Pick Topic
Review Topic
List Experts
Examine Expert
Save Expert
  Site Guide ··   
Hepatitis: HELP
Articles by Eric J. Lawitz
Based on 130 articles published since 2008
||||

Between 2008 and 2019, E. Lawitz wrote the following 130 articles about Hepatitis.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4 · 5 · 6
1 Review Glecaprevir + pibrentasvir (ABT493 + ABT-530) for the treatment of Hepatitis C. 2018

Hubbard, Hope / Lawitz, Eric. ·a Department of Internal Medicine, Division of Gastroenterology , University of Texas Health Science Center , San Antonio , TX , USA. · b Texas Liver Institute , San Antonito , TX , USA. ·Expert Rev Gastroenterol Hepatol · Pubmed #29187007.

ABSTRACT: INTRODUCTION: Glecaprevir (formerly ABT-493, pangenotypic NS3/4A protease inhibitor) and pibrentasvir (formerly ABT-530, pangenotypic NS5A inhibitor) are second generation direct acting antivirals (DAA) for the treatment of chronic Hepatitis C (HCV). It is a fixed dose ribavirin (RBV)-free regimen with activity against genotypes (GT) 1-6. In vitro the two antivirals have synergistic activity with a high barrier to resistance and potent activity against common polymorphisms. It is once daily oral dosing with minimal absorption, primary biliary excretion, and negligible renal excretion, making it safe for patients with renal impairment. This regimen is being reviewed because it is the first pangenotypic regimen suitable for those with renal impairment and prior DAA failure. Areas covered: The key phase 2 and 3 trials which investigated the efficacy and safety of glecaprevir/pibrentasvir are reviewed by methodology, primary end point, baseline demographic data, response rates, and adverse events. Literature search methodology involved reviewing key abstracts presented at the American Association for the Study of Liver Disease and European Association for the Study of Liver. Expert commentary: The advantages and limitations of glecaprevir/pibrentasvir will be reviewed in comparison to its competitor drug on the market.

2 Review Novel treatments for chronic hepatitis C: closing the remaining gaps. 2017

Alkhouri, Naim / Lawitz, Eric / Poordad, Fred. ·The Texas Liver Institute, San Antonio, TX, USA; University of Texas (UT) Health San Antonio, San Antonio, TX, USA. ·Curr Opin Pharmacol · Pubmed #29121533.

ABSTRACT: Direct acting antivirals (DAAs) have revolutionized the treatment of chronic hepatitis C virus (HCV) infection with cure rates >90% for the majority of patients and excellent safety profile. However, there remain certain unmet needs in treating HCV including treatment for patients that failed a prior DAA regimen and for those with advanced chronic kidney disease. In addition, shortening the duration of DAA regimens has the potential to increase compliance and decrease the cost of care. New regimens that were approved by the FDA in 2017 address these unmet needs and will be discussed in this concise review.

3 Review Next-Generation Regimens: The Future of Hepatitis C Virus Therapy. 2015

Vizuete, John / Hubbard, Hope / Lawitz, Eric. ·Division of Gastroenterology and Nutrition, Department of Medicine, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA. Electronic address: johnvizuete@gmail.com. · Division of Gastroenterology and Nutrition, Department of Medicine, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA. ·Clin Liver Dis · Pubmed #26466657.

ABSTRACT: The treatment of chronic hepatitis C virus (HCV) has undergone a period of rapid evolution. The era of combination direct antivirals has led to high rates of sustained viral response (SVR), limited toxicities, and more broad applicability across patient demographics. Even current therapies have their limitations, however, including genotype specificity and variable durations of treatment depending on the presence or absence of cirrhosis. Developing a fixed-duration pangenotypic regimen that can broadly treat all stages of fibrosis with equal rates of SVR in all patients, irrespective of treatment experience, is the goal of future therapies. This article reviews antivirals in development.

4 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.

5 Review Interferon-free, direct-acting antiviral therapy for chronic hepatitis C. 2015

Gutierrez, J A / Lawitz, E J / Poordad, F. ·The Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, USA. ·J Viral Hepat · Pubmed #26083155.

ABSTRACT: The treatment environment for chronic hepatitis C has undergone a revolution, particularly in genotype 1. Gone are interferon-based therapy and its associated tolerability challenges, inadequate response rates and numerous baseline factors that affect response to therapy. New and emerging treatment regimens employ all-oral combinations of direct-acting antiviral agents, and results of clinical trials suggest that these regimens routinely achieve cure rates >90%, even in patients who failed prior interferon-based triple therapy. In 2015, three all-oral FDA-approved regiments will be available for genotype 1 (sofosbuvir /ledipasvir, sofosbuvir/simeprevir, and paritaprevir/r/ombitasvir/dasabuvir). Furthermore, new treatment combinations appear to be more tolerable and require shorter duration of therapy. We provide an overview of the classes of direct-acting antiviral agents (DAAs), the clinical factors affecting their integration into combination therapies and recent findings from trials of such combination therapies in patients with genotype 1 HCV infection.

6 Review Response-guided therapy in patients with genotype 1 hepatitis C virus: current status and future prospects. 2014

Lawitz, Eric J / Membreno, Fernando E. ·The Texas Liver Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA. ·J Gastroenterol Hepatol · Pubmed #24852401.

ABSTRACT: On-treatment responses to antiviral therapy are used to determine duration of therapy in patients being treated for genotype 1 hepatitis C virus infection. Such use of response-guided therapy has successfully reduced exposure of patients to the side-effects of pegylated interferon and ribavirin without jeopardizing overall treatment success. Response-guided therapy is an integral part of treatment using the current standard treatments involving the direct-acting antiviral (DAA) agents--boceprevir or telaprevir--combined with pegylated interferon/ribavirin. Improvements in our understanding of the kinetics of viral load during antiviral therapy have shown us that more potent suppression of viral replication increases the rate of viral eradication, providing impetus for the development of more potent DAAs. Emerging results from clinical trials of these agents--including trials of interferon-free DAA combinations--suggest that very high rates of viral eradication are achievable, even in patients who failed to respond to previous courses of interferon-based therapy. Furthermore, because of these high rates of treatment success, on-treatment assessment of viral response may become unnecessary. The field of hepatitis C virus therapy is evolving rapidly and current trends indicate that the era of simple treatment regimens with high rates of success and good tolerability are near.

7 Review Cyclophilin inhibitors for hepatitis C therapy. 2013

Membreno, Fernando E / Espinales, Jennifer C / Lawitz, Eric J. ·Alamo Medical Research, San Antonio, TX 78215, USA. membreno@alamomedicalresearch.com ·Clin Liver Dis · Pubmed #23177289.

ABSTRACT: This article highlights a unique time in the history of hepatitis C therapy. In the last few years new families of direct-acting antivirals have emerged, that block different viral proteins to interrupt viral replication, such as protease, NS5A inhibitors, and NS5B inhibitors. There are few host-targeted agents in development; currently cyclophilin inhibitors are the only host-targeted agents in advanced development. One of these new agents has now progressed to phase 3 clinical trials; in this review article their potential role as a future therapy to cure hepatitis C is discussed.

8 Review The HCV NS5B nucleoside and non-nucleoside inhibitors. 2011

Membreno, Fernando E / Lawitz, Eric J. ·Alamo Medical Research, San Antonio, TX 78215, USA. ·Clin Liver Dis · Pubmed #21867940.

ABSTRACT: This article introduces one of the most diverse classes of direct-acting antivirals for hepatitis C, the nucleoside and non-nucleoside NS5B polymerase inhibitors. Through a systematic review of the published literature, we describe their structure, mechanism of action, issues with resistance, and clinical effectiveness shown in the latest clinical trials. Direct-acting antiviral combination trials that have already shown some early promising results even in the setting of interferon-sparing antiviral regimens are discussed.

