Ledipasvir and Sofosbuvir Plus Ribavirin for Treatment of HCV Infection in Patients With Advanced Liver Disease

BACKGROUND & AIMS: There are no effective and safe treatments for chronic hepatitis C virus (HCV) infection of patients who have advanced liver disease. METHODS: In this phase 2, open-label study, we assessed treatment with the NS5A inhibitor ledipasvir, the nucleotide polymerase inhibitor sofosbuvir, and ribavirin in patients infected with HCV genotypes 1 or 4. Cohort A enrolled patients with cirrhosis and moderate or severe hepatic impairment who had not undergone liver transplantation. Cohort B enrolled patients who had undergone liver transplantation: those without cirrhosis; those with cirrhosis and mild, moderate, or severe hepatic impairment; and those with fibrosing cholestatic hepatitis. Patients were assigned randomly (1:1) to receive 12 or 24 weeks of a fixed-dose combination tablet containing ledipasvir and sofosbuvir, once daily, plus ribavirin. The primary end point was sustained virologic response at 12 weeks after the end of treatment (SVR12). RESULTS: We enrolled 337 patients, 332 (99%) with HCV genotype 1 infection and 5 (1%) with HCV genotype 4 infection. In cohort A (nontransplant), SVR12 was achieved by 86%-89% of patients. In cohort B (transplant recipients), SVR12 was achieved by 96%-98% of patients without cirrhosis or with compensated cirrhosis, by 85%-88% of patients with moderate hepatic impairment, by 60%-75% of patients with severe hepatic impairment, and by all 6 patients with fibrosing cholestatic hepatitis. Response rates in the 12- and 24-week groups were similar. Thirteen patients (4%) discontinued the ledipasvir and sofosbuvir combination prematurely because of adverse events; 10 patients died, mainly from complications related to hepatic decompensation. CONCLUSION: The combination of ledipasvir, sofosbuvir, and ribavirin for 12 weeks produced high rates of SVR12 in patients with advanced liver disease, including those with decompensated cirrhosis before and after liver transplantation. ClinTrials.gov: NCT01938430

Smoking & risk of advanced liver fibrosis among patients with primary biliary cholangitis: A systematic review & meta-analysis

Background & objectives: Studies have suggested that smoking may accelerate the progression of fibrosis among patients with primary biliary cholangitis (PBC), although the data are limited. The current review was undertaken with the aim to comprehensively analyze this possible association by identifying all relevant studies and summarizing their results. Methods: A comprehensive literature review on MEDLINE and EMBASE databases was performed from inception through February 2019 to identify all relevant studies. Eligible studies included cross-sectional studies that recruited patients with PBC and collected data on the smoking status and presence or absence of advanced liver fibrosis for each participant. Odds ratios (OR) with 95 per cent confidence intervals (CI) was desirable for inclusion or sufficient raw data to calculate the same for this association. Adjusted point estimates from each study were extracted and combined together using the generic inverse variance method of DerSimonian and Laird. I2 statistic, which quantifies the proportion of total variation across studies was used to determine the between-study heterogeneity. Results: Three cross-sectional studies with 544 participants were included. The pooled analysis found a significantly increased risk of advanced liver fibrosis among patients with PBC who were ever-smokers compared to those who were nonsmokers with the pooled OR of 3.00 (95% CI, 1.18-7.65). Statistical heterogeneity was high with I2 of 89 per cent. Interpretation & conclusions: This meta-analysis found that smoking is associated with a significantly higher risk of advanced liver fibrosis among patients with PBC. Further prospective studies are still required to determine whether this association is causal

Nonalcoholic Fatty Liver Disease and Albuminuria: A Systematic Review and Meta-Analysis

