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Background and Aim: Patients with refractory ascites have frequent hospital admissions, which pose exposure risks in the context of the COVID-19 pandemic. The aim of this study was to investigate the safety and efficacy of a novel 12-week, multidisciplinary ambulatory care program allowing frequent low-volume ascitic drainage through a tunneled, intraperitoneal catheter (IPC). Method(s): Adult patients with cirrhosis complicated by refractory ascites were recruited through a liver clinic in a tertiary health service in Melbourne, Australia from April to December 2020. All patients were enrolled in a 12-week multidisciplinary program including medical, nursing, dietetics, and pharmacy support. A Rocket Medical IPC was inserted on day 1 with 1-2 L of ascitic fluid drained over 1-3 sessions per week either at the patients' homes or at the hospital day ward. Patients' demographics, death, complications, and self-reported outcomes were recorded. Result(s): Twelve patients were enrolled with a median of 65-day (interquartile range [IQR]: 16.5-93) IPC duration between April and December 2020 across two periods of COVID-related lockdown in Melbourne, Australia. There were no IPC-related deaths. Early removal was necessitated in three patients due to leakage, nonadherence, and bacteremia. On day 30, the median self-reported health score increased from 50 (IQR: 50-70) to 78 (IQR: 50-85), attributable to a reduction in symptom burden. Conclusion(s): A multidisciplinary IPC program including the use of short-term IPC was safe and associated with a self-reported improvement in perceptions of health. In the context of the COVID-19 pandemic, the program aimed to reduce patient and clinician exposure, which is maintaining engagement and management of decompensated cirrhosis.Copyright © 2021 The Authors. JGH Open: An open access journal of gastroenterology and hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

Immune checkpoint inhibitors (ICIs) have led to major therapeutic advances in the management of malignancy. Despite promising outcomes for some cancers, ICIs are linked to unique side-effects known as immune-related adverse events (IrAEs). These may affect a wide array of organ systems. In particular, ICI-induced hepatitis is diagnostically challenging given its variable natural history and clinical manifestations. The onset of ICI-induced hepatitis often occurs between 6 and 14 weeks after treatment initiation and rarely exhibits delayed presentations or manifests after treatment cessation. We present a case of very delayed-onset ICI-induced hepatitis, stressing the importance of long-term surveillance for immune-indued hepatitis in patients initiated on ICIs even long after treatment cessation.Copyright © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Background and Aim: The coronavirus disease 2019 (COVID-19) pandemic has created challenges in how health care systems provide care for patients with refractory cirrhotic ascites. We aimed to investigate the safety and efficacy of a novel ambulatory care program developed with Hospital in the Home (HITH) to allow frequent low-volume ascitic drainage through a long-term, tunneled, intraperitoneal catheter (IPC; Rocket Medical) in patients with advanced cirrhosis. Method(s): We conducted a prospective cohort study at a Victorian tertiary health care service from April to July 2020. Adult patients with refractory cirrhotic ascites requiring large-volume abdominal paracentesis twice in the past 8 weeks were recruited. We excluded patients otherwise eligible for transjugular intrahepatic portosystemic shunt (TIPS) insertion or liver transplantation and those with Child-Pugh C disease, prior spontaneous bacterial peritonitis, active infection, loculated ascites, or hepatic hydrothorax. All IPCs were inserted by an interventional radiologist and managed for 12 weeks by HITH in lieu of recurrent hospital admission for large-volume paracentesis. The drainage schedule was individualized, with 1-6 L drained by HITH nurses over 1-3 sessions per week, without human albumin infusions. All patients received antibiotic prophylaxis (norfloxacin 400 mg daily or trimethoprim-sulfamethoxazole 160-800 mg daily). The primary endpoint was safety (death related to IPC, rates of bleeding, peritonitis, and cellulitis), with secondary endpoints including symptom burden, IPC attrition rates, and quality of life (EuroQol 5 dimensions). Result(s): Five patients (median age, 60 years; IQR, 53-74; four male) underwent insertion of an IPC. All had Child-Pugh B disease, with a median Model for End-Stage Liver Disease score of 11 (IQR, 9-13). The etiology of liver disease was alcohol (n = 4) and hepatitis C (n = 1). All patients were ineligible for TIPS due to prior hepatic encephalopathy and ineligi

Background and Aim: Chronic liver disease (CLD) is associated with significant morbidity, mortality, and health care resource utilization. There is evidence to support a chronic disease management (CDM) model of care for CLD, but all studies to date have been conducted in liver transplant centers. We aimed to evaluate the cost-effectiveness of a coordinated, multidisciplinary, ambulatory care service for patients with decompensated CLD at a Victorian tertiary health care service. Method(s): We conducted a prospective cohort study of adult patients with decompensated CLD who attended a multidisciplinary liver clinic from May 2019 to May 2020. Patients received regular consultations with a hepatologist, pharmacist, and dietitian, coordinated by a liver clinical nurse consultant. Paper-based and electronic patient education tools and Bluetooth body composition scales were used to improve patient monitoring and self-efficacy. Clinical data were collected from the electronic medical record system, and costing data were obtained from the finance department. The primary endpoint was total cost of liver-related hospital admissions 3 months before, compared with 3 months after, the index clinic appointment. Secondary outcomes evaluated were changes in liver disease severity and mortality. Result(s): Forty-seven patients (median age, 58 years [IQR, 47-69]; 47% male) with decompensated CLD received CDM. The median baseline Charlson Comorbidity Index score was 5 (IQR, 4-7). Liver disease etiologies were alcohol (43%), non-alcoholic fatty liver disease (15%), and concomitant hepatitis C and alcohol (13%). Sixty-six percent of patients were referred following an acute hospital admission, with ascites the most common complication of CLD (60%). Compared with before CDM, there was a statistically significant reduction in unplanned admissions due to ascites (28 vs 15, P = 0.01) but no difference in admissions for other liver-related diagnoses (Fig. 1). The total cost of liver-related

Background and Aim: Patients with refractory ascites have frequent hospital admissions, which pose exposure risks in the context of the COVID-19 pandemic. The aim of this study was to investigate the safety and efficacy of a novel 12-week, multidisciplinary ambulatory care program allowing frequent low-volume ascitic drainage through a tunneled, intraperitoneal catheter (IPC). Method(s): Adult patients with cirrhosis complicated by refractory ascites were recruited through a liver clinic in a tertiary health service in Melbourne, Australia from April to December 2020. All patients were enrolled in a 12-week multidisciplinary program including medical, nursing, dietetics, and pharmacy support. A Rocket Medical IPC was inserted on day 1 with 1-2 L of ascitic fluid drained over 1-3 sessions per week either at the patients' homes or at the hospital day ward. Patients' demographics, death, complications, and self-reported outcomes were recorded. Result(s): Twelve patients were enrolled with a median of 65-day (interquartile range [IQR]: 16.5-93) IPC duration between April and December 2020 across two periods of COVID-related lockdown in Melbourne, Australia. There were no IPC-related deaths. Early removal was necessitated in three patients due to leakage, nonadherence, and bacteremia. On day 30, the median self-reported health score increased from 50 (IQR: 50-70) to 78 (IQR: 50-85), attributable to a reduction in symptom burden. Conclusion(s): A multidisciplinary IPC program including the use of short-term IPC was safe and associated with a self-reported improvement in perceptions of health. In the context of the COVID-19 pandemic, the program aimed to reduce patient and clinician exposure, which is maintaining engagement and management of decompensated cirrhosis.Copyright © 2021 The Authors. JGH Open: An open access journal of gastroenterology and hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

Background and Aim: Chronic liver disease (CLD) is associated with significant morbidity, mortality, and health care resource utilization. There is evidence to support a chronic disease management (CDM) model of care for CLD, but all studies to date have been conducted in liver transplant centers. We aimed to evaluate the cost-effectiveness of a coordinated, multidisciplinary, ambulatory care service for patients with decompensated CLD at a Victorian tertiary health care service. Method(s): We conducted a prospective cohort study of adult patients with decompensated CLD who attended a multidisciplinary liver clinic from May 2019 to May 2020. Patients received regular consultations with a hepatologist, pharmacist, and dietitian, coordinated by a liver clinical nurse consultant. Paper-based and electronic patient education tools and Bluetooth body composition scales were used to improve patient monitoring and self-efficacy. Clinical data were collected from the electronic medical record system, and costing data were obtained from the finance department. The primary endpoint was total cost of liver-related hospital admissions 3 months before, compared with 3 months after, the index clinic appointment. Secondary outcomes evaluated were changes in liver disease severity and mortality. Result(s): Forty-seven patients (median age, 58 years [IQR, 47-69]; 47% male) with decompensated CLD received CDM. The median baseline Charlson Comorbidity Index score was 5 (IQR, 4-7). Liver disease etiologies were alcohol (43%), non-alcoholic fatty liver disease (15%), and concomitant hepatitis C and alcohol (13%). Sixty-six percent of patients were referred following an acute hospital admission, with ascites the most common complication of CLD (60%). Compared with before CDM, there was a statistically significant reduction in unplanned admissions due to ascites (28 vs 15, P = 0.01) but no difference in admissions for other liver-related diagnoses (Fig. 1). The total cost of liver-related

Immune checkpoint inhibitors (ICIs) have led to major therapeutic advances in the management of malignancy. Despite promising outcomes for some cancers, ICIs are linked to unique side-effects known as immune-related adverse events (IrAEs). These may affect a wide array of organ systems. In particular, ICI-induced hepatitis is diagnostically challenging given its variable natural history and clinical manifestations. The onset of ICI-induced hepatitis often occurs between 6 and 14 weeks after treatment initiation and rarely exhibits delayed presentations or manifests after treatment cessation. We present a case of very delayed-onset ICI-induced hepatitis, stressing the importance of long-term surveillance for immune-indued hepatitis in patients initiated on ICIs even long after treatment cessation.Copyright © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Background and Aim: The coronavirus disease 2019 (COVID-19) pandemic has created challenges in how health care systems provide care for patients with refractory cirrhotic ascites. We aimed to investigate the safety and efficacy of a novel ambulatory care program developed with Hospital in the Home (HITH) to allow frequent low-volume ascitic drainage through a long-term, tunneled, intraperitoneal catheter (IPC; Rocket Medical) in patients with advanced cirrhosis. Method(s): We conducted a prospective cohort study at a Victorian tertiary health care service from April to July 2020. Adult patients with refractory cirrhotic ascites requiring large-volume abdominal paracentesis twice in the past 8 weeks were recruited. We excluded patients otherwise eligible for transjugular intrahepatic portosystemic shunt (TIPS) insertion or liver transplantation and those with Child-Pugh C disease, prior spontaneous bacterial peritonitis, active infection, loculated ascites, or hepatic hydrothorax. All IPCs were inserted by an interventional radiologist and managed for 12 weeks by HITH in lieu of recurrent hospital admission for large-volume paracentesis. The drainage schedule was individualized, with 1-6 L drained by HITH nurses over 1-3 sessions per week, without human albumin infusions. All patients received antibiotic prophylaxis (norfloxacin 400 mg daily or trimethoprim-sulfamethoxazole 160-800 mg daily). The primary endpoint was safety (death related to IPC, rates of bleeding, peritonitis, and cellulitis), with secondary endpoints including symptom burden, IPC attrition rates, and quality of life (EuroQol 5 dimensions). Result(s): Five patients (median age, 60 years; IQR, 53-74; four male) underwent insertion of an IPC. All had Child-Pugh B disease, with a median Model for End-Stage Liver Disease score of 11 (IQR, 9-13). The etiology of liver disease was alcohol (n = 4) and hepatitis C (n = 1). All patients were ineligible for TIPS due to prior hepatic encephalopathy and ineligi