9 Clinical Trial Resistance Analysis of a 3-Day Monotherapy Study with Glecaprevir or Pibrentasvir in Patients with Chronic Hepatitis C Virus Genotype 1 Infection. 2018

Ng, Teresa I / Pilot-Matias, Tami / Tripathi, Rakesh / Schnell, Gretja / Krishnan, Preethi / Reisch, Thomas / Beyer, Jill / Dekhtyar, Tatyana / Irvin, Michelle / Lu, Liangjun / Asatryan, Armen / Campbell, Andrew / Yao, Betty / Lovell, Sandra / Mensa, Federico / Lawitz, Eric J / Kort, Jens / Collins, Christine. ·AbbVie, Inc., North Chicago, IL 60064, USA. teresa.ng@abbvie.com. · AbbVie, Inc., North Chicago, IL 60064, USA. tami.pilot-matias@abbvie.com. · AbbVie, Inc., North Chicago, IL 60064, USA. rakesh.l.tripathi@abbvie.com. · AbbVie, Inc., North Chicago, IL 60064, USA. gretja.schnell@abbvie.com. · AbbVie, Inc., North Chicago, IL 60064, USA. preethi.krishnan@abbvie.com. · AbbVie, Inc., North Chicago, IL 60064, USA. thomas.reisch@abbvie.com. · AbbVie, Inc., North Chicago, IL 60064, USA. jill.beyer@abbvie.com. · AbbVie, Inc., North Chicago, IL 60064, USA. tanya.dekhtyar@abbvie.com. · AbbVie, Inc., North Chicago, IL 60064, USA. michelle.irvin@abbvie.com. · AbbVie, Inc., North Chicago, IL 60064, USA. liangjun.lu@abbvie.com. · AbbVie, Inc., North Chicago, IL 60064, USA. armen.asatryan@abbvie.com. · AbbVie, Inc., North Chicago, IL 60064, USA. andrew.campbell@abbvie.com. · AbbVie, Inc., North Chicago, IL 60064, USA. betty.yao@abbvie.com. · AbbVie, Inc., North Chicago, IL 60064, USA. sandra.lovell@abbvie.com. · AbbVie, Inc., North Chicago, IL 60064, USA. federico.mensa@abbvie.com. · Texas Liver Institute, University of Texas Health San Antonio, San Antonio, TX 78215, USA. lawitz@txliver.com. · AbbVie, Inc., North Chicago, IL 60064, USA. jens.kort@abbvie.com. · AbbVie, Inc., North Chicago, IL 60064, USA. christine.collins@abbvie.com. ·Viruses · Pubmed #30154359.

ABSTRACT: Glecaprevir (an NS3/4A protease inhibitor) and pibrentasvir (an NS5A inhibitor) are potent and pangenotypic hepatitis C virus (HCV) direct-acting antivirals. This report describes the baseline polymorphisms and treatment-emergent substitutions in NS3 or NS5A detected in samples from HCV genotype 1-infected patients receiving 3-day monotherapy of glecaprevir or pibrentasvir, respectively. None of the NS3 polymorphisms detected in the 47 baseline samples collected prior to glecaprevir monotherapy conferred reduced susceptibility to glecaprevir. The NS3 A156T substitution, which conferred resistance to glecaprevir but had low replication efficiency, emerged in one genotype 1a-infected patient among the 35 patients with available post-baseline sequence data. Baseline NS5A polymorphisms were detected in 12 of 40 patients prior to pibrentasvir monotherapy; most polymorphisms were single-position NS5A amino acid substitutions that did not confer resistance to pibrentasvir. Among the 19 patients with available post-baseline NS5A sequence data, 3 had treatment-emergent NS5A substitutions during pibrentasvir monotherapy. All treatment-emergent NS5A substitutions were linked multiple-position, almost exclusively double-position, substitutions that conferred resistance to pibrentasvir. Replicons engineered with these double-position substitutions had low replication efficiency. In conclusion, resistance-conferring substitutions emerged in a small number of genotype 1-infected patients during glecaprevir or pibrentasvir monotherapy; unlike other NS5A inhibitors, pibrentasvir did not select single-position NS5A substitutions during monotherapy.

10 Clinical Trial Efficacy and safety of 6 or 8 weeks of simeprevir, daclatasvir, sofosbuvir for HCV genotype 1 infection. 2018

Sulkowski, M S / Feld, J J / Lawitz, E / Felizarta, F / Corregidor, A M / Khalid, O / Ghalib, R / Smith, W B / Van Eygen, V / Luo, D / Vijgen, L / Gamil, M / Kakuda, T N / Ouwerkerk-Mahadevan, S / Van Remoortere, P / Beumont, M. ·Divisions of Infectious Diseases and Hepatology/Gastroenterology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Toronto Center for Liver Disease, Toronto General Hospital, Toronto, ON, Canada. · Texas Liver Institute, University of Texas Health, San Antonio, TX, USA. · Private Practice, Bakersfield, CA, USA. · Borland-Groover Clinic PA, Jacksonville, FL, USA. · Digestive Health Specialists, Winston-Salem, NC, USA. · North Texas GI Surgery Center, Arlington, TX, USA. · NOCCR/VRG, University of Tennessee Medical Center, Knoxville, TN, USA. · Janssen Research and Development, Janssen Pharmaceutica NV, Beerse, Belgium. · Janssen Pharmaceuticals, LLC, Titusville, NJ, USA. · Alios BioPharma, Inc. part of the Janssen Pharmaceutical Companies, South San Francisco, CA, USA. ·J Viral Hepat · Pubmed #29274193.

ABSTRACT: The phase 2, open-label ACCORDION (ClinicalTrials.gov: NCT02349048) study investigated the efficacy, safety and pharmacokinetics of a 6- or 8-week regimen of simeprevir, daclatasvir and sofosbuvir in treatment-naïve patients with chronic hepatitis C virus (HCV) genotype (GT) 1 infection and either early-stage fibrosis or compensated cirrhosis. Patients were assigned to treatment groups according to their fibrosis stage. Early-stage fibrosis: simeprevir 150 mg, daclatasvir 60 mg, sofosbuvir 400 mg once daily for 6 weeks; compensated cirrhosis: same regimen for 8 weeks. The primary endpoint was sustained virologic response 12 weeks after the end of treatment (SVR12). Safety, tolerability and pharmacokinetics of simeprevir, daclatasvir and sofosbuvir were investigated. Sixty-eight patients were treated (6-week group: n = 59; 8-week group: n = 9). SVR12 was achieved by 86.4% (51/59) of patients with early-stage fibrosis and by 100% (9/9) of patients with cirrhosis. The main reason for not achieving SVR12 in the 6-week group was viral relapse (11.9%; 7/59). One patient had on-treatment failure due to an early withdrawal (lost to follow-up due to incarceration). One patient with SVR12 in the 6-week group had a late viral relapse at post-treatment week 24. No clinically significant drug-drug interactions were observed. Adverse events were reported in 63.2% of patients (43/68) and were mainly grade 1/2. None of these led to treatment discontinuation. The 3 direct-acting antiviral regimens of simeprevir, daclatasvir and sofosbuvir were safe and well tolerated in treatment-naïve, HCV GT1-infected patients with early-stage fibrosis or compensated cirrhosis.

11 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 .).

