The U. S. Food and Drug Administration (FDA) has approved both injectable and oral agents for the management of chronic hepatitis B. This document focuses on treatment of chronic hepatitis B infection with FDA approved injectable agents Interferon alfa-2b and Peginterferon alfa-2a. 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.

Note: Please see the following related document for additional information:

• CG-DRUG-07 Hepatitis C Pegylated Interferon Antiviral Therapy

Throughout this document the following abbreviations are used:

• Alanine aminotransferase: (ALT)
• Hepatitis B "e" antigen: (HBeAg)
• Hepatitis B surface antigen: (HBsAg)
• Hepatitis B viral DNA: (HBV DNA)
• Hepatitis B virus: (HBV)
• Hepatocellular Carcinoma: (HCC)

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:

• HBeAg either positive or negative, AND
• Detectable levels of Hepatitis B DNA, AND
• Compensated liver disease; AND
• 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 contraindications are present:

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

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.

Future ICD-10 coding (effective 10/01/2013)
A draft of ICD-10 Coding related to this document, as it might look today, is available for reference and comments at: Appendix 1: Future ICD-10 coding

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 fulminate 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. 

The chronic form of the infection affects an estimated 350 million individuals worldwide and 1.25 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.

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 (Intron-A^®_, Schering Corporation, Kenilworth, NJ) (Lau, 1984; 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, 2009) guidelines indicate that for those with cirrhosis who are HBV DNA +, oral agents may be used for the 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 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):

• Hemoglobin
• WBC count and differential (baseline and weeks 1, 2, 4, 12 and 16 weeks)
• Platelet count (baseline and weeks 1, 2, 4, 8, 12 and 16 weeks)
• Liver function tests (baseline and weeks 1, 2, 4, 8, 12, 16 weeks and 3-6 months post-therapy)
• Thyroid function (baseline and as needed if symptoms of thyroid dysfunction develop)
• Electrolytes

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 a (Pegasys^®_, Hoffman-La Roche Inc., Nutley, NJ) 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:

• HBeAg-positive individuals: end point of treatment is considered seroconversion from HBeAg-positive to negative status.
• HBeAg-negative individuals: end point of treatment is considered sustained normalization of ALT and undetectable HBV DNA by PCR assay.

Child-Pugh Score: (also know 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:

• Childs A (5-6 points): 10 year survival 80-90%;
• Childs B (7-9 points): 5 year survival 60-80% and
• Childs C (10-15 points): 2 year survival less than 50%.
  

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.

Peer Reviewed Publications:

1. Chan H, 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 WGE, 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. Hoofnangle J and Bisceglie AM. Drug therapy: the treatment of chronic viral hepatitis. NEJM. 1997; 336(5):347-356.
4. Janssen 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.
5. Lai CH, et al. A one-year trial of lamivudine for chronic hepatitis B. NEJM. 1998; 339:61-68.
6. Lai CL, et al. Viral hepatitis B. Lancet. 2003; 362:2089-2094.
7. Lampertico P, 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.
8. Lampertico P, et al. Long-term suppression of hepatitis B antigen-negative chronic hepatitis B by 24 month interferon therapy.  Hepatology. 2003; 37:756-763.
9. Lau DT, et al. Long-term follow-up of patients with chronic hepatitis B treated with interferon alfa. Gastroenterology 1987; 113(5):1660-1667.
10. Lau GKK, et al. Peginterferon alfa-2a, lamivudine, and combination for HBeAg-positive chronic hepatitis B. NEJM. 2005; 352(26):2682-2695.
11. Lee WM. Hepatitis B virus infection. NEJM. 1997; 337:1733.
12. Liaw YF, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. NEJM. 2004; 351:1521-1531.
13. Liaw TF, et al. Extended lamivudine therapy in Asian patients with chronic hepatitis B. Gastroenterol. 2000; 119:172-180.
14. Lin SM, et al. Long-term beneficial effect of interferon therapy in patients with chronic hepatitis B infections. Hepatology. 1999; 29:971-975.
15. Marcellin P, et al. Peginterferon alfa-2a alone, lamivudine alone and the two in combination in patients with HBEAg-negative chronic hepatitis B. 2004;351(12):1206-1217.
16. Schiff ER, 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.
17. Sokol EM, et al. Interferon alfa therapy for chronic hepatitis B in children: a multinational randomized controlled trial.1998; 114:988-995.
18. Van Zonneveld M, 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.
19. Wong DKH, et al. Effect of alpha-interferon treatment in patients with hepatitis B e antigen-positive chronic hepatitis B. A meta-analysis. Ann Int Med. 1993; 119(4):312-323. 

Government Agency, Medical Society, and Other Authoritative Publications:

1. American Association for the Study of Liver Disease (AASLD). Lok, AS, McMahon BJ. Chronic Hepatitis B: An Update. 2009. Available at: https://www.aasld.org/practiceguidelines/Documents/Bookmarked%20Practice%20Guidelines/Chronic_Hep_B_Update_2009%208_24_2009.pdf. Accessed on June 19, 2011.
2. American Hospital Formulary Services^® (AHFS). AHFS Drug Information 2011^®_. Bethesda, MD: American Society of Health-System Pharmacists^®_; 2011.
3. Interferon Alfa-2b. In: DrugPoints System [Internet database]. Greenwood Village, Colo: Thomson Healthcare. Updated periodically. Available at: http://www.thomsonhc.com. Accessed on: June 28, 2011.
4. Intron A. [Product Information], Kenilworth, NJ. Schering Corporation; June 2011. Available at: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=7505. Accessed on June 28, 2011.
5. NICE Appraisal Consultation Document: Hepatitis B (chronic)- adefovir dipivoxil and pegylated interferon alpha-2a. Available online at http://www.nice.org.uk/page.aspx?o=268800. Accessed on June 28, 2011.
6. Peginterferon Alfa-2a. In: DrugPoints System [Internet database]. Greenwood Village, Colo: Thomson Healthcare. Updated periodically. Available at: http://www.thomsonhc.com. Accessed on: June 28, 2011.
7. Pegasys [Product Information], Nutley, NJ. Hoffman-La Roche; February 2011. Available at: http://www.gene.com/gene/products/information/pegasys/pdf/pi.pdf. Accessed on June 28, 2011.

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.