Mr. C is a 58-year-old professor of computer science who self-referred himself for discussion of treatment options. First diagnosed in his early twenties with hepatitis B, he reports a history of being hepatitis B surface antigen (HBsAg) positive for at least 30 years' duration. At the time of his initial diagnosis, he was found to be HBsAg positive and told that he was a "healthy carrier" without need of further treatment. He now presents because of abnormal liver enzymes on routine examination, which he pursued because of mild chronic fatigue.

Physical examination revealed a healthy-appearing middle-aged man. There were no peripheral stigmata of chronic liver disease, such as spider angiomas, ascites, or peripheral edema. Splenomegaly was noted, but the exam was otherwise normal. Laboratory data were as follows: alanine aminotransferase (ALT) 250 U/L; aspartate aminotransferase (AST) 180 U/L; total bilirubin 1.1 mg/dL; albumin 3.9 mg/dL; and prothrombin time 14.2 seconds/International Normalized Ratio (INR), 1.0; HBsAg positive; HBeAg negative; HBeAb positive; and HBV DNA 16,000 IU/L (80,000 copies/mL). The complete blood count was normal except for a platelet count of 88,000 mm³. Abdominal ultrasound showed splenomegaly.

DECISION POINT: Would You Recommend Treating This Patient?

Discussion

(b) This patient should be considered for treatment due to the diagnostic and clinical findings that are strongly suggestive of cirrhosis: splenomegaly and decreased platelet count. In light of these findings of cirrhosis, the HBV DNA level of 16,000 IU/L indicates treatment is appropriate.

Some differences exist in current recommendations for treatment of patients with HBV-related cirrhosis.^1,2 The AASLD Practice Guidelines suggest that patients with HBV-related compensated cirrhosis be treated if the HBV DNA titer is >20,000 IU/L (>100,000 copies/mL).² By contrast, the US Treatment Algorithm recommends that patients with compensated cirrhosis due to chronic HBV should be treated if the HBV DNA titer is >2000 IU/L (>10,000 copies/mL).¹

A study by Liaw et al suggests that antiviral therapy—in this study, lamivudine—may reduce the risk of decompensated liver disease and may also decrease the incidence of hepatocellular carcinoma (HCC).³ A total of 651 patients were enrolled, all positive for HBV DNA and HBsAg and with an Ishak fibrosis score of ≥4. Both HBeAg positive and HBeAg negative patients were included in the study. Patients were randomized 2:1 to lamivudine 100 mg/day and placebo for up to 5 years. The primary endpoint was time to disease progression defined as an increase in Child-Pugh score of ≥2, development of HCC, spontaneous bacterial peritonitis, bleeding upper gastrointestinal varices, or liver-related death. The primary end point of disease progression was reached in 7.8% of patients receiving lamivudine compared with 17.7% of patients receiving placebo (P = .001) (Fig. 1).³ Furthermore, the Child-Pugh score increased in 3.4% of the lamivudine group compared with 8.8% of the placebo group (P = .02). Treatment was also noted to be associated with a decreased incidence of HCC: 3.9% in the lamivudine group versus 7.4% in the placebo group (P = .047). Another important finding in this study was the observation that the benefit of treatment was most noticeable among patients who did not develop the YMDD mutation associated with lamivudine resistance.

Figure 1: Kaplan-Meier Estimates of Time to Disease Progression*³

Figure 2: Kaplan-Meier Estimate of Time to Diagnosis of Hepatocellular Carcinoma

Treatment considerations in patients with HBV-related cirrhosis should include the endpoints of therapy, the likelihood of resistance with antiviral therapy, and the possibility that interferon therapy may be associated with a clinically significant flare of hepatitis. After a discussion of risks and benefits of treatment and the pros and cons of available treatment options, Mr. C was started on a nucleoside/tide agent with a better resistance pattern, in this case entecavir. His serum HBV DNA level became undetectable after 8 months and he was continued on treatment indefinitely.

References

1. Keeffe EB, Dieterich DT, Han SH, et al. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States: an update. Clin Gastroenterol Hepatol. 2006;4:936-962.
2. Lok AS, McMahon BJ. Chronic hepatitis B: update of recommendations. Hepatology. 2004;39:857-861.
3. Liaw YF, Sung JJ, Chow WC, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med. 2004;351:1521-1531.