12 Clinical Trial Safety and efficacy of a fixed-dose combination regimen of grazoprevir, ruzasvir, and uprifosbuvir with or without ribavirin in participants with and without cirrhosis with chronic hepatitis C virus genotype 1, 2, or 3 infection (C-CREST-1 and C-CREST-2, part B): two randomised, phase 2, open-label trials. 2017

Lawitz, Eric / Buti, Maria / Vierling, John M / Almasio, Piero L / Bruno, Savino / Ruane, Peter J / Hassanein, Tarek I / Muellhaupt, Beat / Pearlman, Brian / Jancoriene, Ligita / Gao, Wei / Huang, Hsueh-Cheng / Shepherd, Aimee / Tannenbaum, Brynne / Fernsler, Doreen / Li, Jerry J / Grandhi, Anjana / Liu, Hong / Su, Feng-Hsiu / Wan, Shuyan / Dutko, Frank J / Nguyen, Bach-Yen T / Wahl, Janice / Robertson, Michael N / Barr, Eliav / Yeh, Wendy W / Plank, Rebeca M / Butterton, Joan R / Yoshida, Eric M. ·Texas Liver Institute, University of Texas Health San Antonio, San Antonio, TX, USA. Electronic address: lawitz@txliver.com. · Hospital Universitari Vall d Hebron and CIBEREHD del Instituto Carlos III, Barcelona, Spain. · Baylor College of Medicine, Advanced Liver Therapies, Houston, TX, USA. · Biomedical Department of Internal and Specialized Medicine, University of Palermo, Palermo, Italy. · IRCCS Istituto Clinico Humanitas and Humanitas University, Rozzano, Italy. · Ruane Medical and Liver Health Institute, Los Angeles, CA, USA. · Southern California GI and Liver Centers, Coronado, CA, USA. · University Hospital Zurich, Zurich, Switzerland. · Atlanta Medical Center, Atlanta, GA, USA; Emory School of Medicine, Atlanta, GA, USA. · Vilnius University Hospital Santariskiu Klinikos, Centre of Infectious Diseases, Vilnius University, Vilnius, Lithuania. · Merck & Co, Inc, Kenilworth, NJ, USA. · University of British Columbia, Vancouver, BC, Canada. ·Lancet Gastroenterol Hepatol · Pubmed #28802814.

ABSTRACT: BACKGROUND: There is a need for hepatitis C virus (HCV) therapies with excellent efficacy across genotypes and in diverse populations. Part A of the C-CREST-1 and C-CREST-2 trials led to the selection of a three-drug regimen of grazoprevir (MK-5172; an HCV NS3/4A protease inhibitor; 100 mg/day) plus ruzasvir (MK-8408; an NS5A inhibitor; 60 mg/day) plus uprifosbuvir (MK-3682; an HCV NS5B polymerase inhibitor; 450 mg/day). Part B of the studies tested this combination as a single formulation in different treatment durations in a broader population. METHODS: Part B of these randomised, phase 2, open-label clinical trials enrolled individuals from 15 countries who were chronically infected with HCV genotypes 1-6 (HCV RNA ≥10 000 IU/mL) with or without compensated cirrhosis. Those with genotype 1, genotype 2, genotype 4, or genotype 6 were treatment-naive; those with genotype 3 could be treatment-naive or treatment-experienced with pegylated interferon and ribavirin. Randomisation occurred centrally using an interactive voice response system and integrated web response system. Participants were randomly assigned to receive treatment for 8, 12, or 16 weeks with a fixed-dose combination of grazoprevir, ruzasvir, and uprifosbuvir with or without ribavirin. The primary endpoint was the proportion of participants achieving sustained virological response 12 weeks after the end of all study therapy (SVR12), defined as HCV RNA less than the lower limit of quantification (either target detected unquantifiable or target not detected [<15 IU/mL]). The trials are registered at ClinicalTrials.gov, numbers NCT02332707 and NCT02332720. FINDINGS: 676 participants were randomly assigned between Feb 18, 2015, and Aug 16, 2016. In all 675 participants who received at least one dose of study drug (full analysis set), SVR12 for the 8-week regimen of grazoprevir, ruzasvir, and uprifosbuvir with and without ribavirin was achieved in 39 (93% [95% CI 81-99]) of 42 participants with genotype 1a, 45 (98% [88-100]) of 46 with genotype 1b, 54 (86% [75-93]) of 63 with genotype 2, 98 (95% [89-98]) of 103 with genotype 3, and seven (100% [59-100]) of seven participants with genotype 4. SVR12 for the 12-week regimen with and without ribavirin was achieved in 87 (99% [95% CI 94-100]) of 88 participants with genotype 1, 61 (98% [91-100]) of 62 with genotype 2, and four (100% [40-100]) of four with genotype 6. Among participants with cirrhosis who were infected with genotype 3, SVR12 for the 12-week regimen with and without ribavirin was achieved in 28 (97% [95% CI 82-100]) of 29 of those who were treatment-naive and 29 (100% [88-100]) of 29 who were treatment-experienced. SVR12 for the 16-week regimen with and without ribavirin was achieved in 26 (100% [95% CI 87-100]) of 26 participants with genotype 2 infection and 72 (96% [89-99]) of 75 participants with genotype 3 infection. The most common adverse events were headache (143 [22%] of 664), fatigue (129 [19%] of 664), and nausea (83 [13%] of 664). 16 (2%) of 664 participants had serious adverse events. INTERPRETATION: The combined regimen of grazoprevir (100 mg/day), ruzasvir (60 mg/day), and uprifosbuvir (450 mg/day) has the potential to provide a simplified treatment for HCV that is effective and well tolerated in most individuals infected with HCV, as well as a shorter duration of treatment in many individuals. FUNDING: Merck & Co, Inc.

13 Clinical Trial Efficacy of 8 Weeks of Sofosbuvir, Velpatasvir, and Voxilaprevir in Patients With Chronic HCV Infection: 2 Phase 3 Randomized Trials. 2017

Jacobson, Ira M / Lawitz, Eric / Gane, Edward J / Willems, Bernard E / Ruane, Peter J / Nahass, Ronald G / Borgia, Sergio M / Shafran, Stephen D / Workowski, Kimberly A / Pearlman, Brian / Hyland, Robert H / Stamm, Luisa M / Svarovskaia, Evguenia / Dvory-Sobol, Hadas / Zhu, Yanni / Subramanian, G Mani / Brainard, Diana M / McHutchison, John G / Bräu, Norbert / Berg, Thomas / Agarwal, Kosh / Bhandari, Bal Raj / Davis, Mitchell / Feld, Jordan J / Dore, Gregory J / Stedman, Catherine A M / Thompson, Alexander J / Asselah, Tarik / Roberts, Stuart K / Foster, Graham R. ·Mount Sinai Beth Israel, New York, New York; Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address: ira.jacobson@nyumc.org. · Texas Liver Institute, University of Texas Health Science Center, San Antonio, Texas. · New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand. · Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada. · Ruane Medical and Liver Health Institute, Los Angeles, California. · ID Care, Hillsborough, New Jersey. · William Osler Health System, Brampton Civic Hospital, Brampton, Ontario, Canada. · University of Alberta, Edmonton, Alberta, Canada. · Emory University, Atlanta, Georgia. · Atlanta Medical Center, Atlanta, Georgia. · Gilead Sciences, Inc, Foster City, California. · James J. Peters Veterans Affairs Medical Center, Bronx, New York; Icahn School of Medicine at Mount Sinai, New York, New York. · Medical Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany. · Institute of Liver Studies, Kings College Hospital, London, United Kingdom. · Gastroenterology and Nutritional Medical Services, Bastrop, Louisiana. · Digestive Care, South Florida Center of Gastroenterology, Wellington, Florida. · Toronto Western Hospital Liver Centre, Toronto, Ontario, Canada. · St Vincent's Hospital Sydney, University of New South Wales Sydney, Sydney, New South Wales, Australia; Kirby Institute, University of New South Wales Sydney, Sydney, New South Wales, Australia. · Christchurch Hospital, University of Otago, Christchurch, New Zealand. · St. Vincent's Hospital, Melbourne, Victoria, Australia. · Hôpital Beaujon, Université Paris Diderot, INSERM UMR 1149, Centre de Recherche sur l'Inflammation, Clichy, France. · Alfred Hospital, Melbourne, Victoria, Australia. · Royal London Hospital, London, United Kingdom. ·Gastroenterology · Pubmed #28390869.

