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Portal hypertension is a predictor of liver-related clinical events and mortality in patients with hepatitis C and cirrhosis. The effect of interferon-free hepatitis C treatment on portal pressure is unknown. Fifty patients with Child-Pugh-Turcotte (CPT) A and B cirrhosis and portal hypertension (hepatic venous pressure gradient [HVPG] >6 mm Hg) were randomized to receive 48 weeks of open-label sofosbuvir plus ribavirin at Day 1 or after a 24-week observation period. The primary endpoint was sustained virologic response 12 weeks after therapy (SVR12) in patients who received ≥1 dose of treatment. Secondary endpoints included changes in HVPG, laboratory parameters, and MELD and CPT scores. A subset of patients was followed 48 weeks posttreatment to determine late changes in HVPG. SVR12 occurred in 72% of patients (33/46). In the 37 patients with paired HVPG measurements at baseline and the end of treatment, mean HVPG decreased by -1.0 (SD 3.97) mm Hg. Nine patients (24%) had ≥20% decreases in HVPG during treatment. Among 39 patients with pretreatment HVPG ≥12 mm Hg, 27 (69%) achieved SVR12. Four of the 33 (12%) patients with baseline HVPG ≥12 mm Hg had HVPG

SummaryBackground Chronic hepatitis C virus therapy in patients with advanced liver disease remains a clinical challenge. HCV-TARGET collects data in patients treated at tertiary academic and community centres. Aim To assess efficacy of all-oral HCV therapy in advanced liver disease. Methods Between December 2013 and October 2014, 240 patients with a MELD score of ≥10 initiated HCV treatment with an all-oral regimen. Data from the 220 patients who completed 12-week follow-up were analysed. Results Genotype 1 (GT1) patients had higher sustained virological response (SVR) when treated with sofosbuvir plus simeprevir ± ribavirin than with sofosbuvir plus ribavirin (66–74% vs. 54%); GT1b vs GT1a (84% vs. 64%). SVR for GT2 was 72% with sofosbuvir plus ribavirin, while GT3 patients had a substantially lower response (35%). A decrease in MELD score was not clearly related to SVR over the short course of follow-up although some had improvements in MELD score, serum bilirubin and albumin. A predictor of virological response was albumin level while negative predictors were elevated bilirubin level and GT1a. Most patients with GT1 were treated with approximately 12-week duration of sofosbuvir and simeprevir ± ribavirin therapy while GT2 and GT3 patients were treated with approximately 12 and 24 weeks of sofosbuvir plus ribavirin respectively. Conclusions All-oral therapies are effective among patients with advanced liver disease with high levels of success in GT2 and GT1b, and may serve to reduce the severity of liver disease after SVR. Treatment for GT3 patients remains an unmet need. Clinical trial number: NCT01474811

Donor factors influence hepatitis C virus (HCV) disease severity in liver transplant (LT) recipients. Living donors, because they are typically young and have short cold ischemic times, may be advantageous for HCV-infected patients. Among HCV-infected patients in the Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL) surviving >90 days and followed for a median 4.7 years, advanced fibrosis (Ishak stage ≥3) and graft loss were determined. The 5-year cumulative risk of advanced fibrosis was 44% and 37% in living donor LT (LDLT) and deceased donor LT (DDLT) patients (P = 0.16), respectively. Aspartate aminotransferase (AST) activity at LT (hazard ratio [HR] = 1.38 for doubling of AST, P = 0.005) and biliary strictures (HR = 2.68, P = 0.0001) were associated with advanced fibrosis, but LDLT was not (HR = 1.11, 95% confidence interval [CI] 0.73-1.69, P = 0.63). The 5-year unadjusted patient and graft survival probabilities were 79% and 78% in LDLT, and 77% and 75% in DDLT (P = 0.43 and 0.32), with 27% and 20% of LDLT and DDLT graft losses due to HCV (P = 0.45). Biliary strictures (HR = 2.25, P = 0.0006), creatinine at LT (HR = 1.74 for doubling of creatinine, P = 0.0004), and AST at LT (HR = 1.36 for doubling of AST, P = 0.004) were associated with graft loss, but LDLT was not (HR = 0.76, 95% CI: 0.49-1.18, P = 0.23). Conclusion: Donor type does not affect the probability of advanced fibrosis or patient and graft survival in HCV-infected recipients. Thus, while LDLT offers the advantage of shorter wait times, there is no apparent benefit for HCV disease progression. Biliary strictures have a negative effect on HCV fibrosis severity and graft survival, and a high AST at LT may be an important predictor of fibrosis risk post-LT. (Hepatology 2014;59:1311-1319)

