A prospective study of direct-acting antiviral effectiveness and relapse risk in HCV cryoglobulinemic vasculitis by the Italian PITER cohort.

BACKGROUND AND AIMS: Mixed cryoglobulinemia is the most common HCV extrahepatic manifestation. We aimed to prospectively evaluate the cryoglobulinemic vasculitis (CV) clinical profile after a sustained virologic response (SVR) over a medium-term to long-term period. APPROACH AND RESULTS: Direct-acting antiviral-treated cryoglobulinemic patients, consecutively enrolled in the multicentric Italian Platform for the Study of Viral Hepatitis Therapy cohort, were prospectively evaluated. Cumulative incidence Kaplan-Meier curves were reported for response, clinical deterioration, relapse and relapse-free survival rates. Cox regression analysis evaluated factors associated with different outcomes. A clinical response was reported in at least one follow-up point for 373 of 423 (88%) patients with CV who achieved SVR. Clinical response increased over time with a 76% improvement rate at month 12 after the end of treatment. A full complete response (FCR) was reached by 164 (38.8%) patients in at least one follow-up point. CV clinical response fluctuated, with some deterioration of the initial response in 49.6% of patients (median time of deterioration, 19 months). In patients who achieved FCR and had an available follow-up (137 patients) a relapse was observed in 13% and it was transient in 66.7% of patients. The rate of patients without any deterioration was 58% and 41% at 12 and 24 months, respectively. After achieving SVR, a clinical nonresponse was associated with older age and renal involvement; a clinical deterioration/relapse was associated with high pretreatment rheumatoid factor values, and FCR was inversely associated with age, neuropathy, and high cryocrit levels. CONCLUSION: In patients with CV, HCV eradication may not correspond to a persistent clinical improvement, and clinical response may fluctuate. This implies an attentive approach to post-SVR evaluation through prognostic factors and tailored treatment.

Accuracy of FIB-4 to Detect Elevated Liver Stiffness Measurements in Patients with Non-Alcoholic Fatty Liver Disease: A Cross-Sectional Study in Referral Centers.

The identification of advanced fibrosis by applying noninvasive tests is still a key component of the diagnostic algorithm of NAFLD. The aim of this study is to assess the concordance between the FIB-4 and liver stiffness measurement (LSM) in patients referred to two liver centers for the ultrasound-based diagnosis of NAFLD. Fibrosis 4 Index for Liver Fibrosis (FIB-4) and LSM were assessed in 1338 patients. A total of 428 (32%) had an LSM ≥ 8 kPa, whereas 699 (52%) and 113 (9%) patients had an FIB-4 < 1.3 and >3.25, respectively. Among 699 patients with an FIB-4 < 1.3, 118 (17%) had an LSM ≥ 8 kPa (false-negative FIB-4). This proportion was higher in patients ≥60 years, with diabetes mellitus (DM), arterial hypertension or a body mass index (BMI) ≥ 27 kg/m2. In multiple adjusted models, age ≥ 60 years (odds ratio (OR) = 1.96, 95% confidence interval (CI) 1.19−3.23)), DM (OR = 2.59, 95% CI 1.63−4.13), body mass index (BMI) ≥ 27 kg/m2 (OR = 2.17, 95% CI 1.33−3.56) and gamma-glutamyltransferase ≥ 25 UI/L (OR = 2.68, 95% CI 1.49−4.84) were associated with false-negative FIB-4. The proportion of false-negative FIB-4 was 6% in patients with none or one of these risk factors and increased to 16, 31 and 46% among those with two, three and four concomitant risk factors, respectively. FIB-4 is suboptimal to identify patients to refer to liver centers, because about one-fifth may be false negative at FIB-4, having instead an LSM ≥ 8 KPa.

High rates of 30-day mortality in patients with cirrhosis and COVID-19.

