1. Robert S. Brown, Jr., MD, MPH Frank Cardile Professor of Medicine Chief, Center for Liver Disease Columbia University College of Physicians & Surgeons NewYork-Presbyterian Hospital New York, New York Treatment Selection for HBV-Infected Patients With Decompensated Cirrhosis This program is supported by an educational grant from

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3. clinicaloptions.com/hepatitis Treatment Selection for CHB Patients With Decompensated Cirrhosis Faculty Disclosures Robert S. Brown, Jr., MD, MPH, has disclosed that he has received fees for non-CME services from Genentech and Gilead Sciences.

4. clinicaloptions.com/hepatitis Treatment Selection for CHB Patients With Decompensated Cirrhosis Rationale for Treating Patients With Advanced Liver Disease Poor prognosis for HBV-infected patients with decompensated cirrhosis without treatment –Increased risk of hepatocellular carcinoma and death [1] –Estimated 5-yr survival rate: 14% [2] Liver transplant is effective treatment, but ongoing shortage of donor organs and many patients on waitlists Antiviral agents able to effectively and safely suppress HBV replication in this population, leading to improvement or stabilization of liver function [1] 1. Lok AS, et al. Hepatology. 2009;50:661-662. 2. de Jongh FE, et al. Gastroenterol. 1992;103:1630-1635.

5. clinicaloptions.com/hepatitis Treatment Selection for CHB Patients With Decompensated Cirrhosis Approved Agents for the Treatment of Chronic HBV Infection 7 agents approved for first-line treatment of chronic HBV infection –Adefovir, entecavir, interferon alfa-2b, lamivudine, peginterferon alfa-2a, telbivudine, and tenofovir 3 agents recommended as first-line therapy according to major liver disease organizations because of their rapid onset of action, low rate of drug resistance with prolonged use, and generally favorable safety profiles [3,4] –Entecavir, peginterferon alfa-2a, and tenofovir Peginterferon contraindicated in patients with decompensated liver disease because of risk of worsening liver disease and infectious complications [3-5] Therefore, HBV clinicians must chose between entecavir and tenofovir for treatment of decompensated cirrhosis 3. Lok AS, et al. Hepatology. 2009;50:661-662. 4. EASL. J Hepatol. 2012;[Epub ahead of print]. 5. Buster EH, et al. Hepatology. 2007;46:388-394.

6. clinicaloptions.com/hepatitis Treatment Selection for CHB Patients With Decompensated Cirrhosis Tenofovir for Treatment of CHB Patients With Decompensated Cirrhosis Tenofovir studied in a limited number of subjects with CHB-associated decompensated cirrhosis Currently no formal indication for the use of tenofovir in patients with decompensated liver disease Both tenofovir and decompensated liver disease may affect renal function –Therefore, the contribution of tenofovir to renal impairment in this population is difficult to ascertain Risk of lactic acidosis noted in package insert from experience with HIV but no data on lactic acidosis with tenofovir for HBV Tenofovir [package insert]. January 2012.

7. clinicaloptions.com/hepatitis Treatment Selection for CHB Patients With Decompensated Cirrhosis Study 0108: Safety of TDF vs FTC/TDF vs ETV in CHB Pts With Decomp Cirrhosis HBV-infected pts with decompensated liver disease* (N = 112) TDF 300 mg (n = 45) ETV 0.5 mg or 1 mg (n = 22) FTC/TDF 200/300 mg (n = 45) Liaw YF, et al. Hepatology. 2011;53:62-72. Wk 48: interim analysisWk 168 *Patients with 400 copies/mL at or after 24 wks of treatment could begin open-label FTC/TDF; these patients considered failures in efficacy analysis. Randomized, double-blind phase II study

