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This study aimed to investigate the efficacy and safety of sofosbuvir-based therapies for the treatment of cirrhosis from hepatitis C virus (HCV) genotype 2 infection. Data of all consecutive HCV genotype 2 cirrhotic patients who started sofosbuvir-based treatments between January 2015 and March 2017 in eight Italian tertiary hospitals were collected retrospectively. Overall, 273 patients (Child A: 94.5%) were enrolled. In the 194 subjects treated with sofosbuvir/ribavirin, median initial ribavirin dosage was 13.9 mg/kg/day, and therapy duration was 16 weeks. Sustained virological response (SVR) rates were 93.8% in intention-to-treat (ITT) and 95.3% in per-protocol (PP) analyses for the 129 treatment-naïve patients, and 96.9% (ITT) and 98.4% (PP) for the 65 treatment-experienced subjects. Adverse events were reported in 142 patients (73.2%), but only 1.5% discontinued treatment. Eighty-eight subjects with treatment-induced anemia (mild: 34.5%, moderate: 7.7%, severe: 3.1%) had to reduce ribavirin dosage, but SVR rates were comparable to the weight-based dose group, both in ITT (95.4% and 94.3%) and PP (97.7% and 95.2%) analyses, respectively. Moreover, ITT and PP SVR rates were similar between shorter (<20 weeks) (94.1% and 96.0%, respectively) and prolonged (≥20 weeks) regimens (95.7% and 96.7%, respectively). SVR rates in the 79 subjects treated with sofosbuvir/daclatasvir (without ribavirin) were similar (ITT: 96.2%; PP: 97.4%, respectively), without de novo/worsening anemia. In conclusion, in a real-life study centered on genotype 2 patients with well-compensated cirrhosis, sofosbuvir-based regimens were associated with good SVR and tolerability rates, regardless of previous antiviral treatments, without a significant impact of on treatment ribavirin dose reductions., (© 2021 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.)

Liver fibrosis consists in the accumulation of extracellular matrix components mainly derived from activated hepatic stellate cells. This is commonly the result of chronic liver injury repair and represents an important health concern. As liver biopsy is burdened with many drawbacks, not surprisingly there is great interest to find new reliable noninvasive methods. Among the many are new potential fibrosis biomarkers under study, some of the most promising represented by the growth arrest-specific gene 6 (Gas6) serum protein and its family of tyrosine kinase receptors, namely, Tyro3, Axl, and MERTK (TAM). Gas6/TAM system (mainly, Axl and MERTK) has in fact recently emerged as an important player in the progression of liver fibrosis. This review is aimed at giving an overall perspective of the roles played by these molecules in major chronic liver diseases. The most promising findings up to date acknowledge that both Gas6 and its receptor serum levels (such as sAxl and, probably, sMERTK) have been shown to potentially allow for easy and accurate measurement of hepatic fibrosis progression, also providing indicative parameters of hepatic dysfunction. Although most of the current scientific evidence is still preliminary and there are no in vivo validation studies on large patient series, it still looks very promising to imagine a possible future prognostic role for these biomarkers in the multidimensional assessment of a liver patient. One may also speculate on a potential role for this system targeting (e.g., with small molecule inhibitors against Axl) as a therapeutic strategy for liver fibrosis management, always bearing in mind that any such therapeutic approach might face toxicity., Competing Interests: The authors declare that they have no conflicts of interest regarding the publication of this paper., (Copyright © 2019 Carlo Smirne et al.)

Background: Alcohol is a major determinant of the outcome of chronic hepatitis C virus (HCV) infection, but self-reported drinking habits lack reliability. We hypothesized that carriage of high-repetition variants (HRV) of the variable number of tandem repeats (VNTR) in exon III of the dopamine receptor D4 gene, linked to binge-drinking and risk-seeking behavior, might be a proxy measure of alcohol consumption, and aimed to verify whether it may affect histologic outcome., Methods: A cohort of HCV patients with normal or near-normal aminotransferases (N = 128) underwent a liver biopsy as part of diagnostic work-up. None admitted to exceed low-risk alcohol consumption; most (90/128, 70%) described themselves as teetotalers. They received advice on abstaining from alcohol, but not antiviral treatment. After a median follow-up period of 10 years, all underwent a second liver biopsy. HRV allele frequencies were compared with those of a group of healthy blood donors (N = 128) and related to liver histology., Results: HRV allele frequencies were 0.19 in patients and 0.16 in controls (p = 0.182). In the subgroup of patients who admittedly had consumed alcohol, 20/38 (53%) carried HRV, in comparison with 27/90 patients (30%) who had denied to consume alcohol (p = 0.026 by Fisher's exact test). Carriage of HRV was associated with higher histologic grade (p = 0.002) and stage (p = 0.009) at the final biopsy. At multivariate analysis, among a set of variables also including viral genotype, viral load, body mass index, gender, and history of alcohol consumption, only age (OR = 1.06, 95% CI 1.02 to 1.11) and HRV (OR = 3.13, 95% CI 1.28 to 7.68) were independent predictors of significant fibrosis at the end of follow-up., Conclusions: The link between HRV carriage and histologic outcome in a subgroup of HCV patients at low risk of progression underlines the need for intense scrutiny of alcohol habits in hepatitis C., (Copyright © 2013 by the Research Society on Alcoholism.)