Immune checkpoint inhibitors (ICIs) have led to major therapeutic advances in the management of malignancy. Despite promising outcomes for some cancers, ICIs are linked to unique side-effects known as immune-related adverse events (IrAEs). These may affect a wide array of organ systems. In particular, ICI-induced hepatitis is diagnostically challenging given its variable natural history and clinical manifestations. The onset of ICI-induced hepatitis often occurs between 6 and 14 weeks after treatment initiation and rarely exhibits delayed presentations or manifests after treatment cessation. We present a case of very delayed-onset ICI-induced hepatitis, stressing the importance of long-term surveillance for immune-indued hepatitis in patients initiated on ICIs even long after treatment cessation.

BACKGROUND AND AIM: Patients with refractory ascites have frequent hospital admissions, which pose exposure risks in the context of the COVID-19 pandemic. The aim of this study was to investigate the safety and efficacy of a novel 12-week, multidisciplinary ambulatory care program allowing frequent low-volume ascitic drainage through a tunneled, intraperitoneal catheter (IPC). METHODS: Adult patients with cirrhosis complicated by refractory ascites were recruited through a liver clinic in a tertiary health service in Melbourne, Australia from April to December 2020. All patients were enrolled in a 12-week multidisciplinary program including medical, nursing, dietetics, and pharmacy support. A Rocket Medical IPC was inserted on day 1 with 1-2 L of ascitic fluid drained over 1-3 sessions per week either at the patients' homes or at the hospital day ward. Patients' demographics, death, complications, and self-reported outcomes were recorded. RESULTS: Twelve patients were enrolled with a median of 65-day (interquartile range [IQR]: 16.5-93) IPC duration between April and December 2020 across two periods of COVID-related lockdown in Melbourne, Australia. There were no IPC-related deaths. Early removal was necessitated in three patients due to leakage, nonadherence, and bacteremia. On day 30, the median self-reported health score increased from 50 (IQR: 50-70) to 78 (IQR: 50-85), attributable to a reduction in symptom burden. CONCLUSION: A multidisciplinary IPC program including the use of short-term IPC was safe and associated with a self-reported improvement in perceptions of health. In the context of the COVID-19 pandemic, the program aimed to reduce patient and clinician exposure, which is maintaining engagement and management of decompensated cirrhosis.

Background and Aim: Approved hepatitis C virus (HCV) treatments for patients on dialysis are associated with complexities, including drug-drug interactions, baseline resistance testing, use of ribavirin, and risk of hepatotoxicity. Despite higher concentrations of the primary circulating sofosbuvir (SOF) metabolite, GS-331007, in severe renal impairment, real-world case series showed substantial use of SOF-based regimens in this population, with no safety concerns identified. This study evaluated the safety, efficacy, and pharmacokinetics of sofosbuvir-velpatasvir (SOF/VEL) for 12 weeks in patients with HCV infection on dialysis. Method(s): Treatment-naive or -experienced patients, of any genotype, with or without compensated cirrhosis and undergoing hemodialysis or peritoneal dialysis, were enrolled to receive an open-label SOF/VEL (400 mg/100 mg daily) fixed-dose combination once daily for 12 weeks. The primary efficacy end-point was comparison of the sustained virological response 12 weeks after treatment (SVR12) to a prespecified historic control rate of 83%. The primary safety end-point was the proportion of patients who discontinued therapy due to adverse events (AEs). Secondary endpoints included safety, viral resistance, and pharmacokinetics. Result(s): A total of 59 patients were enrolled at 21 sites in Canada, the United Kingdom, Spain, Israel, Australia, and New Zealand. The median age was 60 years (range, 33-91), 59% were male, 53% white, 22% treatment-experienced, and 29% had cirrhosis. Most patients had HCV genotype 1 (42%), 2 (12%), or 3 (27%). Most (92%) were on hemodialysis, with a mean dialysis duration of 7.3 years (range, 0-40). Treatment was well tolerated; no one discontinued therapy due to AEs. One patient was discontinued from therapy on day 74 for non-compliance, with 48% study medication adherence by pill count. Overall, 56/59 patients (95%) achieved SVR12. Two (3%) had virological relapse (one with non-adherence). One patient did not achie

Introduction: Despite highly effective direct-acting antiviral (DAA) therapies for chronic hepatitis C virus (HCV) infection, some patients experience virological relapse. Salvage regimens should include multiple agents to suppress emergence of resistance-associated substitutions (RAS) and minimise treatment failure. The combination of sofosbuvir (SOF) and elbasvir/grazoprevir (ELB/GZR) +/-ribavirin (RBV) is an effective retreatment strategy for HCV genotype (GT)1 and 4 infection. We hypothesised that SOF and ELB/GZR (+/-RBV) would also be an effective salvage regimen for DAA-experienced GT3 patients. Method(s): We evaluated the efficacy and safety of SOF/ELB/GZR +/- RBV in DAA-experienced participants with chronic HCV infection who had prior relapse. Participants were treated at four hospitals between December 2016 and March 2018 for either 12- or 16-weeks. The primary endpoint was sustained virological response at week 12 post-treatment (SVR12) using intention-to-treat analysis. Result(s): There were 40 participants included in the analysis. The mean age was 53 years, 53% had GT3, 33% had GT1 infection and 63% had cirrhosis. Fifty-eight percent were treated for 12 weeks, 42% were treated for 16 weeks and 90% received RBV. The SVR12 rate was 98% overall, 100% in non-GT3 participants and 95% in GT3 participants. One GT3 cirrhotic participant relapsed. ELB/GZR was stopped at week 6 in one GT3 cirrhotic participant who switched to SOF/velpatasvir/RBV for a further 12 weeks and achieved SVR12. RBV dose reduction was required in two participants. Treatment was otherwise well tolerated. Discussion(s): The combination of SOF/ELB/GZR +/- RBV is effective and safe for difficult-to-cure patients who relapse after first-line DAA, including those with cirrhosis and GT3 infection.Copyright © 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Background: Recent prospective studies suggest combination therapy with immunomodulators improves efficacy, but long-term data is limited. Aim(s): To assess whether anti-tumour necrosis factor alpha (anti-TNF) monotherapy was associated with earlier loss of response (LOR) than combination therapy in a real-world cohort with long-term follow up. Method(s): A retrospective audit was conducted of inflammatory bowel disease patients receiving anti-TNF therapy in a tertiary centre and specialist private practices. All patients with accurate data for anti-TNF commencement and adequate correspondence to determine end-points were included. Outcomes measured included time to first LOR, causes and biochemical parameters. Result(s): Two hundred and twenty-four patients were identified; 139 (62.1%) on combination therapy and 85 (37.9%) on monotherapy. Forty-five percent of patients had LOR during follow up until a maximum of 8.5 years; 59.4% on combination therapy and 40.6% on monotherapy (P = 0.533). The median time to LOR was not different between groups; 1069 days for combination therapy and 1489 days for monotherapy (P = 0.533). There was no difference in time to LOR between patients treated with different combination regimens or different anti-TNF agents. Conclusion(s): In this large cohort of patients in a real-world setting, patients treated with anti-TNF monotherapy had similar rates of LOR as patients on anti-TNF combination therapy, at both short- and long-term follow up.Copyright © 2018 Royal Australasian College of Physicians

Background and Aim: Approved hepatitis C virus (HCV) treatments for patients on dialysis are associated with complexities, including drug-drug interactions, baseline resistance testing, use of ribavirin, and risk of hepatotoxicity. Despite higher concentrations of the primary circulating sofosbuvir (SOF) metabolite, GS-331007, in severe renal impairment, real-world case series showed substantial use of SOF-based regimens in this population, with no safety concerns identified. This study evaluated the safety, efficacy, and pharmacokinetics of sofosbuvir-velpatasvir (SOF/VEL) for 12 weeks in patients with HCV infection on dialysis. Method(s): Treatment-naive or -experienced patients, of any genotype, with or without compensated cirrhosis and undergoing hemodialysis or peritoneal dialysis, were enrolled to receive an open-label SOF/VEL (400 mg/100 mg daily) fixed-dose combination once daily for 12 weeks. The primary efficacy end-point was comparison of the sustained virological response 12 weeks after treatment (SVR12) to a prespecified historic control rate of 83%. The primary safety end-point was the proportion of patients who discontinued therapy due to adverse events (AEs). Secondary endpoints included safety, viral resistance, and pharmacokinetics. Result(s): A total of 59 patients were enrolled at 21 sites in Canada, the United Kingdom, Spain, Israel, Australia, and New Zealand. The median age was 60 years (range, 33-91), 59% were male, 53% white, 22% treatment-experienced, and 29% had cirrhosis. Most patients had HCV genotype 1 (42%), 2 (12%), or 3 (27%). Most (92%) were on hemodialysis, with a mean dialysis duration of 7.3 years (range, 0-40). Treatment was well tolerated; no one discontinued therapy due to AEs. One patient was discontinued from therapy on day 74 for non-compliance, with 48% study medication adherence by pill count. Overall, 56/59 patients (95%) achieved SVR12. Two (3%) had virological relapse (one with non-adherence). One patient did not achie

