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Background: This large prospective multicentre cohort study aimed to improve knowledge of therapy for chronic hepatitis C (CHC) in real clinical practice., Methods: A diverse population of adults with CHC including patients with comorbid conditions, laboratory abnormalities and demographic features [comorbidities or special populations (CSP)] who were under-represented or excluded from peginterferon registration studies was treated with peginterferon α-2a (40 kDa) or α-2b (12 kDa) plus ribavirin at the investigator's discretion., Results: During the study, 5399 treatment-naive patients [2527 (46.8%) with CSP] received peginterferon α-2a (n=3513, 65.1%) or peginterferon α-2b (n=1886, 34.9%). The sustained virological response rate was 56.6% (3057/5399) overall, 59.7% (1716/2872) in patients without CSP and 53.1% (1341/2527) in patients with CSP. Significant predictors of sustained virological response included hepatitis C virus genotype 2 or 3 infection, absence of cirrhosis, hepatitis C virus RNA≤500 000 IU/ml, alanine transaminase quotient >3× the upper limit of normal, age ≤65 years, BMI<25 kg/m, at least 80% of the planned exposure to peginterferon and ribavirin and prescription of peginterferon α-2a., Conclusion: The results provide detailed information on the outcome of therapy for CHC in a diverse Italian population that included a large number of patients with CSP and provides an insight into the generalizability of the results obtained in the more restricted setting of randomized registration trials.

To evaluate the impact of liver histology on the management of HCV-related chronic hepatitis, 281 patients with chronic HCV infection who consecutively underwent percutaneous liver biopsy (LB) at one of the 15 participating Italian Units of Infectious Diseases were investigated in 2005. Demographic, aetiological, laboratory and clinical data and information on methods applied to perform ultrasonography (US) and LB were recorded. Males predominated (61.6%), mean age was 47.5 years and the mean BMI 22.3. In each case LB was US-guided or US-assisted. An 18-gauge Menghini-type needle was used in 203 (72.2%) cases. The length of the specimen ranged between 1.5 and 5 cm in 279 (99.3%) cases, it was smaller in two cases, but the diagnosis was still possible. Haemoperitoneum was the only (0.4%) major unpredictable complication; minor complications were also infrequent (4%). Using both clinical and laboratory data and US examination the physician misdiagnosed liver histology in 25% of cases. After LB the physicians changed their opinion on whether to treat with PEG-INF plus ribavirin in 43 (15.5%) cases. Liver histology allows more accurate diagnosis and enables physicians to make the most appropriate choic.

Objective: The objective of this review was to define a core set of recommendations for the treatment of HCV-associated mixed cryoglobulinemia syndrome (MCS) by combining current evidence from clinical trials and expert opinion., Methods: Expert physicians involved in studying and treating patients with MCS formulated statements after discussing the published data. Their attitudes to treatment approaches (particularly those insufficiently supported by published data) were collected before the consensus conference by means of a questionnaire, and were considered when formulating the statements., Results: An attempt at viral eradication using pegylated interferon plus ribavirin should be considered the first-line therapeutic option in patients with mild-moderate HCV-related MCS. Prolonged treatment (up to 72 weeks) may be considered in the case of virological non-responders showing clinical and laboratory improvements. Rituximab (RTX) should be considered in patients with severe vasculitis and/or skin ulcers, peripheral neuropathy or glomerulonephritis. High-dose pulsed glucocorticoid (GC) therapy is useful in severe conditions and, when necessary, can be considered in combination with RTX; on the contrary, the majority of conference participants discouraged the chronic use of low-medium GC doses. Apheresis remains the elective treatment for severe, life-threatening hyper-viscosity syndrome; its use should be limited to patients who do not respond to (or who are ineligible for) other treatments, and emergency situations. Cyclophosphamide can be considered in combination with apheresis, but the data supporting its use are scarce. Despite the limited available data, colchicine is used by many of the conference participants, particularly in patients with mild-moderate MCS refractory to other therapies. Careful monitoring of the side effects of each drug, and its effects on HCV replication and liver function tests is essential. A low-antigen-content diet can be considered as supportive treatment in all symptomatic MCS patients. Although there are no data from controlled trials, controlling pain should always be attempted by tailoring the treatment to individual patients on the basis of the guidelines used in other vasculitides., Conclusion: Although there are few controlled randomised trials of MCS treatment, increasing knowledge of its pathogenesis is opening up new frontiers. The recommendations provided may be useful as provisional guidelines for the management of MCS., (Copyright © 2011. Published by Elsevier B.V.)

The Italian recommendations for the therapy of hepatitis B virus (HBV)-related disease were issued in 2008. Subsequently in 2008 the nucleotide analogue (NA) Tenofovir was approved for antiviral treatment. The introduction of this important new drug has called for the current guidelines update, which includes some additional revisions: (a) the indication for therapy is extended to mild liver fibrosis and the indication for treatment is graded as "possible", "optional" or "mandatory" according to the fibrosis stage; (b) two different treatment strategies are described: first line definite duration treatment with interferon, long-term treatment of indefinite duration with NA; (c) the indication to follow either strategy is also based on the stage of liver fibrosis; (d) virological monitoring is modified to include the definitions of failure and of sustained virological response to interferon therapy; (e) the recommendation to use HBV DNA assays with high sensitivity and wide linear ranges is underlined (f) guidelines on post-treatment follow-up after finite treatment with NA, potential side effects of therapy and non-virological monitoring are defined; (g) definitions and treatment of patients without optimal response to NA are reported; (f) treatment and monitoring of compensated or decompensated cirrhosis and hepatocellular carcinoma are updated., (Copyright © 2010 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Here it is reported the virological dynamic of HBV and HCV, identified in the plasma, peripheral blood mononuclear cells and tissue liver, in a patient with chronic HBV-HCV coinfection. A treatment with pegylated Interferon plus Ribavirin determined a sustained virological response for HCV in all the three studied compartments, but a reactivation of chronic HBV infection was observed. In fact, while at the first observation HBV-DNA was detectable only in the liver tissue, after antiviral therapy it was detectable in all the three compartments; moreover this HBV reactivation was associated with a hepatic flare. Then, the patient was treated with Entecavir, which has been determining the clearance of HBV from the peripheral compartments (plasma and PBMC) until today.

Background: We aim to evaluate in chronic hepatitis B virus-hepatitis C virus (HBV-HCV) coinfection the interplay of these viruses in liver tissue, peripheral blood mononuclear cells (PBMC), and plasma and to analyze the effect on disease course and response to treatment., Methods: We enrolled 19 patients with chronic HBV-HCV coinfection, 20 with chronic HCV and 20 with chronic HBV infection at their first liver biopsy, all were naive for antiviral therapy. The patients' plasma, PBMC and liver biopsy samples were tested for HBV DNA and/or HCV RNA by real-time PCR, according to the presence/absence of hepatitis B surface antigen and antibodies against HCV in the serum., Results: Contemporary presence of HBV DNA and HCV RNA was rare in plasma (5.3% of cases) and PBMC (10.6%), but frequent in liver tissue (52.6%). Of 10 cases circulating only HCV RNA and treated with pegylated interferon (PEG-IFN) plus ribavirin for 12 months, two showed a sustained response, and eight cleared HCV RNA but became HBV-DNA-positive in plasma; these eight had detectable HBV DNA in liver at baseline. One patient, who was plasma HBV-DNA-positive/HCV-RNA-negative at baseline, showed a sustained response after 18 months of PEG-IFN treatment; another, who was plasma HBV-DNA/HCV-RNA-positive at baseline, cleared only HCV RNA during 12 months of PEG-IFN plus ribavirin treatment. Seven cases remained untreated., Conclusion: Despite a reciprocal inhibition in plasma, HBV and HCV frequently coexist in liver tissue, a condition to be taken into consideration when deciding therapy.

