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Background & Aims Emricasan, an oral pan-caspase inhibitor, decreased portal pressure in experimental cirrhosis and in an open-label study in patients with cirrhosis and severe portal hypertension, defined as a hepatic venous pressure gradient (HVPG) ≥12 mmHg. We aimed to confirm these results in a placebo-controlled study in patients with non-alcoholic steatohepatitis (NASH)-related cirrhosis. Methods We performed a multicenter double-blinded study, randomizing 263 patients with NASH-related cirrhosis and baseline HVPG ≥12 mmHg to twice daily oral emricasan 5 mg, 25 mg, 50 mg or placebo in a 1:1:1:1 ratio for up to 48 weeks. The primary endpoint was change in HVPG (ΔHVPG) at week 24. Secondary endpoints were changes in biomarkers (aminotransferases, caspases, cytokeratins) and development of liver-related outcomes. Results There were no significant differences in ΔHVPG for any emricasan dose vs. placebo (−0.21, −0.45, −0.58 mmHg, respectively) adjusted for baseline HVPG, compensation status, and non-selective beta-blocker use. Compensated patients (n = 201 [76%]) tended to have a greater decrease in HVPG (emricasan all vs. placebo, p = 0.06), the decrease being greater in those with higher baseline HVPG (p = 0.018), with a significant interaction between baseline HVPG (continuous, p = 0.024; dichotomous at 16 mmHg [median], p = 0.013) and treatment. Biomarkers decreased significantly with emricasan at week 24 but returned to baseline levels by week 48. New or worsening decompensating events (∼10% over median exposure of 337 days), progression in model for end-stage liver disease and Child-Pugh scores, and treatment-emergent adverse events were similar among treatment groups. Conclusions Despite a reduction in biomarkers indicating target engagement, emricasan was not associated with improvement in HVPG or clinical outcomes in patients with NASH-related cirrhosis and severe portal hypertension. Compensated patients with higher baseline HVPG had evidence of a small treatment effect. Emricasan treatment appeared safe and well-tolerated. Lay summary Cirrhosis (scarring of the liver) is the main consequence of non-alcoholic steatohepatitis (NASH). Cirrhosis leads to high pressure in the portal vein which accounts for most of the complications of cirrhosis. Reducing portal pressure is beneficial in patients with cirrhosis. We studied the possibility that emricasan, a drug that improves inflammation and scarring in the liver, would reduce portal pressure in patients with NASH-related cirrhosis and severe portal hypertension. Our results in a large, prospective, double-blind study could not demonstrate a beneficial effect of emricasan in these patients. Clinical Trial Number Clinical Trials.gov #NCT02960204.

Although patients with cryptogenic cirrhosis have historically been considered as having "burnt-out" non-alcoholic steatohepatitis (NASH), some controversy remains. The aim of this study was to compare outcomes of patients with cryptogenic cirrhosis and NASH-related cirrhosis from a cohort with longitudinal follow-up data.Patients with cryptogenic cirrhosis or NASH cirrhosis were screened for a clinical trial. Patients with5% hepatic steatosis regardless of other histologic features were considered to have cryptogenic cirrhosis. Clinico-laboratory data and adjudicated liver-related events (e.g. decompensation, qualification for transplantation, death) were available.A total of 247 patients with cirrhosis (55.3 ± 7.4 years, 37% male) were included; 144 had NASH cirrhosis and 103 had cryptogenic cirrhosis. During a median follow-up of 29 (IQR 21-33) months (max 45 months), 20.6% of patients had liver-related clinical events. Patients with NASH cirrhosis and cryptogenic cirrhosis were of a similar age and gender, as well as having a similar body mass index, PNPLA3 rs738409 genotype, and prevalence of diabetes (p 0.05). However, patients with cryptogenic cirrhosis had higher serum fibrosis markers and greater collagen content and α-smooth muscle actin expression on liver biopsy. Compared to cirrhotic patients with NASH, patients with cryptogenic cirrhosis experienced significantly shorter mean time to liver-related clinical events (12.0 vs. 19.4 months; p = 0.001) with a hazard ratio of 1.76 (95% CI 1.02-3.06).Populations with NASH and cryptogenic cirrhosis have similar demographics, but patients with cryptogenic cirrhosis have evidence of more active fibrosis and a higher risk of liver-related clinical events. Thus, we believe these patients belong to the same spectrum of disease, with cryptogenic cirrhosis representing a more advanced stage of fibrosis.Significant liver damage and cirrhosis of the liver may develop without a known cause - a liver disease referred to as cryptogenic cirrhosis. In this work we found that, in the presence of metabolic abnormalities, cryptogenic cirrhosis may actually be a part of the non-alcoholic fatty liver disease spectrum. Yet, it appears to be more progressive than typical non-alcoholic fatty liver disease, leading to advanced liver disease at a faster rate.

