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Treatment Selection for HBV-Infected Patients With Decompensated Cirrhosis

Treatment Selection for HBV-Infected Patients With Decompensated Cirrhosis . 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.

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Treatment Selection for HBV-Infected Patients With Decompensated Cirrhosis

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  1. Treatment Selection for HBV-Infected Patients With Decompensated Cirrhosis 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 This program is supported by an educational grant from

  2. About These Slides • Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent • These slides may not be published or posted online without permission from Clinical Care Options (email permissions@clinicaloptions.com) DisclaimerThe materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

  3. 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. 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. 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. 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. Study 0108: Safety of TDF vs FTC/TDF vs ETV in CHB Pts With Decomp Cirrhosis • Randomized, double-blind phase II study Wk 48: interim analysis Wk 168 TDF 300 mg (n = 45) HBV-infected pts with decompensated liver disease* (N = 112) FTC/TDF 200/300 mg (n = 45) ETV 0.5 mg or 1 mg (n = 22) *Patients with < 2 log10 copies/mL decrease in HBV DNA at Wk 8, with virologic breakthrough (≥ 1 log10 copies/mL increase from nadir on 2 consecutive determinations or consecutive HBV DNA ≥ 400 copies/mL after being < 400 copies/mL), or with HBV DNA levels > 400 copies/mL at or after 24 wks of treatment could begin open-label FTC/TDF; these patients considered failures in efficacy analysis. Liaw YF, et al. Hepatology. 2011;53:62-72.

  8. Study 0108: Summary of Coprimary Safety Endpoints Through Wk 48 *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. Liaw YF, et al. Hepatology. 2011;53:62-72.

  9. Study 0108: Median Serum Creatinine by Study Visit • No cases of lactic acidosis reported in any treatment arm 1.0 0.9 0.8 0.7 0.6 Median Creatinine (mg/dL) 0.5 0.4 0.3 0.90 TDF 0.2 0.90 TDF/FTC 0.1 0.80 ETV 0 0 4 8 12 16 20 24 28 32 36 40 44 48 Wks on Study Pts at Risk, n TDF FTC/TDF ETV 454522 454421 424319 404220 394219 394218 404219 384219 374219 374218 384117 374216 374216 Liaw YF, et al. Hepatology. 2011;53:62-72.

  10. Study 0108: Efficacy Results at Wk 48 Liaw YF, et al. Hepatology. 2011;53:62-72.

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

  13. 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 ETV 1.0 mg(n = 100) ADV 10 mg(n = 91) 9 8 7 P < .0001 6 Mean HBV DNA (log10 copies/mL) -3.40 5 4 -4.48 3 2 Limit of detection 300 copies/mL 1 B/L 4 8 12 16 20 24 28 32 36 40 44 48 Treatment (Wks) Patients With MeasurementsETVADV 10091 9888 9280 8780 7673 7166 6961 Liaw YF, et al. Hepatology. 2011;54:91-100.

  14. ETV-048: Improvement in MELD/CTP Scores *Noncompleter = failure. †CTP class C/B to A only. Liaw YF, et al. Hepatology. 2011;54:91-100.

  15. ETV-048: Safety of ETV vs ADV in CHB Patients With Decompensated Cirrhosis • Grade 2 lactic acidosis reported in only 1 ETV-treated patient; it resolved on continued ETV and did not require treatment Liaw YF, et al. Hepatology. 2011;54:91-100.

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

  18. 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 All patients had MELD scores ≥ 22 Lactic acidosis (n = 5) No lactic acidosis (n = 11) All patients had MELD scores ≤ 17 Lange CM, et al. Hepatology. 2009;50:2001-2006.

  19. 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 Characteristics of Lactic Acidosis in 5 Patients Outcome Resolved, OLT, virologic response Patient A pH: 7.2, lactate: 50 mg/dL LA Patient B Death pH: 7.1, lactate: 200 mg/dL LA Resolved,virologic response Patient C pH: 7.4, lactate: 35 mg/dL, BE: -5 mmol/L Lamivudine LA Patient D pH: 7.3, lactate: 65 mg/dL Tenofovir Resolved LA Resolved, virologic response Patient E pH: 7.4, lactate: 26 mg/dL, BE: -6 mmol/L Tenofovir LA 0 Days of ETV Therapy 240 Lange CM, et al. Hepatology. 2009;50:2001-2006.

  20. 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. Summary: Choice of Agent for CHB Patients With Decompensated Cirrhosis

  22. 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 manufacturer’s 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

  23. Go Online for More Information on Treatment Selection for CHB Patients With Decompensated Cirrhosis! Clinical FocusConcise online CME-certified module resembling PowerPoint “handout” format, with large slide thumbnails paired with supporting text discussion that includes interactive polling questions clinicaloptions.com/Cirrhosis

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