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Hepatitis: HELP
Articles by Diana M. Brainard
Based on 96 articles published since 2008
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Between 2008 and 2019, D. Brainard wrote the following 96 articles about Hepatitis.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4
1 Review Clinical Pharmacokinetics and Pharmacodynamics of Ledipasvir/Sofosbuvir, a Fixed-Dose Combination Tablet for the Treatment of Hepatitis C. 2016

German, Polina / Mathias, Anita / Brainard, Diana / Kearney, Brian P. ·Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA, 94404, USA. polina.german@gilead.com. · Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA, 94404, USA. ·Clin Pharmacokinet · Pubmed #27193156.

ABSTRACT: Ledipasvir/sofosbuvir (Harvoni

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

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

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

3 Clinical Trial Ledipasvir/sofosbuvir with or without ribavirin for 8 or 12 weeks for the treatment of HCV genotype 4 infection: results from a randomised phase III study in Egypt. 2019

Shiha, Gamal / Esmat, Gamal / Hassany, Mohamed / Soliman, Reham / Elbasiony, Mohamed / Fouad, Rabab / Elsharkawy, Aisha / Hammad, Radi / Abdel-Razek, Wael / Zakareya, Talaat / Kersey, Kathryn / Massetto, Benedetta / Osinusi, Anu / Lu, Sophia / Brainard, Diana M / McHutchison, John G / Waked, Imam / Doss, Wahid. ·Internal Medicine Department, Mansoura University, Mansoura, Egypt. · Egyptian Liver Research Institute and Hospital (ELRIAH), Mansoura, Egypt. · Endemic Medicine and Hepatogastroenterology Department, Faulty of Medicine, Cairo University, Cairo, Egypt. · National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt. · Tropical Medicine, Port Said University, Port Said, Egypt. · National Liver Institute-Menoufia University, Shebeen El Kom, Egypt. · Gilead Sciences, Foster City, California, USA. ·Gut · Pubmed #29666174.

ABSTRACT: OBJECTIVE: We evaluated the efficacy and safety of ledipasvir/sofosbuvir alone and with ribavirin for 8 and 12 weeks in Egyptian patients with and without cirrhosis, who were infected with hepatitis C virus (HCV) genotype 4, including those who had failed previous treatment with sofosbuvir regimens. DESIGN: In this open-label, multicentre, phase III study, treatment-naive patients were randomised to receive 8 or 12 weeks of ledipasvir/sofosbuvir±ribavirin. Interferon treatment-experienced patients were randomised to receive 12 weeks of ledipasvir/sofosbuvir±ribavirin, while sofosbuvir-experienced or ledipasvir/sofosbuvir-experienced patients received 12 weeks of ledipasvir/sofosbuvir+ribavirin. Randomisation was stratified by cirrhosis status. The primary endpoint was sustained virological response 12 weeks post-treatment (SVR12). RESULTS: We enrolled 255 patients from four centres in Egypt. Among treatment-naive patients, SVR12 rates were 95% and 90% for those receiving 8 weeks of ledipasvir/sofosbuvir alone and with ribavirin, respectively, and 98% for those receiving 12 weeks of ledipasvir/sofosbuvir both alone and with ribavirin. Among interferon-experienced patients, SVR rates were 94% for those receiving 12 weeks of ledipasvir/sofosbuvir and 100% for those receiving 12 weeks of ledipasvir/sofosbuvir plus ribavirin. All patients previously treated with sofosbuvir regimens who received ledipasvir/sofosbuvir plus ribavirin achieved SVR12. The most common adverse events, headache and fatigue, were more common among patients receiving ribavirin. CONCLUSION: Among non-cirrhotic treatment-naive patients with HCV genotype 4, 8 weeks of ledipasvir/sofosbuvir±ribavirin was highly effective. Twelve weeks of ledipasvir/sofosbuvir±ribavirin was highly effective regardless of presence of cirrhosis or prior treatment experience, including previous treatment with sofosbuvir or ledipasvir/sofosbuvir. TRIAL REGISTRATION NUMBER: NCT02487030.

4 Clinical Trial Safety and Efficacy of Ledipasvir-Sofosbuvir With or Without Ribavirin for Chronic Hepatitis C in Children Ages 6-11. 2018

Murray, Karen F / Balistreri, William F / Bansal, Sanjay / Whitworth, Suzanne / Evans, Helen M / Gonzalez-Peralta, Regino P / Wen, Jessica / Massetto, Benedetta / Kersey, Kathryn / Shao, Jiang / Garrison, Kimberly L / Parhy, Bandita / Brainard, Diana M / Arnon, Ronen / Gillis, Lynette A / Jonas, Maureen M / Lin, Chuan-Hao / Narkewicz, Michael R / Schwarz, Kathleen / Rosenthal, Philip. ·University of Washington and Seattle Children's Hospital, Seattle, WA. · Cincinnati Children's Hospital Medical Center, Cincinnati, OH. · Kings College Hospital, London, UK. · Cook Children's Health Care System, Fort Worth, TX. · Auckland Clinical Studies and Starship Child Health, Auckland, New Zealand. · University of Florida College of Medicine and Shands Children's Hospital, Gainesville, FL. · The Children's Hospital of Philadelphia, Philadelphia, PA. · Gilead Sciences, Inc, Foster City, CA. · The Mount Sinai Hospital, New York, NY. · Monroe Carell, Jr. Children's Hospital at Vanderbilt, TN. · Boston Children's Hospital, Boston, MA. · Children's Hospital Los Angeles, Los Angeles, CA. · University of Colorado, School of Medicine and Children's Hospital of Colorado, Aurora, CO. · Johns Hopkins University School of Medicine, Baltimore, MD. · University of California San Francisco, San Francisco, CA. ·Hepatology · Pubmed #30070726.

ABSTRACT: Currently, there are no interferon-free treatments available for hepatitis C virus (HCV)-infected patients younger than 12 years. We evaluated the safety and effectiveness of the all-oral regimen ledipasvir-sofosbuvir ± ribavirin in HCV-infected children aged 6 to <12 years. In an open-label study, patients aged 6 to <12 years received ledipasvir 45 mg-sofosbuvir 200 mg as two fixed-dose combination tablets 22.5/100 mg once daily, with or without ribavirin, for 12 or 24 weeks, depending on HCV genotype and cirrhosis status. The primary efficacy endpoint was sustained virologic response 12 weeks after therapy (SVR12). Twelve patients underwent intensive pharmacokinetic sampling to confirm the appropriateness of the ledipasvir and sofosbuvir dosages. Ninety-two patients were enrolled (88 genotype 1, 2 genotype 3, and 2 genotype 4), with a median age of 9 years (range, 6-11). Most were perinatally infected (97%) and treatment-naive (78%). Two were confirmed to have cirrhosis, while the degree of fibrosis was unknown in 55 patients. The overall SVR12 rate was 99% (91/92; 95% confidence interval, 94%-100%). The single patient not reaching SVR relapsed 4 weeks after completing 12 weeks of treatment. The most common adverse events were headache and pyrexia. One patient had three serious adverse events, which were considered to be not related to study treatment: tooth abscess, abdominal pain, and gastroenteritis. The area under the concentration-time curve and maximum concentration values for sofosbuvir, its primary metabolite GS-331007, and ledipasvir were within predefined pharmacokinetic equivalence boundaries (50%-200%) compared to values in adults in phase 2/3 of the ledipasvir and sofosbuvir studies. Conclusion: Ledipasvir-sofosbuvir was well tolerated and highly effective in children 6 to <12 years old with chronic HCV.

5 Clinical Trial Sofosbuvir-velpatasvir plus ribavirin in Japanese patients with genotype 1 or 2 hepatitis C who failed direct-acting antivirals. 2018

Izumi, Namiki / Takehara, Tetsuo / Chayama, Kazuaki / Yatsuhashi, Hiroshi / Takaguchi, Koichi / Ide, Tatsuya / Kurosaki, Masayuki / Ueno, Yoshiyuki / Toyoda, Hidenori / Kakizaki, Satoru / Tanaka, Yasuhito / Kawakami, Yoshiiku / Enomoto, Hirayuki / Ikeda, Fusao / Jiang, Deyuan / De-Oertel, Shampa / McNabb, Brian L / Camus, Gregory / Stamm, Luisa M / Brainard, Diana M / McHutchison, John G / Mochida, Satoshi / Mizokami, Masashi. ·Musashino Red Cross Hospital, Tokyo, Japan. izumi012@musashino.jrc.or.jp. · Osaka University Hospital, Osaka, Japan. · Hiroshima University Hospital, Hiroshima, Japan. · Nagasaki Medical Center, Nagasaki, Japan. · Kagawa Prefectural Central Hospital, Kagawa, Japan. · Kurume University Hospital, Fukuoka, Japan. · Musashino Red Cross Hospital, Tokyo, Japan. · Yamagata University Hospital, Yamagata, Japan. · Ogaki Municipal Hospital, Gifu, Japan. · Gunma University Hospital, Gunma, Japan. · Nagoya City University Hospital, Aichi, Japan. · Hyogo College of Medicine Hospital, Hyogo, Japan. · Okayama University Hospital, Okayama, Japan. · Gilead Sciences, Inc., Foster City, CA, USA. · Saitama Medical University Hospital, Saitama, Japan. · National Center for Global Health and Medicine, Chiba, Japan. ·Hepatol Int · Pubmed #30030720.