Background & Aims Non-alcoholic steatohepatitis is a leading cause of end-stage liver disease. Hepatic steatosis and lipotoxicity cause chronic necroinflammation and direct hepatocellular injury resulting in cirrhosis, end-stage liver disease and hepatocellular carcinoma. Emricasan is a pan-caspase inhibitor that inhibits excessive apoptosis and inflammation; it has also been shown to decrease portal pressure and improve synthetic function in mice with carbon tetrachloride-induced cirrhosis. Methods This double-blind, placebo-controlled study randomized 217 individuals with decompensated NASH cirrhosis 1:1:1 to emricasan (5 mg or 25 mg) or placebo. Patients were stratified by decompensation status and baseline model for end-stage liver disease-sodium (MELD-Na) score. The primary endpoint comprised all-cause mortality, a new decompensation event (new or recurrent variceal hemorrhage, new ascites requiring diuretics, new unprecipitated hepatic encephalopathy ≥grade 2, hepatorenal syndrome, spontaneous bacterial peritonitis), or an increase in MELD-Na score ≥4 points. Results There was no difference in event rates between either of the emricasan treatment groups and placebo, with hazard ratios of 1.02 (95% CI 0.59–1.77; p = 0.94) and 1.28 (95% CI 0.75–2.21; p = 0.37) for 5 mg and 25 mg of emricasan, respectively. MELD-Na score progression was the most common outcome. There was no significant effect of emricasan treatment on MELD-Na score, international normalized ratio, total serum bilirubin, albumin level or Child-Pugh score. Emricasan was generally safe and well-tolerated. Conclusions Emricasan was safe but ineffective for the treatment of decompensated NASH cirrhosis. However, this study may guide the design and conduct of future clinical trials in decompensated NASH cirrhosis. Lay summary Patients with decompensated cirrhosis related to non-alcoholic steatohepatitis are at high risk of additional decompensation events and death. Post hoc analyses in previous pilot studies suggested that emricasan might improve portal hypertension and liver function. In this larger randomized study, emricasan did not decrease the number of decompensation events or improve liver function in patients with a history of decompensated cirrhosis related to non-alcoholic steatohepatitis. ClinicalTrials.gov Identifier NCT03205345 .

Background & Aims Apoptosis signal-regulating kinase 1 (ASK1) plays a key role in hepatocyte injury, inflammation, and fibrosis in non-alcoholic steatohepatitis (NASH). We evaluated the safety and antifibrotic effect of selonsertib, a selective inhibitor of ASK1, in patients with advanced fibrosis due to NASH. Methods We conducted 2 randomized, double-blind, placebo-controlled, phase III trials of selonsertib in patients with NASH and bridging fibrosis (F3, STELLAR-3) or compensated cirrhosis (F4, STELLAR-4). Patients were randomized 2:2:1 to receive selonsertib 18 mg, selonsertib 6 mg, or placebo once daily for 48 weeks. Liver biopsies were performed at screening and week 48 and non-invasive tests of fibrosis (NITs) were evaluated. The primary efficacy endpoint was the proportion of patients with ≥1-stage improvement in fibrosis without worsening of NASH at week 48. Additional endpoints included changes in NITs, progression to cirrhosis (in STELLAR-3), and liver-related clinical events. Results Neither trial met the primary efficacy endpoint. In STELLAR-3, fibrosis improvement without worsening of NASH was observed in 10% (31/322, p = 0.49 vs. placebo), 12% (39/321, p = 0.93 vs. placebo), and 13% (21/159) of patients in the selonsertib 18 mg, selonsertib 6 mg, and placebo groups, respectively. In STELLAR-4, the primary endpoint was achieved in 14% (51/354; p = 0.56), 13% (45/351; p = 0.93), and 13% (22/172) of patients, respectively. Although selonsertib led to dose-dependent reductions in hepatic phospho-p38 expression indicative of pharmacodynamic activity, it had no significant effect on liver biochemistry, NITs, progression to cirrhosis, or adjudicated clinical events. The rates and types of adverse events were similar among selonsertib and placebo groups. Conclusions Forty-eight weeks of selonsertib monotherapy had no antifibrotic effect in patients with bridging fibrosis or compensated cirrhosis due to NASH. Lay summary Patients with non-alcoholic steatohepatitis (NASH) can develop scarring of the liver (fibrosis), including cirrhosis, which increases the risks of liver failure and liver cancer. We tested whether 48 weeks of treatment with selonsertib reduced fibrosis in patients with NASH and advanced liver scarring. We did not find that selonsertib reduced fibrosis in these patients. Trial registration details Clinicaltrials.gov numbers NCT03053050 and NCT03053063.

