M R Brunetto

Università di Pisa, Pisa, Tuscany, Italy

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Publications (266)1206.33 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Peginterferon lambda-1a (Lambda, Type III IFN) is currently under Phase 3 evaluation as part of combination treatment for HCV infection. The triple regimen of Lambda, daclatasvir (DCV; NS5A inhibitor) and ribavirin (RBV) achieved sustained virologic response (SVR) rates of >90% in a pilot study of patients chronically infected with genotype 1b HCV when treated for 24 weeks. This triple combination regimen was evaluated for 12 weeks of treatment in a cohort of patients with genotype 1b infection (Study AI452-008c). Methods: 24 treatment-naive, non-cirrhotic HCV genotype 1b infected patients were treated with open-label Lambda 180 mcg/week + DCV 60mg daily + RBV 1000-1200mg daily for 12 weeks. The primary endpoint is HCV RNA <LLOQ (25 IU/mL) at 12 weeks post-treatment (SVR12). SVR4 results are reported here with SVR12 available at presentation. Results: Baseline characteristics were male 46%, Caucasian 96%, and IL28B non-CC genotype 67%. Mean baseline HCV RNA was 6.3 (range 5.1–7.4) log10 IU/mL. SVR4 was achieved in 21/23 (91%) patients with available data. Both patients who did not achieve SVR4 experienced relapse posttreatment. No patients discontinued treatment due to AEs or treatment futility; there were no deaths and no serious AEs. The most frequent AEs were asthenia, pruritus, dry skin and diarrhea. One patient each (n=3/24) had a Grade 3/4 lab abnormality of elevated ALT/AST, reduced hemoglobin, or increased bilirubin. Conclusion: 12 weeks of treatment with Lambda + DCV + RBV achieved a high SVR4 rate in treatment-naïve, non-cirrhotic HCV genotype 1b-infected patients. The regimen was generally well tolerated. Observed mITT HCV RNA <LLOQ at end of treatment, n/N (%) 24/24 (100) 24/24 (100) SVR4, n/N (%) 21/23 (91)* 21/24 (88) Post-treatment relapse (n) 2 *1 patient was lost to follow-up (Week 8 undetectable), counted as failure for mITT analysis
    IDWeek 2014 Meeting of the Infectious Diseases Society of America; 10/2014
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    ABSTRACT: Twenty-four weeks of treatment with peginterferon and ribavirin for chronic hepatitis C virus (HCV) genotype 2 or 3 infection produces a sustained virologic response (SVR) in 70%-80% of patients. We performed a randomized, double-blind, phase 2b study to assess whether adding daclatasvir, an NS5A inhibitor active against these genotypes, improves efficacy and shortens therapy.
    Gastroenterology 10/2014; · 12.82 Impact Factor
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    ABSTRACT: Background: Daclatasvir (DCV) is a potent, pangenotypic NS5A inhibitor. Asunaprevir (ASV) is an NS3 protease inhibitor with activity in HCV genotypes (GT) 1 and 4. DCV plus ASV in combination with peginterferon alfa-2a and ribavirin (DCV+ASV+P/R) has previously demonstrated potent antiviral activity in HCV GT 1-infected null responders. This phase 3 study (HALLMARK-QUAD; AI447029) evaluated DCV+ASV+P/R in patients with chronic HCV GT 1 or 4 infection who were prior null or partial responders to peginterferon/ribavirin. Methods: In this open-label study, 354 GT 1 and 44 GT 4-infected patients received 24 weeks of treatment with DCV 60 mg once daily plus ASV 100 mg twice daily in combination with weekly peginterferon alfa-2a 180 g and weight-based ribavirin twice daily. The primary endpoint was sustained virologic response at posttreatment Week 12 (SVR12). Results: The median age of patients was 53 years, 69% were male, 76% were white, and 23% had cirrhosis; 67% of patients were prior null responders and 33% were partial responders. SVR12 was achieved by 93% of GT 1-infected patients and 98% of GT 4-infected patients; one GT 4 patient was not tested for SVR12 but achieved SVR24, yielding an SVR rate of 100% in GT 4-infected patients (Table). Prior P/R response, cirrhosis status, gender, age, race, or IL28B genotype did not influence SVR12. SVR12 rates for GT 1a were 87% (153/176) versus 99% (176/178) for GT 1b. Serious adverse events occurred in 6% of patients; 5% discontinued treatment due to an adverse event. One death occurred at posttreatment week 12 (pneumonia; not considered related to study therapy). Adverse events occurring in ≥20% of patients were fatigue, headache, pruritus, asthenia, influenza-like illness, insomnia and rash. Grade 3/4 laboratory abnormalities included neutropenia (22%), lymphopenia (16%), anemia (6%), thrombocytopenia (4%) and ALT/AST elevations (3%/3%). Conclusion: The QUAD regimen of DCV+ASV+P/R demonstrated high SVR12 rates of 93% and 100% in GT 1 or GT 4 prior non-responders. DCV+ASV+P/R was generally well tolerated; no additional safety and tolerability concerns were observed compared to P/R regimens. These results support the investigation of DCV in all-oral combinations in multiple patient populations across genotypes.