Aim: To evaluate safety and effect on hepatitis B virus (HBV) suppression of a long-term treatment with lamivudine (LAM) at standard (100 mg/d) or double (200 mg/d) dose in chronic hepatitis B., Methods: This was a case study with matched controls (1:3) in patients with chronic hepatitis B with anti-HBe antibodies., Results: Twelve patients received LAM 200 mg/d and 35 LAM 100 mg/d, for a median of 28 mo. A primary response (PR; i.e. negative HBV-DNA with Amplicor assay) was achieved in 100% of LAM-200 patients and 83% of LAM-100 patients. A virological breakthrough occurred in 16.7 and 24.7%, respectively, of the PR-patients, with the appearance of typical LAM resistance mutations in all but one patient. Viremia blips (i.e. transient HBV-DNA below 80 IU/mL in patients who tested negative at Amplicor assay) were detected using a real time polymerase chain reaction (PCR) and occurred in seven out of nine patients with subsequent BT and in four out of 32 patients with end-of-study response (77.7% vs 12.5%; P = 0.001) at chi-square test). At the end of the study, 51.4% of LAM-100 patients and 83.3% of LAM-200 patients had remained stably HBV-DNA negative. Double-dose LAM was well tolerated., Conclusion: Long-term treatment of anti-HBe positive chronic hepatitis B with double dose lamivudine causes a more profound and stable viral suppression as compared to conventional treatment.

Background: The diagnosis of acute hepatitis C (AHC) is based on seroconversion to positive anti-HCV, which is usually not clinically possible., Objective: To determine if avidity of anti-HCV IgG can be used for the diagnosis of AHC infection., Study Design: We enrolled 40 consecutive patients with AHC, 16 drug addicts (IVDA) with exacerbation of chronic hepatitis C (IVDA e-CHC group), 21 non-IVDA with exacerbation of chronic hepatitis C (IVDA-free e-CHC group) and 40 with chronic hepatitis C (CHC group). HCV avidity index (HCV-AI) was determined by ELISA on sera pre-diluted 1:10 with 1M guanidine., Results: On admission, HCV-AI values were significantly lower in the AHC group (mean+/-S.D.: 0.50+/-0.30) than in IVDA-free e-CHC group (0.97+/-0.08, p<0.0001), IVDA e-CHC group (0.90+/-0.29, p<0.0001) or CHC group (1.06+/-0.20, p<0.0001). An HCV-AI lower than 0.7 obtained within the 8th day of illness distinguished patients with AHC infection from the IVDA-free e-CHC cases. An increase in HCV-AI was observed in 24 (72.7%) of 33 in AHC group, in none of 13 in IVDA-free e-CHC group and in 3 (27.3%) of 11 in IVDA e-CHC group., Conclusion: HCV-AI is useful in identifying AHC infection in patients observed within the 8th day from the onset of symptoms.

The primary aim of antiviral therapy in HCV liver cirrhosis is to stop viral replication and, consequently, to prevent the clinical progression of fibrosis, liver decompensation and the onset of hepatocellular carcinoma. However, the results of therapy are different according to the different clinical stages of cirrhosis. In patients with bridging fibrosis or histological cirrhosis international trials have demonstrated that the sustained virological response to the highly active combination of pegylated interferon plus ribavirin was substantially similar to that observed in subjects with chronic hepatitis C without cirrhosis. Few data are available as to the efficacy and tolerability of antiviral treatment in patients with fully developed clinical cirrhosis, with or without decompensation, and all studies to date underscore the difficulties in the management of the more frequent and severe side effects in these patients. In patients with a more severe disease who do not achieve a sustained virological response, an alternative option is to reduce or suppress inflammation and fibrosis progression with long-term suppressive therapy in the hope to prevent clinical deterioration and the onset of hepatocellular carcinoma. Three international trials are currently evaluating the use of antiviral treatment as a maintenance antiviral therapy.

Background: Acute viral hepatitis due to hepatitis A virus is a self-limited illness that infrequently has a severe clinical course., Methods: We analyzed the virological characteristics of acute hepatitis A in a patient with a severe clinical presentation (peak total and conjugated bilirubin levels, 65.5 mg/dL and 40.1 mg/dL, respectively) and a course of disease that lasted 7 months., Results: Hepatitis A virus sequencing revealed coinfection with 2 subgenotypes of hepatitis A virus (Ia and Ib) as etiological factors of the illness., Conclusions: Hepatitis A virus Ia and Ib coinfection may have accounted for the prolonged and severe course of illness.

Unlabelled: The effect of achieving a sustained virological response (SVR) following interferon-alpha (IFNalpha) treatment on the clinical outcomes of patients with HCV-related cirrhosis is unknown. In an attempt to assess the risk of liver-related complications, HCC and liver-related mortality in patients with cirrhosis according to the response to IFNalpha treatment, a retrospective database was developed including all consecutive patients with HCV-related, histologically proven cirrhosis treated with IFNalpha monotherapy between January 1992 and December 1997. SVR was an undetectable serum HCV-RNA by PCR 24 weeks after IFNalpha discontinuation. HCC was assessed by ultrasound every 6 months. Independent predictors of all outcomes were assessed by Cox regression analysis. Of 920 patients, 124 (13.5%) were classified as achieving a SVR. During a mean follow-up of 96.1 months (range: 6-167) the incidence rates per 100 person-years of liver-related complications, HCC and liver-related death were 0, 0.66, and 0.19 among SVR and 1.88, 2.10, and 1.44 among non-SVR (P<0.001 by log-rank test). Multivariate analyses found that non-SVR was associated with a higher risk of liver-related complications (hazard ratio, HR, not applicable), HCC (HR 2.59; 95% CI 1.13-5.97) and liver-related mortality (HR 6.97; 95% CI 1.71-28.42) as compared to SVR., Conclusion: Thus, in patients with HCV-related, histologically proven cirrhosis, achievement of a SVR after IFNalpha therapy was associated with a reduction of liver-related mortality lowering both the risk of complications and HCC development. Irrespective of SVR achievement, all patients should continue surveillance because the risk of occurrence of HCC was not entirely avoided.

To evaluate whether racial factors may be involved in the development of ART-induced lipodystrophy and/or lipid serum abnormalities, we carried-out a case-control study on all 23 consecutive anti-HIV-positive sub-Saharan black African patients observed from September 20fc01 to December 2001 ('Cases') and 23 Caucasian 'Controls' pair-matched for sex, age (+/-5 years), number of CD4 cells (+/-100 cells), clinical stage of HIV infection, overall duration (+/-3 months) of anti-retroviral treatment and type and duration (+/-3 months) of the last anti-retroviral regimen. The cases, as compared with the controls, less frequently showed lipodystrophy (4.4 vs. 65.2%, P<0.001) and hypertriglyceridemia (8.8 vs. 56.5%, P<0.005), whereas the prevalence of subjects with hypercholesterolemia was similar in the two groups (30 and 39.1%, respectively). Overall, the prevalence of patients lacking both lipodystrophy and serum lipid abnormalities was markedly higher for the cases than for the controls (69.5 vs. 13%, P<0.001). This study seems to indicate that anti-retroviral-induced lipodystrophy and hypertriglyceridemia may be associated to some racial factor.

