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Hepatitis: HELP
Articles by David R. Nelson
Based on 83 articles published since 2010
(Why 83 articles?)
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Between 2010 and 2020, D. Nelson wrote the following 83 articles about Hepatitis.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4
1 Guideline HCV Council--critical appraisal of data: recommendations for clinical practice in a rapidly evolving therapeutic landscape. 2016

Reau, Nancy / Fried, Michael W / Nelson, David R / Brown, Robert S / Everson, Gregory T / Gordon, Stuart C / Jacobson, Ira M / Lim, Joseph K / Pockros, Paul J / Reddy, K Rajender / Sherman, Kenneth E. ·Rush University Medical Center, Chicago, IL, USA. · University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. · University of Florida, Gainesville, FL, USA. · Weill Cornell Medical College, New York, NY, USA. · University of Colorado, Aurora, CO, USA. · Henry Ford Medical Center, Detroit, MI, USA. · Yale University School of Medicine, New Haven, CT, USA. · Scripps Translational Science Institute, La Jolla, CA, USA. · University of Pennsylvania, Philadelphia, PA, USA. · University of Cincinnati College of Medicine, Cincinnati, OH, USA. ·Liver Int · Pubmed #26509462.

ABSTRACT: BACKGROUND & AIMS: HCV Council 2014, like its predecessor HCV Council 2011, assembled leading clinicians and researchers in the field of hepatitis C to critically evaluate current data regarding best practices for managing patients with chronic hepatitis C virus (HCV). METHODS: Clinical practice statements were developed that reflect the areas of potential controversy with high clinical impact. Faculty members were responsible for reviewing the literature to support or reject these statements. After a review and comprehensive discussion of the data, the HCV Council faculty voted on the nature of the evidence and the level of support for each statement. RESULTS: The results of the detailed analysis with expert opinion are summarized in this article. CONCLUSION: Numerous questions regarding optimal management of certain populations and clinical scenarios remain unanswered. The discussion in the article provides a summary of evidenced-based expert opinion that may help guide clinicians as additional information is developed.

2 Guideline Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for IFNL3 (IL28B) genotype and PEG interferon-α-based regimens. 2014

Muir, A J / Gong, L / Johnson, S G / Lee, M T M / Williams, M S / Klein, T E / Caudle, K E / Nelson, D R / Anonymous3140771. ·Division of Gastroenterology, Department of Medicine, Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina, USA. · Department of Genetics, Stanford University, Palo Alto, California, USA. · 1] Department of Clinical Pharmacy, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Denver, Colorado, USA [2] Clinical Pharmacy Services, Kaiser Permanente Colorado, Denver, Colorado, USA. · 1] Laboratory for International Alliance on Genomic Research, RIKEN Center for Genomic Medicine, Yokohama, Japan [2] National Center for Genome Medicine, Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan [3] School of Chinese Medicine, China Medical University, Taichung, Taiwan. · Genomic Medicine Institute, Geisinger Health System, Danville, Pennsylvania, USA. · Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. · Department of Medicine, University of Florida, Gainesville, Florida, USA. ·Clin Pharmacol Ther · Pubmed #24096968.

ABSTRACT: Pegylated interferon-α (PEG-IFN-α or PEG-IFN 2a and 2b)- and ribavirin (RBV)-based regimens are the mainstay for treatment of hepatitis C virus (HCV) genotype 1. IFNL3 (IL28B) genotype is the strongest baseline predictor of response to PEG-IFN-α and RBV therapy in previously untreated patients and can be used by patients and clinicians as part of the shared decision-making process for initiating treatment for HCV infection. We provide information regarding the clinical use of PEG-IFN-α- and RBV-containing regimens based on IFNL3 genotype.

3 Guideline An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases. 2011

Ghany, Marc G / Nelson, David R / Strader, Doris B / Thomas, David L / Seeff, Leonard B / Anonymous4180704. ·Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-1800, USA. marcg@intra.niddk.nih.gov ·Hepatology · Pubmed #21898493.

ABSTRACT: -- No abstract --

4 Editorial Public-Private Partnership: Targeting Real-World Data for Hepatitis C Direct-Acting Antivirals. 2017

Mishra, Poonam / Florian, Jeffry / Peter, Joy / Vainorius, Monika / Fried, Michael W / Nelson, David R / Birnkrant, Debra. ·US Food and Drug Administration, Silver Spring, Maryland. · University of Florida, Gainesville, Florida. · University of North Carolina, Chapel Hill, North Carolina. ·Gastroenterology · Pubmed #28757271.

ABSTRACT: -- No abstract --

5 Review Status of Direct-Acting Antiviral Therapy for Hepatitis C Virus Infection and Remaining Challenges. 2019

Baumert, Thomas F / Berg, Thomas / Lim, Joseph K / Nelson, David R. ·INSERM, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France; Université de Strasbourg, Strasbourg, France; Pôle Hépato-digestif, Institut Hospitalo-Universitaire, Nouvel Hôpital Civil, Strasbourg, France. Electronic address: Thomas.Baumert@unistra.fr. · Section of Hepatology, Clinic for Gastroenterology and Rheumatology, University Clinic Leipzig, Leipzig, Germany. · Section of Digestive Diseases and Yale Liver Center, Yale University School of Medicine, New Haven, Connecticut. · Department of Medicine, University of Florida, Gainesville, Florida. Electronic address: nelsodr@ufl.edu. ·Gastroenterology · Pubmed #30342035.

ABSTRACT: Chronic infection with hepatitis C virus is a major cause of liver disease and hepatocellular carcinoma worldwide. After the discovery of hepatitis C virus 3 decades ago, the identification of the structure of the viral proteins, combined with high-throughput replicon models, enabled the discovery and development of direct-acting antivirals. These agents have revolutionized patient care, with cure rates of more than 90%. We review the status of direct-acting antiviral therapies for hepatitis C virus infection and discuss remaining challenges. We highlight licensed compounds, discuss the potential to shorten therapy even further, and review different options for treatment failure and resistance. We also provide an overview of clinical experience with generic agents and evidence for their efficacy. Finally, we discuss the need for new drugs and outline promising targets for future therapies.

6 Review Safety of the 2D/3D direct-acting antiviral regimen in HCV-induced Child-Pugh A cirrhosis - A pooled analysis. 2017

Poordad, Fred / Nelson, David R / Feld, Jordan J / Fried, Michael W / Wedemeyer, Heiner / Larsen, Lois / Cohen, Daniel E / Cohen, Eric / Mobashery, Niloufar / Tatsch, Fernando / Foster, Graham R. ·The Texas Liver Institute/University of Texas Health, San Antonio, TX, USA. Electronic address: poordad@txliver.com. · Division of Gastroenterology, Hepatology & Nutrition, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL, USA. · Toronto Centre for Liver Disease, University of Toronto, Toronto, ON, Canada. · University of North Carolina (UNC) Liver Center, UNC School of Medicine, Chapel Hill, NC, USA. · Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany. · AbbVie Inc., North Chicago, IL, USA. · Blizard Institute of Cell and Molecular Science, Queen Mary University London, London, UK. ·J Hepatol · Pubmed #28645740.

