Long term response to therapy of chronic anti-HBe-positive hepatitis B is poor independent of type and schedule of interferon.

OBJECTIVE: The response rate to alpha interferon (IFN) of chronic anti-HBe-positive hepatitis B is variable. We studied whether type, dose, and schedule of IFN, and type and frequency of posttreatment monitoring, influence the response rate. METHODS: Seventy-two consecutive anti-HBe-positive chronic hepatitis B patients (59 male and 13 female, median age 41 yr) stratified by sex and histology were randomly allocated to three treatment arms. Twenty-seven patients (A) received 10 million units alpha-N1 IFN i.m. t.w. for 24 wk (total dose: 720 million units); 21 (B) received 9 million units alpha-2a IFN i.m. t.w. for 4 wk, followed by 18 million units for 12 wk and 9 million units for 8 wk (972 million units); 24 (C) received 2 alpha-2a IFN courses (9 million units i.m. t.w. for 16 and 12 wk separated by a 6-month interval [756 million units]). Primary response was defined by normal ALT and serum HBV-DNA levels below 10 pg/ml at the end of therapy and sustained response by normal ALT (tested monthly), undetectable HBV-DNA and IgM anti-HBc (<7 I.U. Paul Ehrlich Institute) (tested every 3 months) during the posttreatment follow-up. RESULTS: At the end of treatment, 12, 8, and 13 patients from groups A, B, and C, respectively, were responders. At the 18-month follow-up, two patients in group A and only one in groups B and C maintained the response. Overall, after 34 months (median posttreatment follow-up), three patients were long term responders, whereas three showed a sustained remission after relapse. CONCLUSIONS: The rate of long term response to interferon of anti-HBe-positive chronic hepatitis B is poor, independent of IFN type, dose, or schedule; the more stringent the monitoring, the higher the relapse rate.

Liver cell dysplasia is a major risk factor for hepatocellular carcinoma in cirrhosis: a prospective study.

BACKGROUND/AIMS: In humans, the role of liver cell dysplasia as a preneoplastic lesion is still debated. A prospective, long-term, multicenter study was performed to establish whether liver cell dysplasia in cirrhosis is associated with an increased risk for hepatocellular carcinoma (HCC). METHODS: A cohort of 307 consecutive patients in whom liver cirrhosis was diagnosed by histology was investigated for development of HCC at 6-month intervals by ultrasonography and determination of alpha-fetoprotein levels. RESULTS: At enrollment, liver cell dysplasia was found in 75 patients (24%) and in 53% (P < 0.01) of those positive for hepatitis B surface antigen (HBsAg). After a mean follow-up of 46 months, HCC was detected in 45 cases, and it was significantly more frequent in patients with liver cell dysplasia (P < 0.01) and HBsAg-serum positivity (P < 0.01). Multivariate analysis showed that liver cell dysplasia was the most important risk factor correlated with HCC development. HBsAg positivity and age over 60 years were also independent risk factors for HCC. CONCLUSIONS: These results indicate that liver cell dysplasia is a major risk factor for HCC, and it should be looked for carefully by pathologists in liver biopsy specimens to identify patients requiring more intensive observation.

Breakthrough during recombinant interferon alfa therapy in patients with chronic hepatitis C virus infection: prevalence, etiology, and management.

Recombinant interferon alfa (r-IFN alpha 2) has been shown to normalize the aminotransferase levels in approximately 50% of patients with chronic hepatitis C virus (HCV). Few patients experience a relapse during the treatment, in spite of a complete initial response (breakthrough). We studied 191 HCV Ab-positive patients with histologically proven chronic hepatitis. All of them were treated with r-IFN alpha 2 (3 MU three times a week). A complete response was seen in 54.4%. However, 12 of 104 responders experienced a breakthrough. At the time of breakthrough, neutralizing IFN antibodies were positive in 6 of 12 patients. Binding IFN antibodies were positive in all of these 12 patients. Continued treatment with r-IFN alpha 2, even at higher doses, did not restore the previous response in any patient. All of them were then switched to natural lymphoblastoid IFN, and this rapidly restored a complete response in all of the patients.

Fluctuations in viremia, aminotransferases and IgM antibody to hepatitis B core antigen in chronic hepatitis B patients with disease exacerbations.

We studied the relationships between the serum levels of viremia, aminotransferases and IgM anti-HBc, measured by monthly quantitative assays, in 52 untreated chronic hepatitis B patients (41 anti-HBe+, 11 HBeAg+) followed up for 12-20 months. Forty hepatitis exacerbations were observed in 17/41 anti-HBe+ (41.5%) and in 6/11 HBeAg+ patients (54.5%) (p = NS); all but one were clinically asymptomatic. We analyzed the fluctuations in the serum levels of the three parameters before, during and after the hepatitis exacerbations and found this chronological sequence of events in 96.2% of them: HBV-DNA increase-->ALT flare-->IgM anti-HBc increase. These results suggest that both antiviral immune reactions and ALT flares were triggered by quantitative variations in viremia. HBV-DNA baseline levels before flares were lower in anti-HBe+ (3.9 +/- 1.2 pg/ml) than in HBeAg+ patients (35.3 +/- 5.4 pg/ml) (p < 0.0001) and there was an inverse correlation between basal values and viremia level increases at the time of disease exacerbations (p < 0.001). This suggests that for a hepatitis exacerbation to occur, low basal viremia needed to increase markedly, while moderate increases in HBV-DNA serum levels were sufficient to trigger ALT flares in patients with elevated basal viremia. In conclusion, asymptomatic hepatitis B exacerbations are frequent in the natural history of chronic HBV infection, and monthly monitoring of HBV-DNA, ALT and IgM anti-HBc appears to be a suitable method to evaluate their frequencies and entities. This method can be a helpful guide for clinical and therapeutic decision-making in the single patient with chronic hepatitis B.

Epidemiology of hepatocellular carcinoma in a province of northern Italy: prevalence of the risk factors and incidence in the population.

AIMS: Epidemiologic studies on hepatocellular carcinoma (HCC) in limited geographic areas of Italy are rare, and most of them derive from autopsies. We retrospectively analyzed the prevalence of risk factors (sex, age, HBsAg, alcoholism, cirrhosis) in 137 HCC diagnosed between 1980 and 1989 in a single centre of northern Italy (Bergamo). RESULTS AND CONCLUSIONS: One hundred and nine of the HCC (79.6%) occurred in men (M:F = 3.9:1); 35.8% were HBsAg+ and 41.4% had histories of alcoholism. There were significant differences between men and women as regards prevalence of HBsAg+ (40.4% vs 17.9%; p = 0.046) and alcoholism (47.6% vs 17.9%, p = 0.008). The mean age of the patients was 63.6 years (range, 40-82), with significant differences between men and women (62.4 +/- 08 vs 68.2 +/- 1.4, p = 0.001), between HCC/HBsAg+ and HCC/HBsAg- (59.1 +/- 1.1 vs 66.1 +/- 0.8, p = 0.00001) and between alcoholics and nonalcoholics (61.6 +/- 1.1 vs 64.8 +/- 0.9; p = 0.03). Liver cirrhosis was associated with HCC in 104/122 cases (data not available for 15 patients) without differences in distribution of sex, age, HBsAg+ or alcoholism between HCC with cirrhosis and HCC without cirrhosis. Incidence was calculated for the surrounding territory of the hospital center (10 towns, districts 5 and 6, USSL 30). Fifty-four cases of HCC were found in this area over the 10-year period, in according with a mean standardized incidence rate (Lombardy population 1971) of 11.7/100,000 inhabitants/year (c.i. 95%, 1.49-21.86).