Background: We evaluated the clinical and virological characteristics of hepatitis A virus infection in persons concomitantly infected with hepatitis B virus (HBV) or hepatitis C virus (HCV)., Methods: We enrolled 21 patients with acute hepatitis A and chronic hepatitis with no sign of liver cirrhosis, 13 patients who were positive for hepatitis B surface antigen (case B group), 8 patients who were anti-HCV positive (case C group), and 21 patients with acute hepatitis A without a preexisting liver disease (control A group). Two control groups of patients with chronic hepatitis B (control B group) or C (control C group) were also chosen. All control groups were pair-matched by age and sex with the corresponding case group., Results: Fulminant hepatitis A was never observed, and hepatitis A had a severe course in 1 patient in the case B group and in 1 patient in the control A group. Both patients recovered. On admission, HBV DNA was detected in 1 patient in the case B group (7.7%) and in 13 patients (50%) in the control B group; HCV RNA was found in no patient in the case C group and in 16 patients (81.2%) in the control C group. Of 9 patients in the case B group who were followed up for 6 months, 3 became negative for hepatitis B surface antigen and positive for hepatitis B surface antibody, 2 remained positive for hepatitis B surface antigen and negative for HBV DNA, and 4 became positive for HBV DNA with a low viral load [corrected] Of 6 patients in the case C group who were followed up for 6 months, 3 remained negative for HCV RNA, and 3 had persistently low viral loads., Conclusion: Concomitant hepatitis A was always self-limited, associated with a marked inhibition of HBV and HCV genomes, and possibly had a good prognosis for the underlying chronic hepatitis.

To verify the clinical efficacy of the Desmet classification of chronic hepatitis C we reviewed 801 liver biopsies from patients with HCV-chronic hepatitis (CH). The diagnosis of chronic hepatitis was assessed according to the Desmet classification based on the Knodell Histological Activity Index (HAI) (minimal CH=score 1-3; mild CH= 4-8; moderate CH= 9-12; severe CH= 13-18). Liver fibrosis was assessed according to the Scheuer scoring system. One hundred forty-eight patients had cirrhosis and 653 CH. Of these 653, according to the Desmet classification 145 patients showed minimal, 424 mild, 73 moderate and 11 severe chronic hepatitis. Since the classification underestimated the moderate and severe forms of HCV-related chronic hepatitis, we evaluated the possibility of improving the Desmet classification of chronic hepatitis C using our classification: minimal CH= score 1-3; mild CH= 4-6; moderate CH= 7-8; severe CH= 9-18. According to our classification 145 showed minimal CH, 363 mild CH, 61 moderate CH and 84 severe CH. All the 61 patients who crossed over from mild CH under the Desmet to moderate CH under our classification showed a periportal inflammation of grade 3, and all the 73 patients but 8 who crossed over from moderate to severe showed a grade of periportal inflammation higher than 3. The Desmet classification of HCV-related chronic hepatitis underestimated the severe forms of HCV-CH, while our classification seems to be suitable also for chronic hepatitis C.

The liver histology of 68 consecutive anti-HCV/HCV-RNA positive chronic hepatitis patients who were HBsAg/anti-HBs negative, anti-HBc positive (Case bC group) was compared with that of 68 anti-HCV/HCV-RNA positive chronic hepatitis patients who were HBsAg/anti-HBc negative (control C group). The patients were pair-matched by age (+/-5 years), sex, and risk factors for the acquisition of parenteral infection. Case bC group showed a significantly higher mean fibrosis score (2.3 +/- 1.1) than control C group (1.5 +/- 1.1, P <0.001) and more histological evidence of cirrhosis (22% vs. 7.3%, P <0.05). In addition, the patients in Case bC group showed more severe inflammation of the portal tracts (3.5 +/- 0.8 vs. 3.0 +/- 1.1, P <0.005) and there was a higher prevalence of patients with rhomboid-shaped hepatocytes (26.4% vs. 2.7%, P <0.005), acidophilic bodies (33.8% vs. 1.4%, P <0.0001), sinusoidal inflammation (29.4% vs. 10.3%, P <0.01), lymphoid follicles in the portal tracts (72% vs. 44.1%, P <0.05), Kupffer cell proliferation (29.4% vs. 11.8%, P <0.05), bile duct damage (44.1% vs. 10.3%, P <0.0001), and ductular proliferation (30.9% vs. 2.7%, P <0.001) than in control C group. No difference in these histological features was observed between HBV-DNA negative and positive patients in Case bC group. The data suggest that anti-HBc positive patients with HCV chronic infection have a significantly higher degree of liver fibrosis, and that hepatocellular apoptosis, bile duct damage, and ductular proliferation correlate with the presence of this antibody in the serum.

Background: Few data are available on histological features of chronic hepatitis B (HBV) and C (HCV) virus coinfection., Patients and Methods: We enrolled 142 consecutive patients with viral chronic hepatitis on their first liver biopsy: 27 HBsAg and anti-HCV positive (case BC group), 57 HBsAg positive and anti-HCV negative (control B group) and 58 anti-HCV positive, HBsAg/anti-HBs/anti-HBc negative (control C group)., Results: Patients in the case BC group showed serum HBVDNA (37% vs 71.9%, p < 0.005) and ground-glass hepatocytes (37% vs 66.7%, p < 0.01) less frequently than those in the control B group. The case BC group showed a lower prevalence of patients with detectable HCV-RNA than the control C group (60% vs 92.3%, p < 0.001) and a significantly higher fibrosis score (2.1 +/- 1.2 vs 1.5 +/- 1.1, p < 0.05). Of the 27 patients in the case BC group, 10 lacked serum HCV-RNA and showed significantly higher histological activity index (HAI) and fibrosis scores than those found in the 17 HCV-RNA positive (8.5 +/- 4.4 vs 5.4 +/- 2.4 for HAI, p < 0.05; 3.0 +/- 1.3 vs 1.69 +/- 1.0, p < 0.05 for fibrosis)., Conclusion: Liver histology seems to be more severe in chronic coinfection with HBV and HCV than in single infection, particularly when HCV replication is impaired., (Copyright Urban and Vogel)

To test whether Helicobacter species play a role in the enhancement of liver necro-inflammation and fibrosis and in the development of hepatocellular carcinoma (HCC), we sought DNA sequences of Helicobacter species in liver specimens from patients with viral-related chronic hepatitis, HCC or metastatic liver carcinoma. We enrolled 28 consecutive patients with ultrasound evidence of hepatic nodule(s) on their first liver biopsy: 21 had histological evidence of HCC (Group I) and 7 of metastatic liver carcinoma (Group II). In the same period we observed 27 consecutive patients with chronic hepatitis on their first liver biopsy (Group III). Helicobacter sequences were sought by PCR using primers for the 16S rDNA of Helicobacter spp, designed to amplify a 400 base-pair fragment, and detected by 2% agarose gel and hybridization with a specific biotinylated probe. We used, as positive controls for the DNA extraction from liver tissue, hepatic biopsy sections in which HBV infection was confirmed by HBcAg positivity and in which we amplified HBV-DNA by specific primers; positive controls for the amplification of Helicobacter spp were obtained from gastric biopsy sections in which Helicobacter pylori infection was confirmed by biochemical and histochemical tests. HBV-DNA was found in all five HBcAg positive liver biopsies. Helicobacter spp 16S rDNA was detected in all five biopsy specimens of gastric mucosa and in none of liver specimens from patients in any group. Our data suggest that Helicobacter species were not involved in the pathogenesis of virus-related HCC, chronic hepatitis or liver carcinoma metastasis.

