F. Gea

Effectiveness, safety and clinical outcomes of direct-acting antiviral therapy in HCV genotype 1 infection: results from a Spanish real world cohort.

BACKGROUND & AIMS Clinical trials evaluating second-generation direct-acting antiviral agents (DAAs) have shown excellent rates of sustained virologic response (SVR) and good safety profiles in patients with chronic hepatitis C virus (HCV) genotype 1 infection. We aimed to investigate the effectiveness and safety of two oral DAA combination regimens, ombitasvir/paritaprevir/ritonavir plus dasabuvir (OMV/PTV/r+DSV) and ledipasvir/sofosbuvir (LDV/SOF), in a real-world clinical practice. METHODS Data from HCV genotype 1 patients treated with either OMV/PTV/r+DSV±ribavirin (RBV) (n=1567) or LDV/SOF±RBV (n=1758) in 35 centers across Spain between April 1, 2015 and February 28, 2016 were recorded in a large national database. Demographic, clinical and virological data were analyzed. Details of serious adverse events (SAEs) were recorded. RESULTS The two cohorts were not matched with respect to baseline characteristics and could not be compared directly. The SVR12 rate was 96.8% with OMV/PTVr/DSV±RBV and 95.8% with LDV/SOF±RBV. No significant differences were observed in SVR according to HCV subgenotype (p=0.321 [OMV/PTV/r+DSV±RBV] and p=0.174 [LDV/SOF]) or degree of fibrosis (c0.548 [OMV/PTV/r/DSV±RBV] and p=0.085 [LDV/SOF]). Only baseline albumin level was significantly associated with failure to achieve SVR (p<0.05) on multivariate analysis. Rates of SAEs and SAE-associated treatment discontinuation were 5.4% and 1.7%, in the OMV/PTV/r+DSV subcohort and 5.5% and 1.5% in the LDV/SOF subcohort, respectively. Hepatocellular carcinoma (HCC) recurred in 30% of patients with a complete response to therapy for previous HCC. Incident HCC was reported in 0.93%. CONCLUSIONS In this large cohort of patients managed in the real-world setting in Spain, OMV/PTV/r+DSV and LDV/SOF achieved high rates of SVR12, comparable to those observed in randomized controlled trials, with similarly good safety profiles. LAY SUMMARY In clinical trials, second-generation direct-acting antiviral agents (DAAs) have been shown to cure over 90% of patients chronically infected with the genotype 1 hepatitis C virus and have been better tolerated than previous treatment regimens. However, patients enrolled in clinical trials do not reflect the real patient population encountered in routine practice. The current study, which includes almost 4,000 patients, demonstrates comparable rates of cure with two increasingly used DAA combinations as those observed in the clinical trial environment, confirming that clinical trial findings with DAAs translate into the real-world setting, where patient populations are more diverse and complex.

Daclatasvir plus simeprevir with or without ribavirin for the treatment of chronic hepatitis C virus genotype 1 infection

BACKGROUND & AIMS We evaluated the combination of daclatasvir (pan-genotypic NS5A inhibitor) and simeprevir (NS3/4A protease inhibitor), with or without ribavirin, in hepatitis C virus genotype 1-infected patients. METHODS This phase II, open-label study enrolled treatment-naive patients or prior null responders with genotype 1b (n=147) or 1a (n=21) infection. Genotype 1b-infected patients were randomized 1:1 to receive daclatasvir 30mg plus simeprevir 150mg once daily with or without ribavirin; those who completed the initial 12-week treatment were re-randomized 1:1 to stop treatment or continue treatment through to week 24. Genotype 1a-infected patients received daclatasvir plus simeprevir with ribavirin for 24weeks. The primary endpoint was the proportion of patients with sustained virologic response at posttreatment week 12 (SVR12). RESULTS For genotype 1b, 84.9% (45/53) and 74.5% (38/51) of treatment-naive patients and 69.6% (16/23) and 95.0% (19/20) of prior null responders to peginterferon and ribavirin achieved SVR12 with daclatasvir plus simeprevir alone and with ribavirin, respectively. Treatment duration did not have a well-defined impact on response. For genotype 1a, daclatasvir plus simeprevir with ribavirin provided a 66.7% (8/12) response rate in treatment-naive patients and was not effective in prior null responders. Data suggest that baseline resistance polymorphisms influenced SVR12 rates. Daclatasvir plus simeprevir was well tolerated with or without ribavirin with low incidences of serious adverse events and adverse events leading to discontinuation. CONCLUSIONS Daclatasvir plus simeprevir, with or without ribavirin, was effective with a 12- or 24-week duration in genotype 1b-infected patients and was well tolerated. ClinicalTrials.gov identifier: NCT01628692.