ABSTRACT: BACKGROUND/PURPOSE: In Japan, there is a growing population of patients with chronic hepatitis C virus (HCV) infection who failed a direct-acting antiviral (DAA)-based regimen. In this Phase 3 study, we evaluated sofosbuvir-velpatasvir plus ribavirin in Japanese patients with genotype 1 or 2 HCV infection who previously received DAAs. METHODS: Patients were randomized 1:1 to receive sofosbuvir-velpatasvir plus ribavirin for 12 or 24 weeks. Randomization was stratified by HCV genotype and presence of cirrhosis. The primary endpoint was sustained virologic response 12-week post-treatment (SVR12). RESULTS: Of 117 participants, 81% had HCV genotype 1 infection, 33% had cirrhosis, and 95% had NS5A resistance-associated substitutions (RAS) at baseline. Overall, SVR12 rates were 97% (58/60; 95% CI 88-100%) with 24 weeks of treatment and 82% (47/57; 95% CI 70-91%) with 12 weeks. For HCV genotype 1 and 2 infected patients, the SVR12 rates with 24 weeks of treatment were 98% and 92%, respectively. In both treatment groups, SVR12 rates in HCV genotype 1 patients were statistically superior to a historical control rate of 50% (p < 0.001). For patients with NS5A RASs at baseline, 85% (46/54) in the 12-week group and 96% (54/56) in the 24-week group achieved SVR12. The most common adverse events were upper respiratory tract viral infection, anemia, and headache. Three (2.6%) patients discontinued treatment because of adverse events. CONCLUSION: Sofosbuvir-velpatasvir plus ribavirin was highly effective and well tolerated in Japanese patients who previously failed a DAA-based regimen. Baseline NS5A RASs did not affect treatment outcomes.

6 Clinical Trial Efficacy of Sofosbuvir and Velpatasvir, With and Without Ribavirin, in Patients With Hepatitis C Virus Genotype 3 Infection and Cirrhosis. 2018

Esteban, Rafael / Pineda, Juan A / Calleja, Jose Luis / Casado, Marta / Rodríguez, Manuel / Turnes, Juan / Morano Amado, Luis Enrique / Morillas, Rosa Maria / Forns, Xavier / Pascasio Acevedo, Juan Manuel / Andrade, Raul J / Rivero, Antonio / Carrión, José Antonio / Lens, Sabela / Riveiro-Barciela, Mar / McNabb, Brian / Zhang, Gulan / Camus, Gregory / Stamm, Luisa M / Brainard, Diana M / Subramanian, G Mani / Buti, Maria. ·Hospital Universitario Vall d'Hebron and CIBERehd del Instituto Carlos III, Barcelona, Spain. Electronic address: resteban@vhebron.net. · Unit of Infectious Diseases and Microbiology, Hospital Universitario Virgen de Valme, Sevilla, Spain. · Liver Unit, Hospital Universitario Puerta de Hierro, Majadahonda, Spain, and Universidad Autónoma de Madrid, Madrid, Spain, and CIBERehd. · Complejo Hospitalario Torrecárdenas, Almeria, Spain. · Hospital Universitario Central de Asturias, Oviedo, Spain. · Gastroenterology and Hepatology Department, Complejo Hospitalario Universitario de Pontevedra and IISGS, Pontevedra, Spain. · Unit of Infectious Diseases, University Hospital Alvaro Cunqueiro, Institute of Health Research Galicia Sur, Vigo, Spain. · Hospital Universitari Germans Trias i Pujol, Badalona, Spain, and CIBERehd. · Liver Unit, Hospital Clínic Barcelona, and University of Barcelona, and IDIBAPS, and CIBERehd. · Clinical Management Unit of Digestive Diseases, IBIS, CIBERehd, Hospital Universitario Virgen del Rocío, Sevilla, Spain. · Unidad de Gestión Clínica de Enfermedades Digestivas, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, and IBIMA, and CIBERehd. · Hospital Universitario Reina Sofia/IMIBIC/UCO, Cordoba, Spain. · Liver Section, Gastroenterology Department, Hospital del Mar, Universitat Autònoma de Barcelona, IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain. · Liver Unit Department of Internal Medicine, Hospital Universitari Vall d'Hebron and Universitat Autònoma de Barcelona, Barcelona, Spain, and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain. · Gilead Sciences, Inc, Foster City, California. · Hospital Universitario Vall d'Hebron and CIBERehd del Instituto Carlos III, Barcelona, Spain. ·Gastroenterology · Pubmed #29958855.

ABSTRACT: BACKGROUND & AIMS: In phase 3 trials and real-world settings, smaller proportions of patients with genotype 3 hepatitis C virus (HCV) infection and cirrhosis have a sustained virologic response 12 weeks after treatment (SVR12) with the combination of sofosbuvir and velpatasvir than in patients without cirrhosis. It is unclear whether adding ribavirin to this treatment regimen increases SVRs in patients with genotype 3 HCV infection and cirrhosis. METHODS: We performed a phase 2 trial of 204 patients with genotype 3 HCV infection and compensated cirrhosis (mean age 51 ± 7.4 years) at 29 sites in Spain from August 19, 2016 through April 18, 2017. Patients were assigned to groups given sofosbuvir and velpatasvir for 12 weeks (n = 101) or sofosbuvir and velpatasvir plus ribavirin for 12 weeks (n = 103). The primary efficacy end point was SVR12. RESULTS: The overall rates of SVR12 were 91% (92 of 101; 95% CI 84-96) for the sofosbuvir-velpatasvir group and 96% (99 of 103; 95% CI 90-99) for the sofosbuvir-velpatasvir plus ribavirin group. In the sofosbuvir-velpatasvir group, a smaller proportion of patients with baseline resistance-associated substitutions (RASs) in nonstructural protein 5A (NS5A) achieved an SVR12 (84%) than did patients without (96%). In the sofosbuvir-velpatasvir plus ribavirin group, baseline RASs had less effect on the proportion of patients with an SVR12 (96% for patients with baseline RASs; 99% for patients without). The most common adverse events (which occurred in ≥10% of patients) were asthenia (12%) in the sofosbuvir-velpatasvir group and asthenia (27%), headache (24%), and insomnia (12%) in the sofosbuvir-velpatasvir plus ribavirin group. CONCLUSIONS: Consistent with findings from previous studies, a high rate of patients (91% and 96%) with genotype 3 HCV infection and compensated cirrhosis achieved an SVR12 with sofosbuvir and velpatasvir, with or without ribavirin. Of patients treated with sofosbuvir and velpatasvir without ribavirin, fewer patients with baseline NS5A RASs achieved an SVR12 compared with patients without baseline NS5A. ClinicalTrials.govNCT02781558.

7 Clinical Trial Deferred treatment with sofosbuvir-velpatasvir-voxilaprevir for patients with chronic hepatitis C virus who were previously treated with an NS5A inhibitor: an open-label substudy of POLARIS-1. 2018

Bourlière, Marc / Gordon, Stuart C / Schiff, Eugene R / Tran, Tram T / Ravendhran, Natarajan / Landis, Charles S / Hyland, Robert H / Stamm, Luisa M / Zhang, Jie / Dvory-Sobol, Hadas / Subramanian, G Mani / Brainard, Diana M / McHutchison, John G / Serfaty, Lawrence / Thompson, Alex J / Sepe, Thomas E / Curry, Michael P / Reddy, K Rajender / Manns, Michael P. ·Hépato-Gastroentérologie, Hôpital Saint Joseph, Marseille, France. Electronic address: mbourliere@hopital-saint-joseph.fr. · Henry Ford Health System, Detroit, MI, USA. · Schiff Center for Liver Diseases, University of Miami, Coral Gables, FL, USA. · Cedars-Sinai Medical Center, Los Angeles, CA, USA. · Digestive Disease Associates, Catonsville, MD, USA. · Division of Gastroenterology and Hepatology, Department of Medicine, University of Washington, Seattle, WA, USA. · Gilead Sciences, Foster City, CA, USA. · Service d'Hépatologie, Hôpital Saint-Antoine, Paris, France. · St Vincent's Hospital and the University of Melbourne, Melbourne, Fitzroy, VIC, Australia. · Liver Center, University Gastroenterology, Providence, RI, USA. · Beth Israel Deaconess Medical Center, Boston, MA, USA. · Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA. · Medizinischen Hochschule, Hannover, Germany. ·Lancet Gastroenterol Hepatol · Pubmed #29859740.

