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Hepatitis: HELP
Articles by Michael N. Robertson
Based on 24 articles published since 2009
(Why 24 articles?)
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Between 2009 and 2019, M. N. Robertson wrote the following 24 articles about Hepatitis.
 
+ Citations + Abstracts
1 Clinical Trial Efficacy and safety of elbasvir/grazoprevir in participants with hepatitis C virus genotype 1, 4, or 6 infection from the Asia-Pacific region and Russia: Final results from the randomized C-CORAL study. 2019

Wei, Lai / Jia, Ji Dong / Wang, Fu Sheng / Niu, Jun Qi / Zhao, Xu Min / Mu, Shengmei / Liang, Li Wen / Wang, Zaiqi / Hwang, Peggy / Robertson, Michael N / Ingravallo, Paul / Asante-Appiah, Ernest / Wei, Bo / Evans, Barbara / Hanna, George J / Talwani, Rohit / Duan, Zhong Ping / Zhdanov, Konstantin / Cheng, Pin-Nan / Tanwandee, Tawesak / Nguyen, Van Kinh / Heo, Jeong / Isakov, Vasily / George, Jacob / Anonymous1371156. ·Peking University Hepatology Institute, Beijing Key Laboratory for Hepatitis C and Immunotherapy for Liver Disease, Peking University People's Hospital, Beijing, China. · Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing Key Laboratory of Translational Medicine on Cirrhosis, National Clinical Research Center for Digestive Diseases, Capital Medical University, Beijing, China. · Treatment and Research Center for Infectious Diseases, Beijing 302 Hospital, Beijing, China. · Department of Hepatology, First Hospital, Jilin University, Changchun, Jilin, China. · Merck Sharp & Dohme, Capital Medical University, Beijing, China. · Merck & Co., Inc., Kenilworth, New Jersey, USA. · Artificial Liver Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China. · Military Medical Academy n.a. S.M. Kirov, St. Petersburg, Russia. · National Cheng Kung University, Tainan, Taiwan. · Department of Medicine, Faculty of Medicine Siriraj Hospital, Bangkok, Thailand. · National Hospital of Tropical Diseases, Hanoi, Vietnam. · College of Medicine, Pusan National University and Medical Research Institute, Pusan National University Hospital, Busan, Republic of Korea. · Department of Gastroenterology and Hepatology, Federal Research Center of Nutrition and Biotechnology, Moscow, Russia. · Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Westmead, New South Wales, Australia. ·J Gastroenterol Hepatol · Pubmed #30311701.

ABSTRACT: BACKGROUND AND AIM: Although treatment with direct-acting antivirals has dramatically improved morbidity and mortality attributable to chronic hepatitis C virus infection, universal access to these medicines has been slow in the Asia-Pacific region and Russia. This study evaluated efficacy and safety of elbasvir/grazoprevir in participants with hepatitis C virus infection from Asia-Pacific countries and Russia (C-CORAL). METHODS: C-CORAL was a phase 3, randomized, placebo-controlled study (NCT02251990). Treatment-naive, HIV-negative, cirrhotic and non-cirrhotic participants with chronic hepatitis C genotype 1, 4, or 6 infection were randomized to elbasvir 50 mg/grazoprevir 100 mg once daily for 12 weeks (immediate-treatment group) or placebo followed by deferred treatment with elbasvir/grazoprevir (deferred-treatment group). The primary efficacy outcome was sustained virologic response at 12 weeks, and the primary safety outcome was a comparison between the immediate-treatment group and placebo phase of the deferred-treatment group. RESULTS: A total of 489 participants were randomized (immediate-treatment group, n = 366; deferred-treatment group, n = 123). Sustained virologic response at 12 weeks in the combined immediate/deferred-treatment groups was 94.4% (459/486; 95% confidence interval = 92.4-96.5%). Sustained virologic response at 12 weeks was 98.2% in participants with genotype 1b, 91.9% with genotype 1a, and 66.7% with genotype 6 infection. Similar rates of adverse events and drug-related adverse events were seen in the immediate-treatment group versus placebo phase of the deferred-treatment group (51.0% vs 50.4% and 21.4% vs 21.1%). CONCLUSIONS: Elbasvir/grazoprevir for 12 weeks represents an effective and well-tolerated treatment option for treatment-naive people with genotype 1 infection from Asia-Pacific countries and Russia.

2 Clinical Trial Efficacy of elbasvir and grazoprevir in participants with hepatitis C virus genotype 4 infection: A pooled analysis. 2018

Asselah, Tarik / Reesink, Hendrik / Gerstoft, Jan / de Ledinghen, Victor / Pockros, Paul J / Robertson, Michael / Hwang, Peggy / Asante-Appiah, Ernest / Wahl, Janice / Nguyen, Bach-Yen / Barr, Eliav / Talwani, Rohit / Serfaty, Lawrence. ·Hepatology Department, AP-HP, University Paris Diderot, INSERM UMR1149, Beaujon Hospital, Clichy, France. · Academic Medical Center of the University of Amsterdam, Amsterdam, The Netherlands. · Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark. · Service d'Hépato-Gastroentérologie, Hôpital Haut-Lévêque, CHU Bordeaux, Pessac, France. · Scripps Clinic and Scripps Translational Science Institute, La Jolla, CA, USA. · Merck & Co., Inc., Kenilworth, NJ, USA. · Department of Hepatology, Saint-Antoine Hospital, Paris, France. ·Liver Int · Pubmed #29461687.

ABSTRACT: BACKGROUND & AIMS: The aim of this integrated analysis was to assess the efficacy of the once-daily combination of elbasvir 50 mg and grazoprevir 100 mg, with and without ribavirin in HCV genotype 4 (GT4)-infected participants enrolled in the Phase 2/3 clinical programme with elbasvir/grazoprevir. METHODS: Treatment-naïve and treatment-experienced participants 18 years of age or older with chronic HCV GT4 infection and baseline HCV RNA ≥10 000 IU/mL were included in the analysis. The analysis population was the full analysis set (FAS; all participants who received at least 1 dose of study medication) and a total of 155 HCV GT4 participants were evaluated. The primary endpoint was sustained virologic response at week 12 (SVR12; HCV RNA less than the lower limit of quantitation at 12 weeks after the completion of study therapy). RESULTS: Overall, among GT4-infected participants treated with 12 or 16 weeks of elbasvir/grazoprevir ± ribavirin, the SVR12 efficacy rates were 96.4% (107/111) in treatment-naïve participants and 88.6% (39/44) in treatment-experienced participants. The SVR12 rates were 96.0% (97/101) in treatment-naïve participants treated with 12 weeks of elbasvir/grazoprevir and 100% (8/8) in treatment-experienced participants treated with 16 weeks of elbasvir/grazoprevir plus ribavirin. Efficacy was not impacted by GT4 subtype. CONCLUSIONS: The regimens of 12 weeks of elbasvir/grazoprevir without ribavirin, and 16 weeks of elbasvir/grazoprevir plus ribavirin, were efficacious in HCV GT4-infected treatment-naïve and treatment-experienced participants respectively. Baseline NS5A resistance-associated substitutions did not impact the efficacy of elbasvir/grazoprevir in GT4-infected participants.

3 Clinical Trial Safety and efficacy of an 8-week regimen of grazoprevir plus ruzasvir plus uprifosbuvir compared with grazoprevir plus elbasvir plus uprifosbuvir in participants without cirrhosis infected with hepatitis C virus genotypes 1, 2, or 3 (C-CREST-1 and C-CREST-2, part A): two randomised, phase 2, open-label trials. 2017

Gane, Edward J / Pianko, Stephen / Roberts, Stuart K / Thompson, Alexander J / Zeuzem, Stefan / Zuckerman, Eli / Ben-Ari, Ziv / Foster, Graham R / Agarwal, Kosh / Laursen, Alex L / Gerstoft, Jan / Gao, Wei / Huang, Hsueh-Cheng / Fitzgerald, Brian / Fernsler, Doreen / Li, Jerry J / Grandhi, Anjana / Liu, Hong / Su, Feng-Hsiu / Wan, Shuyan / Zeng, Zhen / Chen, Huei-Ling / Dutko, Frank J / Nguyen, Bach-Yen T / Wahl, Janice / Robertson, Michael N / Barr, Eliav / Yeh, Wendy W / Plank, Rebeca M / Butterton, Joan R / Esteban, Rafael. ·Auckland Clinical Studies, Auckland, New Zealand. Electronic address: edgane@adhb.govt.nz. · Monash Health and Monash University, Melbourne, VIC, Australia. · The Alfred Hospital and Monash University, VIC, Australia. · St Vincent's Hospital Melbourne, Melbourne, VIC, Australia. · University Hospital Frankfurt, Frankfurt, Germany. · Carmel Medical Center, Haifa, Israel. · Sheba Medical Center, Ramat Gan, Israel. · Queen Mary University of London, London, UK. · King's College Hospital, London, UK. · Aarhus University Hospital, Aarhus, Denmark. · Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. · Merck & Co, Inc, Kenilworth, NJ, USA. · Hospital Universitario Val d'Hebron, Barcelona, Spain. ·Lancet Gastroenterol Hepatol · Pubmed #28802816.

