Glecaprevir/pibrentasvir for the treatment of chronic hepatitis C: design, development, and place in therapy.

Direct-acting antiviral (DAA) therapy has changed the landscape of hepatitis C virus (HCV) management and has changed the focus to the possibility of HCV elimination in the near future. Glecaprevir, an NS3/4A protease inhibitor, and pibrentasvir, an HCV NS5A inhibitor, have addressed many of the existing shortcomings in the DAA therapy spectrum. This combination has proven to be a highly efficacious pan-genotypic DAA with a high barrier to resistance as a once-daily, all-oral medication.

Novel educational interventions in residency increase knowledge of chronic liver disease and career interest in hepatology.

Unlabelled: There is an increasing burden of chronic liver disease (CLD) in the United States but a significant shortage of hepatologists. Thus, it is necessary to develop new recruitment strategies to the field of hepatology as well as ensure that non-gastroenterology-trained physicians are able to capably assist in the care of CLD. We established a novel, nonelective, inpatient hepatology rotation that uses required modules in the American Association for the Study of Liver Diseases Curriculum and Training-First Hepatitis B and C curriculums as well as in LiverLearning.

Generic medications for hepatitis C.

The recent development and approval of expensive but highly effective oral agents against hepatitis C has led to restrictions and access limitations in many countries with limited healthcare budgets. Generic formulations of many of these agents are available at a fraction of the retail price in several countries because of generic licensure agreements. The discounted alternatives are only accessible in developing countries and require manufacturing and distribution regulations to ensure the quality and bioequivalence of the new drug formulations.

Faldaprevir, pegylated interferon, and ribavirin for treatment-naïve HCV genotype-1: pooled analysis of two phase 3 trials.

Introduction & Aim: Faldaprevir is a potent once-daily (q.d.) hepatitis C virus (HCV) NS3/4A protease inhibitor.

Retinoid and carotenoid status in serum and liver among patients at high-risk for liver cancer.

Background: Approximately 2.7 million Americans are chronically infected with hepatitis C virus (HCV). HCV patients with cirrhosis form the largest group of persons at high risk for hepatocellular carcinoma (HCC).

Daclatasvir plus asunaprevir for HCV genotype 1b infection in patients with or without compensated cirrhosis: a pooled analysis.

Background & Aims: We compared outcomes by cirrhosis status across studies of the all-oral combination of daclatasvir (DCV) plus asunaprevir (ASV).

Methods: Outcomes from global and Japanese phase 2 and 3 clinical studies of DCV+ASV in patients with genotype (GT) 1b infection were assessed by cirrhosis status. Sustained virological response (SVR) was assessed in individual phase 3 studies; a pooled analysis was carried out for safety outcomes.

Discovery of a Novel Human Pegivirus in Blood Associated with Hepatitis C Virus Co-Infection.

Hepatitis C virus (HCV) and human pegivirus (HPgV), formerly GBV-C, are the only known human viruses in the Hepacivirus and Pegivirus genera, respectively, of the family Flaviviridae. We present the discovery of a second pegivirus, provisionally designated human pegivirus 2 (HPgV-2), by next-generation sequencing of plasma from an HCV-infected patient with multiple bloodborne exposures who died from sepsis of unknown etiology. HPgV-2 is highly divergent, situated on a deep phylogenetic branch in a clade that includes rodent and bat pegiviruses, with which it shares <32% amino acid identity.

Interferon-free regimens containing setrobuvir for patients with genotype 1 chronic hepatitis C: a randomized, multicenter study.

Background & Aims: Setrobuvir is a direct-acting antiviral (DAA) non-nucleoside inhibitor of hepatitis C virus (HCV) polymerase. This study examined interferon-free combinations containing setrobuvir, a ritonavir-boosted protease inhibitor (danoprevir/r) and ribavirin, with/without the nucleoside inhibitor mericitabine in HCV genotype (G)1 patients.

Methods: Non-cirrhotic treatment-naïve patients (N = 110) were randomized to five groups.

A New-Onset Rash in the Setting of Rifaximin Treatment for Hepatic Encephalopathy.

We present one of the first cases in the literature to describe an association between Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and rifaximin treatment in a patient with a recent diagnosis of alcoholic hepatitis, stage 2 hepatic encephalopathy, and no known existing allergies. Although SJS/TEN may be a rare reaction with rifaximin, it should be an important clinical consideration.

Pegylated interferon based therapy with second-wave direct-acting antivirals in genotype 1 chronic hepatitis C.

Within the last few years, treatment of chronic hepatitis C infection has progressed beyond regimens containing the first-wave direct-acting antiviral agents (DAAs) boceprevir and telaprevir, which had high pill burdens as well as low efficacy and safety in treatment-experienced patients. Triple therapy regimens with newer second-wave DAAs combined with pegylated interferon (PEG-IFN) and ribavirin (RBV), have shown rates of sustained virological response never before achieved with previous regimens in treatment-naïve genotype 1 (HCV-1) patients. Additionally, increased response rates have been found with quadruple agent therapy in prior non-responders, partial-responders, and relapsers, including those with cirrhosis.

Randomized study of danoprevir/ritonavir-based therapy for HCV genotype 1 patients with prior partial or null responses to peginterferon/ribavirin.

Background & Aims: Chronic hepatitis C treatment for prior non-responders to peginterferon (PegIFN)/ribavirin remains suboptimal. The MATTERHORN study evaluated regimens containing ritonavir-boosted danoprevir (danoprevir/r) in prior PegIFN alfa/ribavirin non-responders.

