Avatrombopag, an Alternate Treatment Option to Reduce Platelet Transfusions in Patients with Thrombocytopenia and Chronic Liver Disease-Integrated Analyses of 2 Phase 3 Studies.

AIMS: Thrombocytopenia complicates the management of patients with chronic liver disease (CLD) undergoing invasive procedures with a bleeding risk. Until recently, prophylactic platelet transfusion was the only treatment option, but has significant safety and efficacy limitations. Phase 3 data demonstrated the superiority of avatrombopag to placebo in reducing platelet transfusions for bleeding, supporting its recent approval. METHODS: Integrated analyses of pooled data (N = 435) from two randomized, double-blind, placebo-controlled, phase 3 studies assessed the original efficacy endpoints. Additional analyses included subgroup analyses, alternate Baseline platelet count definitions, and another efficacy endpoint. RESULTS: Avatrombopag was superior to placebo in increasing patients not requiring a platelet transfusion or rescue procedure, those achieving a platelet count ≥50 × 109/L on Procedure Day, and the change in platelet counts from Baseline. The avatrombopag treatment effect was consistently positive across clinically important disease and Baseline clinical characteristic subgroups, and using alternate Baseline platelet count cohort definitions. Similarly, more avatrombopag-treated patients achieved ≥50 × 109/L platelets with an increase of ≥20 × 109/L from Baseline. The incidence and severity of adverse events were similar between avatrombopag and placebo. Further, safety data demonstrated a low risk for thromboembolic events and hepatotoxicity. CONCLUSION: These integrated analyses confirmed the superiority of avatrombopag to placebo in reducing platelet transfusions or rescue procedures for bleeding in patients with thrombocytopenia and CLD scheduled to undergo an invasive procedure, and its tolerable safety profile. Importantly, these data warrant reconsideration of clinical decision making regarding the need to treat thrombocytopenia in patients with CLD. This trial was registered with NCT01972529 and NCT01976104.

Integrating next-generation sequencing to endoscopic retrograde cholangiopancreatography (ERCP)-obtained biliary specimens improves the detection and management of patients with malignant bile duct strictures.

OBJECTIVE: Despite improvements in imaging, serum CA19-9 and pathological evaluation, differentiating between benign and malignant bile duct strictures remains a diagnostic conundrum. Recent developments in next-generation sequencing (NGS) have opened new opportunities for early detection and management of cancers but, to date, have not been rigorously applied to biliary specimens. DESIGN: We prospectively evaluated a 28-gene NGS panel (BiliSeq) using endoscopic retrograde cholangiopancreatography-obtained biliary specimens from patients with bile duct strictures. The diagnostic performance of serum CA19-9, pathological evaluation and BiliSeq was assessed on 252 patients (57 trainings and 195 validations) with 346 biliary specimens. RESULTS: The sensitivity and specificity of BiliSeq for malignant strictures was 73% and 100%, respectively. In comparison, an elevated serum CA19-9 and pathological evaluation had sensitivities of 76% and 48%, and specificities of 69% and 99%, respectively. The combination of BiliSeq and pathological evaluation increased the sensitivity to 83% and maintained a specificity of 99%. BiliSeq improved the sensitivity of pathological evaluation for malignancy from 35% to 77% for biliary brushings and from 52% to 83% for biliary biopsies. Among patients with primary sclerosing cholangitis (PSC), BiliSeq had an 83% sensitivity as compared with pathological evaluation with an 8% sensitivity. Therapeutically relevant genomic alterations were identified in 20 (8%) patients. Two patients with ERBB2-amplified cholangiocarcinoma received a trastuzumab-based regimen and had measurable clinicoradiographic response. CONCLUSIONS: The combination of BiliSeq and pathological evaluation of biliary specimens increased the detection of malignant strictures, particularly in patients with PSC. Additionally, BiliSeq identified alterations that may stratify patients for specific anticancer therapies.

Efficacy and safety of a two-drug direct-acting antiviral agent regimen ruzasvir 180 mg and uprifosbuvir 450 mg for 12 weeks in adults with chronic hepatitis C virus genotype 1, 2, 3, 4, 5 or 6.

