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Management of Chronic Hepatitis C in 2013

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. Management of Chronic Hepatitis C in 2013.

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Management of Chronic Hepatitis C in 2013

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  1. 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

  2. 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

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

  4. 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] 1. KanwalF, 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.

  5. Cirrhosis: Treat Before Decompensation! Survival Probability Compensated 100 After first major complication 80 60 Patients (%) 40 20 0 0 12 24 36 48 60 72 84 96 108 120 Mos 38465 37639 34221 28811 2367 1654 1264 793 523 392 251 Pts at Risk, n Fattovich G, et al. Gastroenterology. 1997;112:463-472.

  6. Liver-Related Complications Decrease Following SVR in Cirrhotic Patients No SVR 100 SVR 80 60 Patients With Liver Complications (%) 40 20 0 0 24 48 72 96 120 144 168 Mos 759124 702119 634116 527108 34570 20741 3412 Pts at Risk, n Bruno S, et al. Hepatology. 2007;45:579-587.

  7. Compensated Cirrhosis: HVPG  10 mmHg is the strongest predictor of decompensation 1.0 Log rank test: p<0.01 HR 3.95 (2.29–6.83) 0.8 Baseline HVPG ≥10mmHg Probability of decompensation (ascites, VH, HE) 0.6 0.4 Baseline HVPG <10mmHg 0.2 Ripoll et al (Timolol Study Group). Gastroenterology 2007; 133:481-488. 0 20 40 60 100 80 Months

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

  9. Compensated Cirrhosis: Reduction in HVPG >10% at one-year prevents development of varices 100  HVPG > 10% 80 60 p=0.014 % Free of varices 40  HVPG  10% 20 0 0 12 24 60 72 48 36 Months Groszmann, Garcia-Tsao, Bosch et al. N Engl J Med 2005, 353:2254-2261.

  10. 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 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.

  11. 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

  12. 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 1. Ghany MG, et al. Hepatology. 2011;54:1433-1444. 2. EASL. J Hepatol. 2011;55:245-264.

  13. 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 BOC/TVR + pegIFN* + RBV 80 63-75 40-59 60 SVR (%) 38-44 29-40 40 24-29 20 7-15 5 0 Treatment Naive[1,2] Relapsers[3,4] Partial Responders[3,4] NullResponders[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.

  14. BOC and TVR Potential for Multiple Drug–Drug Interactions • TVR • Substrate of CYP3A • Inhibitor of CYP3A • Substrate and inhibitor of P-gp • BOC • 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)

  15. SPRINT-2: Influence of Baseline Patient and Virus Factors on SVR With BOC/PR BOC + pegIFN-α2b/RBV 48 wks BOC + pegIFN-α2b/RBV RGT 100 85 80 76 71 70 75 67 67 66 63 63 61 59 59 52 SVR (%) 50 41 25 93/133 89/134 118/187 106/179 45/53 41/54 197/313 192/314 211/313 213/319 22/42 14/34 n/N = 44/55 82/115 26/44 0 1b 1a Genotype[1] ≤ 800,000 > 800,000 HCV RNA (IU/mL)[1] F0-2 F3/F4 Fibrosis[1] CC CT TT IL28B[2] 1. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 2. Poordad F, et al. Gastroenterology. 2012;143:608-618.

  16. 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 50 SVR (%) 25 118/149 152/213 64/82 207/281 226/290 45/73 n/N = 45/50 48/68 16/22 0 CC CT TT 1b 1a Genotype[1] < 800,000 ≥ 800,000 HCV RNA (IU/mL)[1] F0-2 F3/F4 Fibrosis[1] 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.

  17. 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

  18. HCV AntiviralsNew Studies Using Current Therapies

  19. 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* 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.

  20. CONCISE: Virologic ResponsesTVR12/PR12 vs. TVR12/PR24 after eRVR T12/PR12 T12/PR24 • 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 100 99 98 97 100 89 87 80 60 Patients (%) 40 20 105/106 51/52 93/104 38/38 74/85 29/30 n/N = 0 eRVR SVR4 SVR12 eRVR: undetectable HCV RNA at Wks 4 and 12. Nelson DR, et al. EASL 2013. Abstract 881. Reproduced with permission.

  21. TARGET-C: TVR With Reduced RBV + Peg-IFN in HCV-Infected Hemodialysis Patients Wk 48 Wk 36 • 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%) Wk 24 Wk 12 n = 12 TVR + PegIFN/RBV 200 mg PegIFN/RBV 400 mg Pts with GT 1 HCV; on hemodialysis (N = 36) n = 12 TVR + PegIFN + Placebo PegIFN/RBV 400 mg n = 12 Placebo +PegIFN/RBV 400 mg PegIFN alfa-2a dosed at 135 µg/wk 100 80 67 63 60 50 50 HCV RNA Undetectable (%) 40 25 25 20 8/12 6/12 3/12 7/12 6/12 3/12 n/N = 0 EOT SVR Basu P, et al. EASL 2013. Abstract 67.