Background & Aims Peginterferon lambda-1a (Lambda) is a type-III interferon with similar antiviral activity to alfa interferons but with a diminished extrahepatic receptor distribution, reducing the risk for extrahepatic adverse events. Methods This was a randomized, blinded, actively-controlled, multicentre phase 2b dose-ranging study in patients chronically infected with HCV genotypes 1–4. Treatment-naive patients received Lambda (120/180/240μg) or peginterferon alfa-2a (alfa; 180μg) once-weekly with ribavirin for 24 (genotypes [GT] 2,3) or 48 (GT1,4) weeks. Results Rates of undetectable HCV-RNA at week 12 (complete early virologic response [cEVR]; primary end point) were significantly higher in GT1,4 patients receiving Lambda vs. alfa (170/304, 56% vs. 38/103, 37%); with similar cEVR rates for GT2,3 (80/88, 91% vs. 26/30, 87%). Rates of undetectable HCV-RNA at week 4 were significantly higher on 180μg (15/102, 15% GT1,4; 22/29, 76% GT2,3) and 240μg (17/104, 16% GT1,4; 20/30, 67% GT2,3) Lambda than alfa (6/103, 6% GT1,4; 9/30, 30% GT2,3). Sustained virologic responses (post-treatment week 24) were comparable between Lambda and alfa for GT1,4 (37–46% Lambda; 37% alfa) and GT2,3 (60–76% Lambda; 53% alfa). Aminotransferase and/or bilirubin elevations were the primary dose-limiting abnormalities for Lambda; a sponsor-mandated 240 to 180μg dose reduction was therefore implemented. Serious adverse events were comparable (3–13% Lambda; 3–7% alfa). Grade 3–4 haemoglobin, neutrophil, and platelet reductions were lower on Lambda than alfa. Among alfa patients, 28/133 (21%) had peginterferon and 31/133 (23%) had ribavirin dose reductions for haematologic abnormalities vs. 0/392 and 8/392 (2%) on Lambda. Lambda demonstrated fewer musculoskeletal (16–28% vs. 47–63%) and influenza-like events (8–23% vs. 40–46%) than alfa. Conclusion Lambda was associated with improved or similar rates of virologic response with fewer extrahepatic adverse events than alfa in chronic HCV infection.