8. clinicaloptions.com/hepatitis Treatment Selection for CHB Patients With Decompensated Cirrhosis Study 0108: Summary of Coprimary Safety Endpoints Through Wk 48 Liaw YF, et al. Hepatology. 2011;53:62-72. Patients, %TDF (n = 45) FTC/TDF (n = 45) ETV (n = 22) Tolerability failures* 6.74.49.1 Confirmed 0.5 mg/dL increase in creatinine or confirmed phosphorus < 2.0 mg/dL 8.9 6.74.5 Confirmed 0.5 mg/dL increase in creatinine 8.9 2.24.5 Confirmed phosphorus < 2.0 mg/dL 2.24.40 Confirmed 0.5 mg/dL increase in creatinine and confirmed phosphorus < 2.0 mg/dL 2.200 *Defined as permanent discontinuation of study drug due to treatment-emergent AE; 6 pts discontinued due to AE (only 1 due to study drug) and 1 pt temporarily discontinued and did not restart. Includes the only pt reaching a coprimary endpoint after FTC/TDF switch.

9. clinicaloptions.com/hepatitis Treatment Selection for CHB Patients With Decompensated Cirrhosis Study 0108: Median Serum Creatinine by Study Visit Liaw YF, et al. Hepatology. 2011;53:62-72. 0.90 TDF 0.90 TDF/FTC 0.80 ETV No cases of lactic acidosis reported in any treatment arm 1.0 Median Creatinine (mg/dL) 0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 4812162024283236404448 Wks on Study 45 45 22 45 44 21 42 43 19 40 42 20 39 42 19 39 42 18 40 42 19 38 42 19 37 42 19 37 42 18 38 41 17 37 42 16 TDF FTC/TDF ETV Pts at Risk, n

10. clinicaloptions.com/hepatitis Treatment Selection for CHB Patients With Decompensated Cirrhosis Study 0108: Efficacy Results at Wk 48 Liaw YF, et al. Hepatology. 2011;53:62-72. Efficacy ResultTDF (n = 45) FTC/TDF (n = 45) ETV (n = 22) HBV DNA < 400 copies/mL, % 70.587.872.7 Median change in MELD score from baseline (IQR) -2.0 (-12 to 3) -2.0 (-18 to 4) -2.0 (-10 to 1) CTP score 2 point decrease, % 25.948.041.7 CTP score 2 point increase, % 02.60 Median change in serum ALT from baseline, U/L -7.0-16.5-25.5 HBeAg loss, % 21.426.70 HBeAg seroconversion, % 21.413.30

11. clinicaloptions.com/hepatitis Treatment Selection for CHB Patients With Decompensated Cirrhosis Entecavir for Treatment of CHB Patients With Decompensated Cirrhosis Virologic, biochemical, serologic, and safety data available from adult subjects with chronic HBV infection and decompensated liver disease These data led to an indication for use of entecavir in adult patients with decompensated liver disease –Dose should be increased to 1.0 mg/day in patients with CrCl 50 mL/min –Appropriate dose adjustments recommended if CrCl < 50 mL/min Patients with decompensated liver disease treated with entecavir may be at higher risk for lactic acidosis Entecavir [package insert]. December 2010.

12. clinicaloptions.com/hepatitis Treatment Selection for CHB Patients With Decompensated Cirrhosis ETV-048: ETV vs ADV in CHB Patients With Evidence of Hepatic Decompensation Randomized, open-label phase IIIb study HBV-infected patients with decompensated liver disease* (N = 191) ETV 1.0 mg (n = 100) ADV 10 mg (n = 91) Liaw YF, et al. Hepatology. 2011;54:91-100. Wk 24Yr 5 Primary efficacy endpoint: mean reduction in serum HBV DNA at Wk 24 Wk 48Wk 96 Follow-up

