Background: Sustained virological response (SVR12) rates at 12 weeks after treatment for HCV-infected patients with decompensated cirrhosis are used when referring to those with moderate functional impairment, while few data are available for those with more severe impairment. The use of the cirrhosis staging system proposed by D'Amico might provide new insights on timing for antiviral therapy.Methods: We investigated efficacy (SVR12), safety, and post-treatment variations in clinical and laboratory parameters in 2612 patients with advanced fibrosis (n = 575) or cirrhosis (n = 2037). Cirrhosis was in the compensated phase (without/with varices) or had previously been in the decompensated stage. Different direct-acting antiviral (DAA) regimens were administered in accordance with scientific guidelines.Results: The SVR12 rate was 97.6% in patients with advanced fibrosis. For patients with cirrhosis, the rate was 96.5% in stage 1, 95.1% in stage 2, 100% in stage 3, 95.7% in stage 4, and 93.6% in stage 5. These rates were independent of gender, age, HCV genotype, and treatment schedule. Positive changes in biochemical parameters and CPT classes following therapy were evident in compensated and previously decompensated patients.Conclusion: Our findings support the use of DAAs in patients with advanced cirrhosis (stages 3-5) who are at greatest risk and have the most to gain from therapy. (C) 2017 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

This retrospective multicentre study aims to evaluate the clinical and epidemiological features of HCV infection in a cohort of immigrants in Italy. Tests were carried out on 194 HCV positive subjects, who represented 5.7% of the participants at baseline screening: the virological (viral load, genotype) and biochemical appearance of their infection was determined, and the disease was staged by histological examination in the patients who had indicated their willingness. Standard therapy (peg-interferon + ribavirin) was implemented in patients who agreed to undergo treatment. The majority of immigrants were of East-European origin (48.4%), females were globally slightly predominant and the average age was 41.4 years. Of the 194 patients, 119 (63.1%) proved to be viraemic: genotype 1 was the most frequent, followed by genotype 4, the latter mainly in African patients. The histological staging of liver disease conducted in 25 patients showed mild hepatitis in 13 subjects, moderate/severe hepatitis in eight subjects and cirrhosis in four. Although 45 out of 119 patients (37.8%) with determinable HCV RNA agreed to undergo treatment, 11 of them independently stopped taking medication before the course of therapy was completed, without any significant side effects. At the sixth month of follow-up, the overall sustained virological response (SVR) was shown by 22/45 patients (48.8%). In our study, migrant populations had higher rates of HCV-related chronic hepatitis than the indigenous population; in some cases the infections were contracted in the country of origin, but in others the infection took place in Italy. The most commonly represented genotype, besides 1, was 4, especially among Africans. The therapeutic management of immigrants proved to be very difficult, mostly but not exclusively because of social factors.

Background & AimsDifferent prevalence of favourable IL28BCC genotype have been reported in studies performed in different countries around the world. Data on distribution of IL28B genotypes in healthy Italian subjects are lacking.MethodsStudies on prospectively collected untreated chronic HCV-infected Italian patients led to conflicting results. To investigate the prevalence of IL28B genotypes in untreated HCV-infected patients and in subjects able to clear HCV, and to compare them to the prevalence registered in healthy Italian controls. To evaluate IL28B prevalence across different HCV genotypes.ResultsIL28BCC was observed in 30.9% of chronic HCV patients, in 71.0% of subjects able to clear HCV infection and in 41.6% of the Italian controls. The frequency of IL28BCC was higher in HCV genotype 2 and 3 than in 1 (38.3 vs. 28.2) (P=0.02). Levels of ALT higher in IL28BCC than in non-CC were observed regardless of HCV genotypes (P=0.0014).ConclusionsIL28BCC frequencies progressively decline from subjects with spontaneous HCV clearance to normal non-infected subjects and to chronically infected. This study suggests that patients with IL28BCC, if genotype 1, are able to clear HCV more often than if genotype 2 and 3 infected, and that CC genotype is associated with higher grade of necro-inflammation.

