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Abstract: Background and aim: There is suspicion of a decrease in warning regarding the hepatitis B virus as a health problem both by the infected individuals and their doctors. The aim of this study was to investigate whether the clinical/virology investigation of chronic hepatitis B virus infected individuals is at present accurate. Methods: The chronic hepatitis B virus surface antigen carriers consecutively attending 13 different hospital divisions in Calabria from July to December 2005 were evaluated to investigate the available information on the grade of their liver disease, their virologic profile and the hepatitis B virus status of their family members. Results: Four-hundred-thirty hepatitis B virus surface antigen positive individuals were enrolled, 417 of whom were Calabrians. Most of them had a diagnosis of chronic liver disease, but a liver biopsy had been performed only in 13.5% of the cases, whereas more than 1/3 of them had not been tested for hepatitis Delta virus co-infection. The majority of these individuals were unaware of the hepatitis B virus status of their family members. Moreover, anti-hepatitis B virus vaccination procedures were not performed in most of the hepatitis B virus surface antigen carrier families. Conclusions: This study revealed that fundamental clinical, virological, and epidemiological aspects of chronic hepatitis B virus infection are not investigated in many hepatitis B virus surface antigen carriers, suggesting that the general knowledge as regards hepatitis B virus is mostly inadequate. [Copyright &y& Elsevier]

Aim: This study aimed to investigate the role of resistance-associated substitutions (RASs) to direct-acting-antivirals (DAAs) in HCV genotype 3 (GT3)., Methods: Within the Italian VIRONET-C network, a total of 539 GT3-infected patients (417 DAA-naïve and 135 DAA-failures, of them, 13 at both baseline and failure) were analysed. Sanger sequencing of NS3/NS5A/NS5B was performed following home-made protocols., Results: The majority of patients were male (79.4%), 91.4% were injection drug users, 49.3% were cirrhotic and 13.9% were HIV co-infected. Phylogenetic analysis classified sequences as GT3a-b-g-h (98%-0.4%-0.2%-1.2%) respectively. Overall, 135 patients failed a DAA regimen: sofosbuvir (SOF)/daclatasvir (DCV) or velpatasvir (VEL)±ribavirin (RBV) (N = 91/15) and glecaprevir (G)/pibrentasvir (P) (N = 9). Moreover, 14.8% of patients were treated with suboptimal regimens for GT3: 3D ± RBV (Paritaprevir/r + Ombitasvir+Dasabuvir, N = 15), SOF + Simeprevir (SIM) (N = 1) or SOF/Ledipasvir (LDV) ± RBV (N = 4). RAS prevalence was 15.8% in DAA-naïve patients. At failure, 81.5% patients showed at least one RAS: 11/25 (44.0%) in NS3, 109/135 (80.7%) in NS5A, 7/111 (6.3%) in NS5B SOF-failures. In NS5A-failures, Y93H RAS was the most prevalent (68.5% vs 5.1% DAA-naïve, P < .001) followed by A30K (12.7% vs 2.8% in DAA-naïve, P < .001). Analysing baseline samples, a higher prevalence of NS5A-RASs was observed before treatment in DAA-failures (5/13, 38.5%) vs DAA-naïves (61/393, 15.5%, P = .04). Regarding 228 DAA-naïve patients with an available outcome, 93.9% achieved a SVR. Interestingly, patients with baseline Y93H and/or A30K had SVR rate of 72.2% vs 95.7% for patients without NS5A-RASs (P = .002)., Conclusions: In this real-life GT3 cohort, the majority of failures harboured resistant variants carrying NS5A-RASs, the most frequent being Y93H. The presence of natural NS5A-RASs before treatment was associated with failure. Further analyses are needed to confirm this observation, particularly for the new current regimens., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background & Aims: Obesity is associated with non-alcoholic fatty liver (NAFL), which may progress towards non-alcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC). Occult hepatitis B virus infection (OBI) may contribute to hepatic damage in patients with chronic liver disease of different aetiologies (eg HCV, alcohol). However, information on the prevalence and clinical impact of OBI in obese individuals is lacking. The aims of this study were to investigate NASH prevalence and risk factors in obese people who underwent bariatric surgery., Methods: Two-hundred and twenty-six subjects (160 females; mean age 42.9 years ±10.8 SD) without evidence of any further cause of liver disease consecutively underwent bariatric surgery in two Italian liver centers. During surgery, all patients underwent liver biopsy for histological evaluation and molecular studies. Liver DNA extracts were tested for PNPLA3, TM6SF2, MBOAT7, IRGM polymorphisms and for OBI. Univariate and multivariate analyses were used to identify predictors of NASH., Results: Histology showed NASH in 115 (50.9%) and NAFL in 111 cases (49.1%). Twenty-nine/226 (12.8%) cases had OBI, 24 (82.8%) of whom had NASH and 5 (17.2%) NAFL, whereas among the 197 OBI-negative cases, 91 (46.2%) had NASH and 106 (53.8%) NAFL (P = .0002). Multivariate analysis showed that older age (P = .03, OR 1.034), alanine aminotransferase values (P = .005, OR 1.023), insulin resistance/diabetes (P = .02, OR 2.257), TM6SF2 polymorphism (P = .04, OR 3.168) and OBI (P = .004, OR 5.503) were independent predictors of NASH., Conclusion: NASH is highly prevalent in obese individuals undergoing bariatric surgery. OBI is one of the strongest risk factors of NASH in these patients., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Hepatitis C virus (HCV) NS3 resistance-associated substitutions (RASs) reduce HCV susceptibility to protease inhibitors. Little is known about NS3 RASs in viral isolates from the liver of chronic hepatitis C (CHC) patients infected with HCV genotype-1a (G1a)., Aim: The objective of this work was to study NS3 variability in isolates from the serum and liver of HCV-G1a-infected patients naïve to direct-acting antivirals (DAAs)., Methods: NS3 variability of HCV-G1a isolates from the serum and liver of 11 naïve CHC patients, and from sera of an additional 20 naïve CHC patients, was investigated by next-generation sequencing., Results: At a cutoff of 1%, NS3 RASs were detected in all the samples examined. At a cutoff of 15%, they were found in 54.5% (6/11) and 27.3% (3/11) of the paired liver and serum samples, respectively, and in 22.5% (7/31) of the overall serum samples examined. Twenty-six out of thirty-one (84%) patients showed NS3 variants with multiple RASs. Phylogenetic analysis showed that NS3 sequences clustered within 2 clades, with 10/31 (32.2%) patients infected by clade I, 15/31 (48.8%) by clade II, and 6/31 (19.3%) by both clades., Conclusions: Though the number of patients examined was limited, NS3 variants with RASs appear to be major components of both intrahepatic and circulating viral quasispecies populations in DAA-naïve patients., (© 2018 S. Karger AG, Basel.)