ABSTRACT: BACKGROUND & AIMS: Patients with chronic hepatitis C virus (HCV) infection have high rates of sustained virologic response (SVR) after 12 weeks of treatment with the nucleotide polymerase inhibitor sofosbuvir combined with the NS5A inhibitor velpatasvir. We assessed the efficacy of 8 weeks of treatment with sofosbuvir and velpatasvir plus the pangenotypic NS3/4A protease inhibitor voxilaprevir (sofosbuvir-velpatasvir-voxilaprevir). METHODS: In 2 phase 3, open-label trials, patients with HCV infection who had not been treated previously with a direct-acting antiviral agent were assigned randomly to groups given sofosbuvir-velpatasvir-voxilaprevir for 8 weeks or sofosbuvir-velpatasvir for 12 weeks. POLARIS-2, which enrolled patients infected with all HCV genotypes with or without cirrhosis, except patients with genotype 3 and cirrhosis, was designed to test the noninferiority of 8 weeks of sofosbuvir-velpatasvir-voxilaprevir to 12 weeks of sofosbuvir-velpatasvir using a noninferiority margin of 5%. POLARIS-3, which enrolled patients infected with HCV genotype 3 who had cirrhosis, compared rates of SVR in both groups with a performance goal of 83%. RESULTS: In POLARIS-2, 95% (95% confidence interval [CI], 93%-97%) of patients had an SVR to 8 weeks of sofosbuvir-velpatasvir-voxilaprevir; this did not meet the criterion to establish noninferiority to 12 weeks of sofosbuvir-velpatasvir, which produced an SVR in 98% of patients (95% CI, 96%-99%; difference in the stratum-adjusted Mantel-Haenszel proportions of -3.2%; 95% CI, -6.0% to -0.4%). The difference in the efficacy was owing primarily to a lower rate of SVR (92%) among patients with HCV genotype 1a infection receiving 8 weeks of sofosbuvir-velpatasvir-voxilaprevir. In POLARIS-3, 96% of patients (95% CI, 91%-99%) achieved an SVR in both treatment groups, which was significantly superior to the performance goal. Overall, the most common adverse events were headache, fatigue, diarrhea, and nausea; diarrhea and nausea were reported more frequently by patients receiving voxilaprevir. In both trials, the proportion of patients who discontinued treatment because of adverse events was low (range, 0%-1%). CONCLUSIONS: In phase 3 trials of patients with HCV infection, we did not establish that sofosbuvir-velpatasvir-voxilaprevir for 8 weeks was noninferior to sofosbuvir-velpatasvir for 12 weeks, but the 2 regimens had similar rates of SVR in patients with HCV genotype 3 and cirrhosis. Mild gastrointestinal adverse events were associated with treatment regimens that included voxilaprevir. ClinicalTrials.gov numbers: POLARIS-2, NCT02607800; and POLARIS-3, NCT02639338.

14 Clinical Trial Sofosbuvir-velpatasvir-voxilaprevir with or without ribavirin in direct-acting antiviral-experienced patients with genotype 1 hepatitis C virus. 2017

Lawitz, Eric / Poordad, Fred / Wells, Jennifer / Hyland, Robert H / Yang, Yin / Dvory-Sobol, Hadas / Stamm, Luisa M / Brainard, Diana M / McHutchison, John G / Landaverde, Carmen / Gutierrez, Julio. ·Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX. · Gilead Sciences, Inc, Foster City, CA. ·Hepatology · Pubmed #28220512.

ABSTRACT: The optimal retreatment strategy for hepatitis C virus (HCV) genotype 1-infected patients who fail direct-acting antiviral (DAA)-based regimens remains unknown. In this phase 2, open-label study conducted at a single center in the United States, patients with HCV genotype 1 infection who previously failed to achieve sustained virological response (SVR) on a DAA-based regimen were randomized to receive treatment with a fixed-dose combination tablet of sofosbuvir-velpatasvir-voxilaprevir with or without ribavirin (RBV) for 12 weeks. Patients were stratified by their cirrhosis and past nonstructural protein (NS) 5A inhibitor exposure. The primary efficacy endpoint was the proportion of patients with SVR at 12 weeks after treatment (SVR12). SVR12 was achieved by 24 of 24 patients (100%; 95% confidence interval [CI], 86-100) receiving sofosbuvir-velpatasvir-voxilaprevir alone and 24 of 25 (96%; 95% CI, 80-100) receiving the same treatment with RBV. None of the patients discontinued sofosbuvir-velpatasvir-voxilaprevir therapy because of an adverse event (AE). The most commonly reported AEs with sofosbuvir-velpatasvir-voxilaprevir alone were diarrhea and bronchitis; and with sofosbuvir-velpatasvir-voxilaprevir plus RBV were fatigue, anemia, gastroenteritis, and nausea. CONCLUSION: A fixed-dose combination of sofosbuvir-velpatasvir-voxilaprevir was well tolerated and effective at achieving virological response in patients with HCV genotype 1 infection and past DAA treatment experience. (Hepatology 2017;65:1803-1809).

15 Clinical Trial Antiviral response and resistance analysis of treatment-naïve HCV infected patients receiving multiple doses of the NS3 protease inhibitor GS-9256. 2017

Mo, Hongmei / Hedskog, Charlotte / Lawitz, Eric / Brainard, Diana M / Yang, Jenny / Delaney, William / Worth, Angela / Miller, Michael D. ·Gilead Sciences Inc, Foster City, CA, USA. Electronic address: Hongmei.Mo@gilead.com. · Gilead Sciences Inc, Foster City, CA, USA. · Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, USA. ·Antiviral Res · Pubmed #28132867.

ABSTRACT: The NS3 protease inhibitor (PI) GS-9256 has demonstrated antiviral activity in a monotherapy study and in combination with other DAAs for treatment of chronic hepatitis C virus (HCV) infection. The resistance profile of GS-9256 was investigated in a phase 1 monotherapy study of patients with HCV genotype (GT) 1 infection. No PI resistance associated substitutions (RASs) at positions 36, 155, 156, 168 and 170 were observed at baseline by population sequencing (15% cutoff) in the 54 patients enrolled in the study, however the PI RAS Q80K were detected in 41% of patients at baseline. In patients who received 75 mg of the investigational protease inhibitor (PI) GS-9256 BID, 300 mg of GS-9256 QD and 200 mg of GS-9256 BID for three days, NS3 RASs (A156V, R155K, D168G/E/N/V) were observed in 9/21, 3/7 and 8/8 post-treatment, respectively. Q80K was not selected in any patients post-treatment. The mean maximal viral load response was -3.0 ± 0.42 log

16 Clinical Trial Short-duration treatment for chronic hepatitis C virus with daclatasvir, asunaprevir, beclabuvir and sofosbuvir (FOURward study). 2017

Sulkowski, Mark S / Flamm, Steve / Kayali, Zeid / Lawitz, Eric J / Kwo, Paul / McPhee, Fiona / Torbeyns, Anne / Hughes, Eric A / Swenson, Eugene S / Yin, Philip D / Linaberry, Misti. ·Viral Hepatitis Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Feinberg School of Medicine Northwestern University, Chicago, IL, USA. · Inland Empire Liver Foundation, Rialto, CA, USA. · The Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, USA. · Indiana University, Bloomington, IN, USA. · Bristol-Myers Squibb, Wallingford, CT, USA. · Bristol-Myers Squibb, Braine l'Alleud, Belgium. · Bristol-Myers Squibb, Princeton, NJ, USA. ·Liver Int · Pubmed #27943563.