  22. HCV Antiviral Therapyfor Genotype 1 Cirrhotics

  23. 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 Fried MW, et al. EASL 2013. Abstract 818.

  24. HCV-TARGET: Baseline Characteristics Fried MW, et al. EASL 2013. Abstract 818.

  25. 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 4TVR Wk 12 BOC Wk 8BOC Wk 12 100 86 80 78 78 80 73 63 61 54 60 54 48 45 43 43 44 Undetectable HCV RNA (%) 40 25 15 20 n = 400 247 101 79 133 25 74 21 16 149 76 37 32 92 28 119 0 Treatment Naive Previous Relapser Previous Partial or Null Response UnknownResponse Fried MW, et al. EASL 2013. Abstract 818. Reproduced with permission.

  26. HCV-TARGET: Safety Assessment in Patients With Cirrhosis Fried MW, et al. EASL 2013. Abstract 818.

  27. CUPICBoceprevir and Telaprevir Treatment Regimens TVR + Peg-IFN α-2a + RBV Peg-IFN α-2a + RBV Follow-up Peg-IFN + RBV BOC + Peg-IFN α-2b + RBV Follow-up 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 72 36 4 0 12 16 48 8 SVR24 Weeks SVR12 Hezode, C, et al. 63rd AASLD; Boston, MA; November 9-13, 2012. Abst. 51. Fontaine H, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 60

  28. CUPICBaseline Demographics and Disease Characteristics * Missing data : 21 Fontaine H, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 60

  29. CUPICVirological Response (ITT): SVR12 TELAPREVIR BOCEPREVIR 100 100 90 90 79% 81% 77 % 80 80 68 % 67% 70 65% 70 62% 57% 56% 60 60 51% 49% 40% 41% Patients with undetectable HCV RNA (Percentage) 50 50 40 40 30 30 20 20 16% 10 10 146 295 234 295 239 295 227 295 200 295 165 295 118 295 31 190 97 190 118 190 124 190 128 190 108 190 79 190 0 0 W60 W60 W4 W8 W12 W16 W24 W48 W4 W8 W12 W16 W24 W48 Fontaine H, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 60

  30. CUPICSVR12 According to HCV G1 Subtype TELAPREVIR BOCEPREVIR 100 100 90 90 P=0.004 P=0.03 80 80 70 70 60 60 51% SVR 12 (ITT ) (Percentage) SVR 12 (ITT ) (Percentage) 50 46% 50 37% 34% 40 40 31% 27% 30 30 20 20 10 10 33/98 75/162 9/33 6/16 24/77 49/96 0 0 Genotype 1a Genotype 1b Undetermined genotype 1 Genotype 1a Genotype 1b Undetermined genotype 1 Fontaine H, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 60

  31. CUPIC: SVR12 Safety Findings Fontaine H, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 60

  32. CUPICPredictors of Death or Severe Complications 44.1 % (15/34) Hezode, C, et al. 63rd AASLD; Boston, MA; November 9-13, 2012. Abst. 51.

  33. 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 BOC = boceprevir; P/R = peginterferon and ribavirin; RGT = response-guided therapy

  34. Patient Characteristics Vierling JM, et al. EASL 2013. Abstract 1430. 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.

  35. 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=180 n=1638 n=107 n=436 n=22 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.

  36. 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 47/70 85/128 168/415 10/35 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.

  37. 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 293/ 544 766/ 889 16/47 40/47 65/73 28/79 0/5 0/17 5/78 *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.

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

  39. 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 4/6 3/7 15/18 16/18 78/84 6/6 8/9 38/39 17/18 58/132 *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.

  40. Significant Medical EventsPatients with Potential Hepatic Decompensation or Sepsis Vierling JM, et al. EASL 2013. Abstract 1430. BOC = boceprevir; IVDU = intravenous drug user; P/R = peginterferon and ribavirin; TW = treatment week; yo = years old.

  41. Limitations of Current Regimens and Prospects for Future Regimens Current • 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

  42. Investigational Agents for HCV in 2013 Interferons Antiviral agents Therapeuticvaccines Hosttarget Cyclophilin miRNA-122 CypA inhibitors Entry Replication, polyprotein processing and/or assembly NS5Bpolymerase inhibitors NS3/4Aprotease inhibitors NS5Areplication complex inhibitors

  43. 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

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