Publications by authors named "Stella De Nicola"

26 Publications

  • Page 1 of 1

Performance of the model for end-stage liver disease score for mortality prediction and the potential role of etiology.

J Hepatol 2021 Jul 30. Epub 2021 Jul 30.

Gastroenterology Unit, ASL Latina, Department of Translational and Precision Medicine, "Sapienza" University of Rome, Italy.

Background & Aims: Although the discriminative ability of the model for end-stage liver disease (MELD) score is generally considered acceptable, its calibration is still unclear. In a validation study, we assessed the discriminative performance and calibration of 3 versions of the model: original MELD-TIPS, used to predict survival after transjugular intrahepatic portosystemic shunt (TIPS); classic MELD-Mayo; and MELD-UNOS, used by the United Network for Organ Sharing (UNOS). We also explored recalibrating and updating the model.

Methods: In total, 776 patients who underwent elective TIPS (TIPS cohort) and 445 unselected patients (non-TIPS cohort) were included. Three, 6 and 12-month mortality predictions were calculated by the 3 MELD versions: discrimination was assessed by c-statistics and calibration by comparing deciles of predicted and observed risks. Cox and Fine and Grey models were used for recalibration and prognostic analyses.

Results: In the TIPS/non-TIPS cohorts, the etiology of liver disease was viral in 402/188, alcoholic in 185/130, and non-alcoholic steatohepatitis in 65/33; mean follow-up±SD was 25±9/19±21 months; and the number of deaths at 3-6-12 months was 57-102-142/31-47-99, respectively. C-statistics ranged from 0.66 to 0.72 in TIPS and 0.66 to 0.76 in non-TIPS cohorts across prediction times and scores. A post hoc analysis revealed worse c-statistics in non-viral cirrhosis with more pronounced and significant worsening in the non-TIPS cohort. Calibration was acceptable with MELD-TIPS but largely unsatisfactory with MELD-Mayo and -UNOS whose performance improved much after recalibration. A prognostic analysis showed that age, albumin, and TIPS indication might be used to update the MELD.

Conclusions: In this validation study, the performance of the MELD score was largely unsatisfactory, particularly in non-viral cirrhosis. MELD recalibration and candidate variables for an update to the MELD score are proposed.

Lay Summary: While the discriminative performance of the model for end-stage liver disease (MELD) score is credited to be fair to good, its calibration, the correspondence of observed to predicted mortality, is still unsettled. We found that application of 3 different versions of the MELD in 2 independent cirrhosis cohorts yielded largely imprecise mortality predictions particularly in non-viral cirrhosis. Thus, we propose a recalibration and suggest candidate variables for an update to the model.
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http://dx.doi.org/10.1016/j.jhep.2021.07.018DOI Listing
July 2021

Chemokine Receptor 5 Has No Major Role in the Severity of Hepatitis C Virus-Related Liver Damage.

Viral Immunol 2018 06 17;31(5):358-361. Epub 2018 Apr 17.

5 Traslational Research Center in Hepatology , Humanitas Research Hospital, Rozzano, Italy .

Total or partial inactivation of the chemokine 5 (CC5) pathway, as caused by the CC5 receptor Δ32 deletion (CCR5Δ32), may result in a profound manipulation of immune surveillance with significant consequences on the course and response to therapy of diverse human infections, including HIV. It has been postulated that in chronic hepatitis C (CHC), such a deregulation of CC5 pathway may compromise T cell-dependent antiviral immune responses, which in turn may favor viral persistence. To test this hypothesis, we investigated a cohort of 100 patients with CHC in whom 12 heterozygous and 1 homozygous CCR5Δ32 mutations were detected compared to 8 and none in 98 healthy controls (13% vs. 8.2%, p = 0.36). As patients with and without CCR5Δ32 mutations were similar in terms of histological activity (p = 0.84) and fibrosis stage (p = 0.20) as well as CCR5 tissue expression, we reasonably exclude that this CCR5 mutation is significantly involved in the pathogenesis of CHC and may be a potential therapeutic target. However, deleted patients showed a significantly higher response to pegylated interferon-alfa (PEG-IFN), suggesting that a dormant immune system is more readily primed by immunostimulation.
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http://dx.doi.org/10.1089/vim.2017.0190DOI Listing
June 2018

12 weeks ombitasvir/paritaprevir-ritonavir + ribavirin achieve high SVR rates in HCV-4 patients with advanced fibrosis.

