Tumor factors associated with clinical outcomes in patients with hepatitis B virus infection and hepatocellular carcinoma.

BACKGROUND AND AIMS: Hepatitis B virus (HBV) infection is a common cause of hepatocellular carcinoma (HCC) in the United States. This study evaluated the impact of surveillance and treatment on HBV-infected HCC patients and identified factors associated with survival. METHODS: From 1981 to 2010, 166 hepatitis B surface antigen (HBsAg)-positive HCC patients were evaluated. Fifty-eight patients had HCC detected by surveillance, while 108 patients presented with HCC. RESULTS: Compared to patients detected by surveillance, those presenting with HCC had more symptoms (65.7% vs 41.4%; P=.002), were more frequently outside of Milan criteria (73.7% vs 29.6%; P<.001), more often presented with diffuse tumors (23.2% vs 1.9%; P<.001), and had a shortened median survival time (9.5 months vs 18.7 months; P=.003). Patients who presented with diffuse tumors were younger and more often male (P=.002-.007), had a higher alpha-fetoprotein (AFP) level (P=.023), and had a median survival time of only 1.68 months. By multivariate analysis, factors that were significantly associated with mortality included diffuse tumors (hazard ratio [HR], 6.30; 95% confidence interval [CI], 3.14-12.66; P<.001), being outside of Milan criteria (HR, 2.02; 95% CI, 1.26-3.23; P=.005), albumin level (HR per 1 standard deviation decrease, 1.4; 95% CI, 1.15-1.72; P=.001), AFP level (HR per 1 log standard deviation increase, 1.38; 95% CI, 1.13-1.67; P=.001), and receiving liver transplantation versus other treatments (HR, 0.08-0.38; 95% CI, 0.03-0.87; P<.001 to P=.022). CONCLUSION: In the United States, HBV-related HCC is a common malignancy, especially among Asian immigrants. Identification of HBsAgpositive subjects and routine HCC surveillance are essential for improving survival in these patients.

Evaluation of current treatment recommendations for chronic hepatitis B: a 2011 update.

BACKGROUND AND AIM: Guidelines for the treatment of chronic hepatitis B have been recently updated in the 2009 European Association for the Study of the Liver consensus statement, the 2008 US Panel, the 2008 Asian-Pacific consensus statement, and the 2009 American Association for the Study of Liver Disease practice guidelines. We sought to determine whether these guidelines identified patients who developed hepatocellular carcinoma (HCC) or who died of non-HCC liver-related deaths for antiviral therapy. METHODS: The criteria described in the new treatment guidelines were matched to the database of 369 hepatitis B surface antigen-positive patients, in whom 30 developed HCC and 37 died of non-HCC liver-related deaths during a mean follow up of 84 months. RESULTS: Using criteria for antiviral therapy as stated by the four current guidelines, 19-30% of patients who died of non-HCC liver-related complications, and 23-53% of patients who developed HCC, would have been excluded for antiviral therapy. If baseline serum albumin levels of ≤ 3.5 g/dL or platelet counts of ≤ 130,000 mm(3) were included into the treatment criteria, then 85-94% of patients who developed liver-related complications would have been recommended for antiviral therapy. Also, the addition of precore A1896 mutants and basal core promoter T1762/A1764 mutants would have identified 98.5-100% of these patients. CONCLUSION: The updated treatment guidelines for hepatitis B still excluded patients who developed serious liver-related complications. The inclusion of baseline serum albumin and platelet counts to current criteria would have identified a majority of these patients for antiviral therapy. These tests should be included into hepatitis B treatment strategies.

A comparison of hepatitis B viral markers of patients in different clinical stages of chronic infection.

PURPOSE: Hepatitis B viral markers may be useful for predicting outcomes such as liver-related deaths or development of hepatocellular carcinoma. We determined the frequency of these markers in different clinical stages of chronic hepatitis B infection. METHODS: We compared baseline hepatitis B viral markers in 317 patients who were enrolled in a prospective study and identified the frequency of these tests in immune-tolerant (IT) patients, in inactive carriers, and in patients with either hepatitis B e antigen (HBeAg)-positive or HBeAg-negative chronic hepatitis or cirrhosis. RESULTS: IT patients were youngest (median age 27 years) and HBeAg-negative patients with cirrhosis were oldest (median age 58 years) (p = 0.03 to <0.0001). The male to female ratio was similar both in IT patients and in inactive carriers, but there was a male preponderance both in patients with chronic hepatitis and in patients with cirrhosis (p < 0.0001). The A1896 precore mutants were most prevalent in inactive carriers (36.4%) and HBeAg-negative patients with chronic hepatitis (38.8%; p < 0.0001), and the T1762/A1764 basal core promoter mutants were most often detected in HBeAg-negative patients with cirrhosis (65.1%; p = 0.02). Genotype A was detected only in 5.3% of IT patients, and genotype B was least often detected in both HBeAg-Positive patients with chronic hepatitis and cirrhosis (p = 0.03). The hepatitis B viral DNA levels were lowest in inactive carriers (2.69 log(10) IU/mL) and highest in IT patients (6.80 log(10) IU/mL; p = 0.02 to <0.0001). At follow-up, HBeAg-positive and HBeAg-negative patients with cirrhosis accounted for 57 of 64 (89.1%) liver-related deaths (p < 0.0001). CONCLUSION: Differences in baseline hepatitis B viral markers were detected in patients in various clinical stages of hepatitis B virus infection. HBeAg-positive and HBeAg-negative patients with cirrhosis accounted for the majority of the liver-related fatalities.