ABSTRACT: BACKGROUND & AIMS: Chronic hepatitis C virus (HCV)-infected patients with cirrhosis are a high-priority population for treatment. To help inform the benefit-risk profile of the all-oral direct-acting antiviral (DAA) combination regimen of ombitasvir, paritaprevir, and ritonavir, with or without dasabuvir (OBV/PTV/r±DSV) in patients with Child-Pugh A cirrhosis, we undertook a comprehensive review of AbbVie-sponsored clinical trials enrolling patients with Child-Pugh A cirrhosis. METHODS: Twelve phase II or III clinical trials of the 2-DAA regimen of OBV/PTV/r±ribavirin (RBV) or the 3-DAA regimen of OBV/PTV/r+DSV±RBV that included patients with Child-Pugh A cirrhosis were reviewed; patients who completed treatment by November 16, 2015 were included in a pooled, post hoc safety assessment. The number and percentage of patients with treatment-emergent adverse events (TEAEs), serious TEAEs, and TEAEs consistent with hepatic decompensation were reported. RESULTS: In 1,066 patients with Child-Pugh A cirrhosis, rates of serious TEAEs and TEAEs leading to study drug discontinuation were 5.3% (95% confidence interval [CI]: 4.1-6.8) and 2.2% (95% CI: 1.4-3.2), respectively. Thirteen patients (1.2%; 95% CI: 0.7-2.1) had a TEAE that was consistent with hepatic decompensation. The most frequent TEAEs consistent with hepatic decompensation were ascites (n=8), esophageal variceal hemorrhage (n=4), and hepatic encephalopathy (n=2). CONCLUSIONS: This pooled analysis in 1,066 HCV-infected patients with Child-Pugh A cirrhosis confirms the safety of OBV/PTV/r±DSV±RBV in this population. These results support the use of OBV/PTV/r±DSV±RBV in this high-priority population. Lay summary: This pooled safety analysis in 1,066 HCV-infected patients with compensated cirrhosis, receiving treatment with ombitasvir, paritaprevir, and ritonavir with or without dasabuvir, with or without ribavirin, shows that the rate of hepatic decompensation events was similar to previously reported rates in untreated patients.

7 Review Oral Direct-Acting Agent Therapy for Hepatitis C Virus Infection: A Systematic Review. 2017

Falade-Nwulia, Oluwaseun / Suarez-Cuervo, Catalina / Nelson, David R / Fried, Michael W / Segal, Jodi B / Sulkowski, Mark S. ·From Johns Hopkins University School of Medicine, Baltimore, Maryland; University of Florida, Gainesville, Florida; and University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. ·Ann Intern Med · Pubmed #28319996.

ABSTRACT: Background: Rapid improvements in hepatitis C virus (HCV) therapy have led to the approval of multiple oral direct-acting antiviral (DAA) regimens by the U.S. Food and Drug Administration (FDA) for treatment of chronic HCV infection. Purpose: To summarize published literature on the efficacy and safety of oral DAAs for treatment of persons with chronic HCV infection. Data Sources: MEDLINE and EMBASE from inception through 1 November 2016. Study Selection: 42 English-language studies from controlled and single-group registered clinical trials of adults with HCV infection that evaluated at least 8 weeks of an FDA-approved interferon-free HCV regimen that included at least 2 DAAs. Data Extraction: Two investigators abstracted data on study design, patient characteristics, and virologic and safety outcomes sequentially and assessed quality independently. Data Synthesis: Six DAA regimens showed high sustained virologic response (SVR) rates (>95%) in patients with HCV genotype 1 infection without cirrhosis, including those with HIV co-infection. Effective treatments for HCV genotype 3 infection are limited (2 DAA regimens). Patients with hepatic decompensation, particularly those with Child-Turcotte-Pugh class C disease, had lower SVR rates (78% to 87%) than other populations. The addition of ribavirin was associated with increased SVR rates for certain DAA regimens and patient groups. Overall rates of serious adverse events and treatment discontinuation were low (<10% in the general population); regimens that included ribavirin had more mild or moderate adverse events than those without. Limitations: Twenty-three studies had moderate risk of bias (10 were open-label single-group trials, 11 had limited information on concealment of the allocation scheme, and 5 had selective outcome reporting). All but 1 of the studies were industry-funded. Heterogeneity of interventions precluded pooling. Conclusion: Multiple oral DAA regimens show high rates of safety, tolerability, and efficacy for treatment of HCV genotype 1 infection, particularly among persons without cirrhosis. Primary Funding Source: Patient-Centered Outcomes Research Institute. (PROSPERO: CRD42014009711).

8 Review Hepatitis C virus: how to provide the best treatment with what I have. 2016

Nelson, David R / Peter, Joy. ·Department of Medicine, University of Florida, Gainesville, FL, USA. · Liver Research Program, University of Florida, Gainesville, FL, USA. ·Liver Int · Pubmed #26725898.

ABSTRACT: The therapeutic landscape for the treatment of chronic hepatitis C virus infection has been rapidly evolving, and by 2016 there will be six approved, all-oral regimens for use in patients in the USA and most of Western Europe. However, as many as patient populations will have limited access to new direct acting antiviral regimens, patients and physicians are often faced with the challenge of selecting the best regimen available, as opposed to the optimal treatment. In this paper, the challenges and opportunities in developing a high cure regimen for different patient populations will be discussed and highlighted through case-based scenarios.

9 Review Development of sofosbuvir for the treatment of hepatitis C virus infection. 2015

Lawitz, Eric / Jacobson, Ira M / Nelson, David R / Zeuzem, Stefan / Sulkowski, Mark S / Esteban, Rafael / Brainard, Diana / McNally, John / Symonds, William T / McHutchison, John G / Dieterich, Douglas / Gane, Edward. ·Texas Liver Institute, University of Texas Health Science Center, San Antonio, Texas. · Icahn School of Medicine at Mount Sinai, New York, New York. · University of Florida, Gainesville, Florida. · Medical Center, Johann Wolfgang Goethe University, Frankfurt am Main, Germany. · Johns Hopkins University School of Medicine, Baltimore, Maryland. · Hospital Universitario Val d'Hebron, Barcelona, Spain. · Gilead Sciences, Foster City, California. · Mount Sinai School of Medicine, New York, New York. · Auckland City Hospital, Auckland, New Zealand. ·Ann N Y Acad Sci · Pubmed #26235748.