The correlation between the length of viremia as detected by reverse transcriptase-polymerase chain reaction (RT-PCR) and the clinical course of hepatitis A virus (HAV) infection was studied. Sixty-six consecutive patients with acute hepatitis A who were admitted to hospital in two infectious disease units in southern Italy were enrolled: 57 had a self-limited course of the disease (typical course), 4 a prolonged course, and 5 relapsing hepatitis. Plasma HAV RNA was sought by RT-PCR, using primers made at 5'-NTR of HAV, designed to amplify a 273-bp fragment and detected by 2% agarose gel and by hybridization with a specific biotinylated probe. In four patients with prolonged acute hepatitis A, the plasma HAV RNA, which was positive on the day of admission to hospital, was found to be negative from day 62, 46, 84, and 105, respectively, after the onset of the symptoms. In patients with relapsing hepatitis, HAV viremia paralleled the clinical and biochemical course of disease. In all patients with a typical self-limiting course, clearance of plasma HAV RNA was observed within 20 days of the onset of symptoms. In most patients, plasma HAV viremia became undetectable before the normalization of serum aminotransferases, underlining the importance of the immune reaction in the pathogenesis of acute hepatitis A. The data also suggest that the detection of plasma HAV RNA after 20 days of illness may predict a prolonged course of the disease, but relapsing hepatitis remains unpredictable on the basis of plasma HAV determination., (Copyright 2003 Wiley-Liss, Inc.)

In 189 anti-HIV positive subjects (130 males and 59 females; median age 32 years, range 17-57) we evaluated the prevalence of patients with hepatitis infections, the role of parenteral and sexual risk factors on the acquisition of these infections and the reciprocal influence between HIV and HCV infections. HCV infection was detected in 53.9% of cases and HBV infection in 8.4%. In only 32% of our patients no marker of hepatitis virus infection was detected. The presence of a hepatitis virus infection was associated to drug addiction; indeed in 91 drug abusers HIV/HCV co-infection was present in 80% of cases and HIV infection alone in 7.7%, p<0.0001. On the other hand, the association between unsafe sexual activity, whether homosexual or heterosexual, and sexual activity with a steady anti-HIV positive partner with HCV infection was less evident, although the high prevalence of anti-HCV in these cases (10.4%, 15.4% and 26.4% respectively) clearly suggests that HIV infection may improve the sexual transmission of HCV. No substantial differences in the level of immunodeficiency, nor in the HIV viral load nor in the frequency of AIDS cases were observed between patients with HIV infection alone and those with HIV/HCV co-infection. In fact, the percentage of patients with AIDS was similar in these two groups. However, we observed a statistically significant association between an advanced HIV clinical stage and the presence of HIV/HCV co-infection (p<0.005), since subjects with co-infection more frequently than with HIV infection alone were in the CDC-B clinical stage. The presence of a more severe liver disease was linked to a multiple hepatitis virus infection, regardless of the degree of immunodeficiency.

This case-control study evaluated the real need for liver biopsy in subjects with persistently normal aminotransferase values over a long period by comparing the histological features of these subjects with those of patients with abnormal aminotransferase values. We considered as "Cases" all 32 consecutive anti-HCV/HCV-RNA positive subjects with at least eight normal serum ALT values during the last twelve months; for each "Case", we selected as a "Control" one anti-HCV/HCV-RNA positive patient with at least two abnormal serum ALT values during the last twelve months. The Cases and Controls were matched for age ( 5 years) and sex. In the Case group, 1 subject showed normal liver tissue, 18 minimal chronic hepatitis (CH) and 13 mild CH. In the Control group, 7 subjects showed minimal CH, 19 mild CH, 3 moderate CH, 1 severe CH and 2 cirrhosis. The subjects in the Control group showed a significantly higher HAI score (5.39+2.81) than those in the Case group (2.96+1.62, p < 0.001). The subjects in the Control group more frequently showed a fibrosis score greater than 1 (28.1%) compared to the Case group (9.4%; p<0.05). Finally, steatosis was more frequent and more severe in the Control group than in the Case group (respectively, 78.1% vs 50%, p < 0.05; and 1.47+1.16 vs 0.6+0.71, p < 0.001). The HAI and fibrosis scores did not correlate with the ALT value, HCV genotype or HCV viral load in either the Case or Control group. Our findings showed that the subjects with a persistently normal serum ALT value had minimal or mild chronic hepatitis, thus demonstrating that a liver biopsy is not indicated for these subjects.

Background: Interferon-alpha plus ribavirin therapy for chronic hepatitis C is associated with adverse effects that lead to therapy discontinuation in up to 27% of patients in randomized controlled trials., Aim: To examine the causes and predictive factors for therapy discontinuation in patients treated in current clinical practice., Methods: We retrospectively enrolled 441 consecutive patients, scheduled to receive interferon-alpha + ribavirin for chronic hepatitis C, in five centres. Patients had been treated with 3 or 6 MU interferon-alpha three times a week plus ribavirin, 800-1200 mg daily, for 6 or 12 months., Results: One hundred and eight [24.5%; confidence interval (CI), 20.5-28.8%] patients failed to finish combination therapy because of adverse events. The discontinuation rate was higher during the first 6 months of treatment; anaemia was an important cause (36.1% of discontinuations); unexplained lipothymia resulted in discontinuation in 11 patients. Female gender [hazard ratio (HR) = 1.85; CI, 1.17-2.92], an interferon-alpha dose > 15 MU/week (HR = 1.79; CI, 1.12-2.86) and no previous interferon-alpha treatment (HR = 1.63; CI, 1.04-2.57) were independent factors associated with discontinuation. The simultaneous presence of these factors identified patients at high risk for discontinuation [odds ratio (OR) = 10; CI, 3.98-25.13]., Conclusions: The study identified some predictive factors for adverse event-related discontinuation, which may improve the safety profile and effectiveness of interferon-alpha + ribavirin combination therapy in chronic hepatitis C.

Background: There are widely discrepant findings on the sexual transmission of hepatitis C virus (HCV), commonly transmitted by the parenteral route. Coinfection with HCV is common in subjects infected with HIV., Goal: This case-control study evaluated the prevalence of anti-HCV in subjects with hetero- or homosexual contact and no history of intravenous drug abuse or blood transfusion, according to the presence or absence of HIV infection., Study Design: In this case-control study, the cases considered were 106 consecutive patients who showed positive anti-HIV test results. For each case, two control subjects were selected who had been screened for HIV infection at the authors' center and found to have anti-HIV-negative test results, and who matched the case in terms age (+/- 5 years), gender, and risk factor for parenterally transmitted infections., Results: The prevalence of subjects with positive test results for hepatitis B surface antigen (HBsAg) was similar between cases and control subjects (4.7% versus 2.4%). Positivity for anti-hepatitis B core antigen in connection with negative test results for HBsAg was observed more frequently in the 106 cases than in the 212 control subjects (33.9% versus 15.6%; P = 0.0003). Anti-HCV positivity was more frequent in the cases than in the control subjects (15.1% versus 5.2%; P = 0.005). In particular, among subjects who had hetero- or homosexual intercourse with a steady partner who had positive anti-HIV test results, anti-HCV positivity was observed in 18.7% of the 32 cases and 1.6% of the 64 control subjects (P = 0.008)., Conclusion: This study demonstrated that in subjects who had only a sexual risk factor for parenterally transmitted infections, HIV may enhance the sexual transmission of HCV.