Background/objectives The relationship between nonalcoholic fatty liver disease (NAFLD) and albuminuria has been shown in many epidemiologic studies, although the results were inconsistent. This meta-analysis was conducted to summarize all available data and to estimate the risk of albuminuria among patients with NAFLD. Methods Comprehensive literature review was conducted utilizing Medline and Embase database through January 2018 to identify studies that compared the risk of albuminuria among patients with NAFLD versus those without NAFLD. Effect estimates from each study were extracted and combined using the random-effect, generic inverse variance method of DerSimonian and Laird. Results Nineteen studies (17 cross-sectional studies and two cohort studies) with 24 804 participants fulfilled the eligibility criteria and were included in this meta-analysis. The risk of albuminuria among patients with NAFLD was significantly higher than those without NAFLD with the pooled odds ratio (OR) of 1.67 [95% confidence interval (CI): 1.32-2.11]. Subgroup analysis demonstrated the significantly increased risk of albuminuria among patients with NAFLD without diabetes with pooled OR of 2.25 (95% CI: 1.65-3.06). However, we found no significant association between albuminuria and NAFLD among diabetic patients [pooled OR 1.28 (95% CI: 0.94-1.75)]. Conclusion A significantly increased risk of albuminuria among patients with NAFLD was observed in this meta-analysis. Physicians should pay more attention to the early detection and subsequent treatment of individuals with microalbuminuria especially in patients with NAFLD

Multicenter Experience using Ledipasvir/Sofosbuvir ± RBV to Treat HCV GT 1 Relapsers after Simeprevir and Sofosbuvir Treatment

Introduction and aim. Approximately 10%-15% of patients with hepatitis C genotype 1 (HCV GT1) experience virological relapse after all-oral antiviral regimen using simeprevir (SMV) and sofosbuvir (SOF). The efficacy and safety of treating such relapsers using ledipasvir/sofosbuvir (LDV/SOF) with/without ribavirin (RBV) has been limited.Objective. Report the virological response and safety of LDV/SOF with/without RBV for 12-24 weeks in treating HCV GT1 relapsers after SMV + SOF.Material and methods. Patients treated with standardized clinical protocol utilizing LDV/SOF with/without RBV at three transplant centers were retrospectively reviewed.Results. Forty-five patients (29% post-LT, 82% male, 13% non-white, 73% subtype 1a, 86% IL28B CT/ TT, 78% F3-4) started LDV/SOF with/without RBV at a median of 22 weeks (range 7-55 weeks) after the last dose of SMV+SOF treatment. Thirty-seven patients received LDV/SOF for 24 weeks (24/37 patients with RBV) and eight patients received LDV/SOF for 12 weeks (5/8 patients with RBV). RBV dose was adjusted for renal function. Sixteen patients who were RBV-ineligible received LDV/SOF without RBV for 12 or 24 weeks. SVR 12 was achieved in 96% (43/45) of patients. Baseline viral load, RBV use, or GT1 subtype did not impact SVR 12. Minimal adverse events were reported in those without RBV; 45% of patients who received RBV developed significant anemia requiring RBV dose reduction and/or discontinuation. In LT recipients, minimal immunosuppression dose adjustments were required and no biopsy-proven acute rejection occurred.Conclusions. Treatment with LDV/SOF with/without RBV for 12-24 weeks was very well tolerated and resulted in high SVR 12 rates (96%) in HCV GT1 relapsers to SMV + SOF treatment

Association between sarcopenia and hepatic encephalopathy: A systematic review and meta-analysis

Studies have suggested that the presence of sarcopenia in patients with cirrhosis could be a predisposing risk factor for hepatic encephalopathy. This systematic review and meta-analysis were conducted to summarize all available evidence on this relationship. A systematic review was carried out in Medline and EMBASE database through December 2018 to identify studies that recruited patients with cirrhosis from any causes and collected data on the presence of minimal or overt hepatic encephalopathy as well as sarcopenia. All study designs (case–control, cohort and cross-sectional studies) were eligible for the meta-analysis. Odds ratio (OR) and 95% confidence interval (CI) were extracted from the included studies and were pooled together using random-effect, generic inverse variance method of DerSimonian and Laird. Five cross-sectional studies with a total of 1,713 patients met our eligibility criteria and were included into the meta-analysis. We found a significantly higher risk of both mild and overt hepatic encephalopathy among cirrhotic patients with sarcopenia when compared with cirrhotic patients without sarcopenia with the pooled OR of 3.34 (95% CI: 1.68–6.67; I2 = 37%) and 2.05 (95% CI: 1.28–3.29; I2 = 61%), respectively. This systematic review and meta-analysis demonstrated a significant association between sarcopenia and hepatic encephalopathy among patients with cirrhosis