Background & Aims Interferon-alfa (IFN)-related cytopenias are common and may be dose-limiting. We performed a genome wide association study on a well-characterized genotype 1 HCV cohort to identify genetic determinants of peginterferon-α (pegIFN)-related thrombocytopenia, neutropenia, and leukopenia. Methods 1604/3070 patients in the IDEAL study consented to genetic testing. Trial inclusion criteria included a platelet (Pl) count ⩾80×10 9 /L and an absolute neutrophil count (ANC) ⩾1500/mm 3 . Samples were genotyped using the Illumina Human610-quad BeadChip. The primary analyses focused on the genetic determinants of quantitative change in cell counts (Pl, ANC, lymphocytes, monocytes, eosinophils, and basophils) at week 4 in patients >80% adherent to therapy (n=1294). Results 6 SNPs on chromosome 20 were positively associated with Pl reduction (top SNP rs965469, p =10 −10 ). These tag SNPs are in high linkage disequilibrium with 2 functional variants in the ITPA gene, rs1127354 and rs7270101, that cause ITPase deficiency and protect against ribavirin (RBV)-induced hemolytic anemia (HA). rs1127354 and rs7270101 showed strong independent associations with Pl reduction ( p =10 −12 , p =10 −7 ) and entirely explained the genome-wide significant associations. We believe this is an example of an indirect genetic association due to a reactive thrombocytosis to RBV-induced anemia: Hb decline was inversely correlated with Pl reduction (r=−0.28, p =10 −17 ) and Hb change largely attenuated the association between the ITPA variants and Pl reduction in regression models. No common genetic variants were associated with pegIFN-induced neutropenia or leucopenia. Conclusions Two ITPA variants were associated with thrombocytopenia; this was largely explained by a thrombocytotic response to RBV-induced HA attenuating IFN-related thrombocytopenia. No genetic determinants of pegIFN-induced neutropenia were identified.

Background & Aims The probability of response to peginterferon and ribavirin is associated with numerous host and virological factors. Attainment of a rapid virological response (RVR), defined as undetectable HCV RNA at week 4 during treatment with peginterferon and ribavirin, is highly predictive of sustained virological response (SVR). The aim of the present study was to determine the relative importance of the kinetics of antiviral response compared to baseline host and virological factors for predicting SVR. Methods A retrospective analysis of 1383 patients, encompassing genotypes 1–4, treated with peginterferon alfa-2a and ribavirin, was performed. Baseline characteristics were compared across HCV genotypes and pretreatment factors associated with RVR were identified. The relative significance of RVR compared to other baseline factors for predicting SVR was analyzed by multiple logistic regression analysis. Results RVR was achieved by 16% of patients with genotype 1 and 71% and 60% of those with genotype 2 and 3, respectively. Among patients who achieved RVR, the rate of SVR was high across all genotypes and ranged from 88% to 100% (genotypes 1–4). Baseline factors predictive of RVR included genotype, younger age, lower initial viral load, higher ALT ratio, absence of advanced fibrosis, and younger age. Notably, the presence of RVR generated the highest odds ratio (5.47, 95% confidence interval 3.97–7.52) for predicting SVR in multiple logistic regression analysis of these factors. Conclusions Attainment of RVR varies by genotype and is associated with several baseline factors. Patients who achieve RVR have the highest rates of SVR, regardless of genotype. These findings have important implications for predicting and managing response-guided combination antiviral therapies.

Assessing hepatitis C virus (HCV)-RNA levels is integral to response-guided therapy. Rules for early discontinuation and determination of treatment duration were mainly established with HCV-RNA assays with a detection limit of 50IU/ml (COBAS Amplicor HCV [CA]). The currently used real-time PCR-based COBAS Ampliprep/COBAS-TaqMan HCV (CAP-CTM) test has a detection limit of approximately 10IU/ml. It is unknown whether shortening of treatment duration to 16/24 weeks in patients with rapid virological response at week 4 (RVR) and viral loads between 10 and 50IU/ml is possible.We reanalysed stored serum from two large, multinational, randomized trials in which patients were treated with peginterferon alfa-2a/ribavirin (n=962). Results of CAP-CTM with truly undetectable HCV RNA and those15IU/ml, which includes patients with residual viraemia (15), were compared with the originally obtained results using the CA assay.RVR rates were comparable for CA (50) and CAP-CTM (15) with 32% and 32% for genotype (gt) 1 and 50% and 49% for gt2/3 patients, respectively. A significantly smaller number of samples really had truly undetectable HCV RNA by the CAP-CTM assay (24% for gt1, 37% for gt2/3). However, sustained virological response rates after shortened treatment (16/24weeks) were not significantly different in patients with a RVR50, a RVR15 and RVR undetectable (82%, 83%, 83% for 24weeks gt1 and 95%, 95%, 94% for 16weeks gt2/3).Shortening the treatment duration to 16/24weeks can be performed on the basis of a RVR with HCV-RNA concentrations15IU/ml by the CAP-CTM assay.

