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The acute phase of hepatitis C virus (HCV) infection represents a key point in the evolution of hepatitis C. The infection either resolves spontaneously, or progresses into chronic disease. However, the asymptomatic nature of acute hepatitis C contributes to difficulties in detection, diagnosis and hence, the assessment of therapy when indicated. Controversies in chronic HCV related to the implications of both selected predictors of treatment outcome and clinical experience with structurally different Peg-IFNs are discussed.

Background: Therapy of chronic hepatitis C non- responders to interferon monotherapy with standard doses of interferon plus ribavirin is usually ineffective. Aim: To evaluate the efficacy and tolerability of high-dose prolonged combination retreatment in non- responder patients. Methods: Patients were retreated for 6 months with 6 MU αIFN on alternate days and 1000 or 1200 mg/day ribavirin. HCV-RNA negative patients continued therapy for an additional 6 months. Results: Forty patients (29 males, mean age 49.7 years, 34 genotype 1b, 11 with F3 fibrosis) were treated. At 6 months, 20 (50%) patients were HCV-RNA negative but six of them discontinued therapy because of adverse events. A sustained response was achieved in 28% of patients (11/40). A sustained response was more frequent among patients with genotype non-1b than in those with genotype 1b (67 vs. 21%, P=0.005) and clearance of HCV-RNA in the first 3 months had a high predictive value for sustained response (100% of sustained responders vs. 24% of non-responders, P=0.0001). Conclusions: High-dose prolonged combination therapy in non-responders to IFN monotherapy leads to a higher rate of sustained response than the standard combination regimen. Tolerability may be a rate-limiting factor. Maximal effectiveness can be predicted in patients with non-1b genotype and in those who clear HCV-RNA soon after starting retreatment.

Aim: To establish the efficacy of combination therapy with ursodeoxycholic acid (UDCA) and colchicine in patients with symptomatic primary biliary cirrhosis (PBC), defined by the presence of liver cirrhosis, pruritus or bilirubin exceeding 2 mg/mL. Methods: A total of 90 patients were randomly assigned to ursodeoxycholic acid 500 mg/daily plus placebo (UDCA group, n=44), or ursodeoxycholic acid at the same dosage plus colchicine, 1 mg/daily (UDCA/C group, n=46). The two groups were comparable for age, sex, stage of disease, severity of pruritus, bilirubin, and Mayo score. All patients underwent clinical, ultrasonographic, and biochemical examinations at entry and then every 6 months up to 3 years of follow-up. Patients with cirrhosis underwent endoscopy every 12 months. In a sub-group of patients without cirrhosis, who consented, liver biopsy was repeated at the end of the study. Results: The number of treatment failures (i.e. dead, orthotopic liver transplantation (OLT), complications of cirrhosis, doubling of bilirubin, untreatable pruritus) was 11 (25%) in the UDCA group and four (9%) in the UDCA/C group (P

Background: In chronic hepatitis C the relation of circulating adhesion molecules to disease features before, during and after therapy has not been completely established. Aim: To analyse the basal levels of circulating adhesins and the changes induced by interferon in these patients. Methods: We studied, using ELISA assays, the serum levels of soluble intercellular adhesion molecule-1 (sICAM-1) and vascular cell adhesion molecule-1 (sVCAM-1) in 52 patients with chronic hepatitis C on entry, prior to finalizing a 6-month course of interferon-α therapy and at the end of the follow-up. Correlations with clinical, virological and histological features, including inflammation and fibrosis, were calculated by Pearson’s r-test. Results: Liver necroinflammation was more closely related to sICAM-1 (r = 0.54, P = 0.0000) than to sVCAM-1 (r = 0.32, P = 0.02). Fibrosis, both as serum pIIIP and histological scoring, was, however, clearly related to sVCAM-1 (1071 ± 291 in patients who scored 0–2 vs. 1870 ± 458 in patients who scored 3–4; P = 0.0000). Severe fibrosis was never found below a sVCAM-1 cut-off threshold of 1300 ng/mL. Levels of both adhesins did not correlate with viraemia and were comparable among 1b and non-1b genotypes. Sustained response to interferon was significantly related to low viraemia (P = 0.03), non-1b type (P = 0.04) and low sICAM-1 (P = 0.04), but not to sVCAM-1. On finalizing therapy, patients with normal transaminases had reduced sICAM-1 (P = 0.0005), but not sVCAM-1 levels. Conclusions: In chronic hepatitis C, sICAM-1 was a marker of liver necroinflammation while sVCAM-1 reflected fibrosis. Both low sVCAM-1 and pIIIP serum concentrations were strictly linked, suggesting that measuring sVCAM-1 could give information on the degree of liver fibroplasia.