ABSTRACT: The nucleotide analog NS5B polymerase inhibitor sofosbuvir was approved by the U.S. Food and Drug Administration (FDA) in December 2013 for the treatment of chronic hepatitis C virus (HCV) infection in combination with ribavirin or peginterferon and ribavirin. Sofosbuvir was developed to meet an urgent medical need for shorter, safer, simplified, more effective HCV treatment regimens and to reduce or eliminate the need for peginterferon. New treatment regimens were especially required for patient populations with limited treatment options, including patients who had failed prior HCV therapy, those with compensated and decompensated cirrhosis, and those who were either intolerant of or had contraindications to interferon. Sofosbuvir plus ribavirin for patients with genotype 2 or 3 HCV infection was the first approved all-oral treatment option. Sofosbuvir is also the backbone of the first regimen available for patients awaiting liver transplantation to prevent HCV recurrence, as well as the first oral interferon-free regimen for patients coinfected with HCV and HIV. This paper describes the development of sofosbuvir up to its original FDA approval.

10 Review Optimal interferon-free therapy in treatment-experienced chronic hepatitis C patients. 2015

Peter, Joy / Nelson, David R. ·Department of Medicine, Division of Gastroenterology and Hepatology, University of Florida, Gainesville, FL, USA. ·Liver Int · Pubmed #25529089.

ABSTRACT: Over the past year, interferon (IFN) free dosing regimens have become available to treat chronic hepatitis C. Offering high rates of sustained virological response (SVR), short treatment and improved tolerability, IFN-free treatment now represents the paradigm for both treatment-naïve and -experienced patients. Patients with prior treatment failure, in particular those with cirrhosis, still represent some of the most difficult to treat, but the availability of multiple agents that can interrupt several steps of the HCV lifecycle affords providers and patients with options that can be combined and individually tailored to each patient's unique needs to obtain high rates of SVR.

11 Review Direct-acting antiviral agents and the path to interferon independence. 2014

Schmidt, Warren N / Nelson, David R / Pawlotsky, Jean-Michel / Sherman, Kenneth E / Thomas, David L / Chung, Raymond T. ·Department of Internal Medicine and Research Service, Veterans Affairs Medical Center, Iowa City, Iowa; Roy G. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa. Electronic address: warren-schmidt@uiowa.edu. · University of Florida, Section of Hepatobiliary Disease, Gainesville, Florida. · National Reference Center for Viral Hepatitis B, C and Delta, Department of Virology, Henri Mondor Hospital, University of Paris-Est, Créteil, France; INSERM U955, Créteil, France. · University of Cincinnati, College of Medicine, Division of Digestive Diseases, Hepatology Section, Cincinnati, Ohio. · Johns Hopkins Medical Institution, Baltimore, Maryland. · GI Division and Liver Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. ·Clin Gastroenterol Hepatol · Pubmed #23872239.

ABSTRACT: Chronic infection with hepatitis C virus (HCV) is a major global health problem; there are approximately 120 to 130 million chronic infections worldwide. Since the discovery of HCV 24 years ago, there has been a relentless effort to develop successful antiviral therapies. Studies of interferon-α-based therapies have helped define treatment parameters, and these treatment strategies have cured a substantial percentage of patients. However, interferon-α must be injected; there are problems with tolerability, adherence, and incomplete response in a large percentage of patients. New drug candidates designed to target the virus or the host have recently been introduced at an unprecedented pace. In phase I-III studies, these agents have exceeded expectations and achieved rates of response previously not thought possible. We are, therefore, entering a new era of therapy for HCV infection and interferon independence.

12 Review New therapeutic strategies in HCV: second-generation protease inhibitors. 2013

Clark, Virginia C / Peter, Joy A / Nelson, David R. ·University of Florida, FL, USA. ·Liver Int · Pubmed #23286850.

ABSTRACT: Telaprevir and boceprevir are the first direct-acting antiviral agents approved for use in HCV treatment and represent a significant advance in HCV therapy. However, these first-generation drugs also have significant limitations related to thrice-daily dosing, clinically challenging side-effect profiles, low barriers to resistance and a lack of pan-genotype activity. A second wave of protease inhibitors are in phase II and III trials and promise to provide a drug regimen with a better dosing schedule and improved tolerance. These second-wave protease inhibitors will probably be approved in combination with PEG-IFN and Ribavirin (RBV), as well as future all-oral regimens. The true second-generation protease inhibitors are in earlier stages of development and efficacy data are anxiously awaited as they may provide pan-genotypic antiviral activity and a high genetic barrier to resistance.

13 Review The role of ribavirin in direct acting antiviral drug regimens for chronic hepatitis C. 2012

Clark, Virginia / Nelson, David R. ·University of Florida, College of Medicine, Gainesville, FL 32610, USA. ·Liver Int · Pubmed #22212579.

ABSTRACT: Despite years of clinical use and extensive research efforts, the mechanism of action of ribavirin (RBV) is not well understood. Although it has only a mild, transient antiviral effect on HCV replication when administered as monotherapy, when combined with interferon, RBV improves sustained virological response (SVR) rates by approximately 25-30%. Proposed mechanisms of action for RBV against HCV include (1) a direct effect against the HCV RNA dependent RNA polymerase; (2) induction of misincorporation of nucleotides leading to lethal mutagenesis; (3) depletion of intracellular pools via inhibition of inosine monophosphate dehydrogenase; (4) alteration in the cytokine balance between a Th2 profile (anti-inflammatory) to a Th1 profile (pro-inflammatory); and (5) potentiating the effect of interferon via up-regulation of genes involved in interferon signalling. Given the lack of a clear understanding of RBV mechanism of action, it has been challenging to confidently position this drug with new direct antiviral agents (DAA). However, early clinical studies provide strong evidence for a benefit of RBV in combination with DAAs for both IFN containing and sparing regimens. The addition of RBV reduces viral breakthroughs and/or relapses, at least when drugs with low to moderate genetic barriers to resistance are paired together. This is particularly true in patients harbouring HCV subtype 1a. Ongoing studies are now addressing the utility of RBV in nucleoside containing DAA regimens, which offer both potent antiviral activity as well as a high genetic barrier to resistance. It is remarkable that the age-old question of the role of RBV in the future of HCV therapy remains as real today as it was two decades ago.

14 Review The role of triple therapy with protease inhibitors in hepatitis C virus genotype 1 naïve patients. 2011

Nelson, David R. ·Clinical and Translational Science Institute, University of Florida, FL 32610, USA. nelsodr@ufl.edu ·Liver Int · Pubmed #21205138.

ABSTRACT: With the introduction of direct-acting oral antiviral agents we are on the verge of a new era that will transform the treatment landscape. This review discusses recent developments in drug discovery for hepatitis C protease inhibitors. First generation protease inhibitors will offer higher sustained viral response rates in naïve populations when combined with standard pegylated interferon and ribavirin. However, these dramatic gains will be partially offset by new challenges in viral resistance and increased adverse events.