Effectiveness and safety of sofosbuvir-based regimens plus an NS5A inhibitor for patients with HCV genotype 3 infection and cirrhosis. Results of a multicenter real-life cohort

Patients with HCV genotype 3 (GT3) infection and cirrhosis are currently the most difficult to cure. We report our experience with sofosbuvir+daclatasvir (SOF+DCV) or sofosbuvir/ledipasvir (SOF/LDV), with or without ribavirin (RBV) in clinical practice in this population. This was a multicenter observational study including cirrhotic patients infected by HCV GT3, treated with sofosbuvir plus an NS5A inhibitor (May 2014‐October 2015). In total, 208 patients were included: 98 (47%) treatment‐experienced, 42 (20%) decompensated and 55 (27%) MELD score >10. In 131 (63%), treatment was SOF+DCV and in 77 (37%), SOF/LDV. Overall, 86% received RBV. RBV addition and extension to 24 weeks was higher in the SOF/LDV group (95% vs 80%, P=.002 and 83% vs 72%, P=.044, respectively). A higher percentage of decompensated patients were treated with DCV than LDV (25% vs 12%, P=.013). Overall, SVR12 was 93.8% (195/208): 94% with SOF+DCV and 93.5% with SOF/LDV. SVR12 was achieved in 90.5% of decompensated patients. Eleven treatment failures: 10 relapses and one breakthrough. RBV addition did not improve SVR (RR: 1.08; P=.919). The single factor associated with failure to achieve SVR was platelet count <75×10E9/mL (RR: 3.50, P=.019). In patients with MELD <10, type of NS5A inhibitor did not impact on SVR12 (94% vs 97%; adjusted RR: 0.49). Thirteen patients (6.3%) had serious adverse events, including three deaths (1.4%) and one therapy discontinuation (0.5%), higher in decompensated patients (16.7% vs 3.6%, P<.006). In patients with GT3 infection and cirrhosis, SVR12 rates were high with both SOF+DCV and SOF/LDV, with few serious adverse events.

Safety and efficacy of triple therapy with peginterferon, ribavirin and boceprevir within an early access programme in Spanish patients with hepatitis C genotype 1 with severe fibrosis: SVRw12 analysis

The addition of protease inhibitors (PIs) changed the hepatitis C virus (HCV) treatment standards and improved sustained viral response (SVR) rates in patients with genotype 1 HCV infection.

Real-World Effectiveness and Safety of Oral Combination Antiviral Therapy for Hepatitis C Virus Genotype 4 Infection

&NA; Patients with hepatitis C virus (HCV) genotype 4 infection are poorly represented in clinical trials of second‐generation direct‐acting antiviral agents (DAAs). More data are needed to help guide treatment decisions. We investigated the effectiveness and safety of DAAs in patients with genotype 4 infection in routine practice. In this cohort study, HCV genotype 4‐infected patients treated with ombitasvir/paritaprevir/ritonavir (OMV/PTVr) + ribavirin (RBV) (n=122) or ledipasvir/sofosbuvir (LDV/SOF) ± RBV (n=130) included in a national database were identified and prospectively followed up. Demographic, clinical and virologic data and serious adverse events (SAEs) were analyzed. Differences between treatment groups mean that data cannot be compared directly. Overall sustained virologic response at Week 12 post treatment (SVR12) was 96.2% with OMV/PTVr+RBV and 95.4% with LDV/SOF±RBV. In cirrhotic patients, SVR12 was 91.2% with OMV/PTVr+RBV and 93.2% with LDV/SOF±RBV. There was no significant difference in SVR12 according to degree of fibrosis in either treatment group (P = .243 and P = .244, respectively). On multivariate analysis, baseline albumin <3.5 g/dL (OMV/PTVr) and bilirubin >2 mg/dL (both cohorts) were significantly associated with failure to achieve SVR (P < .05). Rates of SAEs and SAE‐associated discontinuation were 5.7% and 2.5%, respectively, in the OMV/PTVr subcohort and 4.6% and 0.8%, respectively, in the LDV/SOF subcohort. DAA‐based regimens returned high rates of SVR12, comparable to limited data from clinical trials, in cirrhotic and non‐cirrhotic HCV genotype 4 patients managed in a realworld setting. Safety profiles of both regimens were good and comparable to those reported for other HCV genotypes.

