A man born in American Samoa came to the continental United States to attend college at age 18 years. He was found to have hepatitis B and was referred to a gastroenterologist in 2000 at age 31 years. At that time a liver biopsy showed chronic hepatitis B grade 2, stage 3 disease. His laboratory tests are shown in the Table below. He has always been seropositive for hepatitis B e antigen (HBeAg) and negative for antibody to e antigen (anti-HBe). He was initially treated with interferon alfa for 6 months at 10 MU TIW with little response in terms of viral suppression. There was no HBeAg seroconversion documented. Approximately 1 year later, he had a hepatitis flare-up, as assessed by liver enzymes. For the last 3 years his serum alanine aminotransferase (ALT) levels have been normal, or near normal, and HBV DNA levels have been below 20,000 IU/mL (~ 10⁵ copies/mL). The serum bilirubin and albumin levels have always been within the normal range. He was assessed in July 2005 at the age of 37 years.

Would you treat this patient with antiviral therapy?

1. Yes
2. No

Either answer may be correct. The patient does not meet typical criteria for treatment with antiviral therapy because his ALT levels have been normal for a long time. However, it is a little disturbing that he has shown a propensity for recurrent exacerbations and remissions of hepatitis associated with elevations in serum levels of HBV DNA, so treatment may need to be considered. A new liver biopsy should also be seriously considered.

This case highlights the differences between the AASLD Practice Guidelines^1,2 on management of hepatitis B and the commonly cited algorithm authored by Keeffe and colleagues.³ The Keeffe algorithm emphasizes a greater role for liver biopsy in deciding whether to treat, especially for patients with normal liver enzymes, whereas the AASLD Guidelines do not include a role for liver biopsy. The AASLD Guidelines recommend treating HBeAg positive patients who have detectable HBV DNA and elevated ALT levels, as well as HBeAg negative patients with detectable HBV DNA and elevated ALT especially if cirrhosis is present.² Alternately, Keeffe and colleagues³ point out that in patients with detectable HBV DNA and normal ALT levels, treatment should still be considered if liver biopsy shows significant disease, especially if there is considerable fibrosis. In patients with detectable HBV DNA and elevated ALT levels, treatment could be administered irrespective of liver biopsy.³ The advanced hepatic fibrosis seen on liver biopsy in this patient, albeit several years prior, should positively influence the decision to initiate treatment. Alternatively, another biopsy could be done to assess current status of the liver, although degree of fibrosis is unlikely to have improved much in the interim.

If he were to be treated, there are few data in the peer-reviewed literature that would document the utility of peginterferon therapy. It is important to note that he did not clear HBeAg the first time he was treated with interferon. Thus, the best choice of treatment would be an oral nucleoside or nucleotide analog. The appropriate duration of treatment is also not clear. Perhaps if the patient cleared HBeAg, became anti-HBe positive, and had a sustained reduction in HBV DNA with therapy, treatment could be discontinued after a period of consolidation (at least 6 months). It is more likely that he will need long-term suppressive therapy. Given that the patient is now only 37 years of age, this could entail at least 5 to 10 years of treatment if seroconversion did not take place. Such prolonged therapy would carry a significant risk of development of viral resistance to the agent being used, so a decision to treat should not be made lightly.

If the patient is not treated with an oral agent, ongoing monitoring of liver enzyme levels and HBV DNA at intervals of 3 to 6 months is critical. He had stage 3 fibrosis on liver biopsy as far back as year 2000, indicating significant liver disease, despite the facts that serum aminotransferase levels have been normal and HBV DNA levels are much lower than when he initially presented. Regular follow-up and blood testing are important because a pattern of elevated liver enzymes, not apparent based on a single set of laboratory values, may become more clear over a period of several years. In addition, a patient such as this one who was born outside the continental United States with presumed neonatal infection and active liver disease based on biopsy, should enter a surveillance program for hepatocellular carcinoma at age 40 years or immediately if there is an elevated alpha-fetoprotein level or a family history of liver cancer.

References

1. Lok ASF, McMahon BJ. Chronic hepatitis B. Hepatology. 2001;34:1225-1241.
2. Lok ASF, McMahon BJ. Chronic hepatitis B: updates of recommendations. Hepatology. 2004;39:857-861.
3. Keefe EB, Dieterich DT, Han SH, et al. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States. Clin Gastroenterol Hepatol. 2004;2:87-106.