Background Triple therapy including Telaprevir or Boceprevir still represents in many European countries the standard of care for patients with Hepatitis C Virus genotype 1 infection. The number of patients who received this treatment resulted generally lower than expected. We investigated, among naïve patients, number and characteristics of treatment candidates who were started on triple or dual therapy in comparison to those who were deferred. Patients and Methods 621 naïve treatment candidates were prospectively evaluated at each center. Factors associated with decision to defer or treat with dual or triple therapy were investigated by univariate and multivariate analyses. Rates of Sustained Virological Response and safety profile were analysed. Results Of candidates to treatment, 33% did not received it. It was mostly due to high risk of Interferon-induced decompensation. Of 397 patients who were started on treatment, 266 (67%) received triple, 131 dual. Among patient receiving treatment, unfavorable IL28B, severe liver damage and higher albumin were independently associated with the physician decision to administer triple therapy. Sustained Virological Response after dual therapy was 66.4%, after triple 73.7% (p = 0.14). 142 patients received Telaprevir. The choice of Telaprevir-based therapy was associated with higher Body Mass Index and advanced liver disease. Sustained Virological Response rates were 71.1% after Telaprevir and 76.6% after Boceprevir. Conclusions Individualizing treatment with available regimens allows to maximize Sustained Virological Response and to reduce the number of patients who remain untreated. High proportion of patients with severe liver damage urgently need Interferon free treatment.

Tx shortened: good efficacy Patients with RVR 55/549 (10.0) 23/554 (4.2) 32/554 (5.8) 34/971 (3.5) Patients with cEVR 4/314 (1.3) 7/1166 (0.6) 0/83 (0.0) 2/189 (1.1) Patients with pEVR 0/74 (0.0) 1/748 (0.1) 0/11 (0.0) 0/48 (0.0) Patients without RVR/EVR 1/120 (0.8) 1/588 (0.2) 0/14 (0.0) 0/29 (0.0) Tx shortened: poor efficacy Patients with RVR 7/549 (1.3) 6/554 (1.1) 0/554 (0.0) 1/971 (0.1) Patients with cEVR 7/314 (2.2) 28/1166 (2.4) 0/83 (0.0) 0/189 (0.0) Patients with pEVR 9/74 (12.2) 123/748 (16.4) 1/11 (9.1) 0/48 (0.0) Patients without RVR/EVR 50/120 (41.7) 333/588 (56.6) 4/14 (28.6) 6/29 (20.7) Body weight 180mg/week 1 ( 1200mg/day 8 (0.4) 186 (9.4) 3 (0.3) 16 (1.7)

POSTERSclinical variables, only maternal history of intravenous drug use was related with lower SVR (p = 0.06).In children with HCV g3, SVR was associated with rs8099917 TT (p = 0.016).Conclusions: In children with chronic hepatitis C, polymorphisms in the IL28B gene region were the only predictors of response to peg-IFN/RBV.Increased frequency of parenteral infection, higher viral load, lower ALT and better treatment response (OR: 5) were associated with CC rs12979860 .