ABSTRACT: BACKGROUND: New hepatitis C virus (HCV) therapies with pan-genotypic efficacy are needed. The goals of part A of C-CREST-1 and C-CREST-2 were to compare the efficacies of two doses (300 mg or 450 mg once daily) of uprifosbuvir (MK-3682; NS5B inhibitor) in an 8-week regimen combined with grazoprevir (NS3/4A inhibitor; 100 mg once daily) and an NS5A inhibitor, either elbasvir (50 mg once daily) or ruzasvir (MK-8408; 60 mg once daily), and to evaluate the safety and tolerability of these combination regimens in individuals infected with genotypes 1, 2, or 3. METHODS: Part A of these phase 2, randomised, multicentre, open-label, clinical trials enrolled participants from 11 countries, aged 18 years or older, chronically infected with HCV genotypes 1, 2, or 3, with HCV RNA of at least 10 000 IU/mL, without evidence of cirrhosis, who had not received previous treatment for HCV infection. Within each HCV genotype, participants were randomly assigned (1:1:1:1) with a block size of 4, to open-label treatment to one of four treatment groups: grazoprevir (100 mg/day) plus ruzasvir (60 mg/day) plus uprifosbuvir (300 mg/day); grazoprevir (100 mg/day) plus ruzasvir (60 mg/day) plus uprifosbuvir (450 mg/day); grazoprevir (100 mg/day) plus elbasvir (50 mg/day) plus uprifosbuvir (300 mg/day); or grazoprevir (100 mg/day) plus elbasvir (50 mg/day) plus uprifosbuvir (450 mg/day), according to a computer-generated allocation schedule. Randomisation was centrally implemented using an interactive voice response system and integrated web response system. The primary endpoint was the proportion of participants achieving sustained virological response at 12 weeks (SVR12; HCV RNA less than the lower limit of quantitation at 12 weeks after the end of all study therapy) in the per-protocol analysis set, which included all participants who were randomised and received at least one dose of study drug. The trials are registered with ClinicalTrials.gov, numbers NCT02332707 and NCT02332720. FINDINGS: 241 participants were randomised between Feb 18, 2015, and March 16, 2015. 240 participants completed 8 weeks of treatment and reached follow-up 12 weeks after the end of treatment. Of the four regimens, grazoprevir plus ruzasvir plus uprifosbuvir 450 mg had the most consistently high SVR12 (>90%) for participants infected with genotype 1 (21 [91%] of 23), genotype 2 (15 [94%] of 16), and genotype 3 (20 [91%] of 22). In particular, among those with genotype 2 infection, the grazoprevir plus ruzasvir plus uprifosbuvir 450 mg regimen had a higher SVR12 (15 [94%] of 16) than the grazoprevir plus ruzasvir plus uprifosbuvir 300 mg regimen (ten [71%] of 14), grazoprevir plus elbasvir plus uprifosbuvir 300 mg regimen (11 [69%] of 16), or grazoprevir plus elbasvir plus uprifosbuvir 450 mg regimen (nine [60%] of 15). Overall, the most common adverse events were headache (55 [23%] of 240), fatigue (47 [20%] of 240), and nausea (32 [13%] of 240). Two (<1%) of 240 participants had serious adverse events (pharyngeal abscess and keratitis), which were not considered drug related by the respective investigators. INTERPRETATION: These results support further evaluation of the three-drug direct-acting antiviral agent regimen of grazoprevir 100 mg plus ruzasvir 60 mg plus uprifosbuvir 450 mg among a more diverse HCV-infected population, including those with compensated cirrhosis, previous treatment with an interferon-containing regimen, and HCV-HIV co-infection. FUNDING: Merck & Co, Inc.

4 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.

5 Clinical Trial Grazoprevir, ruzasvir, and uprifosbuvir for hepatitis C virus after NS5A treatment failure. 2017

Wyles, David / Wedemeyer, Heiner / Ben-Ari, Ziv / Gane, Edward J / Hansen, Jesper Bach / Jacobson, Ira M / Laursen, Alex L / Luetkemeyer, Annie / Nahass, Ronald / Pianko, Stephen / Zeuzem, Stefan / Jumes, Patricia / Huang, Hsueh-Cheng / Butterton, Joan / Robertson, Michael / Wahl, Janice / Barr, Eliav / Joeng, Hee-Koung / Martin, Elizabeth / Serfaty, Lawrence / Anonymous2330912. ·University of Colorado School of Medicine, Denver, CO. · Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany. · Sheba Medical Center, Tel Hashomer, Israel. · Auckland Hospital, Auckland, New Zealand. · Aalborg University Hospital, Department of Gastroenterology, Aalborg, Denmark. · Mount Sinai Beth Israel and Icahn School of Medicine at Mount Sinai, New York, NY. · Department of Infectious Diseases, Aarhus University Hospital, Skejby, Aarhus, Denmark. · Zuckerberg San Francisco General Hospital, University of California San Francisco, San Francisco, CA. · ID Care, Hillsborough, NJ. · Monash Medical Centre, Clayton, Victoria, Australia. · Goethe University Hospital, Frankfurt, Germany. · Merck & Co., Inc., Kenilworth, NJ. · Service d'Hépatologie, Hôpital Saint-Antoine, Université Pierre & Marie Curie, Paris, France. ·Hepatology · Pubmed #28688129.

ABSTRACT: People with hepatitis C virus (HCV) infection who have failed treatment with an all-oral regimen represent a challenging treatment population. The present studies evaluated the safety and efficacy of grazoprevir, ruzasvir, and uprifosbuvir, with or without ribavirin, in participants who had failed an NS5A inhibitor-containing regimen. C-SURGE (PN-3682-021) and C-CREST Part C (PN-3682-011 and -012) were open-label, multicenter studies. Participants who had previously relapsed following an NS5A inhibitor-containing all-oral regimen were retreated with grazoprevir 100 mg, ruzasvir 60 mg, and uprifosbuvir 450 mg alone for 24 weeks or with ribavirin for 16 weeks. The primary efficacy endpoint was sustained virologic response (HCV RNA below the limit of quantitation [<15 IU/mL]) 12 weeks after treatment completion (SVR12). In C-SURGE, SVR12 was achieved by 49/49 (100%) and 43/44 (98%) genotype (GT)1 participants in the 24-week no ribavirin arm and the 16-week plus ribavirin arm (lost to follow-up, n = 1), respectively. In C-CREST Part C, SVR12 was achieved by 23/24 (96%) participants treated for 16 weeks with ribavirin (GT1, 2/2 [100%]; GT2, 13/14 [93%]; GT3, 8/8 [100%]). One participant with GT2 infection discontinued study medication after a single dose of grazoprevir, ruzasvir, and uprifosbuvir plus ribavirin due to serious adverse events of vomiting and tachycardia. The presence of baseline resistance-associated substitutions had no impact on SVR12. No participant who completed treatment in either study experienced virologic failure. CONCLUSION: Grazoprevir, ruzasvir, and uprifosbuvir, with or without ribavirin, for 16 or 24 weeks was safe and highly effective in participants with HCV infection who had previously failed NS5A inhibitor-containing therapy. (Hepatology 2017;66:1794-1804).

6 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.

7 Clinical Trial Elbasvir/Grazoprevir for Patients With Hepatitis C Virus Infection and Inherited Blood Disorders: A Phase III Study. 2017

Hézode, Christophe / Colombo, Massimo / Bourlière, Marc / Spengler, Ulrich / Ben-Ari, Ziv / Strasser, Simone I / Lee, William M / Morgan, Leslie / Qiu, Jingjun / Hwang, Peggy / Robertson, Michael / Nguyen, Bach-Yen / Barr, Eliav / Wahl, Janice / Haber, Barbara / Chase, Robert / Talwani, Rohit / Marco, Vito Di / Anonymous4420898. ·Henri Mondor Hospital, Paris, France. · Humanitas Clinical and Research Center, Rozzano, Italy. · Hôpital Saint Joseph, Marseille, France. · University Hospital Bonn, Bonn, Germany. · Sheba Medical Center, Ramat Gan, Israel. · University of Sydney, Sydney, NSW, Australia. · University of Texas Southwestern Medical Center, Dallas, TX. · Merck & Co., Inc, Kenilworth, NJ. · University of Palermo, Palermo, Italy. ·Hepatology · Pubmed #28256747.

ABSTRACT: Direct-acting antiviral agents have not been studied exclusively in patients with inherited blood disorders and hepatitis C virus (HCV) infection. The objective of the randomized, placebo-controlled, phase III C-EDGE IBLD study was to assess the safety and efficacy of elbasvir/grazoprevir (EBR/GZR) in patients with inherited bleeding disorders and HCV infection. One hundred fifty-nine adults with HCV infection and sickle cell anemia, thalassemia, or hemophilia A/B or von Willebrand disease were enrolled at 31 study sites in the United States, Europe, Australia, Canada, Israel, and Thailand. Patients were given an oral, once-daily, fixed-dose combination of EBR/GZR 50 mg/100 mg for 12 weeks and randomized to the immediate-treatment group (ITG) or deferred-treatment group (DTG; placebo followed by active treatment). The primary endpoints were the proportion of patients in the ITG with unquantifiable HCV RNA 12 weeks posttreatment (sustained virological response 12 weeks after completion of study treatment; SVR12) and the comparison of safety in the ITG and DTG. In the ITG, 100 of 107 patients (93.5%) achieved SVR12, 6 relapsed, and 1 was lost to follow-up. SVR12 was achieved in 94.7% (18 of 19), 97.6% (40 of 41), and 89.4% (42 of 47) of patients with sickle cell disease, β-thalassemia, and hemophilia A/B or von Willebrand disease, respectively. Serious adverse events were reported by 2.8% (n = 3) and 11.5% (n = 6) of patients in the ITG and DTG, respectively. Hemoglobin levels and international normalized ratio values were similar in patients receiving EBR/GZR and placebo; among patients with hemoglobinopathies, change in mean hemoglobin levels was similar in those receiving EBR/GZR compared to those receiving placebo. CONCLUSION: These results add to the expanding pool of data available for EBR/GZR, indicating a high level of efficacy and favorable tolerability in patients with HCV infection. (Hepatology 2017;66:736-745).

