Asma Siddique

Insulin Resistance and Other Metabolic Risk Factors in the Pathogenesis of Hepatocellular Carcinoma

Coinciding with the increased incidence of hepatocellular carcinoma (HCC), there has been a significant increase in the global incidence of obesity and diabetes mellitus (DM), the two major risk factors for nonalcoholic steatohepatitis (NASH). There are many causes of HCC, and nonalcoholic fatty liver disease/NASH is now emerging as a leading risk factor owing to the epidemic of obesity and type 2 DM. The mechanisms leading to HCC in obesity and type 2 DM likely involve interactions between several signaling pathways, including oxidative stress, inflammation, oncogenes, adiponectins, and insulin resistance associated with visceral adiposity and diabetes.

Approach to a Patient with Elevated Serum Alkaline Phosphatase

Cholestasis develops either from a defect in bile synthesis, impairment in bile secretion, or obstruction to bile flow, and is characterized by an elevated serum alkaline phosphatase and gamma-glutamyltransferase disproportionate to elevation of aminotransferase enzymes. Key elements to the diagnostic workup include visualization of the biliary tree by cholangiography and evaluation of liver histology. The hope is that recent advances in understanding the genetic factors and immune mechanisms involved in the pathogenesis of cholestasis will lead to newer therapeutic interventions in the treatment of these diseases.

Patient Sex, Reproductive Status, and Synthetic Hormone Use Associate With Histologic Severity of Nonalcoholic Steatohepatitis

BACKGROUND & AIMS: Sex and sex hormones can affect responses of patients with nonalcoholic fatty liver disease (NAFLD) to metabolic stress and development of hepatocyte injury and inflammation. METHODS: We collected data from 3 large U.S. studies of patients with NAFLD (between October 2004 and June 2013) to assess the association between histologic severity and sex, menopause status, synthetic hormone use, and menstrual abnormalities in 1112 patients with a histologic diagnosis of NAFLD. We performed logistic or ordinal logistic regression models, adjusting for covariates relevant to an increase of hepatic metabolic stress. RESULTS: Premenopausal women were at an increased risk of lobular inflammation, hepatocyte ballooning, and Mallory‐Denk bodies than men and also at an increased risk of lobular inflammation and Mallory‐Denk bodies than postmenopausal women (P < .01). Use of oral contraceptives was associated with an increased risk of lobular inflammation and Mallory‐Denk bodies in premenopausal women, whereas hormone replacement therapy was associated with an increased risk of lobular inflammation in postmenopausal women (P < .05). CONCLUSIONS: Being a premenopausal woman or a female user of synthetic hormones is associated with increased histologic severity of hepatocyte injury and inflammation among patients with NAFLD at given levels of hepatic metabolic stress.

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

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.

Efficacy and safety of sofosbuvir-based regimens for treatment in chronic hepatitis C genotype 1 patients with moderately impaired renal function

Background/Aims Treatment of chronic hepatitis C virus (HCV) infection in patients with chronic kidney disease (CKD) is essential. The availability of sofosbuvir (SOF) has dramatically improved overall HCV cure rates, however there is insufficient data regarding its use in patients with CKD. We evaluated SOF in patients with hepatitis C genotype 1 (G1) and moderately impaired renal function. Methods We retrospectively reviewed all patients treated with a SOF-based regimen from December 2013 through September 2015 at Virginia Mason Medical Center. Data was then collected for HCV G1 patients with stage 3 CKD. Results A total of 28 patients with HCV G1 and stage 3 CKD were treated with a SOF-based regimen. Twenty-one patients had stage 3A CKD (estimated glomerular filtration rate [eGFR] 45–60 mL/min/1.73m2) and 7 patients had stage 3B CKD (eGFR 30–45 mL/min/1.73m2). The overall rate of sustained virologic response (SVR) 12 weeks after completion of therapy (SVR12) was 85.7% (24/28). SVR12 in stage 3A CKD patients was 81.0% (17/21) and in stage 3B CKD patients, SVR12 was 100% (7/7). Based on the treatment regimen used, the SVR12 was 81.8% (9/11), 92.3% (12/13), and 75.0% (3/4) for SOF/ledipasvir (LDV), SOF/simeprevir (SIM), and SOF/pegylated interferon (PEG)/ribavirin (RBV), respectively. Greater than 30% reduction eGFR was observed in 4 out of 28 patients. Conclusions SOF-based regimens resulted in high SVR12 rates in patients with moderately impaired renal function. During therapy, HCV patients with CKD should be carefully monitored for worsening renal function.

