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Background & Aims Lysyl oxidase-like 2 contributes to fibrogenesis by catalyzing cross-linkage of collagen. We evaluated the safety and efficacy of simtuzumab, a monoclonal antibody against lysyl oxidase-like 2, in two phase 2b trials of patients with advanced fibrosis caused by nonalcoholic steatohepatitis. Methods We performed a double-blind study of 219 patients with bridging fibrosis caused by nonalcoholic steatohepatitis who were randomly assigned (1:1:1) to groups given weekly subcutaneous injections of simtuzumab (75 or 125 mg) or placebo for a planned duration of 240 weeks. We performed a separate study of 258 patients with compensated cirrhosis randomly assigned (1:1:1) to groups given intravenous infusions of simtuzumab (200 or 700 mg) or placebo every other week. The studies were performed from January 2013 through July 2014 at 80 sites in North America and Europe. Biopsy specimens were collected and analyzed at screening and at weeks 48 and 96; clinical information and serum levels of fibrosis biomarkers were collected throughout the study. The primary end point was change from baseline to week 96 in hepatic collagen content, measured by morphometry of liver specimens, in patients with bridging fibrosis; for patients with cirrhosis, the primary end point was change in hepatic venous pressure gradient from baseline to week 96. Results The 2 studies were stopped after week 96 because of lack of efficacy. All 3 groups of patients with bridging fibrosis—including those given placebo—had significant decreases in hepatic collagen content, but there was no statistically significant difference in decrease between patients receiving simtuzumab 75 mg and those receiving placebo (−0.2%, 95% confidence interval [CI] −1.3 to 1.0, P = .77) or between patients receiving simtuzumab 125 mg and those receiving placebo (−0.4%, 95% CI −1.5 to 0.8, P = .52). In patients with cirrhosis, the mean difference in hepatic venous pressure gradient between the 2 simtuzumab groups and the placebo group was 0.1 mm Hg (95% CI −1.2 to 1.5, P = .84 for 200 mg; 95% CI −1.2 to 1.4, P = .88 for 700 mg). Simtuzumab did not significantly decrease fibrosis stage, progression to cirrhosis in patients with bridging fibrosis, or liver-related clinical events in patients with cirrhosis. Rates of adverse events were similar among groups. Conclusion In two phase 2b trials of patients with bridging fibrosis or compensated cirrhosis associated with nonalcoholic steatohepatitis, simtuzumab was ineffective in decreasing hepatic collagen content or hepatic venous pressure gradient, respectively. Clinicaltrials.gov NCT01672866 and NCT01672879.

Fibrosis is an independent predictor of death in nonalcoholic steatohepatitis (NASH). We assessed the associations between histologic and noninvasive tests (NITs) for fibrosis with clinical and patient-reported outcomes (PROs) in advanced NASH.Patients with advanced NASH (NASH Clinical Research Network stage F3 or F4) were enrolled in 4 multinational clinical trials of simtuzumab and selonsertib. Liver biopsy samples, NIT results, and PROs (Short Form-36, Chronic Liver Disease Questionnaire-NASH, EuroQol-5D, and Work Productivity and Activity Impairment) were prospectively collected.A total of 2154 patients with advanced NASH were included: 52.5% with F4 NASH, 40% male, 72% with type 2 diabetes, baseline liver stiffness of 24.1 ± 14.2 kPa in F4 disease and 14.6 ± 8.0 kPa in F3 disease, baseline mean Enhanced Liver Fibrosis score of 11.4 ± 1.2 in F4 disease and 10.3 ± 1.0 in F3 disease, and a median follow-up of 16 months. Of those with baseline F3 disease, 16.7% experienced disease progression to cirrhosis, whereas for those with F4 disease, 7.3% experienced clinical events (39% ascites, 24% hepatic encephalopathy); patients who progressed had higher baseline NIT scores (all P.0001). Adjusted for baseline levels, increases in NIT scores were also associated with increased risk of disease progression in both the F3 and F4 groups (P.01 for all NITs in F3 and for ELF, NAFLD Fibrosis Score, Fibrosis-4 (FIB-4), and liver stiffness in F4). Higher NIT scores were found to be associated with impairment in PROs: ELF, ≥10.43; Nonalcoholic Fatty Liver Disease Fibrosis Score, ≥1.80; Fibrotest score, ≥0.54; liver stiffness, ≥23.4 kPa. During treatment, patients with decreases in NIT scores experienced improvement of their PRO scores, whereas those with increase in NIT scores had their PRO scores worsen (P.05).Baseline NIT scores and their changes over time are predictors of adverse clinical and PROs in patients with advanced NASH. (ClinicalTrials.gov, Numbers NCT01672866, NCT01672879, NCT03053050, and NCT03053063).