ABSTRACT: BACKGROUND & AIMS: The phase 2, FOURward study (NCT02175966) investigated short-duration therapy (4/6 weeks) with four direct-acting antivirals (DAAs) with distinct mechanisms of action in patients infected with hepatitis C virus (HCV) genotype-1. METHODS: Non-cirrhotic patients were randomized 1:1 to DCV-TRIO (fixed-dose daclatasvir 30 mg, asunaprevir 200 mg and beclabuvir 75 mg) twice-daily + sofosbuvir 400 mg once-daily for 4 or 6 weeks. The primary endpoint was sustained virological response at post-treatment Week 12 (SVR12). Patients without SVR12 were offered retreatment based on the DAA resistance profile at failure; patients with resistance to ≤1 DCV-TRIO component received DCV-TRIO + RBV for 12 weeks. RESULTS: Twenty-eight patients with HCV genotype-1 were enrolled; 79% had genotype-1a infection and median baseline HCV-RNA levels were high (9 × 10 CONCLUSIONS: Short-duration treatment with four DAAs with distinct mechanisms of action was insufficient for most patients with genotype-1 infection and high baseline viraemia. Non-SVR12 was not associated with emergence of NS3 or NS5B RAS and retreatment with DCV-TRIO + RBV for 12 weeks led to SVR in all patients.

17 Clinical Trial Post-treatment resistance analysis of hepatitis C virus from phase II and III clinical trials of ledipasvir/sofosbuvir. 2017

Wyles, David / Dvory-Sobol, Hadas / Svarovskaia, Evguenia S / Doehle, Brian P / Martin, Ross / Afdhal, Nezam H / Kowdley, Kris V / Lawitz, Eric / Brainard, Diana M / Miller, Michael D / Mo, Hongmei / Gane, Edward J. ·University of California San Diego, CA, USA. · Gilead Sciences, Foster City, CA, USA. Electronic address: Hadas.dvory-sobol@gilead.com. · Gilead Sciences, Foster City, CA, USA. · Beth Israel Deaconess Medical Center, Boston, MA, USA. · Swedish Medical Center, Seattle, WA, USA. · Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, USA. · New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand. ·J Hepatol · Pubmed #27923693.

ABSTRACT: BACKGROUND & AIMS: Ledipasvir/sofosbuvir combination treatment in phase III clinical trials resulted in sustained viral suppression in 94-99% of patients. This study characterized drug resistance in treatment failures, which may help to inform retreatment options. METHODS: We performed NS5A and NS5B deep sequencing of hepatitis C virus (HCV) from patients infected with genotype (GT) 1 who participated in ledipasvir/sofosbuvir phase II and III clinical trials. RESULTS: Fifty-one of 2144 (2.4%) (42 GT1a and 9 GT1b) treated patients met the criteria for resistance analysis due to virologic failure following the end of treatment. The majority of patients with virologic failure (38 of 51; 74.5%) had detectable ledipasvir-specific resistance-associated substitutions (RASs) at the time of virologic failure (1% deep sequencing cut-off). The percent of patients with NS5A RASs at virologic failure were 37.5%, 66.7%, 94.7% and 100% in patients treated for 6, 8, 12 and 24weeks, respectively. The common substitutions detected at failure were Q30R/H, and/or Y93H/N in GT1a and Y93H in GT1b. At failure, 35.3% (18/51) of virologic failure patients' viruses had two or more NS5A RASs and the majority of patients harbored NS5A RASs conferring a 100-1000-fold (n=10) or >1000-fold (n=23) reduced susceptibility to ledipasvir. One patient in a phase II study with a known ledipasvir RAS at baseline (L31M) developed the S282T sofosbuvir (NS5B) RAS at failure. CONCLUSIONS: In GT1 HCV-infected patients treated with ledipasvir/sofosbuvir±ribavirin, virologic failure was rare. Ledipasvir resistance in NS5A was selected or enhanced in most patients with virologic failure, one of whom also developed resistance to sofosbuvir. LAY SUMMARY: Clinical studies have shown that combination treatment with ledipasvir/sofosbuvir efficiently cures most patients with genotype 1 hepatitis C infection. For the few patients failing treatment, we show that resistance to ledipasvir was observed in most patients, whereas resistance to sofosbuvir was less common. This has important implications for the selection of optimal retreatment strategies for these patients.

18 Clinical Trial Simeprevir, daclatasvir and sofosbuvir for hepatitis C virus-infected patients with decompensated liver disease. 2017

Lawitz, E / Poordad, F / Gutierrez, J A / Kakuda, T N / Picchio, G / Beets, G / Vandevoorde, A / Van Remoortere, P / Jacquemyn, B / Luo, D / Ouwerkerk-Mahadevan, S / Vijgen, L / Van Eygen, V / Beumont, M. ·Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, USA. · Alios Biopharma, San Francisco, CA, USA. · Janssen Research & Development LLC, Raritan, NJ, USA. · Janssen Pharmaceutica NV, Beerse, Belgium. · Janssen Research & Development LLC, Titusville, NJ, USA. · Janssen Research & Development LLC, Beerse, Belgium. ·J Viral Hepat · Pubmed #27878906.

ABSTRACT: Approximately three million individuals in the United States are chronically infected with hepatitis C virus (HCV). Chronic HCV infection may lead to the development of compensated as well as decompensated liver cirrhosis. The Phase II IMPACT study was conducted in HCV genotype 1- or 4-infected cirrhotic patients with portal hypertension or decompensated liver disease and assessed for the first time the combination of the three direct-acting antivirals simeprevir, daclatasvir and sofosbuvir. Treatment-naïve or treatment-experienced adults with Child-Pugh (CP) score <7 (CP A) and evidence of portal hypertension, or CP score 7-9 (CP B), received 12 weeks of simeprevir 150 mg, daclatasvir 60 mg and sofosbuvir 400 mg, once daily. The primary efficacy endpoint was sustained virologic response 12 weeks after end of treatment (SVR12). Pharmacokinetics and safety were also assessed. Overall, 40 patients were enrolled (CP A: 19; CP B: 21). All 40 patients achieved SVR12. At week 8, the mean pharmacokinetic exposure to simeprevir, sofosbuvir, daclatasvir and GS-331007 (sofosbuvir metabolite) was 2.2-, 1.5-, 1.2- and 1.2-fold higher in patients with CP B than CP A, respectively. Grade 1/2 adverse events (AEs) occurred in 26 of 40 (65%) patients. One CP B patient had a Grade 3 AE (gastrointestinal haemorrhage), which was reported as a serious AE but not considered related to study drugs. Treatment for 12 weeks with simeprevir, daclatasvir and sofosbuvir was generally safe and well tolerated, and resulted in 100% of cirrhotic patients with portal hypertension or decompensated liver disease achieving SVR12.

