Uncontrolled hepatitis B virus (HBV) replication leads to poor clinical outcomes, and new evidence shows a direct correlation between HBV DNA level and the risk of hepatocellular carcinoma (HCC). Those were the main conclusions of the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-Hepatitis B Virus (REVEAL-HBV) Study reported in JAMA earlier this year.¹

The REVEAL-HBV Study is currently the largest and longest study to evaluate the relationship between HCC and serum HBV DNA level. This prospective cohort trial included 3653 persons with untreated hepatitis B (and no hepatitis C) who were recruited at a community-based cancer screening program in Taiwan from 1991 to 1992. Twelve percent of participants reported alcohol consumption. HBV is particularly endemic in Taiwan, where it is usually acquired perinatally or early in childhood. Most infected persons in Taiwan are HBeAg positive, are infected with HBV genotype B or C, have high levels of HBV DNA, and have normal ALT levels.

Over an average of 11.4 years, there were 164 new cases of HCC. The risk of HCC was directly related to HBV DNA level at baseline (Figure 1A). After 13 years of follow-up, 15% of the patients with the highest levels of HBV DNA (≥1 million copies/mL) developed HCC (hazard ratio [HR] = 6.1), compared with only 1.3% of those with undetectable HBV DNA (HR = 1). In addition, there was a particularly strong dose-response relationship between HBV DNA and HCC for the subset of patients (80% of the total cohort) who were HBeAg negative, with a normal ALT, and no cirrhosis at baseline (Figure 1B). In this subgroup, 13.5% of those with HBV DNA ≥1 million copies/mL developed HCC (HR = 17.7) compared with 0.7% of those with undetectable HBV DNA (HR = 1).

Figure 1. Cumulative Incidence of Hepatocellular Carcinoma by Serum
HBV DNA Level at Study Entry in (A) Entire Cohort (N = 3653) and (B) the Subcohort of HBeAg Negative, Normal ALT Patients Without Cirrhosis (n = 2925).

Follow-up HBV DNA level was measured at a median of approximately 10 years. Among those whose HBV DNA level was 10,000 to 99,999 copies/mL at baseline, HCC risk increased if the HBV DNA rose to ≥100,000 copies/mL at follow-up (HR = 3.5). Among those whose baseline HBV DNA was ≥100,000 copies/mL, risk was highest (HR = 10.1) if the level remained in that range at follow-up, whereas the risk was lower (but still elevated) if the HBV DNA level declined (HR = 7.3 for 10,000–99,000 copies/mL at follow-up and HR = 3.8 for <10,000 copies/mL at follow-up).

Other risk factors for HCC in the REVEAL-HBV Study included male gender, advanced age, smoking, alcohol consumption, HBeAg positivity, elevated ALT level, and cirrhosis at baseline. After adjustment for these risk factors, HBV DNA level at baseline remained an independent predictor of HCC (P < .001).

This important study demonstrates that the risk of HCC is related to high HBV DNA levels rather than elevated ALT. High levels of HBV DNA in the serum are already known to be a risk factor for treatment resistance,² as well as progression to cirrhosis and hepatic decompensation.^3-6 The new data from the REVEAL-HBV Study provide further evidence that high HBV DNA is a strong predictor of poor outcome, including HCC. These data support the principle that patients with elevated serum HBV DNA levels (≥10,000 copies/mL) should be closely monitored and treated.

References

1. Chen C-J, Yang H-I, Su J, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA. 2006;295:65-73.
2. Yuen M-F, Sablon E, Hi C-K, Yuan H-J, Lai C-L. Factors associated with hepatitis B virus DNA breakthrough in patients receiving prolonged lamivudine therapy. Hepatology. 2001;34:785-791.
3. Yang H-I, Iloeje UH, Su J, et al. Progression to decompensated cirrhosis in chronic hepatitis B virus infected persons is strongly associated with baseline viral load [abstract 538]. Presented at: 40th Annual Meeting of the European Association for the Study of the Liver; April 13-17, 2005; Paris, France.
4. Iloeje UH, Yang HI, Su J, et al. Viral load not serum ALT is the primary predictor of progression to cirrhosis in persons chronically infected with HBV: results from a long-term prospective study [abstract 497]. Presented at: 40th Annual Meeting of the European Association for the Study of the Liver; April 13-17, 2005; Paris, France.
5. Chen CJ, Yang HI, Su J, et al. Viral load is a strong predictor of liver cirrhosis risk in people chronically infected with hepatitis B virus regardless of hepatitis B e antigen status [abstract 476]. Presented at: 40th Annual Meeting of the European Association for the Study of the Liver; April 13-17, 2005; Paris, France.
6. Iloeje UH, Yang HI, Su J, et al. Serum hepatitis B virus DNA level predicts the incidence of liver cirrhosis in persons chronically infected with HBV [abstract 496]. Presented at: 40th Annual Meeting of the European Association for the Study of the Liver; April 13-17, 2005; Paris, France.