Background & Aims Increased levels of galectin 3 have been associated with nonalcoholic steatohepatitis (NASH) and contribute to toxin-induced liver fibrosis in mice. GR-MD-02 (belapectin) is an inhibitor of galectin 3 that reduces liver fibrosis and portal hypertension in rats and was safe and well tolerated in phase 1 studies. We performed a phase 2b, randomized trial of the safety and efficacy of GR-MD-02 in patients with NASH, cirrhosis, and portal hypertension. Methods Patients with NASH, cirrhosis, and portal hypertension (hepatic venous pressure gradient [HVPG] ≥ 6 mm Hg) from 36 centers were randomly assigned, in a double-blind manner, to groups that received biweekly infusions of belapectin 2 mg/kg (n = 54), 8 mg/kg (n = 54), or placebo (n = 54) for 52 weeks. The primary endpoint was change in HVPG (Δ HVPG) at the end of the 52-week period compared with baseline. Secondary endpoints included changes in liver histology and development of liver-related outcomes. Results We found no significant difference in ΔHVPG between the 2 mg/kg belapectin group and placebo group (–0.28 mm HG vs 0.10 mm HG, P = 1.0) or between the 8 mg/kg belapectin and placebo group (–0.25 mm HG vs 0.10 mm HG, P = 1.0). Belapectin had no significant effect on fibrosis or nonalcoholic fatty liver disease activity score, and liver-related outcomes did not differ significantly among groups. In an analysis of a subgroup of patients without esophageal varices at baseline (n = 81), 2 mg/kg belapectin was associated with a reduction in HVPG at 52 weeks compared with baseline (P = .02) and reduced development of new varices (P = .03). Belapectin (2 mg/kg) was well tolerated and produced no safety signals. Conclusions In a phase 2b study of 162 patients with NASH, cirrhosis, and portal hypertension, 1 year of biweekly infusion of belapectin was safe but not associated with significant reduction in HVPG or fibrosis compared with placebo. However, in a subgroup analysis of patients without esophageal varices, 2 mg/kg belapectin did reduce HVPG and development of varices. ClinicalTrials.gov number: NCT02462967

In the REGENERATE interim analysis, obeticholic acid (OCA) improved liver histology in patients with non-alcoholic steatohepatitis (NASH). Elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels may be associated with fibrosis progression in NASH. We evaluated OCA-mediated improvement in these transaminases, and their utility in monitoring treatment of NASH patients with fibrosis. REGENERATE NASH patients with stage 2 or 3 fibrosis (N=931) were randomized 1:1:1 to placebo, OCA 10 mg, or OCA 25 mg. Changes in ALT and AST (upper limit of normal [ULN], 55 U/L and 34 U/L, respectively) were analysed. Baseline characteristics were well balanced across groups (mean ± SD): age (55±11 years), ALT (79±53 U/L), AST (58±36 U/L); ALT >ULN, 60% (>3×ULN, 8%); AST >ULN, 73% (>3×ULN, 9%). OCA treatment improved transaminase levels at Month 1 through Month 18. In patients with baseline ALT and AST >ULN, ALT normalized in 36% (placebo), 49% (OCA 10 mg), and 66% (OCA 25 mg), and AST normalized in 28%, 42%, and 49% in the respective groups by Month 18. In patients with normal baseline transaminases, elevations to >ULN were greater for placebo than OCA 10 mg or OCA 25 mg. OCA-mediated improvements in transaminases were greater in patients who achieved the REGENERATE primary endpoints (figure 1). OCA treatment rapidly improved and sustained ALT and AST, suggesting transaminase may be useful in monitoring treatment response. OCA-treated patients who did not achieve REGENERATE primary endpoints also had marked improvement in transaminases, suggesting longer-term treatment may result in additional histologic improvement.