The efficacy of short-course (three months), low-dose (3 million units three times a week) interferon as treatment for acute hepatitis C was evaluated in a meta-analysis of controlled trials. Nine studies (five randomized and four nonrandomized) found by MEDLINE search were eligible for analysis. The outcomes assessed were the rate of patients with normal serum aminotransferases (all trials) and without HCV RNA in blood (five trials) after posttreatment follow-up. Eight trials compared interferon to no treatment, and one compared different schedules of interferon. The methodological quality of the studies was high. However, all trials had been planned for a short-term evaluation based on biochemical and virological outcomes alone. Significant differences were observed between interferon and control groups for both the assessable end points. Overall rate differences were +0.31 (P < 0.0001; 95% confidence interval +0.20 to +0.41) for aminotransferases normalization and +0.44 (P < 0.0001; 95% confidence interval +0.33 to +0.56) for HCV RNA clearance. In conclusion, a short course of low-dose interferon administered to patients with acute hepatitis C is significantly more effective than no treatment in obtaining viral clearance and normal aminotransferases 12 months after stopping treatment. Further long-term prospective cohort studies assessing outcomes of clinical relevance (ie, the rate of chronicity of infection and disease) are necessary before recommending interferon for acute hepatitis C.

Primary biliary cirrhosis is characterised by the presence of antimitochondrial antibodies which are directed against components of mitochondrial dehydrogenase complexes. The specificity of antimitochondrial antibodies for primary biliary cirrhosis as detected by immunoblotting was investigated. Commercially available preparations of pyruvate and oxo-glutarate dehydrogenases and beef-heart mitochondria were used as source of antigens. Sera from 47 primary biliary cirrhosis patients (46 of whom were antimitochondrial antibody positive by immunofluorescence), 16 non-primary biliary cirrhosis patients (antimitochondrial antibody positive by immunofluorescence), 23 liver-kidney microsomal antibody positive chronic active hepatitis patients, and 32 patients with connective tissue diseases were examined. Of the 47 subjects with primary biliary cirrhosis, 43 (91%) and 13 (28%) tested positive by immunoblotting for pyruvate and oxo-glutarate dehydrogenase, respectively. Only three primary biliary cirrhosis patients were negative for both antigens, including the only one shown to be antimitochondrial antibody negative by immunofluorescence. The other two patients were positive by immunoblotting with beef-heart mitochondria. In contrast, only three of 16 (19%) non-primary biliary cirrhosis patients who were antimitochondrial antibody positive by immunofluorescence tested positive by immunoblotting (for both pyruvate dehydrogenase and beef-heart mitochondria). None of the 23 liver-kidney microsomal antibody positive and the 32 patients with rheumatic diseases were positive by immunoblotting with any antigen. Our data show that immunoblotting with commercially available oxo-acid dehydrogenases is a reproducible method for the detection of antimitochondrial antibodies highly specific for primary biliary cirrhosis.