Development of hepatocellular carcinoma after seroclearance of hepatitis B surface antigen.

BACKGROUND & AIMS: During the natural course of chronic hepatitis B virus infection, a small proportion of patients experience hepatitis B surface antigen (HBsAg) seroclearance. However, the long-term clinical outcomes of this process are not well established. METHODS: Thirty-five patients with chronic hepatitis B, followed between 1976 and 2008 at a community liver clinic, experienced HBsAg seroclearance. Ten patients were Caucasian and 25 were Asian. These patients continued to undergo surveillance for hepatocellular carcinoma that included test for alpha-fetoprotein levels and abdominal ultrasound examinations. The median follow-up time was 185 months (range, 27-400 months). RESULTS: During the initial visit to the clinic, the median age of the patients was 41 years (range, 1.5-72 years). Eighteen patients (51.4%) were hepatitis B e antigen (HBeAg) positive 25 (71.4%) were hepatitis B virus DNA positive, and 13 (37.1%) had cirrhosis. At the time of HBsAg loss, the median age was 54 years (range, 13-77 years) and all were hepatitis B e antigen- as well as hepatitis B virus DNA negative. During the long-term follow-up, 4 patients with cirrhosis developed hepatocellular carcinoma (HCC), which was discovered by ultrasound examination. Factors associated with development of HCC were low baseline levels of albumin (P = .04), family histories of HBsAg positivity (P = .01) and HCC (P = .04), and age of less than 50 years at the time of HBsAg clearance (P = .03). CONCLUSIONS: HCC can still develop after HBsAg seroclearance. Thus, surveillance should be continued after HBsAg loss in the same manner as for HBsAg positive patients.

Factors associated with progression to hepatocellular carcinoma and to death from liver complications in patients with HBsAg-positive cirrhosis.

BACKGROUND AND AIMS: Hepatitis B viral markers and liver tests were used as predictors for development of hepatocellular carcinoma and progression to end-stage liver disease in 128 cirrhosis patients with hepatitis B. RESULTS: During a median follow-up of 63.5 months, 28 patients (21.9%) developed HCC and 36 (28.1%) died from non-HCC liver deaths. By multivariate analysis, independent predictors of HCC development and their hazard ratios were high alfa-fetoprotein (HR2.83, 95% CI 1.60-5.00, P = 0.0003), negative HBeAg (HR2.33, 95% CI 1.04-5.29, P = 0.04), and low alanine aminotransferase value (HR1.42, 95% CI 1.08-1.89, P = 0.02). Independent predictors of non-HCC liver deaths were HBeAg positivity (HR3.39, 95% CI 1.16-9.93, P = 0.02), decrease albumin (HR1.61, 95% CI 0.99-2.63, P = 0.05), decrease platelet count (HR2.54, 95% CI 1.03-6.25, P = 0.04), high ALT value (HR1.22, 95% CI 1.03-1.43, P = 0.02), and onset of encephalopathy (HR3.34, 95% CI 1.21-9.27, P = 0.02). CONCLUSIONS: HBeAg negativity, elevated AFP, and low ALT values predicted HCC development, while HBeAg positivity, abnormal liver tests, and low platelet counts identified patients with non-HCC liver deaths.

Treatment recommendations for chronic hepatitis B: an evaluation of current guidelines based on a natural history study in the United States.

UNLABELLED: Current guidelines for treatment of chronic hepatitis B include hepatitis B e antigen (HBeAg) status, levels of hepatitis B virus (HBV) DNA, and serum alanine aminotransferase (ALT) values in the setting of either chronic hepatitis or cirrhosis. Based on findings from a prospective study of hepatitis B surface antigen (HBsAg)-positive patients, we determined whether these guidelines included patients who developed hepatocellular carcinoma (HCC) and who died of non-HCC liver-related complications. The criteria for treatment from four published guidelines were matched to a cohort of 369 HBsAg-positive patients enrolled in the study. During a mean follow-up of 84 months, 30 patients developed HCC and 37 died of non-HCC liver-related deaths. Using criteria for antiviral therapy as stated by the four guidelines, only 20%-60% of the patients who developed HCC, and 27%-70% of patients who died of non-HCC liver-related deaths would have been identified for antiviral therapy according to current treatment recommendations. If baseline serum albumin levels of 3.5 mg/dL or less or platelet counts of 130,000 mm(3) or less were added to criteria from the four treatment guidelines, then 89%-100% of patients who died of non-HCC liver-related complications, and 96%-100% of patients who developed HCC would have been identified for antiviral therapy. In addition, if basal core promoter T1762/A1764 mutants and precore A1896 mutants also were included, then 100% of patients who developed HCC would have been identified for treatment. CONCLUSION: This retrospective analysis showed that the current treatment guidelines for chronic hepatitis B excluded patients who developed serious liver-related complications.