HBV, hepatitis B virus. There are several reasons to treat patients with advanced liver disease due to hepatitis B. First, the prognosis for hepatitis B virus (HBV)–infected individuals with decompensated cirrhosis is very poor without treatment. Indeed, there is an increased risk of hepatocellular carcinoma and death in these patients and a low 5‑year survival rate at 14%. Although liver transplantation is an effective treatment, there is a shortage of donor organs and long waiting lists. In addition, patients have better outcomes if they undergo transplantation with an undetectable HBV DNA. Finally, antiviral agents that can effectively and safely suppress the HBV virus may lead to improvement of liver function and removal from the wait list, thereby eliminating the requirement for transplantation.
HBV, hepatitis B virus. There are 7 approved agents for the treatment of chronic hepatitis B, including 2 nucleotides (adefovir and tenofovir), 3 nucleosides (entecavir, lamivudine and telbivudine), and 2 immunomodulatory agents (standard interferon alfa‑2b and peginterferon alfa‑2a). However, because of issues with potency, resistance, and convenience, only 3 agents have been recommended as first‑line therapy by major liver disease organizations; these are the nucleoside entecavir, the nucleotide tenofovir, and peginterferon alfa‑2a. Peginterferon is contraindicated in patients with decompensated liver disease because of worsening of the liver disease, hepatic encephalopathy, and high rates of infection and sepsis. Thus, for patients with decompensated disease, entecavir and tenofovir are the only recommended treatment options. The data on these 2 agents in this population of patients will be reviewed throughout the remainder of this program.
CHB, chronic hepatitis B; HBV, hepatitis B virus. Tenofovir has been studied in a small number of HBV-infected patients with decompensated liver disease, but there is currently no formal indication from the US Food and Drug Administration (FDA) for its use in this setting. Concerns with tenofovir in this population are largely related to its possible impact on renal function. Due to the high rate of renal dysfunction in patients with decompensated cirrhosis and portal hypertension, differentiating renal dysfunction due to the liver disease vs that due to tenofovir is difficult. Finally, there is a risk of lactic acidosis noted in the package insert. However, this is mostly due to data from HIV-infected patients, and there are no data on lactic acidosis with tenofovir when used for HBV.
CHB, chronic hepatitis B; Decomp, decompensated; ETV, entecavir; FTC, emtricitabine; HBV, hepatitis B virus; TDF, tenofovir. Data on the use of tenofovir in HBV-infected patients with decompensated disease have been generated in Study 0108. This double‑blind, phase II study compared tenofovir vs fixed-dose combination tenofovir plus emtricitabine vs entecavir in 112 patients with chronic hepatitis B and hepatic decompensation. Patients will receive treatment until Week 168; interim data are now available at Week 48 of treatment. The coprimary endpoints are tolerability failures, defined as adverse events resulting in permanent treatment discontinuation, and increases in serum creatinine ≥ 0.5 mg/dL above baseline or serum phosphorus values < 2.0 mg/dL. Secondary efficacy endpoints are HBV DNA levels, alanine aminotransferase levels, hepatitis B e antigen (HBeAg)/hepatitis B surface antigen loss and seroconversion, and Child-Turcotte-Pugh (CTP) and Model for End-Stage Liver Disease (MELD) scores.
AE, adverse event; ETV, entecavir; FTC, emtricitabine; TDF, tenofovir. Tolerability failures through Week 48 were similar among treatment arms at 6.7% for the tenofovir arm, 4.4% for the emtricitabine/tenofovir arm, and 9.1% for the entecavir arm. Renal dysfunction, defined as confirmed ≥ 0.5 mg/dL increase in creatinine, occurred in a higher percentage of patients on tenofovir monotherapy vs the other 2 arms (8.9% vs 2.2% vs 4.5% in the tenofovir, emtricitabine/tenofovir, and entecavir arms, respectively), but this did not reach statistical significance. Similarly, there were higher rates of hypophosphatemia in the 2 tenofovir-containing arms at 2.2% for the tenofovir arm, 4.4% for the emtricitabine/tenofovir arm vs 0% for the entecavir arm.
ETV, entecavir; FTC, emtricitabine; TDF, tenofovir. However, a closer examination of the median serum creatinine levels over time in the 3 arms reveals no marked differences between the 2 tenofovir arms vs the entecavir arm, and levels were relatively stable, although it is important to note that virtually all of the patients had normal renal function at study entry. There were no cases of lactic acidosis reported in any treatment arm.
ALT, alanine aminotransferase; CTP, Child-Turcotte-Pugh; ETV, entecavir; HBeAg, hepatitis B e antigen; IQR, interquartile range; FTC, emtricitabine; HBV, hepatitis B virus; MELD, Model for End-Stage Liver Disease; TDF, tenofovir. The efficacy results showed similar rates of HBV DNA < 400 copies/mL at Week 48 of treatment with 70.5% of patients in the tenofovir arm, 87.8% of patients in the emtricitabine/tenofovir arm, and 72.7% of patients in the entecavir arm achieving this endpoint. Median changes in the MELD score were similar across the 3 study arms. More patients in the combination therapy arm had decreases in CTP score, but the results were not statistically significant. Finally, the proportion of patients undergoing HBeAg loss or seroconversion were numerically higher in the tenofovir‑containing arms.