The interleukin 28B (IL-28B) rs12979860 C/T polymorphism is a predictor of spontaneous and treatment-induced hepatitis C virus (HCV) clearance. The C/C genotype is associated with higher serum cholesterol, predictor of a favorable outcome in chronic hepatitis C. Whether IL-28B polymorphism and serum cholesterol play a role in modulating the history of mild hepatitis C is unknown. To clarify this issue, 93 untreated patients infected with HCV with normal or near-normal transaminases and an initial Ishak staging score ≤1 were investigated retrospectively in the longitudinal study (median histological follow-up of 10 years). An additional confirmatory cohort of 143 patients with chronic HCV infection and abnormal levels of transaminases was evaluated in the cross-sectional study. In the longitudinal study, at the end of follow-up, Ishak staging scores progressed more frequently among carriers of a T/* allele who had a baseline serum cholesterol ≤175 mg/dl than in remaining patients: 6/36 (change ≤0), 15/45 (change 1-2), 6/12 (change ≥3), improvement chi-square P < 0.02, OR 3.1, 95% C.I. 1.3-7.7. In the cross-sectional study, the frequency of patients carrying the T/T genotype or serum cholesterol values ≤175 mg/dl increased starting from those with a staging score ≤2 (36/76, 47.4%), to those with a staging score of 3-4 (26/41, 63.4%) and to those with a staging score of 5-6 (20/26, 76.9%, P < 0.01 for linear trend). In conclusion, the interaction between IL-28B rs12979860 T/T genotype and low serum cholesterol concentration is an independent predictor of a worse disease course among patients infected with HCV with normal or near-normal transaminases., (Copyright © 2012 Wiley Periodicals, Inc.)

Background and Aim: Carriage of the apolipoprotein E (Apo E) variants, E2, E3 and E4, affects cholesterol metabolism and may be involved in the persistence of hepatitis C virus (HCV) infection. Our aim was to verify whether carriage of specific Apo E variants modulates the course of hepatitis C., Methods: We studied a cohort of 116 HCV-positive patients (49 male subjects) with persistently normal transaminases and an Ishak staging score ≤ 2 at an initial biopsy. These untreated patients underwent regular clinical monitoring (median histological follow up: 10 years). Apo E variants were genotyped and results were related to the histological outcome., Results: The mean ± standard deviation staging scores were 0.9 ± 0.7 at entry versus 1.9 ± 1.2 at the end of follow up, P < 0.0001. Initial and final staging scores in the E3/E3 homozygotes (n = 74) were 1.0 ± 0.7 versus 2.1 ± 1.3, P < 0.0001, while in the remaining patients (n = 42) they were 0.9 ± 0.6 versus 1.5 ± 1.0, P < 0.002. A synergistic effect was observed between Apo E polymorphisms and baseline serum cholesterol values: patients not carrying any E3 allele, as well as carriers of a single E3 allele with serum cholesterol concentration > 190 mg/dL were more likely to have a favorable outcome (final vs initial staging score increased in 7/66, did not change in 10/46, and decreased in 3/4, P <0.005)., Conclusions: Some of the variability in the natural history of patients with persistently normal transaminases with initially mild hepatitis C can be related to their Apo E genetic background., (© 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.)