ABSTRACT: BACKGROUND: Direct-acting antiviral regimens containing NS5A inhibitors are highly effective treatments for chronic hepatitis C virus (HCV) infection, but are not always successful. In the POLARIS-1 phase 3 study, sofosbuvir-velpatasvir-voxilaprevir for 12 weeks was highly effective in the treatment of chronic HCV infection in patients previously treated with a direct-acting antiviral regimen containing an NS5A inhibitor. We aimed to assess the efficacy and safety of sofosbuvir-velpatasvir-voxilaprevir in patients from the deferred treatment group of POLARIS-1, who were initially assigned to masked placebo treatment. METHODS: This open-label, deferred treatment substudy was done at 73 clinical sites (hospitals and clinics) in the USA, France, Canada, the UK, Germany, Australia, and New Zealand. Patients who received placebo in the primary study and who did not have a new clinically significant illness at the post-treatment week 4 assessment were eligible to enter this substudy. Participants received a combination tablet of sofosbuvir (400 mg), velpatasvir (100 mg), and voxilaprevir (100 mg) once daily for 12 weeks. The primary efficacy outcome was achievement of sustained virological response (defined as HCV RNA concentration below the lower limit of quantification) 12 weeks after the end of treatment (SVR12). The primary safety outcome was the proportion of patients who discontinued treatment due to adverse events. This study is registered with ClinicalTrials.gov, number NCT02607735, and the EU Clinical Trials Register, number 2015-003455-21. FINDINGS: 152 patients received placebo in the primary study and were potentially eligible for participation in the open-label substudy, of whom 147 were enrolled from March 30, 2016, to Oct 12, 2016. All 147 patients completed treatment, and 143 (97%; 95% CI 93-99) achieved SVR12. Four (3%) patients had virological relapse; all had HCV genotype 1a infection and one also had compensated cirrhosis. The most common adverse events were fatigue (31 [21%]), headache (29 [20%]), diarrhoea (28 [19%]), and nausea (21 [14%]). No deaths, treatment discontinuations, or treatment-related serious adverse events occurred. INTERPRETATION: Supporting the results from the blinded portion of the phase 3 primary study, the single-tablet regimen of sofosbuvir-velpatasvir-voxilaprevir for 12 weeks was safe, well tolerated, and highly effective in patients with chronic HCV infection who had previous treatment failure with NS5A inhibitor-containing regimens. A salvage regimen for this population represents an important advance for patients with limited retreatment options. FUNDING: Gilead Sciences.

8 Clinical Trial Ledipasvir/sofosbuvir for treatment-naive and treatment-experienced Chinese patients with genotype 1 HCV: an open-label, phase 3b study. 2018

Wei, Lai / Xie, Qing / Hou, Jin Lin / Tang, Hong / Ning, Qin / Cheng, Jun / Nan, Yuemin / Zhang, Lunli / Li, Jun / Jiang, Jianning / McNabb, Brian / Zhang, Fangqiu / Camus, Gregory / Mo, Hongmei / Osinusi, Anu / Brainard, Diana M / Gong, Guozhong / Mou, Zhuangbo / Wu, Shanming / Wang, Guiqiang / Hu, Peng / Gao, Yanhang / Jia, Jidong / Duan, Zhongping. ·Beijing Key Lab for Hepatitis C and Immunologic Liver Disease, Peking University Hepatology Institute, Peking University People's Hospital, 11 Xizhimen S St, Xicheng District, Beijing, 100044, China. weilai@pkuph.edu.cn. · Ruijin Hospital, Shanghai Jiaotong University, Shanghai, China. · Nanfang Hospital of Southern Medical University, Guangzhou, China. · West China Hospital, Sichuan University, Chengdu, China. · Tongji Hospital of Tongji Medical College, Huanzhong University of Science and Technology, Wuhan, China. · Beijing Ditan Hospital Affiliated to Capital Medical University, Beijing, China. · The Third Hospital of Hebei Medical University, Hebei, China. · The First Affiliated Hospital of Nanchang University, Nanchang, China. · The First Affiliated Hospital with Nanjing Medical University, Nanjing, China. · The First Affiliated Hospital of Guangxi Medical University, Guangxi, China. · Gilead Sciences, Inc., Foster City, USA. · The Second Xiangya Hospital of Central South University, Changsha, China. · Jinan Infectious Disease Hospital, Jinan, China. · Clinical Center of Shanghai Public Health, Shanghai, China. · Peking University First Hospital, Beijing, China. · The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China. · The First Hospital of Jilin University, Changchun, China. · Beijing Friendship Hospital, Capital Medical University, Beijing, China. · Beijing You-An Hospital, Capital Medical University, Beijing, China. ·Hepatol Int · Pubmed #29637511.

ABSTRACT: BACKGROUND: Chronic hepatitis C virus (HCV) infection is a significant medical burden in China, affecting more than 10 million persons. In clinical trials and real-world settings, treatment with ledipasvir/sofosbuvir in patients with genotype 1 HCV infection resulted in high sustained virologic response rates. Ledipasvir/sofosbuvir may provide a highly effective, short-duration, single-tablet regimen for Chinese patients with HCV infection. METHODS: Chinese patients with genotype 1 HCV infection who were HCV treatment naive or treatment experienced, without cirrhosis or with compensated cirrhosis, were treated with open-label ledipasvir/sofosbuvir for 12 weeks. The primary efficacy endpoint was sustained virologic response 12 weeks after completing treatment (SVR12). For treatment-naive patients, SVR12 was compared to a historical rate of 57%. The primary safety endpoint was adverse events leading to permanent discontinuation of study drug; serious adverse events were also evaluated. The presence of resistance-associated substitutions (RASs) was evaluated by viral sequencing. RESULTS: All 206 enrolled patients achieved SVR12 (100%; 95% CI 98-100%), including 106 treatment-naive patients (100%; 95% CI 97-100%), which was superior to a historical SVR rate of 57% (p < 0.001). All patients with baseline NS5A and NS5B RASs (14 and 1% of patients, respectively) achieved SVR12. The most common adverse events were viral upper respiratory tract infection (17%), upper respiratory tract infection (14%), and cough (6%). There were no discontinuations due to adverse events; and no treatment-related serious adverse events were reported. CONCLUSION: Ledipasvir/sofosbuvir is a well tolerated and highly effective treatment for Chinese patients with genotype 1 HCV, regardless of prior treatment experience, cirrhosis status, or the presence of pretreatment RASs.

9 Clinical Trial Sofosbuvir plus ribavirin with or without peginterferon for the treatment of hepatitis C virus: Results from a phase 3b study in China. 2018

Wei, Lai / Xie, Qing / Hou, Jin Lin / Jia, Jidong / Li, Wu / Xu, Min / Li, Jun / Wu, Shanming / Cheng, Jun / Jiang, Jianning / Wang, Guiqiang / Yang, Yongfeng / Mou, Zhuangbo / Gao, Zhi Liang / Gong, Guozhong / Niu, Jun Qi / Hu, Peng / Tang, Hong / Lin, Feng / Dou, Xiaoguang / Li, Lanjuan / Zhang, Lun Li / Nan, Yuemin / Massetto, Benedetta / Yang, Jenny C / Knox, Steven J / Kersey, Kathryn / German, Polina / Mo, Hongmei / Jiang, Deyuan / Brainard, Diana M / Jiang, Jiaji / Ning, Qin / Duan, Zhongping. ·Peking University People's Hospital, Beijing, China. · Shanghai Jiaotong University Ruijin Hospital, Shanghai, China. · Nanfang Hospital of Southern Medical University, Guangzhou, China. · Beijing Friendship Hospital Affiliated with Capital Medical University, Beijing, China. · The First Affiliated Hospital of Kunming Medical University, Kunming, China. · Guangzhou Eighth People's Hospital, Guangzhou, China. · First Affiliated Hospital, Nanjiang Medical University, Nanjing, China. · Clinical Center of Shanghai Public Health, Shanghai, China. · Beijing Ditan Hospital Affiliated with Capital Medical University, Beijing, China. · The First Affiliated Hospital of Guangxi Medical University, Guangxi, China. · Peking University First Hospital, Beijing, China. · The Second Hospital of Nanjing, Nanjing, China. · Jinan Infectious Disease Hospital, Jinan, China. · The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China. · The Second Xiangya Hospital of Central South University, Changsha, China. · The First Hospital of Jilin University, Changchun, China. · The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China. · West China Hospital, Sichuan University, Chengdu, China. · Hainan General Hospital, Hainan, China. · Shengjing Hospital of China Medical University, Shenyang, China. · The First Affiliated Hospital Zhejiang University Medical College, Hangzhou, China. · The First Affiliated Hospital of Nanchang University, Nanchang, China. · The Third Hospital of Hebei Medical University, Hebei, China. · Gilead Sciences, Inc., Foster City, CA, USA. · First Affiliated Hospital of Fujian Medical University, Fujian, China. · Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. · Beijing You'an Hospital Affiliated with Capital Medical University, Beijing, China. ·J Gastroenterol Hepatol · Pubmed #29380415.