19 Clinical Trial Daclatasvir and Peginterferon/Ribavirin for Black/African-American and Latino Patients with HCV infection. 2016

Rodriguez-Torres, Maribel / Lawitz, Eric / Yangco, Bienvenido / Jeffers, Lennox / Han, Steven-Huy / Thuluvath, Paul J / Rustgi, Vinod / Harrison, Stephen / Ghalib, Reem / Vierling, John M / Luketic, Velimir / Zamor, Philippe J / Ravendhran, Natarajan / Morgan, Timothy R / Pearlman, Brian / O'Brien, Christopher / Khallafi, Hicham / Pyrsopoulos, Nikolaos / Kong, George / McPhee, Fiona / Yin, Philip D / Hughes, Eric / Treitel, Michelle. ·Fundación de Investigación, San Juan, Puerto Rico. · Texas Liver Institute, University of Texas Health Science Center, San Antonio, Texas, USA. · Infectious Disease Research Institute, Inc, Tampa, Florida, USA. · Miami VA Medical Center, Miami, Florida, USA. · Pfleger Liver Institute, Los Angeles, California, USA. · Mercy Medical Center, Baltimore, Maryland, USA. · Thomas Starzl Transplant Institute UPMC, Pittsburgh, Pennsylvania, USA. · Brooke Army Medical Center, San Antonio, Texas, USA. · North Texas Research Institute, Arlington, Texas, USA. · Baylor College of Medicine, Houston, Texas, USA. · Virginia Commonwealth University School of Medicine and McGuire Research Institute, Richmond, Virginia, USA. · Carolinas Medical Center, Charlotte, North Carolina, USA. · Digestive Disease Associates, Catonsville, Maryland, USA. · VA Long Beach Healthcare System, Long Beach, California, USA. · Atlanta Medical Center, Atlanta, Georgia, USA. · University of Miami Schiff Center for Liver Diseases, Miami, Florida, USA. · Florida Hospital Transplant Center, Orlando, Florida, USA. · Rutgers-New Jersey Medical School, Newark, New Jersey, USA. · Bristol-Myers Squibb Research and Development, Wallingford, Connecticut, USA. · Bristol-Myers Squibb Research and Development, Princeton, New Jersey, USA. ·Ann Hepatol · Pubmed #27740516.

ABSTRACT:  Background. Patient race and ethnicity have historically impacted HCV treatment response. This phase 3 study evaluated daclatasvir with peginterferon-alfa-2a/ribavirin (pegIFN alfa-2a/RBV) in treatment-naive black/African American (AA), Latino, and white non-Latino patients with chronic HCV genotype 1 infection. MATERIAL AND METHODS: In this single-arm, open-label study, 246 patients received daclatasvir plus pegIFN alfa-2a and weight-based RBV. Patients with an extended rapid virologic response (eRVR; undetectable HCV-RNA at treatment weeks 4 and 12) received 24 weeks of treatment; those without eRVR received an additional 24 weeks of treatment with pegIFN alfa-2a/RBV. The primary endpoint was sustained virologic response at post-treatment week 12 (SVR12; HCV-RNA < 25 IU/mL) compared with the cohort historical rate. RESULTS: Most patients were IL28B non-CC (84.4% black/AA; 77.6% Latino) genotype 1a-infected (72.7%; 81.3%), with HCV-RNA ≥ 800,000 IU/mL (81.3%; 64.5%). SVR12 rates were 50.8% (65/128; 95% confidence interval [CI], 42.1-59.4) for black/AA and 58.9% (63/107; 95% CI, 49.6-68.2) for Latino patients. The majority (55.5%; 58.9%) received 24 weeks treatment; rapid reductions (> 4-log10) in HCV-RNA levels were observed. Only 60.9% (78/128) of black/AA and 63.6% (68/107) of Latino patients completed treatment. On-treatment serious adverse events (SAEs) occurred in 21 patients. Discontinuations due to adverse events (AEs) occurred in 9 black/AA and 6 Latino patients. CONCLUSION: SVR12 rates for black/AA (50.8%) and Latino (58.9%) cohorts treated with daclatasvir plus pegIFN alfa-2a/RBV and the lower bound of the 95% CIs were higher than the estimated historical control (black/AA, 26% SVR; Latino, 36% SVR) treated with pegIFN alfa-2a/RBV. These data support daclatasvir use in all-oral direct-acting antiviral combinations.

20 Clinical Trial Efficacy of Sofosbuvir, Velpatasvir, and GS-9857 in Patients With Genotype 1 Hepatitis C Virus Infection in an Open-Label, Phase 2 Trial. 2016

Lawitz, Eric / Reau, Nancy / Hinestrosa, Federico / Rabinovitz, Mordechai / Schiff, Eugene / Sheikh, Aasim / Younes, Ziad / Herring, Robert / Reddy, K Rajender / Tran, Tram / Bennett, Michael / Nahass, Ronald / Yang, Jenny C / Lu, Sophia / Dvory-Sobol, Hadas / Stamm, Luisa M / Brainard, Diana M / McHutchison, John G / Pearlman, Brian / Shiffman, Mitchell / Hawkins, Trevor / Curry, Michael / Jacobson, Ira. ·Texas Liver Institute, University of Texas Health Sciences Center, San Antonio, Texas. Electronic address: lawitz@txliver.com. · Rush University Medical Center, Chicago, Illinois. · Orlando Immunology Center, Orlando, Florida. · University of Pittsburgh, Pittsburgh, Pennsylvania. · Schiff Center for Liver Diseases, University of Miami Miller School of Medicine, Miami, Florida. · Gastrointestinal Specialists of Georgia, Marietta, Georgia. · GastroOne, Germantown, Tennessee. · Quality Medical Research Center, Nashville, Tennessee. · University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania. · Sinai Medical Center, Los Angeles, California. · Medical Associates Research Group, Inc, San Diego, California. · Infectious Disease Care, Hillsborough, New Jersey. · Gilead Sciences, Foster City, California. · Atlanta Medical Center, Atlanta, Georgia. · The Liver Institute of Virginia, Richmond, Virginia. · Southwest CARE Center, Santa Fe, New Mexico. · Beth Israel Deaconess Medical Center, Boston, Massachusetts. · Mount Sinai Beth Israel, New York, New York. ·Gastroenterology · Pubmed #27486034.

ABSTRACT: BACKGROUND & AIMS: The best regimen to re-treat patients who do not respond to direct-acting antivirals (DAAs) and the feasibility of further shortening regimens is unclear. We assessed the efficacy and safety of the combination of the nucleotide polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the NS3/4A protease inhibitor GS-9857 in patients with hepatitis C virus genotype 1 infection. METHODS: We performed an open-label trial at 32 sites in the United States and at 2 sites in New Zealand of 197 patients with genotype 1 hepatitis C virus infection, with or without compensated cirrhosis, who were treatment-naive or were treated previously with a DAA. Between March 2, 2015, and September 1, 2015, patients received sofosbuvir-velpatasvir (400 mg/100 mg in a fixed-dose combination) plus GS-9857 (100 mg) once daily for 6-12 weeks, plus ribavirin for 1 treatment group consisting of treatment-naive patients with cirrhosis. The primary end point was sustained virologic response 12 weeks after treatment (SVR12). RESULTS: Among treatment-naive patients without cirrhosis, 71% (24 of 34; 95% confidence interval [CI], 53-85) achieved SVR12 after 6 weeks of treatment and 100% (36 of 36; 95% CI, 90%-100%) achieved SVR12 after 8 weeks of treatment. Among treatment-naive patients with cirrhosis, 94% (31 of 33; 95% CI, 80-99) achieved SVR12 after 8 weeks of treatment and 81% (25 of 31; 95% CI, 63-93) achieved SVR12 after 8 weeks of treatment with ribavirin. Among DAA-experienced patients treated for 12 weeks, 100% without cirrhosis (31 of 31; 95% CI, 89-100) and 100% with cirrhosis (32 of 32; 95% CI, 89-100) achieved SVR12. The most common adverse events were headache, diarrhea, fatigue, and nausea. One patient (<1%) discontinued treatment because of adverse events. CONCLUSIONS: In a phase 2 open-label trial, we found 8 weeks of treatment with sofosbuvir-velpatasvir plus GS-9857 to be safe and effective in treatment-naive patients; 12 weeks was safe and effective in patients previously treated with DAAs. The combination was safe and effective in patients with or without compensated cirrhosis. Clinicaltrials.gov no: NCT02378935.