8 Clinical Trial The combination of elbasvir and grazoprevir for the treatment of chronic HCV infection in Japanese patients: a randomized phase II/III study. 2017

Kumada, Hiromitsu / Suzuki, Yoshiyuki / Karino, Yoshiyasu / Chayama, Kazuaki / Kawada, Norifumi / Okanoue, Takeshi / Itoh, Yoshito / Mochida, Satoshi / Toyoda, Hidenori / Yoshiji, Hitoshi / Takaki, Shintaro / Yatsuzuka, Naoyoshi / Yodoya, Etsuo / Iwasa, Takashi / Fujimoto, Go / Robertson, Michael N / Black, Stuart / Caro, Luzelena / Wahl, Janice. ·Department of Hepatology, Toranomon Hospital, 1-3-1 Kajigaya, Takatsu-ku, Kawasaki, Kanagawa, 213-8587, Japan. kumahiro@toranomon.gr.jp. · Department of Hepatology, Toranomon Hospital, 1-3-1 Kajigaya, Takatsu-ku, Kawasaki, Kanagawa, 213-8587, Japan. · Department of Gastroenterology, Sapporo Kosei General Hospital, North-3 East-8, Chuou-ku, Sapporo, Hokkaido, 060-0033, Japan. · Department of Gastroenterology and Metabolism, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan. · Department of Hepatology, Osaka City University Medical School, 1-4-3 Asahimachi, Abeno-ku, Osaka, 545-8585, Japan. · Department of Gastroenterology and Hepatology, Saiseikai Suita Hospital, 1-2 Kawazono-cho, Suita-Shi, Osaka, 564-0013, Japan. · Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi Hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan. · Department of Gastroenterology and Hepatology, Saitama Medical University, 38 Morohongo, Moroyama-machi, Iruma-gun, Saitama, 350-0495, Japan. · Department of Gastroenterology, Ogaki Municipal Hospital, 4-86 Minaminokawa, Ogaki, 503-8502, Japan. · Third Department of Internal Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan. · Department of Gastroenterology/Liver Center, Hiroshima Red Cross Hospital and Atomic-Bomb Survivors Hospital, 1-9-6, Senda-machi, Naka-ku, Hiroshima, 730-8619, Japan. · MSD K.K., 1-13-12 Kudan-kita, Chiyoda-ku, Tokyo, 102-8667, Japan. · Merck & Co.Inc., 2000 Galloping Hill Road, Kenilworth, NJ, 07033, USA. ·J Gastroenterol · Pubmed #27873094.

ABSTRACT: BACKGROUND: Elbasvir (EBR) in combination with grazoprevir (GZR) has demonstrated efficacy in patients with hepatitis C virus (HCV) infections in trials primarily conducted in the USA and Europe. We investigated the safety and efficacy of EBR in combination with GZR in Japanese patients with chronic HCV infection, with or without cirrhosis. METHODS: The study was conducted in two parts. In part 1, noncirrhotic patients were randomized 1:1 to receive EBR (50 mg) in combination with GZR (50 or 100 mg) once daily for 12 weeks. In part 2, noncirrhotic patients were randomized 3:1 to receive immediate or deferred treatment with EBR (50 mg) and GZR (100 mg, determined in part 1) for 12 weeks; cirrhotic patients received open-label immediate treatment. The primary efficacy end point was the rate of sustained virologic response 12 weeks after completion of the study treatment. RESULTS: In part 1, 63 patients were randomized to receive EBR in combination with GZR at a dose of 50 mg (n = 31) or 100 mg (n = 32). The SVR12 rates were 100% with GZR at a dose of 50 mg and 96.8% with GZR at a dose of 100 mg. Tolerability was similar in both arms. In part 2, 301 noncirrhotic patients were randomized to receive immediate treatment (n = 227) or deferred treatment (n = 74), and 35 cirrhotic patients were enrolled. The SVR12 rates were 96.5% and 97.1% after immediate treatment in noncirrhotic and cirrhotic patients respectively. Safety was generally similar between immediate and deferred treatment. CONCLUSION: Treatment with EBR in combination with GZR for 12 weeks is effective and well tolerated in Japanese patients with chronic HCV infection. CLINICALTRIALS. GOV IDENTIFIER: NCT02203149.

9 Clinical Trial Effectiveness of Elbasvir and Grazoprevir Combination, With or Without Ribavirin, for Treatment-Experienced Patients With Chronic Hepatitis C Infection. 2017

Kwo, Paul / Gane, Edward J / Peng, Cheng-Yuan / Pearlman, Brian / Vierling, John M / Serfaty, Lawrence / Buti, Maria / Shafran, Stephen / Stryszak, Paul / Lin, Li / Gress, Jacqueline / Black, Stuart / Dutko, Frank J / Robertson, Michael / Wahl, Janice / Lupinacci, Lisa / Barr, Eliav / Haber, Barbara. ·Indiana University, Indianapolis, Indiana. Electronic address: pkwo@stanford.edu. · Auckland Clinical Studies, Grafton, Auckland, New Zealand. · School of Medicine, China Medical University, Taichung, Taiwan. · Center for Hepatitis C, Atlanta Medical Center, Atlanta, Georgia. · Baylor College of Medicine, Baylor-St. Luke's Medical Center, Houston, Texas. · Service d'Hépatologie, Hôpital Saint-Antoine, APHP, UPMC Paris 6, Paris, France. · Hospital Universitari Vall d'Hebron, and Ciberehd del Instituto Carlos III, Barcelona, Spain. · University of Alberta, Edmonton, Alberta, Canada. · Merck & Co, Inc, Kenilworth, New Jersey. ·Gastroenterology · Pubmed #27720838.

ABSTRACT: BACKGROUND & AIMS: Patients infected with hepatitis C virus (HCV) genotype 1, 4, or 6, with or without cirrhosis, previously treated with peg-interferon and ribavirin, are a challenge to treat. We performed a phase 3 randomized controlled open-label trial to assess the effects of 12 or 16 weeks of treatment with once-daily elbasvir (an HCV NS5A inhibitor, 50 mg) and grazoprevir (an HCV NS3/4A protease inhibitor, 100 mg), in a fixed-dose combination tablet, with or without twice-daily ribavirin, in this patient population. METHODS: We analyzed data from 420 patients (35% with cirrhosis, 64% with a null or partial response to peg-interferon and ribavirin) who were randomly assigned (1:1:1:1) to groups given elbasvir and grazoprevir once daily, with or without twice-daily ribavirin, for 12 or 16 weeks, at 65 study centers in 15 countries in Europe, Asia, and Central and North America. Randomization was stratified by cirrhosis status and type of peg-interferon and ribavirin treatment failure. HCV RNA was measured using COBAS TaqMan v2.0. The primary end point was HCV RNA <15 IU/mL, 12 weeks after completion of treatment (SVR12). We aimed to determine whether the proportion of patients achieving an SVR12 in any group was greater than the reference rate (58%). RESULTS: With 12 weeks of treatment, an SVR12 was achieved by 92.4% of patients given elbasvir and grazoprevir and 94.2% of patients given elbasvir and grazoprevir with ribavirin. With 16 weeks of treatment, an SVR12 was achieved by 92.4% of patients given elbasvir and grazoprevir and 98.1% of patients given elbasvir and grazoprevir with ribavirin. Among patients treated for 12 weeks without ribavirin, virologic failure occurred in 6.8%, 0%, and 12.5% of patients with HCV genotype 1a, 1b, or 4 infection, respectively. Among patients given elbasvir and grazoprevir for 12 weeks, virologic failure occurred in 0% of patients infected with HCV genotypes 1 and 4 who relapsed after completing peg-interferon and ribavirin, and 7.5% infected with HCV genotypes 1 and 4, respectively, with a null or partial response to peg-interferon and ribavirin. Among patients treated for 16 weeks who received ribavirin, there were no incidences of virologic failure. Common adverse events were fatigue (23.1%), headache (19.8%), and nausea (11.0%). CONCLUSIONS: The combination tablet of elbasvir and grazoprevir, with or without ribavirin, was highly efficacious in inducing an SVR12 in patients with HCV genotype 1, 4, or 6 infection failed by previous treatment with peg-interferon and ribavirin, including patients with cirrhosis and/or a prior null response. The treatment was generally well tolerated. ClinicalTrials.gov Number: NCT02105701.

