PURPOSE: To define the criteria to be used to determine the medical necessity of antiviral therapy in the treatment of Chronic Hepatitis B.

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1 COVENTRY Health Care Guidelines for Hepatitis B Therapy SUBJECT: Chronic Hepatitis B Therapy: a. Interferons - Intron A (interferon alfa-2b) and Pegasys (peginterferon alfa-2a) b. Nucleoside analogues - Epivir-HBV (lamivudine); Hepsera (adefovir dipivoxil); Baraclude (entecavir); Tyzeka (telbivudine), and Viread (tenofovir). PURPOSE: To define the criteria to be used to determine the medical necessity of antiviral therapy in the treatment of Chronic Hepatitis B. POLICY & COVERAGE: 1. Chronic Hepatitis B with detectable Hepatitis B e Antigen (HBeAg +) Refer to Appendix I for Treatment Algorithm Covered for patients who meet ALL the following criteria: a. Detectable Hepatitis B e Antigen (HBeAg +) detectable Hepatitis B Surface Antigen (HBsAg) for more than 6 months, b. HBV DNA levels 10 5 copies/ml (20,000 IU/ml) by Polymerase Chain Reaction (PCR), c. ALT > 2 times upper limit of normal (ULN) OR moderate/severe hepatitis/significant fibrosis on biopsy. 2. Chronic Hepatitis B with undetectable Hepatitis B e Antigen (HBeAg -) Refer to Appendix II for Treatment Algorithm Covered for patients who meet ALL the following criteria: a. Undetectable Hepatitis B e Antigen (HBeAg -) detectable Hepatitis B Surface Antigen (HBsAg) for more than 6 months, b. HBV DNA levels 10 5 copies/ml (20,000 IU/ml) by PCR assay, OR c. ALT >2 times ULN, OR d. Moderate/severe hepatitis/significant fibrosis on biopsy. 3. Chronic Hepatitis B with Cirrhosis Refer to Appendix III for Treatment Algorithm Covered for patients who meet ALL the following criteria: a. Diagnosed with compensated cirrhosis b. HBV DNA levels > 10 4 copies/ml by PCR assay, OR c. ALT > 2 times upper limit of normal (ULN).

2 DOSING INFORMATION: Drug Name Intron-A Hep B & HBeAg + Indication Hep B & HBeAg - Hep B & Cirrhosis Usual Adult Dose 5 MU a day or 10 MU 3 times/week Usual Pediatric Dose 6 MU/meter 2 TIW (max. 10 MU TIW) Pegasys * * 180 mcg/week t been established Epivir- HBV 100 mg/day 3 mg/kg/day (max. 100mg/day) Hepsera 10 mg/day t been established Tyzeka 600 mg/day t been established Baraclude * * 0.5 mg/day t been established Viread * * 300 mg/day t been established *Clinical guidelines recommend the use these agents for the respective indications. **Abbreviations & tes: Hep B (Chronic Hepatitis B); HBeAg (Hepatitis B Antigen); MU (million units); TIW (three times a week); Intron A (interferon alfa-2b); Pegasys (peginterferon alfa-2a); Epivir-HBV (lamivudine); Hepsera (adefovir dipivoxil); Tyzeka (telbivudine); Baraclude (entecavir), Viread (tenofovir). ***Dose adjustments for Renal insufficient patients may be different (Refer to PI) AUTHORIZATION PERIOD: Intron A (interferon alfa-2b) Initial approval: 16 Weeks Extended approval(pediatric patients): Additional 8 weeks, review of response to interferon therapy is required to determine continuation of therapy beyond 16 weeks. *t approved for chronic hepatitis B adult patients with detectable Hepatitis B e Antigen (HBeAg+) beyond 16 weeks. Pegasys (peginterferon alfa-2a) for chronic hepatitis B with HBeAg positive OR negative Initial approval: 16 Weeks Extended approval: Additional 32 weeks Review of response to interferon therapy is required to determine continuation of therapy beyond 16 weeks. Pegasys is approvable for a MAXIMUM of 48 Weeks te: Interferon therapy is contraindicated in patients who suffer from decompensated liver disease, autoimmune hepatitis or a history of autoimmune disease, and patients who are immunosuppressed transplant recipients. Epivir-HBV (lamivudine), Hepsera (adefovir dipivoxil), Baraclude (entecavir), Tyzeka (telbivudine), and Viread (tenofovir) are available on Coventry s prescription drug coverage and do not require a prior authorization. NON-COVERAGE: 1. Use not approved by the FDA; and 2. The use is unapproved and not supported by the literature or evidence as an accepted off-label use. (see Off-Label Use Policy for determining accepted use )