15 Review Hepatitis B reactivation and rituximab in the oncology practice. 2010

Villadolid, Jeryl / Laplant, Kourtney D / Markham, Merry Jennifer / Nelson, David R / George, Thomas J. ·Department of Medicine, College of Medicine, University of Florida, Gainesville, Florida 32610-0278, USA. ·Oncologist · Pubmed #20930099.

ABSTRACT: Rituximab use in hematology and oncology practice has significantly and positively improved the clinical outcomes in patients with a wide variety of B-cell lymphoproliferative disorders. However, emerging data reveal that there is a risk of viral hepatitis B reactivation in some patients treated with rituximab. Many of these cases result in treatment delays, inferior oncologic outcomes, increased morbidity, and more rarely fulminant hepatic decompensation and death. Indeed, the rituximab package insert and many clinical practice guidelines have been modified to reflect these concerns. The true incidence and mechanism of reactivation are still being elucidated. This article focuses on the current evidence that supports these recently revised clinical recommendations along with a review of the risk factors for reactivation, suggested monitoring, and preventative interventions.

16 Review New therapies in the management of hepatitis C virus. 2010

Michaels, Anthony J / Nelson, David R. ·Division of Hepatology and Liver Transplantation, Shands Hospital, University of Florida, Gainesville, Florida, USA. ·Curr Opin Gastroenterol · Pubmed #20224396.

ABSTRACT: PURPOSE OF REVIEW: The present review discusses recent developments in drug discovery for hepatitis C. We are on the verge of a new era with the introduction of direct acting oral agents that will transform the treatment landscape. Both healthcare providers and patients need to stay abreast of these changes that will influence decisions to treat. This article will discuss the most promising up-to-date hepatitis C virus antiviral therapies in clinical investigation as well as the associated clinical trial results. RECENT FINDINGS: First generation protease inhibitors will offer higher sustained viral response rates for both naive (70-80%) and treatment-experienced (40-50%) populations when added to standard pegylated interferon and ribavirin. However, these dramatic gains will be partially offset by new challenges with viral resistance and increased adverse events. SUMMARY: There are currently a number of drugs under investigation that target the enzymes involved in hepatitis C virus replication. Year 2011 should bring the approval of the first generation of protease inhibitors that will offer higher cure rates for genotype 1 patients and open the door for the eventual testing of interferon-free regimens.

17 Clinical Trial Efficacy of Glecaprevir and Pibrentasvir in Patients With Genotype 1 Hepatitis C Virus Infection With Treatment Failure After NS5A Inhibitor Plus Sofosbuvir Therapy. 2019

Lok, Anna S / Sulkowski, Mark S / Kort, Jens J / Willner, Ira / Reddy, K Rajender / Shiffman, Mitchell L / Hassan, Mohamed A / Pearlman, Brian L / Hinestrosa, Federico / Jacobson, Ira M / Morelli, Giuseppe / Peter, Joy A / Vainorius, Monika / Michael, Larry C / Fried, Michael W / Wang, Gary P / Lu, Wenjing / Larsen, Lois / Nelson, David R. ·Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan. Electronic address: aslok@med.umich.edu. · Divisions of Infectious Diseases and Gastroenterology/Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland. · AbbVie Inc, Mettawa, Illinois. · Division of Gastroenterology and Hepatology, Medical University of South Carolina, Charleston, South Carolina. · Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, Pennsylvania. · Bon Secours Liver Institute of Richmond, Richmond, Virginia. · Division of Gastroenterology, Hepatology, and Nutrition, University of Minnesota, Minneapolis, Minnesota. · Center for Hepatitis C, Wellstar Health System, Atlanta, Georgia. · Orlando Immunology Center, Orlando, Florida. · Department of Hepatology, New York University Langone Health, New York, New York. · Division of Gastroenterology, Hepatology, and Nutrition, University of Florida, Gainesville, Florida. · Hepatology Research, University of Florida, Gainesville, Florida. · HCV-TARGET Data Coordinating Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. · Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. · Division of Infectious Diseases and Global Medicine, University of Florida, Gainesville, Florida. · AbbVie Inc, North Chicago, Illinois. · Department of Medicine, University of Florida, Gainesville, Florida. ·Gastroenterology · Pubmed #31401140.

ABSTRACT: BACKGROUND & AIMS: Treatment options are limited for patients with hepatitis C (HCV) infection with treatment failure after sofosbuvir plus an NS5A inhibitor. There are some data for the efficacy of glecaprevir/pibrentasvir (G/P) in these patients. We performed a randomized trial of the safety and efficacy of 12 and 16 weeks of G/P, with or without ribavirin, in patients with HCV genotype 1 infection with treatment failure after sofosbuvir and an NS5A inhibitor. METHODS: We performed a phase 3b, open-label study of patients with chronic HCV genotype 1 infection who received previous treatment with sofosbuvir plus an NS5A inhibitor. Patients without cirrhosis were randomly assigned to groups that received G/P for 12 weeks (n = 78, group A) or 16 weeks (n = 49, group B). Patients with compensated cirrhosis were randomly assigned to groups that received G/P and ribavirin for 12 weeks (n = 21, group C) or G/P for 16 weeks (n = 29, group D). The primary end point was a sustained virologic response 12 weeks after treatment. Samples collected at baseline and at time of treatment failure were sequenced for resistance-associated substitutions in NS3 and NS5A. RESULTS: Of the 177 patients in the 4 groups, 81% were men, 79% had HCV genotype 1a infection, and 44% were black. Proportions of patients with sustained virologic response 12 weeks after treatment in groups A, B, C, and D were 90%, 94%, 86%, and 97%, respectively. The treatment failed in 13 (7.3%) patients with HCV genotype 1a infection, 6 (7.9%) in group A, 3 (6.1%) in group B, 3 (6.1%) in group C (6.1%), and 1 (3.4%) in group D. Most patients had baseline resistance-associated substitutions in NS5A. Treatment-emergent resistance-associated substitutions in NS3 and NS5A were observed in 9 and 10 patients with treatment failure, respectively. G/P was well tolerated. Ribavirin increased adverse events but did not increase efficacy. CONCLUSIONS: In a randomized study of patients with chronic HCV genotype 1 infection who received previous treatment with sofosbuvir plus an NS5A inhibitor, 16 weeks treatment with G/P produced sustained virologic response 12 weeks after treatment in >90% of patients, including those with compensated cirrhosis. ClinicalTrials.gov, Number: NCT03092375.

