Renal Outcomes With Tenofovir Alafenamide in Liver Transplant Recipients.

Tenofovir disoproxil fumarate (TDF) is associated with a higher risk of nephrotoxicity compared with entecavir (ETV) or tenofovir alafenamide (TAF). One-fifth of transplant recipients develop chronic kidney disease (CKD) within 5 years after transplantation, contributed by the use of nephrotoxic immunosuppressive medications. Prior studies conducted in the nontransplant setting reported superior renal safety in TAF compared with TDF but data in liver transplant (LT) recipients have so far been limited to small case series.

Sofosbuvir plus ribavirin and sofosbuvir plus ledipasvir in patients with genotype 1 or 3 hepatitis C virus and severe renal impairment: a multicentre, phase 2b, non-randomised, open-label study.

Background: There is a medical need for highly effective, safe, and well tolerated treatments for patients infected with hepatitis C virus (HCV) with severe renal impairment. We investigated the safety and efficacy of sofosbuvir with ribavirin or ledipasvir combined with sofosbuvir in a prospective study of patients with genotype 1 or 3 HCV infection and stage 4-5 chronic kidney disease (creatinine clearance by Cockcroft-Gault ≤30 mL/min) who were not on dialysis.

Methods: This phase 2b, open-label, non-randomised, multicentre study in the USA and New Zealand investigated three sequentially enrolled cohorts of patients.

DAA therapy and long-term hepatic function in advanced/decompensated cirrhosis: Real-world experience from HCV-TARGET cohort.

Background & Aims: Direct-acting antiviral (DAA) therapy is used in patients with HCV-related decompensated cirrhosis with the expectation of improving hepatic function. However, little is known about the long-term hepatic benefit of successful antiviral treatment.

Methods: Patients with advanced/decompensated cirrhosis (model for end-stage liver disease [MELD] ≥10), in whom NS5A-containing DAA therapy was initiated prior to September 2018, were included (from the HCV-TARGET cohort).

Increased Frequency of Heterozygous Alpha-1-Antitrypsin Deficiency in Liver Explants From Nonalcoholic Steatohepatitis Patients.

Cirrhotic explanted livers occasionally have unexpected periodic acid-Schiff-diastase (PASD)-positive globules within the hepatocyte cytoplasm. It is often unclear whether this finding is a nonspecific consequence of cirrhosis or is indicative of an underlying alpha-1-antitrypsin deficiency (A1ATD) contributing to the cirrhosis. In this study, explanted livers were retrospectively evaluated for histopathology (including PASD status with confirmatory alpha-1-antitrypsin [A1AT] immunohistochemistry [IHC]), and chart review provided etiology of liver failure and general clinical parameters.

Cholesterol Crystals in Hepatocyte Lipid Droplets Are Strongly Associated With Human Nonalcoholic Steatohepatitis.

It is unclear what drives the development of fibrosing nonalcoholic steatohepatitis (NASH). We aimed to determine whether cholesterol crystallization within hepatocyte lipid droplets (LDs) distinguishes patients with fibrosing NASH from patients with isolated hepatic steatosis and to study pathways leading to cholesterol accumulation in hepatocyte LDs Patients with fibrosing NASH (n = 16) were compared to patients with isolated steatosis (n = 14). Almost all patients with fibrosing NASH had free cholesterol staining by filipin (16/16) and cholesterol crystals (15/16) in hepatocyte LDs, mostly in association with the LD membrane, compared to only 3/14 with cholesterol crystals and 3/14 with faint filipin staining in patients with isolated steatosis ( < 0.

Effect of NGM282, an FGF19 analogue, in primary sclerosing cholangitis: A multicenter, randomized, double-blind, placebo-controlled phase II trial.

Background & Aims: Primary sclerosing cholangitis (PSC) is an inflammatory, cholestatic and progressively fibrotic liver disease devoid of effective medical intervention. NGM282, an engineered, non-tumorigenic FGF19 analogue, potently regulates CYP7A1-mediated bile acid homeostasis. We assessed the activity and safety of NGM282 in patients with PSC.

Deferred treatment with sofosbuvir-velpatasvir-voxilaprevir for patients with chronic hepatitis C virus who were previously treated with an NS5A inhibitor: an open-label substudy of POLARIS-1.