Dig Liver Dis 2018 07 12;50(7):703-706. Epub 2018 Feb 12.

CRC "A. M.e A. Migliavacca" Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy.

Background: Ombitasvir/paritaprevir-ritonavir (OBT/PTV-r) plus ribavirin (RBV) for 12 weeks in hepatitis C virus (HCV) genotype 4 patients with advanced fibrosis has been only investigated in clinical trials.

Aims: To assess safety and efficacy of OBT/PTV-r + RBV for 12 weeks in real-life HCV-4 patients with advanced fibrosis.

Methods: HCV-4 patients with advanced fibrosis consecutively receiving OBT/PTV-r + RBV for 12 weeks in a single center were enrolled. Fibrosis was staged by transient elastography (TE) (F3: ≥10 kPa; F4 ≥11.9 kPa) or histologically. Sustained virological response (SVR) was defined as undetectable HCV-RNA 12 weeks post-treatment.

Results: Between January 2016 and February 2017, 49 HCV-4 patients were included: median age 54 (39-72) years, 84% males, 59% Egyptians, 35% fibrosis F3 and 65% F4, all Child Pugh class A. Median RBV dose was 1200 (200-1200) mg/day. At ITT analysis, 47 (96%) patients achieved an SVR (100% at PP analysis). SVR was not affected by ancestry (Egyptian vs. Italian 97% vs. 95%, p = 1.0), fibrosis stage (F3 vs. F4 100% vs. 94%, p = .53), presence of baseline resistance associated substitutions (RASs) or RBV reduction.

Conclusions: We report 100% SVR with 12-weeks of OBT/PTV-r + RBV in HCV-4 patients with advanced liver disease, including compensated cirrhotics.
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http://dx.doi.org/10.1016/j.dld.2018.02.003DOI Listing
July 2018

Antiviral treatment of hepatitis C in renal transplant patients - safety issues.

Expert Opin Drug Saf 2017 08 30;16(8):873-876. Epub 2017 Jun 30.

b Humanitas Clinical and Research Center , Rozzano , Italy.

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http://dx.doi.org/10.1080/14740338.2017.1344640DOI Listing
August 2017

Adding embolization to TIPS implantation: A better therapy to control bleeding from ectopic varices?

J Hepatol 2017 07 24;67(1):200-201. Epub 2017 Mar 24.

Hepatology and Gastroenterology Unit, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy.

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http://dx.doi.org/10.1016/j.jhep.2017.03.016DOI Listing
July 2017

HCV-RNA kinetics on-treatment do not predict sustained virologic response in HCV genotype 3 patients receiving sofosbuvir and ribavirin.

J Hepatol 2016 11 25;65(5):1058-1059. Epub 2016 Jul 25.

A.M. and A. Migliavacca Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS CA' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy.

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http://dx.doi.org/10.1016/j.jhep.2016.06.031DOI Listing
November 2016

[Chronic hepatitis C: standard of care and perspective].

Recenti Prog Med 2016 Jul;107(7):349-54

UO Gastroenterologia ed Epatologia, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Università di Milano.

Chronic hepatitis C (HCV) is a major health problem with more than 150 million people infected worldwide. It is the leading cause of cirrhosis, hepatocellular carcinoma and liver transplantation in western countries. Nowadays the disease is curable in most patients as the development of directly acting antivirals against HCV allows between 90 and 95% of patients who receive treatment to achieve viral eradication. This innovation has been made possible by the understanding of the HCV life cycle as well as the development of in vitro models of HCV replication, that have led to the discovery of 3 key steps in the HCV life cycle that can be targeted to halt viral replication. Drugs targeting the NS3 Protease, the NS5A protein as well as the NS5B polymerase are now commercially available in Europe. By combining these drugs for 12 or 24 weeks, most HCV-positive patients can be cured of their infection. Still the treatment cascade requires at the moment expert management, due to the relative complexity and need for individualization of the current regimens, as well as the need for monitoring for side effects during treatment. This, together with low diagnostic rates in the general population and high pricing of directly acting antivirals is a major hurdle to universal treatment of HCV and emphasizes the need for simplier pangenotypic, ribavirin free anti-HCV regimens that are now in advanced phase of development and should enter the field in the next 12-18 months.
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http://dx.doi.org/10.1701/2318.24924DOI Listing
July 2016

The quest for safe and effective treatments of chronic hepatitis C in patients with kidney impairment.