10 Clinical Trial Grazoprevir, Elbasvir, and Ribavirin for Chronic Hepatitis C Virus Genotype 1 Infection After Failure of Pegylated Interferon and Ribavirin With an Earlier-Generation Protease Inhibitor: Final 24-Week Results From C-SALVAGE. 2016

Buti, Maria / Gordon, Stuart C / Zuckerman, Eli / Lawitz, Eric / Calleja, Jose L / Hofer, Harald / Gilbert, Christopher / Palcza, John / Howe, Anita Y M / DiNubile, Mark J / Robertson, Michael N / Wahl, Janice / Barr, Eliav / Forns, Xavier. ·Hospital Universitario Valle Hebron and Ciberehd, Barcelona, Spain. · Henry Ford Health System, Detroit, Michigan. · Carmel Medical Center, Haifa, Israel. · Texas Liver Institute, University of Texas Health Science Center, San Antonio. · Servicio de Gastroenterología y Hepatología, Hospital Universitario Puerta de Hierro, Universidad Autonoma de Madrid, Spain. · Division of Gastroenterology and Hepatology, Medical University of Vienna, Austria. · Merck and Co, Inc, Kenilworth, New Jersey. · Liver Unit, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain. ·Clin Infect Dis · Pubmed #26371152.

ABSTRACT: BACKGROUND: The phase 2 C-SALVAGE study (Hepatitis C-Salvage Study for Patients who Failed DAA/PR Therapy) demonstrated a 96.2% sustained virologic response at 12 weeks (SVR12) rate using the NS3/4A protease inhibitor grazoprevir and the NS5A inhibitor elbasvir together with ribavirin in treatment-experienced patients with chronic hepatitis C virus (HCV) genotype 1 infection. METHODS: C-SALVAGE was a prospective open-label trial of grazoprevir 100 mg once daily and elbasvir 50 mg once daily coadministered with weight-based ribavirin twice daily for 12 weeks in genotype 1-infected cirrhotic and noncirrhotic patients who had failed treatment with ≥ 4 weeks of pegylated interferon and ribavirin plus either boceprevir, telaprevir, or simeprevir. Although the primary efficacy outcome was SVR12, patients were also evaluated 24 weeks after cessation of study therapy. Population sequencing was performed at baseline and periodically in virologic failures throughout the 24-week posttherapy follow-up period. RESULTS: SVR24 rates were 76 of 79 (96.2%) overall, with all 3 relapses occurring by posttherapy week 8. Every NS3 and NS5A variant detected at baseline reappeared at the time of relapse and persisted throughout the available follow-up period. NS3_A156T emerged in virus from each patient at relapse, but rapidly disappeared over the ensuing 2 weeks in 2 patients. NS5A_Y93H emerged in virus from 2 patients at relapse and persisted for the entire follow-up period. CONCLUSIONS: Grazoprevir and elbasvir with ribavirin for 12 weeks maintained HCV suppression for at least 24 weeks posttherapy without late relapses. Baseline resistance-associated variants (RAVs) stably reappeared at relapse in all 3 patients with virologic failure. NS5A_RAVs emerging at relapse persisted for the full 24-week follow-up period. If confirmed, this finding could complicate retreatment of the small number of patients failing regimens containing an NS5A inhibitor. CLINICAL TRIALS REGISTRATION: NCT02105454.

11 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.

12 Clinical Trial Efficacy and safety of grazoprevir (MK-5172) and elbasvir (MK-8742) in patients with hepatitis C virus and HIV co-infection (C-EDGE CO-INFECTION): a non-randomised, open-label trial. 2015

Rockstroh, Jürgen K / Nelson, Mark / Katlama, Christine / Lalezari, Jay / Mallolas, Josep / Bloch, Mark / Matthews, Gail V / Saag, Michael S / Zamor, Philippe J / Orkin, Chloe / Gress, Jacqueline / Klopfer, Stephanie / Shaughnessy, Melissa / Wahl, Janice / Nguyen, Bach-Yen T / Barr, Eliav / Platt, Heather L / Robertson, Michael N / Sulkowski, Mark. ·Bonn University Hospital, Bonn, Germany. Electronic address: juergen.rockstroh@ukb.uni-bonn.de. · Chelsea and Westminster Hospital, London, UK. · Sorbonne Universities, UPMC University of Paris 06, INSERM UMR_S 1136, Pierre Louis Institute of Epidemiology and Public Health, Paris, France; APHP Pitié-Salpêtrière Hospital, Paris, France. · Quest Clinical Research, San Francisco, CA, USA. · Hospital Clinic-University of Barcelona, Barcelona, Spain. · Holdsworth House Medical Practice, Darlinghurst, NSW, Australia. · St Vincent's Hospital, Sydney, NSW, Australia. · University of Alabama at Birmingham, Birmingham, AL, USA. · Division of Hepatology, Carolinas Medical Center, Charlotte, NC, USA. · Royal London Hospital, Bart's Health NHS Trust, London, UK. · Merck & Co, Inc, Kenilworth, NJ, USA. · Johns Hopkins University School of Medicine, Baltimore, MD, USA. ·Lancet HIV · Pubmed #26423374.

ABSTRACT: BACKGROUND: Hepatitis C virus (HCV) infection is a leading cause of morbidity and mortality in patients with HIV-1. The C-EDGE CO-INFECTION study assessed the efficacy, safety, and tolerability of grazoprevir (MK-5172) plus elbasvir (MK-8742) in patients with HCV and HIV co-infection. METHODS: In this uncontrolled, non-randomised, phase 3, open-label, single-arm study, treatment-naive patients with chronic HCV genotype 1, 4, or 6 infection and HIV co-infection, with or without cirrhosis, were enrolled from 37 centres in nine countries across Europe, the USA, and Australia. Patients were either naive to treatment with any antiretroviral therapy (ART) or stable on ART for at least 8 weeks. All patients received grazoprevir 100 mg plus elbasvir 50 mg in a fixed-dose combination tablet once daily for 12 weeks. The primary endpoint was sustained virological response (HCV RNA <15 IU/mL) 12 weeks after the end of therapy (SVR12). The primary population for efficacy analyses was all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, number NCT02105662. FINDINGS: Between June 11, 2014, and Aug 29, 2014, 218 patients were enrolled and received grazoprevir plus elbasvir for 12 weeks, all of whom completed follow-up at week 12. SVR12 was achieved by 210 (96%) of 218 patients (95% CI 92·9-98·4). One patient did not achieve SVR12 because of a non-virological reason, and seven patients without cirrhosis relapsed (two subsequently confirmed as reinfections). All 35 patients with cirrhosis achieved SVR12. The most common adverse events were fatigue (29; 13%), headache (27; 12%), and nausea (20; 9%). No patient discontinued treatment because of an adverse event. Two patients receiving ART had transient HIV viraemia. INTERPRETATION: This HCV treatment regimen seems to be effective and well tolerated for patients co-infected with HIV with or without cirrhosis. These data are consistent with previous trials of this regimen in the monoinfected population. This regimen continues to be studied in phase 3 trials. FUNDING: Merck Sharp & Dohme Corp.

13 Clinical Trial 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. 2015

Zeuzem, Stefan / Ghalib, Reem / Reddy, K Rajender / Pockros, Paul J / Ben Ari, Ziv / Zhao, Yue / Brown, Deborah D / Wan, Shuyan / DiNubile, Mark J / Nguyen, Bach-Yen / Robertson, Michael N / Wahl, Janice / Barr, Eliav / Butterton, Joan R. · ·Ann Intern Med · Pubmed #25909356.

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.

14 Clinical Trial Efficacy and safety of 12 weeks versus 18 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin for hepatitis C virus genotype 1 infection in previously untreated patients with cirrhosis and patients with previous null response with or without cirrhosis (C-WORTHY): a randomised, open-label phase 2 trial. 2015

Lawitz, Eric / Gane, Edward / Pearlman, Brian / Tam, Edward / Ghesquiere, Wayne / Guyader, Dominique / Alric, Laurent / Bronowicki, Jean-Pierre / Lester, Laura / Sievert, William / Ghalib, Reem / Balart, Luis / Sund, Fredrik / Lagging, Martin / Dutko, Frank / Shaughnessy, Melissa / Hwang, Peggy / Howe, Anita Y M / Wahl, Janice / Robertson, Michael / Barr, Eliav / Haber, Barbara. ·Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, USA. Electronic address: lawitz@txliver.com. · Auckland Clinical Studies, Grafton, Auckland, New Zealand. · Atlanta Medical Center, Emory School of Medicine and Medical College of Georgia, Atlanta, GA, USA. · LAIR Centre, Vancouver, BC, Canada. · Vancouver Island Health Authority and University of British Columbia, Victoria, BC, Canada. · Department of Hepatology, Rennes University Hospital, Rennes 1 University, Rennes, France. · CHU Purpan, Digest Dept, UMR 152, IRD Toulouse 3 University, France. · INSERM U954, Centre Hospitalier Universitaire de Nancy, Université de Lorraine, Vandoeuvre-lès-Nancy, France. · University of California, Davis Medical Center, Sacramento, CA, USA. · Monash University and Monash Health, Melbourne, Victoria, Australia. · Texas Clinical Research Institute, Arlington, TX, USA. · Tulane University School of Medicine, New Orleans, LA, USA. · Infectious Diseases, Uppsala University, Sweden. · Institute of Biomedicine, University of Gothenburg, Sweden. · Merck & Co, Whitehouse Station, NJ, USA. ·Lancet · Pubmed #25467591.