18 Clinical Trial A comprehensive assessment of patient reported symptom burden, medical comorbidities, and functional well being in patients initiating direct acting antiviral therapy for chronic hepatitis C: Results from a large US multi-center observational study. 2018

Evon, Donna M / Stewart, Paul W / Amador, Jipcy / Serper, Marina / Lok, Anna S / Sterling, Richard K / Sarkar, Souvik / Golin, Carol E / Reeve, Bryce B / Nelson, David R / Reau, Nancy / Lim, Joseph K / Reddy, K Rajender / Di Bisceglie, Adrian M / Fried, Michael W. ·Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, United States of America. · Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina, United States of America. · Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America. · Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America. · Division of Gastroenterology, Hepatology & Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, United States of America. · Division of Gastroenterology and Hepatology, Department of Medicine, University of California Davis, Davis, California, United States of America. · Division of General Medicine and Clinical Epidemiology, Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, United States of America. · Department of Health Behaviors, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina, United States of America. · Department of Population Health Sciences, Duke University, Durham, North Carolina, United States of America. · Division of Gastroenterology, Hepatology & Nutrition, Department of Medicine, University of Florida, Gainesville, Florida, United States of America. · Department of Internal Medicine, Section of Hepatology, Rush University, Chicago, Illinois, United States of America. · Digestive Diseases, Department of Internal Medicine, Yale University, New Haven, Connecticut, United States of America. · Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University, St. Louis, Missouri, United States of America. ·PLoS One · Pubmed #30067745.

ABSTRACT: BACKGROUND: Symptom burden, medical comorbidities, and functional well-being of patients with chronic hepatitis C virus (HCV) initiating direct acting antiviral (DAA) therapy in real-world clinical settings are not known. We characterized these patient-reported outcomes (PROs) among HCV-infected patients and explored associations with sociodemographic, liver disease, and psychiatric/substance abuse variables. METHODS AND FINDINGS: PROP UP is a large US multicenter observational study that enrolled 1,600 patients with chronic HCV in 2016-2017. Data collected prior to initiating DAA therapy assessed the following PROs: number of medical comorbidities; neuropsychiatric, somatic, gastrointestinal symptoms (PROMIS surveys); overall symptom burden (Memorial Symptom Assessment Scale); and functional well-being (HCV-PRO). Candidate predictors included liver disease markers and patient-reported sociodemographic, psychiatric, and alcohol/drug use features. Predictive models were explored using a random selection of 700 participants; models were then validated with data from the remaining 900 participants. The cohort was 55% male, 39% non-white, 48% had cirrhosis (12% with advanced cirrhosis); 52% were disabled or unemployed; 63% were on public health insurance or uninsured; and over 40% had markers of psychiatric illness. The median number of medical comorbidities was 4 (range: 0-15), with sleep disorders, chronic pain, diabetes, joint pain and muscle aches being present in 20-50%. Fatigue, sleep disturbance, pain and neuropsychiatric symptoms were present in over 60% and gastrointestinal symptoms in 40-50%. In multivariable validation models, the strongest and most frequent predictors of worse PROs were disability, unemployment, and use of psychiatric medications, while liver markers generally were not. CONCLUSIONS: This large multi-center cohort study provides a comprehensive and contemporary assessment of the symptom burden and comorbid medical conditions in patients with HCV treated in real world settings. Pain, fatigue, and sleep disturbance were common and often severe. Sociodemographic and psychiatric markers were the most robust predictors of PROs. Future research that includes a rapidly changing population of HCV-infected individuals needs to evaluate how DAA therapy affects PROs and elucidate which symptoms resolve with viral eradication. TRIAL REGISTRATION: (Clinicaltrial.gov: NCT02601820).

19 Clinical Trial Glecaprevir and Pibrentasvir in Patients with HCV and Severe Renal Impairment. 2017

Gane, Edward / Lawitz, Eric / Pugatch, David / Papatheodoridis, Georgios / Bräu, Norbert / Brown, Ashley / Pol, Stanislas / Leroy, Vincent / Persico, Marcello / Moreno, Christophe / Colombo, Massimo / Yoshida, Eric M / Nelson, David R / Collins, Christine / Lei, Yang / Kosloski, Matthew / Mensa, Federico J. ·From the Liver Unit, Auckland City Hospital, Auckland, New Zealand (E.G.) · the Texas Liver Institute, University of Texas Health, San Antonio (E.L.) · AbbVie, North Chicago, IL (D.P., C.C., Y.L., M.K., F.J.M.) · the Academic Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, Laiko General Hospital, Athens (G.P.) · the James J. Peters Veterans Affairs Medical Center, Bronx, and Icahn School of Medicine at Mount Sinai, New York - both in New York (N.B.) · Imperial College Healthcare, London (A.B.) · Groupe Hospitalier Cochin-Saint Vincent de Paul, Paris (S.P.), and Centre Hospitalier Universitaire de Grenoble, Grenoble (V.L.) - both in France · the Internal Medicine and Hepatology Unit, University of Salerno, Salerno (M.P.), Humanitas Clinical and Research Center, Rozzano (M.C.), and Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico, Università di Milano, Milan (M.C.) - all in Italy · Cliniques Universitaires de Bruxelles Hôpital Erasme, Université Libre de Bruxelles, Brussels (C.M.) · University of British Columbia, Vancouver, Canada (E.M.Y.) · and the Department of Medicine, University of Florida, Gainesville (D.R.N.). ·N Engl J Med · Pubmed #29020583.

ABSTRACT: BACKGROUND: Chronic hepatitis C virus (HCV) infection is more prevalent among patients who have chronic kidney disease than among those who do not have the disease. Patients with chronic kidney disease who also have HCV infection are at higher risk for progression to end-stage renal disease than those who have chronic kidney disease without HCV infection. Patients with both HCV infection and advanced chronic kidney disease have limited treatment options. METHODS: We conducted a multicenter, open-label, phase 3 trial to evaluate the efficacy and safety of treatment with the combination of the NS3/4A protease inhibitor glecaprevir and the NS5A inhibitor pibrentasvir for 12 weeks in adults who had HCV genotype 1, 2, 3, 4, 5, or 6 infection and also had compensated liver disease (with or without cirrhosis) with severe renal impairment, dependence on dialysis, or both. Patients had stage 4 or 5 chronic kidney disease and either had received no previous treatment for HCV infection or had received previous treatment with interferon or pegylated interferon, ribavirin, sofosbuvir, or a combination of these medications. The primary end point was a sustained virologic response 12 weeks after the end of treatment. RESULTS: Among the 104 patients enrolled in the trial, 52% had genotype 1 infection, 16% had genotype 2 infection, 11% had genotype 3 infection, 19% had genotype 4 infection, and 2% had genotype 5 or 6 infection. The sustained virologic response rate was 98% (102 of 104 patients; 95% confidence interval, 95 to 100). No patients had virologic failure during treatment, and no patients had a virologic relapse after the end of treatment. Adverse events that were reported in at least 10% of the patients were pruritus, fatigue, and nausea. Serious adverse events were reported in 24% of the patients. Four patients discontinued the trial treatment prematurely because of adverse events; three of these patients had a sustained virologic response. CONCLUSIONS: Treatment with glecaprevir and pibrentasvir for 12 weeks resulted in a high rate of sustained virologic response in patients with stage 4 or 5 chronic kidney disease and HCV infection. (Funded by AbbVie; ClinicalTrials.gov number, NCT02651194 .).