Background & Aims Patients with chronic hepatitis C virus (HCV) infection have high rates of sustained virologic response (SVR) after 12 weeks of treatment with the nucleotide polymerase inhibitor sofosbuvir combined with the NS5A inhibitor velpatasvir. We assessed the efficacy of 8 weeks of treatment with sofosbuvir and velpatasvir plus the pangenotypic NS3/4A protease inhibitor voxilaprevir (sofosbuvir-velpatasvir-voxilaprevir). Methods In 2 phase 3, open-label trials, patients with HCV infection who had not been treated previously with a direct-acting antiviral agent were assigned randomly to groups given sofosbuvir-velpatasvir-voxilaprevir for 8 weeks or sofosbuvir-velpatasvir for 12 weeks. POLARIS-2, which enrolled patients infected with all HCV genotypes with or without cirrhosis, except patients with genotype 3 and cirrhosis, was designed to test the noninferiority of 8 weeks of sofosbuvir-velpatasvir-voxilaprevir to 12 weeks of sofosbuvir-velpatasvir using a noninferiority margin of 5%. POLARIS-3, which enrolled patients infected with HCV genotype 3 who had cirrhosis, compared rates of SVR in both groups with a performance goal of 83%. Results In POLARIS-2, 95% (95% confidence interval [CI], 93%–97%) of patients had an SVR to 8 weeks of sofosbuvir-velpatasvir-voxilaprevir; this did not meet the criterion to establish noninferiority to 12 weeks of sofosbuvir-velpatasvir, which produced an SVR in 98% of patients (95% CI, 96%–99%; difference in the stratum-adjusted Mantel–Haenszel proportions of -3.2%; 95% CI, -6.0% to -0.4%). The difference in the efficacy was owing primarily to a lower rate of SVR (92%) among patients with HCV genotype 1a infection receiving 8 weeks of sofosbuvir-velpatasvir-voxilaprevir. In POLARIS-3, 96% of patients (95% CI, 91%–99%) achieved an SVR in both treatment groups, which was significantly superior to the performance goal. Overall, the most common adverse events were headache, fatigue, diarrhea, and nausea; diarrhea and nausea were reported more frequently by patients receiving voxilaprevir. In both trials, the proportion of patients who discontinued treatment because of adverse events was low (range, 0%–1%). Conclusions In phase 3 trials of patients with HCV infection, we did not establish that sofosbuvir-velpatasvir-voxilaprevir for 8 weeks was noninferior to sofosbuvir-velpatasvir for 12 weeks, but the 2 regimens had similar rates of SVR in patients with HCV genotype 3 and cirrhosis. Mild gastrointestinal adverse events were associated with treatment regimens that included voxilaprevir. ClinicalTrials.gov numbers: POLARIS-2, NCT02607800; and POLARIS-3, NCT02639338.