BACKGROUND & AIMS: Coronavirus disease 2019 (COVID-19) poses a major health threat to healthy individuals and those with comorbidities, but its impact on patients with cirrhosis is currently unknown. Herein, we aimed to evaluate the impact of COVID-19 on the clinical outcome of patients with cirrhosis. METHODS: In this multicentre retrospective study, patients with cirrhosis and a confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection were enrolled between 1st and 31th March 2020. Clinical and biochemical data at diagnosis of COVID-19 and at the last outpatient visit were obtained through review of medical records. RESULTS: Fifty patients with cirrhosis and confirmed SARS-CoV-2 infection were enrolled (age 67 years, 70% men, 38% virus-related, 52% previously compensated cirrhosis). At diagnosis, 64% of patients presented fever, 42% shortness of breath/polypnea, 22% encephalopathy, 96% needed hospitalization or a prolonged stay if already in hospital. Respiratory support was necessary in 71%, 52% received antivirals, 80% heparin. Serum albumin significantly decreased, while bilirubin, creatinine and prothrombin time significantly increased at COVID-19 diagnosis compared to last available data. The proportion of patients with a model for end-stage liver disease (MELD) score ≥15 increased from 13% to 26% (p = 0.037), acute-on-chronic liver failure and de novo acute liver injury occurred in 14 (28%) and 10 patients, respectively. Seventeen patients died after a median of 10 (4-13) days from COVID-19 diagnosis, with a 30-day-mortality rate of 34%. The severity of lung and liver (according to CLIF-C, CLIF-OF and MELD scores) diseases independently predicted mortality. In patients with cirrhosis, mortality was significantly higher in those with COVID-19 than in those hospitalized for bacterial infections. CONCLUSION: COVID-19 is associated with liver function deterioration and elevated mortality in patients with cirrhosis. LAY SUMMARY: Coronavirus disease 2019 (COVID-19) poses a major health threat to healthy individuals and those with comorbidities. Herein, we assessed its impact on patients with cirrhosis. Infection with COVID-19 was associated with liver function deterioration and elevated mortality in patients with cirrhosis.

Real-world effectiveness and safety of glecaprevir/pibrentasvir in 723 patients with chronic hepatitis C.

BACKGROUND AND AIMS: The efficacy and safety of glecaprevir/pibrentasvir (G/P) for patients infected with hepatitis C virus (HCV) have only been investigated in clinical trials, with no real-world data currently available. The aim of our study was to investigate the effectiveness and safety of G/P in a real-world setting. METHODS: All patients with HCV consecutively starting G/P between October 2017 and January 2018 within the NAVIGATORE-Lombardia Network were analyzed. G/P was administered according to drug label (8, 12 or 16 weeks). Fibrosis was staged either histologically or by liver stiffness measurement. Sustained virological response (SVR) was defined as undetectable HCV-RNA 12 weeks after the end of treatment. RESULTS: A total of 723 patients (50% males) were treated with G/P, 89% for 8 weeks. The median age of our cohort was 58 years, with a median body mass index of 23.9 kg/m2, and median liver stiffness measurement of 6.1 kPa; 84% were F0-2 and 16% were interferon-experienced. Median HCV-RNA was 1,102,600 IU/ml, and 49% of patients had HCV genotype 1 (32% 1b), 28% genotype 2, 10% genotype 3 and 13% genotype 4. The median estimated glomerular filtration rate was 90.2 ml/min, platelet count 209x103/mm3 and albumin 4.3 g/dl. The SVR rates were 94% in intention-to-treat and 99.3% in per protocol analysis (8-week vs. 12 or 16-week: 99.2% vs. 100%). Five patients failed therapy because of post-treatment relapse; a post-treatment NS5A resistance-associated substitution was detected in 1 case. SVR rates were lower in males (p = 0.002) and in HCV genotype-3 (p = 0.046) patients treated for 8 weeks, but independent of treatment duration, fibrosis stage, baseline HCV-RNA, HIV co-infection, chronic kidney disease stage and viral kinetics. Mild adverse events were reported in 8.3% of the patients, and 0.7% of them prematurely withdrew treatment. Three patients died of drug-unrelated causes. CONCLUSIONS: In a large real-world cohort of Italian patients, we confirmed the excellent effectiveness and safety of G/P administered for 8, 12 or 16 weeks. LAY SUMMARY: A large number of patients with hepatitis C virus have been treated with glecaprevir/pibrentasvir (G/P) within the NAVIGATORE-Lombardia Network, in Italy. This is the first real-world study evaluating effectiveness and safety of G/P in patients with hepatitis C virus treated according to international recommendations. This study demonstrated excellent effectiveness (with sustained virological response rates of 99.3%) and safety profiles.

