Clinical UM Guideline



Subject: Hepatitis B Interferon Antiviral Therapy
Guideline #:  CG-DRUG-13 Current Effective Date:    09/27/2017
Status: Reviewed Last Review Date:    08/03/2017

Description

This document focuses on treatment of chronic hepatitis B infection with U.S. Food and Drug Administration (FDA) approved injectable agents Interferon alfa-2b (Intron-A® , Merck Sharp & Dohme Corp., Whitehouse Station, NJ) and Peginterferon alfa-2a (Pegasys® , Hoffman-La Roche Inc., South San Francisco, CA). While oral agents are part of the treatment for chronic hepatitis B and are mentioned in this document, this is not intended to be a comprehensive guideline addressing the overall treatment of chronic hepatitis B.

Clinical Indications

Throughout this document the following abbreviations are used:

Medically Necessary 

Initiation of pharmacologic treatment with a FDA approved injectable agent, Interferon alfa-2b OR Peginterferon alfa- 2a, is considered medically necessary in individuals with confirmed hepatitis B when all of the following criteria have been met:

  1. HBeAg either positive or negative; and
  2. Detectable levels of Hepatitis B DNA; and
  3. Compensated liver disease; and
  4. ALT at least twice the upper limit of normal.

Not Medically Necessary

Interferon alfa- 2b OR Peginterferon alfa- 2a is considered not medically necessary for the treatment of chronic hepatitis B when any of the criteria specified above are not met, or when any of the following are present:

  1. In combination with other chronic hepatitis B FDA approved agents (either oral or injectable); or
  2. Inactive HBeAg carrier state; or
  3. Pregnant women or those who may become pregnant; or
  4. Uncontrolled depression (for example, suicide risk).
Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

HCPCS  
J9214 Injection, interferon, alfa-2b, recombinant; 1 million units [Intron A]
S0145 Injection, pegylated interferon alfa-2a, 180 mcg per ml [Pegasys]
S9559 Home injectable therapy; interferon, including administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment, per diem
   
ICD-10 Diagnosis  
B18.0 Chronic viral hepatitis B with delta-agent
B18.1 Chronic viral hepatitis B without delta-agent
B19.10 Unspecified viral hepatitis B without hepatic coma
B19.11 Unspecified viral hepatitis B with hepatic coma
   
Discussion/General Information

Hepatitis B is a virus targeting the liver. Acute infection with this virus most often results in a self-limited syndrome. Symptoms of acute infection can include fulminant hepatitis (1 to 2% of affected individuals), accompanied by nausea, vomiting and arthralgias of varying severity. In contrast, some individuals with acute hepatitis B infection are completely asymptomatic. More than 90% of all acute infections in adults resolve completely with no sequelae, with chronic infection resulting in only 5% of adults after an acute episode. In contrast, the chronic infection rates in infants who acquire infection perinatally from a mother with chronic Hepatitis B have been reported to be 90%. Since the likelihood of developing significant clinical complications is related to the duration of infection, individuals infected at birth are of special concern.

According to the Centers for Disease Control in 2014, an estimated 240 million individuals worldwide have the chronic form of hepatitis B virus infection and as many as 2.2 million individuals in the United States. Hepatitis B is endemic in Asia and chronic hepatitis B is thus more prevalent in Asian immigrants. The disease is characterized by abnormalities in blood tests of liver function such as ALT and by the persistence of the evidence of the virus in the blood stream (hepatitis B antigen or DNA evidence of the virus) and abnormalities on liver biopsy (CDC, 2016).

Many individuals are unable to recognize the symptoms of chronic hepatitis B which continues to pose challenges with providing recommendations for the management and treatment of the disease. The clinical manifestations of chronic hepatitis B are varied, but a minority (15 to 40%) will develop cirrhosis, hepatic decompensation or hepatocellular carcinoma (HCC). Chronic carriers of the hepatitis virus may have no symptoms, however even from the asymptomatic carrier, the agent is transmissible, and contact with body fluids from a hepatitis B carrier can result in infection. This transmission can occur via sexual contact or other exposure to body fluids in household contacts, occupational exposure in health care workers or to an infant from an infected mother.

