Levels of serum hepatitis B virus (HBV) DNA are used as a marker of efficacy of antiviral therapy. The association between serum HBV DNA levels and risk of hepatocellular carcinoma (HCC) has not been fully evaluated.OBJECTIVES
To investigate the association between serum HBV DNA levels and the incidence of HCC in patients infected with HBV.DESIGN AND INTERVENTION
This prospective cohort study included individuals who were seropositive for HBV surface antigen (HBsAg) and seronegative for hepatitis C antibodies. Exclusion criteria included HCC. All participants were interviewed at study entry and underwent a full health examination, which included abdominal ultrasonography and serologic testing. A 10 ml blood sample from each participant was used for serologic tests, including detection of HBsAg and HBV e antigen (HBeAg). Measurements of serum alanine aminotransferase (ALT) levels, serum HBV DNA levels (by polymerase chain reaction), and serum HBV DNA levels (by in vitro nucleic acid amplification) were taken. Patients were followed-up at regular intervals until the end of study or diagnosis of HCC; repeat serologic testing was performed at each visit. HCC was detected at follow-up or from data from the national cancer registry or national death certification system. HCC was diagnosed by histopathology, a lesion detected by ≥2 imaging modalities or by 1 imaging modality and a serum alpha-fetoprotein level ≥400 ng/ml.OUTCOME MEASURES
The main outcome measures were serum HBV DNA level and incidence of HCC.RESULTS
In total, 3,653 patients (30-65 years old) were included in the study. Over a mean follow-up of 11.4 years and 41,779 person-years, 164 cases of HCC and 364 deaths attributable to HCC were detected. The risk of developing HCC increased with increasing serum HBV DNA level at study entry in a dose-response relationship (hazard ratio [HR] for HCC 1.0, 95% CI 0.5-2.2 for 300-9,999 copies/ml; HR 2.7, 95% CI 1.3-5.6 for 10,000-99,999 copies/ml; HR 8.9, 95% CI 4.6-17.5 for 100,000-999,999 copies/ml; and HR 10.7, 95% CI 5.7-20.1 for ≥1,000,000 copies; P<0.001). This relationship was significant after adjustment for age, sex, alcohol consumption, cirrhosis, serum ALT levels, HBeAg serostatus, and smoking. The dose-response relationship was strongest for individuals who were seronegative for HBeAg, without cirrhosis, and with normal serum ALT levels (HR for HCC 1.4, 95% CI 0.5-3.8 for 300-9,999 copies/ml; HR 4.5, 95% CI 1.8-11.4 for 10,000-99,999 copies/ml; HR 11.3, 95% CI 4.5-28.4 for 100,000-999,999 copies/ml; and HR 17.7, 95% CI 6.8-46.3 for ≥1,000,000 copies/ml; P<0.001). Patients with elevated serum HBV DNA levels at study entry and throughout follow-up had the highest risk for HCC.CONCLUSION
A serum HBV DNA level ≥10,000 copies/ml is a strong risk predictor for developing HCC, and is independent of HBeAg, serum ALT levels, and cirrhosis.