Hepatitis C virus (HCV) replication was assessed before and during alpha-interferon (IFN) treatment in 22 anti-HCV positive patients with posttransfusion or sporadic chronic hepatitis (CH). Eleven patients were “responders” and 11 patients “non-responders” to IFN. Thirteen anti-HCV negative healthy subjects and five anti-HCV negative patients with autoimmune CH served as controls. Serum HCV-RNA was detected by the polymerase chain reaction (PCR) in all untreated anti-HCV positive patients but in none of the anti-HCV negative subjects. PCR primers from the 5′-non-coding (NC) region were more sensitive than primers from a non-structural (NS5) region in detecting HCV-RNA (21/22, 95% vs. 7/22, 32%, respectively). Positive strand HCV-RNA titre and positivity rate for the negative strand were similar in responders and non-responders before IFN treatment, as well as anti-cl00-3 titre by enzyme-linked immunosorbent assay (ELISA), and anti-5-1-1, anti-c33c, anti-c22 positivity rate by immunoblot assay (RIBA). HCV-RNA positivity by both NC and NS primers was more frequent before IFN among responders. During IFN treatment, serum HCV-RNA was detectable, mostly at low titres, in 1 (NC positive) of the 11 responders and in 9 (4 NS positive and 5 NC positive) of the 11 non-responders. Among the four non-responders who were NS positive during IFN, three were NC positive before IFN. Serum HCV-RNA was always found in our post-transfusion or sporadic anti-HCV positive patients with CH. Viraemia generally decreased during IFN treatment, but no available HCV markers clearly distinguished responders from non-responders before IFN treatment. Different NC and NS primers behaviour between responders and non-responders before and during treatment with IFN suggests genomic heterogeneity and may explain non-responsiveness to IFN. © 1992 Wiley-Liss, Inc.

We evaluated the specificity and clinical relevance of anti-hepatitis C virus antibody positivity in 22 HBsAg-negative patients with autoimmune (anti-nuclear, anti-actin or anti-liver-kidney microsomal antibody positive) chronic active hepatitis. An ELISA anti-HCV test and a recombinant immunoblot assay (RIBA-HCV) were used. Thirteen patients (59%) were anti-HCV positive and five (23%) anti-HCV negative by both ELISA and RIBA-HCV tests. Four patients (18%) were borderline positive by ELISA (OD less than 1.0), and three of them (all with severe disease) were negative by RIBA. Histologic necroinflammation, AST/ALT and gamma-globulins levels were higher and response to prednisolone treatment was better in RIBA anti-HCV-negative than in anti-HCV-positive cases. We confirmed with both RIBA and ELISA tests the high prevalence of anti-HCV already reported by ELISA in anti-nuclear and anti-liver-kidney microsomal antibody positive chronic active hepatitis. False positive for anti-HCV (i.e., a positive ELISA test not confirmed by RIBA) occurred only among patients with severe disease. Since RIBA-negative subjects showed the best response to corticosteroid, they might represent the only subset of cases of 'true' autoimmune chronic active hepatitis.

Summary. Hepatitis C virus (HCV) infection is associated with a significant reduction of health related quality of life (QOL), the causes and mechanisms of which are still unknown. To explore whether treatment history could affect QOL, we examined patients with detectable HCV viraemia who had a different therapeutic background. Two hundred sixty-four consecutive subjects with chronic HCV infection and detectable viraemia were enrolled. Of these, 163 were untreated patients, 43 were relapsers, 58 were nonresponders (NR) to nonpegylated interferon (IFN) therapy. To assess QOL, three self-report instruments were employed: the Short Form-36 (SF-36), the Chronic Liver Disease Questionnaire (CLDQ-I) and the World Health Organization Quality of Life assessment (WHOQOL-BREF). Clinical and demographic data were collected, and the QOL scores of HCV-positive patients were compared with those of an Italian normative sample and healthy controls. Further antiviral treatment was offered to untreated and relapsed patients but not to NR. All patient groups displayed lower QOL scores compared with the normative sample and controls. NR displayed lower QOL scores in several areas compared with untreated patients and relapsers. In multivariate regression analyses, being NR and having a physical comorbidity were significantly associated with poorer QOL. Conclusions: Treatment history and expectations and physical comorbidity may affect QOL in HCV-positive patients. Untreated and relapsed patients have comparable levels of QOL and higher scores than NR.