An effective vaccine against hepatitis B is available and current recommendations from the Advisory Committee on Immunization Practices (ACIP) include vaccination for all infants as well as "catch up" vaccination for children or adolescents who have not previously been vaccinated. For infants of hepatitis B infected mothers the ACIP recommends immediate vaccination upon birth. ACIP also recommends immunization of health care workers and public safety workers who have exposure to blood in the workplace and any individuals at high risk for infection. This high risk group is defined as:

Medical indications: individuals on hemodialysis or individuals receiving clotting factors.

Behavioral indications: injection drug users, persons with multiple sex partners within the last 6 months, persons with a recently acquired sexually transmitted disease (STD), all recipients of care at STD clinics, men who have sex with men.

Other indications: Household and sexual contacts of individuals with chronic hepatitis B, clients and staff members of institutions for the developmentally disabled, inmates of correctional facilities, international travelers who will be in countries with high or intermediate prevalence of chronic hepatitis B for more than 6 months.

Treatment for the acute phase of hepatitis B consists of supportive care. Given that acute infections are often subclinical there may be no treatment required and individuals may not be aware of their exposure until well after it occurs. Most individuals clear HBeAg from their serum shortly after their acute infection. The most commonly used definition of the carrier state is the presence of HBeAg in the serum for at least 6 months. Carriers of hepatitis B develop either an inactive carrier state, or chronic hepatitis B infection. Chronic hepatitis B infection is characterized by persistent or intermittent elevation of ALT levels, serum levels that are positive for HBV DNA, and a liver biopsy showing chronic hepatitis. These individuals are at the greatest risk of developing progressive liver injury, cirrhosis and HCC and thus this is the group targeted for treatment.

The goal of drug treatment of chronic hepatitis B is to prevent progressive liver damage and cirrhosis and to decrease the likelihood of development of HCC. While the definitive answer as to the effect of treatment of chronic Hepatitis B on serious hepatic complications, death or HCC remains uncertain, and current treatment options are suboptimal, there is moderate evidence to support efficacy as measured by biochemical, viral and liver histological markers. The evidence for impact of treatment on hepatic complications and incidence of HCC is mostly limited to open label observational studies using interferon alfa-2b (Lin, 1999). As noted earlier, the determination of when to begin treatment and which agent to use is individualized considering subject and drug factors to achieve the greatest likelihood of compliance. Unlike treatment for chronic hepatitis C, there is no data to support the use of combination therapy in the treatment of hepatitis B and there is no indication that genomic subtyping of the virus is helpful in designing treatment regimens.

If chronic hepatitis B infection has progressed to cirrhosis, interferons are generally not recommended. The American Association for the Study of Liver Disease (AASLD, 2016) guidelines indicate that for those with cirrhosis who are HBV DNA +, oral agents may be used for individuals with compensated liver function. There is some concern that use of interferon may increase the risk of hepatic decompensation associated with interferon-induced flares of hepatitis. Individuals with cirrhosis but compensated liver function and without high levels of HBV DNA may be observed. Current AASLD recommendations advise referral for consideration for liver transplant for all chronic hepatitis B individuals with cirrhosis and decompensated liver function.

The clinical decision regarding the timing of treatment should take into consideration multiple specific factors such as age, severity of disease, likelihood of response, likelihood of compliance and co-morbid conditions. When the decision to treat has been made, the determination as to which of the available drugs to use is a clinical decision based on the individual's characteristics. Factors impacting this decision include those related to the drug and those related to the individual. When compared to oral agents, the injectable therapies have a more finite duration of treatment, more durable responses and lack of resistant HBV mutants. The disadvantages of the injectables are their side effects and the difficulties inherent in use of the subcutaneous route of administration. Side effects include significant myalgias and flu like syndrome and depression. As seen with the oral treatments for chronic hepatitis B, hepatic flares or worsening hepatitis can occur after discontinuation of interferon treatment, so careful monitoring for several weeks after the end of treatment is recommended.