Background & Aims Persons with hepatitis C virus (HCV) infection are at risk of progressive liver disease, cirrhosis, and decompensation. We analyzed the effects of the direct-acting antiviral agents elbasvir and grazoprevir in patients with HCV infection and compensated cirrhosis, combining data from 6 clinical trials. Methods We performed an integrated analysis of 402 patients with HCV genotype 1, 4, or 6 infection and Child-Pugh A compensated cirrhosis enrolled in 6 clinical trials. All patients received elbasvir/grazoprevir 50 mg/100 mg once daily, with or without ribavirin, for 12−18 weeks. The primary end point was sustained virologic response 12 weeks after completion of therapy (SVR12), defined as a level of HCV RNA Results Among treatment-naive and treatment-experienced patients receiving elbasvir/grazoprevir for 12 weeks, 97.8% (135 of 138) and 88.9% (48 of 54) achieved SVR12, respectively. Among patients receiving elbasvir/grazoprevir for 12 weeks, addition of ribavirin did not increase the proportion of treatment-naive patients (90.3%, 28 of 31) or treatment-experienced patients who achieved an SVR12 (91.4%, 74 of 81). All (49 of 49) treatment-experienced patients receiving elbasvir/grazoprevir with ribavirin for 16 or 18 weeks, and 93.9% (46 of 49) of patients receiving elbasvir/grazoprevir without ribavirin for 16 or 18 weeks achieved SVR12. Virologic failure was higher among patients with HCV genotype 1a infections compared with patients with genotype 1b or 4 infections, particularly in patients who had not responded to previous interferon therapy. Baseline tests for resistance-associated substitutions (RASs) led to an individualized approach for selecting treatment duration and established a need for ribavirin for patients with HCV genotype 1a infection and RASs, regardless of treatment history. Among patients with HCV genotype 1a infection with and without baseline RASs in HCV nonstructural protein 5A who received elbasvir/grazoprevir for 12 weeks, 73% (8 of 11) and 98% (96 of 98) achieved SVR12, respectively. Both patients with HCV genotype 1a infection with baseline RASs who received 16 or 18 weeks of elbasvir/grazoprevir and ribavirin achieved SVR12. Grade 3 or 4 increases in levels of alanine aminotransferase and aspartate aminotransferase, which did not cause symptoms, were reported in 2.3% (6 of 264) of patients receiving elbasvir/grazoprevir. Serious adverse events were reported in 3% (8 of 264) patients and no patient had a decompensation-related event. Conclusions In an analysis of data from 6 clinical trials, rates of SVR12 ranged from 89% to 100% in patients with HCV genotype 1, 4, or 6 infections and compensated cirrhosis treated with elbasvir/grazoprevir, with or without ribavirin. Addition of ribavirin to a 12-week regimen of elbasvir/grazoprevir had little effect on the proportion of treatment-naive or treatment-experienced patients who achieved an SVR12. However, virologic failure did not occur in any treatment-experienced patients when the duration of elbasvir/grazoprevir and ribavirin therapy was extended to 16 or 18 weeks. Baseline analysis of RASs (or in the absence of this test, a history of nonresponse to interferon) can be used to determine treatment duration and the need for ribavirin in patients with HCV genotype 1a infection. Clinicaltrials.gov ID: NCT02092350, NCT02105662, NCT02105467, NCT02105701, NCT01717326, and NCT02105454.

Background & AimsThe best regimen to re-treat patients who do not respond to direct-acting antivirals (DAAs) and the feasibility of further shortening regimens is unclear. We assessed the efficacy and safety of the combination of the nucleotide polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the NS3/4A protease inhibitor GS-9857 in patients with hepatitis C virus genotype 1 infection.MethodsWe performed an open-label trial at 32 sites in the United States and at 2 sites in New Zealand of 197 patients with genotype 1 hepatitis C virus infection, with or without compensated cirrhosis, who were treatment-naive or were treated previously with a DAA. Between March 2, 2015, and September 1, 2015, patients received sofosbuvir-velpatasvir (400 mg/100 mg in a fixed-dose combination) plus GS-9857 (100 mg) once daily for 6–12 weeks, plus ribavirin for 1 treatment group consisting of treatment-naive patients with cirrhosis. The primary end point was sustained virologic response 12 weeks after treatment (SVR12).ResultsAmong treatment-naive patients without cirrhosis, 71% (24 of 34; 95% confidence interval [CI], 53–85) achieved SVR12 after 6 weeks of treatment and 100% (36 of 36; 95% CI, 90%–100%) achieved SVR12 after 8 weeks of treatment. Among treatment-naive patients with cirrhosis, 94% (31 of 33; 95% CI, 80–99) achieved SVR12 after 8 weeks of treatment and 81% (25 of 31; 95% CI, 63–93) achieved SVR12 after 8 weeks of treatment with ribavirin. Among DAA-experienced patients treated for 12 weeks, 100% without cirrhosis (31 of 31; 95% CI, 89–100) and 100% with cirrhosis (32 of 32; 95% CI, 89–100) achieved SVR12. The most common adverse events were headache, diarrhea, fatigue, and nausea. One patient (

