Journal ArticleDOI
Grazoprevir–Elbasvir Combination Therapy for Treatment-Naive Cirrhotic and Noncirrhotic Patients With Chronic Hepatitis C Virus Genotype 1, 4, or 6 Infection: A Randomized Trial
Stefan Zeuzem,Reem Ghalib,K. Rajender Reddy,Paul J. Pockros,Ziv Ben Ari,Yue Zhao,Deborah D. Brown,Shuyan Wan,Mark J. DiNubile,Bach-Yen Nguyen,Michael N. Robertson,Janice Wahl,Eliav Barr,Joan R. Butterton +13 more
TLDR
Grazoprevir and elbasvir were evaluated in a randomized, blinded, placebo-controlled trial in treatment-naive patients with hepatitis C virus (HCV) infection.Abstract:
BACKGROUND Novel interferon- and ribavirin-free regimens are needed to treat hepatitis C virus (HCV) infection. OBJECTIVE To evaluate the safety and efficacy of grazoprevir (NS3/4A protease inhibitor) and elbasvir (NS5A inhibitor) in treatment-naive patients. DESIGN Randomized, blinded, placebo-controlled trial. (ClinicalTrials.gov: NCT02105467). SETTING 60 centers in the United States, Europe, Australia, Scandinavia, and Asia. PATIENTS Cirrhotic and noncirrhotic treatment-naive adults with genotype 1, 4, or 6 infection. INTERVENTION Oral, once-daily, fixed-dose grazoprevir 100 mg/elbasvir 50 mg for 12 weeks, stratified by fibrosis and genotype. Patients were randomly assigned 3:1 to immediate or deferred therapy. MEASUREMENTS Proportion of patients in the immediate-treatment group achieving unquantifiable HCV RNA 12 weeks after treatment (SVR12); adverse events in both groups. RESULTS Among 421 participants, 194 (46%) were women, 157 (37%) were nonwhite, 382 (91%) had genotype 1 infection, and 92 (22%) had cirrhosis. Of 316 patients receiving immediate treatment, 299 of 316 (95% [95% CI, 92% to 97%]) achieved SVR12, including 144 of 157 (92% [CI, 86% to 96%]) with genotype 1a, 129 of 131 (99% [CI, 95% to 100%]) with genotype 1b, 18 of 18 (100% [CI, 82% to 100%]) with genotype 4, 8 of 10 (80% [CI, 44% to 98%]) with genotype 6, 68 of 70 (97% [CI, 90% to 100%]) with cirrhosis, and 231 of 246 (94% [CI, 90% to 97%]) without cirrhosis. Virologic failure occurred in 13 patients (4%), including 1 case of breakthrough infection and 12 relapses, and was associated with baseline NS5A polymorphisms and emergent NS3 or NS5A variants or both. Serious adverse events occurred in 9 (2.8%) and 3 (2.9%) patients in the active and placebo groups, respectively (difference <0.05 percentage point [CI, -5.4 to 3.1 percentage points]); none were considered drug related. The most common adverse events in the active group were headache (17%), fatigue (16%), and nausea (9%). LIMITATION The study lacked an active-comparator control group and included relatively few genotype 4 and 6 infections. CONCLUSION Grazoprevir-elbasvir achieved high SVR12 rates in treatment-naive cirrhotic and noncirrhotic patients with genotype 1, 4, or 6 infection. This once-daily, all-oral, fixed-combination regimen represents a potent new therapeutic option for chronic HCV infection. PRIMARY FUNDING SOURCE Merck & Co.read more
Citations
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A novel, potent, and orally bioavailable thiazole HCV NS5A inhibitor for the treatment of hepatitis C virus.
Teng-Kuang Yeh,Iou-Jiun Kang,Tsu-An Hsu,Yen-Chun Lee,Chung-Chi Lee,Sheng-Ju Hsu,Ya-Wen Tian,Hui-Yun Yang,Chiung-Tong Chen,Yu-Sheng Chao,Andrew Yueh,Jyh-Haur Chern +11 more
TL;DR: Pharmacokinetic studies demonstrated that compound 27a had an excellent pharmacokinetic profiles with a superior oral exposure and desired bioavailability after oral administration in both rats and dogs, and therefore it was selected as a developmental candidate for the treatment of HCV infection.
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Determinants of Infection Outcome in HCV-Genotype 4.
TL;DR: Hematitis C virus genotype 4 (HCV-4) is the least studied and needs better understanding to control disease dissemination and progression, which compromises the life quality of chronic HCV-infected patients.
Journal ArticleDOI
No Pharmacokinetic Interactions Between Elbasvir or Grazoprevir and Buprenorphine/Naloxone in Healthy Participants and Participants Receiving Stable Opioid Agonist Therapy.
Hwa-Ping Feng,Zifang Guo,Luzelena Caro,William L. Marshall,William L. Marshall,Fang Liu,Deborah Panebianco,Pavan Vaddady,April M. Barbour,Christina Reitmann,Patricia Jumes,Jocelyn Gilmartin,Dennis Wolford,Robert Valesky,Monika Martinho,Joan R. Butterton,Marian Iwamoto,Iain Fraser,Iain Fraser,Lynn Webster,Wendy W. Yeh +20 more
TL;DR: No dose adjustment for BUP/NAL, EBR, or GZR is required for patients with HCV infection receiving EBR/GZR and BUP-NAL maintenance therapy.