In addition, the following laboratory values should be monitored at baseline and periodically during interferon therapy unless otherwise indicated (see below):

It is reported that side effects require modifications in dose or discontinuation of therapy in up to 35% of subjects treated with interferons. Should side effects or significant laboratory abnormalities occur, the dose should be reduced by 50%. If symptoms or abnormalities do not reverse, the interferon should be discontinued.

The data regarding the use of interferons in children is more limited than for adults. However, interferon alfa-2b (Intron-A) has a pediatric indication and the American Association for the Study of Liver Disease guidelines indicate that the response to treatment and the side effect profile in children resembles those seen in adults. There is no data available regarding the use of peginterferon-alfa 2a for the treatment of chronic hepatitis B in children (1-17 years old).

There is no direct comparison data regarding clinical outcomes between interferons across clinical trials due to differences between the approved agents due to the variable definitions of response, study design, heterogeneous study populations and lack of standardization of HBV DNA. The difference between these agents is primarily in dosing schedule, which may have an impact on compliance and member acceptance of chronic therapy.

Response to treatment:

Definitions

Child-Pugh Score: (also known as Child-Turcotte-Pugh score): A scoring system for severity of liver disease and likelihood of survival based on the presence of: degenerative disease of the brain (encephalopathy), the escape or accumulation of fluid in the abdominal cavity (ascites), laboratory measures of various substances in the blood (see table below), and the presence of other co-existing diseases; after calculating the CTP score using a table similar to the one below, individuals can be classified into one of three categories:

Variable

1 Point

2 Points

3 Points

Encephalopathy None Moderate Severe
Ascites None Mild Moderate
Albumin (mg/dL) greater than 3.5 2.8-3.5 less than 2.8
Prothombin time (International Normalized ratio) prolonged less than 4 4-6 greater than 6

Bilirubin (mg/dL)

Primary biliary cirrhosis

Cirrhosis/primary

Primary sclerosing cholangitis

1-4 4-10 greater than 10
All other diseases less than 2 1-3 greater than 3

Compensated liver disease: Child-Pugh score less than or equal to 6 (class A) in cirrhotic individuals before or during treatment.

Decompensated liver disease: Child-Pugh score greater than 6 (class B or class C) in cirrhotic individuals before or during treatment.

References

Peer Reviewed Publications:

  1. Chan H, Leung NW, Hui AY, et al. A randomized, controlled trial of combination therapy for chronic hepatitis B: comparing pegylated interferon-alfa2b and lamivudine with lamivudine alone. Ann Int Med. 2005; 142:240-250.
  2. Cooksley WG, Piratvisuth T, Lee SD, et al. Peginterferon alfa-2a (40kDa): an advance in the treatment of hepatitis B e antigen-positive chronic hepatitis B. J Viral Hepatitis. 2003; 10:298-305.
  3. Janssen H, van Zonneveld M, Senturk H, et al. Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomized trial. Lancet. 2005; 365:123-129.
  4. Lai CL, Ratziu V, Yuen MF, Poynard T. Viral hepatitis B. Lancet. 2003; 362:2089-2094.
  5. Lampertico P, Del Ninno E, Manzin A, et al. A randomized, controlled trial of a 24 month course of interferon alfa 2b in patients with chronic hepatitis B who had hepatitis B virus DNA without hepatitis Be antigen in serum. Hepatology. 1997; 26:1621-1625.
  6. Lampertico P, Del Ninno E, Vigano M, et al. Long-term suppression of hepatitis B antigen-negative chronic hepatitis B by 24 month interferon therapy. Hepatology. 2003; 37:756-763.
  7. Lau GK, Piratvisuth T, Luo KX, et al. Peginterferon alfa-2a, lamivudine, and combination for HBeAg-positive chronic hepatitis B. NEJM. 2005; 352(26):2682-2695.
  8. Liaw YF, Leung NW, Chang TT, et al. Extended lamivudine therapy in Asian patients with chronic hepatitis B. Gastroenterol. 2000; 119:172-180.
  9. Liaw YF, Sung JJ, Chow WC, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. NEJM. 2004; 351:1521-1531.
  10. Lin SM, Sheen IS, Chien RN, et al. Long-term beneficial effect of interferon therapy in patients with chronic hepatitis B infections. Hepatology. 1999; 29:971-975.
  11. Marcellin P, Lau GK, 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):1206-1217.
  12. Schiff ER, Dienstag JL, Karayalcin S, et al. Lamivudine and 24 weeks of lamivudine/interferon combination therapy for hepatitis B e antigen positive chronic hepatitis B in interferon non-responders. J Hepatol. 2003; 818-826.
  13. Van Zonneveld M, Flink HJ, Verhey E, et al. The safety of pegylated interferon alpha-2b in the treatment of chronic hepatitis B: predictive factors for dose reduction and treatment discontinuation. Aliment Pharmacol Ther. 2005; 21:1163-1171. 