Adult-to-adult living donors and recipients were studied to characterize patterns of liver growth and identify associated factors in a multicenter study. Three hundred and fifty donors and 353 recipients in the Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL) receiving transplants between March 2003 and February 2010 were included. Potential predictors of 3-month liver volume included total and standard liver volumes (TLV and SLV), Model for End-Stage Liver Disease (MELD) score (in recipients), the remnant and graft size, remnant-to-donor and graft-to-recipient weight ratios (RDWR and GRWR), remnant/TLV, and graft/SLV. Among donors, 3-month absolute growth was 676 ± 251 g (mean ± SD), and percentage reconstitution was 80% ± 13%. Among recipients, GRWR was 1.3% ± 0.4% (8 0.8%). Graft weight was 60% ± 13% of SLV. Three-month absolute growth was 549 ± 267 g, and percentage reconstitution was 93% ± 18%. Predictors of greater 3-month liver volume included larger patient size (donors and recipients), larger graft volume (recipients), and larger TLV (donors). Donors with the smallest remnant/TLV ratios had larger than expected growth but also had higher postoperative bilirubin and international normalized ratio at 7 and 30 days. In a combined donor-recipient analysis, donors had smaller 3-month liver volumes than recipients adjusted for patient size, remnant or graft volume, and TLV or SLV (P = 0.004). Recipient graft failure in the first 90 days was predicted by poor graft function at day 7 (HR = 4.50, P = 0.001) but not by GRWR or graft fraction (P 0.90 for each). Both donors and recipients had rapid yet incomplete restoration of tissue mass in the first 3 months, and this confirmed previous reports. Recipients achieved a greater percentage of expected total volume. Patient size and recipient graft volume significantly influenced 3-month volumes. Importantly, donor liver volume is a critical predictor of the rate of regeneration, and donor remnant fraction affects postresection function. Liver Transpl 21:79-88, 2015. © 2014 AASLD.

Patients with chronic hepatitis C who have not had a sustained hepatitis C virus (HCV)-RNA response or serum alanine transaminase (ALT) response to a 6-month course of interferon (IFN) may respond to higher dose retreatment with consensus interferon (CIFN). Some nonresponders to initial IFN treatment have a transient response defined as undetectable HCV RNA or normalization of ALT during treatment, but subsequently have a "breakthrough" while still on treatment. The aim of this study was to determine if nonresponders who had breakthroughs responded differently to CIFN retreatment than nonresponders without breakthroughs using data from a large, multicenter trial. ALT and HCV RNA were monitored frequently during initial IFN therapy (either 9 mcg CIFN or 3 MU IFN-alpha2b 3 times per week). HCV-RNA breakthroughs were observed in 86 of 467 (18%) of all treated patients, and ALT breakthroughs were observed in 90 of 467 (19%) of all treated patients. There was no association between breakthroughs and the presence of either binding or neutralizing anti-IFN antibodies. When the patients who were nonresponders to initial IFN treatment were retreated with CIFN (15 mcg) for 12 months, 27% of those with viral breakthroughs had a sustained viral response compared with 8% in prior nonresponders without breakthroughs (P =.102). Sustained ALT responses were observed in 39% with breakthroughs compared with 10% in those without breakthroughs (P =.014). The data suggest that prior nonresponders with breakthroughs have a greater chance of responding to retreatment than do nonresponders without breakthroughs. However, most breakthrough patients would be missed unless repeated HCV-RNA testing were conducted during therapy.

Summary Background Several direct-acting antivirals for chronic hepatitis C virus (HCV) infection are available, but they are limited by tolerability and dosing schedules. Once-daily daclatasvir, a potent NS5A replication complex inhibitor, was generally well tolerated in phase 1 studies. We assessed daclatasvir in combination with pegylated interferon (peginterferon) and ribavirin for chronic HCV. Methods In this double-blind, parallel-group, dose-finding, phase 2a study, treatment-naive patients with HCV genotype-1 infection (without cirrhosis) from 14 centres in the USA and France were randomly assigned (1:1:1:1) to receive peginterferon alfa-2a (180 μg per week) and ribavirin (1000–1200 mg daily) plus placebo or 3 mg, 10 mg, or 60 mg of daclatasvir taken once daily, for 48 weeks. The primary efficacy endpoint was undetectable HCV RNA at 4 weeks and 12 weeks after start of treatment (extended rapid virological response, eRVR). Analysis was of all participants who received one dose of study drug. We used descriptive analyses to compare results. This study is registered with ClinicalTrials.gov, number NCT00874770. Findings 48 patients were randomly assigned (12 per group); all received at least one dose of study drug. 15 patients discontinued treatment before week 48. Five of 12 patients (42%, 80% CI 22–64%) who received 3 mg daclatasvir achieved eRVR, compared with ten of 12 (83%, 61–96%) who received 10 mg daclatasvir, nine of 12 (75%, 53–90%) who received 60 mg daclatasvir, and one of 12 (8%, 1–29%) who received placebo. Adverse events and discontinuations as a result of adverse events occurred with similar frequency across groups. Interpretation Daclatasvir seems to be a potent NS5A replication complex inhibitor that increases the antiviral potency of peginterferon and ribavirin. Our findings support the further development of regimens containing 60 mg daclatasvir for the treatment of chronic genotype-1 HCV infection. Funding Bristol-Myers Squibb.