13. clinicaloptions.com/hepatitis Treatment Selection for CHB Patients With Decompensated Cirrhosis ETV-048: Mean HBV DNA Change From Baseline Through Wk 48 Difference in HBV DNA responses favoring ETV persisted when analyzed by subgroup (LAMr or HBeAg status), although magnitude of differences varied Liaw YF, et al. Hepatology. 2011;54:91-100. Mean HBV DNA (log 10 copies/mL) B/L 9 8 7 6 5 4 3 2 1 4812162024283236404448 Treatment (Wks) Limit of detection 300 copies/mL P <.0001 -3.40 -4.48 ETV 1.0 mg (n = 100) ADV 10 mg (n = 91) Patients With Measurements ETV ADV 100 91 98 88 92 80 87 80 76 73 71 66 69 61

14. clinicaloptions.com/hepatitis Treatment Selection for CHB Patients With Decompensated Cirrhosis ETV-048: Improvement in MELD/CTP Scores Liaw YF, et al. Hepatology. 2011;54:91-100. Parameter Wk 24Wk 48 ETVADVETVADV Mean MELD score change from BL (SE) -2.0 (0.45)-0.9 (0.46)-2.6 (0.62)-1.7 (0.50) CTP score improvement or no worsening,* n/N (%) 66/100 (66) 65/91 (71) 61/100 (61) 61/91 (67) CTP score 2 point reduction,* n/N (%) 32/100 (32) 22/91 (24) 35/100 (35) 25/91 (27) CTP class improvement, n/N (%) 25/93 (27) 22/81 (27) 35/93 (38) 29/81 (36) *Noncompleter = failure. CTP class C/B to A only.

15. clinicaloptions.com/hepatitis Treatment Selection for CHB Patients With Decompensated Cirrhosis ETV-048: Safety of ETV vs ADV in CHB Patients With Decompensated Cirrhosis Liaw YF, et al. Hepatology. 2011;54:91-100. Grade 2 lactic acidosis reported in only 1 ETV-treated patient; it resolved on continued ETV and did not require treatment Safety Parameter, n (%)ETV (n = 102) ADV (n = 89) Any AE 91 (89)86 (97) Grade 3-4 AEs 55 (54)42 (47) Serious AEs 70 (69)59 (66) Discontinuation due to AEs 7 (7)5 (6) Death 23 (23)29 (33) Serum creatinine 0.5 mg/dL increase from baseline 17 (17)21 (24) ALT flare 2 (2)18 (20) HCC 12 (12)18 (20) Liver transplantation 11 (11)3 (3)

16. clinicaloptions.com/hepatitis Treatment Selection for CHB Patients With Decompensated Cirrhosis Efficacy of ETV in Treatment-Naive CHB Patients With Decompensated Cirrhosis Prospective, nonrandomized study: 70 patients with HBV-related decompensated cirrhosis treated with ETV 0.5 mg/day –Virologic responses compared in 55 patients treated for 12 mos in decompensated group vs 144 patients with compensated cirrhosis treated with ETV 0.5 mg/day Characteristics, % Compensated Group (n = 144) Decompensated Group* (n = 55) Mo 6Mo 12Mo 6Mo 12 Serum HBV DNA undetectable 44.478.558.289.1 HBeAg seroconversion 17.824.418.522.2 HBeAg loss 25.641.133.348.1 ALT normalization 75.775.078.276.4 *P values not significant for any parameter at any time point between compensated and decompensated group. Shim JH, et al. J Hepatol. 2010;52:176-182.

17. clinicaloptions.com/hepatitis Treatment Selection for CHB Patients With Decompensated Cirrhosis Improved CTP and MELD Scores in Decomp CHB Patients Treated With ETV Shim JH, et al. J Hepatol. 2010;52:176-182. Change in CTP Score Through 12 Mos 8 6 4 2 8.1 ± 1.7 P <.001 10 12 6.6 ± 2.4 At 12 Mos At Pretreatment Change in MELD Score Through 12 Mos 16 12 10 2 11.1 ± 3.8 P <.001 18 20 8.8 ± 2.3 At 12 Mos At Pretreatment 14 8

