366 Sofosbuvir and Simeprevir Effectively Treat Hepatitis C Virus Genotype 1 Infection After Liver Transplantation in a Multi-Center Experience

AASLD Abstracts

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An Integrated Safety, Efficacy, and Virology Analysis of >500 Patients With Compensated Cirrhosis Treated With Ledipasvir/Sofosbuvir With or Without Ribavirin K. Rajender Reddy, Christoph Sarrazin, Mark Sulkowski, Masao Omata, Stefan Zeuzem, Jordan J. Feld, Eric Lawitz, Robert H. Hyland, Xiao Ding, Jenny C. Yang, Hadas DvorySobol, Steven J. Knox, Phil Pang, G. M. Subramanian, John G. McHutchison, Alessandra Mangia, Edward Gane, Masashi Mizokami, Nezam H. Afdhal, Marc Bourliere

Sofosbuvir and Simeprevir Effectively Treat Hepatitis C Virus Genotype 1 Infection After Liver Transplantation in a Multi-Center Experience Whitney E. Jackson, Tehilla Apfel, Naim Alkhouri, Binu John, Xaralambos B. Zervos, Nizar N. Zein, Ibrahim A. Hanouneh Background: The interferon-free antiviral regimen, Sofosbuvir (SOF) and Simeprevir (SMV), with or without ribavirin (RBV) has been reported to achieve high sustained virologic response (SVR) rates with few adverse effects when treating patients with hepatitis C genotype 1 (HCV GT1) infection. However, there is scarcity of safety and efficacy data in this regimen after liver transplantation (LT). Aim and Methods: We aim to report the safety, tolerability and efficacy of SOF+SMV to treat LT recipients with recurrent HCV GT1 in a multi-center cohort study. Results: 81 patients with HCV GT1 met criteria to be considered for treatment. 67 patients have received SOF+SMV following LT to date: 69% male, 57% subtype 1a, 82% HCV with RNA >800,000 IU/mL, 22% advanced hepatic fibrosis (stage 3-4), 1% decompensated cirrhosis, 6% cholestatic recurrence, and 6% kidney transplant recipients. 58% previously failed or did not tolerate interferon-based treatments. Median time from LT to treatment was 48 months (range 5 - 300 months). All patients had estimated GFR >30 mL/min. Tacrolimus was primary immunosuppression in 84% of patients and minimal immunosuppression dose adjustments were required during treatment. Patients have been followed for a median of 16 weeks (range 4 - 36 weeks). Of the 54 patients who completed therapy, 48 patients (89%) achieved undetectable HCV RNA at the end of treatment; and 29 patients (83%) achieved undetectable HCV RNA at week 4 post-treatment (table). Two patients never achieved undetectable HCV RNA throughout the course of treatment - one with decompensated cirrhosis and previously failed telaprevir-based therapy, and the second with fibrosing cholestatic hepatitis. Four patients discontinued treatment prematurely due to significant adverse events: acute kidney injury, hepatic artery thrombosis, sepsis and gastrointestinal bleeding. Two patients developed biopsy-proven acute cellular rejection during the course of therapy. Conclusions: SOF+SMV combination therapy is well-tolerated and results in high virological response rates in recurrent HCV GT1 infection after liver transplantation. Complete SVR12 data will be reported at the meeting. Virological Response Rates