Background: Direct-acting antiviral regimens containing NS5A inhibitors are highly effective treatments for chronic hepatitis C virus (HCV) infection, but are not always successful. In the POLARIS-1 phase 3 study, sofosbuvir-velpatasvir-voxilaprevir for 12 weeks was highly effective in the treatment of chronic HCV infection in patients previously treated with a direct-acting antiviral regimen containing an NS5A inhibitor. We aimed to assess the efficacy and safety of sofosbuvir-velpatasvir-voxilaprevir in patients from the deferred treatment group of POLARIS-1, who were initially assigned to masked placebo treatment.

Sofosbuvir-based regimens for the treatment of chronic hepatitis C in severe renal dysfunction.

Sofosbuvir (SOF) is a nonstructural 5B polymerase inhibitor with activity in all hepatitis C virus (HCV) genotypes and is the backbone of many anti-HCV drug regimens. SOF is converted into inactive metabolites that undergo renal excretion. Patients with an estimated glomerular filtration rate (eGFR) < 30 mL/minute/1.

Safety and Effectiveness of Ledipasvir and Sofosbuvir, With or Without Ribavirin, in Treatment-Experienced Patients With Genotype 1 Hepatitis C Virus Infection and Cirrhosis.

Background & Aims: We aimed to evaluate the safety and effectiveness of 12 or 24 weeks treatment with ledipasvir and sofosbuvir, with or without ribavirin, in treatment-experienced patients with hepatitis C virus (HCV) genotype 1 infection and cirrhosis in routine clinical practice. Patients were followed in a multi-center, prospective, observational cohort study (HCV-TARGET).

Methods: We collected data from 667 treatment-experienced adults with chronic genotype 1 HCV infection who began treatment with ledipasvir and sofosbuvir, with or without ribavirin, from 2011 through September 15, 2016, according to the regional standards of care, at academic (n = 39) and community (n = 18) centers in the United States, Canada, Germany, and Israel.

IRE1α promotes viral infection by conferring resistance to apoptosis.

The unfolded protein response (UPR) is an ancient cellular pathway that detects and alleviates protein-folding stresses. The UPR components X-box binding protein 1 (XBP1) and inositol-requiring enzyme 1α (IRE1α) promote type I interferon (IFN) responses. We found that -deficient mouse embryonic fibroblasts and macrophages had impaired antiviral resistance.

Sofosbuvir, Velpatasvir, and Voxilaprevir for Previously Treated HCV Infection.

Background: Patients who are chronically infected with hepatitis C virus (HCV) and who do not have a sustained virologic response after treatment with regimens containing direct-acting antiviral agents (DAAs) have limited retreatment options.

Methods: We conducted two phase 3 trials involving patients who had been previously treated with a DAA-containing regimen. In POLARIS-1, patients with HCV genotype 1 infection who had previously received a regimen containing an NS5A inhibitor were randomly assigned in a 1:1 ratio to receive either the nucleotide polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the protease inhibitor voxilaprevir (150 patients) or matching placebo (150 patients) once daily for 12 weeks.

Expanding access to transplantation with hepatitis C-positive donors: A new perspective on an old issue.

With the need for organs far exceeding supply, donors previously exposed to hepatitis B (HBV) and hepatitis C (HCV) viral infections should be considered for transplantation. Although many centers have protocols for transplanting organs from HBV core antibody-positive (HBcAb+) donors into select recipients, in the era of direct-acting antivirals (DAAs), a new focus should be placed on HCV-positive donors. The transmission rate from HCV antibody-positive (HCVAb+) nucleic acid testing negative (HCV NAT-) donors is expected to be very low, and we encourage use of such organs in HCV recipients provided a normal biopsy, appropriate counseling, and careful post-transplant monitoring.

Glecaprevir and pibrentasvir for 12 weeks for hepatitis C virus genotype 1 infection and prior direct-acting antiviral treatment.