    IDWeek 2014 Meeting of the Infectious Diseases Society of America; 10/2014
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    ABSTRACT: Background: ABT-450 is an HCV NS3/4A protease inhibitor dosed with ritonavir (r) 100mg, identified by AbbVie and Enanta. Ombitasvir (formerly ABT-267) is an NS5A inhibitor, and dasabuvir (formerly ABT-333) is an NS5B RNA polymerase inhibitor. The randomized phase 3 PEARL trials evaluated the safety and efficacy of the 3D regimen of ABT-450/ritonavir/ombitasvir and dasabuvir with or without ribavirin (RBV) in HCV genotype 1-infected patients. SVR12 rates >90% were achieved in all treatment arms. Safety outcomes in these trials according to baseline demographics are reported. Methods: Non-cirrhotic HCV GT1b treatment-experienced (PEARL II) and treatment-naive (PEARL III) patients, and non-cirrhotic HCV GT1a treatment-naive patients (PEARL IV) were randomized to co-formulated ABT-450/r/ombitasvir (150mg/100mg/25mg QD) + dasabuvir (250mg BID) with RBV or placebo/no RBV. The percentage of patients experiencing any treatment-emergent adverse event (AE), severe AE, serious AE, and AE leading to treatment discontinuation was determined according to sex, age, race, ethnicity, and history of diabetes. Homogeneity of treatment effect across subgroups for each event type was assessed using the Breslow-Day test. Results: A total of 910 patients received at least one dose of study treatment in the PEARL-II (n=186), PEARL-III (n=419), and PEARL-IV (n=305) trials. Most patients experienced at least 1 AE, but the majority of events were mild. There were no statistically significant differences in event rates according to the categories analyzed (Table). AEs occurring in >20% of patients in both the 3D+RBV and 3D groups were fatigue (29.9% and 26.5%) and headache (24.4% and 25.3%). Overall, 4 patients (0.4%, 2 in each treatment group) discontinued due to AEs (3D+RBV arm: 1 patient with anxiety, dyspnea, pyrexia and tachycardia, and 1 with pancreatitis that started prior to dosing; 3D arm: 1 patient with diverticulitis and 1 patient with drug abuse). Conclusion: The 3D regimen of ABT-450/r/ombitasvir + dasabuvir with or without RBV was well tolerated in non-cirrhotic HCV GT1-infected patients, with low rates of discontinuation. The AE profile of the regimen was similar with and without RBV regardless of age, gender, race, ethnicity, or history of diabetes.
    IDWeek 2014 Meeting of the Infectious Diseases Society of America; 10/2014
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    ABSTRACT: HBV-DNA integration frequently occurs in HBV-related hepatocellularcarcinoma (HCC), but whether HBV antigens are expressed in HCC cells and can be targeted by immune therapeutic strategies remains controversial. Here we first characterized HBV antigen expression in HCC metastases occurring in a patient who had undergone liver transplantation for HBV-related HCC. We then deployed, for the first time in HCC, autologous T cells genetically modified to express a HBsAg specific T cell receptor as therapy against chemoresistant extrahepatic metastases. We confirmed that HBV antigens were expressed in HCC metastases (but not the donor liver) and demonstrated that tumor cells were recognized in vivo by lymphocytes engineered to express an HBV-specific T cell receptor (TCR). Gene-modified T cells survived, expanded and mediated a reduction in HBsAg levels without exacerbation of liver inflammation or other toxicity. Whilst clinical efficacy was not established in this subject with end-stage metastatic disease, we confirm the feasibility of providing autologous TCR redirected therapy against HCC and advocate the strategy as a novel therapeutic opportunity in Hepatitis B associated malignancies.