Background: Patients with HCV and cirrhosis represent a population in most need of treatment; however, with interferon and ribavirin (RBV)-based therapy, such patients had been more difficult to treat and cure and are often underrepresented in clinical trials. Ledipasvir/sofosbuvir (LDV/SOF) phase 2 and 3 studies included >500 patients with compensated cirrhosis. We analyzed the overall efficacy and safety, and further evaluated the impact of baseline HCV NS5A resistance associated variants (RAVs) on sustained virologic response in a population of HCV infected patients with cirrhosis. Methods: Treatment-naïve or treatment-experienced patients with chronic HCV genotype 1 (GT1) infection and compensated cirrhosis who had participated in phase 2 or 3 studies and had received LDV/SOF +/RBV for 12 or 24 weeks were included in this pooled analysis. Results: Five hundred thirteen subjects with compensated cirrhosis were identified. The majority (91%) of patients had cirrhosis diagnosed by biopsy or fibroscan (>12.5 kPa). Of the 292 patients on whom a fibroscan was performed, 137/292 (47%) had a value >20 kPa. The majority were treatmentexperienced (353, 69%), male (342, 67%), GT1a (306, 60%), and IL28B non-CC (405, 79%). Two hundred forty patients (68% of the treatment- experienced patients) had previously received a protease inhibitor-containing regimen. One hundred thirteen (22%) initiated therapy with a baseline platelet count of <100,000 cells/μL. Sixty-three (12%) initiated therapy with a baseline albumin <3.5 g/dL. The patients received one of four regimens: 12 weeks of LDV/SOF (118, 23%), or LDV/SOF+RBV (204, 40%), or 24 weeks of LDV/SOF (133, 26%) or LDV/SOF+RBV (58, 11%). Overall, 96% (493/513) achieved SVR12. Among treatment-experienced patients, 12 weeks of LDV/SOF resulted in a 90% SVR rate, while adding RBV or extending treatment duration increased this rate to ≥96%. With a 1% cutoff, 94/511 (18%) cirrhotic patients were identified as having BL NS5A RAVs. SVR results by regimen and patient group and the effect of baseline NS5A RAVs on SVR will be presented. Safety in patients with cirrhosis was similar to that previously reported in patients without cirrhosis. Adverse events including anemia were more frequent in patients who received RBV. No other trends in adverse events or serious adverse events were noted. Conclusions: Based on these results, LDV/SOF is effective, safe, and well-tolerated for the treatment of HCV GT1 infection in patients with compensated cirrhosis. LDV/SOF regimens for 12 and 24 weeks were efficacious in treatment-naïve cirrhotic patients with baseline HCV NS5A RAVs. High SVR rates were also achieved among treatment-experienced patients with cirrhosis when RBV was added to 12 weeks of LDV/SOF or when treatment was extended to 24 weeks.

367 Effectiveness of Sofosbuvir-Based Hepatitis C (HCV) Antiviral Regimens in a Large U.S. Veteran Cohort Lisa I. Backus, Pamela S. Belperio, Troy A. Shahoumian, Larry A. Mole

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Aim: Assess the effectiveness of sofosbuvir (SOF)-based regimens in genotype (GT) 1 and 2 hepatitis C virus (HCV)-infected veterans treated in routine medical practice. Methods: This observational, intent-to-treat cohort analysis used the Department of Veterans Affairs' Clinical Case Registry to identify all GT1 and GT2 HCV-infected veterans initiating SOFbased regimens with recommended treatment duration of 12 weeks by 9 May 2014 and ending therapy by 31 July 2014. Patients were excluded for HIV, liver transplantation, undetectable baseline HCV RNA, death, or change in regimens. SVR was determined at least 12 weeks after the end of treatment with data available through 16 November 2014. SVR rates were compared with Pearson's Chi-square with Yates' correction. Multivariate models included age, sex, race/ethnicity, treatment history, cirrhosis (defined by FIB-4>3.25), 4week on-treatment HCV RNA and, for GT1, treatment regimen. Results: In total, 760 veterans with GT1 (n=572) and GT2 (n=188) initiated SOF-based regimens of 12 weeks recommended duration and comprise the cohort. Among GT1 patients the mean age was 60.3 years, 95% were male, 28% were black, 41% were treatment experienced, and 58% had a FIB-4>3.25; 61% received SOF+peginterferon(PEG)+ribavirin(RBV), 29% received SOF+simeprevir(SIM) and 10% received SOF+SIM+RBV. Among GT2 patients the mean age was 61.0 years, 98% were male, 9% were black, 23% were treatment experienced and 46% had a FIB-4>3.25; 96% received SOF+RBV and 4% received SOF+PEG+RBV. At the time of this abstract, SVR data were available for 78% of GT1 patients (n=444) and 77% of GT2 patients (n=140). In GT1 and GT2 patients there were no differences in SVR rates by the baseline characteristics of age, sex, race/ethnicity, or HCV RNA when analyzed with regimens combined or separate; additionally, in GT1 patients no difference in SVR rates were observed for those with GT1a or b, or prior protease inhibitor experience. SVR rates by GT and regimen are shown in the table. In multivariate models for GT1, patients were less likely to achieve SVR with prior treatment experience (OR 0.58, 95%CI 0.37-0.89, p= 0.014), FIB-4>3.25 (OR 0.46, 95%CI 0.29-0.74, p=0.001), SOF+PEG+RBV compared to SOF+SIM±RBV (OR 0.42, 95%CI 0.26-0.67, p<0.001), or a 4 week on-treatment HCV RNA≥43 compared to undetectable (OR 0.29, 95%CI 0.12-0.68, p=0.004). For GT2, patients were less likely to achieve SVR with a FIB-4>3.25 (OR 0.23, 95%CI 0.08-0.21, p=0.004) or a 4 week on-treatment HCV RNA≥43 (OR 0.14, 95%CI 0.03-0.57, p=0.006). Conclusions: In this large real-world cohort, GT1 and GT2 HCV-infected patients with cirrhosis or HCV RNA≥43 at week 4 of treatment were significantly less likely to achieve SVR. For GT1, a SOF+SIM±RBV regimen was associated with a higher likelihood of SVR. Complete SVR data for the entire cohort will be reported. SVR Rates For GT1 and GT2 HCV-Infected Veterans by GT and Regimen

