Mordechai Rabinovitz

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.

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

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. (Hepatology 2015;61:1127–1135)

Surgically-induced Weight Loss Significantly Improves Nonalcoholic Fatty Liver Disease and the Metabolic Syndrome

Objective:To evaluate the effects of surgical weight loss on fatty liver disease in severely obese patients. Summary Background Data: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. Methods: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. Results: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. Conclusion: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.

Risk for Depression During Interferon-Alpha Treatment Is Affected by the Serotonin Transporter Polymorphism

BACKGROUND Major depressive disorder (MDD) occurs in a subset of patients receiving interferon-alpha treatment, although many are resilient to this side effect. Genetic differences in the serotonin reuptake transporter promoter (5-HTTLPR) may interact with the inflammatory system and influence depression risk. METHODS A cohort of 71 nondepressed hepatitis C patients about to receive interferon-alpha was prospectively followed, employing a diagnostic structured clinical interview (Structured Clinical Interview for DSM-IV Axis I Disorders [SCID-I]) and self-report questionnaires. Patients were genotyped for the 5-HTTLPR (L(G), L(A), and S) and the variable number of tandem repeats (VNTR) polymorphism in the second intron. Kaplan-Meier analyses were used to compare major depression incidence. Genotype effects on sleep quality (Pittsburgh Sleep Quality Index) and Beck Depression Inventory (BDI) were assessed using mixed-effect repeated-measure analyses. RESULTS The L(A) allele was associated with a decreased rate of developing MDD (Mantel-Cox log rank test p < .05) with the L(A)/L(A) genotype being the most resilient. This genotype was also associated with better sleep quality [F(61.2,2) = 3.3, p < .05]. The ability of baseline sleep quality to predict depression incidence disappeared when also including genotype in the model. Conversely, the relationship of neuroticism with depression incidence (B = .07, SE = .02, p < .005) was not mitigated when including genotype. CONCLUSIONS Using a prospective design, 5-HTTLPR is associated with MDD incidence during interferon-alpha treatment. Preliminary evidence that this effect could be mediated by effects on sleep quality was observed. These findings provide support for a possible interaction between inflammatory cytokine (interferon-alpha) exposure and 5-HTTLPR variability in MDD.

Cytokine-induced depression during IFN-α treatment: the role of IL-6 and sleep quality

Depressive symptoms, poor sleep quality, and systemic markers of inflammation (e.g., interleukin (IL)-6) are frequently associated. Interferon-alpha (IFN-alpha) therapy results in Major Depressive Disorder (MDD) in some people, offering the possibility to elucidate the relationship of MDD to sleep and inflammation during treatment. In particular, delineating the temporal relations among these factors could help inform their causal relationships. To this end, a cohort of 95 non-depressed hepatitis C patients was followed prospectively for four consecutive months during IFN-alpha therapy. We found that higher pre-treatment levels of circulating IL-6 predicted incidence of MDD (X(2)(1)=7.7; p<0.05). Time-lagged mixed-effect analyses supported uni-directional associations in which IL-6 predicted next months PSQI scores (F(47,11.6)=78.4; p<0.0005), and PSQI scores predicted next months depressive Beck Depression Inventory-II (BDI) scores (F(16,22.6)=3.4; p<0.005). In addition, on any given month of treatment, IL-6 levels predicted BDI symptoms the following month (F(16,97.5)=7.3; p<0.0005), and conversely BDI predicted next months IL-6 (F(14,7.4)=5.2; p<0.05) - providing evidence for a positive feedback relationship between depressive symptoms and systemic inflammation. These data provide further evidence that high levels of inflammation and poor sleep quality may be risk factors for IFN-alpha induced depression. Furthermore, these findings highlight the complex temporal relationships that exist among sleep, depression, and inflammation, and support the need for further prospective investigations to elucidate the dynamics that underlie depression during IFN-alpha treatment.

Simultaneous occurrence of primary sclerosing cholangitis and autoimmune chronic active hepatitis in a patient with ulcerative colitis

SummaryThe simultaneous occurrence of PSC and autoimmune CAH in a patient with ulcerative colitis is described. Although each disease is a well documented complication of UC, their combination has never been reported. The diagnosis of PSC was based on typical findings on ERCP and liver biopsy and that of CAH was based on typical findings on liver biopsy supported by HLA typings and a remarkable response to a combination of glucocorticoids and azathioprine. The difficulties in establishing the diagnosis and the management of such patients are discussed.

Prevalence of endoscopic findings in 510 consecutive individuals with cirrhosis evaluated prospectively.

Upper gastrointestinal hemorrhage is one of the more important complications of cirrhosis and a major cause of death in such patients. The main sites of bleeding are esophageal varices, gastritis, and peptic ulcers. In order to determine the prevalence of either potential bleeding lesions or of other endoscopic findings in hemodynamically stable individuals with various etiologies of cirrhosis, 510 consecutive cirrhotic patients, evaluated for possible orthotopic liver transplantation (OLTx) underwent an upper gastrointestinal endoscopy for combined diagnostic and therapeutic purposes. The patients were divided into two main groups: 319 patients with parenchymal liver disease and 191 patients with cholestatic liver disease. Gastritis was found significantly more often in patients with parenchymal liver disease than in those with cholestatic liver disease (49.8% vs 30.9%; P <0.001). In contrast, the prevalence of esophagitis, esophageal and gastric varices, gastric ulcer, duodenal ulcer, and duodenitis was similar in both groups. Normal endoscopic findings were present in 5.0% of the parenchymal group and 11.5% of the cholestatic group (P <0.02). Ascites and encephalopathy were found significantly more often in subjects with parenchymal liver disease as compared to those with cholestatic liver disease. Portal hypertension and its degree, as assessed by the presence and size of esophageal varices, was similar in both groups, and in both groups there was a statistically significant qualitative trend of increasing prevalence of esophageal varices with increasing severity of disease as estimated using Pugh-Childs criteria.

Colonic disease in cirrhosis

Colonic disease is relatively uncommon in cirrhosis. To determine the prevalence of colonic lesions in cirrhosis of all types, cirrhotics evaluated for possible liver transplantation underwent combined pan upper endoscopy and colonoscopy. The patients were divided into two main groups, 248 with parenchymal liver disease (nonviral and viral) and 164 with cholestatic liver disease. The prevalence of the various colonic lesions identified was: polyps, 8.4%; nonspecific edema, 19.9%; inflammatory changes, 11.6%; hemorrhoids, 25.2%; and rectal varices, 3.6%. Normal findings were present in 42.4%. Except for an increased prevalence (P less than 0.05) of edema and a reduced prevalence (P less than 0.001) of inflammatory changes in the parenchymal liver disease group, the prevalence for all other lesions was similar in the two groups. Esophageal varices were present in most patients with hemorrhoids and in all with rectal varices. The degree of portal hypertension and/or disease severity was associated with hemorrhoids but not with rectal varices. The higher prevalence of inflammatory changes in the cholestatic group was because one fourth of this group had an inflammatory bowel disease.

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.