Ruzasvir (MK-8408, an NS5A inhibitor) and uprifosbuvir (MK-3682, a nonstructural protein 5B nucleotide inhibitor) are highly potent direct-acting antiviral agents for the treatment of hepatitis C virus (HCV) infection. A phase III clinical trial evaluating the two-drug combination of ruzasvir 60 mg plus uprifosbuvir 450 mg suggested suboptimal efficacy in certain HCV genotypes (C-BREEZE 1; NCT02759315). The aim of the present study was to evaluate the efficacy and safety of ruzasvir in combination with uprifosbuvir administered at a higher dose than that assessed in the earlier study (C-BREEZE 2: NCT02956629/Merck protocol PN041). Treatment-naïve or interferon (with or without ribavirin)-experienced participants with or without compensated cirrhosis were enrolled. All participants received ruzasvir 180 mg plus uprifosbuvir 450 mg once daily for 12 weeks. The primary objectives were the proportion of participants with HCV RNA <15 lU/mL at 12 weeks after the end of study therapy (SVR12), and safety and tolerability of the study drug. Overall, 282 participants were enrolled. SVR12 (n/N) was 91.3% (42/46) in participants infected with HCV genotype (GT) 1a; GT1b, 96.7% (29/30); GT2, 91.5% (43/47); GT3, 73.8% (45/61); GT4, 98.2% (55/56); GT5, 100.0% (18/18); and GT6, 90.9% (20/22). Adverse events (AEs) were reported by 61.3% of participants; drug-related AEs were reported by 33.3%. The most frequent (≥5% of participants) drug-related AEs in all participants were fatigue (7.8%) and headache (7.4%). In conclusion, the two-drug combination of ruzasvir 180 mg plus uprifosbuvir 450 mg for 12 weeks was highly effective and well tolerated in participants infected with HCV GT1, GT2, GT4, GT5 and GT6, with a lower efficacy in GT3-infected persons.

Post-infantile giant cell hepatitis: A single center's experience over 25 years.

BACKGROUND: Giant cell hepatitis in the adult population remains very poorly defined with only 100 case reports published in the literature over the last three decades. AIM: To present our center's experience in an attempt to learn about the predisposing factors, outcomes and efficacy of proposed therapeutic interventions for giant cell hepatitis. METHODS: A retrospective chart review was conducted through the electronic records of the University of Pittsburgh Medical Center. We queried 36726 liver biopsy reports from January 1, 1991 to December 6, 2016. Our search yielded 50 patients who were identified as carrying a definite diagnosis of post-infantile giant cell hepatitis (PIGCH) by pathology. The data collected included demographic information, laboratory data (liver function tests, autoimmune markers) and transplant status. In order to better analyze patient characteristics and outcomes, subjects were separated into a non-transplant (native) liver group and a post-liver transplant (allograft) group. RESULTS: The incidence of PIGCH was approximately 0.14% of all biopsies queried in the 25-year period. The mean age was 48 years with 66% females. Liver function tests were classified as 38.2% cholestatic, 35.3% hepatocellular and 26.5% mixed. Autoimmune hepatitis was found to be the most prevalent predisposing factor leading to PIGCH constituting 32% of cases. Management consisted mainly of immunosuppression, viral targeted therapy, supportive care and in six cases liver transplantations. CONCLUSION: The diagnosis of PIGCH remains clinically challenging and requires a high index of suspicion as well as a thorough history, physical examination, serological workup and liver biopsy. Treatment of the underlying cause can result in clinical stability in a large number of cases.

Clinical Profile and Natural Course in a Large Cohort of Patients With Hypertriglyceridemia and Pancreatitis.

GOALS: To report the clinical profile and natural course in a large series of patients with hypertriglyceridemia (HTG) and acute pancreatitis (AP). BACKGROUND: The natural history of HTG-related pancreatitis is poorly defined. STUDY: Medical records of 121 patients with serum triglycerides (TG) levels of ≥500 mg/dL suffering 225 attacks of AP between January 2001 to August 2013 treated at the University of Pittsburgh Medical Center were retrospectively studied. Structured data were collected on initial presentation and long-term outcomes (mean follow-up 64.7±42.8 mo). AP severity was classified using Revised Atlanta Classification. RESULTS: Most patients were young-middle aged (mean 44±12.7 y), male (70%), white (78%), and had sentinel AP (63%). Peak serum TG recorded was ≥1000 mg/dL in 48%. At least 1 secondary risk factor (diabetes, high-risk drinking, obesity, offending medications) was present in the majority (78%). Sentinel AP attack varied in severity between mild (41%), moderate (26%), and severe (33%). Recurrent AP attacks occurred in 32%, often in patients with poorly controlled diabetes, alcoholism, and TG levels. A cumulative increase in prevalence of pancreatic and/or peripancreatic necrosis was observed, with 45% patients having it at some time during observation. Local complications were higher in patients with serum TG ≥1000 mg/dL. Chronic pancreatitis was noted in 16.5% patients (new-onset in 9%). CONCLUSIONS: Patients with HTG-related pancreatitis have a high prevalence of secondary risk factors. Frequent recurrences in them are usually due to poor control of secondary factors or TG. Serum TG ≥1000 mg/dL increases the risk of local complications. A subset can have or develop chronic pancreatitis.

