Summary 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.
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.
To evaluate the effects of surgical weight loss on fatty liver disease in severely obese patients.
Nonalcoholic fatty liver disease (NAFLD), a spectrum that extends to liver fibrosis and cirrhosis, ...is rising at an alarming rate. This increase is occurring in conjunction with the rise of severe obesity and is probably mediated in part by metabolic syndrome (MS). Surgical weight loss operations, probably by reversing MS, have been shown to result in improvement in liver histology.
Patients who underwent laparoscopic surgical weight loss operations from March 1999 through August 2004, and who agreed to have an intraoperative liver biopsy followed by at least one postoperative liver biopsy, were included.
There were 70 patients who were eligible. All patients underwent laparoscopic operations, the majority being laparoscopic Roux-en-Y gastric bypass. The mean excess body weight loss at time of second biopsy was 59% +/- 22% and the time interval between biopsies was 15 +/- 9 months. There was a reduction in prevalence of metabolic syndrome, from 70% to 14% (P < 0.001), and a marked improvement in liver steatosis (from 88% to 8%), inflammation (from 23% to 2%), and fibrosis (from 31% to 13%; all P < 0.001). Inflammation and fibrosis resolved in 37% and 20% of patients, respectively, corresponding to improvement of 82% (P < 0.001) in grade and 39% (P < 0.001) in stage of liver disease.
Surgical weight loss results in significant improvement of liver morphology in severely obese patients. These beneficial changes may be associated with a significant reduction in the prevalence of the metabolic syndrome.
Abstract Objective Interferon-α2 (IFN-α) injections may be capable of triggering depression in some individuals. The first objective was to further characterize this depression and, secondly, to ...examine whether pre-treatment temperament was correlated with subsequent vulnerability to IFN-α. Methods Twenty-three initially euthymic adults undergoing year-long PEG-IFN-α treatment for hepatitis C were evaluated at baseline and then prospectively monitored using both the Structured Clinical Interview for DSM-IV (SCID) and self-report questionnaires. Results A major depressive episode developed within 3 months in 39%. Principal component analysis of the change in self-report scores after 1 month of treatment demonstrated three orthogonal factors: (i) a specific increase in depression as manifested in the Beck Depression Inventory (BDI) and Hospital Anxiety and Depression Scale (HADS), (ii) an increase in hostility and anxiety, (iii) and a generalized combination of worse symptoms including somatic symptoms on the Symptom Check List (SCL-90). BDI at 1 month was predicted by baseline BDI ( r =0.76, P =.004). Hostility at 1 month was predicted by low baseline agreeableness ( r =0.75, P =.01). Controlling for baseline BDI scores, categorical major depression was predicted by combined high baseline neuroticism and low agreeableness (combined r =0.66, P =.03). Conclusion These initial results (i) support the depressogenic nature of IFN-α treatment in a subset of vulnerable individuals, (ii) indicate that some individuals are also independently vulnerable to worsened hostility, and (iii) suggest that it may be possible to clinically predict these vulnerabilities in initially euthymic subjects.
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.
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).
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.
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.
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).
Elevations in hepatic lipid peroxidation and CYP2E1 expression that are seen in NAFLD improve significantly with weight loss induced by bariatric surgery.
Abstract 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.
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 NS5A 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. (Hepatology 2015;61:1127–1135)
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.
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.
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
-amplified cholangiocarcinoma received a trastuzumab-based regimen and had measurable clinicoradiographic response.
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.
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.
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.
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.
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.
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.
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