ABSTRACT: BACKGROUND: There is a high medical need for an interferon-free, all-oral, short-duration therapy for hepatitis C virus (HCV) that is highly effective across diverse patient populations, including patients with cirrhosis or previous null response to pegylated interferon (peginterferon) plus ribavirin (PR-null responders). We aimed to assess the efficacy, safety, and effective treatment duration of grazoprevir (an HCV NS3/4A protease inhibitor) combined with elbasvir (an HCV NS5A inhibitor) with or without ribavirin in patients with HCV genotype 1 infection with baseline characteristics of poor response. METHODS: The C-WORTHY trial is a randomised, open-label phase 2 trial of grazoprevir plus elbasvir with or without ribavirin; here we report findings for two cohorts of previously untreated patients with cirrhosis (cohort 1) and those with previous PR-null response with or without cirrhosis (cohort 2) enrolled in part B of the study. Eligible patients were adults aged 18 years or older with chronic HCV genotype 1 infection and HCV RNA concentrations of 10 000 IU/mL or higher in peripheral blood. We randomly assigned patients to receive grazoprevir (100 mg daily) and elbasvir (50 mg daily) with or without ribavirin for 12 or 18 weeks. Randomisation was done centrally with an interactive voice response system; patients and study investigators were masked to treatment duration up to week 12 but not to treatment allocation. The primary endpoint was the proportion of patients achieving HCV RNA less than 25 IU/mL at 12 weeks after end of treatment (SVR12), assessed by COBAS TaqMan version 2.0. This study is registered with ClinicalTrials.gov, number NCT01717326. FINDINGS: We describe findings for 253 patients enrolled in cohort 1 (n=123) or cohort 2 (n=130). In cohort 1, we randomly assigned 60 patients to the 12-week regimen (31 with ribavirin and 29 with no ribavirin) and 63 to the 18-week regimen (32 with ribavirin and 31 with no ribavirin); in cohort 2, we randomly assigned 65 patients to the 12-week regimen (32 with ribavirin and 33 with no ribavirin) and 65 to the 18-week regimen (33 with ribavirin and 32 with no ribavirin. High SVR12 rates were achieved irrespective of the use of ribavirin or extension of the treatment duration from 12 to 18 weeks; SVR12 rates ranged from 90% (95% CI 74-98; 28/31; cohort 1, 12 weeks, ribavirin-containing) to 100% (95% CI 89-100; 33/33; cohort 2, 18 weeks, ribavirin-containing). Among patients treated for 12 weeks with grazoprevir plus elbasvir without ribavirin, 97% (95% CI 82-100, 28/29) of patients in cohort 1 and 91% (76-98, 30/33) of patients in cohort 2 achieved SVR12. Adverse events reported in more than 10% of patients were fatigue (66 patients, 26% [95% CI 21-32]), headache (58 patients, 23% [95% CI 18-29]), and asthenia (35 patients, 14% [95% CI 10-19]). INTERPRETATION: Treatment with grazoprevir plus elbasvir, both with and without ribavirin and for both 12 and 18 weeks' treatment duration, showed high rates of efficacy in previously untreated patients with cirrhosis and previous PR-null responders with and without cirrhosis. These results support the phase 3 development of grazoprevir plus elbasvir. FUNDING: Merck & Co, Inc.

15 Clinical Trial Efficacy and safety of 8 weeks versus 12 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin in patients with hepatitis C virus genotype 1 mono-infection and HIV/hepatitis C virus co-infection (C-WORTHY): a randomised, open-label phase 2 trial. 2015

Sulkowski, Mark / Hezode, Christophe / Gerstoft, Jan / Vierling, John M / Mallolas, Josep / Pol, Stanislas / Kugelmas, Marcelo / Murillo, Abel / Weis, Nina / Nahass, Ronald / Shibolet, Oren / Serfaty, Lawrence / Bourliere, Marc / DeJesus, Edwin / Zuckerman, Eli / Dutko, Frank / Shaughnessy, Melissa / Hwang, Peggy / Howe, Anita Y M / Wahl, Janice / Robertson, Michael / Barr, Eliav / Haber, Barbara. ·Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: msulkowski@jhmi.edu. · Department of Hepatology and Gastroenterology, Hôpital Henri Mondor, AP-HP, Université Paris-Est, INSERM U955, Créteil, France. · Department of Infectious Diseases, Rigshospitalet, Copenhagen, Denmark. · Baylor College of Medicine, Houston, Texas, USA. · Infectious Diseases Service, Hospital Clínic-Barcelona, Spain. · University Paris Descartes, Hospital Cochin, APHP and INSERM, Paris, France. · South Denver Gastroenterology, Englewood, CO, USA. · Advanced Medical & Pain Management Research Clinic, Miami, FL, USA. · Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, Copenhagen, Denmark. · ID Care, Hillsborough, NJ, USA. · Liver Unit, Department of Gastroenterology, Tel-Aviv Medical Center, Tel-Aviv, Israel. · Hôpital Saint Antoine, APHP and INSERM UMR_938, Université Pierre & Marie Curie, Paris, France. · Service d'hépato-gastroentérologie, Hôpital Saint-Joseph, Marseille, France. · Orlando Immunology Center, Orlando, FL, USA. · Liver Unit, Carmel Medical Center, Technion Faculty of Medicine, Haifa, Israel. · Merck & Co, Inc, Whitehouse Station, NJ, USA. ·Lancet · Pubmed #25467560.

ABSTRACT: BACKGROUND: Both hepatitis C virus (HCV) mono-infected and HIV/HCV co-infected patients are in need of safe, effective, all-oral HCV regimens. In a phase 2 study we aimed to assess the efficacy and safety of grazoprevir (MK-5172; HCV NS3/4A protease inhibitor) and two doses of elbasvir (MK-8742; HCV NS5A inhibitor) in patients with HCV mono-infection and HIV/HCV co-infection. METHODS: The C-WORTHY study is a phase 2, multicentre, randomised controlled trial of grazoprevir plus elbasvir with or without ribavirin in patients with HCV; here, we report findings for previously untreated (genotype 1) patients without cirrhosis who were HCV mono-infected or HIV/HCV co-infected. Eligible patients were previously untreated adults aged 18 years or older with chronic HCV genoype 1 infection and HCV RNA at least 10 000 IU/mL in peripheral blood without evidence of cirrhosis, hepatocellular carcinoma, or decompensated liver disease. In part A of the study we randomly assigned HCV-mono-infected patients to receive 12 weeks of grazoprevir (100 mg) plus elbasvir (20 mg or 50 mg) with or without ribavirin (arms A1-3); in part B we assigned HCV-mono-infected patients to 8 or 12 weeks of grazoprevir (100 mg) plus elbasvir (50 mg) with or without ribavirin (arms B1-3) and HIV/HCV co-infected patients to 12 weeks of therapy with or without ribavirin. The primary endpoint was the proportion of patients achieving HCV RNA less than 25 IU/mL 12 weeks after end of treatment (SVR12). Randomisation was by presence or absence of ribavirin, 8 or 12 weeks of treatment, and dosage of elbasvir. Patients were stratified by gentoype 1a versus 1b. The patients, investigators, and study site personnel were masked to treatment group assignements but the funder was not. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT01717326. FINDINGS: 218 patients with HCV mono-infection (n=159) and HIV/HCV co-infection (n=59) were enrolled. SVR12 for patients treated for 12 weeks with or without ribavirin ranged from 93-98% in mono-infected and 87-97% in co-infected patients. SVR12 rates in mono-infected and co-infected patients treated for 12 weeks without ribavirin were 98% (95% CI 88-100; 43/44) and 87% (95% CI 69-96; 26/30), respectively, and with ribavirin were 93% (95% CI 85-97; 79/85) and 97% (95% CI 82-100; 28/29), respectively. Among mono-infected patients with genotype 1a infection treated for 8 weeks, SVR12 was 80% (95% CI 61-92; 24/30). Five of six patients who discontinued early for reasons other than virological failure had HCV RNA less than 25 IU/mL at their last study visit. Virological failure among patients treated for 12 weeks occurred in seven patients (7/188, 4%) and was associated with emergence of resistance-associated variants to one or both drugs. The safety profile of grazoprevir plus elbasvir with or without ribavirin was similar in mono-infected and co-infected patients. No patient discontinued due to an adverse event or laboratory abnormality. The most common adverse events were fatigue (51 patients, 23%), headache (44, 20%), nausea (32, 15%), and diarrhoea (21, 10%). INTERPRETATION: Once-daily grazoprevir plus elbasvir with or without ribavirin for 12 weeks in previously untreated HCV-mono-infected and HIV/HCV-co-infected patients without cirrhosis achieved SVR12 rates of 87-98%. These results support the ongoing phase 3 development of grazoprevir plus elbasvir. FUNDING: Merck & Co, Inc.

16 Clinical Trial The combination of MK-5172, peginterferon, and ribavirin is effective in treatment-naive patients with hepatitis C virus genotype 1 infection without cirrhosis. 2014

Manns, Michael P / Vierling, John M / Bacon, Bruce R / Bruno, Savino / Shibolet, Oren / Baruch, Yaacov / Marcellin, Patrick / Caro, Luzelena / Howe, Anita Y M / Fandozzi, Christine / Gress, Jacqueline / Gilbert, Christopher L / Shaw, Peter M / Cooreman, Michael P / Robertson, Michael N / Hwang, Peggy / Dutko, Frank J / Wahl, Janice / Mobashery, Niloufar. ·Hannover Medical School, Hannover, Germany; German Center for Infection Research (DZIF), Hannover-Braunschweig, Germany. Electronic address: manns.michael@mh-hannover.de. · Baylor College of Medicine, Houston, Texas. · Saint Louis University, Saint Louis, Missouri. · A. O. Fatebenefratelli and Oftalmico, Milan, Italy. · Liver Unit, Department of Gastroenterology, Tel-Aviv Medical Center, Tel-Aviv, Israel. · Liver Unit, Rambam Health Care Campus, Haifa, Israel. · University Paris-Diderot, Clichy, France. · Merck & Co, Inc, Whitehouse Station, New Jersey. ·Gastroenterology · Pubmed #24727022.