Background & AimsAlthough hepatitis C virus (HCV) infection is common in patients with end-stage renal disease, highly efficacious, well-tolerated, direct-acting antiviral regimens have not been extensively studied in this population. We investigated the safety and efficacy of ombitasvir co-formulated with paritaprevir and ritonavir, administered with dasabuvir (with or without ribavirin) in a prospective study of patients with stage 4 or 5 chronic kidney disease (CKD).MethodsWe performed a single-arm, multicenter study of treatment-naïve adults with HCV genotype 1 infection, without cirrhosis and with CKD stage 4 (estimated glomerular filtration rate, 15–30 mL/min/1.73 m2) or stage 5 (estimated glomerular filtration rate

Background The once-daily fixed-dose combination tablet of sofosbuvir/velpatasvir/voxilaprevir(SOF/VEL/VOX) was evaluated for the treatment of genotype 1–6 HCV infection in four Phase 3 studies in direct-acting antiviral (DAA)-experienced (POLARIS-1 and POLARIS-4) and DAA-naive (POLARIS-2 and POLARIS-3) patients with and without compensated cirrhosis. DAA-experienced patients received treatment for 12 weeks, and DAA-naive patients received treatment for 8 weeks. Overall SVR12 rates were >95% across all the studies. This post-hoc analysis assesses efficacy in patients with and without traditional negative predictors of response. Methods This was a retrospective analysis of data from 1056 patients treated with SOF/VEL/VOX in the Phase 3 studies. Presence of cirrhosis was determined by histology, Fibrotest/APRI, or Fibroscan. Viral load and other clinical and laboratory assessments were determined prior to treatment with SOF/VEL/VOX. Prior treatment records were source verified, and race was self-reported by the patient to the investigator. Results Overall, 38% of patients had cirrhosis, 70% had HCV RNA ≥800,000 IU/mL, 59% of the DAA-experienced patients had received an NS5A inhibitor-containing regimen, 20% of the DAA-naive patients had prior treatment failure with pegylated interferon +ribavirin, 12% were ≥65 years old and 10% were black. Conclusions The POLARIS-1, POLARIS-2, POLARIS-3, and POLARIS-4 studies enrolled a diverse patient population that included a significant number of patients with historically negative predictors of response including cirrhosis and prior exposure to DAA-containing regimens. High SVR12 rates for the ribavirin-free regimen of SOF/VEL/VOX were achieved across subgroups.

We evaluated the effects of baseline hepatitis C virus (HCV) NS5A, NS5B, and NS3 resistance-associated substitutions (RASs) on response to the combination of ledipasvir and sofosbuvir, with or without ribavirin, in patients with HCV genotype 1 infection.We analyzed data from 2144 participants in phase 2 and 3 studies of patients with HCV genotype 1a or b infection who received the combination of ledipasvir (90 mg) and sofosbuvir (400 mg) (ledipasvir/sofosbuvir) once daily, with or without ribavirin twice daily. Population and/or deep sequence analyses of the HCV NS3, NS5A, and NS5B genes were performed on blood samples collected at baseline.Overall, 16.0% of patients had detectable baseline RASs in NS5A. Among patients with HCV genotype 1b infection, there was no significant effect of baseline RASs in NS5A on sustained viral response 12 weeks after the end of treatment (SVR12) with ledipasvir/sofosbuvir and only a small effect in patients with HCV genotype 1a infection. RASs in NS5A that increased the half-maximal effective concentration to ledipasvir by more than 100-fold reduced the rate of SVR12 in treatment-naive patients given ledipasvir/sofosbuvir for 8 weeks (P = .011), but not for 12 weeks. These same baseline NS5A RASs reduced the percentage of treatment-experienced patients who achieved an SVR12 to 12 weeks (but not 24 weeks) ledipasvir/sofosbuvir (P .001). These RASs had a small effect in patients given ledipasvir/sofosbuvir in combination with ribavirin for 12 weeks. Overall, 2.5% of patients had baseline NS5B nucleotide inhibitor RASs (L159F, N142T, S282G, or L320S) and all achieved an SVR12. Of patients previously treated with protease inhibitors, 53.7% had RASs in NS3 and 96.5% achieved an SVR12.Baseline RASs in NS5A have minimal effects on patient responses to ledipasvir/sofosbuvir therapy. When these RASs do have effects, they could be largely overcome by extending treatment duration or through treatment intensification.