Clinical outcomes in patients with bile leaks treated via ERCP with regard to the timing of ERCP: a large multicenter study.

BACKGROUND AND AIMS: Postsurgical or traumatic bile duct leaks (BDLs) can be safely and effectively managed by endoscopic therapy via ERCP. The early diagnosis of BDL is important because unrecognized leaks can lead to serious adverse events (AEs). Our aim was to evaluate the relationship between timing of endotherapy after BDL and the clinical outcomes, AEs, and long-term results of endoscopic therapy. METHODS: We conducted a multicenter, retrospective study on patients with BDLs who underwent ERCP between 2006 and 2014. Data were assembled on patient demographics, etiology of BDL, and procedural details. Endotherapy for BDLs were classified a priori into 3 groups based on timing of ERCP from time of biliary injury: within 1 day of BDL, on day 2 or 3 after BDL, and greater than 3 days after BDL. The relationship among timing of ERCP after BDL injury and outcomes, procedure-related AEs, and patient AEs and mortality were evaluated. RESULTS: From February 2006 to June 2014, 518 patients (50% male; mean age, 51.7 years) underwent ERCP for therapy of BDLs. The etiology of the BDL was laparoscopic cholecystectomy (70.7%), post-liver transplantation (11.2%), liver resection (14.1%), trauma (2.5%), and other causes (1.5%). Endotherapy was performed by placing a transpapillary stent alone (73.5%) or with a sphincterotomy (26.5%). The timing of ERCPs was as follows: ≤1 day = 57 patients, day 2 or 3 = 140 patients, and >3 days = 321 patients. There was no statistical difference in patient demographics, etiology/site of BDL, or type of endotherapy performed among the 3 groups. On multivariate analysis there was no statistically significant difference in BDL success rate for ERCPs performed within 1 day compared with those performed on day 2 or 3 or after 3 days of bile duct injury (91.2%, 90%, and 88.5%, respectively; P = .77). Similarly, there was no significant difference in the overall patient AE rate among the 3 groups (21.1%, 22.9%, and 24.6%, respectively; P = .81). AEs in men occurred significantly more frequently when compared with women, even after adjusting for age, BDL etiology, and location of leak (27.6% vs 19.9%; OR, 1.53; P = .04). Patients whose BDL was due to a cholecystectomy had a lower AE and mortality rate compared with those who had biliary injury from other etiologies (OR, .42; P < .001). CONCLUSIONS: The overall success rates and AEs after ERCP were not dependent on the timing of the procedure relative to the discovery of the bile leak. This suggests that ERCP in these patients can usually be performed in an elective, rather than an urgent, manner.

Efficacy and safety of simeprevir and sofosbuvir with and without ribavirin in subjects with recurrent genotype 1 hepatitis C postorthotopic liver transplant: the randomized GALAXY study.

This prospective, randomized, phase 2 study in subjects with recurrent hepatitis C virus (HCV) genotype 1 postorthotopic liver transplant evaluated once-daily simeprevir 150 mg + sofosbuvir 400 mg, with and without ribavirin 1000 mg. Primary endpoint was proportion of subjects with week 12 sustained virologic response (SVR12). Thirty-three subjects without cirrhosis were randomized 1:1:1 into three arms (stratified by genotype/subtype and Q80K): Arm 1, simeprevir + sofosbuvir + ribavirin, 12 weeks; Arm 2, simeprevir + sofosbuvir, 12 weeks; Arm 3, simeprevir + sofosbuvir, 24 weeks; 13 additional subjects (two with cirrhosis, 11 without cirrhosis) entered Arm 3. All 46 subjects received at least one dose of study drug; median age, 60 years; 73.9% male; 80.4% White; 71.7% genotype/subtype 1a [12 (36.4%) of these had Q80K]; median 4.5 years post-transplant. Among randomized subjects, SVR12 was achieved by 81.8% in Arm 1, 100% in Arm 2, and 93.9% in Arm 3; two subjects did not achieve SVR12: one viral relapse (follow-up week 4; Arm 1) and one missing follow-up week 12 data. In total, five subjects had a serious adverse event, considered unrelated to treatment per investigator. Simeprevir exposure was increased relative to the nontransplant setting, but not considered clinically relevant. Simeprevir + sofosbuvir treatment, with or without ribavirin, was efficacious and well tolerated (ClinicalTrials.gov Identifier: NCT02165189).