    Journal of hepatology. 10/2014;
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    ABSTRACT: BACKGROUND AND AIMS: The virus/host interplay mediates liver pathology in chronic HBV infection. MiRNAs play a pivotal role in virus/host interactions and are detected in both serum and HBsAg-particles, but studies of their dynamics during chronic infection and antiviral therapy are missing. We studied serum miRNAs during different phases of chronic HBV infection and antiviral treatment. METHODS: MiRNAs were profiled by miRCURY-LNA-Universal-RT-miRNA-PCR (Exiqon-A/S) and qPCR-panels-I/II-739-miRNA-assays and single-RT-q-PCRs. Two cohorts of well-characterized HBsAg-carriers were studied (median follow-up 34-52 months): a) training-panel (141 sera) and HBsAg-particles (32 samples) from 61 HBsAg-carriers and b) validation-panel (136 sera) from 84 carriers. RESULTS: Thirty-one miRNAs were differentially expressed in inactive-carriers (IC) and chronic-hepatitis-B (CHB) with the largest difference for miR-122-5p, miR-99a-5p and miR-192-5p (liver-specific-miRNAs), over-expressed in both sera and HBsAg-particles of CHB (ANOVA/U-test p-values: <0.000001/0.000001; <0.000001/0.000003; <0.000001/0.000005, respectively) and significantly down-regulated during- and after-treatment in sustained-virological-responders (SVR). MiRNA-profiles of IC and SVR clustered in the heatmap. Liver-miRNAs were combined with miR-335, miR-126 and miR-320a (internal controls) to build a MiR-B-Index with 100% sensitivity, 83.3% and 92.5% specificity (-1.7 cut-off) in both training and validation cohorts to identify IC. MiR-B-Index (-5.72, -20.43/14.38) correlated with ALT (49, 10/2056 U/l, ρ = -0.497, p<0.001), HBV-DNA (4.58, undetectable/>8.3 Log10 IU/mL, ρ = -0.732, p<0.001) and HBsAg (3.40, 0.11/5.49 Log10 IU/mL, ρ = -0.883, p<0.001). At multivariate analysis HBV-DNA (p = 0.002), HBsAg (p<0.001) and infection-phase (p<0.001), but not ALT (p = 0.360) correlated with MiR-B-Index. In SVR to Peg-IFN/NUCs MiR-B-Index improved during-therapy and post-treatment reaching IC-like values (5.32, -1.65/10.91 vs 6.68, 0.54/9.53, p = 0.324) beckoning sustained HBV-immune-control earlier than HBsAg-decline. CONCLUSIONS: Serum miRNA profile change dynamically during the different phases of chronic HBV infection. We identified a miRNA signature associated with both natural-occurring and therapy-induced immune control of HBV infection. The MiR-B-Index might be a useful biomarker for the early identification of the sustained switch from CHB to inactive HBV-infection in patients treated with antivirals.
    PLoS ONE 10/2014; Volume 9(Issue 10):e110782. · 3.53 Impact Factor
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    ABSTRACT: Serum hepatitis B surface antigen (HBsAg) levels may predict treatment response in chronic hepatitis B (CHB). We examined the association between changes in HBsAg levels and response to treatment in the BE-LOW study.
    Journal of hepatology. 08/2014;
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    ABSTRACT: To evaluate the safety and efficacy of daclatasvir, an HCV NS5A inhibitor with pangenotypic activity, administered with peginterferon-alfa-2a/ribavirin.