20 Clinical Trial Glecaprevir plus pibrentasvir for chronic hepatitis C virus genotype 1, 2, 4, 5, or 6 infection in adults with compensated cirrhosis (EXPEDITION-1): a single-arm, open-label, multicentre phase 3 trial. 2017

Forns, Xavier / Lee, Samuel S / Valdes, Joaquin / Lens, Sabela / Ghalib, Reem / Aguilar, Humberto / Felizarta, Franco / Hassanein, Tarek / Hinrichsen, Holger / Rincon, Diego / Morillas, Rosa / Zeuzem, Stefan / Horsmans, Yves / Nelson, David R / Yu, Yao / Krishnan, Preethi / Lin, Chih-Wei / Kort, Jens J / Mensa, Federico J. ·Liver Unit, Hospital Clinic, CIBEREHD, IDIBAPS, University of Barcelona, Barcelona, Spain. Electronic address: xforns@clinic.cat. · University of Calgary, Calgary, AB, Canada. · AbbVie, North Chicago, IL, USA. · Liver Unit, Hospital Clinic, CIBEREHD, IDIBAPS, University of Barcelona, Barcelona, Spain. · Texas Digestive Disease Consultants, Arlington, TX, USA. · Louisiana Research Center, Shreveport, LA, USA. · Private Practice, Bakersfield, CA, USA. · Southern California Liver Centers and Southern California Research Center, Coronado, CA, USA. · Gastroenterology-Hepatology Center Kiel, Kiel, Germany. · Liver Unit, Hospital General Universitario Gregorio Marañón, CIBERehd, Madrid, Spain. · Liver Section and CIBERehd, Department of Gastroenterology, Hospital Universitari Germans Trias i Pujol, Badalona, Spain. · Johann Wolfgang Goethe University, Frankfurt, Germany. · Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium. · Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL, USA. ·Lancet Infect Dis · Pubmed #28818546.

ABSTRACT: BACKGROUND: The once-daily, ribavirin-free, pangenotypic, direct-acting antiviral regimen, glecaprevir coformulated with pibrentasvir, has shown high rates of sustained virological response in phase 2 and 3 studies. We aimed to assess the efficacy and safety of 12 weeks of coformulated glecaprevir and pibrentasvir in patients with hepatitis C virus (HCV) infection and compensated cirrhosis. METHODS: We did this single-arm, open-label, multicentre phase 3 study at 40 sites in Belgium, Canada, Germany, South Africa, Spain, and the USA. We enrolled patients aged 18 years or older with HCV genotype 1, 2, 4, 5, or 6 infection and compensated cirrhosis. Patients were either HCV treatment-naive or had not responded to treatment with interferon or pegylated interferon with or without ribavirin, or sofosbuvir plus ribavirin with or without pegylated interferon. Oral glecaprevir (300 mg) coformulated with pibrentasvir (120 mg) was administered once daily for 12 weeks. The primary efficacy endpoint was sustained virological response at post-treatment week 12 (HCV RNA <15 IU/mL). We assessed efficacy and safety in all patients who received at least one dose of study drug (intention-to-treat population). This study is registered with ClinicalTrials.gov, number NCT02642432. FINDINGS: Between Dec 7, 2015, and May 4, 2016, we enrolled 146 patients with compensated cirrhosis, of whom 48 (33%) had genotype 1a HCV infection, 39 (27%) had genotype 1b infection, 34 (23%) had genotype 2 infection, 16 (11%) had genotype 4 infection, two (1%) had genotype 5 infection, and seven (5%) had genotype 6 infection. 12 weeks after treatment, 145 patients (99%, 95% CI 98-100) achieved sustained virological response, with one (1%) relapse at post-treatment week 8. We recorded 101 (69%) adverse events, of which 65 (64%) were mild. The most common adverse events were fatigue (n=28 [19%]) and headache (n=20 [14%]). 11 (8%) patients had serious adverse events, none of which were deemed related to study drugs. No patients had elevations in alanine aminotransferase and no patients prematurely discontinued treatment because of adverse events. INTERPRETATION: Our results show that 99% of patients treated with once-daily glecaprevir plus pibrentasvir achieved a sustained virological response at 12 weeks. Furthermore, this drug regimen had a favourable safety profile in previously treated or untreated patients with chronic HCV genotype 1, 2, 4, 5, or 6 infection and compensated cirrhosis. These findings could help simplify treatment algorithms and reduce treatment burden. FUNDING: AbbVie.

21 Clinical Trial Elbasvir plus grazoprevir in patients with hepatitis C virus infection and stage 4-5 chronic kidney disease: clinical, virological, and health-related quality-of-life outcomes from a phase 3, multicentre, randomised, double-blind, placebo-controlled trial. 2017

Bruchfeld, Annette / Roth, David / Martin, Paul / Nelson, David R / Pol, Stanislas / Londoño, Maria-Carlota / Monsour, Howard / Silva, Marcelo / Hwang, Peggy / Arduino, Jean-Marie / Robertson, Michael / Nguyen, Bach-Yen / Wahl, Janice / Barr, Eliav / Greaves, Wayne. ·Department of Renal Medicine, Karolinska University Hospital, Stockholm, Sweden. Electronic address: annette.bruchfeld@ki.se. · Division of Nephrology and Hypertension, University of Miami Miller School of Medicine, Miami, FL, USA. · Division of Hepatology, University of Miami Miller School of Medicine, Miami, FL, USA. · Clinical and Translational Science Institute, University of Florida, Gainesville, FL, USA. · Unité d'Hépatologie, Hôpital Cochin; Université Paris Descartes; and UMS20, Institut Pasteur; Paris, France. · Liver Unit, Hospital Clinic Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain. · Hepatology and Transplant Medicine, Houston Methodist Hospital, Houston, TX, USA. · Hepatology and Liver Transplant Units, Hospital Universitario Austral, Buenos Aires, Argentina. · Merck & Co, Kenilworth, NJ, USA. ·Lancet Gastroenterol Hepatol · Pubmed #28576451.