Introduction: Despite highly effective direct-acting antiviral (DAA) therapies for chronic hepatitis C virus (HCV) infection, some patients experience virological relapse. Salvage regimens should include multiple agents to suppress emergence of resistance-associated substitutions (RAS) and minimise treatment failure. The combination of sofosbuvir (SOF) and elbasvir/grazoprevir (ELB/GZR) +/-ribavirin (RBV) is an effective retreatment strategy for HCV genotype (GT)1 and 4 infection. We hypothesised that SOF and ELB/GZR (+/-RBV) would also be an effective salvage regimen for DAA-experienced GT3 patients. Method(s): We evaluated the efficacy and safety of SOF/ELB/GZR +/- RBV in DAA-experienced participants with chronic HCV infection who had prior relapse. Participants were treated at four hospitals between December 2016 and March 2018 for either 12- or 16-weeks. The primary endpoint was sustained virological response at week 12 post-treatment (SVR12) using intention-to-treat analysis. Result(s): There were 40 participants included in the analysis. The mean age was 53 years, 53% had GT3, 33% had GT1 infection and 63% had cirrhosis. Fifty-eight percent were treated for 12 weeks, 42% were treated for 16 weeks and 90% received RBV. The SVR12 rate was 98% overall, 100% in non-GT3 participants and 95% in GT3 participants. One GT3 cirrhotic participant relapsed. ELB/GZR was stopped at week 6 in one GT3 cirrhotic participant who switched to SOF/velpatasvir/RBV for a further 12 weeks and achieved SVR12. RBV dose reduction was required in two participants. Treatment was otherwise well tolerated. Discussion(s): The combination of SOF/ELB/GZR +/- RBV is effective and safe for difficult-to-cure patients who relapse after first-line DAA, including those with cirrhosis and GT3 infection.Copyright © 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Background: Recent prospective studies suggest combination therapy with immunomodulators improves efficacy, but long-term data is limited. Aim(s): To assess whether anti-tumour necrosis factor alpha (anti-TNF) monotherapy was associated with earlier loss of response (LOR) than combination therapy in a real-world cohort with long-term follow up. Method(s): A retrospective audit was conducted of inflammatory bowel disease patients receiving anti-TNF therapy in a tertiary centre and specialist private practices. All patients with accurate data for anti-TNF commencement and adequate correspondence to determine end-points were included. Outcomes measured included time to first LOR, causes and biochemical parameters. Result(s): Two hundred and twenty-four patients were identified; 139 (62.1%) on combination therapy and 85 (37.9%) on monotherapy. Forty-five percent of patients had LOR during follow up until a maximum of 8.5 years; 59.4% on combination therapy and 40.6% on monotherapy (P = 0.533). The median time to LOR was not different between groups; 1069 days for combination therapy and 1489 days for monotherapy (P = 0.533). There was no difference in time to LOR between patients treated with different combination regimens or different anti-TNF agents. Conclusion(s): In this large cohort of patients in a real-world setting, patients treated with anti-TNF monotherapy had similar rates of LOR as patients on anti-TNF combination therapy, at both short- and long-term follow up.Copyright © 2018 Royal Australasian College of Physicians

INTRODUCTION: Despite highly effective direct-acting antiviral (DAA) therapies for chronic hepatitis C virus (HCV) infection, some patients experience virological relapse. Salvage regimens should include multiple agents to suppress emergence of resistance-associated substitutions (RAS) and minimise treatment failure. The combination of sofosbuvir (SOF) and elbasvir/grazoprevir (ELB/GZR) ±ribavirin (RBV) is an effective retreatment strategy for HCV genotype (GT)1 and 4 infection. We hypothesised that SOF and ELB/GZR (±RBV) would also be an effective salvage regimen for DAA-experienced GT3 patients. METHODS: We evaluated the efficacy and safety of SOF/ELB/GZR ± RBV in DAA-experienced participants with chronic HCV infection who had prior relapse. Participants were treated at four hospitals between December 2016 and March 2018 for either 12- or 16-weeks. The primary endpoint was sustained virological response at week 12 post-treatment (SVR12) using intention-to-treat analysis. RESULTS: There were 40 participants included in the analysis. The mean age was 53 years, 53% had GT3, 33% had GT1 infection and 63% had cirrhosis. Fifty-eight percent were treated for 12 weeks, 42% were treated for 16 weeks and 90% received RBV. The SVR12 rate was 98% overall, 100% in non-GT3 participants and 95% in GT3 participants. One GT3 cirrhotic participant relapsed. ELB/GZR was stopped at week 6 in one GT3 cirrhotic participant who switched to SOF/velpatasvir/RBV for a further 12 weeks and achieved SVR12. RBV dose reduction was required in two participants. Treatment was otherwise well tolerated. DISCUSSION: The combination of SOF/ELB/GZR ± RBV is effective and safe for difficult-to-cure patients who relapse after first-line DAA, including those with cirrhosis and GT3 infection.

PURPOSE/BACKGROUND: To evaluate the safety and efficacy of all-oral therapy for HCV using combinations of 3 direct-acting antiviral drugs: grazoprevir, an NS3/4A protease inhibitor; MK-3682, an NS5B polymerase inhibitor, and either elbasvir or MK-8408, which are NS5A inhibitors. METHOD(S): In Part A of 2 ongoing randomized, dose-ranging, parallel-group, multicenter, open-label Phase 2 trials, 93 GT1 (46 GT1a, 47 GT1b), 61 GT2, and 86 GT3-infected treatment-naive, non-cirrhotic patients with chronic HCV infection were dosed once-daily for 8 weeks duration with one of 4 regimens including grazoprevir (100 mg), MK-3682 (300 mg or 450 mg), and either elbasvir (50 mg) or MK-8408 (60 mg). RESULT(S): GT1: Across treatment arms, 45/46 (98%) GT1a and 46/47 (98%) GT1b patients achieved sustained virologic response 12 weeks after end of study therapy (SVR12). In the 2 relapsers, population sequencing did not detect NS3, NS5B, or NS5A resistance associated variants (RAVs) conferring >=5-fold potency shifts at baseline or following relapse. GT2: The grazoprevir/ MK-3682 (450 mg)/MK-8408 regimen was highly effective, with SVR12 among 15/16 (94%) of GT2-infected patients, but regimens containing the 300 mg dose of MK-3682 and/or elbasvir resulted in lower efficacy (SVR12 in 29/45 (64%) GT2 patients; 60-71% across the 3 arms). Relapses were more common among patients who harbored an L31M/I NS5A variant at baseline. No treatment-emergent RAVs were observed. GT3: Across arms, SVR12 was achieved among 78/86 (91%) of GT3-infected patients; response was comparable across arms (86-95%). Eight GT3 patients relapsed. SVR12 was lower among GT3-infected patients who harbored an NS5A A30K, L31M, or Y93H RAV at baseline compared with patients without these RAVs at baseline (5/11 [45%] vs 72/74 [97%], respectively). Two of 8 GT3 relapsers acquired NS5A Y93H. All 240 patients completed the full 8 weeks of dosing. All regimens were generally well tolerated, and no cardiac or renal safety signals

Background While the necessity of treatment of hepatitis C virus (HCV)-infected patients with advanced liver disease is widely accepted, the benefit of treating patients without significant liver disease is less well established. Our aim was to assess the effect of treating HCV in patients with no or minimal fibrosis (Metavir stage F0-F1) on patient-reported outcomes (PROs). Methods HCV-infected patients with F0-F1 from 16 clinical trials were included. PROs were collected before, during, and after treatment. Results A total of 1548 HCV-infected patients with F0-F1 were included (mean age 46 years, 43% male, 81% treatment-naive). Patients were treated with interferon (IFN) + sofosbuvir (SOF) + ribavirin (RBV) (n = 91) or SOF + RBV with or without ledipasvir (n = 479) or IFN- and RBV-free regimens with SOF + ledipasvir or SOF + velpatasvir or SOF + velpatasvir + voxilaprevir (n = 978). By the end of treatment, patients receiving IFN-containing regimens experienced significant decreases in most PRO domains (-4.5 to -28.7 on a 0-100 scale), while subjects treated with IFN-free RBV-containing regimens had a modest impairment (-2.3 to -8.9) (P <=.01). In contrast, treatment with regimens without IFN and RBV led to PRO improvements (+1.2 to +10.9). Regardless of the regimen, sustained virologic responses (SVRs) at 12 and 24 weeks were universally associated with PRO improvements (+2.1 to +14.7, P <.0001. Conclusions HCV-infected subjects with no or minimal fibrosis treated with IFN- and RBV-free regimens experienced on-treatment and post-SVR PRO improvements.Copyright © The Author(s) 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved.

Patients with hepatitis C virus (HCV) who have virological failure (VF) after treatment containing a nonstructural protein 5A (NS5A) inhibitor have limited retreatment options. MAGELLAN-1 Part 2 was a randomized, open-label, phase 3 study to evaluate the efficacy and safety of ribavirin (RBV)-free glecaprevir and pibrentasvir (G/P; 300 mg/120 mg) in patients with chronic HCV and past VF on at least one NS3/4A protease and/or NS5A inhibitor-containing therapy. Patients with compensated liver disease, with or without cirrhosis, and HCV genotype (GT) 1, 4, 5, or 6 were randomized 1:1 to receive 12 or 16 weeks of G/P. The primary endpoint was sustained virological response (SVR) at 12 weeks posttreatment (SVR12). Among 91 patients treated, 87 had GT1 and 4 had GT4 infection. SVR12 was achieved by 89% (39 of 44) and 91% (43 of 47) of patients who received 12 and 16 weeks of G/P, respectively. Virological relapse occurred in 9% (4 of 44) of patients treated with 12 weeks of G/P; there were no relapses with 16 weeks of treatment. Past treatment history with one class of inhibitor (protease or NS5A) had no impact on SVR12, whereas past treatment with both classes of inhibitors was associated with lower SVR12 rate. The most common adverse event (AE) was headache (>=10% of patients), and there were no serious AEs assessed as related to study drugs or AEs leading to discontinuation. Conclusion(s): Sixteen weeks of G/P treatment achieved a high SVR12 rate in patients with HCV GT1 infection and past failure to regimens containing either NS5A inhibitors or NS3 protease inhibitors. (Hepatology 2018;67:1253-1260).Copyright © 2017 The Authors. Hepatology published by Wiley Periodicals, Inc. on behalf of American Association for the Study of Liver Diseases.