Background The once-daily fixed-dose combination tablet of sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) was evaluated for the treatment of genotype 1–6 HCV infection in four phase 3 studies in patients with and without compensated cirrhosis. This analysis describes the safety of SOF/VEL/VOX across 4 Phase 3 studies. Methods Treatment-emergent adverse events (AEs) and laboratory abnormalities were assessed in patients who received SOF/VEL/VOX or placebo for 12 weeks (POLARIS-1), SOF/VEL/VOX or SOF/VEL for 12 weeks (POLARIS-4), or SOF/VEL/VOX for 8 weeks or SOF/VEL for 12 weeks (POLARIS-2 and POLARIS-3). SAEs and deaths were followed until post-treatment Week 24. Data were pooled by treatment regimen. Results 1056 patients were treated with SOF/VEL/VOX for 8 (n=611) or 12 (n=445) weeks, 700 received SOF/VEL for 12 weeks. 38% had compensated cirrhosis, 28% had a BMI≥30 kg/m2, 36% were female, and 12% were ≥65 years old. AEs are presented in the table. Two deaths were reported, one illicit drug overdose and one attributed to hypertension (on post-treatment Day 76), neither were related to treatment. SAEs and discontinuations were more frequent in the placebo group and occurred with similar frequency in the other groups; none were related to study treatment. Headache, fatigue, nausea, and diarrhoea were the most common AEs. Mild diarrhoea and nausea occurred more frequently in the SOF/VEL/VOX groups. Overall, 5.1%–6.6% of patients who received SOF/VEL/VOX or SOF/VEL had Grade 3 or 4 laboratory abnormalities. Among patients receiving VOX, one patient each had a Grade 3 elevation in ALT and bilirubin (table 1). Conclusions SOF/VEL/VOX for 8 or 12 weeks in the POLARIS studies was well tolerated with a low frequency of Grade 3 or 4 AEs, SAEs, and AEs leading to discontinuation. The frequency of AEs in the SOF/VEL/VOX groups was similar to SOF/VEL and placebo groups, with higher rates of mild diarrhoea and nausea compared to SOF/VEL. References 1. Time to get control. A review of the care received by patients who had a severe gastrointestinal haemorrhage. NCEPOD 2015. 2. Shaheen AAM, Kaplan GG, Myers RP.Weekend versus weekday admissions and mortality from gastrointestinal haemorrhage caused by peptic ulcer disease. Clinical Gastroenterology and Hepatology2009;7:303–310.

The combination of a hepatitis C virus (HCV) protease inhibitor, peginterferon, and ribavirin is the standard of care for patients with HCV genotype 1 infection. We report the efficacy and safety of response-guided therapy with danoprevir (a potent second-generation protease inhibitor), peginterferon alfa-2a (40 KD), and ribavirin in these patients.Treatment-naïve patients (N = 237) were randomly assigned to groups given 12 weeks of danoprevir (300 mg every 8 hours; 600 mg every 12 hours, and 900 mg every 12 hours) or placebo plus peginterferon alfa-2a and ribavirin, followed by peginterferon alfa-2a and ribavirin. Patients given danoprevir who had an extended rapid virologic response (eRVR4-20: HCV RNA15 IU/mL during weeks 4-20) stopped therapy at week 24; those without an eRVR4-20 continued therapy to 48 weeks. Patients who were given placebo received 48 weeks of peginterferon alfa-2a and ribavirin. The primary efficacy end point was sustained virologic response (SVR: HCV RNA15 IU/mL after 24 weeks without treatment).Rates of SVR were higher among patients given danoprevir 300 mg (68%), 600 mg (85%), and 900 mg (76%) than placebo (42%) (95% confidence interval: 26%-59%). Seventy-nine percent of patients given danoprevir 600 mg had an eRVR4-20; among these, 96% had an SVR. Serious adverse events were reported in 7% to 8% of patients given danoprevir and 19% given placebo. Four patients given danoprevir (1 patient in the 600-mg group and 3 in the 900-mg group) had reversible, grade 4 increases in alanine aminotransferase, which led to early discontinuation of the 900-mg arm of the study.The combination of danoprevir, peginterferon alfa-2a, and ribavirin leads to high rates of SVR in patients with HCV genotype 1 infection, but high doses of danoprevir can lead to grade 4 increases in alanine aminotransferase. Studies of lower doses of danoprevir with ritonavir, to reduce overall danoprevir exposure while maintaining potent antiviral activity, are underway; Clinicaltrials.gov number, NCT00963885.

