Even among hepatitis B patients who achieve other markers of disease remission or "cure," seroclearance of hepatitis B surface antigen (HBsAg) is a rare event.

Two studies presented at the recent 58th Annual Meeting of the American Association for the Study of Liver Diseases in Boston (November 2-6, 2007) looked at predictors of HBsAg clearance and long-term outcomes in patients with chronic hepatitis B.

Study 1

In the first study, researchers in Hong Kong conducted a large-scale longitudinal study investigating virological, histological, and clinical aspects -- including the risk of development of hepatocellular carcinoma (HCC) -- in patients with HBsAg seroclearance.

The study included 298 patients (211 male and 87 female; median age at presentation 43 years) with HBsAg seroclearance. Participants were followed up every 3-6 months for clinical assessment. Intrahepatic HBV DNA and covalently closed circular DNA (cccDNA) were measured by real-time PCR. Serum HBV DNA was measured by the Artus HBV RG Test. Liver stiffness was assessed using transient elastography (FibroScan).

Results

• The median age at the time of HBsAg seroclearance was 49.6 years.

• The total median follow-up duration was 108.9 months and the median follow-up duration after HBsAg seroclearance was 36.4 months.

• Liver biopsies were performed on 29 patients a median 48.6 months after HBsAg seroclearance.

• All patients had detectable intrahepatic HBV DNA (median 1.68 copies/cell).

• cccDNA was detectable in 23 patients (79.3%; median 0.03 copies/cell).

• Of the 29 patients who underwent liver biopsies, 9 had sera available within 1 year and 16 patients had samples between 5 and 10 years after HBsAg seroclearance for HBV DNA analysis.

• All 9 patients of the former patients had undetectable HBV DNA (<1.1 IU/mL) within 1 year of HBsAg seroclearance.

• 4 of 16 of the latter group (25%) had detectable HBV DNA levels between 5 and 10 years after HBsAg seroclearance (median 2.37 IU/mL).

• Of the 26 patients with adequate liver tissue samples for histological examination, 4 had mild fibrosis (stage F1) and 5 had minimal necroinflammation.

• FibroScan was performed on 76 and 78 patients who had HBsAg seroclearance at age <50 and > 50 years, respectively.

• Significant fibrosis (liver stiffness > 8.1 kPa) was observed only in 7.9% (6 of 76) patients with HBsAg seroclearance at age < 50 compared to 29.5% (23 of 78) with HBsAg seroclearance at age > 50 (P = 0.001).

• 7 patients developed HCC at a median age of 69 years.

• Kaplan-Meier analysis showed that the risk of HCC development in patients with HBsAg seroclearance at age < 50 was significantly less than those with seroclearance at age > 50 (P = 0.004).

Based on these findings, the investigators concluded, "Although serum HBV DNA was detectable in only a small proportion of patients with HBsAg seroclearance, intrahepatic HBV DNA was still present in all patients. Nevertheless, patients who cleared HBsAg at age < 50 had significantly less fibrosis and lower chance of HCC development than those with HBsAg seroclearance at > 50 years."

Study 2

In the second study, Greek researchers conducted a long-term follow-up study to assess rates of and possible factors associated with HBsAg seroclearance. The study included 1139 initially HBsAg seropositive asymptomatic adult HBV carriers in eastern and northern Greece enrolled between 1990 and 1999. Most (59%) were men and the average age was 32 years.

Participants were prospectively followed for a period up to 17 years (1990-2007). Viral markers, liver biochemistry, and physical examination performed at entry and every 6-24 months. Abdominal ultrasound was done at entry and every 3-4yrs. Serum HBV DNA levels were measured using the Amplicor HBV Monitor kit. HBsAg status at the last follow-up was also tested.

Results

• Serum HBsAg cleared in 137 patients (12%) at a mean age of 41 years after study entry.

• The cumulative probability of HBsAg seroclearance after 17 years was only 5.3% for HBV carriers younger than 20 years at study entry (ranging from 1.9% in low endemic areas to 21% in high endemic areas).

• The probability was about 27% for those with age > 20 years at study entry (ranging form 11% in low to 45% in high endemic areas).

• Hepatitis relapse occurred in 182 patients (16%) 0.5 to 16 years after study entry, as indicated by ALT levels elevated > 1.5 x the upper limit of normal and detectable serum HBV DNA.

• During the follow-up period, age at entry and sustained remission of hepatitis were significantly associated with HBeAg seroclearance (P<0.05).

• The multivariate-adjusted odds ratios (95% CI) of HBeAg seroclearance were:

• 1.21 (1.32-2.43) for serum ALT level at study entry > 40 IU versus < 40 IU;

• 6.26 (1.87-34.47) for age < 20 years versus > 20 years;

• 2.18 (7.25-23.91) for serum HBV DNA <103 versus >103 copies/mL.

"The cumulative rate of HBsAg seroclearance was 30% in asymptomatic carriers after 17 years of follow-up," the investigators concluded. "Longer follow-up period and sustained remission were associated with a significantly increased HBsAg seroclearance rate."

11/20/07

References

D Wong, C Lai, J Fung, and others. Large Scale Longitudinal Study of Chronic Hepatitis B Patients with Hepatitis B Surface Antigen Seroclearance. 58th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2007). Boston, MA. November 2-6, 2007. Abstract 900.

S Kotsiou, G Zacharakis, J Koskinas, and others. Factors associated with HBsAg seroclearance in asymptomatic carriers of endemic areas during a long follow-up period of up to 17 years. AASLD 2007. Abstract 913.