Introduction: Immunotherapy is an increasingly important component of care in the management of several advanced malignancies, including metastatic melanoma and non-small cell lung cancer. Immune-mediated adverse events to therapy involving the gastrointestinal tract have been described, namely, autoimmune colitis and hepatitis. We aimed to evaluate the incidence, risk factors, and management of the gastrointestinal-related autoimmune side effects of checkpoint inhibitor therapy. Method(s): We conducted a retrospective audit of the files of all patients who received checkpoint inhibitor therapy at a major tertiary referral center from January 1, 2015, to June 1, 2017. We focused on the cytotoxic T-lym-phocyte-associated antigen 4 (CTLA-4) inhibitor ipilimumab and the programmed cell death 1 (PD-1) inhibitors nivolumab and pembrolizumab. We analyzed the data in two groups: patients who developed any autoimmune complications while being treated with checkpoint inhibitor therapy and patients who did not. We assessed for differences in pre-existing autoimmune comorbidities and liver function test results over a 16-week period from commencement of their therapy. We then performed an in-depth review of the management of the patients who developed autoimmune colitis and hepatitis. Result(s): We identified 56 patients receiving checkpoint inhibitor ther-apy, of whom 45 patients (80.4%) received nivolumab, seven (12.5%) received ipilimumab, and one (1.8%) received pembrolizumab. Three patients received both nivolumab and ipilimumab (5.4%). A total of 14/56 patients (33%) developed an autoimmune-related side effect. Of these 14 patients, four (28.6%) developed autoimmune colitis and one (7.1%) developed autoimmune hepatitis. The other common autoim-mune complications were hyperthyroidism (2, 14.3%), pneumonitis (2, 14.3%), and hypophysitis (2, 14.3%). There was no statistically significant difference between the two groups at baseline with respect to age, sex, or ethnicity. B

Background: HCV GT3-infected patients are a challenging population in urgent need of optimally effective therapies. In a previous study in GT3 infection (ALLY-3), 12 weeks of DCV (pangenotypic NS5A inhibitor) plus SOF (nucleoside NS5B inhibitor) achieved 96% sustained virologic response at posttreatment week 12 (SVR12) in patients without cirrhosis and 63% in patients with cirrhosis. In ALLY-3+, the efficacy and safety of DCV+SOF with RBV for 12 vs 16 weeks were evaluated in HCV GT3 patients with compensated advanced fibrosis or cirrhosis. Method(s): Open-label, phase 3b study in HCV GT3-infected treatment-naive or -experienced patients with compensated advanced fibrosis or cirrhosis. Patients were randomized 1:1 to receive 12 weeks vs 16 weeks of DCV (60 mg QD) + SOF (400 mg QD) + RBV (weight based), stratified by advanced fibrosis or cirrhosis status. An interim analysis of efficacy (SVR at posttreatment week 4 [SVR4]) and safety outcomes is reported. SVR12 (primary endpoint) data will be available for presentation. Result(s): 50 patients were treated (12 weeks, 24; 16 weeks, 26). Most were male (80%), white (98%), and treatment experienced (74%; 10% prior relapse on SOF+RBV); 72% had cirrhosis and 52% had HCV RNA >=6 million IU/mL. Baseline characteristics were comparable between arms. Overall SVR4 by intention-to-treat analysis was 92%. In the 12- and 16-week arms, SVR4 was 88% and 96%, respectively. In the 12-week arm SVR4 was 83% in those with cirrhosis and 100% in those with advanced fibrosis; in the 16-week arm SVR4 was 94%, and 100%, respectively (Table). There were no virologic breakthroughs. Relapse occurred in 3 patients (1 in 16-week and 2 in 12-week arm). Four of 5 patients (80%) with prior relapse on SOF+RBV achieved SVR4. There was 1 death (12- week arm; not treatment-related). Treatment was well tolerated - the most common adverse events (AEs) were insomnia (30%), fatigue (26%) and headache (24%). One patient had a grade 3 hemoglobin reduction. Ther

Background and Aims: To evaluate a retreatment regimen for patients who had virologic relapse following 8 weeks of a 3-drug direct-acting antiviral (DAA) combination: MK-3682 (an NS5B polymerase nucleotide inhibitor), grazoprevir (GZR, an NS3/4A protease inhibitor), and either elbasvir (EBR) or ruzasvir (RZR, MK- 8408) which are NS5A inhibitors. Method(s): Genotype (GT)1-, 2-, and 3-infected, non-cirrhotic patients with chronic HCV infection who relapsed after 8 weeks of therapy with one of 4 regimens that included a 3-DAA combination of MK- 3682 (300 mg or 450 mg), GZR (100 mg), and either EBR (50 mg) or RZR (60 mg) were offered open-label retreatment with 16 weeks of a fixed-dose combination (FDC) of once-daily MK3 [MK-3682 (450 mg)/GZR (100 mg)/RZR (60 mg)] + ribavirin (RBV). Next-generation sequencing with a 15% thresholdwas used to test for resistanceassociated substitutions (RASs). Result(s): Twenty-four of 26 eligible patients were enrolled, 2 with GT1, 14 with GT2, and 8 with GT3 infection. All RASs observed at time of failure of initial therapy were also detected at initiation of retreatment. Overall, 21/24 (88%) patients had RASs in >1 class. High-impact NS5A RASs (>5-fold reduction in susceptibility to RZR) were detected in 11/14 (79%) of GT2-infected patients (L31M/I). Among GT3-infected patients, 2/8 (25%) had one (A30K or Y93H), 4/8 (50%) had two (A30K, L31M, S62L or Y93H) high-impact NS5A RASs; 1/8 (13%) had both Y93H and a high-impact NS3 RAS (Q168R) that resulted in >5-fold reduction in susceptibility to GZR. 1/8 (13%) GT3- infected and 2/2 (100%) GT1 infected patients had no high-impact RASs detected. Of all patients who received at least one dose of study drug (full analysis set), the SVR24 rates were 2/2 (100%) in GT1 patients, 13/14 (93%) in GT2 patients, and 8/8 (100%) in GT3 patients. The only patient who did not achieve SVR24 was a GT2-infected patient who withdrew after a single dose because of adverse events (AEs) of vomiting and tachycardi

Background and Aims: The REV1TAL study is the largest real-world evaluation of ritonavir boosted paritaprevir with ombitasvir and dasabuvir (PrOD)+/-ribavirin in hepatitis C genotype 1 in cirrhotic patients. The aims of this study were to (a) compare the efficacy of PrOD-based therapy between cirrhotic and non-cirrhotic patients, (b) explore baseline demographic factors that influence SVR and (c) ascertain the frequency, nature and predictive factors for serious adverse events. Method(s): There were 451 patients from 20 centres in Australia with hepatitis C genotype 1 with complete SVR and cirrhosis data thatwere included in the analysis. Patient information including baseline demographics, virologic and on-treatment biochemical and haematological indices together with details on serious adverse events and early discontinuations were collected locally by treating clinicians. Result(s): Of 451 patients included, 340 had cirrhosis (75.4%). Overall SVR rates were 95.1% with no significant differences in SVR between cirrhotic and non-cirrhotic individuals. The regimen was particularly effective in subgenotype 1b with an overall SVR of 99.2%. Serious adverse events occurred in 10.9% of patients; 89.8% were cirrhotic. Hepatic decompensation occurred in 2.7% of patients but there were no deaths. Hepatocellular carcinoma occurred in 1.8% of patients (2.4% of cirrhotic group). On multivariate analysis, only baseline bilirubin and early cessation of therapy influenced SVR. Onmultivariate analysis of factors predictive of serious adverse events, Child-Pugh Class B was the only significant factor in the overall group, but in the cirrhotic group baseline albumin and creatinine were significant predictive factors for developing a serious adverse event. Conclusion(s): In a real-world setting PrOD antiviral therapy is highly effective therapy for hepatitis C genotype 1 in both cirrhotic and noncirrhotic patients. Important determinants of treatment failure include early cessation o

Background: Limited data exist on the outcomes of ritonavir-boosted paritaprevir with ombitasvir and dasabuvir (PrOD) +/- ribavirin in a real-world setting. The aim of this study was to compare the efficacy and safety of PrOD-based therapy in hepatitis C genotype 1 patients with and without cirrhosis, and to explore pretreatment factors predictive of sustained viral response (SVR) and serious adverse events (SAEs) on treatment. Method(s): 451 patients with hepatitis C genotype 1 treated in 20 centres across Australia were included. Baseline demographic, clinical and laboratory information, on-treatment biochemical, virological and haematological indices and details on serious adverse events were collected locally. Result(s): Cirrhosis was present in 340 patients (75.4%). Overall SVR was 95.1% with no differences in SVR between the cirrhosis and non-cirrhosis groups (94.7% versus 96.4%). SVR in subgenotypes 1a and 1b was 93.1% and 99.2%, respectively. On multivariate analysis, baseline bilirubin level and early treatment cessation predicted SVR. SAEs occurred in 10.9% of patients including hepatic decompensation (2.7%) and hepatocellular carcinoma (1.8%). On multivariate analysis of factors predictive of SAEs in the overall group, Child-Turcotte-Pugh (CTP) B was the only significant factor, while in those with cirrhosis, baseline albumin and creatinine levels were significant. Conclusion(s): In this large real-world cohort of HCV genotype 1 subjects, treatment with PrOD was highly effective and similar to clinical trials. Important determinants of reduced SVR include early cessation of therapy and baseline bilirubin concentration. SAEs were not infrequent with CTP B patients being at greatest risk.Copyright © 2017 International Medical Press.

Background & Aims: Patients with chronic hepatitis C virus infection and advanced fibrosis (Metavir F3) or cirrhosis (Metavir F4) have been identified as a priority group for immediate treatment. We evaluated the safety and efficacy of sofosbuvir-velpatasvir in patients with hepatitis C virus genotype 1-6 infection and compensated cirrhosis or advanced fibrosis. Method(s): This retrospective analysis included 501 patients with compensated cirrhosis or advanced fibrosis (F3/F4), as defined by >0.59 on Fibrotest, >9.5 kPa on Fibroscan, or F3/F4 (Metavir) or F4 (Ishak) on liver biopsy. Patients received sofosbuvir-velpatasvir for 12 weeks. Sustained virological response 12 weeks after treatment was determined. Result(s): Forty-four per cent of patients had cirrhosis. Sustained virological response 12 weeks after treatment was achieved by 98% of patients (490/501; 95% confidence interval, 96-99). Sustained virological response 12 weeks after treatment rates were 100% for hepatitis C virus genotypes 2 (85/85), 4 (60/60), 5 (13/13), and 6 (20/20). Sustained virological response 12 weeks after treatment rates were 98% (167/170) in hepatitis C virus genotype 1 patients and 95% (145/153) in hepatitis C virus genotype 3 patients. Among patients with cirrhosis 96% (212/220) achieved sustained virological response 12 weeks after treatment, vs 99% (278/281) for those with advanced fibrosis. Sustained virological response 12 weeks after treatment was 98% (306/311) for treatment-naive patients and 97% (184/190) for treatment-experienced patients. No patients discontinued treatment due to adverse events. Eight patients reported nine serious adverse events; none was considered related to study procedures or drugs. Conclusion(s): Sofosbuvir plus velpatasvir is highly effective and safe for treating patients with hepatitis C virus genotypes 1, 2, 3, 4, 5 or 6 and advanced fibrosis or compensated cirrhosis.Copyright © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Background and Aims: Limited data on the long-term persistence of NS5A and NS3 HCV resistance associated substitutions (RASs) are available after treatment with clinically relevant HCV regimens. The aim of this study was to evaluate the persistence of NS3, NS5A and NS5B nucleotide inhibitor (NI) RASs in patients not achieving SVR in Gilead-sponsored treatment studies who were enrolled in a followup Sequence Registry. Method(s): Patients who did not achieve SVR following treatment with a DAA-containing regimen in a Gilead treatment protocol were eligible for enrollment into the Sequence Registry where they were followed for up to an additional 144 weeks. Patients had NS5A, NS3 and/or NS5B regions sequenced if they were exposed to an NSS5A inhibitor (ledipasvir [LDV] or velpatasvir [VEL]), an NS3 inhibitor (vedroprevir [VDV] or voxilaprevir [VOX]), and/or an NS5B NI (sofosbuvir [SOF]), respectively. Patients were discontinued if they received HCV treatment or once RASs were no longer detectable. Results are reported using a 15% cutoff. Result(s): Treatment-emergent NS5A and NS3 RASs were observed at the time of virologic failure (VF) in 95% and 93% of registry enrolled patients treated with non-SOF based regimens, respectively. NS5A and NS3 RASs were present at Week 144 in 63% and 25% of non-SOF treated patients, respectively. Treatment-emergent NS5A resistance was observed in 48% of registry enrolled patients at the time of VF with a SOF-based regimen. No treatment-emergent NS3 RASs were detected among the SOF/VEL/VOX failures enrolled in the study (Table). More than 1 NS5A RAS was detected in 47% and 7% of patients treated with non-SOF and SOF-based regimens, respectively. Treatment-emergent NS5B NI RASs were observed in 13/227 (6%) patients treated with a SOF-based regimens at the time of VF. No S282T was observed in any patient. Conclusion(s): Among patients enrolled in this follow up registry, treatment-emergent RASs at the time of VF as well as long-term persist