ABSTRACT: BACKGROUND: In the C-SURFER study, therapy with the all-oral elbasvir plus grazoprevir regimen for 12 weeks in patients with chronic hepatitis C virus (HCV) infection and stage 4-5 chronic kidney disease resulted in a high rate of virological cure compared with placebo. Here, we report sustained virological response (SVR), safety data, health-related quality-of-life (HRQOL), and virological resistance analyses in patients in C-SURFER who received immediate antiviral therapy or who received placebo before therapy. METHODS: In this phase 3, multicentre, randomised, placebo-controlled study, we randomly assigned adults with HCV genotype 1 infection and stage 4-5 chronic kidney disease enrolled at 68 centres worldwide to either elbasvir 50 mg plus grazoprevir 100 mg once per day for 12 weeks (immediate treatment group) or placebo for 12 weeks followed by elbasvir 50 mg plus grazoprevir 100 mg once per day for 12 weeks beginning at week 16 (deferred treatment group). The primary safety and efficacy endpoints for the immediate treatment group and placebo phase of the deferred treatment group have been reported previously. Here, we report safety and efficacy data for the treatment phase of the deferred treatment group, as well as HRQOL assessed using the 36-Item Short Form Health Survey for all groups, and baseline and treatment-emergent resistance-associated substitutions (RASs). SVR at 12 weeks (SVR12) was assessed in the modified full analysis set (FAS), defined as all patients excluding those who did not receive at least one dose of study drug, who died, or who discontinued the study before the end of treatment for reasons determined to be unrelated to HCV treatment. This trial is registered with ClinicalTrials.gov, Number NCT02092350. FINDINGS: Between March 30 and Nov 28, 2014, 235 patients were enrolled and received at least one dose of study drug. The modified FAS included 116 patients assigned to immediate treatment and 99 assigned to deferred treatment. 115 (99·1%; 95% CI 95·3-100·0) of 116 assigned to immediate treatment achieved SVR12 compared with 97 (98·0%; 92·9-99·7) of 99 assigned to deferred treatment. In patients with genotype 1a infections, SVR12 was achieved by 11 (84·6%) of 13 patients with detectable baseline NS5A RASs and in 98 (100%) of 98 without. HRQOL did not differ at week 12 between immediate treatment and the placebo phase of deferred treatment. Safety was generally similar between patients receiving immediate treatment and those receiving placebo in the deferred treatment group. One serious adverse event during deferred treatment (interstitial nephritis) and one during the placebo phase of deferred treatment (raised lipase concentration) were deemed related to study drug. Four patients died, one who received immediate treatment (cardiac arrest) and three who received deferred treatment (aortic aneurysm, pneumonia, and unknown cause); all four deaths were considered unrelated to study drugs. Of the three deaths in the deferred treatment group, one occurred during placebo treatment and two occurred before starting active treatment. There were no notable differences in aminotransferase elevations in the deferred treatment group compared with the immediate treatment group, and no patients in the deferred treatment group had total bilirubin elevations. INTERPRETATION: These data add to the growing body of clinical evidence for the fixed-dose combination regimen of elbasvir plus grazoprevir for 12 weeks and support use of this therapy in patients with HCV genotype 1 infection and stage 4-5 chronic kidney disease. FUNDING: Merck Sharp & Dohme.

22 Clinical Trial On-treatment HCV RNA as a predictor of sustained virological response in HCV genotype 3-infected patients treated with daclatasvir and sofosbuvir. 2016

Kowdley, Kris V / Nelson, David R / Lalezari, Jacob P / Box, Terry / Gitlin, Norman / Poleynard, Gary / Rabinovitz, Mordechai / Ravendhran, Natarajan / Sheikh, Aasim M / Siddique, Asma / Bhore, Rafia / Noviello, Stephanie / Rana, Khurram. ·Swedish Medical Center, Seattle, WA, USA. kris.kowdley@swedish.org. · University of Florida, Gainesville, FL, USA. · Quest Clinical Research, San Francisco, CA, USA. · Clinical Research Centers of America, LLC, Murray, UT, USA. · Atlanta Gastroenterology Associates, Atlanta, GA, USA. · Digestive Health Specialists, Winston-Salem, NC, USA. · University of Pittsburgh, Pittsburgh, PA, USA. · Digestive Disease Associates, Baltimore, MD, USA. · Gastrointestinal Specialists of Georgia, Marietta, GA, USA. · Virginia Mason Medical Center, Seattle, WA, USA. · Bristol-Myers Squibb Research and Development, Princeton, NJ, USA. · Bristol-Myers Squibb Research and Development, Wallingford, CT, USA. ·Liver Int · Pubmed #27188960.

ABSTRACT: BACKGROUND AND AIMS: 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. METHODS: In ALLY-3, treatment-naive and -experienced patients, with or without cirrhosis, were treated with daclatasvir + sofosbuvir for 12 weeks. HCV RNA kinetics and categorical virological responses on treatment were assessed. The proportions of responders and nonresponders by study week, and time to first undetectable HCV RNA, were analysed for utility in predicting treatment outcome. RESULTS: Overall, HCV RNA levels declined rapidly during Week 1 of treatment in both treatment-naive and -experienced cohorts. Although patients with cirrhosis had a slower initial virological response as measured by the proportion of patients with HCV RNA below the lower limit of quantification at Week 1, responses converged thereafter. Positive and negative predictive values calculated for on-treatment responses were generally comparable with the overall SVR12 rate and were therefore limited indicators of outcome. SVR12 rates were not impacted by time to first undetectable HCV RNA. CONCLUSIONS: On-treatment responses are not useful predictors of ultimate virological response to the daclatasvir + sofosbuvir regimen.

23 Clinical Trial Grazoprevir plus elbasvir in treatment-naive and treatment-experienced patients with hepatitis C virus genotype 1 infection and stage 4-5 chronic kidney disease (the C-SURFER study): a combination phase 3 study. 2015

Roth, David / Nelson, David R / Bruchfeld, Annette / Liapakis, AnnMarie / Silva, Marcelo / Monsour, Howard / Martin, Paul / Pol, Stanislas / Londoño, Maria-Carlota / Hassanein, Tarek / Zamor, Philippe J / Zuckerman, Eli / Wan, Shuyan / Jackson, Beth / Nguyen, Bach-Yen / Robertson, Michael / Barr, Eliav / Wahl, Janice / Greaves, Wayne. ·Division of Nephrology and Hypertension, University of Miami Miller School of Medicine, Miami, FL, USA. Electronic address: d.roth@med.miami.edu. · Clinical and Translational Science Institute, University of Florida, Gainesville, FL, USA. · Department of Renal Medicine, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden. · Yale University Digestive Disease, Yale New Haven Hospital Transplant Center, New Haven, CT, USA. · Hospital Universitario Austral, Pilar, Argentina. · Hepatology & Transplant Medicine, Houston Methodist Hospital, Houston, TX, USA. · Division of Hepatology, University of Miami Miller School of Medicine, Miami, FL, USA. · Unité d'Hépatologie, Hôpital Cochin; Université Paris Descartes; and UMS20, Institut Pasteur; Paris, France. · Liver Unit, Hospital Clinic Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain. · Southern California Research Center, Coronado, CA, USA. · Division of Hepatology, Carolinas Medical Center, Charlotte, NC, USA. · Liver Unit, Carmel Medical Center Technion Faculty of Medicine, Haifa, Israel. · Merck & Co, Inc, Kenilworth, NJ, USA. ·Lancet · Pubmed #26456905.