Journal ArticleDOI
Management of Post-Liver Transplant Recurrence of Hepatitis C
TL;DR: This innovation has allowed post-liver transplant patients with HCV recurrence access to interferon-free therapies with extraordinary efficacy, safety, tolerability, and fewer drug–drug interactions.
Journal ArticleDOI
Antiviral Activity, Safety, and Tolerability of Multiple Ascending Doses of Elbasvir or Grazoprevir in Participants Infected With Hepatitis C Virus Genotype-1 or -3.
Wendy W. Yeh,Iain P. Fraser,Patricia Jumes,Amelia S. Petry,Inge De Lepeleire,Martine Robberechts,Christina Reitmann,Kristien Van Dyck,Xiaobi Huang,Zifang Guo,Deborah Panebianco,Robert B. Nachbar,Edward O'Mara,John A. Wagner,Joan R. Butterton,Frank J. Dutko,Valentin S. Moiseev,Zhanna Kobalava,Andreas Hüser,Sorin Visan,Christian Schwabe,Edward Gane,Serghei Popa,Nelea Ghicavii,Markus Uhle,Frank Wagner +25 more
TL;DR: Oral administration of elbasvir or grazoprevir once daily exhibited potent antiviral activity in participants with chronic GT1 or GT3 HCV infections, and the results of these proof-of-concept studies provided preliminary data for the selection of the dosages ofElbasvir and grazopRevir to test in Phase II and III clinical studies.
References
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Sofosbuvir for previously untreated chronic hepatitis C infection
Eric Lawitz,Alessandra Mangia,David L. Wyles,Maribel Rodriguez-Torres,Tarek Hassanein,Stuart C. Gordon,Michael Schultz,M. Davis,Zeid Kayali,K. Rajender Reddy,Ira M. Jacobson,Kris V. Kowdley,L. Nyberg,G. Mani Subramanian,Robert H. Hyland,Sarah Arterburn,Deyuan Jiang,John McNally,Diana M. Brainard,William T. Symonds,John G. McHutchison,Aasim Sheikh,Zobair M. Younossi,Edward Gane +23 more
TL;DR: In a single-group study of sofosbuvir combined with peginterferon-ribavirin, patients with predominantly genotype 1 or 4 HCV infection had a rate of sustained virologic response of 90% at 12 weeks.
Journal ArticleDOI
Ledipasvir and Sofosbuvir for Untreated HCV Genotype 1 Infection
Nezam H. Afdhal,Stefan Zeuzem,Paul Y. Kwo,Mario Chojkier,Norman Gitlin,Massimo Puoti,Manuel Romero-Gómez,Jean-Pierre Zarski,Kosh Agarwal,Peter Buggisch,Graham R. Foster,Norbert Bräu,Maria Buti,Ira M. Jacobson,G. Mani Subramanian,Xiao Ding,Hongmei Mo,Jenny C. Yang,Phillip S. Pang,William T. Symonds,John G. McHutchison,Andrew J. Muir,Alessandra Mangia,Patrick Marcellin +23 more
TL;DR: Once-daily ledipasvir-sofosbuvir with or without ribavirin for 12 or 24 weeks was highly effective in previously untreated patients with HCV genotype 1 infection.
Journal ArticleDOI
Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis
Kris V. Kowdley,Stuart C. Gordon,K. Rajender Reddy,Lorenzo Rossaro,David E. Bernstein,Eric Lawitz,Mitchell L. Shiffman,Eugene R. Schiff,Reem Ghalib,Michael J. Ryan,Vinod K. Rustgi,Mario Chojkier,Robert Herring,Adrian M. Di Bisceglie,Paul J. Pockros,G. Mani Subramanian,Di An,Evguenia S. Svarovskaia,Robert H. Hyland,Phillip S. Pang,William T. Symonds,John G. McHutchison,Andrew J. Muir,David Pound,Michael W. Fried +24 more
TL;DR: Leadipasvir-sofosbuvir for 8 weeks was associated with a high rate of sustained virologic response among previously untreated patients with HCV genotype 1 infection without cirrhosis, and results indicated noninferiority of the 8-week ledipas Viral-SofosBuvir regimen.
Journal ArticleDOI
Treatment of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin.
Jordan J. Feld,Kris V. Kowdley,Eoin Coakley,Samuel H. Sigal,David R. Nelson,Darrell H. G. Crawford,Ola Weiland,Humberto Aguilar,Junyuan Xiong,Tami Pilot-Matias,Barbara DaSilva-Tillmann,Lois Larsen,Thomas Podsadecki,B. Bernstein +13 more
TL;DR: In previously untreated patients with HCV genotype 1 infection and no cirrhosis, a 12-week multitargeted regimen of ABT-450/r-ombitasvir and dasabuvir with ribavirin was highly effective and was associated with a low rate of treatment discontinuation.
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