18. clinicaloptions.com/hepatitis Treatment Selection for CHB Patients With Decompensated Cirrhosis Lactic Acidosis in Decompensated CHB Patients Treated With ETV Evaluation of 16 patients with decompensated liver cirrhosis treated with ETV 5 developed lactic acidosis between 4 and 240 days after starting ETV Lactic acidosis correlated with MELD score (P =.002), INR (P =.003), bilirubin (P =.003), and creatinine (P =.008) Lactic Acidosis During Treatment With ETV No lactic acidosis (n = 11) Lactic acidosis (n = 5) All patients had MELD scores 22 All patients had MELD scores 17 Lange CM, et al. Hepatology. 2009;50:2001-2006.

19. clinicaloptions.com/hepatitis Treatment Selection for CHB Patients With Decompensated Cirrhosis Resolved, OLT, virologic response Outcome Death Resolved, virologic response Resolved Resolved, virologic response Severity/Outcomes of Lactic Acidosis in Decomp CHB Patients Treated With ETV Lactic acidosis reversible after ETV D/C (n = 4) 1 death due to lactic acidosis Conclusion: ETV should be used cautiously in CHB pts with high MELD score Lange CM, et al. Hepatology. 2009;50:2001-2006. Characteristics of Lactic Acidosis in 5 Patients Patient A Patient B Patient C Patient D Patient E pH: 7.1, lactate: 200 mg/dL pH: 7.2, lactate: 50 mg/dL pH: 7.3, lactate: 65 mg/dL pH: 7.4, lactate: 26 mg/dL, BE: -6 mmol/L pH: 7.4, lactate: 35 mg/dL, BE: -5 mmol/L Tenofovir Lamivudine 0240Days of ETV Therapy LA

20. clinicaloptions.com/hepatitis Treatment Selection for CHB Patients With Decompensated Cirrhosis Choice of Agent in Decompensated Cirrhotics With LAM Resistance ETV monotherapy not a recommended strategy for patients with LAM resistance due to increased risk of ETV resistance over time in this population [20] –Guidelines recommend adding or switching to TDF [21,22] Therefore, TDF may be preferred in decompensated cirrhotic patients with LAM-resistant HBV infection Small pilot study showed combination therapy with ETV plus TDF effective and well tolerated in CHB patients with decompensated cirrhosis [23] 20. Sherman M, et al. Hepatology. 2008;48:99-108. 21. Lok AS, et al. Hepatology. 2009;50:661-662. 22. EASL. J Hepatol. 2012;[Epub ahead of print]. 23. Amarapurkar D. EASL 2009. Abstract 901.

21. clinicaloptions.com/hepatitis Treatment Selection for CHB Patients With Decompensated Cirrhosis Summary: Choice of Agent for CHB Patients With Decompensated Cirrhosis TenofovirEntecavir Limited data supporting efficacy and safety No specific indication in this population May be preferred in patients with lamivudine resistance Concerns regarding nephrotoxicity Risk of lactic acidosis, as with all nucleoside analogues More extensive data supporting efficacy and safety Specific indication in this population at 1.0 mg/day Risk of lactic acidosis specifically studied and reported in this population

22. clinicaloptions.com/hepatitis Treatment Selection for CHB Patients With Decompensated Cirrhosis Special Considerations When Managing HBV Tx in Decompensated Cirrhotics Higher rate of serious hepatic adverse events observed in this population, particularly in those with CTP class C disease, compared with rates in patients with compensated liver function Therefore, clinical and laboratory parameters should be closely monitored in this patient population –On-treatment monitoring every 3 mos –Monitor renal function before and during therapy –Adjust dosing frequency of entecavir and tenofovir per manufacturers recommendations as needed Therapy for patients with cirrhosis should be long term –Decompensated patients who undergo HBeAg seroconversion still might develop HCC or have progression of liver disease –Continue therapy until HBV DNA undetectable and patient has lost HBsAg

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