ABSTRACT: BACKGROUND AND AIM: Sofosbuvir is a nucleotide analog inhibitor of the hepatitis C virus (HCV) NS5B RNA polymerase with pangenotypic potency. This phase 3b study evaluated the safety and efficacy of sofosbuvir + ribavirin ± peginterferon in Chinese patients infected with HCV genotype 1, 2, 3, or 6. METHODS: Patients with genotype 1 or 6 received sofosbuvir + peginterferon/ribavirin for 12 weeks or sofosbuvir + ribavirin for 24 weeks, depending on prior treatment and interferon eligibility. Patients with genotype 2 or 3 received sofosbuvir + ribavirin for 12 or 24 weeks, respectively. The primary endpoint was sustained virologic response at 12 weeks after the end of treatment (SVR12). RESULTS: Of 389 patients, 42% had genotype 1, 16% genotype 2, 32% genotype 3, and 9% genotype 6. Half were male, 58% were treatment-naïve, and 15% had cirrhosis. SVR12 rates for patients receiving 12 weeks of sofosbuvir + peginterferon/ribavirin were 94% (95% confidence interval [CI], 87-98%) for HCV genotype 1 and 97% (95% CI, 84-100%) for genotype 6. SVR12 rates for those receiving sofosbuvir + ribavirin for 24 weeks were 95% (95% CI, 87-99%) for genotype 1, 100% (95% CI, 40-100%) for genotype 6, and 95% (95% CI, 90-98%) for genotype 3. For genotype 2 patients receiving sofosbuvir + ribavirin for 12 weeks, the SVR12 rate was 92% (95% CI, 83-97%). Twenty patients (5%) relapsed. Ten (3%) experienced serious adverse events. Three (< 1%) discontinued treatment because of adverse events, of whom one died because of treatment-unrelated adverse events. CONCLUSIONS: Sofosbuvir-based regimens were highly effective and safe in Chinese patients with HCV genotype 1, 2, 3, or 6, suggesting sofosbuvir could serve as the backbone for HCV treatment in China irrespective of genotype.

10 Clinical Trial Ledipasvir-sofosbuvir for treating Japanese patients with chronic hepatitis C virus genotype 2 infection. 2018

Asahina, Yasuhiro / Itoh, Yoshito / Ueno, Yoshiyuki / Matsuzaki, Yasushi / Takikawa, Yasuhiro / Yatsuhashi, Hiroshi / Genda, Takuya / Ikeda, Fusao / Matsuda, Takuma / Dvory-Sobol, Hadas / Jiang, Deyuan / Massetto, Benedetta / Osinusi, Anu O / Brainard, Diana M / McHutchison, John G / Kawada, Norifumi / Enomoto, Nobuyuki. ·Tokyo Medical and Dental University, Tokyo, Japan. · Kyoto Prefectural University of Medicine, Kyoto, Japan. · Yamagata University, Yamagata, Japan. · Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan. · Iwate Medical University, Iwate, Japan. · National Hospital Organization Nagasaki Medical Center, Nagasaki, Japan. · Juntendo University Shizuoka Hospital, Shizuoka, Japan. · Okayama University, Okayama, Japan. · Gilead Sciences K.K., Tokyo, Japan. · Gilead Sciences, Inc., Foster City, CA, USA. · Osaka City University, Osaka, Japan. · University of Yamanashi, Yamanashi, Japan. ·Liver Int · Pubmed #29297980.

ABSTRACT: BACKGROUND & AIMS: Japanese patients with chronic hepatitis C virus (HCV) genotype 2 infection have high rates of sustained virological response (SVR) following 12 weeks of treatment with the nucleotide polymerase inhibitor sofosbuvir in combination with ribavirin, which was the standard of care at the time this study was undertaken. We assessed the efficacy of 12 weeks of treatment with a ribavirin-free regimen of ledipasvir-sofosbuvir. METHODS: In an open-label, Phase 3 trial we enrolled Japanese patients with chronic HCV genotype 2 infection, with or without compensated cirrhosis. In Cohort 1, participants were randomized 1:1 to receive ledipasvir-sofosbuvir (n = 106) or sofosbuvir + ribavirin (n = 108) for 12 weeks. In Cohort 2, 25 ribavirin-intolerant or -ineligible patients received ledipasvir-sofosbuvir for 12 weeks. The primary endpoint was SVR 12 weeks after therapy (SVR12). In Cohort 1 non-inferiority was assessed with a prespecified margin of 10%. RESULTS: One-third (33%) of patients were treatment experienced, and 14% had cirrhosis. In Cohort 1, SVR12 rates were 96% (95% CI, 91% to 99%) with ledipasvir-sofosbuvir and 95% (95% CI, 90% to 98%) with sofosbuvir plus ribavirin, thus achieving non-inferiority. Among ribavirin-intolerant/ineligible patients in Cohort 2, SVR12 was 96% (95% CI, 80% to 100%) with ledipasvir-sofosbuvir. Overall, the most common adverse events were nasopharyngitis, anaemia, and headache; anaemia was only observed in patients receiving ribavirin. The percentage of patients who discontinued treatment because of an adverse event was low (1%). CONCLUSIONS: Among Japanese patients with HCV genotype 2, 12 weeks of treatment with ledipasvir-sofosbuvir resulted in high rates of SVR12 that were non-inferior to sofosbuvir + ribavirin.

11 Clinical Trial Ledipasvir-Sofosbuvir for 8 Weeks in Non-Cirrhotic Patients with Previously Untreated Genotype 1 HCV Infection ± HIV-1 Co-Infection. 2018

Isakov, Vasily / Gankina, Natalia / Morozov, Viacheslav / Kersey, Kathryn / Lu, Sophia / Osinusi, Anu / Svarovskaia, Evguenia / Brainard, Diana M / Salupere, Riina / Orlova-Morozova, Elena / Zhdanov, Konstantin. ·Department of Gastroenterology and Hepatology, Federal Research Center for Nutrition, Biotechnology and Food Safety, Kashirskoe shosse, 21, Moscow, 115446, Russian Federation. vasily.isakov@gmail.com. · Clinical and Diagnostic Department, Krasnoyarsk Regional Center for Prevention and Control of AIDS and Infectious Diseases, Krasnoyarsk, Russian Federation. · Hepatolog, LLC, Samara, Russian Federation. · Clinical Research, Gilead Sciences, Foster City, CA, USA. · Department of Internal Medicine, Tartu University Hospital, Tartu, Estonia. · Moscow Regional Center for Prevention and Control of AIDS and Infectious Diseases, Moscow, Russian Federation. · Department of Infectious Diseases, Military Medical Academy, St Petersburg, Russian Federation. ·Clin Drug Investig · Pubmed #29177645.

ABSTRACT: BACKGROUND AND OBJECTIVES: The efficacy of < 12 weeks of hepatitis C virus (HCV) treatment in patients co-infected with HCV and human immunodeficiency virus type 1 (HIV-1) has not been established. We assessed the efficacy and safety of ledipasvir-sofosbuvir for 8 weeks in HCV mono-infected and HCV/HIV-1 co-infected patients. METHODS: We enrolled patients mono-infected with genotype 1 HCV or co-infected with HCV and HIV-1 who were HCV treatment-naive and did not have cirrhosis. HCV/HIV-1 co-infected patients were either not receiving antiretroviral treatment and had a CD4 T-cell count > 500 cells/mm RESULTS: The SVR12 rate was 100% (67/67) for HCV mono-infected patients and 97% (57/59) for HCV/HIV-1 co-infected patients. Two patients relapsed by the week 4 post-treatment visit. Overall, the most common adverse events were headache (52%) and upper abdominal pain (26%). There were no serious adverse events or treatment discontinuations due to adverse events. No HCV/HIV-1 co-infected patients receiving antiretroviral treatment experienced HIV virologic rebound, and no clinically meaningful changes in CD4 T-cell counts were observed in any co-infected patient. CONCLUSIONS: Non-cirrhotic, treatment-naive patients with genotype 1 HCV mono-infection and HCV/HIV-1 co-infection achieved high rates of SVR12 with 8 weeks of treatment with ledipasvir/sofosbuvir. ClinicalTrials.gov identifier: NCT02472886.