Direct-Acting Antivirals in Hepatitis C Virus-Associated Diffuse Large B-cell Lymphomas.

BACKGROUND: International guidelines suggest hepatitis C virus (HCV) eradication by direct-acting antivirals (DAAs) after first-line immunochemotherapy (I-CT) in patients with HCV-positive diffuse large B-cell lymphoma (DLBCL), although limited experiences substantiate this recommendation. Moreover, only a few data concerning concurrent administration of DAAs with I-CT have been reported. SUBJECTS, MATERIALS, AND METHODS: We analyzed hematological and virological outcome and survival of 47 consecutive patients with HCV-positive DLBCL treated at 23 Italian and French centers with DAAs either concurrently (concurrent cohort [ConC]: n = 9) or subsequently (sequential cohort [SeqC]: n = 38) to first-line I-CT (mainly rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone [R-CHOP]-like). RESULTS: Median age was 61 years, 89% of patients had stage III/IV, and 25% presented evidence of cirrhosis. Genotype was 1 in 56% and 2 in 34% of cases. Overall, 46 of 47 patients obtained complete response to I-CT. All patients received appropriate DAAs according to genotype, mainly sofosbuvir-based regimens (n = 45). Overall, 45 patients (96%) achieved sustained virological response, 8 of 9 in ConC and 37 of 38 in SeqC. DAAs were well tolerated, with only 11 patients experiencing grade 1-2 adverse events. Twenty-three patients experienced hepatic toxicity (grade 3-4 in seven) following I-CT in SeqC, compared to only one patient in ConC. At a median follow-up of 2.8 years, two patients died (2-year overall survival, 97.4%) and three progressed (2-year progression-free survival, 93.1%). CONCLUSION: Excellent outcome of this cohort of HCV-positive DLBCL suggests benefit of HCV eradication by DAAs either after or during I-CT. Moreover, concurrent DAAs and R-CHOP administration appeared feasible, effective, and ideally preferable to deferred administration of DAAs for the prevention of hepatic toxicity. IMPLICATIONS FOR PRACTICE: Hepatitis C virus (HCV)-associated diffuse large B-cell lymphomas (DLBCLs) represent a great therapeutic challenge, especially in terms of hepatic toxicity during immune-chemotherapy (I-CT) and long-term hepatic complications. The advent of highly effective and toxicity-free direct-acting antivirals (DAAs) created an exciting opportunity to easily eradicate HCV shortly after or in concomitance with first-line immunochemotherapy (usually R-CHOP). This retrospective international study reports the real-life use of the combination of these two therapeutic modalities either in the concurrent or sequential approach (DAAs after I-CT) in 47 patients. The favorable reported results on long-term outcome seem to support the eradication of HCV with DAAs in all patients with HCV-positive DLBCL. Moreover, the results from the concurrent approach were effective and safe and displayed an advantage in preventing hepatic toxicity during I-CT.

Contrast imaging techniques to diagnose hepatocellular carcinoma in cirrhotics outside regular surveillance.