Liver Int 2016 06;36(6):791-3

UO Gastroenterologia ed Epatologia, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano, Milan, Italy.

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http://dx.doi.org/10.1111/liv.13123DOI Listing
June 2016

Quantification of Core Antigen Monitors Efficacy of Direct-acting Antiviral Agents in Patients With Chronic Hepatitis C Virus Infection.

Clin Gastroenterol Hepatol 2016 09 1;14(9):1331-6. Epub 2016 Apr 1.

A.M. and A. Migliavacca Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS CA' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy.

Background & Aims: Widespread use of direct-acting antiviral (DAA) agents to treat patients with hepatitis C virus (HCV) infection has reduced the need for monitoring of HCV RNA levels, because viral kinetics do not predict sustained virologic response (SVR) to these drugs. However, the performance of cheaper tests such as the assay to quantify HCV core antigen (HCV Ag) has not been determined. We investigated the accuracy of the HCV Ag test in predicting which patients receiving DAAs will achieve SVRs at week 12 (SVR12).

Methods: We performed a prospective study of 58 patients infected with HCV genotypes 1-5 (45% with HCV genotype 1, 72% with cirrhosis) receiving DAA therapy from the Liver Center at the Università degli Studi of Milan in Italy from January to March 2015. We collected blood samples and measured levels of HCV Ag and HCV RNA at baseline, after 2 and 4 weeks of treatment, the end of treatment, and 12 weeks after treatment ended. We compared the ability of these assays to predict which patients would have SVR12.

Results: The median baseline level of HCV RNA was 5.79 log10 IU/mL (range, 3.51-7.31 log10 IU/mL) and of HCV Ag was 3226.87 fmol/L (range, 17.30-54,927.00 fmol/L). HCV Ag became undetectable in 71% of patients at week 2, 84% at week 4, and 93% at the end of treatment. HCV RNA became undetectable in 10% of patients at week 2, 43% at week 4, and 100% at the end of treatment (P < .0001). Concordance between the tests in identifying patients who would achieve SVR12 was 40% at week 2, 55% at week 4, and 95% at the end of treatment. Fifty-three of 58 patients (91%) achieved an SVR12; the test for HCV Ag identified 97% of these patients. The tests for HCV Ag and HCV RNA predicted which patients would have SVR12 with positive predictive values of 90% vs 83%, respectively, at week 2 and 89% vs 92%, respectively, at week 4.

Conclusions: Tests that measure HCV Ag monitor efficacy of DAA therapy for HCV infection as well as assays that measure HCV RNA and can be recommended for clinical practice. However, measurement of HCV RNA after treatment can rule out relapse in HCV Ag-positive patients.
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http://dx.doi.org/10.1016/j.cgh.2016.03.035DOI Listing
September 2016

The eradication of HCV.

Minerva Gastroenterol Dietol 2016 Mar 7;62(1):63-75. Epub 2015 Oct 7.

Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy -

Hepatitis C virus (HCV) infection is a major health problem that affects about 3% of the world's population. Chronic infection can evolve into cirrhosis, end-stage liver disease and hepatocellular carcinoma. Since the discovery of the virus, great advances were made in its diagnostics and therapeutics. HCV has the peculiarity of being a curable infection, as persistent virus eradication can be achieved through therapy. The recent advent of direct-acting antiviral agents (DAAs), which can be combined to provide short and well-tolerated all-oral regimens, has allows higher rates of sustained viral response (SVR) for all HCV genotypes, also in patients previously considered as "difficult to treat" and in patients with advanced cirrhosis, in whom antiviral treatment was contraindicated in the past. While on the one hand this could make eradicating HCV a reality, still several other measures are necessary for this goal to be attained, including HCV-infected patients identification, broad access to therapy and need to target categories at highest risk of HCV infection and transmission. Ideally in the coming decades we would like to first control the disease by reducing morbidity and mortality, subsequently to reduce transmission and incidence to an acceptable level, and finally to achieve virus eradication worldwide. But this ideal progression requires a huge effort in terms of diagnosis, treatment and prevention of disease transmission.
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March 2016

Transmembrane 6 superfamily member 2 gene E167K variant impacts on steatosis and liver damage in chronic hepatitis C patients.