12 Clinical Trial Efficacy of Ledipasvir and Sofosbuvir Treatment of HCV Infection in Patients Coinfected With HBV. 2018

Liu, Chun-Jen / Chuang, Wan-Long / Sheen, I-Shyan / Wang, Horng-Yuan / Chen, Chi-Yi / Tseng, Kuo-Chih / Chang, Ting-Tsung / Massetto, Benedetta / Yang, Jenny C / Yun, Chohee / Knox, Steven J / Osinusi, Anu / Camus, Gregory / Jiang, Deyuan / Brainard, Diana M / McHutchison, John G / Hu, Tsung-Hui / Hsu, You-Chun / Lo, Gin-Ho / Chu, Chi-Jen / Chen, Jyh-Jou / Peng, Cheng-Yuan / Chien, Ron-Nan / Chen, Pei-Jer. ·Graduate Institute of Clinical Medicine, Hepatitis Research Center and Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan. Electronic address: cjliu@ntu.edu.tw. · Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan. · Chang Gung Memorial Hospital (CGMH), Taoyuan, Taiwan. · Mackay Memorial Hospital, Taipei, Taiwan. · Chia-Yi Christian Hospital, Chia-Yi, Taiwan. · Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chia-Yi, Taiwan. · National Cheng Kung University Hospital, Tainan, Taiwan. · Gilead Sciences, Foster City, California. · Chang Gung Memorial Hospital (CGMH), Kaohsiung, Taiwan. · Changhua Christian Hospital, Changhua, Taiwan. · E-DA Hospital, Kaohsiung, Taiwan. · Taipei Veterans General Hospital, Taipei, Taiwan. · Chi Mei Hospital, Tainan, Taiwan. · China Medical University Hospital, Taichung, Taiwan. · Chang Gung Memorial Hospital, Keelung, Taiwan. · Graduate Institute of Clinical Medicine, Hepatitis Research Center and Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan. Electronic address: peijerchen@ntu.edu.tw. ·Gastroenterology · Pubmed #29174546.

ABSTRACT: BACKGROUND & AIMS: There have been reports of reactivation of hepatitis B virus (HBV) infection during treatment of hepatitis C virus (HCV) infection with direct-acting antiviral agents. We performed a prospective study of risks and outcomes of HCV infection treatment with ledipasvir and sofosbuvir in patients with HBV infection. METHODS: We performed a phase 3b, multicenter, open-label study in Taiwan of 111 patients with HCV infection (61% HCV genotype 1, 39% HCV genotype 2 infection; 62% women, 16% with compensated cirrhosis) along with HBV infection. All but 1 were positive for the hepatitis B surface antigen (HBsAg); 1 patient who was HBsAg-positive at screening was found to be HBsAg-negative at baseline. Overall, 33% of participants had received prior treatment for HCV and 5% had previously been treated for HBV; no patient was on HBV therapy at the start of the study. All patients received a fixed-dose combination of 90 mg of the HCV NS5A inhibitor ledipasvir with 400 mg of the NS5B nucleotide analogue inhibitor sofosbuvir, once daily for 12 weeks. The primary endpoint was sustained virologic response 12 weeks after the end of therapy. RESULTS: All 111 patients (100%) achieved a sustained virologic response. Of the 37 patients with baseline HBV DNA below 20 IU/mL, 31 (84%) had at least 1 episode of quantifiable HBV DNA through posttreatment week 12. Of the 74 patients with baseline HBV DNA levels of 20 IU/mL or more, 39 (53%) had increases of HBV DNA greater than 1 log CONCLUSIONS: In a prospective study, the combination of ledipasvir and sofosbuvir for 12 weeks produced a sustained virologic response in 100% of patients with HCV infection who were coinfected with HBV. Most patients had an increase in level of HBV DNA not associated with signs or symptoms. ClinicalTrials.gov no: NCT02613871.

13 Clinical Trial Intrapatient viral diversity and treatment outcome in patients with genotype 3a hepatitis C virus infection on sofosbuvir-containing regimens. 2018

Bhardwaj, N / Ragonnet-Cronin, M / Murrell, B / Chodavarapu, K / Martin, R / Chang, S / Miller, M D / Feld, J J / Sulkowski, M / Mangia, A / Wertheim, J O / Osinusi, A / McNally, J / Brainard, D / Mo, H / Svarovskaia, E S. ·Clinical Virology, Gilead Sciences, Foster City, CA, USA. · University of California San Diego, San Diego, CA, USA. · Toronto Centre for Liver Disease, University of Toronto, Toronto, ON, Canada. · Johns Hopkins University, Baltimore, MD, USA. · Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy. ·J Viral Hepat · Pubmed #29112331.

ABSTRACT: Treatment with the direct-acting antiviral agent (DAA) sofosbuvir (SOF), an NS5B inhibitor, and velpatasvir (VEL), an NS5A inhibitor, demonstrates viral cure rates of ≥95% in hepatitis C virus (HCV) genotypes (GT) 1-6. Here, we investigated intrapatient HCV diversity in NS5A and NS5B using Shannon entropy to examine the relationship between viral diversity and treatment outcome. At baseline, HCV diversity was lowest in patients infected with HCV GT3 as compared to the other GTs, and viral diversity was greater in NS5A than NS5B (P < .0001). Treatment outcome with SOF/VEL or the comparator regimen of SOF with ribavirin (RBV) was not correlated with baseline diversity. However, among persons treated with SOF/VEL, a decrease in diversity from baseline was observed at relapse in the majority virologic failures, consistent with a viral bottleneck event at relapse. In contrast, an increase in diversity was observed in 27% of SOF+RBV virologic failures. We investigated whether the increase in diversity was due to an increase in the transition rate, one mode of potential RBV-mediated mutagenesis; however, we found no evidence of this mechanism. Overall, we did not observe that viral diversity at baseline influenced treatment outcome, but the diversity changes observed at relapse can improve our understanding of RBV viral suppression in vivo.

14 Clinical Trial Nonstructural protein 5A resistance profile in patients with chronic hepatitis C treated with ledipasvir-containing regimens without sofosbuvir. 2018

Kitrinos, K M / Corsa, A C / Worth, A / Hedskog, C / Brainard, D M / Miller, M D / Mo, H. ·Gilead Sciences, Inc., Foster City, CA, USA. ·J Viral Hepat · Pubmed #28833932.

ABSTRACT: The study aimed to evaluate the effects of baseline hepatitis C virus (HCV) nonstructural protein 5A (NS5A) resistance-associated substitutions (RASs) on sustained virologic response to ledipasvir (LDV)-containing regimens in the absence of sofosbuvir (SOF) in patients with HCV genotype (GT) 1 infection across 6 phase 2 clinical studies. We analysed data from 1103 patients who received either LDV + vedroprevir (NS3 protease inhibitor) + tegobuvir (NS5B inhibitor) ± ribavirin or LDV + ribavirin + pegylated interferon. Population sequencing of HCV NS5A was performed at baseline and at virologic failure from patient plasma samples. Of 1045 patients with available baseline sequences, 747 (67.7%) had GT1a, and 298 (26.9%) had GT1b infection. The overall prevalence of NS5A RASs at baseline was 9.4%; 7.6% (57/747) and 13.8% (41/298) of patients with GT1a and GT1b infection, respectively. The majority of GT1a-infected patients with NS5A RASs at baseline had a single NS5A RAS (78.9%) at NS5A positions K24R, M28T, Q30H/L, L31M and Y93H/N/C/S. The spectrum of NS5A RASs detected in GT1b patients was much less diverse compared to GT1a patients, with all patients harbouring a single NS5A RAS either L31M or Y93H/C. For patients treated with LDV-containing regimens in the absence of SOF, the presence of baseline NS5A RASs was associated with low SVR rates. In patients with virologic failure, nearly all had either pre-existing and/or emergent NS5A RASs: 287/287 (100%) and 40/42 (95.2%) patients with GT1a and GT1b infection, respectively. Three novel NS5A substitutions were identified as emergent NS5A RASs: K26E and S38F in GT1a; and L31I in GT1b. In conclusion, the presence of NS5A RASs at baseline reduced the SVR rate in patients treated with LDV in combination vedroprevir + tegobuvir ± ribavirin or ribavirin + pegylated interferon. Virologic failure was associated with the detection of NS5A RASs in nearly all patients. These results suggest that the resistance barrier may differ depending on HCV drug combination and may be more important than that of the individual DAAs.

