G. Diodati

Effectiveness of interferon alfa on incidence of hepatocellular carcinoma and decompensation in cirrhosis type C

BACKGROUND/AIMS The role of interferon alfa treatment in improving morbidity endpoints in patients with chronic hepatitis C infection is currently under debate. The aim of this study was to evaluate the effectiveness of interferon in preventing hepatocellular carcinoma and decompensation in cirrhosis type C. METHODS A retrospective cohort study was carried out on 329 consecutive Caucasian patients with cirrhosis followed for a mean period of 5 years at seven tertiary care university hospitals. Inclusion criteria were biopsy-proven cirrhosis, anti-HCV positivity, abnormal serum aminotransferase levels and absence of complications of cirrhosis. RESULTS The yearly incidence of hepatocellular carcinoma was 2.3% for 136 untreated patients and 1.0% for 193 patients treated with interferon alfa. The yearly incidence of hepatic decompensation was 5.7 for untreated and 1.5 for the treated patients. Fourteen (7%) of 193 treated patients showed sustained aminotransferase normalization and none of them developed complications of cirrhosis. At enrollment, untreated patients were older and had more severe liver disease than patients treated with interferon. After adjustment for clinical and serologic differences at entry between treated and untreated patients, the 5-year estimated probability of the occurrence of hepatocellular carcinoma was 2.1% and 2.7% and of decompensation was 7% and 11% for treated and untreated cases, respectively. CONCLUSIONS This analysis did not detect any significant benefit of interferon alfa on morbidity in patients with compensated cirrhosis type C, although it suggests a reduction in complications of cirrhosis for those with a sustained response to therapy, and it indicates the need for better therapies.

Treatment with interferon(s) of community-acquired chronic hepatitis and cirrhosis type C

Two hundred and thirty-four patients with chronic non-A, non-B hepatitis, 86% positive for anti-HCV by ELISA, were treated with recombinant interferon-alpha 2a or with natural (human-leukocytes-derived) interferon-alpha using different dosage and periods of administration. Interim analysis of follow-up data indicate that 65-70% of patients treated initially with 6 MU, thrice weekly, of recombinant interferon-alpha 2a achieved a complete biochemical response (normalization of alanine aminotransferase: ALT) during therapy compared to 56-58% of those treated with 3 MU, thrice weekly, of recombinant or natural interferon-alpha. A 12-month schedule of interferon administration appeared superior to a 6-month schedule in reducing the probability of reactivation of liver disease after therapy withdrawal, although further data are needed to confirm such a conclusion. The probability of response to interferon in terms of maintaining normal ALT after withdrawal did not appear to be influenced by sex, while it was significantly higher in patients aged below 45 years and in those without cirrhosis.

Antibodies to hepatitis C virus in patients with hepatocellular carcinoma

To study the potential relationship between the hepatitis C virus (HCV), the major etiologic agent of parenterally transmitted non-A, non-B hepatitis, and the development of hepatocellular carcinoma (HCC), we tested the presence of anti-HCV antibodies in sera from a large panel of HCC patients of different racial and geographical origins. Anti-HCV antibodies were detected in 82 out of 114 (71.9%) HBsAg-negative HCC patients and in 15 out of 53 (28.3%) HBsAg-positive patients. No significant difference in the prevalence of anti-HCV antibodies was found in the HBsAg-negative HCC patients when they were divided according to presence of anti-HBs and/or anti-HBc antibodies, or absence of all hepatitis B virus (HBV) serological markers. The prevalence of anti-HCV antibodies was similar in HCC patients of Caucasian and African origin. No differences were noted when the patients were grouped according to sex. The mechanisms by which HCV might contribute to the development of HCC need to be further investigated. As for HBV infection, the necro-inflammation associated with HCV infection may induce cirrhosis, regeneration and eventually malignant transformation. The finding that few anti-HCV patients had HCC which is not superimposed on cirrhosis suggests that HCV could, however, exert some direct effect on the development of HCC.