Hepatology 2015 Jul 6;62(1):111-7. Epub 2015 May 6.

Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Unlabelled: Steatosis and inherited host factors influence liver damage progression in chronic hepatitis C (CHC). The transmembrane 6 superfamily member 2 (TM6SF2) gene E167K variant increases liver fat and risk of progressive steatohepatitis by interfering with lipoprotein secretion. Our aim was to determine whether the E167K variant affects histological severity of steatosis, necroinflammation, and fibrosis in a cross-sectional cohort of 815 Italian therapy-naïve CHC patients. The association with clinically significant fibrosis was replicated in 645 Swiss/German patients. The TM6SF2 E167K variant was genotyped by TaqMan assays, steatosis graded according to the nonalcoholic fatty liver disease activity score, and necroinflammation and fibrosis graded and staged according to Ishak in Italian, and to Metavir in Swiss/German patients. The E167K variant was detected in 69 (9%) Italian patients and was associated with more severe steatosis, independently of confounders (P = 0.038). The association between E167K and steatosis severity was present in patients not infected by genotype 3 (G3) HCV (P = 0.031), but not in those infected by G3 HCV (P = 0.58). Furthermore, the E167K variant was associated with more severe necroinflammation (Ishak grade; adjusted P = 0.037) and nearly associated with more severe fibrosis (Ishak stage; adjusted P = 0.058). At multivariate logistic regression analysis, the E167K variant was independently associated with histologically probable or definite cirrhosis (Ishak stage S6; odds ratio [OR]: 2.19; 95% confidence interval [CI]: 1.18-3.93; P = 0.010). After further conditioning for steatosis and necroinflammation, the E167K variant remained associated with cirrhosis (OR, 3.15; 95% CI: 1.60-5.99; P < 0.001). In Swiss/German patients, the E167K variant was independently associated with clinically significant fibrosis Metavir stage F2-F4 (OR, 1.81; 95% CI: 1.12-3.02; P = 0.016).

Conclusion: TM6SF2 E167K variant impacts on steatosis severity and is associated with liver damage and fibrosis in patients with CHC.
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http://dx.doi.org/10.1002/hep.27811DOI Listing
July 2015

Interaction between PNPLA3 I148M variant and age at infection in determining fibrosis progression in chronic hepatitis C.

PLoS One 2014 29;9(8):e106022. Epub 2014 Aug 29.

Department of Internal Medicine, Fondazione IRCCS Ca' Granda Ospedale Policlinico Milano, Milano, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano, Italy.

Background And Aims: The PNPLA3 I148M sequence variant favors hepatic lipid accumulation and confers susceptibility to hepatic fibrosis and hepatocellular carcinoma. The aim of this study was to estimate the effect size of homozygosity for the PNPLA3 I148M variant (148M/M) on the fibrosis progression rate (FPR) and the interaction with age at infection in chronic hepatitis C (CHC).

Methods: FPR was estimated in a prospective cohort of 247 CHC patients without alcohol intake and diabetes, with careful estimation of age at infection and determination of fibrosis stage by Ishak score.

Results: Older age at infection was the strongest determinant of FPR (p<0.0001). PNPLA3 148M/M was associated with faster FPR in individuals infected at older age (above the median, 21 years; -0.64±0.2, n = 8 vs. -0.95±0.3, n = 166 log10 FPR respectively; p = 0.001; confirmed for lower age thresholds, p<0.05), but not in those infected at younger age (p = ns). The negative impact of PNPLA3 148M/M on fibrosis progression was more marked in subjects at risk of altered hepatic lipid metabolism (those with grade 2-3 steatosis, genotype 3, and overweight; p<0.05). At multivariate analysis, PNPLA3 148M/M was associated with FPR (incremental effect 0.08±0.03 log10 fibrosis unit per year; p = 0.022), independently of several confounders, and there was a significant interaction between 148M/M and older age at infection (p = 0.025). The association between 148M/M and FPR remained significant even after adjustment for steatosis severity (p = 0.032).

Conclusions: We observed an interaction between homozygosity for the PNPLA3 I148M variant and age at infection in determining fibrosis progression in CHC patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0106022PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4149487PMC
June 2015

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

Int J Mol Sci 2014 Apr 25;15(5):7213-24. Epub 2014 Apr 25.

Division of Gastroenterology and Hepatology, Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan 20100, Italy.