Hepatitis B virus (HBV) infection plays a major role in hepatocellular carcinoma (HCC) development. Much evidence suggests that HBV also maintains its pro-oncogenic properties in cases of occult HBV infection (OBI). Mutations of the beta-catenin and p53 genes (CTNNB1 and TP53, respectively) may be associated with HCC occurrence in patients with overt HBV infection, whereas such genetic mutations have not been investigated in HCC patients with OBI thus far. We investigated the genetic heterogeneity of CTNNB1 exon 3 and all of the TP53 exons in tumor DNA extracts from a unique cohort of 61 HCC patients (all previously tested for HBV DNA and for its integration into the host's genome), including 34 OBI-positive, 20 HBV surface antigen (HBsAg)/OBI-negative, and 7 HBsAg-positive cases. No CTNNB1 exon 3 mutations or TP53 mutations were detected in any case. The homo- or heterozygous TP53 R72P polymorphism was found in 18 of 61 cases (29.5%), although no differences in its prevalence between OBI and non-OBI cases as well as between cases with and without viral integration were revealed. In conclusion, CTNNB1 and TP53 somatic mutations seem to be a rare event in patients with HCC in our area and in cases with either overt or occult HBV infection., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Hepatitis E virus (HEV) is a major cause of acute hepatitis in developing countries, whereas it is not considered a major health problem in Western World., Aims: To investigate the spread of HEV and its possible role in causing acute hepatitis in Southern Italy., Methods: Four hundred and thirty patients observed from April to December 2009 were studied and grouped as follows: 55 individuals with acute hepatitis (AH), 33 of whom cryptogenic; 321 individuals with chronic liver diseases (CLD), (278 Italians and 43 immigrants); 54 individuals without liver disease (control-group). Serum samples from all cases were tested for IgG anti-HEV antibodies and those positive to this test as well as all AH cases were also tested both for IgM anti-HEV and HEV RNA., Results: Two of 33 (6%) cryptogenic AH cases were associated with HEV infection as shown by positive IgM anti-HEV test. Both these patients had not travelled to areas at high HEV endemicity. HEV RNA was not found in any sample tested. IgG anti-HEV antibodies were detected in 5.7% of Italians with CLD and 3.7% of the control-group. No immigrant was found positive for any HEV marker., Conclusion: Autochthonous HEV infection is present in Southern Italy where it may cause AH., (Copyright © 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

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.)