CHB, chronic hepatitis B; CrCl, creatinine clearance; HBV, hepatitis B virus. Turning now to entecavir for the treatment of decompensated HBV-related cirrhosis, recent data (discussed below) have led to a specific FDA-approved indication for the use of entecavir in adult patients with decompensated liver disease. As noted, the dose of entecavir should be increased to 1 mg/day in patients with creatinine clearances ≥ 50 mL/min regardless of previous lamivudine or other nucleoside exposure. Appropriate dose adjustments as stated in the package insert must be made if the creatinine clearance is < 50 mL/min. Finally, patients with decompensated disease treated with entecavir may be at higher risk for lactic acidosis.
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 YorkThis program is supported by an educational grant fromOriginally posted 6/26/20112at clinicaloptions.com/ss/Cirrhosis
Treatment Selection for CHB Patients With Decompensated Cirrhosisclinicaloptions.com/hepatitis 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 This abbreviated slideset was posted to SlideShare to publicize the availability of the full slideset. These slides may not be published or posted online without permission from CCO (email firstname.lastname@example.org)DisclaimerThe materials published on the Clinical Care Options Web site reflect the views of the authors of theCCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providingeducational grants. The materials may discuss uses and dosages for therapeutic products that have notbeen approved by the United States Food and Drug Administration. A qualified healthcare professionalshould be consulted before using any therapeutic product discussed. Readers should verify all informationand data before treating patients or using any therapies described in these materials.
Treatment Selection for CHB Patients With Decompensated Cirrhosisclinicaloptions.com/hepatitis Faculty Disclosures Robert S. Brown, Jr., MD, MPH, has disclosed that he has received fees for non-CME services from Genentech and Gilead Sciences.
Treatment Selection for CHB Patients With Decompensated Cirrhosisclinicaloptions.com/hepatitis 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 – Estimated 5-yr survival rate: 14% 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 function1. Lok AS, et al. Hepatology. 2009;50:661-662. 2. de Jongh FE, et al. Gastroenterol. 1992;103:1630-1635.
Treatment Selection for CHB Patients With Decompensated Cirrhosisclinicaloptions.com/hepatitis 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 cirrhosis3. 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.
Treatment Selection for CHB Patients With Decompensated Cirrhosisclinicaloptions.com/hepatitis 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 HBVTenofovir [package insert]. January 2012.
Treatment Selection for CHB Patients With Decompensated Cirrhosisclinicaloptions.com/hepatitis 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 FTC/TDF 200/300 mg liver disease* (n = 45) (N = 112) 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 log 10 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.
Treatment Selection for CHB Patients With Decompensated Cirrhosisclinicaloptions.com/hepatitis Study 0108: Summary of Coprimary Safety Endpoints Through Wk 48 Patients, % TDF FTC/TDF ETV (n = 45) (n = 45) (n = 22) Tolerability failures* 6.7 4.4 9.1 Confirmed ≥ 0.5 mg/dL increase in creatinine or confirmed phosphorus < 2.0 mg/dL 8.9† 6.7 4.5 Confirmed ≥ 0.5 mg/dL increase in creatinine 8.9† 2.2 4.5 Confirmed phosphorus < 2.0 mg/dL 2.2 4.4 0 Confirmed ≥ 0.5 mg/dL increase in creatinine and confirmed phosphorus 2.2 0 0 < 2.0 mg/dL *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.
Treatment Selection for CHB Patients With Decompensated Cirrhosisclinicaloptions.com/hepatitis Study 0108: Median Serum Creatinine by Study Visit 1.0 Median Creatinine (mg/dL) 0.9 0.8 0.7 0.6 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 45 45 42 40 39 39 40 38 37 37 38 37 37 FTC/TDF 45 44 43 42 42 42 42 42 42 42 41 42 42 ETV 22 21 19 20 19 18 19 19 19 18 17 16 16 No cases of lactic acidosis reported in any treatment armLiaw YF, et al. Hepatology. 2011;53:62-72.
Treatment Selection for CHB Patients With Decompensated Cirrhosisclinicaloptions.com/hepatitis Study 0108: Efficacy Results at Wk 48 Efficacy Result TDF FTC/TDF ETV (n = 45) (n = 45) (n = 22) HBV DNA < 400 copies/mL, % 70.5 87.8 72.7 Median change in MELD score -2.0 -2.0 -2.0 from baseline (IQR) (-12 to 3) (-18 to 4) (-10 to 1) CTP score ≥ 2 point decrease, % 25.9 48.0 41.7 CTP score ≥ 2 point increase, % 0 2.6 0 Median change in serum ALT from baseline, U/L -7.0 -16.5 -25.5 HBeAg loss, % 21.4 26.7 0 HBeAg seroconversion, % 21.4 13.3 0Liaw YF, et al. Hepatology. 2011;53:62-72.
Treatment Selection for CHB Patients With Decompensated Cirrhosisclinicaloptions.com/hepatitis 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 acidosisEntecavir [package insert]. December 2010.
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