Unlabelled: 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.
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http://dx.doi.org/10.3390/ijms15057213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4057668PMC
April 2014

Second wave anti-HCV protease inhibitors: too little too late?

Liver Int 2014 Aug;34(7):e168-70

Division of Gastroenterology and Hepatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milano, Italy; Università degli Studi di Milano, Milano, Italy.

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http://dx.doi.org/10.1111/liv.12543DOI Listing
August 2014

Telaprevir in a patient with chronic hepatitis C and cryoglobulinemic glomerulonephritis.

Antivir Ther 2014 6;19(5):527-31. Epub 2013 Sep 6.

Centro A.M. e A. Migliavacca, First Division of Gastroenterology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 
Università degli Studi di Milano, Milano, Italy.

Mixed cryoglobulinemia (MC), the most common extrahepatic manifestation of HCV, may lead to renal involvement ranging from mild urinary abnormalities to nephritic syndrome, eventually evolving to renal failure requiring renal replacement therapy. HCV eradication with pegylated interferon (PEG-IFN) and ribavirin (RBV) is the only curative treatment for MC-related membranoproliferative glomerulonephritis. The addition of directly acting antivirals (DAAs) to PEG-IFN and RBV has significantly improved sustained virological response rates in HCV genotype 1 patients. Safety and efficacy of this regimen in patients with membranoproliferative glomerulonephritis has not been proved yet. Here, we report the case of a woman with HCV-1-related cryoglobulinemic membranoproliferative glomerulonephritis presenting with severe nephritic syndrome and rapidly progressive renal failure, who received successful treatment with the DAA telaprevir in conjunction with PEG-IFN and RBV. Triple therapy was safe and effective, leading to HCV eradication and complete resolution of acute renal failure.
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http://dx.doi.org/10.3851/IMP2684DOI Listing
July 2015

Cirrhosis and rapid virological response to peginterferon plus ribavirin determine treatment outcome in HCV-1 IL28B rs12979860 CC patients.

Biomed Res Int 2013 9;2013:580796. Epub 2013 Jul 9.

Centro AM e A Migliavacca, First Division of Gastroenterology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Università degli Studi di Milano, Milano, Italy.

Background: The rs12979860 CC genotype of the interleukin 28B (IL28B) polymorphism is associated with high rates of sustained virological response (SVR) to peginterferon (PegIFN) and ribavirin (Rbv) in hepatitis C virus genotype-1 (HCV-1) patients. The impact of baseline predictors of treatment outcome and their interplay with viral kinetics in HCV-1 CC patients has not been fully evaluated.

Aim: To identify baseline and on-therapy predictors of treatment failure in HCV-1 IL28B CC patients.

Methods: Treatment-naïve HCV-1 patients, compliant to PegIFN and Rbv who did not discontinue treatment for nonvirological reasons, were analyzed.

Results: 109 HCV-1 IL28B CC were studied. Sixty were males, 39 with BMI >25, 69 with >600,000 IU/mL HCV RNA, 15 with HCV1a, and 30 with cirrhosis. Overall, 75 (69%) achieved an SVR; cirrhosis was the only baseline predictor of treatment failure (OR: 2.58, 95% CI: 1.07-6.21) as SVR rates were 53% in cirrhotics versus 75% in noncirrhotics (P = 0.03). HCV RNA undetectability (<50 IU/mL) at week 4 (RVR) was achieved by 58 patients (53%). The SVR rates were independent of RVR in noncirrhotics, 76% (34/45) RVR (+) and 74% (25/34) RVR (-) (P = 0.9). In cirrhotic patients, SVR rates were significantly higher in RVR (+) compared to RVR (-) (10/13 (77%) versus 6/17 (35%) P = 0.03).

Conclusions: In HCV-1 IL28B CC patients, cirrhosis is the only clinical baseline predictor of PegIFN and Rbv treatment failure. However, in IL28B CC cirrhotics, the achievement of RVR identifies those patients who still have high rates of SVR to Peg-IFN/Rbv therapy.
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http://dx.doi.org/10.1155/2013/580796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3722882PMC
March 2014

Failure of Intravenous Silibinin Monotherapy to Prevent Hepatitis C Genotype 2A Liver Graft Reinfection.

Hepat Mon 2012 Jun 30;12(6):411-4. Epub 2012 Jun 30.