Natural History After Acute Necrotizing Pancreatitis: a Large US Tertiary Care Experience.

BACKGROUND: Most studies of acute necrotizing pancreatitis (ANP) focus on short-term outcomes. We evaluated long-term survival and outcomes following ANP. METHODS: Patients treated for ANP at the University of Pittsburgh Medical Center from 2001 to 2008 were studied. Data on presentation and course during initial hospitalization and follow-up (median 34 months) was extracted. RESULTS: Mean age of patients (n = 167) was 53 ± 16 years; 70 % were male, 94 % white, 71 % transfers, 52 % biliary etiology, and 78 % had first-attack of acute pancreatitis. Majority had severe disease with high Acute Physiology and Chronic Health Evaluation II (APACHE-II) score (median 11), length of stay (median 26 days), intensive care unit (ICU) admission (87 %), presence of systemic inflammatory response syndrome (SIRS) (90 %), persistent organ failure (60 %), and infected necrosis (50 %). Intervention was needed in 74 %. Eighteen (10.8 %) patients died during index hospitalization, 9 (5.4 %) during the first year, and 13 (7.8 %) after 1 year. Median survival was significantly shorter when compared with age- and sex-matched US general population (9.1 vs. 26.1 years, p < 0.001). Increasing age (HR 1.05), persistent organ failure (HR 4.5), and >50 % necrosis (HR 3.8) were independent predictors of death at 1 year. In eligible patients, new-onset diabetes, oral pancreatic enzyme replacement therapy, and disability were noted in 45, 25, and 53 %, respectively. CONCLUSION: ANP significantly impacts long-term survival. A high proportion of patients develop functional derangement and disability following ANP.

Efficacy of Sofosbuvir, Velpatasvir, and GS-9857 in Patients With Genotype 1 Hepatitis C Virus Infection in an Open-Label, Phase 2 Trial.

BACKGROUND & AIMS: The 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. METHODS: We 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). RESULTS: Among 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 (<1%) discontinued treatment because of adverse events. CONCLUSIONS: In a phase 2 open-label trial, we found 8 weeks of treatment with sofosbuvir-velpatasvir plus GS-9857 to be safe and effective in treatment-naive patients; 12 weeks was safe and effective in patients previously treated with DAAs. The combination was safe and effective in patients with or without compensated cirrhosis. Clinicaltrials.gov no: NCT02378935.

On-treatment HCV RNA as a predictor of sustained virological response in HCV genotype 3-infected patients treated with daclatasvir and sofosbuvir.

BACKGROUND AND AIMS: Many currently available direct-acting antiviral (DAA) regimens are less effective against HCV genotype 3 than against other HCV genotypes. The all-oral, pangenotypic DAA combination of daclatasvir (NS5A inhibitor) + sofosbuvir (nucleotide NS5B inhibitor) was studied in genotype 3-infected treatment-naive and -experienced patients (ALLY-3) who achieved rates of sustained virological response at post-treatment Week 12 (SVR12) of 90 and 86% respectively. In this analysis, we assessed whether on-treatment responses to daclatasvir + sofosbuvir in genotype 3-infected patients could predict treatment outcome. METHODS: In ALLY-3, treatment-naive and -experienced patients, with or without cirrhosis, were treated with daclatasvir + sofosbuvir for 12 weeks. HCV RNA kinetics and categorical virological responses on treatment were assessed. The proportions of responders and nonresponders by study week, and time to first undetectable HCV RNA, were analysed for utility in predicting treatment outcome. RESULTS: Overall, HCV RNA levels declined rapidly during Week 1 of treatment in both treatment-naive and -experienced cohorts. Although patients with cirrhosis had a slower initial virological response as measured by the proportion of patients with HCV RNA below the lower limit of quantification at Week 1, responses converged thereafter. Positive and negative predictive values calculated for on-treatment responses were generally comparable with the overall SVR12 rate and were therefore limited indicators of outcome. SVR12 rates were not impacted by time to first undetectable HCV RNA. CONCLUSIONS: On-treatment responses are not useful predictors of ultimate virological response to the daclatasvir + sofosbuvir regimen.