Interferon antibodies in patients with chronic hepatitic C virus infection treated with recombinant interferon alpha-2α

Patients treated with alpha-2a interferon for chronic hepatitis C may produce anti-interferon antibodies whose effect, if any, on the individual response to therapy has not been fully clarified. The prevalence and kinetics of anti-interferon, including those of neutralizing type, have been studied in 60 patients with chronic hepatitis C enrolled in a randomized controlled trial of recombinant alpha-2a interferon. Thirty patients received interferon while 30 were untreated controls. Two different methods, an enzyme immunoassay and an antiviral neutralization bioassay, were used and serial serum samples from each patient were analyzed. Enzyme immunoassay-positive anti-interferon appeared in 60.7% of treated patients within 6 months of therapy; antiviral neutralization bioassay-positive anti-interferon appeared in 52.9% of these enzyme immunoassay-positive patients, and was associated with high enzyme immunoassay reactivity and long-term persistence. Anti-interferon was detected in 75% of patients showing no response to interferon. Antibodies were also detected in three out of six patients who showed alanine aminotransferase normalization persisting up to the end of treatment and in 8 out of 14 patients who showed an initial marked reduction or even normalization of alanine aminotransferase, followed by reactivation of liver damage during treatment. Interestingly, patients who became anti-interferon positive before complete alanine aminotransferase normalization later showed reactivation of liver damage independently of interferon dose reduction, while patients who became positive for anti-interferon after complete alanine aminotransferase normalization either did not reactivate or did so only after interferon dose reduction.(ABSTRACT TRUNCATED AT 250 WORDS)

Hepatitis C virus genotypes: distribution and clinical significance in patients with cirrhosis type C seen at tertiary referral centres in Europe

The aim of this study was to evaluate the distribution and clinical significance of hepatitis C virus (HCV) genotypes in European patients with compensated cirrhosis due to hepatitis C (Child class A) seen at tertiary referral centres. HCV genotypes were determined by genotype‐specific primer PCR in 255 stored serum samples obtained from cirrhotics followed for a median period of 7 years. Inclusion criteria were biopsy‐proven cirrhosis, absence of complications of cirrhosis and exclusion of all other potential causes of chronic liver disease. The proportion of patients with types 1b, 2, 3a, 1a, 4 and 5 were 69%, 19%, 6%, 5%, 0.5% and 0.5%, respectively. Kaplan–Meier 5‐year risk of hepatocellular carcinoma (HCC) was 6% and 4% for patients infected by type 1b and non‐1b, respectively (P=0.8); the corresponding figures for decompensation were 18% and 7% (P=0.0009) and for event‐free survival were 79% and 89% (P=0.09), respectively. After adjustment for baseline clinical and serological features, HCV type 1b did not increase the risk for HCC [adjusted relative risk=1.0 (95% confidence interval=0.47–2.34)], whereas it increased the risk for decompensation by a factor of 3 (1.2–7.4) and decreased event‐free survival by a factor of 1.7 (0.9–3.10). In conclusion, type 1b and, to a lesser extent, type 2, are the most common HCV genotypes in European patients with cirrhosis. HCV type 1b is not associated with a greater risk for HCC, but increases the risk for decompensation by threefold in patients with cirrhosis.

Relationship between serum HCV markers and response to interferon therapy in chronic hepatitis C: Evaluation of HCV genotypes during and after long-term follow-up

Hepatitis C virus is the most frequent cause of chronic non-A, non-B hepatitis, and the antibodies to structural and nonstructural proteins encoded by viral genome have been suggested to be markers of ongoing HCV infection. We studied the behavior of these antibodies during interferon therapy in 18 patients with chronic hepatitis C and also during a follow-up period of at least four years. A significant decrease of anti-HCV titer was found only in patients who had shown positive response to therapy and all of them were anti-HCV negative at the end of follow-up. Analysis by recombinant immunoblotting assay showed that only anti-c100 were affected by interferon therapy, whereas anti-c22 and anti-c33 were not modified. Using polymerase chain reaction to detect small amounts of HCV genome in serum, we could confirm that the behavior of HCV-RNA during and after interferon therapy is similar to that of anti-HCV and the loss of anti-c100 seems to be closely related to HCV-RNA disappearance from serum. Our patients with chronic hepatitis C were found to be of type 1b and 2, according to the recent score of Simmonds, and the clearance of serum HCV-RNA during treatment and its sustained negative status are closely related to genotype 2 and to long-term positive response to interferon.