The sustained response to interferon-alpha treatment was evaluated in 147 anti-HCV/HCV-RNA-positive, HBsAg-negative, chronic hepatitis patients, according to HCV genotypes and the presence or absence of anti-HBs and anti-HBc. These patients had been included in a controlled study on the safety, tolerability, and efficacy of three types of interferon-alpha given at a dose of 3 MU three times weekly for 52 weeks. One hundred and two patients had HCV genotype 1, 42 a non-1 HCV genotype and 3 multiple HCV genotypes; 46 were anti-HBs and anti-HBc negative (group A), 50 anti-HBs and anti-HBc positive (group B), and 51 anti-HBs negative and anti-HBc positive ("isolated" anti-HBc, group C). Serum HBV-DNA was detected by polymerase chain reaction in 15 of the 51 (29.4%) patients in group C and in none of those in groups A or B. The Sustained Response rate was higher in patients with a non-1 HCV genotype than those with HCV genotype 1 (31% vs. 17.7%, P > 0.1). Fewer patients in group C showed a sustained response than in group A or group B (7.8% vs. 30.4%, P = 0.009 and 7.8% vs 28%, P = 0.017, respectively). Moreover, the sustained response rate was high in patients with a non-1 genotype, both in group A (42.8%) and in group B (42.8%), intermediate in patients with HCV genotype 1 (23.3% in group A and 22.2% in group B) and low in group C, irrespective of HCV genotype (8.3% for genotype 1 and 7.1% for other genotypes). The data indicate that patients with HCV chronic hepatitis and isolated anti-HBc show a poor response to IFN-alpha, irrespective of the HCV genotype., (Copyright 2001 Wiley-Liss, Inc.)

To improve our knowledge for future hepatitis A virus (HAV) vaccination strategies we carried out a multicentre study on naturally acquired immunological protection against HAV in patients with chronic hepatitis in Italy. We enrolled 830 consecutive patients with chronic hepatitis on their first observation at one of the six Italian liver units participating in the study. Six hundred and fifty-eight patients (79.3%) were positive for total anti-HAV and 172 (20.7%) were negative. The anti-HAV negative patients were younger (median age 33, range 11-78) than the anti-HAV positive (median age 56, 18-87). There was a higher prevalence of cases with circulating anti-HAV among the 508 patients residing in southern Italy than in the 322 residing in northern Italy (88.8% vs. 64%, P < 0.001). No significant difference in the anti-HAV prevalence was observed between patients from northern Italy and those from southern Italy aged 0-30 years or in those over 60 years, while in those 31-60 years old there was a higher prevalence of anti-HAV positive patients from southern Italy (90.2% vs. 65.8%, P < 0.0001). Of the patients with liver cirrhosis in this study, only 3 of the 26 (11.5%) from northern Italy and 8 of the 228 (3.5%) from southern Italy had no immunological protection against HAV infection. The data suggest that the number of patients with chronic liver disease without naturally acquired immunity against HAV is substantial in Italy, particularly in the north of the country, and that new vaccination strategies are needed.

The optimal therapy for patients with chronic hepatitis C who have not responded to interferon (IFN) is still an unsolved issue. The aim of this study was to evaluate the efficacy and tolerability of a high dose of IFN-alpha2a plus amantadine for chronic hepatitis C patients who were non-responders to a previous course of IFN. Forty consecutive patients with chronic hepatitis C, genotype 1b, who had not responded to IFN-alpha, were randomized to receive: (i) IFN 4.5 MU daily plus amantadine 200 mg/day for 4 weeks and then IFN 6 MU thrice weekly plus amantadine 200 mg/day for an additional 5 months (group A) or (ii) IFN alone at the same dosage and duration (group B). After 1 month of therapy, normal alanine aminotransferase (ALT) values were observed in three of 21 (14.3%) patients in group A and in three of 19 (15.8%) in group B; serum hepatitis C virus (HCV)-RNA clearance was observed in one patient (4.8%) in group A and in six (31.6%) in group B. At the end of treatment, six patients (28.6%) in group A and three (15.8%) in group B had normal ALT levels; however, HCV-RNA in serum was detectable in all of them at levels comparable to the basal values; an ALT relapse occurred within 3 months of stopping therapy. The combination of daily IFN plus amantadine was ineffective in this setting.

To evaluate whether HCV genotype and a "silent" HBV infection may be related to a more severe clinical presentation of liver disease, 205 anti-HCV/HCV-RNA positive, HBsAg/anti-HBs negative patients with chronic hepatitis (113 males and 92 females; median age 55 years, range 18-77), were studied on presentation at the Liver Unit from January 1993 to December 1997. Presence of serum anti-HBc, in the absence of HBsAg and anti-HBs, was considered a marker of "silent" HBV infection. Of the 205 patients, 134 had undergone percutaneous liver biopsy. Two main diagnosis groups were established: the mild liver disease group (76 patients), and the severe liver disease group (109 patients); 20 patients who had refused to undergo liver biopsy were not included in the clinical and virological evaluation because the diagnosis was uncertain. The prevalence of severe liver disease was similar in the genotype 1 and non-1 groups (61.3% of 98 patients with genotype 1 and 52.9% of 70 patients with a non-1 genotype). Instead, the 88 patients with "silent" HBV infection showed a higher percentage of severe liver disease than the 97 anti-HBc negative patients (72.7% vs. 46.4%, respectively: P < 0.0005). Of the 88 anti-HBc positive patients, the prevalence of those with severe liver disease was similar in the 32 cases with serum HBV-DNA as detected by PCR and in the 56 HBV-DNA negative (81.2% vs. 67.8%, P = 0.4). The relation between "silent" HBV infection and severe liver disease was observed both in genotype 1 and non-1 infected patients. Nevertheless, the anti-HBc negative patients infected by genotype 1 showed a severe liver disease more frequently than those infected by a non-1 genotype, with a difference that is significant to the statistical analysis (P < 0.05). The findings suggest that "silent" HBV infection in anti-HCV positive chronic hepatitis enhances the severity of the liver disease. Evidence was also found that in patients without "silent" HBV infection there is a correlation between the presence of HCV genotype 1 and the severity of liver disease., (Copyright 2001 Wiley-Liss, Inc.)

We studied 648 hepatitis B surface antigen (HBsAg)- and/or anti-hepatitis C virus (HCV)-positive patients to evaluate the virologic and clinical characteristics of multiple hepatitis viral infection. We defined as Case B-C an HBsAg/anti-HCV positive patient and as Case b-C an anti-HCV/anti-HBc-positive, HBsAg/anti-HBs-negative patient. For each Case B-C we scheduled as Control-B an HBsAg positive and anti-HCV negative patient and as Control-C an HBsAg/anti-HBs/anti-hepatitis B core antigen (HBc)-negative and anti-HCV-positive patient. Control group C was used as the control also for Case group b-C. Serum HBV DNA by molecular hybridization was found more frequently in Control group B (54% of 161 patients) than in Case group B-C (35.7% of 84, P <.01). The prevalence of HBV wild type was similar in Case group B-C (14. 3%) and in Control group B (17.4%), whereas the e-minus strain was less frequent in Case group B-C (10.7% vs. 33%; P <.01). HBV DNA by polymerase chain reaction (PCR) was detected in 40.8% of 71 patients in Case group b-C. HCV RNA was detected more frequently in Control group C (90.7% of 130 patients) than in Case group B-C (65.2% of 69, P <.0001). Moderate or severe chronic hepatitis or cirrhosis were more frequent in Case group B-C (62.9% of 65 patients) than in Control group B (46.7% of 90, P <.05) or C (40.8% of 98, P <.005), and in Case group b-C (71.1% of 76) than in Control group C. Thus, in multiple hepatitis we observed a reciprocal inhibition of the viral genomes and a more severe liver disease. In Case group b-C, serum HBV DNA was frequent and the clinical presentation was severe.