1359 FIRST SVR DATA WITH THE NUCLEOSIDE ANALOGUE POLYMERASE INHIBITOR MERICITABINE (RG7128) COMBINED WITH PEGINTERFERON/RIBAVIRIN IN TREATMENT-NAIVE HCV G1/4 PATIENTS: INTERIM ANALYSIS FROM THE JUMP-C TRIAL P. Pockros, D. Jensen, N. Tsai, R.M. Taylor, A. Ramji, C. Cooper, R. Dickson, A. Tice, S. Stancic, D. Ipe, J.A. Thommes, J.M. Vierling. Scripps Clinic Research Center, La Jolla, CA, Center for Liver Diseases, University of Chicago Hospitals, Chicago, IL, Hawaii Medical Center, Honolulu, HI, The University of Kansas Hospital Medical Center, Kansas City, KS, USA; Division of Gastroenterology, University of British Columbia, Vancouver, BC, The Ottawa Hospital, Ottowa, ON, Canada; Dartmouth-Hitchcock Medical Center, Lebanon, NH, Infections Limited Hawaii, Honolulu, HI, Roche, Nutley, NJ, Genentech, South San Francisco, CA, Baylor College of Medicine, Houston, TX, USA E-mail: pockros.paul@scrippshealth.org Introduction: Mericitabine (RG7128, MCB) is a potent, selective nucleoside inhibitor of the HCV NS5B RNA-dependent RNA polymerase with activity across all HCV genotypes. MCB has demonstrated a high barrier to resistance without treatmentemergent resistance observed to date. Methods: JUMP-C is an ongoing randomised, double-blind, placebocontrolled phase 2b study in treatment naive patients infected with HCV G1/4. The trial objective was to compare a response guided therapy regimen of MCB plus peginterferon alfa-2a/ribavirin (P/R) with P/R alone. Patients randomised to arm A achieving an extended RVR (eRVR; HCVRNA

E.J. Lawitz1, T.D. Boyer2, G.T. Everson3, I.M. Jacobson4, W. Lee5, J.G. McHutchison6, P.J. Pockros7, M.L. Shiffman8, J.M. Vierling9, S. Cruickshank10, B. Armstrong11, T.C. Rodell12, D. Apelian12 1Alamo Medical Research, San Antonio, TX, 2University of Arizona, Tucson, AZ, 3Department of Medicine, University of Colorado Denver, Aurora, CO, 4Department of Medicine, Weill Cornell Medical College, New York, NY, 5Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, 6Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, 7The Scripps Clinical Research Center, La Jolla, CA, 8Hepatology Section, Virginia Commonwealth University Medical Center, Richmond, VA, 9Department of Medicine and Surgery, Baylor College of Medicine, Houston, TX, 10Cruickshank and Associates, Santa Barbara, CA, 11QST Consultations, Allendale, MI, 12GlobeImmune, Inc., Louisville, CO, USA

13.6±1.8 g/dL [8.8–17.5], respectively. After 12W, a complete early virological response was obtained in 34 (83%) boceprevir patients and in 35 (61%) telaprevir patients (p = 0.026). Among 17 boceprevir and 16 telaprevir patients, 14 (82%) and 7 (43%) achieved an end of treatment response (EOT) with an undetetectable viral load, respectively (p = 0.032). Among 9 boceprevir and 5 telaprevir patients, 6 and 1 achieved SVR12, respectively. Among 6 patients in the boceprevir group, 3 achieved SVR24. In the telaprevir group, 29 patients discontinued therapy (serious adverse events, n = 13; virological breakthrough, n = 6; non-response, n = 9). In the boceprevir group, 14 patients discontinued therapy (serious adverse events, n = 5; virological breakthrough, n = 2; non-response, n = 4; retransplantation, n = 1). Four patients died in a context of infectious disorders: boceprevir, n = 2 (W20/W24); telaprevir, n = 2 (W2/W9). The most common side effect was anemia in 85% of patients: 95% and 96% in boceprevir and telaprevir groups received erythropoietin alone or combined with ribavirin dose reduction. Conclusion: In liver transplanted patients, EOT rate was 82% and 38% with boceprevir and telaprevir, respectively. Among the overall population, 44% of patients discontinued therapy because of treatment failure or occurrence of serious adverse events.