ABSTRACT: BACKGROUND & AIMS: MK-5172 is an inhibitor of the hepatitis C virus (HCV) nonstructural protein 3/4A protease; MK-5172 is taken once daily and has a higher potency and barrier to resistance than licensed protease inhibitors. We investigated the efficacy and tolerability of MK-5172 with peginterferon and ribavirin (PR) in treatment-naive patients with chronic HCV genotype 1 infection without cirrhosis. METHODS: We performed a multicenter, double-blind, randomized, active-controlled, dose-ranging, response-guided therapy study. A total of 332 patients received MK-5172 (100, 200, 400, or 800 mg) once daily for 12 weeks in combination with PR. Patients in the MK-5172 groups received PR for an additional 12 or 36 weeks, based on response at week 4. Patients in the control group (n = 66) received a combination of boceprevir and PR, dosed in accordance with boceprevir's US product circular. RESULTS: At 24 weeks after the end of therapy, sustained virologic responses were achieved in 89%, 93%, 91%, and 86% of the patients in the groups given the combination of PR and MK-5172 (100, 200, 400, or 800 mg), respectively, vs 61% of controls. In the MK-5172 group receiving 100 mg, 91% of patients had undetectable levels of HCV RNA at week 4 and qualified for the short duration of therapy. The combination of MK-5172 and PR generally was well tolerated. Transient increases in transaminase levels were noted in the MK-5172 groups given 400 and 800 mg, at higher frequencies than in the MK-5172 groups given 100 or 200 mg, or control groups. CONCLUSIONS: Once-daily MK-5172 (100 mg) with PR for 24 or 48 weeks was highly effective and well tolerated among treatment-naive patients with HCV genotype 1 infection without cirrhosis. Studies are underway to evaluate interferon-free MK-5172-based regimens. ClinicalTrials.gov number: NCT01353911.

17 Article Elbasvir/grazoprevir and sofosbuvir for hepatitis C virus genotype 3 infection with compensated cirrhosis: A randomized trial. 2018

Foster, Graham R / Agarwal, Kosh / Cramp, Matthew E / Moreea, Sulleman / Barclay, Stephen / Collier, Jane / Brown, Ashley S / Ryder, Stephen D / Ustianowski, Andrew / Forton, Daniel M / Fox, Ray / Gordon, Fiona / Rosenberg, William M / Mutimer, David J / Du, Jiejun / Gilbert, Christopher L / Asante-Appiah, Ernest / Wahl, Janice / Robertson, Michael N / Barr, Eliav / Haber, Barbara. ·Queen Mary University, London, UK. · Institute of Liver Studies, Kings College Hospital, London, UK. · South West Liver Unit, Derriford Hospital and Peninsula Schools of Medicine and Dentistry, Plymouth, UK. · Bradford Teaching Hospitals Foundation Trust, Bradford, UK. · Glasgow Royal Campus, Glasgow, UK. · John Radcliffe Hospital, Oxford, UK. · Imperial College Healthcare NHS Trust, London, UK. · NIHR Biomedical Unit in Gastrointestinal and Liver Diseases at Nottingham University Hospital NHS Trust and The University of Nottingham, Nottingham, UK. · North Manchester General Hospital, Manchester, UK. · St. Georges University of London, London, UK. · Gartnavel General Hospital, Glasgow, UK. · Hepatology Joint Clinical Research Unit, Bristol, UK. · Institute for Liver and Digestive Health, University College London, London, UK. · QE Hospital, Birmingham, UK. · Merck & Co., Inc., Kenilworth, NJ. ·Hepatology · Pubmed #29473975.

ABSTRACT: Many direct-acting antiviral regimens have reduced activity in people with hepatitis C virus (HCV) genotype (GT) 3 infection and cirrhosis. The C-ISLE study assessed the efficacy and safety of elbasvir/grazoprevir (EBR/GZR) plus sofosbuvir (SOF) with and without ribavirin (RBV) in compensated cirrhotic participants with GT3 infection. This was a phase 2, randomized, open-label study. Treatment-naive participants received EBR/GZR + SOF + RBV for 8 weeks or EBR/GZR + SOF for 12 weeks, and peginterferon/RBV treatment-experienced participants received EBR/GZR + SOF ± RBV for 12 weeks or EBR/GZR + SOF for 16 weeks. The primary endpoint was HCV RNA <15 IU/mL 12 weeks after the end of treatment (sustained virologic response at 12 weeks [SVR12]). Among treatment-naive participants, SVR12 was 91% (21/23) in those treated with RBV for 8 weeks and 96% (23/24) in those treated for 12 weeks. Among treatment-experienced participants, SVR12 was 94% (17/18) and 100% (17/17) in the 12-week arm, with and without RBV, respectively, and 94% (17/18) in the 16-week arm. Five participants failed to achieve SVR: 2 relapsed (both in the 8-week arm), 1 discontinued due to vomiting/cellulitis (16-week arm), and 2 discontinued (consent withdrawn/lost to follow-up). SVR12 was not affected by the presence of resistance-associated substitutions (RASs). There was no consistent change in insulin resistance, and 5 participants reported serious adverse events (pneumonia, chest pain, opiate overdose, cellulitis, decreased creatinine). High efficacy was demonstrated in participants with HCV GT3 infection and cirrhosis. Treatment beyond 12 weeks was not required, and efficacy was maintained regardless of baseline RASs. CONCLUSION: Data from this study support the use of EBR/GZR plus SOF for 12 weeks without RBV for treatment-naive and peginterferon/RBV-experienced people with GT3 infection and cirrhosis (ClinicalTrials.gov NCT02601573). (Hepatology 2018;67:2113-2126).

18 Article The safety and efficacy of elbasvir and grazoprevir in participants with hepatitis C virus genotype 1b infection. 2018

Zeuzem, Stefan / Serfaty, Lawrence / Vierling, John / Cheng, Wendy / George, Jacob / Sperl, Jan / Strasser, Simone / Kumada, Hiromitsu / Hwang, Peggy / Robertson, Michael / Wahl, Janice / Barr, Eliav / Talwani, Rohit / Platt, Heather. ·Goethe University Hospital, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany. zeuzem@em.uni-frankfurt.de. · Service d'Hépatologie, Hôpital Saint-Antoine, Université Pierre and Marie Curie, Paris, France. · Baylor College of Medicine, Advanced Liver Therapies, Houston, TX, USA. · Department of Gastroenterology and Hepatology, Royal Perth Hospital, Perth, WA, Australia. · Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, NSW, Australia. · Institute for Clinical and Experimental Medicine (IKEM), Prague, Czech Republic. · AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, NSW, Australia. · Department of Hepatology, Toranomon Hospital, Tokyo, Japan. · Merck & Co., Inc., Kenilworth, NJ, USA. ·J Gastroenterol · Pubmed #29344726.

ABSTRACT: BACKGROUND: Genotype 1b (GT1b) is the most common subtype of the hepatitis C virus (HCV). We present an integrated analysis of 1070 participants with HCV GT1b infection from 30 countries who received elbasvir/grazoprevir for 12 weeks. METHODS: This is a retrospective analysis of data from participants with chronic HCV GT1b infection enrolled in 11 phase II/III clinical trials. All participants received elbasvir 50 mg plus grazoprevir 100 mg once daily for 12 weeks. The primary end point of all studies was sustained virologic response 12 weeks after completion of therapy (SVR12, HCV RNA < 15 IU/ml). RESULTS: SVR12 was 97.2% (1040/1070). Of the 30 participants who failed to attain SVR12, 15 relapsed and 15 had nonvirologic failure. Among participant subgroups, SVR12 was high in those with compensated cirrhosis (188/189, 99.5%), HIV co-infection (51/54, 94.4%), and baseline viral load > 800,000 IU/ml (705/728, 96.8%). Resistance-associated substitutions (RASs) at NS5A positions 28, 30, 31, or 93 were present in 21.6% of participants at baseline. SVR12 was 99.6% (820/823) in participants without baseline NS5A RASs and 94.7% (215/227) in those with baseline NS5A RASs. Serious adverse events occurred in 3.2% (34/1070) of participants, nine of which occurred after study medication was completed. CONCLUSIONS: Elbasvir/grazoprevir for 12 weeks represents an effective treatment option for participants with HCV GT1b infection. SVR12 was high in all participant subgroups, including those with compensated cirrhosis, HIV co-infection, and high baseline viral load. CLINICALTRIALS. GOV IDENTIFIERS: The trials discussed in this paper were registered with Clinicaltrial.gov as the following: NCT02092350 (C-SURFER), NCT02105662 (C-EDGE Co-Infection), NCT02105467 (C-EDGE treatment-naive), NCT02105701 (C-EDGE treatment-experienced), NCT01717326 (C-WORTHy), NCT02251990 (C-CORAL), NCT02105688 (C-EDGE COSTAR), NCT02252016 (C-EDGE IBLD), NCT02115321 (C-SALT), NCT02203149 (Japan phase 2/3 study), NCT02358044 (C-EDGE Head-2-Head).