21 Clinical Trial Clinical Resistance to Velpatasvir (GS-5816), a Novel Pan-Genotypic Inhibitor of the Hepatitis C Virus NS5A Protein. 2016

Lawitz, Eric J / Dvory-Sobol, Hadas / Doehle, Brian P / Worth, Angela S / McNally, John / Brainard, Diana M / Link, John O / Miller, Michael D / Mo, Hongmei. ·Texas Liver Institute, University of Texas Health Science Center, San Antonio, Texas, USA. · Gilead Sciences, Foster City, California, USA Hadas.Dvory-Sobol@Gilead.com. · Gilead Sciences, Foster City, California, USA. ·Antimicrob Agents Chemother · Pubmed #27353271.

ABSTRACT: Velpatasvir (VEL, GS-5816) is a novel pan-genotypic hepatitis C virus (HCV) nonstructural protein 5A (NS5A) inhibitor with activity against genotype 1 (GT1) to GT6 HCV replicons. In a phase 1b 3-day monotherapy study, patients treated with a 150-mg dose of GS-5816 had a mean maximal HCV RNA decline of ≥3.3 log10 IU/ml in GT1a, -1b, -2, -3, and -4. This report characterizes virologic resistance to VEL in these patients. NS5A resistance-associated substitutions (RASs) were detected by deep sequencing (1% cutoff) pretreatment in 22/70 patients, i.e., 10/35 (29%) patients with GT1a, 1/8 (13%) with GT1b, 4/8 (50.0%) with GT2, 5/17 (29.4%) with GT3, and 2/2 (100.0%) with GT4. In GT1a and GT3 patients, pretreatment RASs were associated with a slightly reduced HCV RNA response compared to that of patients without pretreatment RASs; among patients with GT1b, GT2, and GT4, no significant difference in response was observed in those with or without pretreatment RASs. Following treatment, the pattern of emergent RASs was more complex for GT1a than for the other genotypes. In GT1a, substitutions emerged at positions M28, Q30, L31, P32, H58, E92, and Y93, with the most prevalent substitutions at positions Y93, M28, and L31. RASs were observed at two positions in GT1b and GT2 (Y93 and L31), three positions in GT3 (Y93, L31, and E92), and four positions in GT4 (L28, M31, P32L, and Y93). RASs that were present pretreatment persisted through the 48-week follow-up period; however, RASs emerging during treatment were more likely to decline both in prevalence and in frequency within the viral population during follow-up. (This study has been registered at ClinicalTrials.gov under registration no. NCT01740791.).

22 Clinical Trial Ledipasvir/sofosbuvir-based treatment of patients with chronic genotype-1 HCV infection and cirrhosis: results from two Phase II studies. 2016

Lawitz, Eric / Poordad, Fred / Hyland, Robert H / Wang, Jing / Liu, Lin / Dvory-Sobol, Hadas / Brainard, Diana M / McHutchison, John G / Gutierrez, Julio A. ·Texas Liver Institute and the University of Texas Health Science Center, San Antonio, TX, USA. · Gilead Sciences, Inc., Foster City, CA, USA. ·Antivir Ther · Pubmed #27348483.

ABSTRACT: BACKGROUND: Ledipasvir/sofosbuvir ± ribavirin administered for 12 weeks to patients with genotype-1 HCV infection and compensated cirrhosis is effective and well-tolerated. The Phase II TRILOGY-1 and TRILOGY-2 studies investigated whether ledipasvir/sofosbuvir plus the non-nucleotide NS5B inhibitor GS-9669 or the NS3/4A protease inhibitor vedroprevir could reduce treatment duration and/or eliminate the need for ribavirin in genotype-1 HCV-infected patients with compensated cirrhosis. METHODS: In TRILOGY-1, 100 cirrhotic patients were randomized (1:1:1) to 8 weeks of ledipasvir/sofosbuvir plus ribavirin, ledipasvir/sofosbuvir plus GS-9669 250 mg or ledipasvir/sofosbuvir plus GS-9669 500 mg. In TRILOGY-2, 46 previously treated cirrhotic patients were randomized (1:1) to 8 weeks of ledipasvir/sofosbuvir plus vedroprevir ± ribavirin. The primary end points were the proportion of patients with sustained virological response 12 weeks after treatment discontinuation (SVR12) and safety. RESULTS: In both studies, most patients were male (each 65%) and white (92-96%), infected with HCV genotype-1a (62-70%) and had IL28B non-CC genotypes (82-87%). In total, 37-39% of patients were Hispanic or Latino. SVR12 rates were similar across treatment arms in TRILOGY-1 (82-91%) and TRILOGY-2 (88-95%); no patient had on-treatment virological failure. Two serious adverse events (acute myocardial infarction and cardiomyopathy) were reported in two patients participating in TRILOGY-1, both of whom had pre-existing cardiac conditions. Laboratory abnormalities were infrequent. CONCLUSIONS: All ledipasvir/sofosbuvir-based regimens were well-tolerated. To shorten therapy and eliminate ribavirin, use of a more potent third agent or a third agent with a different mechanism of action may be required.

23 Clinical Trial Prevalence of Resistance-Associated Substitutions in HCV NS5A, NS5B, or NS3 and Outcomes of Treatment With Ledipasvir and Sofosbuvir. 2016

Sarrazin, Christoph / Dvory-Sobol, Hadas / Svarovskaia, Evguenia S / Doehle, Brian P / Pang, Phillip S / Chuang, Shu-Min / Ma, Julie / Ding, Xiao / Afdhal, Nezam H / Kowdley, Kris V / Gane, Edward J / Lawitz, Eric / Brainard, Diana M / McHutchison, John G / Miller, Michael D / Mo, Hongmei. ·Medizinische Klinik 1, Goethe University Hospital, Frankfurt, Germany. · Gilead Sciences, Inc, Foster City, California. Electronic address: Hadas.Dvory-Sobol@Gilead.com. · Gilead Sciences, Inc, Foster City, California. · Beth Israel Deaconess Medical Center, Boston, Massachusetts. · Swedish Medical Center, Seattle, Washington. · New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand. · Texas Liver institute, University of Texas Health Science Center, San Antonio, Texas. ·Gastroenterology · Pubmed #27296509.

ABSTRACT: BACKGROUND & AIMS: We evaluated the effects of baseline hepatitis C virus (HCV) NS5A, NS5B, and NS3 resistance-associated substitutions (RASs) on response to the combination of ledipasvir and sofosbuvir, with or without ribavirin, in patients with HCV genotype 1 infection. METHODS: We analyzed data from 2144 participants in phase 2 and 3 studies of patients with HCV genotype 1a or b infection who received the combination of ledipasvir (90 mg) and sofosbuvir (400 mg) (ledipasvir/sofosbuvir) once daily, with or without ribavirin twice daily. Population and/or deep sequence analyses of the HCV NS3, NS5A, and NS5B genes were performed on blood samples collected at baseline. RESULTS: Overall, 16.0% of patients had detectable baseline RASs in NS5A. Among patients with HCV genotype 1b infection, there was no significant effect of baseline RASs in NS5A on sustained viral response 12 weeks after the end of treatment (SVR12) with ledipasvir/sofosbuvir and only a small effect in patients with HCV genotype 1a infection. RASs in NS5A that increased the half-maximal effective concentration to ledipasvir by more than 100-fold reduced the rate of SVR12 in treatment-naive patients given ledipasvir/sofosbuvir for 8 weeks (P = .011), but not for 12 weeks. These same baseline NS5A RASs reduced the percentage of treatment-experienced patients who achieved an SVR12 to 12 weeks (but not 24 weeks) ledipasvir/sofosbuvir (P < .001). These RASs had a small effect in patients given ledipasvir/sofosbuvir in combination with ribavirin for 12 weeks. Overall, 2.5% of patients had baseline NS5B nucleotide inhibitor RASs (L159F, N142T, S282G, or L320S) and all achieved an SVR12. Of patients previously treated with protease inhibitors, 53.7% had RASs in NS3 and 96.5% achieved an SVR12. CONCLUSIONS: Baseline RASs in NS5A have minimal effects on patient responses to ledipasvir/sofosbuvir therapy. When these RASs do have effects, they could be largely overcome by extending treatment duration or through treatment intensification.