Endotherapy is effective for pancreatic ductal disruption: A dual center experience.

BACKGROUND AND STUDY AIMS: Pancreatic duct (PD) disruptions occur as a result of different etiologies and can be managed medically, endoscopically, or surgically. The aim of this study was to provide an evaluation on the efficacy of endotherapy for treatment of PD disruption in a large cohort of patients and identify factors that predict successful treatment outcome. PATIENTS AND METHODS: We retrospectively evaluated consecutive patients who underwent endoscopic retrograde pancreatography (ERP) for transpapillary pancreatic stent placement for PD disruption from 2008 to 2013 at two tertiary referral institutions. PD disruption was defined as extravasation of contrast from the pancreatic duct as seen on ERP. Therapeutic success was defined by resolution of PD leak on ERP, clinical, and/or imaging evaluation. RESULTS: We evaluated 107 patients (58% male, mean age 53 years) with PD disruption. Etiologies of PD disruption were acute pancreatitis (36%), post-operative (31%), chronic pancreatitis (29%), and trauma (4%). PD disruption was successfully bridged by a stent in 45 (44%) patients. Two patients developed post-sphincterotomy bleeding, two had stent migration, and two patients died as a result of post-ERP related complications. Placement of a PD stent was successful in 103/107 (96%) patients. Therapeutic success was achieved in 80/107 (75%) patients. Non-acute pancreatitis etiologies and absence of complete duct disruption were independent predictors of therapeutic success. CONCLUSIONS: Endoscopic therapy using a transpapillary stent for PD disruption is safe and effective. Absence of complete duct disruption and non-AP etiologies determine a favorable endoscopic outcome.

Sofosbuvir With Velpatasvir in Treatment-Naive Noncirrhotic Patients With Genotype 1 to 6 Hepatitis C Virus Infection: A Randomized Trial.

BACKGROUND: Effective, pangenotypic treatments for hepatitis C virus (HCV) infection are needed. OBJECTIVE: To assess the safety and efficacy of sofosbuvir with velpatasvir in patients infected with HCV genotypes 1 to 6. DESIGN: Randomized, phase 2, open-label study. (ClinicalTrials.gov: NCT01858766). SETTING: 48 U.S. sites. PATIENTS: 377 treatment-naive noncirrhotic patients. In part A, patients infected with HCV genotypes 1 to 6 were randomly assigned to sofosbuvir, 400 mg, with velpatasvir, 25 or 100 mg, for 12 weeks. In part B, patients with genotype 1 or 2 HCV infection were randomly assigned to sofosbuvir, 400 mg, and velpatasvir, 25 or 100 mg, with or without ribavirin for 8 weeks. MEASUREMENTS: Sustained virologic response at 12 weeks (SVR12). RESULTS: In part A, SVR12 rates were 96% (26 of 27) with velpatasvir, 25 mg, and 100% (28 of 28) with velpatasvir, 100 mg, for genotype 1; 93% (25 of 27) in both groups for genotype 3; and 96% (22 of 23) with velpatasvir, 25 mg, and 95% (21 of 22) with velpatasvir, 100 mg, for genotypes 2, 4, 5, and 6. In part B, for genotype 1, SVR12 rates were 87% (26 of 30) with velpatasvir, 25 mg; 83% (25 of 30) with velpatasvir, 25 mg, plus ribavirin; 90% (26 of 29) with velpatasvir, 100 mg; and 81% (25 of 31) with velpatasvir, 100 mg, plus ribavirin. For genotype 2, SVR12 rates were 77% (20 of 26) with velpatasvir, 25 mg; 88% (22 of 25) with velpatasvir, 25 mg, plus ribavirin; 88% (23 of 26) with velpatasvir, 100 mg; and 88% (23 of 26) with velpatasvir, 100 mg, plus ribavirin. Adverse events included fatigue (21%), headache (20%), and nausea (12%). One patient committed suicide. LIMITATION: The study was open-label, no inferential statistics were planned, and sample sizes were small. CONCLUSION: Twelve weeks of sofosbuvir, 400 mg, and velpatasvir, 100 mg, was well-tolerated and resulted in high SVR in patients infected with HCV genotypes 1 to 6. PRIMARY FUNDING SOURCE: Gilead Sciences.

Sofosbuvir Plus Velpatasvir Combination Therapy for Treatment-Experienced Patients With Genotype 1 or 3 Hepatitis C Virus Infection: A Randomized Trial.