Background While the necessity of treatment of hepatitis C virus (HCV)-infected patients with advanced liver disease is widely accepted, the benefit of treating patients without significant liver disease is less well established. Our aim was to assess the effect of treating HCV in patients with no or minimal fibrosis (Metavir stage F0-F1) on patient-reported outcomes (PROs). Methods HCV-infected patients with F0-F1 from 16 clinical trials were included. PROs were collected before, during, and after treatment. Results A total of 1548 HCV-infected patients with F0-F1 were included (mean age 46 years, 43% male, 81% treatment-naive). Patients were treated with interferon (IFN) + sofosbuvir (SOF) + ribavirin (RBV) (n = 91) or SOF + RBV with or without ledipasvir (n = 479) or IFN- and RBV-free regimens with SOF + ledipasvir or SOF + velpatasvir or SOF + velpatasvir + voxilaprevir (n = 978). By the end of treatment, patients receiving IFN-containing regimens experienced significant decreases in most PRO domains (-4.5 to -28.7 on a 0-100 scale), while subjects treated with IFN-free RBV-containing regimens had a modest impairment (-2.3 to -8.9) (P <=.01). In contrast, treatment with regimens without IFN and RBV led to PRO improvements (+1.2 to +10.9). Regardless of the regimen, sustained virologic responses (SVRs) at 12 and 24 weeks were universally associated with PRO improvements (+2.1 to +14.7, P <.0001. Conclusions HCV-infected subjects with no or minimal fibrosis treated with IFN- and RBV-free regimens experienced on-treatment and post-SVR PRO improvements.Copyright © The Author(s) 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved.

Patients with hepatitis C virus (HCV) who have virological failure (VF) after treatment containing a nonstructural protein 5A (NS5A) inhibitor have limited retreatment options. MAGELLAN-1 Part 2 was a randomized, open-label, phase 3 study to evaluate the efficacy and safety of ribavirin (RBV)-free glecaprevir and pibrentasvir (G/P; 300 mg/120 mg) in patients with chronic HCV and past VF on at least one NS3/4A protease and/or NS5A inhibitor-containing therapy. Patients with compensated liver disease, with or without cirrhosis, and HCV genotype (GT) 1, 4, 5, or 6 were randomized 1:1 to receive 12 or 16 weeks of G/P. The primary endpoint was sustained virological response (SVR) at 12 weeks posttreatment (SVR12). Among 91 patients treated, 87 had GT1 and 4 had GT4 infection. SVR12 was achieved by 89% (39 of 44) and 91% (43 of 47) of patients who received 12 and 16 weeks of G/P, respectively. Virological relapse occurred in 9% (4 of 44) of patients treated with 12 weeks of G/P; there were no relapses with 16 weeks of treatment. Past treatment history with one class of inhibitor (protease or NS5A) had no impact on SVR12, whereas past treatment with both classes of inhibitors was associated with lower SVR12 rate. The most common adverse event (AE) was headache (>=10% of patients), and there were no serious AEs assessed as related to study drugs or AEs leading to discontinuation. Conclusion(s): Sixteen weeks of G/P treatment achieved a high SVR12 rate in patients with HCV GT1 infection and past failure to regimens containing either NS5A inhibitors or NS3 protease inhibitors. (Hepatology 2018;67:1253-1260).Copyright © 2017 The Authors. Hepatology published by Wiley Periodicals, Inc. on behalf of American Association for the Study of Liver Diseases.

PURPOSE/BACKGROUND: To evaluate the safety and efficacy of all-oral therapy for HCV using combinations of 3 direct-acting antiviral drugs: grazoprevir, an NS3/4A protease inhibitor; MK-3682, an NS5B polymerase inhibitor, and either elbasvir or MK-8408, which are NS5A inhibitors. METHOD(S): In Part A of 2 ongoing randomized, dose-ranging, parallel-group, multicenter, open-label Phase 2 trials, 93 GT1 (46 GT1a, 47 GT1b), 61 GT2, and 86 GT3-infected treatment-naive, non-cirrhotic patients with chronic HCV infection were dosed once-daily for 8 weeks duration with one of 4 regimens including grazoprevir (100 mg), MK-3682 (300 mg or 450 mg), and either elbasvir (50 mg) or MK-8408 (60 mg). RESULT(S): GT1: Across treatment arms, 45/46 (98%) GT1a and 46/47 (98%) GT1b patients achieved sustained virologic response 12 weeks after end of study therapy (SVR12). In the 2 relapsers, population sequencing did not detect NS3, NS5B, or NS5A resistance associated variants (RAVs) conferring >=5-fold potency shifts at baseline or following relapse. GT2: The grazoprevir/ MK-3682 (450 mg)/MK-8408 regimen was highly effective, with SVR12 among 15/16 (94%) of GT2-infected patients, but regimens containing the 300 mg dose of MK-3682 and/or elbasvir resulted in lower efficacy (SVR12 in 29/45 (64%) GT2 patients; 60-71% across the 3 arms). Relapses were more common among patients who harbored an L31M/I NS5A variant at baseline. No treatment-emergent RAVs were observed. GT3: Across arms, SVR12 was achieved among 78/86 (91%) of GT3-infected patients; response was comparable across arms (86-95%). Eight GT3 patients relapsed. SVR12 was lower among GT3-infected patients who harbored an NS5A A30K, L31M, or Y93H RAV at baseline compared with patients without these RAVs at baseline (5/11 [45%] vs 72/74 [97%], respectively). Two of 8 GT3 relapsers acquired NS5A Y93H. All 240 patients completed the full 8 weeks of dosing. All regimens were generally well tolerated, and no cardiac or renal safety signals

Introduction: Immunotherapy is an increasingly important component of care in the management of several advanced malignancies, including metastatic melanoma and non-small cell lung cancer. Immune-mediated adverse events to therapy involving the gastrointestinal tract have been described, namely, autoimmune colitis and hepatitis. We aimed to evaluate the incidence, risk factors, and management of the gastrointestinal-related autoimmune side effects of checkpoint inhibitor therapy. Method(s): We conducted a retrospective audit of the files of all patients who received checkpoint inhibitor therapy at a major tertiary referral center from January 1, 2015, to June 1, 2017. We focused on the cytotoxic T-lym-phocyte-associated antigen 4 (CTLA-4) inhibitor ipilimumab and the programmed cell death 1 (PD-1) inhibitors nivolumab and pembrolizumab. We analyzed the data in two groups: patients who developed any autoimmune complications while being treated with checkpoint inhibitor therapy and patients who did not. We assessed for differences in pre-existing autoimmune comorbidities and liver function test results over a 16-week period from commencement of their therapy. We then performed an in-depth review of the management of the patients who developed autoimmune colitis and hepatitis. Result(s): We identified 56 patients receiving checkpoint inhibitor ther-apy, of whom 45 patients (80.4%) received nivolumab, seven (12.5%) received ipilimumab, and one (1.8%) received pembrolizumab. Three patients received both nivolumab and ipilimumab (5.4%). A total of 14/56 patients (33%) developed an autoimmune-related side effect. Of these 14 patients, four (28.6%) developed autoimmune colitis and one (7.1%) developed autoimmune hepatitis. The other common autoim-mune complications were hyperthyroidism (2, 14.3%), pneumonitis (2, 14.3%), and hypophysitis (2, 14.3%). There was no statistically significant difference between the two groups at baseline with respect to age, sex, or ethnicity. B

Background: Limited data exist on the outcomes of ritonavir-boosted paritaprevir with ombitasvir and dasabuvir (PrOD) +/- ribavirin in a real-world setting. The aim of this study was to compare the efficacy and safety of PrOD-based therapy in hepatitis C genotype 1 patients with and without cirrhosis, and to explore pretreatment factors predictive of sustained viral response (SVR) and serious adverse events (SAEs) on treatment. Method(s): 451 patients with hepatitis C genotype 1 treated in 20 centres across Australia were included. Baseline demographic, clinical and laboratory information, on-treatment biochemical, virological and haematological indices and details on serious adverse events were collected locally. Result(s): Cirrhosis was present in 340 patients (75.4%). Overall SVR was 95.1% with no differences in SVR between the cirrhosis and non-cirrhosis groups (94.7% versus 96.4%). SVR in subgenotypes 1a and 1b was 93.1% and 99.2%, respectively. On multivariate analysis, baseline bilirubin level and early treatment cessation predicted SVR. SAEs occurred in 10.9% of patients including hepatic decompensation (2.7%) and hepatocellular carcinoma (1.8%). On multivariate analysis of factors predictive of SAEs in the overall group, Child-Turcotte-Pugh (CTP) B was the only significant factor, while in those with cirrhosis, baseline albumin and creatinine levels were significant. Conclusion(s): In this large real-world cohort of HCV genotype 1 subjects, treatment with PrOD was highly effective and similar to clinical trials. Important determinants of reduced SVR include early cessation of therapy and baseline bilirubin concentration. SAEs were not infrequent with CTP B patients being at greatest risk.Copyright © 2017 International Medical Press.

