment failure combined (total treatment duration = 8 weeks). CI = confidence interval; HCV = hepatitis C virus; SVR = sustained virologic response; TW = treatment week.

SVR According to TW8 Virologic Response Vierling JM, et al. EASL 2013. Abstract 1430. SVR rates were high in all patients with undetectable HCV RNA at TW8, intermediate in those with >3 log10 decline at TW8, and low in those with <3 log10 decline at TW8, regardless of METAVIR fibrosis score Few F0-2 and no F3-4 patients with detectable HCV RNA and <3 log10 decline in HCV RNA at TW8 achieved SVR 766/ 889 293/ 544 40/47 16/47 65/73 28/79 5/78 0/5 0/17 *Treatment-naive patients and those with previous treatment failure combined. BOC = boceprevir; CI = confidence interval; HCV = hepatitis C virus; PR = peginterferon plus ribavirin; SVR = sustained virologic response.

Predictors of SVR in F3/F4 Patients Receiving BOC/PR Vierling JM, et al. EASL 2013. Abstract 1430. 1 2 3 4 5 6 7 8 10.57 (5.23 – 21.36); P<0.0001 2.64 (1.33 – 5.21); P=0.0053 2.23 (1.18 – 4.24); P=0.0141 2.55 (1.05 – 6.20); P=0.0383 1.76 (0.90 – 3.44); P=0.0971 1.08 (0.43 – 2.72); P=0.8636 9 10 Odds Ratio (95% CI) TW8: undetectable vs. detectable HCV-RNA TW4: ≥1log decline vs. <1 log decline Male vs. female Baseline viral load ≤800,000 IU/mL vs. >800,000 IU/mL G1b vs. G1a Non-black vs. black CI = confidence interval; G = genotype; TW = treatment week.

Vierling JM, et al. EASL 2013. Abstract 1430. SVR According to Treatment Duration in Patients with Undetectable HCV RNA at TW8 receiving BOC/PR* Vierling JM, et al. EASL 2013. Abstract 1430. 279 /306 351 /367 58/132 4/6 3/7 15/18 16/18 78/84 6/6 8/9 17/18 38/39 *Treatment-naive patients and those with previous treatment failure combined. BOC = boceprevir; CI = confidence interval; HCV = hepatitis C virus; PR = peginterferon plus ribavirin; SVR = sustained virologic response.

Vierling JM, et al. EASL 2013. Abstract 1430. Significant Medical Events Patients with Potential Hepatic Decompensation or Sepsis Vierling JM, et al. EASL 2013. Abstract 1430. Patient ID (Study) Baseline Data Event Treatment regimen (weeks of treatment) Outcome Cirrhotic Patients 016301 (PROVIDE) Male, 64 yo; F4. History of ascites Platelets, 108K Albumin, 3.7 g/L Decompensated cirrhosis with ascites and encephalopathy (confusion) BOC/P/R (TW6) Discontinued treatment; events resolved 012072 (RESPOND-2) Female, 51 yo; F4 Platelets, 170K Albumin, 3.5 g/L Bleeding esophageal varices and portal hypertension P/R (TW2) 000603 (PEG2a study) Male, 48 yo; F4 Diabetic, IVDU Platelets, 135K Albumin, 3.8 g/L Multi-organ failure with total bilirubin peak 17.4 mg/dL (Staphylococcus pneumonia, resulting in multi-organ failure) (TW12) Died of multi-organ failure Non-Cirrhotic Patients 000005 Male, 52 yo; F2 Platelets, 280K Albumin, 4.2 g/L Possible urosepsis (negative blood and urine cultures) (TW3) Discontinued treatment; event resolved 001868 (SPRINT-2) Male, 58 yo; F2 Platelets, 192K Ascites (Hospitalized with severe epiglottitis and neutropenia; developed acute renal failure; treatment discontinued; ascites and oedema noted 12 days later) 12 days after discontinuing BOC/P/R (TW12) Discontinued treatment for other AEs; ascites resolved BOC = boceprevir; IVDU = intravenous drug user; P/R = peginterferon and ribavirin; TW = treatment week; yo = years old.

Limitations of Current Regimens and Prospects for Future Regimens Must be eligible for pegIFN/ RBV High pill burden, TID dosing of PIs (at present); parenteral IFN Multiple adverse events Selection of resistance – associtaed variants with treatment failure Only effective for genotype 1 Risk of resistance with poor adherence Future Increasingly IFN free Lower pill burden, daily dosing; Better tolerated Limited resistance-associated variants Pangenotypic Higher barrier to resistance with some classes GT, genotype; IFN, interferon; pegIFN, peginterferon; PI, protease inhibitor; RBV, ribavirin; TID, 3 times daily.

Investigational Agents for HCV in 2013 Interferons Antiviral agents Therapeutic vaccines Host target miRNA-122 Cyclophilin Entry Replication, polyprotein processing and/or assembly CypA inhibitors Cyp, cyclophilin; HCV, hepatitis C virus. NS5B polymerase inhibitors NS3/4A protease inhibitors NS5A replication complex inhibitors

Management of Chronic Hepatitis C in 2013 Regimens containing Peg-IFN are contraindicated for patients with cirrhosis who have all but one of the following: Compensated cirrhosis Decompensated cirrhosis Albumin <3.5 mg/dL and Platelets <100,000 mm3 ESRD HCC, hepatocellular carcinoma; SVR, sustained virologic response.