BACKGROUND: Effective treatment options are needed for patients with genotype 1 or 3 hepatitis C virus (HCV) infection in whom previous therapy has failed. OBJECTIVE: To assess the efficacy and safety of sofosbuvir plus velpatasvir, with and without ribavirin, in treatment-experienced patients. DESIGN: Randomized, phase 2, open-label study. (ClinicalTrials.gov: NCT01909804). SETTING: 58 sites in Australia, New Zealand, and the United States. PATIENTS: Treatment-experienced adults with genotype 3 HCV infection without cirrhosis (cohort 1) and with compensated cirrhosis (cohort 2) and patients with genotype 1 HCV infection that was unsuccessfully treated with a protease inhibitor with peginterferon and ribavirin (50% could have compensated cirrhosis) (cohort 3). INTERVENTION: All patients received 12 weeks of treatment that included 400 mg of sofosbuvir once daily. Patients in each cohort were randomly assigned to 25 mg of velpatasvir once daily with or without ribavirin or 100 mg of velpatasvir once daily with or without ribavirin. MEASUREMENTS: Proportion of patients with sustained virologic response at week 12 after treatment (SVR12). RESULTS: In cohort 1, SVR12 rates were 85% with 25 mg of velpatasvir, 96% with 25 mg of velpatasvir plus ribavirin, 100% with 100 mg of velpatasvir, and 100% with 100 mg of velpatasvir plus ribavirin. In cohort 2, SVR12 rates were 58% with 25 mg of velpatasvir, 84% with 25 mg of velpatasvir plus ribavirin, 88% with 100 mg of velpatasvir, and 96% with 100 mg of velpatasvir plus ribavirin. In cohort 3, SVR12 rates were 100% with 25 mg of velpatasvir, 97% with 25 mg of velpatasvir plus ribavirin, 100% with 100 mg of velpatasvir, and 96% with 100 mg of velpatasvir plus ribavirin. The most common adverse events were headache, fatigue, and nausea. LIMITATION: Treatment assignments were not blinded, and no inferential statistics were planned. CONCLUSION: Treatment with 400 mg of sofosbuvir plus 100 mg of velpatasvir for 12 weeks was well-tolerated and highly effective in treatment-experienced patients with genotype 1 or 3 HCV infection. PRIMARY FUNDING SOURCE: Gilead Sciences.

All-oral 12-week treatment with daclatasvir plus sofosbuvir in patients with hepatitis C virus genotype 3 infection: ALLY-3 phase III study.

UNLABELLED: Treatment options for patients with hepatitis C virus (HCV) genotype 3 infection are limited, with the currently approved all-oral regimens requiring 24-week treatment and the addition of ribavirin (RBV). This phase III study (ALLY-3; ClinicalTrials.gov: NCT02032901) evaluated the 12-week regimen of daclatasvir (DCV; pangenotypic nonstructural protein [NS]5A inhibitor) plus sofosbuvir (SOF; pangenotypic NS5B inhibitor) in patients infected with genotype 3. Patients were either treatment naïve (n = 101) or treatment experienced (n = 51) and received DCV 60 mg plus SOF 400 mg once-daily for 12 weeks. Coprimary endpoints were the proportions of treatment-naïve and treatment-experienced patients achieving a sustained virological response (SVR) at post-treatment week 12 (SVR12). SVR12 rates were 90% (91 of 101) and 86% (44 of 51) in treatment-naïve and treatment-experienced patients, respectively; no virological breakthrough was observed, and ≥99% of patients had a virological response (VR) at the end of treatment. SVR12 rates were higher in patients without cirrhosis (96%; 105 of 109) than in those with cirrhosis (63%; 20 of 32). Five of seven patients who previously failed treatment with an SOF-containing regimen and 2 of 2 who previously failed treatment with an alisporivir-containing regimen achieved SVR12. Baseline characteristics, including gender, age, HCV-RNA levels, and interleukin-28B genotype, did not impact virological outcome. DCV plus SOF was well tolerated; there were no adverse events (AEs) leading to discontinuation and only 1 serious AE on-treatment, which was unrelated to study medications. The few treatment-emergent grade 3/4 laboratory abnormalities that were observed were transient. CONCLUSION: A 12-week regimen of DCV plus SOF achieved SVR12 in 96% of patients with genotype 3 infection without cirrhosis and was well tolerated. Additional evaluation to optimize efficacy in genotype 3-infected patients with cirrhosis is underway.

Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study.

BACKGROUND: Interferon-free regimens are needed to treat hepatitis C virus (HCV) infections. We investigated the efficacy of combined simeprevir and sofosbuvir. METHODS: We enrolled patients with chronic HCV genotype 1 infections who had previously not responded to pegylated interferon (peginterferon) and ribavirin or were treatment naive. Patients were randomly assigned in a 2:1:2:1 ratio to receive 150 mg simeprevir and 400 mg sofosbuvir daily for 24 weeks with (group 1) or without (group 2) ribavirin or for 12 weeks with (group 3) or without (group 4) ribavirin, in two cohorts: previous non-responders with METAVIR scores F0-F2 (cohort 1) and previous non-responders and treatment-naive patients with METAVIR scores F3-F4 (cohort 2). The primary endpoint was sustained virological response 12 weeks after stopping treatment (SVR12). Analysis was done by intention to treat. Safety data from cohorts 1 and 2 were pooled for analysis. This study is registered with ClinicalTrials.gov, number NCT01466790. FINDINGS: 168 patients were enrolled and randomised, and 167 started treatment (n=80 in cohort 1 and n=87 in cohort 2). SVR12 was achieved in 154 (92%) patients (n=72 [90%, 95% CI 81-96] in cohort 1 and n=82 [94%, 87-98] in cohort 2). The most common adverse events in the pooled groups were fatigue (n=52 [31%]), headache (n=33 [20%]), and nausea (n=26 [16%]). Grade 4 adverse events were seen in one (2%) of 54 patients in each of groups 1 and 3 and in three (10%) of 31 patients in group 2, whereas grade 3-4 events were reported in less than 5% of all patients, except increased blood amylase concentration. Serious adverse events were seen in four (2%) patients, all in groups 1 and 2. Four (2%) patients discontinued all study treatment because of adverse events, three before week 12. INTERPRETATION: Combined simeprevir and sofosbuvir was efficacious and well tolerated. FUNDING: Janssen.

IL28B polymorphism is associated with both side effects and clearance of hepatitis C during interferon-alpha therapy.

Interferon-α (IFN-α) treatment for hepatitis C virus (HCV) is complicated by depression and related neurovegetative side effects. Recent genome-wide scans identified IL28B gene polymorphisms that associated with HCV clearance. Whether the IL28B polymorphism is also associated with these adverse effects of IFN-α would affect its clinical usefulness. One hundred thirty-three patients were prospectively examined using the Beck Depression Inventory-II and a Structured Clinical Interview for Diagnostic and Statistical Manual-IV (DSM-IV) during IFN-α treatment. The candidate C/T single-nucleotide polymorphism upstream from IL28B (rs1297860) was genotyped and assessed for association with individual items from the Beck Depression Inventory-II. We confirmed that the IL28B polymorphism was associated with differences in sustained viral response (F = 3.38; P < 0.05), with the T/T genotype faring worst. However, the T/T genotype was associated with less appetite (P < 0.05), energy (P < 0.05), and sleep complaints (P < 0.05) during treatment. Only 3.1% of patients with T/T developed major appetite complaints, whereas 10.1% and 8.9% of those with the C/T and C/C genotype did, respectively. Only 10.8% of patients with T/T developed major sleep complaints, whereas 16.1% and 20.7% of those with the C/T and C/C genotype did. However, IL28B genotype did not predict development of major depressive disorder (χ(2) = 0.12; P = 0.94). The allele (C) was associated with both better viral clearance and more subjective appetite, energy, and sleep complaints. This has implications for the management of patients with HCV. If genotyping is used to better target therapy, this may co-enrich the population for likelihood of also suffering from these side effects.

Labile anger during interferon alfa treatment is associated with a polymorphism in tumor necrosis factor alpha.