Background and Aims: To evaluate a retreatment regimen for patients who had virologic relapse following 8 weeks of a 3-drug direct-acting antiviral (DAA) combination: MK-3682 (an NS5B polymerase nucleotide inhibitor), grazoprevir (GZR, an NS3/4A protease inhibitor), and either elbasvir (EBR) or ruzasvir (RZR, MK- 8408) which are NS5A inhibitors. Method(s): Genotype (GT)1-, 2-, and 3-infected, non-cirrhotic patients with chronic HCV infection who relapsed after 8 weeks of therapy with one of 4 regimens that included a 3-DAA combination of MK- 3682 (300 mg or 450 mg), GZR (100 mg), and either EBR (50 mg) or RZR (60 mg) were offered open-label retreatment with 16 weeks of a fixed-dose combination (FDC) of once-daily MK3 [MK-3682 (450 mg)/GZR (100 mg)/RZR (60 mg)] + ribavirin (RBV). Next-generation sequencing with a 15% thresholdwas used to test for resistanceassociated substitutions (RASs). Result(s): Twenty-four of 26 eligible patients were enrolled, 2 with GT1, 14 with GT2, and 8 with GT3 infection. All RASs observed at time of failure of initial therapy were also detected at initiation of retreatment. Overall, 21/24 (88%) patients had RASs in >1 class. High-impact NS5A RASs (>5-fold reduction in susceptibility to RZR) were detected in 11/14 (79%) of GT2-infected patients (L31M/I). Among GT3-infected patients, 2/8 (25%) had one (A30K or Y93H), 4/8 (50%) had two (A30K, L31M, S62L or Y93H) high-impact NS5A RASs; 1/8 (13%) had both Y93H and a high-impact NS3 RAS (Q168R) that resulted in >5-fold reduction in susceptibility to GZR. 1/8 (13%) GT3- infected and 2/2 (100%) GT1 infected patients had no high-impact RASs detected. Of all patients who received at least one dose of study drug (full analysis set), the SVR24 rates were 2/2 (100%) in GT1 patients, 13/14 (93%) in GT2 patients, and 8/8 (100%) in GT3 patients. The only patient who did not achieve SVR24 was a GT2-infected patient who withdrew after a single dose because of adverse events (AEs) of vomiting and tachycardi

Background: HCV GT3-infected patients are a challenging population in urgent need of optimally effective therapies. In a previous study in GT3 infection (ALLY-3), 12 weeks of DCV (pangenotypic NS5A inhibitor) plus SOF (nucleoside NS5B inhibitor) achieved 96% sustained virologic response at posttreatment week 12 (SVR12) in patients without cirrhosis and 63% in patients with cirrhosis. In ALLY-3+, the efficacy and safety of DCV+SOF with RBV for 12 vs 16 weeks were evaluated in HCV GT3 patients with compensated advanced fibrosis or cirrhosis. Method(s): Open-label, phase 3b study in HCV GT3-infected treatment-naive or -experienced patients with compensated advanced fibrosis or cirrhosis. Patients were randomized 1:1 to receive 12 weeks vs 16 weeks of DCV (60 mg QD) + SOF (400 mg QD) + RBV (weight based), stratified by advanced fibrosis or cirrhosis status. An interim analysis of efficacy (SVR at posttreatment week 4 [SVR4]) and safety outcomes is reported. SVR12 (primary endpoint) data will be available for presentation. Result(s): 50 patients were treated (12 weeks, 24; 16 weeks, 26). Most were male (80%), white (98%), and treatment experienced (74%; 10% prior relapse on SOF+RBV); 72% had cirrhosis and 52% had HCV RNA >=6 million IU/mL. Baseline characteristics were comparable between arms. Overall SVR4 by intention-to-treat analysis was 92%. In the 12- and 16-week arms, SVR4 was 88% and 96%, respectively. In the 12-week arm SVR4 was 83% in those with cirrhosis and 100% in those with advanced fibrosis; in the 16-week arm SVR4 was 94%, and 100%, respectively (Table). There were no virologic breakthroughs. Relapse occurred in 3 patients (1 in 16-week and 2 in 12-week arm). Four of 5 patients (80%) with prior relapse on SOF+RBV achieved SVR4. There was 1 death (12- week arm; not treatment-related). Treatment was well tolerated - the most common adverse events (AEs) were insomnia (30%), fatigue (26%) and headache (24%). One patient had a grade 3 hemoglobin reduction. Ther

Background and Aims: The REV1TAL study is the largest real-world evaluation of ritonavir boosted paritaprevir with ombitasvir and dasabuvir (PrOD)+/-ribavirin in hepatitis C genotype 1 in cirrhotic patients. The aims of this study were to (a) compare the efficacy of PrOD-based therapy between cirrhotic and non-cirrhotic patients, (b) explore baseline demographic factors that influence SVR and (c) ascertain the frequency, nature and predictive factors for serious adverse events. Method(s): There were 451 patients from 20 centres in Australia with hepatitis C genotype 1 with complete SVR and cirrhosis data thatwere included in the analysis. Patient information including baseline demographics, virologic and on-treatment biochemical and haematological indices together with details on serious adverse events and early discontinuations were collected locally by treating clinicians. Result(s): Of 451 patients included, 340 had cirrhosis (75.4%). Overall SVR rates were 95.1% with no significant differences in SVR between cirrhotic and non-cirrhotic individuals. The regimen was particularly effective in subgenotype 1b with an overall SVR of 99.2%. Serious adverse events occurred in 10.9% of patients; 89.8% were cirrhotic. Hepatic decompensation occurred in 2.7% of patients but there were no deaths. Hepatocellular carcinoma occurred in 1.8% of patients (2.4% of cirrhotic group). On multivariate analysis, only baseline bilirubin and early cessation of therapy influenced SVR. Onmultivariate analysis of factors predictive of serious adverse events, Child-Pugh Class B was the only significant factor in the overall group, but in the cirrhotic group baseline albumin and creatinine were significant predictive factors for developing a serious adverse event. Conclusion(s): In a real-world setting PrOD antiviral therapy is highly effective therapy for hepatitis C genotype 1 in both cirrhotic and noncirrhotic patients. Important determinants of treatment failure include early cessation o

Background and Aims: Limited data on the long-term persistence of NS5A and NS3 HCV resistance associated substitutions (RASs) are available after treatment with clinically relevant HCV regimens. The aim of this study was to evaluate the persistence of NS3, NS5A and NS5B nucleotide inhibitor (NI) RASs in patients not achieving SVR in Gilead-sponsored treatment studies who were enrolled in a followup Sequence Registry. Method(s): Patients who did not achieve SVR following treatment with a DAA-containing regimen in a Gilead treatment protocol were eligible for enrollment into the Sequence Registry where they were followed for up to an additional 144 weeks. Patients had NS5A, NS3 and/or NS5B regions sequenced if they were exposed to an NSS5A inhibitor (ledipasvir [LDV] or velpatasvir [VEL]), an NS3 inhibitor (vedroprevir [VDV] or voxilaprevir [VOX]), and/or an NS5B NI (sofosbuvir [SOF]), respectively. Patients were discontinued if they received HCV treatment or once RASs were no longer detectable. Results are reported using a 15% cutoff. Result(s): Treatment-emergent NS5A and NS3 RASs were observed at the time of virologic failure (VF) in 95% and 93% of registry enrolled patients treated with non-SOF based regimens, respectively. NS5A and NS3 RASs were present at Week 144 in 63% and 25% of non-SOF treated patients, respectively. Treatment-emergent NS5A resistance was observed in 48% of registry enrolled patients at the time of VF with a SOF-based regimen. No treatment-emergent NS3 RASs were detected among the SOF/VEL/VOX failures enrolled in the study (Table). More than 1 NS5A RAS was detected in 47% and 7% of patients treated with non-SOF and SOF-based regimens, respectively. Treatment-emergent NS5B NI RASs were observed in 13/227 (6%) patients treated with a SOF-based regimens at the time of VF. No S282T was observed in any patient. Conclusion(s): Among patients enrolled in this follow up registry, treatment-emergent RASs at the time of VF as well as long-term persist

Background & Aims: Patients with chronic hepatitis C virus infection and advanced fibrosis (Metavir F3) or cirrhosis (Metavir F4) have been identified as a priority group for immediate treatment. We evaluated the safety and efficacy of sofosbuvir-velpatasvir in patients with hepatitis C virus genotype 1-6 infection and compensated cirrhosis or advanced fibrosis. Method(s): This retrospective analysis included 501 patients with compensated cirrhosis or advanced fibrosis (F3/F4), as defined by >0.59 on Fibrotest, >9.5 kPa on Fibroscan, or F3/F4 (Metavir) or F4 (Ishak) on liver biopsy. Patients received sofosbuvir-velpatasvir for 12 weeks. Sustained virological response 12 weeks after treatment was determined. Result(s): Forty-four per cent of patients had cirrhosis. Sustained virological response 12 weeks after treatment was achieved by 98% of patients (490/501; 95% confidence interval, 96-99). Sustained virological response 12 weeks after treatment rates were 100% for hepatitis C virus genotypes 2 (85/85), 4 (60/60), 5 (13/13), and 6 (20/20). Sustained virological response 12 weeks after treatment rates were 98% (167/170) in hepatitis C virus genotype 1 patients and 95% (145/153) in hepatitis C virus genotype 3 patients. Among patients with cirrhosis 96% (212/220) achieved sustained virological response 12 weeks after treatment, vs 99% (278/281) for those with advanced fibrosis. Sustained virological response 12 weeks after treatment was 98% (306/311) for treatment-naive patients and 97% (184/190) for treatment-experienced patients. No patients discontinued treatment due to adverse events. Eight patients reported nine serious adverse events; none was considered related to study procedures or drugs. Conclusion(s): Sofosbuvir plus velpatasvir is highly effective and safe for treating patients with hepatitis C virus genotypes 1, 2, 3, 4, 5 or 6 and advanced fibrosis or compensated cirrhosis.Copyright © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Background and Aim: Iron-deficiency anemia is one of the most prevalent medical conditions in Australia. In addition to iron supplementation, endoscopic evaluation is standard of care for all patients with iron-deficiency anemia without a clear underlying cause. We aimed to evaluate the safety, efficacy, and cost-benefit of ferric carboxymaltose (FCM) infusions on the same day as endoscopic evaluation. Method(s): We conducted a retrospective audit of all patient files for patients who received FCM infusions across a major tertiary referral center and a large private endoscopy day hospital from 1 January 2015 to 31 December 2016. We analyzed the data in two groups: an intervention group who received FCM infusions and endoscopy on the same day and a control group who underwent endoscopy on the same day as the intervention group but who did not receive FCM infusions on that day. Outcomes measured included biochemical parameters at entry and at 6 weeks, adverse events, and time in the endoscopy unit. The groups were matched for date, procedure, and sex. Result(s): We identified a total of 313 patients who received same-day endoscopy and FCM infusion. We evaluated 95 of these patients: 34 in the intervention group and 61 controls. Baseline characteristics (Table 1) were similar in the two groups. There were five adverse events in each group; however, in the intervention group, only one of these occurred following the FCM infusion. Same-day infusions increased time in endoscopy (191.6 vs 154.7 min; P = 0.01). All biochemical indices significantly improved in the intervention group (Table 2). Cost data were available for 14 intervention and 27 control patients (Table 3). Same-day FCM infusions resulted in an average cost-benefit of $229.70 per patient when compared with separate admissions for endoscopy and hospital-in-the-home for the FCM infusion. Conclusion(s): This novel study highlights that FCM infusions on the day of endoscopy appear to be safe and effective for pat

