By Liz Highleyman

The R.E.V.E.A.L.-HBV trial was designed to assess the incidence of and risk factors for hepatocellular carcinoma (HCC) in patients with hepatitis B virus (HBV) infection.

Previously published results from the study showed that HBV viral load was a significantly predictor of HCC. However, that analysis included individuals with liver cirrhosis at baseline, and did not evaluate the usefulness of serial HBV DNA or alanine aminotransferase (ALT) measurements in predicting HCC risk.

The present analysis, presented at the 43rd annual meeting of the European Association for the Study of the Liver (EASL) last week in Milan, looked at HCC risk taking into account changes in HBV DNA and ALT over time.

This analysis included participants who were hepatitis B surface antigen (HBsAg) seropositive, negative for antibodies against hepatitis C virus (HCV), and did not have liver cirrhosis at study entry. All follow-up blood samples for the 1564 patients with a baseline HBV DNA of 104 copies/mL or greater were tested; for the 2020 subjects with lower baseline viral load, only the baseline samples were analyzed.

Newly developed HCC was ascertained through data linkage with computerized profiles of the National Cancer Registry and Death Certification System in Taiwan, and confirmed using established criteria. Time-dependent Cox's proportional hazard models were used to derive multivariable adjusted hazard ratios, which included entry and follow-up HBV DNA levels as time-independent and time-dependent variables.

Results

• 3584 subjects contributed a total of 42,878 person-years of follow-up.

• During follow-up, there were 131 new cases of HCC, or a crude incidence rate of 305.5 per 100,000 person-years.

• In the regression model adjusting for sex, age, cigarette smoking, alcohol consumption, and hepatitis B "e" antigen (HBeAg) status, HCC risk increased with rising ALT and HBV DNA levels (P for trend < 0.001).

• In a model integrating both baseline and follow-up HBV DNA levels, adjusted hazard ratios were (with reference HBV DNA < 300 copies/mL):

• 4.5 for HBV DNA levels of 300-9999 copies/mL;
• 3.6 for HBV DNA 10,000-99,999 copies/mL;
• 4.2 for HBV DNA 100,000-999,999 copies/mL;
• 7.3 for HBV DNA > 106 copies/mL.

• The corresponding adjusted hazard ratios for serum ALT levels were (with reference ALT <16 U/L):

• 1.8 for ALT 16 to < 45 U/L;
• 3.8 for ALT of 45 U/L or higher.

• Age, sex, HBeAg status, and alcohol consumption were also important predictors of HCC risk.

Conclusion

"These results confirm that increasing HBV DNA level remains a significant predictor of HCC after taking follow-up HBV DNA and change in serum ALT into account," the investigators concluded. "The persistence of high HBV load leads to the highest HCC risk."

They recommended that, "Long-term monitoring of HBV viral load is essential for the management of chronic hepatitis B."

Genomics Research Center, Academia Sinica, Taipei, Taiwan; Graduate Institute Of Epidemiology, College of Public Health, National Taiwan University, Taipei, Taiwan; Global Epidemiology And Outcomes Research and Global Clinical Research, Bristol-Myers Squibb Company, Wallingford, CT.

4/29/08

Reference
CJ Chen, HI Yang, J Su, and others. Serial monitoring of viral load and serum alanine aminotranferase level and the risk of hepatocellular carcinoma (HCC): R.E.V.E.A.L.-HBV study update. 43rd annual meeting of the European Association for the Study of the Liver (EASL 2008). Milan, Italy. April 23-27, 2008.