Unlabelled: Although direct-acting antiviral (DAA) therapies for chronic hepatitis C virus (HCV) infection have demonstrated high rates of sustained virologic response, virologic failure may still occur, potentially leading to the emergence of viral resistance, which can decrease the effectiveness of subsequent treatment. Treatment options for patients who failed previous DAA-containing regimens, particularly those with nonstructural protein 5A inhibitors, are limited and remain an area of unmet medical need. This phase 2, open-label study (MAGELLAN-1) evaluated the efficacy and safety of glecaprevir (GLE) + pibrentasvir (PIB) ± ribavirin (RBV) in HCV genotype 1-infected patients with prior virologic failure to HCV DAA-containing therapy.

Management of Post-Liver Transplant Recurrence of Hepatitis C.

Cirrhosis due to chronic hepatitis C (HCV) is the leading indication for liver transplantation in North America and Europe. HCV re-infection post-transplant is nearly universal and if left untreated negatively affects patient and graft survival. Until recently, treatment options for HCV were limited to interferon (IFN)-based therapies which had low sustained viral response (SVR) rates and were poorly tolerated in the post-transplant setting.

High antiviral activity of NS5A inhibitor ABT-530 with paritaprevir/ritonavir and ribavirin against hepatitis C virus genotype 3 infection.

Background & Aims: ABT-530 is a next-generation hepatitis C virus (HCV) NS5A inhibitor with potent pangenotypic antiviral activity in vitro. Paritaprevir is an NS3/4A protease inhibitor codosed with ritonavir that displays in vitro activity against HCV genotypes 1-4 and 6.

Methods: Efficacy, pharmacokinetics and safety of ABT-530 with paritaprevir/ritonavir and ribavirin were evaluated in this phase 2, open-label, multicentre study in treatment-naïve non-cirrhotic patients with genotype 3 infection.

Aging of Liver Transplant Registrants and Recipients: Trends and Impact on Waitlist Outcomes, Post-Transplantation Outcomes, and Transplant-Related Survival Benefit.

Background & Aims: Epidemiologic factors have generated increased demand for liver transplantation among older patients. We aimed to describe trends in age among liver transplant registrants and recipients and the effect of age on waitlist and post-transplantation outcomes and on transplant-related survival benefit.

Methods: We obtained data from the United Network for Organ Sharing on adults who were listed for liver transplantation (N = 122,606) or underwent liver transplantation (N = 60,820) from 2002 to 2014 in the United States.

Fulminant hepatitis B reactivation leading to liver transplantation in a patient with chronic hepatitis C treated with simeprevir and sofosbuvir: a case report.

Introduction: Hepatitis B and C coinfection is commonly seen in clinical practice. In coinfected individuals, high levels of hepatitis C viremia are often associated with low levels of serum hepatitis B DNA. Hepatitis B reactivation in hepatitis C-infected patients treated with pegylated interferon and ribavirin has been reported, but severe or fulminant reactivation is uncommon.

Liver regeneration and energetic changes in rats following hepatic radiation therapy and hepatocyte transplantation by ³¹P MRSI.

Background & Aims: Radiation-induced liver damage (RILD) is a poorly understood and potentially devastating complication of hepatic radiation therapy (RT) for liver cancers. Previous work has demonstrated that hepatocyte transplantation (HT) can ameliorate RILD in rats. We hypothesized that RT inhibits generation of cellular ATP and suppresses hepatic regeneration.

The hepatic stem cell niche: identification by label-retaining cell assay.

Unlabelled: Label retention assays remain the state-of-the-art approach to identify the location of intraorgan epithelial stem cell niches, in situ and in vivo. They are commonly used in organs with rapid cell turnover but have not been applied to the liver, where cell turnover is very slow. We used a sublethal dose of acetaminophen administered coincident with bromodeoxyuridine to load possible hepatic stem cells in mice with label and then administered a second, sublethal chase of acetaminophen to accomplish "washout" of label from transit amplifying cell populations.

Noninvasive evaluation of liver repopulation by transplanted hepatocytes using 31P MRS imaging in mice.

Hepatocyte transplantation (HT) is being explored as a substitute for liver transplantation for the treatment of liver diseases. For the clinical application of HT, a preparative regimen that allows preferential proliferation of transplanted cells in the host liver and a noninvasive method to monitor donor cell engraftment, proliferation, and immune rejection would be useful. We describe an imaging method that employs the creatine kinase (CK) gene as a marker of donor hepatocytes.