Background and Aim: Primary sclerosing cholangitis (PSC) is a progressive cholestatic liver disease with no proven effective medical therapy. Several randomized controlled trials have investigated the safety and efficacy of either high- or low-dose ursodeoxycholic acid (UDCA) compared with placebo as a potential treatment strategy, with conflicting results. The aim of this meta-analysis was to determine the efficacy and safety of high-dose (>15 mg/kg/day) versus low-dose (<= 15 mg/kg/day)UDCAin treating PSC. Method(s): We searched the Cochrane Library, MEDLINE, Embase, and the Web of Science for eligible studies comparing high- or low-dose UDCA in adult patients with PSC from 1990 to 2017. The primary end points evaluated were patient mortality, liver transplantation, clinical symptoms (fatigue and/or pruritus), serum biochemistry, progression of liver histology, and adverse events. The Mantel-Haenszel method was used to estimate the pooled risk ratios for binary outcomes, and Cohen's weighted mean difference for continuous outcomes. Heterogeneity was measured using the chi-squared test. Result(s): Fourteen studies (12 randomized controlled trials and two phase 3 studies) with 883 patients were included. Eight studies investigated low doses (10-15 mg/kg/day), four studies assessed high doses (17-30 mg/kg/ day), and two studies used both high- and low-doseUDCAin parallel. There were no significant differences between high- and low-dose UDCA with respect to mortality (relative risk [RR], 1.08; 95% CI, 0.35-3.29), progression of liver histology (RR, 0.27; 95% CI, 0.03-2.7), and adverse events (RR, 0.55; 95% CI, 0.09-3.38). There were no significant differences between high-dose UDCA and placebo with respect to mortality (RR, 0.98; 95% CI, 0.36-2.65), treatment failure (RR, 1.15; 95% CI, 0.96-2.24), adverse events (RR, 1.08; 95% CI, 0.96-2.24), cholangiographic deterioration (RR, 0.59; 95% CI, 0.27-1.30), clinical symptoms (fatigue and/or pruritus) (RR, 5; 95% CI, 0.26

Background New hepatitis C virus (HCV) therapies with pan-genotypic efficacy are needed. The goals of part A of C-CREST-1 and C-CREST-2 were to compare the efficacies of two doses (300 mg or 450 mg once daily) of uprifosbuvir (MK-3682; NS5B inhibitor) in an 8-week regimen combined with grazoprevir (NS3/4A inhibitor; 100 mg once daily) and an NS5A inhibitor, either elbasvir (50 mg once daily) or ruzasvir (MK-8408; 60 mg once daily), and to evaluate the safety and tolerability of these combination regimens in individuals infected with genotypes 1, 2, or 3. Methods Part A of these phase 2, randomised, multicentre, open-label, clinical trials enrolled participants from 11 countries, aged 18 years or older, chronically infected with HCV genotypes 1, 2, or 3, with HCV RNA of at least 10 000 IU/mL, without evidence of cirrhosis, who had not received previous treatment for HCV infection. Within each HCV genotype, participants were randomly assigned (1:1:1:1) with a block size of 4, to open-label treatment to one of four treatment groups: grazoprevir (100 mg/day) plus ruzasvir (60 mg/day) plus uprifosbuvir (300 mg/day); grazoprevir (100 mg/day) plus ruzasvir (60 mg/day) plus uprifosbuvir (450 mg/day); grazoprevir (100 mg/day) plus elbasvir (50 mg/day) plus uprifosbuvir (300 mg/day); or grazoprevir (100 mg/day) plus elbasvir (50 mg/day) plus uprifosbuvir (450 mg/day), according to a computer-generated allocation schedule. Randomisation was centrally implemented using an interactive voice response system and integrated web response system. The primary endpoint was the proportion of participants achieving sustained virological response at 12 weeks (SVR12; HCV RNA less than the lower limit of quantitation at 12 weeks after the end of all study therapy) in the per-protocol analysis set, which included all participants who were randomised and received at least one dose of study drug. The trials are registered with ClinicalTrials.gov, numbers NCT02332707 and NCT02332720. Findings 2

Introduction: Pyoderma gangrenosum (PG) is rare cutaneous condition characterized by ulcerative lesions with neutrophilic infiltrates, which can be seen in patients with systemic diseases, including inflammatory bowel disease (IBD). Tacrolimus and pimecrolimus are calcineurin inhibitors (CNIs) that can be applied topically for the management of PG; however, to date there have only been small-scale cohort studies and small case series evaluating their efficacy. We present six cases of topical CNI use in patients with IBD and report their safety and efficacy in the management of PG. Method(s): We reviewed six patients with IBD who were managed with either topical tacrolimus (0.03%-0.1%) or pimecrolimus (1%) for PG across three tertiary centres. Result(s): Our cases are summarized in Table 1. The cohort was predominantly female (83%), with a mean age of 32.8 years, with severe stricturing (50%) or fistulizing Crohn's disease (50%), including one patient who expressed both phenotypes. Overall, 67% of our cohort were anti-tumor necrosis factor (anti-TNF)-experienced and 83% had previous diseaserelated surgical resections. The mean time to first clinical response was 3.2 weeks (range, 1-8 weeks). The mean duration of treatment was 12.2 weeks, excluding one patient who is still in the seventh week of treatment. Complete resolution of the lesion was achieved in 83% of patients; however, there was recurrence in two patients at 2 weeks and 12 months, respectively. Response was recaptured in these two patients with CNI therapy at 1 week and 4 weeks, respectively. There were no documented side effects to either CNI. Conclusion(s): In our case series, topical therapy with tacrolimus or pimecrolimus appears to be a safe and effective option in the management of PG among both anti-TNF-experienced and -naive patients with IBD. Treatment response was noted to be rapid and seen as early as Week 1. There are currently no recommendations on the optimal treatment formulation and duratio

Background & Aims The efficacy of NS5A inhibitors for the treatment of patients chronically infected with hepatitis C virus (HCV) can be affected by the presence of NS5A resistance-associated substitutions (RASs). We analyzed data from 35 phase I, II, and III studies in 22 countries to determine the pretreatment prevalence of various NS5A RASs, and their effect on outcomes of treatment with ledipasvir-sofosbuvir in patients with genotype 1 HCV. Methods NS5A gene deep sequencing analysis was performed on samples from 5397 patients in Gilead clinical trials. The effect of baseline RASs on sustained virologic response (SVR) rates was assessed in the 1765 patients treated with regimens containing ledipasvir-sofosbuvir. Results Using a 15% cut-off, pretreatment NS5A and ledipasvir-specific RASs were detected in 13% and 8% of genotype 1a patients, respectively, and in 18% and 16% of patients with genotype 1b. Among genotype 1a treatment-naive patients, SVR rates were 91% (42/46) vs. 99% (539/546) for those with and without ledipasvir-specific RASs, respectively. Among treatment-experienced genotype 1a patients, SVR rates were 76% (22/29) vs. 97% (409/420) for those with and without ledipasvir-specific RASs, respectively. Among treatment-naive genotype 1b patients, SVR rates were 99% for both those with and without ledipasvir-specific RASs (71/72 vs. 331/334), and among treatment-experienced genotype 1b patients, SVR rates were 89% (41/46) vs. 98% (267/272) for those with and without ledipasvir-specific RASs, respectively. Conclusions Pretreatment ledipasvir-specific RASs that were present in 8-16% of patients have an impact on treatment outcome in some patient groups, particularly treatment-experienced patients with genotype 1a HCV. Lay summary The efficacy of treatments using NS5A inhibitors for patients with chronic hepatitis C virus (HCV) infection can be affected by the presence of NS5A resistance-associated substitutions (RASs). We reviewed results from 35 clinical t

People with hepatitis C virus (HCV) infection who have failed treatment with an all-oral regimen represent a challenging treatment population. The present studies evaluated the safety and efficacy of grazoprevir, ruzasvir, and uprifosbuvir, with or without ribavirin, in participants who had failed an NS5A inhibitor-containing regimen. C-SURGE (PN-3682-021) and C-CREST Part C (PN-3682-011 and -012) were open-label, multicenter studies. Participants who had previously relapsed following an NS5A inhibitor-containing all-oral regimen were retreated with grazoprevir 100 mg, ruzasvir 60 mg, and uprifosbuvir 450 mg alone for 24 weeks or with ribavirin for 16 weeks. The primary efficacy endpoint was sustained virologic response (HCV RNA below the limit of quantitation [<15 IU/mL]) 12 weeks after treatment completion (SVR12). In C-SURGE, SVR12 was achieved by 49/49 (100%) and 43/44 (98%) genotype (GT)1 participants in the 24-week no ribavirin arm and the 16-week plus ribavirin arm (lost to follow-up, n = 1), respectively. In C-CREST Part C, SVR12 was achieved by 23/24 (96%) participants treated for 16 weeks with ribavirin (GT1, 2/2 [100%]; GT2, 13/14 [93%]; GT3, 8/8 [100%]). One participant with GT2 infection discontinued study medication after a single dose of grazoprevir, ruzasvir, and uprifosbuvir plus ribavirin due to serious adverse events of vomiting and tachycardia. The presence of baseline resistance-associated substitutions had no impact on SVR12. No participant who completed treatment in either study experienced virologic failure. Conclusion(s): Grazoprevir, ruzasvir, and uprifosbuvir, with or without ribavirin, for 16 or 24 weeks was safe and highly effective in participants with HCV infection who had previously failed NS5A inhibitor-containing therapy. (Hepatology 2017;66:1794-1804).Copyright © 2017 by the American Association for the Study of Liver Diseases.