19 Article Safety and Efficacy of Elbasvir/Grazoprevir in Patients With Hepatitis C Virus Infection and Compensated Cirrhosis: An Integrated Analysis. 2017

Jacobson, Ira M / Lawitz, Eric / Kwo, Paul Y / Hézode, Christophe / Peng, Cheng-Yuan / Howe, Anita Y M / Hwang, Peggy / Wahl, Janice / Robertson, Michael / Barr, Eliav / Haber, Barbara A. ·Mount Sinai Beth Israel and Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address: ijacobson@chpnet.org. · Texas Liver Institute, University of Texas Health Science Center, San Antonio, Texas. · Indiana University School of Medicine, Indianapolis, Indiana. · Henri Mondor Hospital, Créteil, France. · China Medical University Hospital, Taichung City, Taiwan. · Merck & Co., Inc, Kenilworth, New Jersey. ·Gastroenterology · Pubmed #28193518.

ABSTRACT: BACKGROUND & AIMS: Persons with hepatitis C virus (HCV) infection are at risk of progressive liver disease, cirrhosis, and decompensation. We analyzed the effects of the direct-acting antiviral agents elbasvir and grazoprevir in patients with HCV infection and compensated cirrhosis, combining data from 6 clinical trials. METHODS: We performed an integrated analysis of 402 patients with HCV genotype 1, 4, or 6 infection and Child-Pugh A compensated cirrhosis enrolled in 6 clinical trials. All patients received elbasvir/grazoprevir 50 mg/100 mg once daily, with or without ribavirin, for 12-18 weeks. The primary end point was sustained virologic response 12 weeks after completion of therapy (SVR12), defined as a level of HCV RNA <15 IU/mL. RESULTS: Among treatment-naïve and treatment-experienced patients receiving elbasvir/grazoprevir for 12 weeks, 97.8% (135 of 138) and 88.9% (48 of 54) achieved SVR12, respectively. Among patients receiving elbasvir/grazoprevir for 12 weeks, addition of ribavirin did not increase the proportion of treatment-naïve patients (90.3%, 28 of 31) or treatment-experienced patients who achieved an SVR12 (91.4%, 74 of 81). All (49 of 49) treatment-experienced patients receiving elbasvir/grazoprevir with ribavirin for 16 or 18 weeks, and 93.9% (46 of 49) of patients receiving elbasvir/grazoprevir without ribavirin for 16 or 18 weeks achieved SVR12. Virologic failure was higher among patients with HCV genotype 1a infections compared with patients with genotype 1b or 4 infections, particularly in patients who had not responded to previous interferon therapy. Baseline tests for resistance-associated substitutions (RASs) led to an individualized approach for selecting treatment duration and established a need for ribavirin for patients with HCV genotype 1a infection and RASs, regardless of treatment history. Among patients with HCV genotype 1a infection with and without baseline RASs in HCV nonstructural protein 5A who received elbasvir/grazoprevir for 12 weeks, 73% (8 of 11) and 98% (96 of 98) achieved SVR12, respectively. Both patients with HCV genotype 1a infection with baseline RASs who received 16 or 18 weeks of elbasvir/grazoprevir and ribavirin achieved SVR12. Grade 3 or 4 increases in levels of alanine aminotransferase and aspartate aminotransferase, which did not cause symptoms, were reported in 2.3% (6 of 264) of patients receiving elbasvir/grazoprevir. Serious adverse events were reported in 3% (8 of 264) patients and no patient had a decompensation-related event. CONCLUSIONS: In an analysis of data from 6 clinical trials, rates of SVR12 ranged from 89% to 100% in patients with HCV genotype 1, 4, or 6 infections and compensated cirrhosis treated with elbasvir/grazoprevir, with or without ribavirin. Addition of ribavirin to a 12-week regimen of elbasvir/grazoprevir had little effect on the proportion of treatment-naïve or treatment-experienced patients who achieved an SVR12. However, virologic failure did not occur in any treatment-experienced patients when the duration of elbasvir/grazoprevir and ribavirin therapy was extended to 16 or 18 weeks. Baseline analysis of RASs (or in the absence of this test, a history of nonresponse to interferon) can be used to determine treatment duration and the need for ribavirin in patients with HCV genotype 1a infection. Clinicaltrials.gov ID: NCT02092350, NCT02105662, NCT02105467, NCT02105701, NCT01717326, and NCT02105454.

20 Article The cost-effectiveness of testing for NS5a resistance-associated polymorphisms at baseline in genotype 1a-infected (treatment-naïve and treatment-experienced) subjects treated with all-oral elbasvir/grazoprevir regimens in the United States. 2017

Elbasha, E H / Robertson, M N / Nwankwo, C. ·Merck & Co., Inc., Kenilworth, NJ, USA. ·Aliment Pharmacol Ther · Pubmed #27910116.

ABSTRACT: BACKGROUND: The presence of baseline NS5A resistance-associated variants (RAVs) impacted treatment response in HCV genotype 1a (GT1a)-infected patients treated with elbasvir/grazoprevir (EBR/GZR) for 12 weeks, but not patients treated with EBR/GZR and ribavirin (RBV) for 16 weeks. AIMS: To assess the cost-effectiveness of baseline testing for NS5A RAVs in EBR/GZR-treated patients compared without testing, and with current treatments for GT1a patients. METHODS: We simulated the course of treatment with EBR/GZR, ledipasvir/sofosbuvir (LDV/SOF) and ombitasvir/paritaprevir/ritonavir+dasabuvir (3D) with or without RBV and natural history of disease of GT1a patients. Treatment-related data from clinical trials were used in a state-transition model of the natural history of chronic HCV GT1a infection and liver disease to project lifetime costs (US$2015) and quality-adjusted life years (QALY). Other clinical and economic inputs were estimated from published sources. We conducted base case and sensitivity analyses. RESULTS: RAVs testing-guided treatment with EBR/GZR resulted in more QALYs than EBR/GZR without testing, 3D+RBV, or LDV/SOF8. This strategy was cost-saving relative to 3D+RBV or LDV/SOF8 and was cost-effective compared with EBR/GZR without testing. LDV/SOF12 was not cost-effective compared with the EBR/GZR RAVs testing-based strategy. Treatment with EBR/GZR guided by RAVs testing is the most effective regimen among treatment-experienced patients without cirrhosis and cirrhotic patients. In sensitivity analysis, RAVs testing was cost-effective in 48-55% and 63-85% among noncirrhotic and cirrhotic patients respectively. CONCLUSIONS: RAVs testing before treatment with EBR/GZR is likely to be a cost-effective alternative to the use of EBR/GZR without testing, LDV/SOF, or 3D among GT1a treatment-naïve or treatment-experienced patients.

21 Article Short-duration treatment with elbasvir/grazoprevir and sofosbuvir for hepatitis C: A randomized trial. 2017

Lawitz, Eric / Poordad, Fred / Gutierrez, Julio A / Wells, Jennifer T / Landaverde, Carmen E / Evans, Barbara / Howe, Anita / Huang, Hsueh-Cheng / Li, Jerry Jing / Hwang, Peggy / Dutko, Frank J / Robertson, Michael / Wahl, Janice / Barr, Eliav / Haber, Barbara. ·Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX. · Merck & Co., Inc, Kenilworth, NJ. ·Hepatology · Pubmed #27770561.

ABSTRACT: Direct-acting antiviral agents (DAAs) represent the standard of care for patients with hepatitis C virus (HCV) infection. Combining DAAs with different mechanisms may allow for shorter treatment durations that are effective across multiple genotypes. The aim of the C-SWIFT study was to identify the minimum effective treatment duration across multiple genotypes. C-SWIFT was an open-label, single-center trial in treatment-naïve patients with chronic HCV genotype (GT)1 or 3 infection. All patients received elbasvir (EBR) 50 mg/grazoprevir (GZR) 100 mg with sofosbuvir (SOF) 400 mg for 4-12 weeks. Patients with GT1 infection who failed therapy were eligible for retreatment with EBR/GZR+SOF and ribavirin for 12 weeks. The primary efficacy endpoint was sustained virological response [SVR]12 (SVR of HCV RNA <15 IU/mL 12 weeks after the end of therapy). Rates of SVR12 were 32% (10 of 31) and 87% (26 of 30) in patients without cirrhosis with GT1 infection treated for 4 and 6 weeks and 80% (16 of 20) and 81% (17 of 21) in GT1-infected patients with cirrhosis treated for 6 and 8 weeks. Among GT3-infected patients without cirrhosis, SVR12 was 93% (14 of 15) and 100% (14 of 14) after 8 and 12 weeks. SVR12 in GT3-infected patients with cirrhosis was 83% (10 of 12) after 12 weeks of treatment. Twenty-three GT1-infected patients who relapsed following initial treatment completed retreatment; all achieved SVR12. In the initial treatment phase, there was one serious adverse event of pneumonia, which led to treatment discontinuation, and during retreatment, 1 patient discontinued ribavirin because of pruritus. CONCLUSION: Data from this study support the use of 8-week treatment regimens that maintain high efficacy, even for patients with HCV GT3 infection. Retreatment of patients who failed short-duration therapy was achieved through extended treatment duration and addition of ribavirin. (Hepatology 2017;65:439-450).