To evaluate the impact of new antiretroviral combinations (HAART: Highly Active Anti Retroviral Therapy) on HCV replication and liver enzyme levels, we analysed the changes in HCV viremia and aminotransferase levels in HIV and HCV co-infected patients. Moreover, to evaluate the influence of HCV infection on the efficacy of HAART, we compared the virological, immunological and biochemical response to antiretroviral combinations in anti-HIV positive subjects with or without HCV infection. We enrolled eight consecutive outpatients with HIV-HCV coinfection and with indications for HAART (Group A). For each patient in group A, we selected an anti-HIV negative patient with indications for HAART, pair-matched for age, sex, risk factor for HIV infection, presumed duration of infection, number of CD4 cells, HIV viremia and treatment schedule (Group B). A statistically significant increase in CD4 in both groups was found at 1st, 3rd and 6th month of antiretroviral therapy. A decrease in HIV-RNA in both groups was observed at 1st and 6th month of treatment. The percentage of patients with undetectable HIV-RNA at the 1st month was higher in Group B than in Group A (8/8 vs. 3/8, p = 0.025). Basal HCV-RNA viremia was very high in each case and no variations during treatment were observed. During therapy the aminotransferase levels slightly decreased in Group A and consistently increased in Group B. In Group A the differences were not significant to the statistical analysis; in Group B the aminotransferase levels at 3rd and 6th month were significantly higher than those observed at the baseline.

To evaluate the interference between HBV, HCV and HDV and the clinical impact of coinfection as compared with single HBV or HCV infection, we unrolled 618 HBsAg and/or anti-HCV positive subjects (337 with liver biopsy and 281 without liver biopsy) at their first observation at one of the seven Italian Liver Units from 1993 to 1997 (Padova, Rome, Sassari, Naples, Bari, Messina, Palermo). Serum HBV-DNA by dot-blot was found more frequently in patients with HBV infection alone (52% of 133 cases) than in those with HBV-HCV coinfection (28% of 64 cases, p<0.005) or in those with HBV-HDV-HCV coinfection (12% of 25 cases, p<0.0005) or with HBV-HDV coinfection (13% of 8 cases, p<0.05). We observed a higher prevalence of HCV-RNA positive cases in the patients with HCV infection alone (91.2% of 114 cases) than in those with HBV-HCV coinfection (64.5% of 62 cases, p<0.0001) or with HBV-HDV-HCV infection (19% of 21 cases, p<0.0001). These observations suggest a reciprocal inhibition of HBV and HCV genome in multiple hepatitis viral infection. A severe liver disease was more frequently observed in patients with HBV-HCV coinfection (66%) than in those with a single HBV infection (43%, p<0.05) or HCV infection (46%, p<0.05). Anti-HCV positive/anti-HBc positive patients, lacking both HBsAg and anti-HBs, compared with the anti-HCV positive/anti HBc negative ones, more frequently showed severe clinical presentation and less frequently had a sustained response to a-IFN treatment.

The aims of the study were to evaluate the long-term efficacy and tolerability of different doses of interferon-alpha (IFN alpha) and different durations of treatment in chronic hepatitis C by comparing 3 or 6 mega units (MUs) three times weekly given for either 12 or 24 months, and the possibility of obtaining a response in non-responder patients by increasing the dose or by administering IFN daily. A total of 504 patients with non-cirrhotic chronic hepatitis C enrolled in a multicentre study were consecutively assigned to receive either 3 (255 patients) or 6 MU (249 patients) of lymphoblastoid IFN alpha 3 times a week (tiw). At the 12th month of therapy, patients with normal aminotransferase (AMT) in both groups were either given IFN for an additional 12 months with an unmodified or halved dose, or else discontinued therapy. For patients with unmodified AMT levels after 6 months of therapy, the IFN dose was doubled in the 3-MU group, while it was administered at 3 MU daily in the 6-MU group. When no improvement was achieved, therapy was discontinued; otherwise it was prolonged until the 18th month. Patients were followed up for 12 months after discontinuing IFN. Of the 255 patients enrolled at 3 MU, therapy was stopped during the first 6 months in 36 patients (14.1%) because of side effects, and in 24 (9.4%) because of lack of cooperation. Of the remaining 195 patients at the 6th month of therapy, 119 (61%) had normal and 76 (39%) unmodified AMT levels; 14 of the 76 normalized AMT after doubling the dose of IFN, but only 5 (6.6%) had a sustained response. Of the 119 patients with normal AMT, 40 discontinued IFN at the 12th month (schedule A), 39 remained at 3 MU tiw (schedule B) and 40 were given a dose of 1.5 MU tiw (schedule C) for an additional 12 months. At the end of follow-up, 23/40 (57.5%) patients in schedule A, 31/39 (79.5%) on schedule B and 29/40 (72.5%) on schedule C still had normal AMT (A vs. B p = 0.04). In an intention-to-treat analysis, the sustained response rate for patients enrolled at 3 MUs, including the 5 initial non-responders, was 34.5%. Of the 249 patients enrolled at 6 MU, therapy was discontinued during the first 6 months for 39 (15.7%) because of side effects, and for 27 (10.8%) because of lack of cooperation. Of the remaining 183 patients at the 6th month of therapy, 110 (60%) had normal and 73 (40%) unmodified AMT levels. Of the 73 patients, 55 accepted the daily regimen and 8 of them (14.5%) showed a sustained response. Of the 110 patients with normal AMT, 32 (29.1%), despite normalization of AMT, spontaneously discontinued IFN or reduced the dose because of a poor quality of life, while 78 continued with 6 MU until the 12th month, when therapy was discontinued for 28 (schedule A1); 24 patients were given an unmodified dose (schedule B1) and 26 a halved dose (schedule C1) for an additional 12 months. At the end of follow-up, 18/28 (64.3%) patients on schedule A1, 19/24 (79.2%) on schedule B1 and 19/26 (73.1%) on C1 still had normal AMT (p = NS). In an intention-to-treat evaluation, the sustained response rate for patients enrolled at 6 MU, including the 8 from the daily treatment, was 25.7% (64/249). HCV viraemia was undetectable 1 year after discontinuation of IFN in 72.6% of patients with a sustained response. Sustained response was observed in 36.4% of patients with minimal, 46.6% of those with mild, and 33.3% with moderate or severe histological activity (p = NS). The rate of sustained response was lower in patients with genotype 1b (23.6%) than in those with genotype 2a (67.8%, p = 0.002) or genotype 3 (50%, p = 0.03), irrespective of the histological activity. In conclusion, 6 MU IFN alpha are no more effective than 3 MU in inducing a sustained response in treatments of both 12 and 24 months. A 24-month treatment is more effective than a 12-month treatment in maintaining a biochemical response after discontinuation of IFN. In terms of efficacy, compliance and cost, 3 MU for 24 months app