ABSTRACT: BACKGROUND: Chronic hepatitis C virus (HCV) infection in patients with stage 4-5 chronic kidney disease increases the risk of death and renal graft failure, yet patients with hepatitis C and chronic kidney disease have few treatment options. This study assesses an all-oral, ribavirin-free regimen in patients with HCV genotype 1 infection and stage 4-5 chronic kidney disease. METHODS: In this phase 3 randomised study of safety and observational study of efficacy, patients with HCV genotype 1 infection and chronic kidney disease (stage 4-5 with or without haemodialysis dependence) were randomly assigned to receive grazoprevir (100 mg, NS3/4A protease inhibitor) and elbasvir (50 mg, NS5A inhibitor; immediate treatment group) or placebo (deferred treatment group) once daily for 12 weeks. Randomisation was done centrally with an interactive voice response system. An additional cohort of patients who were not randomised received the same regimen open-label and underwent intensive pharmacokinetic sampling. The primary efficacy outcome was a non-randomised comparison of sustained virological response at 12 weeks (SVR12) after the end of therapy for the combined immediate treatment group and the pharmacokinetic population with a historical control. The primary safety outcome was a randomised comparison between the immediate treatment group and the deferred treatment group. After 4 weeks of follow-up (study week 16), unmasking occurred and patients in the deferred treatment group received grazoprevir and elbasvir. The primary efficacy hypothesis was tested at a two-sided significance level (type I error) of 0·05 using an exact test for a binomial proportion. Safety event rates were compared between immediate treatment and deferred treatment groups using the stratified Miettinen and Nurminen method with baseline dialysis status as the strata. The study is registered at ClinicalTrials.gov, number NCT02092350. FINDINGS: 224 patients were randomly assigned to the immediate treatment group with grazoprevir and elbasvir (n=111) or the deferred treatment group (n=113), and 11 were assigned to the intensive pharmacokinetic population. Overall, 179 (76%) were haemodialysis-dependent, 122 (52%) had HCV genotype 1a infection, 189 (80%) were HCV treatment-naive, 14 (6%) were cirrhotic, and 108 (46%) were African American. Of the 122 patients receiving grazoprevir and elbasvir, six were excluded from the primary efficacy analysis for non-virological reasons (death, lost-to-follow-up [n=2], non-compliance, patient withdrawal, and withdrawal by physician for violent behaviour). No patients in the combined immediate treatment group and intensive pharmacokinetic population and five (4%) in the deferred treatment group discontinued because of an adverse event. Most common adverse events were headache, nausea, and fatigue, occurring at similar frequencies in patients receiving active and placebo drugs. SVR12 in the combined immediate treatment group and intensive pharmacokinetic population was 99% (95% CI 95·3-100·0; 115/116), with one relapse 12 weeks after end of treatment when compared with a historical control of 45%, based on meta-analyses of interferon-based regimens used in clinical trials of patients infected with HCV who are on haemodialysis. INTERPRETATION: Once-daily grazoprevir and elbasvir for 12 weeks had a low rate of adverse events and was effective in patients infected with HCV genotype 1 and stage 4-5 chronic kidney disease. FUNDING: Merck Sharp & Dohme Corp.

24 Clinical Trial Virological outcomes and treatment algorithms utilisation in observational study of patients with chronic hepatitis C treated with boceprevir or telaprevir. 2015

Sterling, R K / Kuo, A / Rustgi, V K / Sulkowski, M S / Stewart, T G / Fenkel, J M / El-Genaidi, H / Mah'moud, M A / Abraham, G M / Stewart, P W / Akushevich, L / Nelson, D R / Fried, M W / Di Bisceglie, A M. ·Virginia Commonwealth University Health System, Richmond, VA, USA. ·Aliment Pharmacol Ther · Pubmed #25627020.

ABSTRACT: BACKGROUND: HCV-TARGET is a longitudinal observational study of chronic hepatitis C virus (HCV) patients treated with direct-acting anti-viral agents (DAAs) in a US consortium of 90 academic and community medical centres. AIM: To assess utilisation of response-guided therapy (RGT) and sustained virological response (SVR) of a large cohort of patients. METHODS: Patients received peginterferon (PEG-IFN), ribavirin and either telaprevir or boceprevir. Demographical, clinical and virological data were collected during treatment and follow-up. RGT and treatment futility stopping rules was assessed at key time points. RESULTS: Of 2084 patients, 38% had cirrhosis and 56% had received prior treatment for HCV. SVR rates were 31% (95% CI: 24-40) and 50% (95% CI: 44-56) in boceprevir patients with and without cirrhosis, respectively. SVR rates were 46% (95% CI: 42-50) and 60% (95% CI: 57-64) in telaprevir patients with and without cirrhosis, respectively. Early clearance of virus, IL28B genotype, platelet counts and diabetes were identified as predictors of SVR among boceprevir patients, while early clearance of virus, IL28B, cirrhosis, HCV subtype, age, haemoglobin, bilirubin and albumin levels were identified as predictors of SVR for telaprevir patients. CONCLUSIONS: In academic and community centres, triple therapy including boceprevir or telaprevir led to SVR rates somewhat lower than those noted in large phase 3 clinical trials. Response rates were consistently higher among patients without cirrhosis compared to those with cirrhosis regardless of DAA used and prior treatment response. Trial registration clinicaltrials.gov NCT01474811.

25 Clinical Trial All-oral 12-week treatment with daclatasvir plus sofosbuvir in patients with hepatitis C virus genotype 3 infection: ALLY-3 phase III study. 2015

Nelson, David R / Cooper, James N / Lalezari, Jacob P / Lawitz, Eric / Pockros, Paul J / Gitlin, Norman / Freilich, Bradley F / Younes, Ziad H / Harlan, William / Ghalib, Reem / Oguchi, Godson / Thuluvath, Paul J / Ortiz-Lasanta, Grisell / Rabinovitz, Mordechai / Bernstein, David / Bennett, Michael / Hawkins, Trevor / Ravendhran, Natarajan / Sheikh, Aasim M / Varunok, Peter / Kowdley, Kris V / Hennicken, Delphine / McPhee, Fiona / Rana, Khurram / Hughes, Eric A / Anonymous5140818. ·University of Florida, Gainesville, FL. ·Hepatology · Pubmed #25614962.

ABSTRACT: 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.

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