INTRODUCTION AND AIM: The American Association for the Study of the Liver (AASLD) recommends contrast computerized tomography (CT-scan) and magnetic resonance (MRI) to diagnose hepatocellular carcinoma (HCC) arising in cirrhotic patients under semiannual surveillance with abdominal ultrasound (US). A US guided fine needle biopsy (FNB) serves the same purpose in radiologically undiagnosed tumors and incidentally detected nodules in cirrhotics outside surveillance. In this population, we evaluated the performance of radiological diagnosis of HCC according to 2010 AASLD recommendations. MATERIALS AND METHODS: All cirrhotic patients with a liver nodule incidentally detected by US were prospectively investigated with a sequential application of CT-scan/MRI examination and a FNB. RESULTS: Between 2011 and 2015, 94 patients (mean age 67 years) had a liver nodule (total 120) detected by US in the context of histologically confirmed cirrhosis. Mean nodules diameter was 40 (10-160) mm, 87 (73%) <5cm. At histology, 84 (70%) nodules were HCC, 8 (7%) intrahepatic cholangiocarcinoma, 6 (5%) metastases, 2 (2%) neuroendocrine tumors and 20 (16%) benign lesions. Hyperenhancement in arterial phase followed by wash-out in venous phases on at least one radiological technique was demonstrated in 62 nodules (61 HCC, 1 high grade dysplastic nodule), with a specificity of 97% (IC95%: 85-100%), sensitivity 73% (IC95%: 62-81%) and diagnostic accuracy 80%, being 64% for ≥5cm HCC. Sensitivity of AFP >200ng/mL was 12% (IC95%: 6-23%). CONCLUSION: A single contrast imaging technique showing a typical contrast pattern confidently identifies HCC also in cirrhotic patients with an incidental liver nodule, thereby reducing the need for FNB examinations.

Management of HCV-Related Liver Disease in Hemophilia and Thalassemia.

Chronic infection with the hepatitis C virus (HCV) has long been the dominant complication of substitution therapy in patients with inherited blood disorders and the cause of anticipated death due to end-stage liver disease. In hemophilia, transmission of HCV with clotting factors concentrates started to be curbed in the mid-1980s following the adoption of procedures of virus inactivation of concentrates based on heat, whereas in the 1990s treatment of HCV infection with interferon monotherapy was attempted, however, with little success. The advent of combination therapy of interferon with ribavirin led to a substantial improvement of treatment outcome (40% rate of cure), that however was still of limited efficacy in patients with advanced liver disease, those with high load of HCV genotype 1, and patients coinfected with the human immunodeficiency virus. In this latter population, while the course of hepatitis C was accelerated as a consequence of immunodeficiency, the advent of highly active antiretroviral therapy led acquired immunodeficiency syndrome (AIDS) to decline and hepatitis C to progressively emerge as a dominant cause of mortality, in parallel. In patients with thalassemia, transfusion-related transmission of HCV was efficiently interrupted in 1992 with the advent of sensitive screening tests for testing donors for HCV, whereas treatment with interferon and ribavirin of infected thalassemics was constrained by an increased risk of anemia due to the hemolytic properties of ribavirin coupled with interferon-induced bone marrow suppression. The advent of safe and potent regimens based on the oral administration of direct antiviral agents has revolutionized therapy of HCV in patients with congenital blood diseases, providing substantial clinical benefits and making elimination of infection in these populations, possible.

Modeling cost-effectiveness and health gains of a "universal" versus "prioritized" hepatitis C virus treatment policy in a real-life cohort.

We evaluated the cost-effectiveness of two alternative direct-acting antiviral (DAA) treatment policies in a real-life cohort of hepatitis C virus-infected patients: policy 1, "universal," treat all patients, regardless of fibrosis stage; policy 2, treat only "prioritized" patients, delay treatment of the remaining patients until reaching stage F3. A liver disease progression Markov model, which used a lifetime horizon and health care system perspective, was applied to the PITER cohort (representative of Italian hepatitis C virus-infected patients in care). Specifically, 8,125 patients naive to DAA treatment, without clinical, sociodemographic, or insurance restrictions, were used to evaluate the policies' cost-effectiveness. The patients' age and fibrosis stage, assumed DAA treatment cost of €15,000/patient, and the Italian liver disease costs were used to evaluate quality-adjusted life-years (QALY) and incremental cost-effectiveness ratios (ICER) of policy 1 versus policy 2. To generalize the results, a European scenario analysis was performed, resampling the study population, using the mean European country-specific health states costs and mean treatment cost of €30,000. For the Italian base-case analysis, the cost-effective ICER obtained using policy 1 was €8,775/QALY. ICERs remained cost-effective in 94%-97% of the 10,000 probabilistic simulations. For the European treatment scenario the ICER obtained using policy 1 was €19,541.75/QALY. ICER was sensitive to variations in DAA costs, in the utility value of patients in fibrosis stages F0-F3 post-sustained virological response, and in the transition probabilities from F0 to F3. The ICERs decrease with decreasing DAA prices, becoming cost-saving for the base price (€15,000) discounts of at least 75% applied in patients with F0-F2 fibrosis. CONCLUSION: Extending hepatitis C virus treatment to patients in any fibrosis stage improves health outcomes and is cost-effective; cost-effectiveness significantly increases when lowering treatment prices in early fibrosis stages. (Hepatology 2017;66:1814-1825).