15 Clinical Trial Sofosbuvir, Velpatasvir, and Voxilaprevir for Previously Treated HCV Infection. 2017

Bourlière, Marc / Gordon, Stuart C / Flamm, Steven L / Cooper, Curtis L / Ramji, Alnoor / Tong, Myron / Ravendhran, Natarajan / Vierling, John M / Tran, Tram T / Pianko, Stephen / Bansal, Meena B / de Lédinghen, Victor / Hyland, Robert H / Stamm, Luisa M / Dvory-Sobol, Hadas / Svarovskaia, Evguenia / Zhang, Jie / Huang, K C / Subramanian, G Mani / Brainard, Diana M / McHutchison, John G / Verna, Elizabeth C / Buggisch, Peter / Landis, Charles S / Younes, Ziad H / Curry, Michael P / Strasser, Simone I / Schiff, Eugene R / Reddy, K Rajender / Manns, Michael P / Kowdley, Kris V / Zeuzem, Stefan / Anonymous3070908. ·From Hospital Saint Joseph, Marseille (M.B.), and University Hospital of Bordeaux, Pessac (V.L.) - both in France · Henry Ford Health System, Detroit (S.C.G.) · Northwestern University, Chicago (S.L.F.) · Ottawa Hospital Research Institute, Ottawa (C.L.C.), and St. Paul's Hospital, Vancouver, BC (A.R.) - both in Canada · Huntington Medical Research Institutes, Pasadena (M.T.), Cedars-Sinai Medical Center, Los Angeles (T.T.T.), and Gilead Sciences, Foster City (R.H.H., L.M.S., H.D.-S., E.S., J.Z., K.C.H., G.M.S., D.M.B., J.G.M.) - all in California · Digestive Disease Associates, Catonsville, MD (N.R.) · Baylor College of Medicine, Houston (J.M.V.) · Monash Health and Monash University, Clayton, VIC (S.P.), and Royal Prince Alfred Hospital, Sydney (S.I.S.) - both in Australia · Icahn School of Medicine at Mount Sinai (M.B.B.) and Columbia University Medical Center (E.C.V.) - both in New York · ifi-Institute for Interdisciplinary Medicine, Hamburg (P.B.), Hannover Medical School, Hannover (M.P.M.), and Johann Wolfgang Goethe University Medical Center, Frankfurt (S.Z.) - all in Germany · University of Washington (C.S.L.) and Swedish Medical Center (K.V.K.) - both in Seattle · Gastro One, Germantown, TN (Z.H.Y.) · Beth Israel Deaconess Medical Center, Boston (M.P.C.) · University of Miami, Miami (E.R.S.) · and University of Pennsylvania, Philadelphia (K.R.R.). ·N Engl J Med · Pubmed #28564569.

ABSTRACT: BACKGROUND: Patients who are chronically infected with hepatitis C virus (HCV) and who do not have a sustained virologic response after treatment with regimens containing direct-acting antiviral agents (DAAs) have limited retreatment options. METHODS: We conducted two phase 3 trials involving patients who had been previously treated with a DAA-containing regimen. In POLARIS-1, patients with HCV genotype 1 infection who had previously received a regimen containing an NS5A inhibitor were randomly assigned in a 1:1 ratio to receive either the nucleotide polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the protease inhibitor voxilaprevir (150 patients) or matching placebo (150 patients) once daily for 12 weeks. Patients who were infected with HCV of other genotypes (114 patients) were enrolled in the sofosbuvir-velpatasvir-voxilaprevir group. In POLARIS-4, patients with HCV genotype 1, 2, or 3 infection who had previously received a DAA regimen but not an NS5A inhibitor were randomly assigned in a 1:1 ratio to receive sofosbuvir-velpatasvir-voxilaprevir (163 patients) or sofosbuvir-velpatasvir (151 patients) for 12 weeks. An additional 19 patients with HCV genotype 4 infection were enrolled in the sofosbuvir-velpatasvir-voxilaprevir group. RESULTS: In the three active-treatment groups, 46% of the patients had compensated cirrhosis. In POLARIS-1, the rate of sustained virologic response was 96% with sofosbuvir-velpatasvir-voxilaprevir, as compared with 0% with placebo. In POLARIS-4, the rate of response was 98% with sofosbuvir-velpatasvir-voxilaprevir and 90% with sofosbuvir-velpatasvir. The most common adverse events were headache, fatigue, diarrhea, and nausea. In the active-treatment groups in both trials, the percentage of patients who discontinued treatment owing to adverse events was 1% or lower. CONCLUSIONS: Sofosbuvir-velpatasvir-voxilaprevir taken for 12 weeks provided high rates of sustained virologic response among patients across HCV genotypes in whom treatment with a DAA regimen had previously failed. (Funded by Gilead Sciences; POLARIS-1 and POLARIS-4 ClinicalTrials.gov numbers, NCT02607735 and NCT02639247 .).

16 Clinical Trial Sofosbuvir and ribavirin in adolescents 12-17 years old with hepatitis C virus genotype 2 or 3 infection. 2017

Wirth, Stefan / Rosenthal, Philip / Gonzalez-Peralta, Regino P / Jonas, Maureen M / Balistreri, William F / Lin, Chuan-Hao / Hardikar, Winita / Kersey, Kathryn / Massetto, Benedetta / Kanwar, Bittoo / Brainard, Diana M / Shao, Jiang / Svarovskaia, Evguenia / Kirby, Brian / Arnon, Ronen / Murray, Karen F / Schwarz, Kathleen B. ·Helios Medical Center, Witten/Herdecke University, Wuppertal, Germany. · University of California San Francisco, San Francisco, CA. · University of Florida College of Medicine and Shands Children's Hospital, Gainesville, FL. · Boston Children's Hospital, Boston, MA. · Cincinnati Children's Hospital Medical Center, Cincinnati, OH. · Children's Hospital Los Angeles, Los Angeles, CA. · The Royal Children's Hospital Melbourne, Parkville, VIC, Australia. · Gilead Sciences, Inc, Foster City, CA. · The Mount Sinai Hospital, New York, NY. · University of Washington School of Medicine and Seattle Children's Hospital, Seattle, WA. · Johns Hopkins University School of Medicine, Baltimore, MD. ·Hepatology · Pubmed #28543053.

ABSTRACT: Children with chronic hepatitis C virus infection have limited treatment options. We evaluated the all-oral combination of sofosbuvir and ribavirin in adolescents aged 12-17 with hepatitis C virus genotype 2 or 3 (ClinicalTrials.gov NCT02175758). Fifty-two patients received sofosbuvir 400 mg once daily and weight-based ribavirin twice daily for 12 (genotype 2) or 24 (genotype 3) weeks. The pharmacokinetics of sofosbuvir and its metabolite GS-331007 were evaluated by intensive plasma sampling at day 7 in the first 10 patients enrolled and by sparse sampling in all patients throughout treatment. The primary efficacy endpoint was the percentage of patients with a sustained virologic response 12 weeks after treatment (SVR12). The median age of patients was 15 years, and 75% had genotype 3. Eighty-three percent of patients were treatment-naive, and 73% were infected by vertical transmission. Forty percent were assessed as not having cirrhosis; the remainder did not have a cirrhosis determination. Overall, SVR12 was achieved by 98% of patients (51/52; 95% confidence interval, 90%-100%). SVR12 rates were 100% (13/13) for patients with genotype 2 and 97% (38/39) for those with genotype 3. The single patient who did not achieve SVR12 was lost to follow-up after achieving SVR4. The most commonly reported adverse events were nausea (27%) and headache (23%). When compared with the exposure in adults treated in phase 2 and 3 sofosbuvir studies, the area under the curve and maximum concentration for sofosbuvir and GS-331007 in adolescents were within predefined pharmacokinetic equivalence boundaries of 50%-200%. CONCLUSION: Sofosbuvir and ribavirin was safe and highly effective in adolescents with chronic hepatitis C virus genotype 2 or 3 infection. (Hepatology 2017;66:1102-1110).

17 Clinical Trial Ledipasvir-Sofosbuvir Plus Ribavirin in Treatment-Naive Patients With Hepatitis C Virus Genotype 3 Infection: An Open-Label Study. 2017

Feld, Jordan J / Ramji, Alnoor / Shafran, Stephen D / Willems, Bernard / Marotta, Paul / Huchet, Emmanuelle / Vachon, Marie-Louise / Svarovskaia, Evguenia S / Huang, K C / Hyland, Robert H / Yun, Chohee / Massetto, Benedetta / Brainard, Diana M / McHutchison, John G / Tam, Edward / Bailey, Robert / Cooper, Curtis / Yoshida, Eric M / Greenbloom, Susan / Elkhashab, Magdy / Borgia, Sergio / Swain, Mark G. ·Toronto Centre for Liver Disease, University of Toronto, Ontario. · GI Research Institute, Vancouver, British Columbia. · University of Alberta, Edmonton. · Centre hospitalier de l'Université de Montréal, Quebec. · London Health Sciences Centre, Ontario. · Clinique médicale l'Actuel, Montreal, Quebec. · CHU de Québec-Université Laval, Canada. · Gilead Sciences, Inc, Foster City, California. · LAIR Centre, Vancouver, British Columbia. · GI Research, Edmonton, Alberta. · Ottawa Hospital Research Institute, Ontario. · Vancouver General Hospital, British Columbia. · Toronto Digestive Disease Associates Inc, Vaughan. · Toronto Liver Centre. · William Osler Health System, Toronto, Ontario. · University of Calgary, Alberta, Canada. ·Clin Infect Dis · Pubmed #28535298.

