www.hivandhepatitis.com

EASL 2009: Does HBV Viral Load Level Predict Development of Liver Fibrosis?

Two studies presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL 2009) last month in Copenhagen looked at the association between HBV DNA level and development of fibrosis, with findings suggesting that the role of HBV viral load differs for hepatitis B "e" antigen (HBeAg) negative and HBeAg positive individuals.

Over years or decades, chronic hepatitis B virus (HBV) infection can lead to advanced liver disease including cirrhosis and hepatocellular carcinoma (HCC). Studies have shown that sustained HBV clearance reduces the risk of disease progression, but it is unclear whether HBV DNA levels in patients with persistent viremia is associated with disease severity. This is an important consideration, because viral load could potentially be used to guide decisions about when to start treatment, which is only required if liver disease is progressing.

HBV Viral Load

In the first study, C. Croagh and colleagues from Australia evaluated the prevalence of significant fibrosis or cirrhosis and examined the relationship between serum HBV DNA and alanine aminotransferase (ALT) levels, and liver inflammation and fibrosis scores in chronic hepatitis B patients.

The investigators reviewed the St Vincent's Hospital HBV database to identify patients with chronic hepatitis B who had undergone liver biopsy. Baseline demographic, biochemical, serological, and virological variables were correlated with biopsy results. Complete data on baseline serum markers and liver biopsy were available for 394 patients.

Liver fibrosis was scored according to the Metavir system (fibrosis stages F0 through F4; histological activity stages A0 through A3). Significant fibrosis was defined as F2-F4 and significant inflammation as A2-A3.

Results

• The prevalence of stage F2-F4 liver fibrosis was 58% in HBeAg negative patients with HBV DNA > 25,000 IU/ml, compared with 36% for HBeAg negative patients with HBV viral load below this level (P = 0.005).
• The fibrosis prevalence in HBeAg negative patients with high viral load was also higher than that of HBeAg positive individuals, at 40% (P = 0.002).
• In a logistic regression analysis, a significant interaction was observed between HBV DNA and HBeAg status with regard to F2-F4 fibrosis (P < 0.001).
• The odds ratio for risk of F2-F4 fibrosis with a 1 log IU/ml increase in HBV DNA was 1.42 (about 40% higher) for HBeAg negative patients, but only 0.71 (slightly lower) for HBeAg positive individuals.
• A similar interaction was found between HBV DNA level and HBeAg status with regard to stage A2-A3 liver inflammation (P < 0.013).
• The odds ratio for risk of A2-A3 inflammation with a 1 log IU/ml HBV DNA increase was 1.17 (roughly equal) for HBeAg negative patients and 0.59 (almost half) for HBeAg positive patients.
• Increasing baseline ALT level was associated with greater prevalence of significant fibrosis and inflammation in both HBeAg positive and HBeAg negative patients.

"The prevalence of significant fibrosis is highest in HBeAg negative patients with viral load of > 25,000, but is not insignificant in HBeAg negative patients with lower levels of viremia," the investigators concluded.

"Increasing HBV DNA levels correlate with increasing prevalence of significant fibrosis and inflammation in HBeAg negative disease, however in HBeAg positive disease the correlation is inverse," they added.

Department of Gastroenterology, St Vincent's Hospital, Melbourne, Australia; Molecular Research and Development, Victorian Infectious Diseases Reference Laboratory, Melbourne, Australia.

Age and ALT

In the second study, researchers from Hong Kong aimed to determine which clinical factors might help predict advanced fibrosis in HBeAg positive chronic hepatitis B patients.

The investigators prospectively studied 453 treatment-naive HBeAg positive patients referred for liver stiffness measurement by transient elastography (FibroScan), a non-invasive method of estimating fibrosis. Individuals with other causes of liver diseases besides hepatitis B were excluded.

Based on the researchers' previous histological (biopsy) validation, insignificant fibrosis was defined as liver stiffness ≤ 6.0 kPa (kiloPascals), while advanced fibrosis was defined as liver stiffness > 9.0 kPa when ALT was normal. When ALT was elevated (up to 5 x the upper limit of normal [ULN]), the corresponding thresholds were ≤ 7.5 kPa and > 12.0 kPa, respectively.

Results

• Among 74 patients with available liver biopsy results, the selected liver stiffness thresholds had 90% sensitivity to exclude and 95% specificity to confirm stage F3-F4 fibrosis.
• Based on liver stiffness, 48% of patients had insignificant fibrosis and 30% had advanced fibrosis.
• In a multivariate analysis, age and ALT were independently associated with liver stiffness.
• However, male sex, obesity, and higher HBV DNA level were not independent predictors of greater liver stiffness.
• The risk of advanced fibrosis began to increase when ALT was higher than 0.5 x ULN (odds ratio 5.0; P< 0.001).
• Among the 47 patients aged 35 or older with ALT ≤ 0.5 x ULN, 83% had liver stiffness measurements suggesting insignificant fibrosis, while 2% (1 patient) had advanced fibrosis.
• Among the 217 participants younger than 35 with ALT > 0.5 x ULN, 28% had liver stiffness suggestive of insignificant fibrosis and 37% had advanced fibrosis.

Based on these findings, the researchers concluded, "Risk of advanced liver fibrosis increased in HBeAg positive patients aged over 35 years with ALT > 0.5x ULN," but did not correlate with higher HBV viral load.

Chinese University of Hong Kong, Hong Kong, Hong Kong S.A.R.

5/29/09

References

C Croagh, S Bell, Y Kong, and others. Prevalence of Significant Fibrosis and Correlations between Histological Inflammation and Fibrosis Scores and Serum Hepatitis B (HBV) DNA Levels in Chronic Hepatitis B. 44th Annual Meeting of the European Association for the Study of the Liver (EASL 2009). Copenhagen, Denmark. April 22-26, 2009.

HL Chan, GL Wong, PC Choi, and others. Clinical Factors Predicting Advanced Liver Fibrosis in Hepatitis B e Antigen Positive Chronic Hepatitis B. 44th Annual Meeting of the European Association for the Study of the Liver (EASL 2009). Copenhagen, Denmark. April 22-26, 2009.