Background: Occult hepatitis B virus (HBV) infection frequently occurs in patients with HBV surface antigen (HBsAg)-negative chronic liver disease, and much evidence suggests that it is a risk factor for hepatocellular carcinoma (HCC) development. However, to the authors' knowledge, no follow-up study has been performed to date evaluating HCC occurrence over time in chronic hepatitis patients with or without occult HBV infection., Methods: A cohort of the 380 HBsAg-negative chronic hepatitis patients attending the study institution between 1991-2000 were evaluated and tested for occult HBV DNA by analysis of liver biopsy specimens., Results: There were 135 patients (35.5%) with occult HBV and 245 patients (64.5%) without occult HBV. Cirrhosis was significantly associated with occult HBV infection (P = 0.01). One hundred thirty-four of these patients were followed for a minimum of 50 months (median, 82.8 +/- 32.6 mos). Fifty-three patients (39%) were occult HBV carriers and 81 (61%) were not. Nine patients developed HCC during the follow-up; eight were positive and one was negative for occult HBV (P = 0.002)., Conclusions: The current observational cohort study showed that, among the HBsAg-negative patients with chronic hepatitis, HCC develops for the most part in carriers of occult HBV. Therefore, the evaluation of HBV genomes in chronic hepatitis patients appears to be a powerful tool for the identification of individuals at higher risk of HCC development., ((c) 2006 American Cancer Society.)

The tissue tropism and possible correlation with liver disease of the TT virus (TTV) as well as its prevalence and genotype distribution remain undefined. TTV-DNA was investigated in paired sera and tissue samples from 144 patients, and sera and cerebrospinal fluids (CSF) from additional six subjects. Of the 144 tissue samples, 128 were liver biopsy specimens from subjects with hepatic disease while 16 were surgically obtained nonliver specimens from patients with extrahepatic disease. TTV cloning, sequencing and genotype analyses were performed on isolates from sera, tissue specimens and peripheral blood mononuclear cells of two patients with hepatic and four patients with extrahepatic pathologies, as well as from sera and CSFs of two subjects. TTV was found in 100% of the examined tissues and in 60.1 and 50% of sera from patients with hepatic and extrahepatic pathologies, respectively. Moreover, TTV was detected in four of the six CSFs analysed but only in two correspondent sera. Genotyping revealed the coexistence of multiple TTV genotypes and genetic variants in each infected individual, and the analysis of TTV mRNA showed the presence of transcripts in all the six different tissues studied. These results indicate that the entire adult population in our area is more likely infected by TTV, although several subjects are not viraemic and that TTV infects many different human tissues and is able to invade the central nervous system.

Non-organ-specific autoantibodies (NOSAs) are frequently found in patients with hepatitis C virus (HCV) chronic infection. Genetics is likely involved in the development of autoimmune reactivities, and differences in the prevalence of HCV-related autoantibodies among populations of various geographic areas should be expected. We evaluated the prevalence and the clinical impact of NOSAs in a series of HCV-infected patients from southern Italy. We studied 283 consecutive anti-HCV positive patients (162 men, 121 women, mean age 54.5 +/- 13.5 years), 94 of whom were cirrhotics and 189 noncirrhotics. Serum from each patient and from 41 hepatitis B surface antigen (HBsAg)-positive/anti-HCV negative control subjects were tested (dilution 1:40) for autoantibodies by indirect immunofluorescence. Qualitative/quantitative HCV-RNA determinations were also performed. The prevalence of NOSAs was significantly higher in anti-HCV-positive subjects than in HBsAg-positive patients (P < 0.006). Autoantibodies were significantly associated with both cirrhosis (P < 0.0001) and older age (P < 0.05). No significant association between NOSAs and either female gender or virological parameters (HCV-RNA positivity, viral load, and genotype) was found. In conclusion, the autoantibody positivity in HCV-infected patients from southern Italy is significantly related to cirrhosis and older age, although its general prevalence is similar to that reported in populations from the north of the country.