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Centers for Disease Control. Viral hepatitis- hepatitis B information. August 4, 2016. Available at: http://www.cdc.gov/hepatitis/hbv/hbvfaq.htm#a2. Accessed on June 21, 2017.
  2. Interferon Alfa Monograph. Lexicomp® Online, American Hospital Formulary Service® (AHFS® ) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised April 6, 2016. Accessed on June 21, 2017.
  3. Interferon Alfa-2b. In: DrugPoints® System (electronic version). Truven Health Analytics, Greenwood Village, Co. Updated June 16, 2017. Available at: http://www.micromedexsolutions.com. Accessed on: June 21, 2017.
  4. Intron A. [Product Information], Whitehouse Station, NJ. Merck Sharp & Dohme Corp.; June 17, 2017. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/103132s5195lbl.pdf . Accessed on June 21, 2017.
  5. National Institute of Diabetes and Digestive and Kidney Diseases. Hepatitis B. Available at: https://www.niddk.nih.gov/health-information/liver-disease/viral-hepatitis/hepatitis-b#7 . Accessed on June 22, 2017.
  6. Pegasys. [Product Information], South San Francisco, CA. Hoffmann-La Roche, Inc. March 18, 2015. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/103964s5264lbl.pdf. Accessed on June 21, 2017.
  7. Peginterferon Alfa-2a. In: DrugPoints® System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated November 16, 2016. Available at: http://www.micromedexsolutions.com. Accessed on: June 21, 2017.
  8. Peginterferon Alfa-2a Monograph. Lexicomp® Online, American Hospital Formulary Service® (AHFS® ) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised October 26, 2015. Accessed on June 21, 2017.
  9. Terrault NA, Bzowej NH, Chang KM, et al. AASLD guidelines for treatment of chronic hepatitis B. January 2016. Available at: http://onlinelibrary.wiley.com/doi/10.1002/hep.28156/pdf . Accessed on June 21, 2017.
Index

Chronic Hepatitis B
Interferon
Interferon Alfa-2b
Intron-A
Pegasys
Peginterferon Alfa-2a

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

History

Status

Date

Action

Reviewed 08/03/2017 Medical Policy & Technology Assessment Committee (MPTAC) review. Reformatted clinical indications section. Updated References section.
Revised 08/04/2016 MPTAC review. Updated formatting in clinical indications section. Corrected grammatical error in MN and NMN statements. Clarified NMN statement. Updated Description, Discussion, and References. Removed ICD-9 codes from Coding section.
Reviewed 08/06/2015 MPTAC review. Updated Discussion and References.
Reviewed 08/14/2014 MPTAC review. Description and References updated.
Reviewed 08/08/2013 MPTAC review. Updated References and Websites.
Reviewed 08/09/2012 MPTAC review. Updated Discussion, Websites and References.
Revised 08/18/2011 MPTAC review. Revised medically necessary and not medically necessary statements. Definitions added. Websites and References updated.
Reviewed 08/19/2010 MPTAC review. Websites and References updated.
Revised 08/27/2009 MPTAC review. Clarified not medically necessary statement. Dosing table and Place of service removed. Definitions added and references updated.
Reviewed 11/20/2008 MPTAC review. Clarified medically necessary statement. References updated
Reviewed 11/29/2007 MPTAC review. References and coding updated.
Reviewed 12/07/2006 MPTAC review. References updated.
New 12/01/2005 MPTAC initial guideline development.