    Gut 07/2014; · 10.73 Impact Factor
  • Maurizia Rossana Brunetto, Ferruccio Bonino
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    ABSTRACT: Chronic hepatitis B (CHB) results from the inability of the host's immune system to control viral replication. Interferon-α (IFN-α) therapy can convert CHB into inactive hepatitis B virus (HBV) infection in 20-30% of the treated patients. In spite of the low response rate, IFN-α therapy has the advantage of having a limited duration and being effective even after therapy, as demonstrated by a much higher incidence of HBsAg clearance in responders to IFN-α than in naturally occurring inactive HBsAg carriers. IFN-α has multiple antiviral, antiproliferative, and immunomodulatory activities and targets: cellular genes (IFN-stimulated genes) activating different pathways of antiviral defense in infected and noninfected cells, HBV replication blocking the RNA-containing core particle formation and accelerating their decay, degrading pregenomic RNA, and modulating the nuclear viral minichromosome (covalently closed circular DNA) activity by targeting its epigenetic regulation and both innate and adaptive immune response. The interference of viral heterogeneity and genetic polymorphisms of the host on IFN-α susceptibility is under investigation. Only a better understanding of the complex interplay between the different activities of IFN-α would warrant the amelioration of current therapeutic strategies and the design of new therapeutic approaches. The study of on-treatment dynamics of HBV infection by means of combined quantitative monitoring of serum HBV DNA and HBsAg warrant tailoring treatment at the single-patient level and can help to make treatment more cost-effective by using the different combinations of currently available antivirals, including IFN, more appropriately. Integrated molecular and clinical knowledge in a systems medicine fashion is mandatory to further improve antiviral therapy in CHB. © 2014 S. Karger AG, Basel.
    Intervirology 01/2014; 57(3-4):163-70. · 1.89 Impact Factor
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    Maurizia Rossana Brunetto
    Journal of Hepatology 12/2013; · 9.86 Impact Factor
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    ABSTRACT: Background: Daclatasvir (DCV) is a first-in-class NS5A replication complex inhibitor, active against HCV genotype (GT)1-6 in vitro. Study AI444-031 evaluated DCV 60mg QD + peginterferon-alfa-2a (peg-alfa) 180mcg weekly and ribavirin (RBV) 400mg BID for 12 or 16 weeks in patients with chronic HCV GT2 or GT3 infection. Methods: Adult treatment-nave patients were randomly assigned to DCV/peg-alfa/RBV for 12 or 16 weeks or placebo/peg-alfa/RBV for 24 weeks. DCV/peg-alfa/RBV recipients without protocol-defined response (PDR; HCV RNA <LLOQ week-4 and undetectable week-10) discontinued DCV at week 12 and received 12 additional weeks of peg-alfa/RBV. The primary efficacy endpoint was SVR24. Results: Baseline characteristics were well-balanced in the DCV 12-week (N=50), DCV 16-week (N=50) and placebo (N=51) arms; more patients with GT3 (18/80, 22.5%) than GT2 (1/71, 1.4%) were cirrhotic. 78%-88% of DCV recipients achieved PDR. SVR24 rates were higher in GT2 than GT3 with all regimens; within each genotype, SVR24 rates were similar in DCV arms and higher than placebo/peg-alfa/RBV. In DCV arms, one GT2 and 12 GT3 patients relapsed. In GT3, relapse was higher among cirrhotics (3/7, 43%) than non-cirrhotics (3/19, 16%) in the 12-week arm but similar in the 16-week arm (1/4, 25% vs 5/20, 25%). There were 7 on-treatment serious AEs (DCV, 4; placebo, 3); no deaths. AEs were typical of those associated with peg-alfa/RBV. Conclusion: Shorter treatment duration (12 or 16 weeks) with DCV/peg-alfa/RBV demonstrated higher SVR rates than 24 weeks of peg-alfa/RBV in patients with GT2 or GT3 infection, with higher SVR rates in GT2 with all regimens. These results support further evaluation of DCV-containing regimens for different HCV genotypes. GT 2 GT 3 Response, n (%) DCV 12 wk (N=24) DCV 16 wk (N=23) PBO 24 wk (N=24) DCV 12 wk (N=26) DCV 16 wk (N=27) PBO 24 wk (N=27) Protocol-defined response 21 (88) 18 (78) - 22 (85) 22 (82) - End of treatment response (HCV RNA undetectable) 23 (96) 21 (91) 22 (92) 25 (96) 24 (89) 21 (78) SVR12 (HCV RNA <LLOQ 12 weeks posttreatment) 21 (88) 19 (83) 17 (71) 18 (69) 21 (78) 14 (52) SVR24 (HCV RNA undetectable 24 weeks posttreatment)* 20 (83) 19 (83) 15 (63) 18 (69) 18 (67) 16 (59) *Failure to achieve SVR reflects relapse or missing data at posttreatment week 24