1181 PHARMACOGENOMIC ANALYSIS REVEALS IMPROVED VIROLOGIC RESPONSE IN ALL IL-28B GENOTYPES IN NAIVE GENOTYPE 1 CHRONIC HCV PATIENTS TREATED WITH GI-5005 THERAPEUTIC VACCINE PLUS PEG-IFN/RIBAVIRIN J.G. McHutchison, A.J. Thompson, I.M. Jacobson, T.D. Boyer, E.R. Schiff, G.T. Everson, J.M. Vierling, M.L. Shiffman, R.S. Brown, A.M. Di Bisceglie, S.C. Gordon, W.M. Lee, Z. Guo, T.H. King, B. Armstrong, T.C. Rodell, D. Apelian. Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, Center for the Study of Hepatitis C, Weill Cornell Medical College, New York, NY, Department of Medicine, University of Arizona College of Medicine, Tucson, AZ, Center for Liver Diseases, University of Miami School of Medicine, Miami, FL, Department of Medicine, University of Colorado Denver, Aurora, CO, Department of Medicine and Surgery, Baylor College of Medicine, St. Luke’s Episcopal Hospital, Houston, TX, Liver Institute of Virginia, Bon Secours Health System, Newport News, VA, Columbia University College of Physicians & Surgeons, New York, NY, Saint Louis University, St. Louis, MO, Henry Ford Hospital, Detroit, MI, Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, GlobeImmune, Inc., Louisville, CO, QST Consultations, LTD, Allendale, MI, USA E-mail: mchut001@mc.duke.edu

276 WEEK 4 HCVRNA IS THE OPTIMAL PREDICTOR OF SVR IN BOTH HIV POSITIVE AND NEGATIVE SUBJECTS WITHIN THE AUSTRALIAN TRIAL IN ACUTE HCV G.V. Matthews, J. Grebely, M. Hellard, B. Yeung, P. Marks, W. Rawlinson, J. Kaldor, G.J. Dore, ATAHC Study Group. National Centre in HIV Epidemiology and Clinical Research (NCHECR), University of New South Wales, Sydney, NSW, Burnet Institute, Melbourne, VIC, Virology Division, SEALS Microbiology, Prince of Wales Hospital, Sydney, NSW, Australia E-mail: gmatthews@nchecr.unsw.edu.au

Background Evaluation of ethanol use before and after liver transplantation is presently hindered by the limited detection period of ethanol itself, a lack of other proven markers, and reliance on patients9 verbal history. Fatty acid ethyl esters (FAEEs) are direct metabolites of ethanol that persist at least 48 hours in blood after drinking and have been used as ethanol biomarkers. Fatty acids, a substrate for FAEE synthesis, are affected by immunosuppressive medications. Low levels of ethanol, from endogenous intestinal fermentation or mouthwash, could potentially lead to spuriously increased FAEE levels in the setting of lipid-increasing immunosuppresion. Our FAEE assay detected all three predominant FAEEs (ethyl palmitate, ethyl oleate, and ethyl stearate) in all 76 samples from recently drinking individuals. We assessed whether FAEEs are detectable in plasma samples from abstinent liver transplant recipients. Methods Thirty-five plasma samples from 30 abstinent liver transplant recipients (M:F 19:11) were analyzed; abstinence was confirmed by the Timeline Followback instrument and breath ethanol analysis. Levels of ethyl palmitate, ethyl oleate, and ethyl stearate were measured by gas chromatography-mass spectrometry after lipid extraction and solid phase extraction of the samples. Ions 88.1 and 101.1 were monitored. Results At the time of sampling, immunosuppressive regimens included tacrolimus in 26, sirolimus in 21, prednisone in 8, cyclosporine in 8, and mycophenolate mofetil in 6 participants. Regimens included 1, 2, and 3 immunosuppressants in 6, 22, and 6 of the participants, respectively. FAEE levels above the lower limit of quantitation, 60 nM, were not found in any participant. Twenty-two samples had no measurable FAEE and 13 had trace levels, 2-38 nM, which are not distinguishable from instrument contamination due to previous FAEE-containing samples. In all the samples with trace amounts, only one of three FAEEs was present. Conclusion There were no false-positive FAEE assays in this cohort of abstinent post liver transplant recipients, regardless of immunosuppressive treatment. FAEE monitoring in a low-dose ethanol consumption experiment is the next step in validation of this promising method of ethanol use detection in this population.