Background/Aims Seven genomic loci, implicated by single nucleotide polymorphisms (SNPs), have recently been associated with progression to advanced fibrosis (fibrosis risk) in patients with chronic hepatitis C virus. Other variants in these loci have not been examined but may be associated with fibrosis risk independently of or due to linkage disequilibrium with the original polymorphisms. Methods We carried out dense genotyping and association testing of additional SNPs in each of the 7 regions in Caucasian case control samples. Results We identified several SNPs in the toll-like receptor 4 ( TLR4 ) and syntaxin binding protein 5-like ( STXBP5L ) loci that were associated with fibrosis risk independently of the original significant SNPs. Haplotypes consisting of these SNPs in TLR4 and STXBP5L were strongly associated with fibrosis risk (global P =3.04×10 −5 and 4.49×10 −6 , respectively). Conclusions Multiple variants in TLR4 and STXBP5L genes modulate risk of liver fibrosis. These findings are of relevance for understanding the pathogenesis of HCV-induced liver disease in Caucasians and may be extended to other ethnicities as well.

Background/Aims In chronic hepatitis C, disease progression and clinical manifestations are heterogenous. To clarify the role and interactions of viral and host factors in inducing liver cell injury, we examined the associations of several virological and metabolic variables with serum alanine aminotransferase levels. Methods Patients with chronic hepatitis C enrolled in three phase III clinical trials of peginterferon alfa-2a (40KD) plus ribavirin (two studies analysing ‘elevated' and one persistently ‘normal' alanine aminotransferase) were included. Results Multivariate analyses of 2881 patients before treatment and of 1403 patients with a sustained virological response indicated that gender, viral factors (genotype, HCV RNA titer) and indicators of metabolic syndrome (body mass index, blood pressure, blood glucose, cholesterol and triglyceride concentration) were associated with alanine aminotransferase levels. In addition, hepatitis C virus infection influenced serum lipids concentration according to a genotype-specific effect. Conclusions Heterogeneity in alanine aminotransferase levels in patients with chronic hepatitis C partially depends on the degree of derangement of fat and carbohydrate metabolism. As this is the result of an interaction of chronic hepatitis C infection with the patient's individual characteristics, treatment decisions should not be based on alanine aminotransferase level alone but rather on global evaluation of the patient.

Background/Aims: We have evaluated the effect of granulocyte macrophage colony-stimulating factor (GM-CSF) when utilized either alone or in combination with interferon for treatment of chronic hepatitis C virus (HCV). Methods: A total of 71 patients with chronic HCV, elevated alanine aminotransferase and normal hepatic function were enrolled into these studies. Nineteen patients who had previously failed to achieve both biochemical and virologic response during interferon therapy were treated with increasing doses of GM-CSF alone (65–250 μg/m 2 three times weekly) for 6 months. Another 52 patients who had not been previously treated with interferon entered a randomized controlled trial; 25 were treated with interferon alone (3 mU three times weekly) and 27 with a combination of interferon+GM-CSF (3 mU+250 μg/m 2 three times weekly). All patients were treated for 6 months. Both groups were well matched for age, sex, race, serum alanine aminotransferase, HCV-RNA titer, liver histology score and cirrhosis. Results: None of the patients treated with GM-CSF alone developed either biochemical or virologic response at any of the treatment dosages and mean HCV-RNA titer remained unchanged from baseline during this therapy. For patients in the randomized controlled trial, biochemical and virologic responses were observed in 54% of interferon-treated patients compared to 31.8% for those treated with interferon+GM-CSF. Long-term sustained virologic response was observed in only one patient in each group. No significant differences were observed in HCV-RNA titer during the course of treatment. GM-CSF treatment was associated with a significant increase in total white blood cell count and absolute eosinophil count, which peaked within the first month of therapy and declined spontaneously during the remaining 5 months. Conclusion: GM-CSF either alone or in combination with interferon does not appear to be effective for treatment of chronic HCV.