    IDWeek 2013 Meeting of the Infectious Diseases Society of America; 10/2013
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    ABSTRACT: Hepatitis C virus (HCV) vaccines may be able to increase viral clearance in combination with antiviral therapy. We analysed viral dynamics and HCV-specific immune response during retreatment for experienced patients in a phase Ib study with E1E2MF59 vaccine. Seventy-eight genotype 1a/1b patients [relapsers (30), partial responders (16) and nonresponders (32) to interferon-(IFN)/ribavirin-(RBV)] were randomly assigned to vaccine (V:23), Peg-IFNα2a-180-ug/qw and ribavirin 1000-1200-mg/qd for 48 weeks (P/R:25), or their combination (P/R + V:30). Vaccine (100 μg/0.5 mL) was administered intramuscularly at week 0-4-8-12-24-28-32-36. Neutralizing of binding (NOB) antibodies and lymphocyte proliferation assay (LPA) for E1E2-specific-CD4 + T cells were performed at week 0-12-16-48. Viral kinetics were analysed up to week 16. The vaccine was safe, and a sustained virological response (SVR) was achieved in 4 P/R + V and 2 P/R patients. Higher SVR rates were observed in prior relapsers (P/R + V = 27.3%; P/R = 12.5%). Higher NOB titres and LPA indexes were found at week 12 and 16 in P/R + V as compared to P/R patients (P = 0.023 and 0.025, P = 0.019 and <0.001, respectively). Among the 22 patients with the strongest direct antiviral effects of IFN (ε ≥ 0.800), those treated with P/R + V (10) reached lower HCV-RNA levels (P = 0.026) at week 16. HCV E1E2MF59 vaccine in combination with Peg-IFNα2a + RBV was safe and elicited E1E2 neutralizing antibodies and specific CD4 + T cell proliferation. Upon early response to IFN, vaccinations were associated with an enhanced second phase viral load decline. These results prompt phase II trials in combination with new antiviral therapies.
    Journal of Viral Hepatitis 08/2013; · 3.08 Impact Factor
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    ABSTRACT: We investigated whether HBV genotype influences on-treatment HBsAg kinetics and/or the end-of-treatment HBsAg levels associated with long-term virological response in HBeAg-negative chronic hepatitis B patients treated with peginterferon alfa-2a ± lamivudine in the Phase III trial. All patients (n = 230) who participated in long-term follow-up were included according to the availability of HBsAg levels measurements. Long-term virological response was defined as HBV DNA ⩽10,000 cp/mL (1786 IU/mL) at 5 years post-treatment. Genotype-specific end-of-treatment HBsAg levels associated with long-term virological response (identified by ROC analysis) were assessed in 199 patients with HBsAg measurements available at baseline and end-of-treatment. HBsAg kinetics according to genotype and long-term virological response were investigated in the 117 patients with additional samples available at weeks 12, 24 and 72. Baseline HBsAg levels were significantly higher for A than B, C and D genotypes (p<0.05). On-treatment HBsAg kinetics varied according to HBV genotype. The difference between responders and non-responders was greatest for genotype A from weeks 12 to 24; for genotypes B and D from baseline to week 12; there was no significant difference over any timeframe for genotype C. High positive predictive values for long-term virological response could be obtained by applying end-of-treatment genotype-specific cut-offs: 75%, 47%, 71% and 75% for genotypes A (<400 IU/mL), B (<50 IU/mL), C (<75 IU/mL) and D (<1000 IU/mL), respectively. On-treatment HBsAg kinetics vary between HBV genotypes. Genotype-specific monitoring timeframes and end-of-treatment thresholds could ameliorate response-guided treatment of HBeAg-negative chronic hepatitis B.