Background: Although treatment of HCV subjects with advanced liver disease is widely accepted, the benefit of treatment for HCV patients without significant liver disease is less well established. Aim(s): To assess the PRO impact of treating HCV patients with none or minimal fibrosis (F0-F1). Method(s): HCV Patients with F0-F1 from 16 clinical trials were included. PROs were collected before, during and after treatment using SF-36 V2, FACIT-F, CLDQ-HCV, and WPAI-HCV. Result(s): 1,548 HCV patients with F0-F1 were included (age 46>11 years, 43% male, 82% Caucasian, 64% employed, 81% treatment-naive, 57% genotype 1). Patients were treated with pegylated interferon+ribavirin+ sofosbuvir (PEG-IFN+SOF+RBV) (N=91) or SOF+RBV+/- ledipasvir (LDV)(N=479) or IFN-and RBV-free regimens with LDV/SOF or SOF/velpatasvir (VEL) or SOF/VEL/voxilaprevir (VOX) (N=978). There were no PRO differences at baseline for 3 groups (all p<0.01). By end of treatment, F0-F1 patients receiving IFN+ regimens experienced significant decreases in most PRO domains (-4.5 to-28.7 on a 0-100 scale), while subjects treated RBV+ regimens had a modest impairment of PROs (-2.3 to-8.9) (all p<0.01). In contrast, treatment with regimen without IFN/RBV led to PRO improvement (+1.2 to + 10.9) (Figure). Regardless of regimen, SVR-12 and-24 were universally associated with PRO improvements (+3.9 to +14.7, all p<0.0001). In multivariate analysis, receiving an IFN+ (>=-5.3 to-28.5, p<0.01) or RBV+ regimens (>=-2.4 to-10.6, p<0.01) were predictive of PRO impairments during and after treatment. Conclusion(s): HCV subjects with none or minimal fibrosis treated with IFN/RBV-free regimens experience on-treatment and post-SVR PRO improvements. The stage of liver disease has no bearing on the PRO benefits of HCV patients treated with the new anti-viral regimens (Figure presented).

Introduction: Decompensated cirrhosis is a major health-care issue associated with increased morbidity and mortality and reduced quality of life. The Delphi panel of quality indicators (QIs) for cirrhosis care was derived in 2010. We investigated the impact on clinical outcomes of adherence to these QIs for ascites, variceal hemorrhage, and hepatic encephalopathy (HE). Method(s): From 2011 to 2016, 197 patients were admitted to Monash Health, a tertiary referral center, with their first hepatic decompensation. We assessed adherence to the QIs and the association of adherence with 30-day readmission, death within 90 days of index admission, and length of stay (LOS). Multivariate logistic regression analysis was used to assess the association between QI adherence and clinical outcomes. Result(s): Therewere no significant differences in age and sex among the three groups at baseline. Patients presenting with HE had significantly higher Model for End-stage Liver Disease (MELD) and MELD-Na scores compared with those presenting with ascites or variceal hemorrhage (P < 0.001) (Table 1). The main etiology of liver disease for the pooled cohort was alcohol use (67.01%) and hepatitis C (29.44%). The overall mean +/- SD length of admission was 8.90 +/- 9.79 days. Rates of adherence to the QIs are shown in Table 2, with a lower rate of adherence to QIs of care for HE compared with ascites or variceal hemorrhage, which did not reach statistical significance (P = 0.53). Adherence to general care QIs, such as documentation of MELD score and hepatitis A/B status, was low. The independent predictors of 90-day mortality for all patients with decompensated cirrhosis (Table 3) included overall adherence rate to all QIs (odds ratio [OR], 0.95; P = 0.001) and MELD score (OR, 1.12; P < 0.001). No QIs significantly predicted 30-day readmission rate or LOS. Conclusion(s): Our study found a low rate of adherence to QIs of care for HE and general care. We found that overall adherence to the D

Background & Aims The efficacy of NS5A inhibitors for the treatment of patients chronically infected with hepatitis C virus (HCV) can be affected by the presence of NS5A resistance-associated substitutions (RASs). We analyzed data from 35 phase I, II, and III studies in 22 countries to determine the pretreatment prevalence of various NS5A RASs, and their effect on outcomes of treatment with ledipasvir-sofosbuvir in patients with genotype 1 HCV. Methods NS5A gene deep sequencing analysis was performed on samples from 5397 patients in Gilead clinical trials. The effect of baseline RASs on sustained virologic response (SVR) rates was assessed in the 1765 patients treated with regimens containing ledipasvir-sofosbuvir. Results Using a 15% cut-off, pretreatment NS5A and ledipasvir-specific RASs were detected in 13% and 8% of genotype 1a patients, respectively, and in 18% and 16% of patients with genotype 1b. Among genotype 1a treatment-naïve patients, SVR rates were 91% (42/46) vs. 99% (539/546) for those with and without ledipasvir-specific RASs, respectively. Among treatment-experienced genotype 1a patients, SVR rates were 76% (22/29) vs. 97% (409/420) for those with and without ledipasvir-specific RASs, respectively. Among treatment-naïve genotype 1b patients, SVR rates were 99% for both those with and without ledipasvir-specific RASs (71/72 vs. 331/334), and among treatment-experienced genotype 1b patients, SVR rates were 89% (41/46) vs. 98% (267/272) for those with and without ledipasvir-specific RASs, respectively. Conclusions Pretreatment ledipasvir-specific RASs that were present in 8–16% of patients have an impact on treatment outcome in some patient groups, particularly treatment-experienced patients with genotype 1a HCV. Lay summary The efficacy of treatments using NS5A inhibitors for patients with chronic hepatitis C virus (HCV) infection can be affected by the presence of NS5A resistance-associated substitutions (RASs). We reviewed results from 35 clinical t

Background New hepatitis C virus (HCV) therapies with pan-genotypic efficacy are needed. The goals of part A of C-CREST-1 and C-CREST-2 were to compare the efficacies of two doses (300 mg or 450 mg once daily) of uprifosbuvir (MK-3682; NS5B inhibitor) in an 8-week regimen combined with grazoprevir (NS3/4A inhibitor; 100 mg once daily) and an NS5A inhibitor, either elbasvir (50 mg once daily) or ruzasvir (MK-8408; 60 mg once daily), and to evaluate the safety and tolerability of these combination regimens in individuals infected with genotypes 1, 2, or 3. Methods Part A of these phase 2, randomised, multicentre, open-label, clinical trials enrolled participants from 11 countries, aged 18 years or older, chronically infected with HCV genotypes 1, 2, or 3, with HCV RNA of at least 10 000 IU/mL, without evidence of cirrhosis, who had not received previous treatment for HCV infection. Within each HCV genotype, participants were randomly assigned (1:1:1:1) with a block size of 4, to open-label treatment to one of four treatment groups: grazoprevir (100 mg/day) plus ruzasvir (60 mg/day) plus uprifosbuvir (300 mg/day); grazoprevir (100 mg/day) plus ruzasvir (60 mg/day) plus uprifosbuvir (450 mg/day); grazoprevir (100 mg/day) plus elbasvir (50 mg/day) plus uprifosbuvir (300 mg/day); or grazoprevir (100 mg/day) plus elbasvir (50 mg/day) plus uprifosbuvir (450 mg/day), according to a computer-generated allocation schedule. Randomisation was centrally implemented using an interactive voice response system and integrated web response system. The primary endpoint was the proportion of participants achieving sustained virological response at 12 weeks (SVR12; HCV RNA less than the lower limit of quantitation at 12 weeks after the end of all study therapy) in the per-protocol analysis set, which included all participants who were randomised and received at least one dose of study drug. The trials are registered with ClinicalTrials.gov, numbers NCT02332707 and NCT02332720. Findings 2

Background and Aim: Iron-deficiency anemia is one of the most prevalent medical conditions in Australia. In addition to iron supplementation, endoscopic evaluation is standard of care for all patients with iron-deficiency anemia without a clear underlying cause. We aimed to evaluate the safety, efficacy, and cost-benefit of ferric carboxymaltose (FCM) infusions on the same day as endoscopic evaluation. Method(s): We conducted a retrospective audit of all patient files for patients who received FCM infusions across a major tertiary referral center and a large private endoscopy day hospital from 1 January 2015 to 31 December 2016. We analyzed the data in two groups: an intervention group who received FCM infusions and endoscopy on the same day and a control group who underwent endoscopy on the same day as the intervention group but who did not receive FCM infusions on that day. Outcomes measured included biochemical parameters at entry and at 6 weeks, adverse events, and time in the endoscopy unit. The groups were matched for date, procedure, and sex. Result(s): We identified a total of 313 patients who received same-day endoscopy and FCM infusion. We evaluated 95 of these patients: 34 in the intervention group and 61 controls. Baseline characteristics (Table 1) were similar in the two groups. There were five adverse events in each group; however, in the intervention group, only one of these occurred following the FCM infusion. Same-day infusions increased time in endoscopy (191.6 vs 154.7 min; P = 0.01). All biochemical indices significantly improved in the intervention group (Table 2). Cost data were available for 14 intervention and 27 control patients (Table 3). Same-day FCM infusions resulted in an average cost-benefit of $229.70 per patient when compared with separate admissions for endoscopy and hospital-in-the-home for the FCM infusion. Conclusion(s): This novel study highlights that FCM infusions on the day of endoscopy appear to be safe and effective for pat

Background and Aim: Primary sclerosing cholangitis (PSC) is a progressive cholestatic liver disease with no proven effective medical therapy. Several randomized controlled trials have investigated the safety and efficacy of either high- or low-dose ursodeoxycholic acid (UDCA) compared with placebo as a potential treatment strategy, with conflicting results. The aim of this meta-analysis was to determine the efficacy and safety of high-dose (>15 mg/kg/day) versus low-dose (<= 15 mg/kg/day)UDCAin treating PSC. Method(s): We searched the Cochrane Library, MEDLINE, Embase, and the Web of Science for eligible studies comparing high- or low-dose UDCA in adult patients with PSC from 1990 to 2017. The primary end points evaluated were patient mortality, liver transplantation, clinical symptoms (fatigue and/or pruritus), serum biochemistry, progression of liver histology, and adverse events. The Mantel-Haenszel method was used to estimate the pooled risk ratios for binary outcomes, and Cohen's weighted mean difference for continuous outcomes. Heterogeneity was measured using the chi-squared test. Result(s): Fourteen studies (12 randomized controlled trials and two phase 3 studies) with 883 patients were included. Eight studies investigated low doses (10-15 mg/kg/day), four studies assessed high doses (17-30 mg/kg/ day), and two studies used both high- and low-doseUDCAin parallel. There were no significant differences between high- and low-dose UDCA with respect to mortality (relative risk [RR], 1.08; 95% CI, 0.35-3.29), progression of liver histology (RR, 0.27; 95% CI, 0.03-2.7), and adverse events (RR, 0.55; 95% CI, 0.09-3.38). There were no significant differences between high-dose UDCA and placebo with respect to mortality (RR, 0.98; 95% CI, 0.36-2.65), treatment failure (RR, 1.15; 95% CI, 0.96-2.24), adverse events (RR, 1.08; 95% CI, 0.96-2.24), cholangiographic deterioration (RR, 0.59; 95% CI, 0.27-1.30), clinical symptoms (fatigue and/or pruritus) (RR, 5; 95% CI, 0.26