22 Article Elbasvir-Grazoprevir to Treat Hepatitis C Virus Infection in Persons Receiving Opioid Agonist Therapy: A Randomized Trial. 2016

Dore, Gregory J / Altice, Frederick / Litwin, Alain H / Dalgard, Olav / Gane, Edward J / Shibolet, Oren / Luetkemeyer, Anne / Nahass, Ronald / Peng, Cheng-Yuan / Conway, Brian / Grebely, Jason / Howe, Anita Y M / Gendrano, Isaias N / Chen, Erluo / Huang, Hsueh-Cheng / Dutko, Frank J / Nickle, David C / Nguyen, Bach-Yen / Wahl, Janice / Barr, Eliav / Robertson, Michael N / Platt, Heather L / Anonymous13430878. ·From The Kirby Institute, UNSW Australia, Sydney, Australia; Yale School of Medicine, New Haven, Connecticut; Montefiore Medical Center, Bronx, New York; Akershus University Hospital, Lorenskog, Norway; Auckland Clinical Studies, Auckland, New Zealand; Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; University of California, San Francisco, San Francisco, California; ID Care, Hillsborough, New Jersey; China Medical University, Taichung, Taiwan; Vancouver Infectious Diseases Centre, Vancouver, British Columbia, Canada; and Merck & Co., Kenilworth, New Jersey. ·Ann Intern Med · Pubmed #27537841.

ABSTRACT: Background: Hepatitis C virus (HCV) infection is common in persons who inject drugs (PWID). Objective: To evaluate elbasvir-grazoprevir in treating HCV infection in PWID. Design: Randomized, placebo-controlled, double-blind trial. (ClinicalTrials.gov: NCT02105688). Setting: Australia, Canada, France, Germany, Israel, the Netherlands, New Zealand, Norway, Spain, Taiwan, the United Kingdom, and the United States. Patients: 301 treatment-naive patients with chronic HCV genotype 1, 4, or 6 infection who were at least 80% adherent to visits for opioid agonist therapy (OAT). Intervention: The immediate-treatment group (ITG) received elbasvir-grazoprevir for 12 weeks; the deferred-treatment group (DTG) received placebo for 12 weeks, no treatment for 4 weeks, then open-label elbasvir-grazoprevir for 12 weeks. Measurements: The primary outcome was sustained virologic response at 12 weeks (SVR12), evaluated separately in the ITG and DTG. Other outcomes included SVR24, viral recurrence or reinfection, and adverse events. Results: The SVR12 was 91.5% (95% CI, 86.8% to 95.0%) in the ITG and 89.5% (95% CI, 81.5% to 94.8%) in the active phase of the DTG. Drug use at baseline and during treatment did not affect SVR12 or adherence to HCV therapy. Among 18 patients with posttreatment viral recurrence through 24-week follow-up, 6 had probable reinfection. If the probable reinfections were assumed to be responses, SVR12 was 94.0% (CI, 89.8% to 96.9%) in the ITG. One patient in the ITG (1 of 201) and 1 in the placebo-phase DTG (1 of 100) discontinued treatment because of an adverse event. Limitation: These findings may not be generalizable to PWID who are not receiving OAT, nor do they apply to persons with genotype 3 infection, a common strain in PWID. Conclusion: Patients with HCV infection who were receiving OAT and treated with elbasvir-grazoprevir had high rates of SVR12, regardless of ongoing drug use. These results support the removal of drug use as a barrier to interferon-free HCV treatment for patients receiving OAT. Primary Funding Source: Merck & Co.

23 Article Efficacy and safety of grazoprevir + ribavirin for 12 or 24 weeks in treatment-naïve patients with hepatitis C virus genotype 1 infection. 2016

Gane, E / Ben Ari, Z / Mollison, L / Zuckerman, E / Bruck, R / Baruch, Y / Howe, A Y M / Wahl, J / Bhanja, S / Hwang, P / Zhao, Y / Robertson, M N. ·Auckland Clinical Studies, Auckland, New Zealand. edgane@adhb.govt.nz. · Liver Disease Center, Sheba Medical Center, Ramat Gan, Israel. · The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. · Fremantle Hepatitis Services, Fremantle Hospital, Fremantle, WA, Australia. · Liver Unit, Carmel Medical Center Technion Faculty of Medicine, Haifa, Israel. · Department of Gastroenterology and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. · Liver Unit, Rambam Healthcare Campus and the Technion Faculty of Medicine, Haifa, Israel. · Merck & Co., Inc., Kenilworth, NJ, USA. ·J Viral Hepat · Pubmed #27291249.

ABSTRACT: Grazoprevir (GZR) is a second-generation hepatitis C virus NS3/4A protease inhibitor. The aim of this study was to evaluate GZR plus ribavirin (RBV) in patients with HCV GT1 infection. Noncirrhotic, IL28B CC patients with HCV genotype 1 infection were randomized to GZR 100 mg once daily and RBV for 12 or 24 weeks. Patients in the 12-week arm with detectable HCV RNA at treatment week 4 (TW4) had treatment extended to 24 weeks (response-guided therapy, RGT). The primary endpoint was sustained virologic response (SVR12) at follow-up week 12 (HCV RNA <25 IU/mL) in the per-protocol (PP) population (excluding patients with important protocol deviations). Twenty-six patients were randomized and 22 were included in the PP population. SVR12 was 58.3% (7 of 12) and 90% (9 of 10) in the RGT and 24-week arms, respectively. Seven PP patients had virologic failure, including one patient in the 24-week arm who relapsed after follow-up week 12. All three breakthrough patients had wild-type (WT) virus at baseline and developed breakthrough at TW6 or TW12 with Y56H, A156T and D168A/N mutations. Of the five relapse patients, four had WT at baseline (at relapse three had WT and one had V55A and D168A), and one had S122A/T at baseline and S122T at relapse. There were no serious adverse events (AEs), discontinuations due to AEs or grade 3/4 elevations in total and/or direct bilirubin. Grazoprevir plus RBV was associated with a rapid and sustained suppression of HCV RNA. These results support further evaluation of grazoprevir-based regimens (NCT01716156; protocol P039).

24 Article Grazoprevir and elbasvir plus ribavirin for chronic HCV genotype-1 infection after failure of combination therapy containing a direct-acting antiviral agent. 2015

Forns, Xavier / Gordon, Stuart C / Zuckerman, Eli / Lawitz, Eric / Calleja, Jose L / Hofer, Harald / Gilbert, Christopher / Palcza, John / Howe, Anita Y M / DiNubile, Mark J / Robertson, Michael N / Wahl, Janice / Barr, Eliav / Buti, Maria. ·Liver Unit, Hospital Clinic, IDIBAPS and CIBEREHD, Barcelona, Spain. Electronic address: xforns@clinic.ub.es. · Henry Ford Health System, Detroit, MI, USA. · Carmel Medical Center, Haifa, Israel. · The Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, USA. · Servicio de Gastroenterología y Hepatología, Hospital Universitario Puerta de Hierro, Universidad Autonoma de Madrid, Madrid, Spain. · Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria. · Merck and Co., Inc., Kenilworth, NJ, USA. · Hospital Universitario Valle Hebron and Ciberehd, Barcelona, Spain. ·J Hepatol · Pubmed #25895428.

ABSTRACT: BACKGROUND & AIMS: The Phase-2 C-SALVAGE study evaluated an investigational interferon-free combination of grazoprevir (a NS3/4A protease inhibitor) and elbasvir (a NS5A inhibitor) with ribavirin for patients with chronic HCV genotype-1 infection who had failed licensed DAA-containing therapy. METHODS: C-SALVAGE was an open-label study of grazoprevir 100 mg and elbasvir 50 mg QD with weight-based ribavirin BID for 12 weeks in cirrhotic and non-cirrhotic patients with chronic HCV genotype-1 infection who had not attained SVR after ⩾4 weeks of peginterferon and ribavirin plus either boceprevir, telaprevir, or simeprevir. Exclusion criteria included decompensated liver disease, hepatocellular carcinoma, and HIV or HBV co-infection. The primary efficacy outcome was SVR12 defined as a HCV RNA level below the assay limit of quantification 12 weeks after the end of treatment. RESULTS: Of the 79 patients treated with ⩾1 dose of study drug, 66 (84%) patients had a history of virologic failure on a regimen containing a NS3/4A protease inhibitor; 12 of the other 13 patients discontinued prior treatment because of adverse experiences. At entry, 34 (43.6%) of 78 evaluable patients harbored NS3 RAVs. SVR12 rates were 76/79 (96.2%) overall, including 28/30 (93.3%) patients with genotype 1a infection, 63/66 (95.5%) patients with prior virologic failure, 43/43 (100%) patients without baseline RAVs, 31/34 (91.2%) patients with baseline NS3 RAVs, 6/8 (75.0%) patients with baseline NS5A RAVs, 4/6 (66.7%) patients with both baseline NS3 and RAVs, and 32/34 (94.1%) cirrhotic patients. None of the five reported serious adverse events were considered drug-related. CONCLUSIONS: Grazoprevir and elbasvir plus ribavirin for 12 weeks provides a promising new treatment option for patients after failure of triple therapy containing an earlier-generation protease inhibitor.