Background/Aims: Prediction of sustained virological response (SVR) during treatment would allow clinicians to identify patients most likely to benefit from therapy. Methods: Retrospective analysis of data from 1121 adults with chronic hepatitis C treated for 48 weeks with peginterferon alfa-2a (40 KD) 180 mu g/week plus placebo or ribavirin (1000/1200 mg/day), or interferon alfa-2b 3 MIU three times/week plus ribavirin in a randomized, multinational, study. Results: 67% of patients treated with peginterferon alfa-2a (40 KD)/ribavirin with early virological responses (HCV RNA negative or >= 2 log(10) decrease) at week 12 had SVRs at week 72 (HCV RNA < 50 IU/mL). The negative predictive value (NPV) was 97%. The probability of an SVR increased with the rapidity of HCV RNA suppression. The highest SVR rates were achieved in patients with rapid virological responses at week 4, but the corresponding NPV (74%) is too low for a decision criterion. In patients with early virological responses by week 12, the SVR rate was approximate to 20 % lower in those who received < 80 % compared with patients who received > 80 % of the planned ribavirin dose. Conclusions: Early, sustained suppression of HCV replication portends an SVR. Cessation of treatment may be contemplated in patients without a >= 2 log(10) reduction in HCV RNA after 12 weeks. (c) 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Background/Aims : The current standard for the determination of sustained virologic response in patients treated for hepatitis C is undetectable hepatitis C virus (HCV) RNA 24 weeks following the completion of therapy. Sensitive molecular tests may permit earlier determination of sustained virologic response following the completion of therapy in end-of-treatment responders. Methods : We examined this possibility in 1441 patients, who received 48 weeks of treatment with either standard or pegylated interferon α-2a. HCV RNA was determined by polymerase chain reaction assay (Amplicor HCV Monitor vs. 2.0) at baseline and monitored at 4-week intervals throughout the treatment and 24-week post-treatment follow-up periods. Results : End-of-treatment and sustained response were achieved in 624 and 342 patients, respectively. For all treatments, relapse was most frequent at weeks 52 and 56 and became rare following week 60. Only six patients out of 348 patients (2%) became HCV RNA positive between weeks 60 and 72. Analysis of baseline characteristics failed to identify a specific set of parameters associated with early relapse. Conclusions : This finding suggests that determination of HCV RNA levels at 12 weeks of follow-up may be sufficient for making decisions related to the management of most patients treated with standard or pegylated interferon α.

Primary endpoint was SVR 24 weeks post-therapy (Roche TaqMan LLD = 9.3 IU/mL). Relapse was the proportion of patients with undetectable HCV-RNA at end of treatment and detectable posttreatment. Results: In treatment-naive patients, anemia and EPO use occurred in: BOC 49.4% (363/734) and 43.3% (318/734), respectively; PR control, 29.7% (108/363) and 24.0% (87/363), respectively. In both placebo and BOC groups, SVR was more frequent in patients who developed anemia compared to those who did not (P < 0.001, Table). In previous-treatment-failure patients, anemia and EPO use occurred in: BOC 48.6% (157/323) and 43.3% (140/323), respectively; PR control, 25% (20/80) and 21.2% (17/80), respectively. In the BOC group, SVR was more frequent in patients who developed anemia compared to those who did not (P< 0.001, Table). In both patient groups, EPO was prescribed in 78.5% of anemic patients treated with BOC (408/520) and 68.0% (87/128) of those in the PR control group. Conclusions: Higher SVR rates were observed among previously untreated and previous-treatment-failure patients who developed anemia during BOC or control PR therapy. Since ~80% of anemic patients took EPO, additional research is needed to understand the relationship of SVR, R dose reduction, and EPO use.

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

289 DISCREPANCIES BETWEEN DEFINITIONS OF NULL RESPONSE TO TREATMENT WITH PEGINTERFERON-ALFA-2A AND RIBAVIRIN: IMPLICATIONS FOR NEW HCV DRUG DEVELOPMENT G. Picchio, D. Luo, S. George, A. Kwong, T. Kieffer, J. Mc Hutchison, J.-M. Pawlotsky. Tibotec, Inc, Yardley, PA, Vertex Pharmaceuticals Incorporated, Cambridge, MA, Duke University Medical Center, Durham, NC, USA; Hopital Henri Mondor, Creteil, France E-mail: gpicchio@its.jnj.com

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