Persistence of hepatocellular carcinoma risk in hepatitis C patients with a response to IFN and cirrhosis regression.

BACKGROUND AND AIM: In patients with HCV-related cirrhosis, a sustained virological response may lead to cirrhosis regression. Whether histological changes translate into prevention of long-term complications, particularly hepatocellular carcinoma is still unknown. This was investigated in a cohort of histological cirrhotics who had been prospectively followed-up for 10 years after the achievement of a sustained virological response to IFN. METHODS: In all, 38 sustained virological response cirrhotics who underwent a liver biopsy 5 years post-SVR were prospectively followed to assess the impact of cirrhosis regression on clinical endpoints. RESULTS: During a follow-up of 86 (30-96) months from liver biopsy, no patients developed clinical decompensation, whilst 5 (13%) developed hepatocellular carcinoma after 79 (7-88) months. The 8-year cumulative probability of hepatocellular carcinoma was 17%, without differences between patients with or without cirrhosis regression (19% [95% CI 6%-50%] vs 14% [95% CI 4%-44%], P = .88). Patients who developed or did not an hepatocellular carcinoma had similar rates of residual cirrhosis (P = 1.0), collagen content (P = .48), METAVIR activity (P = .34), portal inflammation (P = .06) and steatosis (P = .17). At baseline, patients who developed an hepatocellular carcinoma had higher γGT (HR 1.03, 95% CI 1.00-1.06; P = .014) and glucose (HR 1.02, 95% CI 1.00-1.02; P = .012) values; moreover, they had increased Forns Score (HR 12.8, 95% CI 1.14-143.9; P = .039), Lok Index (HR 6.24, 95% CI 1.03-37.6; P = .046) and PLF (HR 19.3, 95% CI 1.72-217.6; P = .016) values. One regressor died of lung cancer. The 8-year cumulative survival probability was 97%, independently on cirrhosis regression (96% vs 100%, P = 1.0) or hepatocellular carcinoma (100% vs 97%, P = 1.0). CONCLUSIONS: Post-SVR cirrhosis regression does not prevent hepatocellular carcinoma occurrence.

The association of IL28B genotype with the histological features of chronic hepatitis C is HCV genotype dependent.

The interleukin 28B (IL28B) rs12979860 polymorphism is associated with treatment outcome in hepatitis C virus (HCV) genotype 1 and 4 patients. Its association with the histological features of chronic hepatitis C and disease severity needs further clarifications. To assess the correlation between IL28B genotype, HCV genotype and liver biopsy findings in untreated patients. MATERIALS AND METHODS: Pre-treatment liver biopsies from 335 HCV Caucasian patients (59% males, age 50 years) enrolled in the MIST study were staged for fibrosis and inflammation according to the METAVIR and the Ishak scoring systems; steatosis was dichotomized as <5% or ≥5%. IL28B was typed by Taqman Single Nucleotide Polymorphism (SNP) genotyping assay. HCV genotype was 1 in 151 (45%), 2 in 99 (30%), 3 in 50 (15%) and 4 in 35 (10%) patients. IL28B genotype was CC in 117 (34%), CT in 166 (49%) and TT in 52 (15%). At univariate analysis, the IL28B CC genotype was associated with severe portal inflammation in HCV-1 patients (CC vs. CT/TT: 86% vs. 63%, p = 0.005), severe lobular inflammation in HCV-2 patients (CC vs. CT/TT: 44% vs. 23%, p = 0.03), and less fatty infiltration in HCV-1 patients (CC vs. CT/TT: 72% vs. 51%, p = 0.02). Despite the lack of any association between IL28B and fibrosis stage, in HCV-3 patients IL28B CC correlated with METAVIR F3-F4 (CC vs. CT/TT: 74% vs. 26%, p = 0.05). At multivariate analysis, the genotype CC remained associated with severe portal inflammation in HCV-1, only (Odds Ratio (OR): 95% Confidence Interval (CI): 3.24 (1.23-8.51)). IL28B genotype is associated with the histological features of chronic hepatitis C in a HCV genotype dependent manner, with CC genotype being independently associated with severe portal inflammation.