Paritaprevir/r/Ombitasvir + Dasabuvir 8 weeks in HCV-genotype 1b with mild-moderate fibrosis: Results from a Real World Cohort

The interferon‐free regimen paritaprevir/ritonavir, ombitasvir + dasabuvir (PTV/r/OBV/DSV) has shown high efficacy in patients with hepatitis C virus (HCV) genotype 1b infection when administered for 8 or 12 weeks, but data regarding the 8‐week treatment are scarce. The aim of our study was to assess the efficacy and safety of the 8‐week administration of PTV/r/OBV/DSV in a real‐world cohort.

Effectiveness and safety of elbasvir/grazoprevir therapy in patients with chronic HCV infection: Results from the Spanish HEPA-C real-world cohort

In randomized controlled trials of patients with chronic HCV infection, elbasvir/grazoprevir (EBR/GZR) demonstrated high cure rates and a good safety profile. This study assessed the effectiveness and safety of EBR/GZR, with and without ribavirin, in a real‐world HCV patient cohort. HEPA‐C is a collaborative, monitored national registry of HCV patients directed by the Spanish Association for the Study of the Liver and the Networked Biomedical Research Centre for Hepatic and Digestive Diseases. Patients entered into HEPA‐C between December 2016 and May 2017, and treated with EBR/GZR with at least end‐of‐treatment response data, were included. Demographic, clinical and virologic data were analysed, and adverse events (AEs) recorded. A total of 804 patients were included in the study. The majority were male (57.9%), with a mean age of 60 (range, 19‐92) years. Genotype (GT) distribution was GT 1, 86.8% (1a, 14.3%; 1b, 72.5%); GT 4, 13.2% and 176 patients (21.9%) were cirrhotic. Overall, among 588 patients with available data, 570 (96.9%) achieved sustained virologic response at 12 weeks post‐treatment (SVR12). SVR12 rates by genotype were GT 1a, 97.7%; GT 1b, 98.6%; and GT 4, 98.1%. No significant differences in SVR12 according to fibrosis stage were observed. Eighty patients experienced an AE, resulting in treatment discontinuation in three. In this large cohort of patients with chronic HCV managed in a real‐world setting in Spain, EBR/GZR achieved high rates of SVR12, comparable to those observed in randomized controlled trials, with a similarly good safety profile.

Effectiveness of ribavirin use associated with direct-acting antivirals in the treatment of non-cirrhotic patients with genotype 1a or 4 HCV infection in real-world practice

effectiveness. Methods: Retrospective, multicentric national study that included patients treated according to clinical practice in Spain. Data were collected from the HEPA-C National Registry (AEEH-CIBERehd). The study evaluated data from patients with genotype 1 or 4 treated in 41 Spanish centers, from1April to 30October 2016. Theprimaryendpoint for effectiveness was sustained viral response at week 12 (SVR12). Results: A total of 3,412 patients were included in the study, 56.4% males, mean age of 58 years, most of the genotype 1b (68.8%) (genotype 1a:22%; genotype 4:7%). Patient distribution according to the degree of fibrosis: F4 (52%), F3 (18%), F2 (19%) and F0–1 (9%). 27.2% of patients received LDV/SOF, 27.4% LDV/SOF + RBV, 24.8% OBV/ PTV/rtv/DSV + RBV, 17.5% OBV/PTV/rtv/DSV and 2.6% OBV/PTV + RBV. 54.8% received RBV. Regarding treatment duration, 82.9% of patients received 12 weeks of treatment, 14.3% 24 weeks and 2.8% 8 weeks. 72.4% were treated according to the SmPC. The most frequent reason for lack of adherence to the SmPC was the addition of RBV (84% of prescriptions were non-concordant), followed by not adding RBV when it was recommended (6.9%), prolonged treatment duration (4.5%) and shortened treatment duration (2.5%). SVR12 in patients treated according to SmPC was 96.1%, while in patients with nonconcordant prescriptions was 96.7% (p = 0.44). In patients with shortened treatment duration, SVR12 was significantly lower than in the rest of patients (82.6% vs. 97%, p < 0.05). Conclusions: 72.4% of patients received treatment according to the SmPC. Themajority of deviations were due to RBV use. Therewere no statistically significant differences in SVR between patients treated according to the SmPC and those receiving non-concordant prescriptions. However, there was an impact in SVR for patients who were treated for less time than recommended.