Angela Maria e Antonio Migliavacca Center for Liver Disease, First Division of Gastroenterology, Fondazione IRCCS Ca' Granda ospedale Maggiore Policlinico, University of Milan, Milan, Italy.

Background: Hepatitis C virus (HCV) recurrence after orthotopic liver transplantation (OLT) remains a serious problem in the clinical management of post-oLT patients. Recently, two case reports have described successful prevention of HCV liver graft reinfection with intravenous silibinin (SIL) monotherapy in two carriers of genotype 3a and 1a/4 HCV. Based on these findings, we decided to offer such a therapy to a 65 year old woman on the oLT list.

Case Presentation: A 65 year old patient with HCV 2a cirrhosis, a previous relapse to PegIFn and Rbv therapy, was listed for oLT due to hepatocellular carcinoma. She started SIL monotherapy 24 hours before oLT. After an initial HCV-RnA decline following surgery,a progressive HCV RnA increase was observed. For this reason, SIL was stopped after 15 days of monotherapy.

Conclusions: SIL has multiple anti-HCV mechanisms of action, most of them have been characterized in vitro only. Our case report shows that the antiviral effect of SIL might be HCV genotype dependent, as recently suggested by a study, showing no effect of SIL on the HCV-2a subgenomic replicon model. our case reinforces the need for controlled studies to assess the efficacy of silibinin therapy in HCV infected patients before it can be broadly used in all clinical settings.
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http://dx.doi.org/10.5812/hepatmon.6135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3412559PMC
June 2012

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

Hepatology 2012 Nov 14;56(5):1681-7. Epub 2012 Oct 14.

First Division of Gastroenterology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Italy.

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.
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http://dx.doi.org/10.1002/hep.25867DOI Listing
November 2012

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

Hepatology 2012 Feb 3;55(2):336-42. Epub 2012 Jan 3.

Centro AM e A Migliavacca, First Division of Gastroenterology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Università degli Studi di Milano, Milan, Italy.

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.
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http://dx.doi.org/10.1002/hep.24683DOI Listing
February 2012

The course of esophageal varices in patients with hepatitis C cirrhosis responding to interferon/ribavirin therapy.

Antivir Ther 2011 ;16(5):677-84

AM Migliavacca Center for Liver Disease, First Division of Gastroenterology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy.

Background: Gastrointestinal haemorrhage from ruptured esophageal varices (EV) is a significant cause of morbidity and mortality in patients with HCV-related cirrhosis. The risk of developing EV and bleeding is influenced by hepatitis severity, which can be attenuated by successful interferon (IFN) therapy. Our aim was to prospectively assess whether a successful IFN therapy modifies development and/or progression of EV in patients with HCV-related compensated cirrhosis.

Methods: Child-Pugh A patients with either no or small (F1) EV underwent surveillance with repeated endoscopy during and after completion of IFN-based therapy.

Results: A total of 127 patients (59 years, 79 males, 65 HCV-1/4 and 17 F1 EV) received weight-based ribavirin (RBV) combined with either IFN-α2b 3 MU three times per week (n=36), weekly pegylated (PEG)-IFN-α2b 1.5 μg/kg (n=68) or weekly PEG-IFN-α2a 180 μg (n=23). Patients were followed-up for 18-108 months after treatment completion with a median endoscopic follow-up of 68 months for the 62 patients with a sustained virological response (SVR) and 57 months for the 65 non-SVR patients (P=0.3). De novo EV developed in 10 (9.1%) patients including 2/57 SVR and 8/53 non-SVR (3.5% versus 15.1%; P=0.047), whereas EV progressed in size in 3 patients, including 1/5 SVR and 2/12 non-SVR (P=0.87). Two non-SVR patients bled from EV and one died.

Conclusions: A successful IFN therapy prevents or delays the de novo onset of EV in patients with compensated cirrhosis due to HCV, but does not abrogate the need for continued endoscopic surveillance.
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http://dx.doi.org/10.3851/IMP1807DOI Listing
February 2012

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

J Hepatol 2012 Feb 12;56(2):341-7. Epub 2011 Jul 12.

A.M. Migliavacca Center for Liver Disease, 1st Division of Gastroenterology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy.

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.
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http://dx.doi.org/10.1016/j.jhep.2011.05.022DOI Listing
February 2012

Genetic variation in the interleukin-28B gene is not associated with fibrosis progression in patients with chronic hepatitis C and known date of infection.