Rationale: Newly approved direct acting antiviral (DAA) regimens for Chronic Hepatitis C (HCV) achieve excellent response rates with unprecedented attainment of sustained virologic response (SVR12) in clinical trials. "Real world" effectiveness of HCV DAA therapy in special populations, particularly minority populations, is lacking. Aim: To assess SVR12 rates and identify pre treatment predictors of SVR12 in a non-Caucasian cohort.Methods: A prospective cohort study consecutively enrolled mono-infected, non-Caucasian patients undergoing DAA treatment for HCV. Enrolled subjects (N=54) were treated with one of the following: 1) pegylated interferon alfa-2a (IFN) + sofosbuvir (SOF) + ribavirin (RBV) for 12 weeks; 2) SOF + RBV for 12 or 24 weeks; and 3) SOF + simeprevir (SMV) for 12 weeks in accordance with AASLD guidelines and genotype. End of treatment response and SVR12 were defined as HCV RNA undetectable or below the lower limit of detection at regimen completion and at 12 weeks post therapy, respectively. Multivariate logistic regression was conducted to identify significant predictors of SVR12 controlling for age, gender, and BMI. Results: The majority of participants were Hispanic (64.8%) followed by Asian (18.5%) and African American (16.7%). Baseline clinical and viral demographics were recorded [Table 1] and included: 59.3% cirrhotic, 57.5% genotype 1, mean viral load 2,703,207 IU/mL and previous interferon experience: naive, 57.4%; non response 33.3%; and relapse 9.3%. DAA regimens utilized: IFN + SOF + RBV, 27.8%; SOF + RBV, 48.1%; and SOF + SMV, 24.1%. End of treatment response was 96% (52/54). SVR 12 rate was 81.5% (8 relapsers, 2 non responders to DAA therapy). Patients with pretreatment fasting glucose

Fibrosis stage was assessed by liver biopsy scores, FibroScan scores, or FibroTest scores. Post-treatment relapse shown through post-treatment week 12 for 3D+RBV arm and through post-treatment week 4 for TPV+pegIFN/RBV arm. Non-virologic treatment failure includes premature drug discontinuation and missing SVR data. *P-value ≤ 0.05 for the comparison with the TPV+pegIFN/RBV arm. For SVR4, P-value is based on logistic regression. Fisher's exact test was used for comparison of AE frequency.

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-naive 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

Rationale: Newly approved direct acting antiviral (DAA) regimens for Chronic Hepatitis C (HCV) achieve excellent response rates with unprecedented attainment of sustained virologic response (SVR12) in clinical trials. "Real world" effectiveness of HCV DAA therapy in special populations, particularly minority populations, is lacking. Aim: To assess SVR12 rates and identify pre treatment predictors of SVR12 in a non-Caucasian cohort.Methods: A prospective cohort study consecutively enrolled mono-infected, non-Caucasian patients undergoing DAA treatment for HCV. Enrolled subjects (N=54) were treated with one of the following: 1) pegylated interferon alfa-2a (IFN) + sofosbuvir (SOF) + ribavirin (RBV) for 12 weeks; 2) SOF + RBV for 12 or 24 weeks; and 3) SOF + simeprevir (SMV) for 12 weeks in accordance with AASLD guidelines and genotype. End of treatment response and SVR12 were defined as HCV RNA undetectable or below the lower limit of detection at regimen completion and at 12 weeks post therapy, respectively. Multivariate logistic regression was conducted to identify significant predictors of SVR12 controlling for age, gender, and BMI. Results: The majority of participants were Hispanic (64.8%) followed by Asian (18.5%) and African American (16.7%). Baseline clinical and viral demographics were recorded [Table 1] and included: 59.3% cirrhotic, 57.5% genotype 1, mean viral load 2,703,207 IU/mL and previous interferon experience: naive, 57.4%; non response 33.3%; and relapse 9.3%. DAA regimens utilized: IFN + SOF + RBV, 27.8%; SOF + RBV, 48.1%; and SOF + SMV, 24.1%. End of treatment response was 96% (52/54). SVR 12 rate was 81.5% (8 relapsers, 2 non responders to DAA therapy). Patients with pretreatment fasting glucose