P1158 EFFICACY AND SAFETY OF BOCEPREVIR-BASED THERAPY IN HCVG1 TREATMENT-EXPERIENCED PATIENTS WITH ADVANCED FIBROSIS/CIRRHOSIS: THE ITALIAN AND SPANISH NPP EARLY ACCESS PROGRAM

P1158 EFFICACY AND SAFETY OF BOCEPREVIR-BASED THERAPY IN HCVG1 TREATMENT-EXPERIENCED PATIENTS WITH ADVANCED FIBROSIS/CIRRHOSIS: THE ITALIAN AND SPANISH NPP EARLY ACCESS PROGRAM S. Bruno, S. Bollani, J.M. Pascasio, A.L. Zignego, V. Di Marco, C. Magni, M. Rizzetto, A. Ciancio, A. Alberti, S. Piovesan, A. Mangia, J. De la Revilla, J.R. Larrubia, F. Gea, S. Babudieri, R. Perez-Alvarez, C. Colletta, R. Barcena, X. Forns, M. Romero-Gomez, M. Koch, M. Massari, M. Caremani, J. Crespo, J.M. Navarro, J. Arenas, M.B. Delgado, M. Pirisi, M. Zuin, A. Licata, F. Mazzotta, A. Colombo, M. Russello, I. Fermandez, T. Santantonio, C.M. Fernandez-Rodriguez, F. Farina, B. Ruiz Antoran, P. Maisonneuve, A. Craxì, J.L. Calleja, Italian and Spanish (IAS)-BOC Study Group. AO Fatebenefratelli e Oftalmico, Milano, Italy; Hospital Universitario Virgen del Rocio, Sevilla, Spain; Università degli Studi di Firenze, Firenze, Università degli Studi di Palermo, Palermo, AO L Sacco, Milano, Università di Torino, Torino, Università di Padova, Padova, IRCCS Casa del Sollievo e della Sofferenza, San Giovanni Rotondo, Italy; Hospital Universitario Puerta de Hierro, Madrid, Hospital Universitario de Guadalajara, Guadalajara, Hospital U. La Paz, Madrid, Spain; Università degli Studi di Sassari, Sassari, Italy; Hospital Universitario Central de Asturias, Oviedo, Spain; COQ Ospedale Madonna del Popolo, Omegna, Italy; Hospital Universitario Ramon y Cajal, Madrid, Hospital Clinic, Barcelona, Hospital Universitario de Valme, Sevilla, Spain; AO S Filippo Neri, Roma, IRCCS – ASMN Reggio Emilia, Reggio Emilia, AO di Arezzo, Arezzo, Italy; Hospital Universitario Marques de Valdecilla., Santander, Hospital Costa del Sol, Marbella, Hospital Donostia, Donostia, Hospital Universitario A Coruña, La Coruna, Spain; Università degli Studi di Novara, Novara, Università degli Studi di Milano, Milano, Azienda Ospedaliera di Siena, Siena, AO S Anna, Como, ARNAS Garibaldi, Catania, Italy; Hospital Universitario 12 de Octubre, Madrid, Spain; Università di Foggia, Foggia, Italy; Hospital U. Fundacion Alcorcon, Alcorcon, Spain; Ospedale Cà Foncello, Treviso, Epidemiology and Biostatistics, Istituto Europeo di Oncologia, Milano, Italy E-mail: savino.bruno@fbf.milano.it