ABSTRACT: Background: Patients chronically infected with genotype 3 hepatitis C virus (HCV) have faster disease progression and are less responsive to current direct-acting antiviral regimens than patients infected with other genotypes. We conducted an open-label trial to evaluate the safety, tolerability, and efficacy of ledipasvir and sofosbuvir plus ribavirin in patients with genotype 3 HCV infection. Methods: We enrolled treatment-naive patients with and without compensated cirrhosis at 15 sites in Canada. All patients were treated with ledipasvir-sofosbuvir (90 mg and 400 mg) plus weight-based ribavirin for 12 weeks. The primary endpoint was sustained virologic response 12 weeks after treatment (SVR12). Secondary endpoints included evaluation of baseline and treatment-emergent drug resistance. Results: Of the 111 patients enrolled, 105 (95%) had subtype 3a HCV and 39 (35%) had compensated cirrhosis. SVR12 was achieved by 99 of 111 patients (89%; 95% confidence interval, 82%-94%). Of the 39 patients with cirrhosis, 31 (79%) achieved SVR12, compared with 68 of 72 (94%) patients without cirrhosis. No treatment-emergent resistance mutations occurred in those who failed treatment. One patient discontinued treatment due to liver cancer and died 22 days after treatment discontinuation. The most common adverse events were fatigue (51%), headache (36%), and nausea (23%). Conclusions: In this multicenter trial involving treatment-naive patients with genotype 3 HCV, 12 weeks of ledipasvir-sofosbuvir provided a high level of SVR in those without cirrhosis. Clinical Trials Registration: NCT02413593.

18 Clinical Trial Sofosbuvir-velpatasvir with ribavirin for 24 weeks in hepatitis C virus patients previously treated with a direct-acting antiviral regimen. 2017

Gane, Edward J / Shiffman, Mitchell L / Etzkorn, Kyle / Morelli, Giuseppe / Stedman, Catherine A M / Davis, Mitchell N / Hinestrosa, Federico / Dvory-Sobol, Hadas / Huang, K C / Osinusi, Anu / McNally, John / Brainard, Diana M / McHutchison, John G / Thompson, Alex J / Sulkowski, Mark S / Anonymous2580906. ·Auckland Clinical Studies, Auckland, New Zealand. · Liver Institute of Virginia, Richmond, VA. · Borland Groover Clinic, Jacksonville, FL. · University of Florida, Gainesville, FL. · Christchurch Hospital and University of Otago, Christchurch, New Zealand. · South Florida Center of Gastroenterology, Wellington, FL. · Orlando Immunology Center, Orlando, FL. · Gilead Sciences, Inc, Foster City, CA. · St. Vincent's Hospital, Melbourne, Australia. · Johns Hopkins University School of Medicine, Baltimore, MD. ·Hepatology · Pubmed #28498551.

ABSTRACT: The optimal retreatment strategy for patients chronically infected with hepatitis C virus who experience virologic failure after treatment with direct-acting antiviral-based therapies remains unclear. In this multicenter, open-label, phase 2 study, we evaluated the efficacy and safety of a fixed-dose combination of sofosbuvir-velpatasvir (400 mg/100 mg) plus weight-adjusted ribavirin administered for 24 weeks in patients who did not achieve sustained virologic response after prior treatment with direct-acting antiviral regimens that included the nucleotide analogue nonstructural protein 5B inhibitor sofosbuvir plus the nonstructural protein 5A inhibitor velpatasvir with or without the nonstructural protein 3/4A protease inhibitor voxilaprevir. The primary efficacy endpoint was the proportion of patients achieving sustained virologic response at 12 weeks after the cessation of treatment. In total, 63 of 69 (91%; 95% confidence interval, 82%-97%) patients achieved sustained virologic response at 12 weeks, including 36 of 37 (97%; 95% confidence interval, 86%-100%) patients with hepatitis C virus genotype 1 infection, 13 of 14 (93%; 95% confidence interval, 66%-100%) patients with genotype 2 infection, and 14 of 18 (78%; 95% confidence interval, 52%-94%) patients with genotype 3 infection. Most adverse events were of mild or moderate severity. The most frequently reported adverse events were fatigue, nausea, headache, insomnia, and rash. One patient (1%) with genotype 1a infection discontinued all study drugs due to an adverse event (irritability). CONCLUSION: Retreatment of patients who previously failed direct-acting antiviral-based therapies with sofosbuvir-velpatasvir plus ribavirin for 24 weeks was well tolerated and effective, particularly those with hepatitis C virus genotype 1 or 2 infection. (Hepatology 2017;66:1083-1089).

19 Clinical Trial Ledipasvir-sofosbuvir for 6 weeks to treat acute hepatitis C virus genotype 1 or 4 infection in patients with HIV coinfection: an open-label, single-arm trial. 2017

Rockstroh, Jürgen K / Bhagani, Sanjay / Hyland, Robert H / Yun, Chohee / Dvory-Sobol, Hadas / Zheng, Wei / Brainard, Diana M / Ingiliz, Patrick / Lutz, Thomas / Boesecke, Christoph / Nelson, Mark. ·University Hospital, Bonn, Germany. Electronic address: juergen.rockstroh@ukb.uni-bonn.de. · Royal Free Hospital, London, UK. · Gilead Sciences, Foster City, CA, USA. · Center for Infectiology, Berlin, Germany. · Infektiologikum, Frankfurt/Main, Frankfurt, Germany. · University Hospital, Bonn, Germany. · Chelsea and Westminster Hospital NHS Foundation Trust, London, UK. ·Lancet Gastroenterol Hepatol · Pubmed #28397698.

ABSTRACT: BACKGROUND: The latest European Association for the Study of the Liver (EASL) guidelines now recommend that patients with acute hepatitis C virus (HCV) infection should be treated with a combination of sofosbuvir and an NS5A inhibitor for 8 weeks. However, the ideal duration of treatment with interferon-free regimens, particularly in HIV-coinfected individuals, remains unknown. We assessed the efficacy and safety of 6 weeks of ledipasvir-sofosbuvir for acute genotype 1 or 4 HCV in HIV-1-coinfected patients. METHODS: This open-label, single-arm trial, done in Germany and the UK, included patients with acute HCV genotype 1 or 4 and HIV-1. At screening, patients were either receiving HIV antiretrovirals and had HIV RNA less than 200 copies per mL, or not receiving antiretrovirals and had a CD4 T-cell count of greater than 500 cells per μL. All patients received ledipasvir-sofosbuvir once daily for 6 weeks. The primary efficacy endpoint was the proportion of patients with sustained virological response 12 weeks after the end of treatment (SVR12). This study is registered with ClinicalTrials.gov, number NCT02457611. FINDINGS: Between June 11, 2015, and Jan 8, 2016, we enrolled and treated 26 patients. All (100%) were men, 24 (92%) were white, and 25 (96%) were receiving antiretroviral treatment. 19 (73%) had genotype 1a and seven (27%) had genotype 4 HCV. Overall, 20 (77%; 95% CI 56-91) of 26 patients achieved SVR12: 15 (79%) of 19 with genotype 1a, and five (71%) of seven with genotype 4. Of six patients not achieving SVR12, three relapsed, two achieved sustained virological response 4 weeks after the end of treatment but were lost to follow-up, and one was reinfected. The most common adverse events were fatigue (seven participants [27%]), nasopharyngitis (seven [27%]), and headache (six [23%]). No patient discontinued or interrupted therapy due to adverse events. No HIV rebound occurred during the study. INTERPRETATION: The rate of cure with a fixed-dose combination of ledipasvir-sofosbuvir for patients with acute genotype 1 or 4 HCV infection and HIV-1 coinfection is similar to historic rates with interferon-based treatment, but with shorter treatment duration and more favourable safety outcomes. FUNDING: Gilead Sciences.

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

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

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

21 Clinical Trial Sofosbuvir and Velpatasvir for the Treatment of Hepatitis C Virus in Patients Coinfected With Human Immunodeficiency Virus Type 1: An Open-Label, Phase 3 Study. 2017

Wyles, David / Bräu, Norbert / Kottilil, Shyam / Daar, Eric S / Ruane, Peter / Workowski, Kimberly / Luetkemeyer, Anne / Adeyemi, Oluwatoyin / Kim, Arthur Y / Doehle, Brian / Huang, K C / Mogalian, Erik / Osinusi, Anu / McNally, John / Brainard, Diana M / McHutchison, John G / Naggie, Susanna / Sulkowski, Mark / Anonymous930902. ·Division of Infectious Diseases, Denver Health and Hospital Authority, Colorado. · James J. Peters Veterans Affairs Medical Center, Bronx. · Icahn School of Medicine at Mount Sinai, New York City, New York. · Institute of Human Virology, University of Maryland, Baltimore. · Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance. · Ruane Medical and Liver Health Institute, Los Angeles, California. · Emory University, Atlanta, Georgia. · University of California, San Francisco. · CORE Center, Cook County Health and Hospitals System and Rush University Medical Center, Chicago, Illinois. · Massachusetts General Hospital and Harvard Medical School, Boston. · Gilead Sciences, Foster City, California. · Duke University, Durham, North Carolina. · Johns Hopkins University School of Medicine, Baltimore, Maryland. ·Clin Infect Dis · Pubmed #28369210.