    Journal of Hepatology 07/2013; · 9.86 Impact Factor
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    ABSTRACT: To detect HBV rtM204V/I lamivudine resistant strains in serum of patients with acute hepatitis B and to assess their biological and clinical significance METHODS: 80 HBV DNA-positive patients with symptomatic acute hepatitis B observed from 1999 to 2010 were enrolled. A plasma sample obtained at the first observation was tested for HBV mutants in the polymerase region by direct sequencing; the antiviral drug-resistant rtM204V/I mutations, the most frequent HBV mutants in Italy, were also sought by the more sensitive allele-specific polymerase chain reaction (PCR). No HBV mutation associated with resistance to nucleos(t)ide analogues was identified by direct sequencing, whereas allele-specific PCR identified HBV strains carrying the substitution rtM204V/I in 11 (13.7%) patients. Compared with those with the HBV wild strain, patients with rtM204V/I more frequently showed severe acute hepatitis B (36.4 % vs 8.7 %; p<0.05) and lower values of serum HBV DNA (1.77x10(6) ± 4.76x10(6) vs. 1.68x10(8) ± 5.46x10(8)). In addition, a multivariate analysis identified the presence of a pre-existing HCV chronic infection as independently associated with severe acute hepatitis B (p<0.05). HBV rtM204V/I lamivudine-resistant strains were detected in serum of 11 (13.7%) patients with acute hepatitis B by allele-specific polymerase chain reaction. The frequent association of rtM204V/I with a more severe acute hepatitis B and with a lower viral load may suggest that greater and/or more prolonged immune pressure might have induced their selection.
    The Journal of infection 06/2013; · 4.13 Impact Factor
  • Ferruccio Bonino, Maurizia Rossana Brunetto
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    ABSTRACT: Occult HBV infection (OBI) is defined as persistence of HBV genomes (with detectable or undetectable serum HBV DNA) in the liver of serum HBsAg negative individuals. It represents the HBsAg negative phase of the natural history of HBV infection in individuals with self-limited acute hepatitis B or in HBsAg carriers or chronic hepatitis B patients who lose HBsAg either naturally or after antiviral therapy and maintain lifelong anti-HBc in serum (with or without anti-HBs and\or anti-HBe). Rarely it may occur as primary “occult” infection when caused by minute viral amounts unable to induce humoral immune response. HBsAg negative infections stem from lifelong intrahepatic persistence of HBV-ccc-DNA under the host’s immune control and may lead to HBsAg positive reactivation after immunosuppressive therapies or epigenetic modifications. HBV reactivation can be avoided by pre-emptive antiviral therapy with nucleos(t)ide analogs. OBI in chronic liver disease of other etiologies may contribute to the development of hepatocellular-carcinoma.
    Current Hepatitis Reports 06/2013; 12(2).
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    ABSTRACT: BACKGROUND: HBeAg-negative chronic hepatitis B (CHB) is the most frequent and difficult to treat viral hepatitis worldwide. HBV-DNA and HBsAg serum levels, which help the early identification of non-responders to peg-interferon (PEG-IFN), prompt more flexible individualized therapeutic strategies exploiting the benefits of both PEG-IFN and nucleos(t)ide analogs (NAs). We assessed the cost-effectiveness of week-12 HBV-DNA\HBsAg stopping rule for early interruption and switch to currently most effective NAs treatments (entecavir-ETV or tenofovir-TDF). METHODS: A decision-analytic Markov model was developed in health-related states: CHB, compensated and decompensated cirrhosis, hepatocarcinoma, liver transplant, post-liver transplant, death and virologic response, relapse, HBsAg clearance. Simulated strategies were: 1) ETV/TDF in CHB; 2) ETV/TDF delayed until compensated cirrhosis (CC); 3) first-line-PEG-IFN followed by switch to ETV/TDF for either patients meeting week-12 stopping rule or week-48 null-responders/relapsers ; 4) first-line PEG-IFN followed by switch to ETV/TDF delayed until CC. ETV and TDF were considered alternatively for a total of 8 strategies. A lifetime simulation horizon was applied. RESULTS: Early treatment strategies using NAs with or without first-line PEG-IFN provided the highest results (about 22-life-years and 15-QALYs). Delayed treatments until cirrhosis development resulted in poorer outcomes. The average per-patient lifetime costs ranged from €33,500 (TDF in CC) to €68,900 (TDF in CHB). Costs using ETV were 20-50% higher. First-line-PEG-IFN strategies resulted ranging from dominant (i.e. more effective and less costly) to highly cost-effective, even though differences in QALY were always very narrow. CONCLUSIONS: The cost-effectiveness of antiviral therapy of HBeAg-negative CHB could be improved significantly using first-line PEG-IFN followed by a switch to NAs in either patients meeting week-12 HBV-DNA/HBsAg stopping rule or week-48 non responders/relapsers.