SUMMARY. Nonorgan-specific autoantibodies (NOSA) are common in patients with chronic hepatitis C virus infection. It is unclear whether serological markers of autoimmunity segregate in a cohort of cases with more severe liver damage. We assessed the relationship between NOSA and demographic, biochemical and histological features in 502 subjects with anti-HCV positive, HCV-RNA positive, HBsAg negative chronic hepatitis consecutively referred to four Italian liver units. Percutaneous liver biopsy was performed in all subjects. A single pathologist scored the biopsies using histology activity index classification. The overall prevalence of positivity for any NOSA was 36.9%. Antinuclear antibodies, anti-smooth muscle antibodies, and anti-liver/kidney microsomal antibodies were found in 15.7, 27.3 and 2.2% of cases. Multivariate analysis showed that c-globulin >2 g/dL was the only independent predictor of the likelihood of NOSA positivity (OR, 2.1; 95% CI, 1.3–3.4). No other clinical (age, gender, ALT, HCV genotype) or histological features (grading and staging score, bile ductular damage) were linked to NOSA. Antiviral therapy in 155 subjects with NOSA did not cause any adverse events related to autoimmunity during and after treatment. The presence of NOSA in patients with chronic HCV hepatitis is not related to specific demographic features and has no impact on the biochemical and histological profile of the liver disease at presentation and the response to antiviral treatment.

Host and viral variables interact in determining the course and responsiveness to therapy of any viral infection. Presence of cirrhosis, serum levels of hepatitis C virus (HCV) RNA and the genotype of infecting virus are considered predictive of response to interferon (IFN) in chronic HCV infection. We evaluated these parameters in relation to IFN therapy in a cohort of anti-HCV-positive subjects with chronic hepatitis or cirrhosis. HCV RNA was detected by polymerase chain reaction (PCR) and by the branched DNA assay (bDNA), to quantify viraemia. HCV typing was performed by reverse-hybridization line probe assay. HCV RNA was detected in almost all anti-HCV-positive subjects with liver disease, PCR being more sensitive than bDNA. Hepatitis C viraemia was lowest in cirrhosis. Low pretreatment viraemia selected for those patients with chronic hepatitis obtaining a high rate of sustained response to IFN. The role of HCV type was less clearcut, due to the high prevalence in our population of type 1 (especially subtype 1b, accounting for 80% of cases). A trend towards a better response of non-1b genotypes was confirmed. This may be related to higher HCV RNA levels in type 1b-infected subjects. Cirrhosis remains however, independently from virological features, the strongest predictor of non-response to IFN.

In this open, pilot study, interferon (IFN) alpha-2b seemed effective in the treatment of hepatitis C virus (HCV) infection in patients with beta-thalassaemia. In seven of nine patients who completed the study alanine aminotransferase activities returned to normal, and a completely stable response 24 months after treatment was seen in five. Liver biopsy specimen showed a clear reduction in portal, periportal, and lobular necroinflammation in all five cases. Three patients stopped treatment early because of side effects.

was unreliable in 15 obese patients(8.9%). 54 patients (37.5%) had an histological and 90 (62.5%) a clinical diagnosis of cirrhosis. All patients underwent endoscopy. LS and SS were measured under US control. Results: In the subgroup with haemodinamic evaluation, we found a significant correlation between HVPG value and SSM(Linear regression analysis: r = 0.671; p =0.009). 9 of them had the highest SS value(75 kPa). Mean HVPG was significant different between patients with SSM lower or equal 75 kPa(12.5mmHg vs 19.1mmHg, p =0.013) without significant differences for bilirubin, albumin or INR values(p=ns). All 9 patients with SSM=75kPa had large esophageal varices(6 F2, 3 F3). In the whole cohort of patients, 80 (55.6%) had EV and 28 (19.4%) had large EV(F2 or F3). The AUROCs of LS and SS were almost the same(0.76 vs 0.73) for the prediction of EV but SSM was significantly better than LSM to predict large EV(AUROCs:0.84 vs 0.72). The best cut-offs of LS and SS for the diagnosis of cirrhosis with EV were 21kPa(Sens. 71%, Spec. 72%) and 47kPa(Sens. 79%, Spec. 70%) respectively. Twenty-four patients with a LSM

p, TIPS dysfunction was observed in two patients: in one, ith recurrent features of intestinal ischaemia, the shunt was orrected with an additional stent. In the other one, with recurent variceal bleeding, a spleno-renal shunt was performed. ne patient developed two episodes of hepatic encephalopahy few days after the procedure. One patient died after nine onths for hepatocellular carcinoma. onclusions. TIPS is technically feasible in the majority of atients with chronic portal vein thrombosis and portal caveroma and may be considered among the therapeutic options f this infrequent cause of portal hypertension.