Real-World Single-Center Experience with Sofosbuvir-Based Regimens for the Treatment of Chronic Hepatitis C Genotype 1 Patients.

Background/Aims The approval of sofosbuvir (SOF), a direct-acting antiviral, has revolutionized the treatment of chronic hepatitis C virus (HCV). Methods We assessed the sustained virological response (SVR) of SOF-based regimens in a real-world single-center setting for the treatment of chronic HCV genotype 1 (G1) patients. This was a retrospective review of chronic HCV G1 adult patients treated with a SOF-based regimen at Virginia Mason Medical Center between December 2013 and August 2015. Results The cohort comprised 343 patients. Patients received SOF+ledipasvir (LDV) (n=155), SOF+simeprevir (SIM) (n=154), or SOF+peginterferon (PEG)+ribavirin (RBV) (n=34). Of the patients, 50.1% (n=172) had cirrhosis. The SVR rate was 92.2% for SOF/LDV, 87.0% for SOF/SIM, and 82.4% for SOF/PEG/RBV. Compared with the cirrhotic patients, the patients without cirrhosis had a higher SVR (96.8% vs 85.5%, p=0.01, SOF/LDV; 98.2% vs 80.6%, p=0.002, SOF/SIM; 86.4% vs 75.0%, p=0.41, SOF/PEG/RBV). In this study, prior treatment experience adversely affected the response rate in subjects treated with SOF/PEG/RBV. Conclusions In this single-center, real-world setting, the treatment of chronic HCV G1 resulted in a high rate of SVR, especially in patients without cirrhosis.

Tu1013 On-Treatment HCV RNA As a Predictor of Sustained Virologie Response in HCV Genotype 3 - Infected Patients Treated With Daclatasvir and Sofosbuvir: Analysis of Phase 3 Ally-3 Study

A S L D A b st ra ct s rates in patients treated with DCV/ASV/BCV combined with RBV and in patients with GT1b subtype. Other baseline factors such as age, gender, BMI, IL28B genotype, HCV RNA >800,000 IU/mL, and platelet count <100 × 109/L did not appear to impact SVR12 rates in either cohort (Table). Similarly, race did not appear to influence SVR12 rates; of the 20 black patients enrolled in the study, all 20 achieved SVR12. Prior null response to pegIFN did not significantly impact outcome in the treatment-experienced cohort. Baseline resistanceassociated variants (RAVs) in NS5A (28, 30, 31, 93) or NS3 (168) did not impact SVR: 26/ 28 patients with NS5A RAVs and 2/2 patients with NS3 RAVs achieved SVR12. NS5B-P495 was not detected at baseline. Among patients with virologic failure, RAVs were detected in NS5A (Q30, Y93, L31), NS3 (R155, D168) and NS5B (P495, P421). Conclusion: The alloral fixed-dose combination of DCV, ASV, and BCV achieved high rates of SVR12 in patients with HCV genotype 1 infection and compensated cirrhosis. The strongest predictors of SVR12 were GT1b and use of RBV. Factors often associated with reduced responses to less potent regimens, such as advanced age, black race, prior null response to pegIFN, high baseline HCV RNA levels, low platelet counts, non-CC IL28B genotype, and baseline NS5A or NS3 RAVs did not appear to impact SVR12 rates.

Adding N-acetylcysteine to prednisolone reduced early mortality in severe alcoholic hepatitis

Source Citation Nguyen-Khac E, Thevenot T, Piquet MA, et al; AAH-NAC Study Group. Glucocorticoids plus N-acetylcysteine in severe alcoholic hepatitis. N Engl J Med. 2011;365:1781-9. 22070475