Cryptogenic chronic liver disease and serum or liver hepatitis B virus markers. Their possible correlations and etiologic significance.

In an attempt to evaluate a possible correlation between cryptogenic chronic liver disease and a present or past hepatitis B virus (HBV) infection, we studied 17 patients with hepatitis B surface antigen (HBsAg)-negative, nonalcoholic chronic liver disease; 9 of them were positive for serum HBsAg detected by a solid-phase enzyme immunoassay with monoclonal antibody (M-EIA) and 8 were negative for the same marker. Liver hepatitis B core antigen (HBcAg), studied by an indirect immunofluorescence technique, was present in 55.5% of the patients positive for serum HBsAg by M-EIA. In the same group of patients, liver HBV-DNA was found in 66.6% of the patients. On the other hand, only 1 patient without serum positivity for HBsAg by M-EIA was positive for liver HBcAg and HBV-DNA. None of our patients showed serum positivity for HBV-DNA sequences. We conclude that HBV infection may be a possible cause of cryptogenic chronic liver disease; this HBV-related, HBsAg-negative chronic liver disease seems to have no viral replication or undetectable levels of HBV-DNA in serum. HBsAg, detected by a monoclonal assay, seems to be a suitable marker to identify this subgroup of patients with HBsAg-negative chronic liver disease.

Hepatitis C virus infection and replication in patients with hepatocellular carcinoma

To evaluate the risk of hepatocellular carcinoma (HCC) development in cirrhosis of viral etiology, 239 consecutive patients with cirrhosis were followed prospectively. At entry, 20.9% of patients were hepatitis B surface antigen (HBsAg)- positive, 68.9% were anti-hepatitis C virus (HCV)-positive, and 6.7% were both HBsAg- and anti-HCV positive. Twenty-six (10.8%) patients developed HCC during follow-up. HCC appeared in 18.7% of HBsAg-positive patients, in 11.7% of anti-HCV-positive patients, and in 33.3% of patients positive for both HBsAg and anti-HCV. By univariate analysis, age above 59 years (P = 0.025), duration of cirrhosis (P = 0.014), and positivity for both HBsAg and anti-HCV (P = 0.004) were related to HCC development. By multivariate analysis, age (P = 0.038) and positivity for both HBsAg and anti-HCV (P = 0.004) were independently related to HCC incidence. Serum HCV-RNA was investigated by polymerase chain reaction (PCR) in 7 anti-HCV positive patients developing HCC and was positive in 42.8% before and 85.7% after tumor development. Concurrent HBV and HCV infection is a significant risk factor for HCC development in our cirrhotic patients. Enhancement of HCV replication seems to occur in anti-HCV positive cirrhotic patients when they develop HCC.

Cryptogenic chronic active liver disease. Evaluation of serum aminoterminal peptide of type III procollagen as a marker of histological activity

SummarySera from 64 patients with HBsAg-negative chronic liver disease with or without cirrhosis were investigated for aminoterminal peptide of type III procollagen (sP-III-P) as a suitable marker of hepatic fibrosis; 244 healthy control subjects were included in the study. A close correlation (p<0.01) between sP-III-P levels and histological activity was observed; on the contrary, no correlation was found between the same serum marker of liver fibroplasia and biochemical activity or clinical severity of the disease. We conclude that sP-III-P as a suitable marker of liver overload of collagen fibers is strongly correlated with the histological activity of the disease. Local immune reactions produce soluble substances that might stimulate fibroblastic activity. The test has a significant sensitivity and a very high specificity as a marker of chronic liver disease with histological activity.