Background & Aims The benefit of individualizing treatment for patients with genotype 3 HCV infection on the basis of viral clearance at week 4 (wk4-R) has not been firmly establishedMethods Four hundred and fourteen patients received Peginterferon alpha-2b plus 1000-1200 mg of ribavirin daily according with body weight > or <75 kg Patients were randomized to standard 24 weeks (Std24) or to a 12 or 36 weeks variable treatment duration (Var12/36) In the variable treatment arm patients with or without wk4-R were allocated to either 12 or 36 weeks durationResults At treatment week 4 HCV RNA was undetectable in 262 patients (63 3%) 136 in the Std24 and 126 in the Van 2/36 group (p = 0 41) In patients with wk4-R end-of-treatment (EOT) responses were 80 4% (Cl 85 4-95 3) and 97 6% (Cl 949-99 9) in the two arms respectively (p = 0 019) In patients without wk4-R, corresponding rates were 61 9% (50 6-73 2) and 75 3% (CI 65 9-846) (p = 0 08) SVR was attained in 302 patients 71 4% (Cl 65 3-77 6) in the St24 group and 743% (CI 58 4-80 3) in the variable 12/36 arm Among patients with wk4-R SVR was 81 6% (Cl 75 1-88 1) and 82 5% (75 9-89 1) respectively In patients without wk4-R SVR amounted to 52 1% (Cl 40 4-63 7) and 61 7 (CI 51 1-72 3) in the two arms (p = 0 25)Conclusions HCV genotype 3 patients with week4-R may be treated safely with 12 weeks of therapy provided that sufficiently high doses of ribavirin are administered For patients still viremic at treatment week 4 SVR rates were numerically higher after 36 weeks of treatment than after the currently recommended 24 weeks (C) 2010 European Association for the Study of the Liver Published by Elsevier B V All rights reserved

Aliment Pharmacol Ther 31, 1346–1353SummaryBackground The optimal dose of ribavirin to be used in combination with Peg‐IFN in patients with HCV genotypes 2 and 3 undergoing short treatment has not been established.Aim To explore the relationship between starting ribavirin doses, expressed as mg/kg body weight and both rapid viral response at treatment week 4 (RVR) and sustained virological response (SVR) in patients treated for 12–14 weeks with peg‐interferon α‐2b and ribavirin.Methods A post hoc analysis of data collected from two multicenter clinical trials was performed. Multiple regression analyses were employed to identify independent baseline and on‐treatment predictors of RVR and SVR. For each dose of ribavirin, the empirical estimated probability of response was computed and the continuous exposure index was dichotomized by using a recursive partitioning and amalgamation method.Results A nonlinear relationship was ascertained between ribavirin dose and RVR, but not SVR. A dose of 15.2 mg/kg was selected as the best splitting value for discriminating RVR vs. non‐RVR. Regression analysis identified low baseline viraemia, genotype 2 and high ribavirin dose as independent prognostic factors for RVR. The likelihood of an SVR was not correlated with baseline ribavirin dose, but was independently predicted by adherence to the full dose throughout treatment and normal platelet counts.Conclusions Starting high ribavirin doses appears capable of increasing the rate of RVR in patients with HCV genotypes 2 and 3 undergoing short treatment. Maintenance of the full planned dose throughout treatment is essential for achieving optimal SVR rates.

A. Mangia1, O. Dalgard2, N. Minerva3, H. Verbaan4, G. Scotto5, D. Bacca6, E. Agostinacchio7, K. Bjoro8, V. Carretta9, V. Piazzolla1, R. Cozzolongo10, M. Romano11, L. Mottola1, A. Andriulli12. 1Liver Unit, IRCCS ‘Casa Sollievo della Sofferenza’, San Giovanni Rotondo, Italy; 2Medical Department, Aker University Hospital, Oslo, Norway; 3Medical Department, Hospital, Canosa, Italy; 4Department of Surgery, Division of Gastroenterology and Hepatology, University Hospital, Malmoe, Sweden; 5Infectious Diseases Department, University Hospital, Foggia, 6Medical Department, Hospital, Casarano, 7Medical Department, ‘Santa Rita’ Hospital, Bari, Italy; 8Medical Department, RiksHospital, Oslo, Norway; 9Medical Department, Hospital, Venosa, 10Gastroenterology Department, IRCCS ‘S. De Bellis’, Castellana Grotte, 11Medical Department, ‘S. Pertini’ Hospital, Roma, 12Gastroenterology Department, IRCCS ‘Casa Sollievo della Sofferenza’, San Giovanni Rotondo, Italy E-mail: a.mangia@tin.it