Ledipasvir/Sofosbuvir With Ribavirin Is Safe and Efficacious in Decompensated and Post Liver Transplantation Patients With HCV Infection: Preliminary Results of the Prospective SOLAR 2 Trial Edward Gane, Michael P. Manns, Xavier Forns, Didier Samuel, Michael R. Charlton, Jill Denning, Sarah Arterburn, Theo S. Brandt-Sarif, Phil Pang, John G. McHutchison, David Mutimer Background: Treatment options for patients with chronic hepatitis C (HCV) who have decompensated liver disease or who have undergone liver transplantation are limited. We evaluated the safety and efficacy of ledipasvir/sofosbuvir (LDV/SOF) fixed dose combination with ribavirin (RBV) in such patients in Europe, Canada, Australia and New Zealand. Methods: We enrolled HCV genotype 1 or 4 treatment-naïve or treatment-experienced patients with decompensated liver disease or post-liver transplantation with recurrent HCV. Patients were randomized to receive 12 or 24 weeks of treatment stratified into 6 groups: patients without transplant and either 1) Child-Pugh-Turcotte (CPT) B cirrhosis, or 2) CPT C cirrhosis; or patients with recurrent HCV after liver transplantation and were either 3) without cirrhosis (F0 to F3), 4) CPT A cirrhosis, 5) CPT B cirrhosis, or 6) CPT C cirrhosis. Results: 327 patients were randomized. Most were male (76%), white (94%), and IL28B non-CC (80%). 159 (49%) had HCV genotype (GT) 1a, 131 (40%) GT 1b, and 37 (11%) GT 4. Mean baseline HCV RNA was 6.2 log10 IU/mL. 41 of 227 cirrhotic patients (18%) had a MELD score >15. 222 (68%) patients have completed study treatment and 171 (52%) have reached post treatment week 4, so far. Nine patients in the advanced liver disease group and 3 patients in the post-transplantation group have discontinued study treatment. 62 patients (19%) experienced serious adverse events (SAEs). Eight SAEs in 8 patients were considered related to study treatment; anemia (4), fall, diarrhea, malaise, and hyperbilirubemia. The most common adverse events were fatigue, anemia, nausea and headache. SVR4 by patient population are presented in table below. Conclusions: Administration of LDV/ SOF+RBV in patients with decompensated cirrhosis and recurrent HCV post transplantation has been well tolerated and resulted in high SVR4 rates in these very difficult to treat populations treated with either 12 or 24 weeks of this regimen. SVR 12 results will be presented.

AASLD Abstracts

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