ABSTRACT: Background: A safe, simple, effective, and pan-genotypic regimen to treat hepatitis C virus (HCV) infection in patients coinfected with human immunodeficiency virus type 1 (HIV-1) remains a medical need. We assessed the efficacy and safety of the NS5B polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir for HCV in patients coinfected with HIV-1. Methods: This phase 3, open-label, single-arm study at 17 sites in the United States enrolled patients with HCV of any genotype and HIV-1 coinfection, including those with compensated cirrhosis. All patients received sofosbuvir-velpatasvir once daily for 12 weeks. The primary endpoint was sustained virologic response 12 weeks after treatment (SVR12). Efficacy and safety were assessed in all patients receiving at least 1 dose of treatment. Results: Of 106 patients, 91 (86%) were men, 48 (45%) were black, and 19 (18%) had cirrhosis. SVR12 was achieved by 101 of 106 (95% [95% confidence interval {CI}, 89%-99%]) patients: 74 of 78 (95% [95% CI, 87%-99%]) with genotype 1; all 11 (100% [95% CI, 72%-100%]) with genotype 2; 11 of 12 (92% [95% CI, 62%-100%]) with genotype 3; and all 5 (100% [95% CI, 48%-100%]) with genotype 4. All 19 patients with cirrhosis had SVR12. Two patients relapsed, 2 were lost to follow-up, and 1 withdrew consent. Two discontinued treatment due to adverse events and 2 had serious adverse events. The most common adverse events were fatigue (25%), headache (13%), upper respiratory tract infection (8%), and arthralgia (8%). Conclusions: Sofosbuvir-velpatasvir for 12 weeks was safe and provided high rates of SVR12 in patients coinfected with HCV and HIV-1. Clinical Trials Registration: NCT02480712.

22 Clinical Trial Sofosbuvir Plus Ribavirin Without Interferon for Treatment of Acute Hepatitis C Virus Infection in HIV-1-Infected Individuals: SWIFT-C. 2017

Naggie, Susanna / Marks, Kristen M / Hughes, Michael / Fierer, Daniel S / Macbrayne, Christine / Kim, Arthur / Hollabaugh, Kimberly / Roa, Jhoanna / Symonds, Bill / Brainard, Diana M / McHutchison, John G / Peters, Marion G / Kiser, Jennifer J / Chung, Raymond / Anonymous5130900. ·Duke University Medical Center, Durham, North Carolina, USA. · Weill Cornell, New York, USA. · Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA. · Icahn School of Medicine at Mount Sinai, New York, USA. · University of Colorado, Aurora, USA. · Massachusetts General Hospital, Boston, USA. · Social & Scientific Systems, Inc., Silver Spring, Maryland, USA. · Roivant, New York, USA. · Gilead Sciences, Inc., Foster City, California, USA. · University of California, San Francisco, USA. ·Clin Infect Dis · Pubmed #28329053.

ABSTRACT: Background: Historically, acute hepatitis C virus (HCV) infection was treated with shorter durations of interferon-containing therapies. In the era of direct-acting antivirals (DAAs), it is unclear whether the efficacy of treatment achieved in chronic infection can be maintained with abbreviated courses of therapy during the acute phase. Methods: The sofosbuvir-containing regimens without interferon for treatment of acute HCV in HIV-1 infected individuals (SWIFT-C) is an open-label, 2-cohort clinical trial in which the first cohort assessed for the safety and efficacy of 12 weeks of sofosbuvir plus ribavirin for the treatment of acute HCV infection in participants with chronic human immunodeficiency virus type 1 (HIV-1) infection. This is a preplanned analysis of the first cohort, which had a planned accrual of 17 participants. Results: Seventeen men (11 Hispanic, 6 white, median age 45 years) were enrolled. Most (88%) had HCV genotype-1 infection and few (24%) had the favorable IL28B CC genotype. Median baseline HCV RNA was 2 280 000 IU/mL (interquartile range, 272 000-4 230 000). Ten participants (59%) achieved the primary outcome of SVR12 (90% confidence interval, 36%-78%), failing to establish noninferiority. All treatment failures were due to viral relapse (41%). There were no premature treatment discontinuations. The only factor that differed between participants who achieved SVR vs those who relapsed was ribavirin concentration at the end of treatment. Conclusion: Sofosbuvir-ribavirin for 12 weeks for the treatment of acute HCV genotype-1 infection in HIV-1-infected persons results in a high relapse rate. Preliminary studies of DAA combination therapies suggest improved response rates, although the adequate duration of therapy remains unclear. Clinical Trials Registration: NCT02128217.

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

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

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

24 Clinical Trial Preclinical Pharmacokinetics and First-in-Human Pharmacokinetics, Safety, and Tolerability of Velpatasvir, a Pangenotypic Hepatitis C Virus NS5A Inhibitor, in Healthy Subjects. 2017

Mogalian, Erik / German, Polina / Kearney, Brian P / Yang, Cheng Yong / Brainard, Diana / Link, John / McNally, John / Han, LingLing / Ling, John / Mathias, Anita. ·Clinical Pharmacology, Gilead Sciences, Inc., Foster City, California, USA erik.mogalian@gilead.com. · Clinical Pharmacology, Gilead Sciences, Inc., Foster City, California, USA. · Drug Metabolism and Pharmacokinetics, Gilead Sciences, Inc., Foster City, California, USA. · Clinical Research, Gilead Sciences, Inc., Foster City, California, USA. · Medicinal Chemistry, Gilead Sciences, Inc., Foster City, California, USA. · Biostatistics, Gilead Sciences, Inc., Foster City, California, USA. · Bioanalytics, Gilead Sciences, Inc., Foster City, California, USA. ·Antimicrob Agents Chemother · Pubmed #28193657.

ABSTRACT: Preclinical characterization of velpatasvir (VEL; GS-5816), an inhibitor of the hepatitis C virus (HCV) NS5A protein, demonstrated that it has favorable

25 Clinical Trial Efficacy of Ledipasvir Plus Sofosbuvir for 8 or 12 Weeks in Patients With Hepatitis C Virus Genotype 2 Infection. 2017

Gane, Edward J / Hyland, Robert H / Yang, Yin / Svarovskaia, Evguenia / Stamm, Luisa M / Brainard, Diana M / McHutchison, John G / Stedman, Catherine A M. ·Liver Transplant Unit, Auckland City Hospital and University of Auckland, Auckland, New Zealand. Electronic address: edgane@adhb.govt.nz. · Gilead Sciences, Inc, Foster City, California. · Department of Gastroenterology, Christchurch Hospital and University of Otago, Christchurch, New Zealand. ·Gastroenterology · Pubmed #28137593.

ABSTRACT: BACKGROUND & AIMS: Patients with chronic hepatitis C virus (HCV) genotype 2 have high rates of response to treatment with sofosbuvir and ribavirin. However, ribavirin is associated with hemolytic events and is poorly tolerated by some patients. We evaluated the effectiveness of sofosbuvir and ledipasvir in treatment-naïve and treatment-experienced patients with HCV genotype 2, comparing 12 versus 8 weeks of treatment. METHODS: This Phase 2, open-label study included 2 cohorts in New Zealand. The first received a fixed-dose combination tablet of ledipasvir-sofosbuvir (90/400 mg) once daily for 12 weeks. If this cohort had a 90% rate of sustained virologic response (SVR) 4 weeks after treatment, a second cohort receiving 8 weeks of ledipasvir-sofosbuvir was to be enrolled. The primary endpoint in both cohorts was the percentage of patients with HCV RNA <15 IU/mL 12 weeks after therapy (SVR12). RESULTS: SVR12 rates were 96% (25/26; 95% CI, 80%-100%) for 12 weeks and 74% (20/27; 95% CI, 54%-89%) for 8 weeks of ledipasvir-sofosbuvir. The single patient receiving 12 weeks of ledipasvir-sofosbuvir who did not reach SVR12 did not complete treatment because of withdrawing consent after receiving 1 dose of study drug. Six of the 7 patients who did not reach SVR12 after 8 weeks of treatment experienced virologic relapse after stopping therapy. The most common adverse events were headache (26% of patients), fatigue (21%), and nausea (17%). No patients discontinued treatment because of an adverse event. CONCLUSIONS: For treatment-naïve and -experienced patients, ledipasvir-sofosbuvir for 12 weeks is highly effective for the treatment of HCV genotype 2 (ClinicalTrials.gov: NCT02202980).

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