In hepatitis C virus (HCV) genotypes 2 and 3 patients, the high rate of relapse after 12 to 16 weeks of antiviral therapy is the main concern for shortening treatment duration. This study was undertaken to delineate predictors of relapse after short treatment in patients with undetectable HCV RNA at treatment week 4 (RVR), and to report in RVR patients with relapse the sustained virological response (SVR) after a second 24-week course of therapy. RVR patients received pegylated interferon (Peg-IFN) alfa-2b (1.5 mu g/kg) and ribavirin (1000-1200 mg/day) for 12 weeks; those who relapsed were retreated with the same drug doses but for the wended standard duration of 24 weeks. Logistic regression analysis was applied to delineate predictors of relapse by using age, sex, route of transmission, body mass index (BMI), serum alanine aminotransferase (AI:D, HCV genotypes, serum HCV RNA levels, and platelet counts as covariates. Of 718 patients with genotypes 2 and 3 who were started on therapy, 496 (69.1%) had undetectable HCV RNA at week 4. Of them, 409 patients (82.5%, CI 79.1-85.8) attained SVR, and 67 (14.1%, CI 10.4-16.5) relapsed. At regression analysis, only platelet count less than 140,000 mm(3) [odds ratio, 2.51; confidence interval (0), 1.49-4.20] and BMI 30 or higher (odds ratio, 1.7; CI, 1.03-2.70) were independently associated with relapse. Forty-three of 67 patients with relapse agreed to be re-treated, and an SVR was achieved in 30 (70.0%) of them. Conclusion: We recommend 12 weeks course of therapy for patients with undetectable HCV RNA at treatment week 4, providing they present with no advanced fibrosis and low BMI. (HEPATOLOGY 2009,49:358-363.)

It was hypothesized that in hepatitis C virus (HCV) genotype 1 patients, variable treatment duration individualized by first undetectable HCV RNA is as effective as standard 48-week treatment. Patients (n = 696) received peginterferon alfa-2a, 180 mg/week, or peginterferon alfa-2b, 1.5 mg/kg/week, plus ribavirin, 1000-1200 mg/day, for 48 weeks (standard, n = 237) or for 24, 48, or 72 weeks if HCV-RNA–negative at weeks 4, 8, or 12, respectively (variable, n = 459). Sustained virologic response (SVR) was achieved in 45.1% [95% confidence interval (CI) 38.8-51.4] of the patients in the standard group and in 48.8% (CI 44.2-53.3) of the patients in the variable group (P = 0.37). The percentages of patients who first achieved undetectable HCV RNA at weeks 4, 8, or 12 were 26.7%, 27.8%, and 11.3%, respectively. In the standard treatment group, 87.1%, 70.3%, and 38.1% of patients who first achieved undetectable HCV RNA at 4, 8, or 12 weeks attained SVRs, respectively. In the variable group, corresponding SVR rates were 77.2%, 71.9%, and 63.5%. Low viremia levels and young age were independent predictors of response at week 4 [rapid virologic response (RVR)]. RVR patients with baseline viremia ≥400,000 IU/mL achieved higher SVR rates when treated for 48 weeks rather than 24 weeks (86.8% versus 73.1%, P = 0.14). The only predictive factor of SVR in RVR patients was advanced fibrosis. Conclusion: Variable treatment duration ensures SVR rates similar to those of standard treatment duration, sparing unnecessary side effects and costs. (HEPATOLOGY 2007.)