The diagnostic accuracy of Fibroscan for cirrhosis is influenced by liver morphometry in HCV patients with a sustained virological response.

BACKGROUND & AIMS: Transient elastography (TE) is a validated non-invasive tool to evaluate hepatic fibrosis in patients with hepatitis C virus (HCV) infection. Whether TE may sense changes of liver fibrosis following therapeutic HCV eradication has never been evaluated. METHODS: 37 HCV cirrhotics with paired pre- and post-sustained virological response (SVR) liver biopsies (LB) underwent TE at the time of post-SVR LB. Liver fibrosis was staged with the METAVIR scoring system and the area of fibrosis (%) was assessed morphometrically. RESULTS: Thirty-three patients had valid TE measurements after 61 (48-104) months from an SVR, and 20 (61%) of them had cirrhosis regression. On post-SVR LB, the median area of fibrosis was 2.3%, being significantly reduced from baseline (p<0.0001). Median TE value was 9.8 kPa being lower in regressed vs. not regressed patients (9.1 kPa vs. 12.9 kPa, p=0.01). TE was <12 kPa in 5 (38%) F4 patients and in 19 (95%) ≤F3 patients (p=0.0007). The diagnostic accuracy of TE for diagnosing F4 after treatment was 61% sensitivity, 95% specificity, 12.3 LR+, 0.4 LR-, and AUROC 0.77. A significant correlation was found between TE and both fibrosis stage (r=0.56; p=0.001) and morphometry (r=0.56, p=0.001) as well as between fibrosis stage and area of fibrosis (r=0.72, p=0001). CONCLUSIONS: Following therapeutic eradication of HCV, the predictive power of the viremic cut-off of 12 kPa was low as a consequence of liver remodelling and fibrosis reabsorption. LB still remains the only reliable approach to stage liver fibrosis following an SVR.

Natural killer cell dynamic profile is associated with treatment outcome in patients with chronic HCV infection.

BACKGROUND & AIMS: A substantial proportion of patients with chronic hepatitis C virus infection treated with pegylated interferon α/ribavirin fail to achieve sustained virological response (SVR). Since growing evidence suggests that innate immunity may influence treatment responses, we examined natural killer (NK) cell phenotypic and functional changes during standard antiviral therapy. METHODS: Expression of several NK-cell regulatory molecules was evaluated by flow cytometry in 37 consecutive patients with chronic HCV infection at baseline and at different time points during and after discontinuation of treatment. Cytokine production was evaluated by intracellular staining. Cytolytic potential was assessed as degranulation and as antibody-dependent cytotoxicity. RESULTS: Baseline frequencies of CD56(dim) NK cells and perforin content were significantly higher, whereas CD16 expression was lower in SVR vs. non-responder subjects. Analysis by linear regression for repeated measures during the first 12 weeks showed significantly increased frequencies of activated (CD69(+)) NK cells in rapid virological responders (RVR) and identified a typical NK cell profile associated with SVR, featuring higher NK perforin content, lower CD16 expression, and higher proportion of CD56(dim)/CD16(-) cells. Moreover, SVR patients displayed higher natural and antibody-dependent NK cell cytotoxicity. IL28B rs12979860 CC homozygosis was significantly associated with SVR, independently of NK-cell phenotype and function. CONCLUSIONS: Different NK-cell phenotypic and functional features, in patients with chronic hepatitis C treated with standard therapy, were observed between non-responder vs. SVR patients, suggesting a potential role of NK cells in the response to treatment.

A morphometric and immunohistochemical study to assess the benefit of a sustained virological response in hepatitis C virus patients with cirrhosis.