OBJECTIVE: Inflammatory cytokines may influence both labile anger and depression. Both psychiatric conditions can occur during interferon alfa-based treatments. Evidence also indicates a central nervous system role for tumor necrosis factor alpha (TNF-alpha), whose expression may be increased by interferon alfa. A polymorphism in the promoter region of TNF-alpha has been associated with various inflammatory illnesses. We therefore hypothesized that this TNF-alpha polymorphism would influence susceptibility to psychiatric symptoms during interferon alfa therapy. METHODS: One hundred five patients with hepatitis C, initially without active major depression (major depressive disorder), were treated with interferon alfa and then prospectively monitored using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, the Beck Depression Inventory II, the Anger Irritability and Assault Questionnaire, and circulating TNF-alpha levels. The A-308G polymorphism (rs1800629) was determined using the 5'-nuclease assay. Repeated-measure mixed-effect analyses compared changes in symptoms over time. RESULT: Beck Depression Inventory II score increased during interferon alfa therapy (F = 6.2; P < 0.001), with 27% developing MDD. The TNF-alpha A allele was associated with worsened labile anger (F = 2.5; P < 0.05) and fatigue (F = 2.9; P < 0.05) during treatment but not with major depression incidence (chi = 0.0; P = 0.99) or increased Beck Depression Inventory II (F = 1.2; P = 0.31). Labile anger was not predicted by the serotonin transporter polymorphism (F = 0.8; P = 0.59). DISCUSSION: During treatment with an exogenous cytokine, vulnerability to worsening labile anger-distinct from major depression-is associated with genetic variability in TNF-alpha. This has implications both for patients being treated with interferon alfa and our understanding of genetic vulnerability for different subtypes of dysphoric and mood disorders.

Bariatric surgery-induced weight loss reduces hepatic lipid peroxidation levels and affects hepatic cytochrome P-450 protein content.

OBJECTIVE: To evaluate the effects of surgical weight loss on hepatic lipid peroxidation levels and cytochrome P-450 protein expression in patients with nonalcoholic fatty liver disease (NAFLD). SUMMARY BACKGROUND DATA: NAFLD and nonalcoholic steatohepatitis (NASH) affect hepatic cytochrome P-450 (CYP) protein expression and activity, and CYP2E1 may play a role in the pathogenesis of NAFLD and NASH through induction of oxidative stress and lipid peroxidation. NAFLD and NASH are associated with increased systemic lipid peroxidation levels and elevated hepatic CYP2E1 activity, but hepatic CYP3A4/5 activity is decreased. METHODS: Liver biopsies from 20 patients with NAFLD who underwent bariatric surgery were obtained intraoperatively and at 15 +/- 7 months following surgery. Hepatic malondialdehyde (MDA) levels (a marker of lipid peroxidation), CYP2E1 and CYP3A4/5 protein expression, and steatosis, as a percent of total area, were measured by immunohistochemistry followed by digital image quantitation. RESULTS: Following weight loss, as reflected by reduced BMI (54 +/- 9 vs. 37 +/- 9 kg/m2; P < 0.001), features of the metabolic syndrome, grade and stage of liver disease, and liver histology were all significantly improved (P < 0.01). Hepatic MDA staining (35 +/- 18% vs. 23 +/- 14%; P = 0.02), CYP2E1 protein content (68 +/- 9% vs. 56 +/- 11%; P < 0.001), and steatosis (17 +/- 7% vs. 2 +/- 3%; P < 0.001) were significantly reduced following weight loss. CYP3A4/5 protein content was unchanged (57 +/- 13% vs. 55 +/- 13%; P = 0.433). The reduction in lipid peroxidation was independently associated with changes in CYP2E1 protein expression after bariatric surgery (r = 0.477; P = 0.033). CONCLUSION: Elevations in hepatic lipid peroxidation and CYP2E1 expression that are seen in NAFLD improve significantly with weight loss induced by bariatric surgery.

Poor sleep quality predicts onset of either major depression or subsyndromal depression with irritability during interferon-alpha treatment.

Major depressive disorder (MDD) often occurs during pegylated IFN-alpha2 (IFN-alpha) treatment. Identifying who is at risk for MDD in this population is essential, and epidemiological studies suggest that sleep may be related to depression risk. Controlling for pre-existing depression symptoms, we therefore examined whether sleep quality prior to IFN-alpha treatment would predict subsequent MDD incidence during IFN-alpha treatment. Adults with hepatitis C but without current clinical MDD (n=86) were evaluated prior to IFN-alpha treatment and then prospectively monitored during treatment using self-report measures of sleep quality (PSQI), depression (BDI), and anger and irritability (AIAQ), as well as with Structured Clinical Interviews for DSM-IV Axis I Disorders (SCID-I). During IFN-alpha treatment, 19% developed MDD, 19% developed subsyndromal depression with irritability, and one developed mania. Controlling for baseline depression symptoms and past history of depression, patients with worse sleep quality (PSQI > or = 10) prior to treatment had a significantly shorter time until they developed MDD or any severe psychiatric problem. These findings may have important implications for understanding, predicting, and possibly preventing depression, particularly in individuals treated with IFN-alpha.