Methods: Prior partial responders (N=152) were randomized to 24 weeks of twice-daily danoprevir/r 100/100mg, mericitabine 1000 mg and ribavirin 1000/1200 mg (IFN-free); danoprevir/r plus PegIFN alfa-2a/ribavirin (triple); or danoprevir/r, mericitabine and PegIFN alfa-2a/ribavirin (Quad).

Human immunodeficiency virus and coinfection with hepatitis B and C.

In HIV-infected individuals, coinfection with HBV and/or HCV is common because of shared modes of transmission. It is known that HIV accelerates progression of liver disease and results in increased morbidity and mortality associated with viral hepatitis, but it is less clear if viral hepatitis has a direct effect on HIV. Treatment of viral hepatitis improves outcomes and should be considered in all HIV-infected patients.

Retreatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin.

Background: In this phase 3 trial we evaluated the efficacy and safety of the interferon-free combination of ABT-450 with ritonavir (ABT-450/r), ombitasvir (also known as ABT-267), dasabuvir (also known as ABT-333), and ribavirin for the retreatment of HCV in patients who were previously treated with peginterferon-ribavirin.

Methods: We enrolled patients with HCV genotype 1 infection and no cirrhosis who had previously been treated with peginterferon-ribavirin and had a relapse, a partial response, or a null response. Patients were randomly assigned in a 3:1 ratio to receive coformulated ABT-450/r-ombitasvir (at a once-daily dose of 150 mg of ABT-450, 100 mg of ritonavir, and 25 mg of ombitasvir) and dasabuvir (250 mg twice daily) with ribavirin (1000 or 1200 mg daily) or matching placebos during the 12-week double-blind period.

Predicting early and sustained virological responses in prior nonresponders to pegylated interferon alpha-2b plus ribavirin retreated with peginterferon alpha-2a plus ribavirin and the benefit-risk ratio of retreatment.

Goals: To evaluate the predictive value of complete early virological response (cEVR) on sustained virological response (SVR) following retreatment with peginterferon alpha-2a (40 kDa) plus ribavirin in previous nonresponders to peginterferon alpha-2b (12 kDa).

Background: In the randomized multinational retreatment with Pegasys in patients not responding to PegIntron therapy study, a 72-week regimen of peginterferon alpha-2a (40 kDa) plus ribavirin improved SVR rates over a standard 48-week regimen in previous nonresponders to peginterferon alpha-2b (12 kDa). cEVR, defined as hepatitis C virus RNA <50 IU/mL at treatment week 12, was an important predictor of SVR.

Future therapies for chronic hepatitis C.

Therapy for hepatitis C has been fairly stagnant for the past decade, but the past few years have seen major progress and evolution, beginning with the approval of two HCV protease inhibitors in 2011. In spite of considerable improvements in response rates with these agents, a need for additional agents with improved potency and tolerability remains. Toward this goal and over the course of just a few months, the HCV therapy pipeline has already become crowded with direct-acting antivirals, host-targeted agents and unique interferons, all of which are positioned to be part of the next wave of therapeutic options.

Hepatitis C virus: a critical appraisal of new approaches to therapy.

The HCV council 2011 convened 11 leading clinicians and researchers in hepatitis C virus from academic medical centers in the United States to provide a forum for the practical and comprehensive evaluation of current data regarding best practices for integrating new direct-acting antiviral agents into existing treatment paradigms. The council investigated 10 clinical practice statements related to HCV treatment that reflect key topical areas. Faculty members reviewed and discussed the data related to each statement, and voted on the nature of the evidence and their level of support for each statement.

The importance of rapid viral suppression in the era of directly acting antiviral therapy for hepatitis C virus.

An increased understanding of viral kinetics has allowed clinicians to tailor therapy for hepatitis C virus through identifying patients who have the best chance of viral eradication and those for whom therapy will likely fail. Nonetheless, sustained viral response rates with pegylated interferon (PegIFN) and ribavirin remain disappointingly low. However, exciting advancements in the field of hepatitis C therapy include the development of new direct-acting antiviral agents, which offer much higher rates of sustained viral eradication when used in combination with PegIFN and ribavirin.

Safety profile of standard- vs. high-dose peginterferon alfa-2a plus standard-dose ribavirin in HCV genotype 1/4 patients: pooled analysis from 5 randomized studies.

Objective: This analysis examines the safety profile of standard- versus high-dose peginterferon alfa-2a.

Methods: Data were pooled from five trials including HCV genotype 1- or 4-infected naive and treatment-experienced patients (n = 2,940). Patients were randomized to receive peginterferon alfa-2a at 180 μg/week (standard-dose; n = 1,672) or 360 μg/week (high-dose; n = 1,268) plus ribavirin 1,000/1,200 mg/day for 12 weeks; after 12 weeks, all received standard dose.

Recommendations for standardized nomenclature and definitions of viral response in trials of hepatitis C virus investigational agents.

Outdated virological response terms used at key trial timepoints in clinical trials with first-generation direct-acting antivirals plus pegylated interferon and ribavirin have failed to keep pace with hepatitis C virus (HCV) drug development. A more intuitive and flexible nomenclature capable of adapting to continuing advances in HCV drug development is needed. Assistance in standardization of the field was provided by members of the Hepatitis C Virus Drug Development Advisory Group, a project of the Forum for Collaborative HIV Research with participation from the American Association for the Study of Liver Diseases, European Association for the of the liver, and the Infectious Diseases Society of America.