International audience; BACKGROUND & AIMS:Twenty-four weeks of treatment with peginterferon and ribavirin for chronic hepatitis C virus (HCV) genotype 2 or 3 infection produces a sustained virologic response (SVR) in 70%-80% of patients. We performed a randomized, double-blind, phase 2b study to assess whether adding daclatasvir, a nonstructural protein 5A (NS5A) inhibitor that is active against these genotypes, improves efficacy and shortens therapy.METHODS:Patients with HCV genotype 2 or 3 infection (n = 151), enrolled at research centers in North America, Europe, or Australia, were assigned randomly to groups given 12 or 16 weeks of daclatasvir (60 mg once daily), or 24 weeks of placebo, each combined with peginterferon alfa-2a and ribavirin. Treatment was extended to 24 weeks for recipients of daclatasvir who did not meet the criteria for early virologic response. The primary end point was SVR at 24 weeks after treatment (SVR24).RESULTS:Baseline characteristics were similar among patients within each HCV genotype group. However, the 80 patients with HCV genotype 3, compared with the 71 patients with HCV genotype 2, were younger (mean age, 45 vs 53 y, respectively), and a larger proportion had cirrhosis (23% vs 1%, respectively). Among patients with HCV genotype 2 infection, an SVR24 was achieved by 83%, 83%, and 63% of those in the daclatasvir 12-week group, the daclatasvir 16-week group, or the placebo group, respectively; among patients with HCV genotype 3 infection, an SVR24 was achieved by 69%, 67%, and 59% of patients in these groups, respectively. Differences between genotypes largely were attributable to the higher frequency of post-treatment relapse among patients infected with HCV genotype 3. In both daclatasvir arms for both HCV genotypes, the lower bound of the 80% confidence interval of the difference in SVR24 rates between the daclatasvir and placebo arms was above -20%, establishing noninferiority. Safety findings were similar among groups, and were typical of those expected from peginterferon alfa and ribavirin therapy.CONCLUSIONS:Twelve or 16 weeks of treatment with daclatasvir, in combination with peginterferon alfa-2a and ribavirin, is a well tolerated and effective therapy for patients with HCV genotype 2 or 3 infections. Daclatasvir-containing regimens could reduce the duration of therapy for these patients. Clinicaltrials.gov number: NCT01257204.

connectivity and negative correlations with right frontal parietal ICN precentral gyrus connectivity. Sex x disease related differences were observed in the default mode network (DMN), right frontal parietal areas, and left frontal parietal areas with increasing levels of EALs. Conclusions: Intrinsic connectivity networks are altered in IBS compared to HC in the context of early adverse life trauma, and these differences are further evident in the pain and emotion regions for females compared to the somatosensory and cognitive regions for males. Consistent with other research, these results suggest that an increased sensitivity to emotion and pain in female IBS compared to male IBS may be associated with altered connectivity integrity with increasing levels of early life adversity.

Introduction On treatment, a poor therapeutic response to peginterferon (P)/ribavirin (R) is defined as a Method Patients in the lead-in arm (N=240) received 4 weeks of PR followed by telaprevir (T) 750 mg 8 hourly for 12 weeks combined with PR followed by 32 weeks of PR alone. Control patients (N=121) received 48 weeks of PR. All patients received pegylated interferon alfa-2a. Results 10% of prior relapsers and 31–40% of partial responders (shaded cells), had Conclusion Poor interferon responders on treatment (