UNLABELLED: Although annular fibrosis is the hallmark of cirrhosis, other microscopic changes that affect liver function such as sinusoid capillarization or loss of metabolic zonation are common. A sustained virological response (SVR) may halt fibrosis deposition in hepatitis C virus (HCV)-infected patients, but its impact on the other cirrhosis-associated lesions is unknown. The aim of this study was to assess the impact of an SVR on cirrhosis-related histopathological features. Paired pre- and posttreatment liver biopsies from 38 HCV patients with cirrhosis with an SVR were analyzed. Fibrosis was staged using the METAVIR scoring system, and the area of fibrosis was measured using morphometry. Ductular proliferation, metabolic zonation, sinusoid capillarization, and hepatic stellate cell activation were assessed by anti-cytokeratin-7, anti-glutamine synthetase (GS), anti-cytochrome P4502E1 (CYP2E1), anti-CD34, and anti α-smooth muscle actin (αSMA). After 61 months from an SVR, cirrhosis regression was observed in 61%, and the collagen content decreased in 89%. Although periportal and lobular necroinflammation vanished, portal inflammation persisted in 66%. Ductular proliferation decreased in 92%. Before treatment, metabolic zonation was lost, as shown by GS and CYP2E1, in 71% and 88%, respectively, with normalization in 79% and 73%, after an SVR. Conversely, no changes in sinusoidal capillarization were observed after treatment, as assessed by CD34 (P = 0.41) and αSMA (P = 0.95). Finally, no differences in all the immunohistochemical scores emerged whether or not cirrhosis persisted. CONCLUSION: Cirrhosis regression and decreased fibrosis are frequently observed among HCV patients with cirrhosis with an SVR. Despite ductular proliferation vanishing and lobular zonation restoration, portal inflammation and sinusoidal capillarization may not regress after viral eradication.

Sustained virological response prevents the development of insulin resistance in patients with chronic hepatitis C.

UNLABELLED: Hepatitis C virus (HCV) infection is associated with insulin resistance (IR), which is a condition known to influence the progression of liver fibrosis and the response to pegylated interferon (PEG-IFN)/ribavirin (RBV) therapy. We aimed to assess whether a sustained virological response (SVR) after antiviral therapy prevents the development of IR in the long term. Members of the Milan Safety Tolerability study cohort, who received PEG-IFNα2a/RBV or PEG-IFNα2b/RBV, underwent a homeostasis model assessment (HOMA) at the baseline and 24 months after treatment completion. For all patients (n = 431), a liver biopsy sample was scored for grading, staging (Ishak), and steatosis. At the baseline, IR (HOMA value > 2) was detected in 48 patients (12%), and it was associated with body weight (P = 0.03), an HCV load < 0.6 × 10(6) IU/L (P = 0.006), fibrosis staging ≥ 4 (P = 0.01), and moderate to severe steatosis (P = 0.03). IR did not influence the rates of end-of-treatment response (75% versus 69%, P = 0.4), SVR (63% versus 60%, P = 0.8), or relapse (19% versus 24%, P = 0.5). After treatment, IR developed in 49 of the 384 nondiabetic patients (14%). Although the mean baseline and posttreatment HOMA values were similar in SVR patients (1.11 ± 0.8 versus 1.18 ± 1.1, P = 0.25), patients experiencing treatment failure showed a significant increase in the mean HOMA value at the follow-up visit (1.20 ± 0.85 versus 1.49 ± 1.3, P = 0.007), and there was an increased rate of de novo IR in non-SVR patients versus SVR patients (17% versus 7%, P = 0.007). According to a logistic regression analysis, treatment failure (odds ratio = 2.81, 95% confidence interval = 1.39-5.67, P = 0.004) and a 10% body mass index increase (odds ratio = 6.42, 95% confidence interval = 1.69-24.3, P = 0.006) were significantly associated with the development of de novo IR. CONCLUSION: In nondiabetic patients with chronic HCV, the achievement of SVR with PEG-IFN and RBV prevents the development of de novo IR.

Interleukin 28B polymorphism predicts pegylated interferon plus ribavirin treatment outcome in chronic hepatitis C genotype 4.