24 Clinical Trial Efficacy of Direct-Acting Antiviral Combination for Patients With Hepatitis C Virus Genotype 1 Infection and Severe Renal Impairment or End-Stage Renal Disease. 2016

Pockros, Paul J / Reddy, K Rajender / Mantry, Parvez S / Cohen, Eric / Bennett, Michael / Sulkowski, Mark S / Bernstein, David E / Cohen, Daniel E / Shulman, Nancy S / Wang, Deli / Khatri, Amit / Abunimeh, Manal / Podsadecki, Thomas / Lawitz, Eric. ·Division of Gastroenterology/Hepatology, Scripps Clinic and Scripps Translational Science Institute, La Jolla, California. · Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, Pennsylvania. · The Liver Institute at Methodist Dallas, Dallas, Texas. · Infectious Disease Development, AbbVie Inc, North Chicago, Illinois. · Medical Associates Research Group, San Diego, California. · Division of Infectious Diseases and Gastroenterology/Hepatology, Johns Hopkins University, Baltimore, Maryland. · Division of Gastroenterology, North Shore University Hospital, Manhasset, New York. · Global Pharmaceutical Development, AbbVie Inc, North Chicago, Illinois. · Statistics and Computer Sciences, AbbVie Inc, North Chicago, Illinois. · Clinical Pharmacokinetics, AbbVie Inc, North Chicago, Illinois. · Department of Gastroenterology, The Texas Liver Institute, University of Texas Health Science Center, San Antonio, Texas. Electronic address: lawitz@txliver.com. ·Gastroenterology · Pubmed #26976799.

ABSTRACT: BACKGROUND & AIMS: Although hepatitis C virus (HCV) infection is common in patients with end-stage renal disease, highly efficacious, well-tolerated, direct-acting antiviral regimens have not been extensively studied in this population. We investigated the safety and efficacy of ombitasvir co-formulated with paritaprevir and ritonavir, administered with dasabuvir (with or without ribavirin) in a prospective study of patients with stage 4 or 5 chronic kidney disease (CKD). METHODS: We performed a single-arm, multicenter study of treatment-naïve adults with HCV genotype 1 infection, without cirrhosis and with CKD stage 4 (estimated glomerular filtration rate, 15-30 mL/min/1.73 m(2)) or stage 5 (estimated glomerular filtration rate, <15 mL/min/1.73 m(2) or requiring hemodialysis). Twenty patients were given ombitasvir co-formulated with paritaprevir and ritonavir, administered with dasabuvir for 12 weeks. Patients with HCV genotype 1a infections also received ribavirin (n = 13), whereas those with genotype 1b infection did not (n = 7). The primary end point was sustained virologic response (serum HCV RNA <25 IU/mL) 12 weeks after treatment ended (SVR12). We collected data on on-treatment adverse events (AEs), serious AEs, and laboratory abnormalities. RESULTS: All 20 patients completed 12 weeks of treatment. Eighteen of the 20 patients achieved SVR12 (90%; 95% confidence interval: 69.9-97.2). One patient death after the end of the treatment (unrelated to the treatment) and 1 relapse accounted for the 2 non-SVRs. Adverse events were primarily mild or moderate, and no patient discontinued treatment due to an AE. Four patients experienced serious AEs; all were considered unrelated to treatment. Ribavirin therapy was interrupted in 9 patients due to anemia; 4 received erythropoietin. No blood transfusions were performed. CONCLUSIONS: In a clinical trial, the combination of ombitasvir, paritaprevir, and ritonavir, administered with dasabuvir, led to an SVR12 in 90% of patients with HCV genotype 1 infection and stage 4 or 5 CKD. The regimen is well tolerated, though RBV use may require a reduction or interruption to manage anemia. ClinicalTrials.gov ID NCT02207088.

25 Clinical Trial GS-9857 in patients with chronic hepatitis C virus genotype 1-4 infection: a randomized, double-blind, dose-ranging phase 1 study. 2016

Rodriguez-Torres, M / Glass, S / Hill, J / Freilich, B / Hassman, D / Di Bisceglie, A M / Taylor, J G / Kirby, B J / Dvory-Sobol, H / Yang, J C / An, D / Stamm, L M / Brainard, D M / Kim, S / Krefetz, D / Smith, W / Marbury, T / Lawitz, E. ·Fundación de Investigación, Rio Piedras, Puerto Rico. · PRA Health Sciences, Philadelphia, PA, USA. · Avail Clinical Research, LLC, DeLand, FL, USA. · Kansas City Research Institute, Kansas City, MO, USA. · Comprehensive Clinical Research, Berlin, NJ, USA. · Saint Louis University Medical Center, Saint Louis, MO, USA. · Gilead Sciences, Inc., Foster City, CA, USA. · WCCT Global, Costa Mesa, CA, USA. · PRA Health Sciences, Marlton, NJ, USA. · New Orleans Center for Clinical Research, University of Tennessee Medical Center, Knoxville, TN, USA. · Orlando Clinical Research Center, Orlando, FL, USA. · Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, USA. ·J Viral Hepat · Pubmed #26957110.

ABSTRACT: GS-9857, an inhibitor of the hepatitis C virus (HCV) nonstructural protein (NS) 3/4A, demonstrates potent activity against HCV genotypes 1-6 and improved coverage against commonly encountered NS3 resistance-associated variants (RAVs). In this study, the safety, tolerability, antiviral activity and pharmacokinetics (PK) of GS-9857 were evaluated in patients with chronic HCV genotype 1-4 infection. Patients with genotype 1-4 infection received placebo or once-daily GS-9857 at doses ranging from 50 to 300 mg for 3 days under fasting conditions. GS-9857 was well tolerated; all reported adverse events (AEs) were mild or moderate in severity. Diarrhoea and headache were the most commonly reported AEs. Grade 3 or 4 laboratory abnormalities were observed in 17% of patients receiving GS-9857; there were no Grade 3 or 4 abnormalities in alanine aminotransferase, aspartate aminotransferase or alkaline phosphatase levels. GS-9857 demonstrated potent antiviral activity in patients with chronic HCV infection, achieving mean and median maximum reductions in HCV RNA of ≥3 log10 IU/mL following administration of a 100-mg dose in patients with HCV genotype 1a, 1b, 2, 3 or 4 infection. The antiviral activity of GS-9857 was unaffected by the presence of pretreatment NS3 RAVs. In patients with genotype 1-4 infection, GS-9857 exhibited linear PK and was associated with a median half-life of 29-42 h, supporting once-daily dosing. Thus, the tolerability, efficacy and pharmacokinetic profile of GS-9857 support its further evaluation for treatment of patients with chronic HCV infection.

Next