Background: The aim of the study was to perform a comprehensive diagnostic evaluation of six popular, non-proprietary, indirect markers of liver fibrosis in a cohort of patients with chronic hepatitis C representing the full spectrum of disease severity., Methods: A total of 167 consecutive, hepatitis C virus RNA positive, untreated patients with chronic hepatitis C were studied. Liver biopsy with histological evaluation and age/platelet index, aspartate aminotransferase/alanine aminotransferase ratio, aspartate aminotransferase to platelet ratio index, Bonacini's discriminant score, Forn's fibrosis index and FibroIndex were assessed in all patients., Results: The area under the receiver operating characteristic curves of the six tests was always greater when performed to discriminate patients with METAVIR score F4 than when assessed to discriminate patients with METAVIR score > or =F2. At step-wise discriminant analysis the only indirect marker of fibrosis entered was FibroIndex, with the following correct classification of the patients: total=52.1, patients with scores F0-F1=62.2, patients with scores F2-F3=26.0 and patients with score F4=68.4., Conclusions: The ability to correctly classify patients using a panel of non-proprietary indirect markers of liver fibrosis is far from being ideal. Among them, FibroIndex appears to possess the best discriminating capacity. The simultaneous use of several indirect markers of liver fibrosis does not improve their diagnostic accuracy.

Background and Aim: Per protocol annual liver biopsy represents the gold standard in the assessment of graft fibrosis progression due to recurrent hepatitis C after liver transplantation. Non-invasive liver fibrosis tests have been proposed as surrogate markers of liver fibrosis in hepatitis C virus (HCV)-positive immune-competent patients. No data are available in the literature on the usefulness of non-invasive liver fibrosis tests in liver transplanted patients with recurrent HCV infection., Methods: A total of 102 annual per protocol liver biopsies performed in 51 consecutive HCV-positive recipients (31 men), with a follow-up period lasting up to 5 years, were included and evaluated in this study. At each time point, the following non-invasive liver fibrosis tests were calculated: aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio, age-platelet index, AST to platelet ratio index (APRI), Forns' fibrosis index and Bonacini's discriminant score., Results: In discriminating patients with histological fibrosis score >2, APRI provided the best area under the receiver operating characteristic curves (AUROC) (0.801), in comparison to the other four non-invasive liver fibrosis tests. The AUROC of APRI was better in female (0.871) than in male (0.753) recipients. Among female recipients, an APRI value >1.4 was 91% sensitive and 75% specific in detecting a staging score >2. The corresponding values among male recipients were 60% and 77%, respectively., Conclusions: Among non-invasive liver fibrosis tests, APRI has the highest diagnostic value in discriminating liver transplanted patients with progression to significant liver fibrosis, although its accuracy is influenced by recipient sex.

Background: Experimental evidence and clinical studies suggest that the renin-angiotensin system and its inhibitors may play a role in regulating the mechanisms of liver fibrosis development. The present study aimed to verify whether carriage of specific angiotensin-converting enzyme (ACE) insertion (I)/deletion (D) allelic variants, modulating angiotensin II generation, could affect the outcome of recurrent hepatitis C after liver transplantation, via several metabolic pathways., Methods: Forty-five (29 men) recipients, with a median histological follow-up of 60 months after orthotopic liver transplantation (OLT), were studied. ACE gene I/D polymorphism was assessed by means of a polymerase chain reaction procedure. Fibrosis progression was evaluated annually during the follow-up., Results: Weight gain 1 year post-OLT (defined as an increase in body mass index, BMI, of >0.5 kg/m(2)) was significantly more common among D/ carriers (22/22 vs. 16/23, P < 0.005); patients who 1 year after OLT had an increase in their BMI value of >0.5 kg/m(2) more frequently had a triglycerides/cholesterol ratio of

To ascertain whether single nucleotide polymorphisms (SNPs) regulating the expression of interferon-gamma (IFN-gamma), IFN-gamma receptor-1 (IFNGR-1), interleukin-6 (IL-6), IL-10, IL-18, and tumor necrosis factor-alpha (TNF-alpha) may be associated with early fibrosis progression of recurrent hepatitis C, 50 liver transplantation recipients (32 men, 18 women, median age 56 years) with a median histologic follow-up time of 54 months were studied; 98 healthy blood donors served as controls. Cytokine SNPs were determined by means of previously described PCR-based methods. On the basis of the SNP studies, a low, intermediate, or high producer cytokine phenotype was attributed to each patient. Only 1 of the 17 low IL-10 producers reached an Ishak staging score > 2, in contrast to 20 of the 33 patients who were intermediate or high IL-10 producers (Mantel-Cox, p < 0.005). Recipients who were low IL-10 producers and high IFN-gamma producers had significantly slower fibrosis progression in comparison to intermediate/high IL-10 producers and low IFN-gamma producers (p < 0.005). In conclusion, cytokine SNPs resulting in high and low producer phenotypes of both Th1 and Th2 cytokines appear to modulate the course of recurrent hepatitis C. Low IL-10 producers are those with the slowest histologic fibrosis progression.