In 1983, a pilot project of universal hepatitis B vaccination was introduced in a hyperendemic area in southern Italy (Afragola) and is ongoing to date. In this area before the start of vaccination, we found significant evidence of HBV endemicity: the acute viral hepatitis B incidence in the general population averaged 63/100,000; the HBsAg and anti-HBc prevalence rates were 13.4% and 66.9%, respectively; there was involvement of hepatitis B virus (HBV) in 48.1% of chronic liver pathologies (46.3%) in chronic viral hepatitis, 49.5% in cirrhosis and 71.7% in hepatocellular carcinoma cases). We studied the acute viral hepatitis incidence during the vaccination period from 1983 to 1997 and compared the HBsAg and anti-HBc prevalences in 1978 to those in 1997, after 15 years of vaccination. The HBV-related chronic pathology prevalence was also studied. We found a remarkable drop in the acute viral hepatitis incidence, from an average annually of 63/100,000 in the five years before vaccination to 3/100,000 in the last five years of vaccination. In addition, the HBsAg carrier prevalence in the general population decreased from 13.4% in 1978 to 3.7% in 1997. The percentage dropped in children and adolescents from 6.8% to 0.7%, in young people from 10.2% to 1.1% and in adults from 15.8% to 4.0%. The anti-HBc carrier prevalence, found to be 66.9% in 1978, was 34.2% in 1997. Finally, we found a much less significant involvement of HBV in chronic liver pathologies; in fact, it was present in only 18.2% of cases in 1997 and in 48.2% in 1982. In the light of the data, we can assert that universal hepatitis B vaccination has had a substantial effect on HBV endemicity in the Afragola area. We believe that the reduction found in the incidence of acute viral hepatitis B and HBV-related chronic liver pathologies is connected to the decrease in HBV carriers in the area, which therefore reduces the risk of contagion for the unvaccinated.

To test the hypothesis that households of anti-HCV positive subjects might be at increased risk of HCV infection, a case-control study was carried out comparing 518 family members of 205 anti-HCV positive subjects (index carriers) with 281 family members of 100 anti-HCV negative subjects (index controls), consecutively observed in ten gastroenterology units in different Italian regions. The index carriers were age and sex matched to the index controls and their households were similar with respect to the main sociodemographic characteristics. Anti-HCV antibodies were found in 6.9% (36/518) of household members of index carriers and in 3.2% (9/281) of household members of index controls (p < 0.05). The results of multiple logistic regression analysis showed that being over 50 years of age was the sole independent predictor for a household contact of the likelihood of being anti-HCV positive (O.R. 3.6; C.I. 95% = 1.5-8.2). Being in the household of an anti-HCV index carrier was marginally associated to anti-HCV positivity (O.R. 2.0; C.I. 95% = 0.9-4.6). No association was found for sex, area of residence, family size, lowest level of schooling, or any type of family relationship. These findings are not in compliance with the statement that household contacts of HCV carriers are at increased risk of HCV infection. The 3.2% anti-HCV prevalence rate observed among household contacts of anti-HCV negative index controls may suggest that the true anti-HCV prevalence in the general population in Italy is nearly 2.5 times as high as the 1.3% found in Italian blood donors.

Following the decrease in HAV endemic levels in the last decades, nowadays in Italy most people aged less than 30 years are susceptible to the infection. We have tested for serum anti HAV IgG 194 chronic hepatitis patients from Naples to evaluate the level of protection against HAV in a category of patients in whom an acute necrosis due to HAV might induce liver failure. The study shows that 90.7% of Neapolitan chronic hepatitis patients has serologic evidence of prior HAV infection. Specifically, 98.1% of the patients over 40 years of age, but only 54.6% of those under 40 tested positive for anti HAV IgG. 102 patients had cirrhosis and only one tested negative. The data suggest that HAV vaccination in susceptible chronic hepatitis patients should be judged by the physicians in care on the basis of the severity of disease, patient's age, real risk of exposure to the infection, and level of education.

To detect HIV antigens in circulating complement fixing immune complexes (ICs) we assessed an ELISA using wells of microtitre plates coated with F(ab)2 anti-C3b and monoclonal antibodies anti-HIV gp120 and anti-HIV p24. We tested 24 anti-HIV positive subjects (Group A), 10 anti-HIV negative subjects at risk of acquiring HIV infection (Group B), 20 normal controls (Group C) and 2 seroconversion panels. We found HIV antigens in ICs in all sera from seroconversion panels, in 25.5% of sera from subjects in Group A, in 28.6% of sera from subjects in Group B and in no serum from subjects in Group C. A subject in Group B acquired HIV infection during the observation. HIV antigens in ICs by our assay were detected 8 months before Anti-HIV and Ag by commercial ELISA.

To detect the presence of anti-HIV IgA in HIV infected subjects and in seronegative subjects at risk of infection, we assessed a Western Blot using nitrocellulose strips with HIV separated proteins. We tested at least 2 different serum samples from 9 anti-HIV positive subjects (Group A), 9 anti-HIV negative subjects at risk of infection (Group B) and 9 controls (Group C). One subject in Group B became anti-HIV positive during the observation. Anti-HIV IgA were detected in all patients of Group A, in 66.6% of patients of Group B and in no patient of Group C. The subject who seroconverted during the observation showed positivity for IgA anti-HIV in both serum samples, while anti-HIV IgG became detectable only on the second serum sample. A newborn from a seropositive mother showed maternal anti-HIV IgG on the first 2 out of 3 serum samples while showed anti-HIV IgA positivity on the third sample only. This child is still anti-HIV negative.

To detect HlV proviral DNA in lymphocytes from subjects at risk of acquiring HIV infection, we assessed a Polymerase Chain Reaction Assay using the SK38 and SK39 primers for the amplification and the SK19 probe for the hybridization. The detection of amplified HIV-DNA was obtained by a new colorimetric method, the DNA enzyme immunoassay (DEIA). The PCR we performed allowed to detect HIV-pDNA in lymphocytes of 13 out of 64 subjects at risk of acquiring HIV infection. Seven of these 13 became anti-HIV positive during a follow up of 8 months.

In order to determine the prevalence of multiple infections with hepatitis viruses in chronic HBsAg carriers in Naples, to assess the interaction between HBV, HDV and HCV infections and to evaluate the influence of multiple virus hepatitis infections on the clinical presentation, we studied 198 HBsAg chronic carriers observed consecutively from 1971 to 1988 at our Liver Unit. Of the 198 HBsAg chronic carriers, 171 had undergone percutaneous liver biopsy. The presence of HBcAg or HDAg in the liver biopsy was considered a marker of HBV or HDV replication, respectively; the presence of anti-HCV was considered a marker of HCV infection. Anti-HCV was observed in 13.6% of the 22 subjects with normal liver, in 27.7% of the 47 patients with minimal chronic hepatitis, in 40% of the 50 with mild chronic hepatitis, in 70.6% of the 17 with moderate hepatitis, in 66.7% of the 3 with severe chronic hepatitis and in 65.6% of the 32 with active cirrhosis. Anti-HCV positive cases were antiHD positive more frequently than the anti-HCV negative (59.2% vs. 43%, p = 0.05). HDV infection exerted a clear inhibition on the HBV genome. Among the 171 HBsAg chronic carriers, the finding of an active chronic hepatitis (moderate chronic hepatitis + severe chronic hepatitis + active cirrhosis) is less frequent in subjects with HBV replication alone than in those with HDV replication or HCV infection. Patients with both HBV replication and HCV infection and those with both HDV replication and HCV infection showed a very high prevelance of active chronic hepatitis.

