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High HBV Viral Load Predicts Liver Fibrosis and Cancer


High hepatitis B virus (HBV) DNA levels were associated with worse liver fibrosis, hepatitis reactivation, and development of hepatocellular carcinoma (HCC) in hepatitis B "e" antigen (HBeAg) negative patients in 2 recent studies described in the July 2011 Journal of Viral Hepatitis.

Over years or decades, chronic hepatitis B can cause severe liver disease including cirrhosis and hepatocellular carcinoma. But the factors that lead to advanced disease progression in some patients but not others are not fully understood.

Liver Fibrosis

In the first study, Faisal Sanai from King Abdulaziz Medical City in Riyadh, Saudi Arabia, and colleagues compared occurrence of moderate-to-severe fibrosis (Metavir stage F2 or higher) and predictive factors among chronic hepatitis B patients with HBV DNA viral load above or below 2000 or 20,000 IU/mL.

The researchers performed prospective liver biopsies on 203 HBeAg negative patients. Most (86%) had HBV genotype D. Participants were categorized into 4 groups:

  • Group 1 (n = 55): HBV DNA > 20,000 IU/mL and persistently elevated (> 40 U/L) alanine aminotransferase (ALT);
  • Group 2 (n = 34): HBV DNA > 20,000 IU/mL and persistently normal ALT;
  • Group 3 (n = 40): HBV DNA < 20,000 IU/mL and persistently elevated ALT;
  • Group 4 (n = 74): HBV DNA < 20,000 IU/mL and persistently normal ALT.

They later re-analyzed all groups using a lower viral load cut-off of 2000 IU/mL.


  • Stage F2 or higher fibrosis was detected in 72.7% of patients in Group 1, 52.9% in Group 2, 57.5% in Group 3, and 18.9% in Group 4.
  • There were no significant differences when using an HBV DNA cut-off of 20,000 vs 2000 IU/mL, although there was a trend toward less fibrosis in Group 2.
  • In a multivariate analysis, being in Group 4 -- that is, having viral load < 20,000 and normal ALT -- and milder necroinflammatory grade (A0-A1) were independent predictors of lower fibrosis risk (odds ratio 0.03 and 0.14, respectively).
  • The specificity, positive predictive value, and negative predictive value of persistently elevated AL for detection of stage F2 or higher fibrosis were 80%, 69%, and 65%, respectively, using the 2000 IU/mL viral load cut-off.
  • Values were 86%, 73%, and 63%, respectively, using the 20,000 IU/mL cut-off.
  • Sensitivity improved marginally using the lower viral load cut-off (51% vs 42%, respectively).

"Significant fibrosis is prevalent in a large proportion of HBeAg negative patients with high viremia and persistently normal ALT," the study authors concluded. "Lower HBV DNA cut-offs could be adopted with marginal gains in fibrosis detection and without loss of diagnostic accuracy."

Hepatitis Reactivation and Liver Cancer

In the second study, Takahide Nakazawa from Kitasato University in Sagamihara, Japan, and colleagues looked at the time course and predictive factors for hepatitis reactivation and development of liver cancer, and their association with HBV DNA level, among 104 HBeAg negative patients with persistently normal ALT.


  • During an average follow-up period of about 6 years, 5 participants (4.8%) developed liver cancer and 14 (13.5%) experienced hepatitis reactivation.
  • At 5 years the cumulative rates of liver cancer and hepatitis reactivation were 2.4% and 13.7%, respectively.
  • At 10 years the corresponding rates were 9.9% and 15.5%, respectively.
  • In a univariate analysis, HBV DNA viral load > 5 log copies/mL was the only predictor of liver cancer.
  • In a multivariate analysis, HBV DNA > 5 log copies/mL and ALT between 20 and 40 IU/L were independent predictors of hepatitis reactivation.
  • Because there was no independent association between ALT level and development of liver cancer, the researchers proposed that HBV DNA level was an "essential predictor."
  • Baseline HBV DNA level was related to future levels, and was not subject to wide fluctuations.

"Our results showed that an HBV DNA level of > 5 log copies/mL predicts subsequent hepatocarcinogenesis and hepatitis reactivation in HBeAg negative carriers with persistently normal ALT," the researchers concluded. "As the baseline HBV DNA level reflects the future level, appropriate clinical management according to the viral level is expected to decrease future risk."

Investigator affiliations:

Sanai study: Department of Hepatobiliary Sciences, King Abdulaziz Medical City, Riyadh; Division of Gastroenterology, Department of Medicine, King Faisal Specialist Hospital & Research Center, Riyadh; Gastroenterology Department, Riyadh Military Hospital, Riyadh; Division of Gastroenterology, Department of Medicine, King Fahad General Hospital, Jeddah; Department of Molecular Virology, Research Center, King Faisal Specialist Hospital & Research Center, Riyadh; Department of Medicine, King Abdulaziz Medical City, Al-Ahsa; Division of Gastroenterology, Department of Medicine, King Khalid University Hospital, King Saud University, Riyadh; Clinical Research Center, King Abdullah International Medical Research Center, National Guard Health Affairs, Riyadh; Liver Disease Research Center, King Saud University, Riyadh, Kingdom of Saudi Arabia.

Nakazawa study: Department of Gastroenterology, Kitasato University East Hospital, Sagamihara; Nakazawa Medical Clinic, Sagamihara; Department of Clinical Laboratory, Kitasato University East Hospital, Sagamihara, Japan.



FM Sanai, A Helmy, KI Bzeizi, et al. Discriminant value of serum HBV DNA levels as predictors of liver fibrosis in chronic hepatitis B. Journal of Viral Hepatitis 18(7):e217-25 (abstract). July 2011.

T Nakazawa, A Shibuya, A Takeuchi, et al. Viral level is an indicator of long-term outcome of hepatitis B virus e antigen-negative carriers with persistently normal serum alanine aminotransferase levels. Journal of Viral Hepatitis 18(7):e191-199 (abstract). July 2011.