By Liz Highleyman

Over years or decades, a proportion of people with chronic hepatitis B virus (HBV) infection will develop liver cirrhosis and hepatocellular carcinoma (HCC). It is difficult to predict which patients will develop advanced liver disease, but elevate alanine aminotransferase (ALT) levels -- an indicator of liver inflammation -- is one risk factor.

As reported at the Digestive Disease Week (DDW 2009) annual meeting last week in Chicago, Hwai Yang and colleagues with the REVEAL-HBV Study Group sought to shed further light on the relationship between elevated ALT and HBV DNA level -- an indicator of active viral replication.

The researchers previously showed that elevated serum HBV DNA predicts future changes in serum ALT, which in turn is associated with liver disease progression. In the present analysis, they looked at the influence of HBV genotype and specific gene mutations on this association.

The analysis focused on a subgroup of 1986 participants in the REVEAL-HBV study cohort who had normal serum ALT at baseline (< 45 U/L) and had at least 3 ALT tests during follow-up. Within this group, 854 patients (43%), representing a total 10,354 person-years of follow-up, had an adequate HBV DNA sample to allow complete description of the viral genotype and the mutations of interest.

Baseline ALT was categorized as < 15 U/L or 15-44 U/L. The researchers used multiple logistic regression to derive adjusted odds ratios (ORs) for risk factors. The model was adjusted for HBV genotypes B, C, or B+C, and precore 1896 and basal core promoter 1762/1764 mutations.

Results

320 of 854 patients (37.5%) had at least 1 ALT elevation documented during follow-up.

Male sex, higher baseline HBV DNA, and higher baseline serum ALT level were significantly associated with future ALT elevation:

Male sex: adjusted OR 2.6;

Baseline ALT 15-44 U/L: adjusted OR 1.4 vs < 15 U/L;

Baseline HBV DNA 300-9999 copies/mL: adjusted OR 0.8 vs < 300 copies/mL;

Baseline HBV DNA 10,000-99,999 copies/mL: adjusted OR 2.3;

Baseline HBV DNA 100,000-999,999 copies/mL: adjusted OR 4.6;

Baseline HBV DNA > 1 million copies/mL: adjusted OR 5.5.

Serum HBV DNA level was the strongest predictor of ALT elevation during long-term follow-up.

The trend for HBV DNA level was highly statistically significant (P < 0.0001).

HBV genotype, hepatitis B "e" antigen (HBeAg) positive or negative status, precore G1896A, and basal core promoter A1762T/G1764A mutants did not predict serum ALT elevation.

The association between serum HBV DNA and ALT elevation still held after stratifying by HBV genotype and precore and BCP mutations.

Based on these findings, the investigators concluded, "The association between serum HBV DNA viral load and elevation of ALT level remains the same even after adjusting for HBV genotype or the presence of specific gene mutations in this cohort."

"High viral load remained the most important risk factor for ALT elevation regardless of genotype, precore and BCP mutations," they stated. "Lowering serum HBV viral load might be the key to prevent future elevation of ALT level."

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

6/9/09

Reference
HI Yang, UH Iloeje, J Su (for the R.E.V.E.A.L.-HBV Study Group). Association between HBV Replication and Serum ALT Changes is not Dependent on HBV Genotype and Mutants. Digestive Disease Week (DDW 2009). Chicago. May 30-June 4, 2009. Abstract W1800.