    Antiviral therapy 03/2013; · 3.07 Impact Factor
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    ABSTRACT: To investigate the durability of response to peginterferon alfa-2a up to 5 years post-treatment and factors associated with response in hepatitis B e-antigen (HBeAg)-negative patients. HBeAg-negative patients received peginterferon alfa-2a (180 μg/week) ± lamivudine (100 mg/day) for 48 weeks as part of a multicenter, randomized study. The planned 5-year efficacy analysis included patients (n = 230) enrolled in the long-term follow-up study. On-treatment hepatitis B surface antigen (HBsAg) decline kinetics were analyzed retrospectively in a subgroup of patients with HBsAg data available at baseline, weeks 12, 24, and 48 on-treatment, and 6 months post-treatment (n = 120). Receiver operating characteristic analyses identified the on-treatment HBsAg levels associated with response at 1 and 5 years post-treatment. HBV DNA ≤2,000 IU/mL and HBsAg clearance at 5 years post-treatment were achieved by 23 and 12% of patients, respectively. High rates of HBsAg clearance at 5 years post-treatment were achieved by patients with HBV DNA ≤2,000 IU/mL at 1 year post-treatment (28%). Rates of HBV DNA ≤2,000 IU/mL at 1 year post-treatment were 47.2 and 43.4% in patients with ≥10% decline from baseline at weeks 12 and 24, respectively, compared with 16.4% (p = 0.0003) and 13.2% (p < 0.0004) in patients with a <10% decline. Rates of HBsAg clearance at 5 years post-treatment were 22.6 and 22.4% in patients with ≥10% decline at weeks 12 and 24, respectively, compared with 7.5% (p = 0.0161) and 3.8% (p < 0.0001) in patients with <10% decline. Peginterferon alfa-2a results in increasing rates of HBsAg clearance during post-treatment follow-up in HBeAg-negative patients. On-treatment decline in HBsAg is significantly associated with long-term post-treatment response.
    Hepatology International 03/2013; 7(1):88-97. · 2.64 Impact Factor
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    ABSTRACT: Genome-wide association studies (GWAS) have successfully identified several loci associated with primary biliary cirrhosis (PBC) risk. Pathway analysis complements conventional GWAS analysis. We applied the recently developed linear combination test for pathways to datasets drawn from independent PBC GWAS in Italian and Canadian subjects. Of the Kyoto Encyclopedia of Genes and Genomes and BioCarta pathways tested, 25 pathways in the Italian dataset (449 cases, 940 controls) and 26 pathways in the Canadian dataset (530 cases, 398 controls) were associated with PBC susceptibility (P<0.05). After correcting for multiple comparisons, only the eight most significant pathways in the Italian dataset had FDR <0.25 with tumor necrosis factor/stress-related signaling emerging as the top pathway (P=7.38 × 10(-4), FDR=0.18). Two pathways, phosphatidylinositol signaling and hedgehog signaling, were replicated in both datasets (P<0.05), and subjected to two additional complementary pathway tests. Both pathway signals remained significant in the Italian dataset on modified gene set enrichment analysis (P<0.05). In both GWAS, variants nominally associated with PBC were significantly overrepresented in the phosphatidylinositol pathway (Fisher exact P<0.05). These results point to established and novel pathway-level associations with inherited predisposition to PBC that, on further independent replication and functional validation, may provide fresh insights into PBC etiology.Genes and Immunity advance online publication, 7 February 2013; doi:10.1038/gene.2013.1.