Objectives: To verify the value of indirect serum markers in the non-invasive assessment of liver fibrosis in patients with persistently normal or near normal alanine aminotransferases levels (NALT)., Design and Methods: Forty HCV RNA positive, untreated patients with NALT (30 non-drinkers) underwent two liver biopsies, with a median interval of 78.5 months. The AST/ALT ratio, age-platelet index, AST to platelet ratio index (APRI), Forns fibrosis index and Bonacini's discriminant score were simultaneously determined., Results: In 19 patients, worsening of fibrosis was observed at the second biopsy in comparison to the index biopsy. Among non-drinkers, an APRI >0.4 had a 100% sensitivity in identifying subjects with significant liver fibrosis (Ishak staging score >2) and an APRI < or =0.4 had a 100% negative predictive value in excluding significant liver fibrosis., Conclusions: APRI performs better, in comparison to all other markers, in correctly classifying patients with NALT with no progression to significant liver fibrosis.

Background: The histological outcome of chronic hepatitis C is better among carriers of the apolipoprotein E (ApoE) epsilon4 allele, for reasons unknown. The orthotopic liver transplantation (OLT) setting allows to separate the role played by liver-derived ApoE (graft) from ApoE of different origin (recipient)., Patients and Methods: Forty-six OLT recipients with recurrent hepatitis C were studied. Grafts and recipients were genotyped for ApoE. In a follow-up extending up to 4 years, the serum triglycerides-to-cholesterol ratio (T/C ratio) was measured 1 year after OLT, whereas fibrosis progression was assessed yearly and expressed as fibrosis units/month (FU/mo)., Results: A T/C ratio < or =0.75 was observed in 13/15 cases in which both donor and recipient were epsilon4 carriers, 10/19 cases in which epsilon4 alleles were of exclusive recipient's origin and 5/12 cases in which epsilon4 alleles were of exclusive donor's origin or absent (P<0.02). One year after OLT, a fibrosis progression < or =0.100 FU/mo was associated with a low T/C ratio (24/34 vs. 4/12, P<0.05). An Ishak staging score >2 was reached later by male recipients who were epsilon4 carriers (P<0.002)., Conclusions: Recipient's carriage of ApoE epsilon4 affects fibrosis progression of recurrent hepatitis C through gender-specific mechanisms, associated with a peculiar, ApoE-associated, lipid profile.

The course of hepatitis C virus (HCV) infection carriers with normal/near-normal aminotransferases (NALT) is usually mild; however, in a few, fibrosis progression occurs. We aimed to verify whether monitoring by liver biopsy might be replaced by noninvasive methods and to identify factors associated with fibrosis progression in patients with persistently normal alanine aminotransferases. We studied 40 untreated HCV-RNA-positive subjects (22 male; median age, 44 years), who underwent two liver biopsies, with a median interval of 78.5 months, during which alanine aminotransferase concentrations (median number of determinations: 12) never exceeded 1.2 times the upper normal limit. Within 9 months from the second biopsy, they were tested by the shear elasticity probe (Fibroscan) and the artificial intelligence algorithm FibroTest. METAVIR fibrosis scores were analyzed in relationship to demographic, clinical, and viral parameters. Weighted kappa analysis was used to verify whether the results of noninvasive methods agreed with histology. Significant fibrosis (> or = F2), present at the first biopsy in only one patient (2.5%), was observed at the second biopsy in 14 patients (35%). At multivariate analysis, excess alcohol consumption in the past (>20 g/d; P = .017) and viral load (>8.0 x 10(6) copies/mL; P = .021) were independent predictors of progression. In identifying patients with significant fibrosis, inter-rater agreement was excellent for Fibroscan (weighted kappa = 1.0), and poor for FibroTest (weighted kappa = -0.041). In conclusion, among HCV carriers with NALT, Fibroscan is superior to the FibroTest in the noninvasive identification of fibrosis, for which excess alcohol consumption in the past and high viral load represent risk factors.