Hepatology 2011 Oct 19;54(4):1127-34. Epub 2011 Aug 19.

Istituto Nazionale Genetica Molecolare, Milano, Italy.

Unlabelled: Polymorphisms in the interleukin-28B (IL28B) region are associated with spontaneous and treatment-induced viral clearance in hepatitis C virus (HCV) infection. Nevertheless, it is unknown whether genetic variation at the IL28B locus influences the natural history of chronic HCV infection. Thus, we asked whether an association between IL28B polymorphisms and liver fibrosis progression existed. We studied 247 consecutive patients with chronic HCV, an accurate estimate of the date of infection, and a liver biopsy performed before any treatment. No patient had a history of alcohol abuse or coinfection with other viruses. We assessed the role of rs8099917 and rs12979860 polymorphisms and the effect of host and environmental factors on fibrosis progression. Blood transfusion (75%) was the main modality of infection. Median age at infection was 21 years, and median interval between infection and liver biopsy was 25 years. One hundred twenty-nine patients (52%) were infected by HCV-1, 74 (30%) by HCV-2, 34 (14%) by HCV-3, and 10 (4%) by HCV-4. Bridging fibrosis/cirrhosis (Ishak ≥ 4) was detected in 24% of patients. Age at infection had a marked effect on fibrosis progression by both a linear model and Cox proportional-hazard regression (P < 2E-16). A 12.1% increase in the hazard of advanced fibrosis was estimated for each additional year at infection, suggesting that this was the major explanatory variable in this cohort. Male gender (P < 0.05), HCV genotype 3 (P < 0.001) and steatosis (P < 0.05) were also associated with faster fibrosis progression. Conversely, the two IL28B polymorphisms had no impact on fibrosis progression.

Conclusion: In HCV patients with a known date of infection, IL28B genotype was not associated with fibrosis progression rate or with the risk of developing advanced liver fibrosis.
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http://dx.doi.org/10.1002/hep.24503DOI Listing
October 2011

Patatin-like phospholipase domain-containing 3 I148M polymorphism, steatosis, and liver damage in chronic hepatitis C.

Hepatology 2011 Mar 11;53(3):791-9. Epub 2011 Feb 11.

Department of Internal Medicine, Università degli Studi, Fondazione IRCCS Ospedale Maggiore Policlinico "Ca' Granda" IRCCS, Milan, Italy.

Unlabelled: Steatosis has been reported to negatively influence the natural history of chronic hepatitis C (CHC), but controversy remains over its causal role due to the confounding effect of adiposity, insulin resistance, and diabetes. The rs738409 C>G patatin-like phospholipase domain-containing 3 (PNPLA3) single nucleotide polymorphism (SNP), encoding for the I148M protein variant, influences liver fat without affecting insulin resistance and body composition. The aim of this study was to evaluate the effect of the rs738409 CG genotype on liver fat and fibrosis in CHC patients. We also explored the possible effect of PNPLA3 genotype on other steatosis-related complications, namely, treatment failure and hepatocellular carcinoma (HCC) development. To this end we considered two independent series of 325 and 494 CHC patients with available DNA and liver biopsy followed at tertiary referral centers in northern Italy. The rs738409 genotype was determined by a Taqman assay. The rs738409 GG genotype, observed in 10% of patients, was associated with steatosis independently of age, sex, body mass index (BMI), diabetes, alcohol intake, and viral genotype (odds ratio [OR] 1.90, 95% confidence interval [CI] 1.4-2.7; P < 0.001). The association with rs738409 genotype was confirmed for severe steatosis, was independent of alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) values, and was observed in all viral genotypes but the 3. The rs738409 GG genotype was associated with fibrosis stage and cirrhosis (OR 1.47, 95% CI 1.2-1.9; P = 0.002), treatment response (n = 470; OR 0.63, 95% CI 0.4-0.8; P = 0.006), and HCC occurrence (n = 325; OR 2.16, 95% CI 1.3-3.6; P = 0.002), independently of confounders.

Conclusion: The rs738409 PNPLA3 genotype influences steatosis development in CHC and is independently associated with cirrhosis and other steatosis-related clinical outcomes, such as lack of response to antiviral treatment and possibly HCC.
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http://dx.doi.org/10.1002/hep.24123DOI Listing
March 2011
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