Summary. We determined whether triple therapy comprising amantadine (AMA), ribavirin (RBV) and either peginterferon (PEG‐IFN) α‐2a or conventional IFN α‐2a would improve sustained virological response (SVR) rates over dual therapy with IFN α‐2a and RBV in patients with chronic HCV infection. A total of 362 treatment‐naïve patients were randomized to 48 weeks of treatment with: PEG‐IFN α‐2a 180 μg/week (group A) or IFN α‐2a 3 MU tiw (groups B and C). All patients received RBV 1000 or 1200 mg/day and those in groups A and B received AMA 200 mg/day. SVR was defined as an undetectable HCV RNA after 24 weeks of untreated follow‐up. At the end of therapy, 74.4% (95% CI 0.66–0.82) of patients in group A were HCV RNA‐negative compared with 42.5% (95% CI 0.33–0.50) of those in group B (P = 0.0001) and 48.8% (95% CI 0.40–0.56) of those in group C. SVR was achieved in a significantly greater proportion of patients in group A compared with groups B and C: 65.3% (95% CI 0.53–0.56), 33.3% (95% CI 0.25–0.41) and 44.6% (95% CI 0.36–0.53; P = 0.0001) respectively. In patients with genotype 1, SVR rates were 55.2, 22.8 and 28.8% with the three regimens respectively. Factors independently associated with SVR were HCV genotype 2 or 3, therapy with PEG‐IFN, female gender and age. In treatment‐naïve patients with chronic hepatitis C, triple therapy with PEG‐IFN α‐2a, RBV and AMA produces higher SVR than dual or triple therapy with conventional IFN α‐2a.

BACKGROUND:We hypothesized that in patients with hepatitis C virus (HCV) genotype 2 or 3 in whom HCV RNA is not detectable after 4 weeks of therapy, 12 weeks of treatment is as effective as 24 weeks.METHODS:A total of 283 patients were randomly assigned to a standard 24-week regimen of peginterferon alfa-2b at a dose of 1.0 mug per kilogram weekly plus ribavirin at a dose of 1000 mg or 1200 mg daily, on the basis of body weight. Of these, 70 patients were assigned to the 24-week regimen (standard-duration group) and 213 patients to a variable regimen (variable-duration group) of 12 or 24 weeks, depending on whether tests for HCV RNA were negative or positive at week 4. The primary end point was HCV that was not detectable by polymerase-chain-reaction (PCR) assay 24 weeks after the completion of therapy.RESULTS:In the standard-duration group, 45 (64 percent) patients had HCV that was not detectable by PCR assay at week 4, as compared with 133 (62 percent) in the variable-duration group (difference [the rate in the standard-duration group minus that in the variable-duration group], 2 percent; 95 percent confidence interval, -11 to 15 percent). Fifty-three patients (76 percent) in the standard-duration group and 164 patients (77 percent) in the variable-duration group had a sustained virologic response (difference, -1 percent; 95 percent confidence interval, -13 to 10 percent). Fewer patients in the variable-duration group receiving the 12-week regimen had adverse events and withdrew than in the group receiving the 24-week regimen (P=0.045). The rate of relapse (defined as HCV not detectable at the end of treatment but detectable at the end of follow-up) was 3.6 percent in the standard-duration group and 8.9 percent in the variable-duration group (P=0.16). Overall, the rate of sustained virologic response was 80 percent among patients with HCV genotype 2 and 66 percent among those with genotype 3 (P<0.001).CONCLUSIONS:A shorter course of therapy over 12 weeks with peginterferon alfa-2b and ribavirin is as effective as a 24-week course for patients with HCV genotype 2 or 3 who have a response to treatment at 4 weeks.

A. Mangia1, N. Minerva3, G.L. Ricci10, M. Romano8, V. Carretta4, M. Persico9, D. Bacca6, F. Spirito1, F. Vinelli2, M. Annese5, A. Giangaspero7, G. Scotto2, A. Andriulli1. 1IRCCS CSS San Giovanni Rotondo (FG), San Giovanni Rotondo, Italy; 2Ospedali Riuniti Foggia, Universita Di Foggia, Foggia, Italy; 3Medicina Ospedali Di Canosa, Canosa, Italy; 4Medicina Ospedali Di Venosa, Venosa, Italy; 5Medicina Ospedali Di Policoro, Policoro, Italy; 6Medicina Ospedali Di Casarano, Casarano, Italy; 7Medicina Ospedali Di Bari, Bari, Italy; 8Ospedale ’S. Pertini’, Roma, Italy; 9Universita Di Napoli, Napoli, Italy; 10Universita ‘La Sapienza’, Roma, Italy