3 Appendix I: Treatment Algorithm for Chronic Hepatitis B with HBeAg + HBeAg + Detectable HBsAg > 6 months HBV DNA 10 5 c/ml or 20,000 IU/ml(PCR) HBV DNA < 10 5 c/ml or <20,000 IU/ml (PCR) Treatment Monitor every 6-12 months rmal ALT ( 2 x ULN) Biopsy, if >40 yrs, ALT persistently high normal (2xULN), or with family history of HCC Treatment, if biopsy shows moderate/severe inflammation or significant fibrosis. Low efficacy with current treatment. Observe; consider treatment when ALT becomes elevated. Elevated ALT (>2 x ULN) Treat with either one of the following: IFN-α Nucleoside Analogs (NA) Intron A (standard) (for 16 Weeks) Pegasys (pegylated) (for 48 Weeks) Epivir- HBV** (1 year) Hepsera Viread Baraclude Tyzeka** HBV DNA 2 Log 10 Drop (Continue treatment) HBV DNA <2 Log 10 Drop alternative NA. End Point: Seroconversion from HBeAg to Anti-HBe. For treatment with NA, complete at least 6 months of additional treatment after appearance of Anti-HBe. ** t recommended due to high rate of drug resistance.

4 Appendix II: Treatment Algorithm for Chronic Hepatitis B with HBeAg - HBeAg - Detectable HBsAg > 6 months HBV DNA 10 5 c/ml or 20,000 IU/ml(PCR) Elevated ALT (>2 x ULN) HBV DNA > 10 4 c/ml or >2000 IU/ml (PCR) rmal ALT (1-2 x ULN) HBV DNA < 10 4 c/ml or <2000 IU/ml (PCR) ALT ULN Consider liver biopsy. Treatment, if biopsy shows moderate/severe inflammation or significant fibrosis. Observe; treat if HBV DNA or ALT becomes higher. Treat with either one of the following: IFN-α Nucleoside Analogs (NA) Intron A (standard) (1 year) Pegasys (pegylated) (1 year) Epivir- HBV** (>1 year) Hepsera (>1 Year) Viread Baraclude (>1 Year) Tyzeka** (>1 Year) HBV DNA 2 Log 10 Drop (Continue treatment) HBV DNA <2 Log 10 Drop alternative NA. End Point: Sustained rmalization of ALT and Undetectable HBV DNA by PCR Assay ** t recommended due to high rate of drug resistance.

5 Appendix III: Treatment Algorithm for Chronic Hepatitis B with Cirrhosis HBeAg +/- HBV DNA (PCR) Detectable HBV DNA (PCR) Undetectable Compensated Decompensated Compensated Decompensated HBV DNA < 2000 IU/ml HBV DNA > 2000 IU/ml Observe Refer for Liver Transplant Consider treatment if ALT elevated (ALT > 2x ULN) Coordinate treatment with transplant center. Treatment should be promptly initiated with a NA that can produce rapid viral suppression with low risk of drug resistance. Epivir-HBV (or Tyzeka) + Hepsera or Baraclude Life-long treatment is recommended. IFN-α (standard or pegylated) should not be used. Lifelong treatment recommended if recurrent hepatitis B post-liver transplantation. Treatment with NA-- Epivir-HBV**, Hepsera, Tyzeka**, Viread, or Baraclude as initial therapy. Patients should receive long-term treatment; may stop in HBeAg+ patients if confirmed HBeAg seroconversion and have completed at least 6 months of consolidation therapy; may stop in HBeAg- patients if confirmed HBsAg clearance. IFN-α use associated with flares of hepatitis and risk of hepatic decompensation. ** t recommended due to high rate of drug resistance.

