In patients with chronic hepatitis B who are negative for hepatitis B e antigen and have low viral loads, serum levels of hepatitis B surface antigen can be used to predict risk for hepatocellular carcinoma (HCC), Dr. Tai-Chung Tseng and colleagues reported in the May issue of Gastroenterology.
In such patients, high levels of hepatitis B surface antigen (HBsAg) indicate higher risk for liver cancer, regardless of low hepatitis B DNA levels, said Dr. Tseng of the Buddhist Tzu Chi General Hospital Taipei, and associates.
HBV DNA levels are considered the major driver of disease progression in patients with chronic hepatitis B, and those with low viral loads are usually considered to be at low risk for developing HCC. However, even these patients still carry some risk for the malignancy, with an estimated annual incidence of 0.06%.
"Therefore, identification of factors predictive of HCC other than viral load in these ‘low-risk’ patients remains [imperative]," the investigators wrote (Gastroenterology 2012 Feb. 13 [doi:10.1053/j.gastro.2012.02.007]).
"Recently, HBsAg quantification has become increasingly recognized as a marker for evaluating viral replication and possible host immune control over HBV infection. A lower HBsAg level is associated with ... a lower risk of hepatitis activity," they noted.
So Dr. Tseng and colleagues assessed a large cohort of treatment-naive patients who had chronic HBV infection with genotypes B or C, but no cirrhosis. The study subjects and had been enrolled in a study of HBsAg loss in 1985-1995, and study enrollment later was extended until 2000.
The study population comprised 2,688 HBV carriers aged 28 and older at baseline who underwent frequent liver function tests, serum sampling, and abdominal ultrasonography for HCC surveillance. Approximately 61% of them were men.
The average duration of follow-up was 14.7 years (range, 2.5 to 25.8 years). A total of 191 patients developed HCC during that time, with an overall incidence of 4.8 cases per 1,000 person-years.
The average interval between baseline and development of HCC was 11 years (range, 2.5 to 24.5 years).
As expected, HBeAg positivity, higher levels of HBV DNA, and higher levels of alanine aminotransferase all were associated with a higher rate of HCC. Other factors known to raise the risk of HCC did so in this study, including older age, male gender, and infection with genotype C.
HBsAg level also was found to correlate with HCC risk, in a dose-response manner. However, it was not as strong as the other predictors in the study population as a whole or in the subgroup of patients who were HBeAg positive.
But the researchers were particularly interested in patients who were HBeAg-negative and had low viral loads, and thus were lacking the two risk factors that best predicted HCC risk.
In a univariate analysis, the hazard ratio (HR) for developing HCC was 5.4 in such patients who had a high (1,000 IU/mL or greater) HBsAg level, compared with those who had an HBsAg level lower than 1,000 IU/mL.
Further multivariate analysis showed that a high HBsAg level remained an independent risk factor for HCC, with an HR of 13.7.
"These data suggest that HBsAg level may complement HBV DNA level in predicting HCC development," especially in patients with low viral loads, Dr. Tseng and colleagues said.
They proposed that patients with low viral loads but high HBsAg levels "may harbor more hepatocytes with HBV integration than those who have a low HbsAg level. Therefore, the higher risk of HCC ... may be attributed to the increased genomic instability as a result of integrated viral sequences, which play an important role in hepatocarcinogenesis."
In this study population, the subgroup of patients who had both a low HBV DNA level and a low HBsAg level showed a cumulative incidence of HCC of only 0.2%, which is similar to the level reported in control subjects in previous studies. Thus, a low HbsAg level accompanied by a low HBV DNA level appears to reflect adequate host immune control against HBV infection and can be used to identify patients at low risk for developing HCC.
Clinicians "urgently require a good indictor to stop nucleotide analogue therapy in HBeAg-negative patients. If an HbsAg level of less than 1000 IU/mL could be reliably used to define low-risk or inactive HBV carriers, we may adopt this cutoff level as the intermediate treatment goal," assuming that the results of this study are confirmed in future research, the authors wrote.
This study was supported by the Buddhist Tzu-Chi General Hospital Taipei Branch, the National Taiwan University Hospital, the Department of Health, and the National Science Council. Dr. Tseng’s associates reported ties to Abbott, Bayer, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, and Roche.