Background/aims: To evaluate a possible variation in hepatitis D virus endemicity in Italy, the data from a multicentre study concerning HBsAg chronic carriers first observed in 31 liver units during 1992 were compared with the corresponding figures from a similar study performed in 1987., Methods/results: In both studies the methodology for the recruitment of cases was the same. The overall anti-HD prevalence in 1992 was 14.4%, a significantly lower rate than that observed in 1987 (23.4%, p < 0.01). The decrease significantly (p < 0.01) affected both males and females; it occurred in all geographical areas, although to a greater extent in northern regions. It was evident in subjects below 50 years of age, but not in subjects older than 50. A significant reduction in the anti-HD prevalence was seen in all forms of chronic hepatitis., Conclusions: These findings indicate a lower level of hepatitis D virus endemicity in Italy, probably as a consequence of the reported decreased pool of HBsAg chronic carriers, the reduced size of families, the improved socio-economic conditions and changes in intravenous drug abuser behaviour. All these factors may have affected the strength of hepatitis D virus infection which has greatly reduced the spread of the virus.

In a multicenter retrospective study, we reviewed the etiology of chronic hepatitis (CH) in Italy during the period 1980-1989, before the laboratory diagnosis of HCV hepatitis had become possible. Among the 5,461 patients investigated, 31.3% had HBV-CH, 5.5% HDV-CH, 3.0% serological markers of autoimmune hepatitis and 3.7% post-transfusion NANB CH. Alcohol abuse was considered responsible in 10.9% of the cases and a diagnosis of crytogenic CH was made in 42.5%. Considering that most cryptogenic cases were actually due to chronic HCV infection, we may assume that as many as two-thirds of our cases were due to a hepatitis virus infection. Some differences were observed between patients with chronic hepatitis of different etiologies. Drug abuse was frequently recorded only in HDV-CH; patients with HBV-CH and HCV-CH were younger than those in other etiological groups; a histological picture of chronic active hepatitis was more frequently recorded in HDV-CH and autoimmune CH. The only identifiable geographical differences observed were a higher prevalence of HDV-CH in the south and of alcoholic chronic liver diseases in the north. During the period under observation, we noted a clear reduction in the percentages of HBV chronic hepatitis cases after 1984 and, accordingly, the mean age of HBV-CH progressively increased from 1980 to 1989 by almost a year each year. This observation is in agreement with recent data suggesting a reduction in HBV endemicity in Italy in recent years.

We studied a series of 268 chronic hepatitis C patients (31 chronic persistent hepatitis CPH, 69 mild chronic active hepatitis CAH, 125 severe CAH, and 43 active cirrhosis) enrolled from 1988 to 1991 in different therapeutic protocols using lymphoblastoid or recombinant interferon (IFN) at a dosage of 3 mega units (M.U.), three times a week for 12 months. Of these patients 54.8% showed a complete response (normalization of aminotransferases), 14.2% a partial response (decrease in aminotransferases of over 50%), 27.6% no response, and 3.4% a substantial progressive increase in the liver enzymes during IFN (becoming worse). The prevalence of non responders was lower in CPH (9.7%) than in CAH patients (31.9% in the mild form and 20.8% in the severe), and significantly higher in patients with cirrhosis (53.5%). No correlation was observed between non response and the baseline aminotransferase level or the patient's sex. Patients under 35 had a better response to IFN when compared with patients 36-50 years. This is probably due to the higher prevalence of CPH patients with a good response to IFN in the youngest group. No effect was gained in non responders by increasing the dose or shifting from recombinant to lymphoblastoid IFN; three patients were then treated with steroids, but only one benefitted. For 5 of the 9 patients who became worse, steroids were started after discontinuation of IFN therapy, and they induced a favorable response only for the 3 who had developed autoantibodies during IFN treatment.

Hepatitis B virus DNA was determined in the sera of 198 chronic hepatitis B surface antigen (HBsAg) carriers by the spot hybridization technique. The results were correlated with hepatitis Be antigen (HBeAg) and antibody (anti-HBe), delta antibody (anti-HD) and liver histology. All subjects had a liver biopsy. The prevalence of HBV DNA was 63% in HBeAg-positive subjects and 8.8% in anti-HBe positives. HBV DNA was not found more frequently in chronic HBsAg carriers who had histological evidence of liver disease than in carriers without such evidence. Anti-HD was detected in 48.5% of subjects, with an increasing trend (p less than 0.001) according to the severity of liver disease. Among patients with more severe liver disease (CAH and cirrhosis), HBV DNA and HBeAg were detected less frequently in anti-HD-positive than in anti-HD-negative subjects (7% vs. 42.3%, p less than 0.001 and 7% vs. 34.4%, p less than 0.005, respectively). These findings indicate that HDV infection jointly affects both HBeAg status and HBV DNA.

A six-month analysis of a controlled trial on the treatment of chronic hepatitis B in children shows that prednisone priming followed by alpha-interferon 2A was effective in 6 of 9 treated patients in reducing HBV replication and disease activity.

To obtain data on the clinical presentation and the course of the disease of biopsy-proven chronic persistent hepatitis (CPH), we coordinated a multicentre retrospective study on 1197 patients observed in 16 liver units throughout Italy from 1975 to 1985. Most patients were asymptomatic and CPH was often diagnosed either after a chance finding of liver enlargement, or increased serum aminotransferases and/or HBsAg antigenemia. Of the 1197 patients, 534 (44.6%) were HBsAg-positive and 663 (55.4%) were HBsAg-negative. HBeAg was tested in 356 of the 534 positive cases and detected in 58.4% of them. This percentage was higher (80%) in patients under 20. Hepatitis delta virus infection (HD-Ag in liver tissue and/or anti-HD in serum) was detected in 28 (14.7%) of the 191 patients tested on presentation. Liver function tests showed mild hepatic involvement in both HBsAg-positive and negative cases, a pronounced derangement being observed only in patients with HDV infection. A second liver biopsy was performed in 212 patients (144 HBsAg positive and 68 HBsAg negative) and the outcome of the disease was evaluated only in these 212 patients. Of the 144 HBsAg-positive cases followed-up from one to ten years (median 4 years), 47 recovered, 70 remained unchanged and 27 developed chronic active hepatitis or cirrhosis. Clearance of HBsAg was uncommon even in patients who recovered. Being under 15 years of age favourably affected the course of the disease, while HDV infection was correlated to an unfavourable outcome. Among those patients who were HBeAg positive on presentation and who underwent a second affect the outcome. Of the 68 HBsAg-negative clearly affect the outcome.(ABSTRACT TRUNCATED AT 250 WORDS)

Thirty-four persistent healthy carriers of HBsAg (serum HBsAg detectable for longer than 3 months with normal liver function tests and normal liver histology or slight aspecific abnormalities) were discovered by routine testing of household relatives of B virus hepatitis patients. The carriers were followed-up for 11 to 37 months by clinical control, liver function tests and liver needle biopsy. None carrier had previous jaundice. During the follow-up period, in 17 of the 34 subjects, was there no evidence of deterioration in either clinical state, liver function of pathological findings. In 5 of the 34 carriers, HBsAg disappeared from serum after a period ranging from 6 to 12 months. The remaining 12 cases developed clinical and histological picture of acute viral hepatitis after 6 to 29 months (mean 12 months). Of these 12 patients, 6 recovered and become HBsAg; 2 remained HBsAg healthy carriers despite normalization of biochemical and histological abnormalities; 3 progressed from the acute stage to antigen positive CAH. The remaining one case could not be followed-up after the acute hepatitis. Our data indicate that the outcome of the HBsAg carrier state is unpredictable and stress the need of long-term follow-up surveillance.