6 REFERENCES: 1. Marcellin P, Lau GKK, Bonino F, et al. Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med. 2004;351(12): Lok ASF, McMahon B. Chronic hepatitis B. Hepatology 2001; 34: Hepatitis B Foundation. Available at: Accessed: January Manesis EK, Hadziyannis SJ. Interferon alpha treatment and retreatment of hepatitis B e antigennegative chronic hepatitis B. Gastroenterology 2001;121: Papatheodoridis GV, Manesis E, Hadziyannis SJ. The long-term outcome of interferon-alpha treated and untreated patients with HBeAg-negative chronic hepatitis B. J Hepatol 2001;34: Lok AS, Heathcote EJ, Hoofnagle JH. Management of hepatitis B: 2000 summary of a workshop. Gastroenterology 2001;120: Roche Laboratories Inc. Pegasys (peginterferon alfa 2a). Prescribing Information. Nutley, NJ: Roche; May Bristol-Myers Squibb Company. Baraclude (entecavir). Prescribing Information. Princeton, NJ: Bristol-Myers Squibb; March GlaxoSmithKline. Epivir-HBV (lamivudine). Prescribing Information. Research Triangle Park, NC. GlaxoSmithKline; December Gilead Sciences, Inc.Viread (tenofovir). Prescribing Information. Gilead Sciences; October Gilead Sciences, Inc. Hepsera (Adefovir dipivoxil). Prescribing Information. Gilead Sciences; August Schering Corporation. Intron A (interferon alfa 2b). Prescribing Information. Kenilworth, NJ: Schering Corporation; March Keeffe EB, Dieterich DT, Han SHB, et al. A Treatment Algorithm for the Management of Chronic Hepatitis B Infection in the United States. Clinical Gastroenterology and Hepatology 2004;2: Lok ASF, McMahon BJ, Practice Guidelines Committee: American Association for the Study of Liver Diseases (AASLD). Chronic hepatitis B: update of recommendations. Hepatology. 2004; 39: vartis. Tyzeka (telbivudine). Prescribing Information. vartis; October Lok ASF, McMahon BJ. American Association for the Study of Liver Diseases (AASLD) Practice guidelines: Chronic hepatitis B. Hepatology. Feb, : Loki AS, McMahon BJ. AASLD Practice Guideline: Chronic Hepatitis B: Update Hepatology 2009; 50(3):1-36. DISCLAIMER: Coventry Health Care, Inc. (CHC) medical policies, technology assessments, and medical reviews (collectively CHC Policies ) are developed by CHC to provide guidance in administering plan benefits and constitute neither offers of coverage nor medical advice. Access to CHC Policies is provided for general reference purposes only and does not infer guaranteed coverage. CHC does not provide health care services or supplies. Providers are expected to exercise their independent medical judgment in rendering the most appropriate care. State and federal law, as well as health plan policy terms and conditions and CHC Policies in effect on the date that any service is rendered, including but not limited to definitions and specific inclusions/exclusions, take precedence over clinical policy and must be considered first in determining eligibility for coverage. Coverage may also differ for CHC Medicare and/or Medicaid members based on any applicable Centers for Medicare & Medicaid Services (CMS) coverage statements including National Coverage Determination (NCD), Local Medical Review Policies (LMRP), and/or Local Coverage Determinations (LCD). As clinical technology is continually updated, CHC policies are subject to periodic updates. Do not rely on printed versions of CHC policies as they may be outdated. part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or means without the written consent of CHC. Dec 2010