    Genes and immunity 02/2013; · 4.22 Impact Factor
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    ABSTRACT: The Gunther's vector-free method (GM), using PCR-amplified full length HBV-DNA (fl-HBV-DNA), is currently the best in-vitro HBV replication system despite the low intracellular HBV-DNA production. The replication efficiency and HBsAg secretion of 12 isolates from HBsAg/HBeAg positive sera by GM, Monomer-Linear-Sticky-Ends-DNA (MLSE) and Monomer-Circular-Closed (MCC) were compared in HuH7 cells. Eight of 12 genomes (67%) were replication competent by GM; however Direct Sequencing (DS) showed that more than 80% of input DNA was undigested in spite of SapI treatment. Replication Intermediates (RI) were detected earlier (24 vs 48hours) and in higher amounts (2.51± 0.32 and 6.43± 0.43 fold) by MCC than GM or MLSE. By MCC 10 of 12 genomes (83%) were replication competent and 7 produced high RI levels. RI and HBsAg kinetics correlated positively in MCC (R=0.696, p=0.017 overall; R=0.928, p=0.008), but not in GM (R=- 0.437, p=0.179 overall; R=-0.395, p=0.439) in genotype D isolates. In conclusion, HBV-DNA circularization prior transfection improves in vitro viral replication and replication competent HBsAg production, mimicking better the in vivo conditions.
    Journal of virological methods 02/2013; · 2.13 Impact Factor
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    ABSTRACT: Autoimmune Hepatitis (AIH) is an unresolving inflammation of the liver of unknown cause. Diagnosis requires the exclusion of other conditions and the presence of characteristic features such as specific autoantibodies. Presently, these autoantibodies have relatively low sensitivity and specificity and are identified by immunostaining of cells or tissues, therefore there is a diagnostic need for better and easy to assess markers. To identify new AIH-specific autoantigens, we developed a protein microarray comprising 1626 human recombinant proteins, selected in silico for being secreted or membrane-associated. We screened sera from AIH patients on this microarray and compared their reactivity with sera from healthy donors and patients with chronic viral hepatitis C. We identified six human proteins that are specifically recognized by AIH sera. Serum reactivity to combination of these six autoantigens allows identification of AIH patients with high sensitivity (77%+/-4) and specificity (91%+/-8). Of the six autoantigens, the IL4 Receptor (CD124), which is expressed on the surface of both lymphocytes and hepatocytes, showed the highest individual sensitivity and specificity for AIH. Remarkably, sera of patients inhibited STAT6 phosphorylation induced by IL4 binding to CD124, demonstrating these autoantibodies are functional and suggesting IL4 neutralisation has a pathogenetic role in AIH.
    Molecular &amp Cellular Proteomics 09/2012; · 7.25 Impact Factor

Publication Stats

5k Citations
1,206.33 Total Impact Points

Institutions

  • 2001–2014
    • Università di Pisa
      • Department of Clinical and Experimental Medicine
      Pisa, Tuscany, Italy
  • 2013
    • Unité Inserm U1077
      Caen, Lower Normandy, France
    • IMS Health
      Parsippany, New Jersey, United Kingdom
  • 2001–2013
    • Azienda Ospedaliero-Universitaria Pisana
      Pisa, Tuscany, Italy
  • 2011
    • Victorian Infectious Diseases Reference Laboratory
      Melbourne, Victoria, Australia
    • Hannover Medical School
      • Department of Gastroenterology, Hepatology and Endocrinology
      Hannover, Lower Saxony, Germany
    • Erasmus MC
      • Department of Gastroenterology and Hepatology
      Rotterdam, South Holland, Netherlands
  • 2006–2007
    • Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico
      Milano, Lombardy, Italy
    • Santa Chiara Hospital
      Trient, Trentino-Alto Adige, Italy
  • 1989–2005
    • Università degli Studi di Torino
      • Dipartimento di Scienze Mediche
      Torino, Piedmont, Italy
  • 1988–2005
    • Ospedale San Giovanni Battista, ACISMOM
      Torino, Piedmont, Italy
  • 2003
    • Ain Shams University
      • Department of Pediatrics
      Cairo, Muhafazat al Qahirah, Egypt
  • 2000
    • Second University of Naples
      • Faculty of Medicine and Surgery
      Caserta, Campania, Italy
  • 1998
    • Ospedale Amedeo di Savoia
      Torino, Piedmont, Italy
  • 1997
    • Università degli Studi di Bari Aldo Moro
      Bari, Apulia, Italy
  • 1993–1996
    • Azienda Ospedaliera Bolognini Seriate
      Seriate, Lombardy, Italy
  • 1991–1993
    • Max Planck Institute of Biochemistry
      München, Bavaria, Germany
  • 1988–1993
    • University of Bologna
      • Department of Experimental, Diagnostic and Specialty Medicine DIMES
      Bolonia, Emilia-Romagna, Italy