UNLABELLED: Single nucleotide polymorphisms (SNPs) near the interleukin 28B (IL28B) region are the strongest baseline predictors of a sustained virologic response (SVR) to peg-interferon (PegIFN) and ribavirin (Rbv) in patients with hepatitis C virus (HCV) genotype 1 infection. Whether this holds true for HCV-4 patients too is unknown. The aim was to investigate the predictive power of the rs12979860 IL28B SNP for a response to Peg-IFN and Rbv in HCV-4 patients. All HCV-4 patients consecutively treated between September 2004 and June 2010 with PegIFN and Rbv at two liver centers at the Maggiore Hospital Milan (Italy) underwent TaqMan SNP Genotyping assays for testing rs12979860 genotype. Of 112 treated patients (98 males, 75 of Egyptian descent, 26 with cirrhosis) 103 were included in the final analysis; five discontinued treatment for nonvirologic reasons and four did not consent to genetic testing. Twenty-four (23%) were genotype CC, 65 (63%) CT, and 14 (14%) TT. Overall, 50 (49%) achieved an SVR: 21 (88%) CC patients versus 29 (37%) CT/TT (P < 0.0001). CC patients more often had a rapid virologic response (RVR) than CT/TT patients (12, 50% versus 23, 29%; P = 0.08), while also showing lower relapse rates (0% [0/21] versus 36% [16/45] P = 0.0013). In non-RVR patients, SVR rates were higher in CC than CT/TT patients (9 [75%] versus 13 [23%] P = 0.001). By logistic regression, the IL28B rs12979860 CC genotype was an independent predictor of SVR with an odds ratio of 8.0 (95% confidence interval 2.00-32.01; P = 0.003). CONCLUSION: The IL28B rs12979860 SNP may have an added value in the treatment algorithm of HCV-4 patients because it is the strongest predictor of an SVR to PegIFN/Rbv therapy.

Approaches for Selective Vaccinations in Cirrhotic Patients.

Bacterial and viral infections are common in cirrhotic patients, and their occurrence is associated with the severity of liver disease. Bacterial infection may increase the probability of death by 3.75 times in patients with decompensated cirrhosis, with ranges of 30% at 1 month and 63% at 1 year after infection. We illustrate the indications and the modalities for vaccinating cirrhotic patients. This topic is important for general practitioners and specialists.

Hyporesponsiveness to PegIFNα2B plus ribavirin in patients with hepatitis C-related advanced fibrosis.

BACKGROUND & AIMS: The success of pegylated-interferon (PegIFN)/ribavirin (Rbv) therapy of chronic hepatitis C is compromised by liver fibrosis. Whether fibrosis equally affects the two PegIFNα-based therapies is unknown. To assess the response to the two PegIFN regimens in patients with different degree of liver fibrosis. METHODS: A sub-analysis of the MIST study: 431 consecutive naïve patients randomly assigned, based on HCV genotype, to receive either (A) PegIFNα2a 180 µg/wk plus daily Rbv 800-1200 mg or (B) PegIFNα2b 1.5 µg/kg/week plus daily Rbv 800-1200 mg, were stratified according to Ishak staging (S) into mild (S0-S2) or moderate (S3, S4) fibrosis and cirrhosis (S5, S6). RESULTS: In A the sustained virological response (SVR) rates were not significantly influenced by fibrosis stage (71% in S0-S2, 66% in S3, S4, 53% in S5, S6, p=0.12), compared to B where the SVR rates differed according to fibrosis stage (65%, 46%, and 38%, p=0.004, respectively). This was even more so in HCV-1/4 patients treated with PegIFNα2b where the SVR rates were twice as many in S0-S2 vs. S≥3 (44% vs. 22%, p=0.02), while in A the SVR rates were similar between the two fibrosis subgroups (S0-S2: 47% vs. S≥3: 48%, p=0.8). By logistic regression analysis genotype 1/4 and lack of rapid virological response were independent predictors of treatment failure in both treatment groups, while S≥3 fibrosis was associated to PegIFNα2b treatment failure, only (OR 2.83, 95% CI 1.4-5.68, p=0.004). CONCLUSIONS: Liver fibrosis was an independent moderator of treatment outcome in patients receiving PegIFNα2b, not in those receiving PegIFNα2a.