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Hepatitis: HELP
Articles by Diana M. Brainard
Based on 116 articles published since 2010
(Why 116 articles?)
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Between 2010 and 2020, D. Brainard wrote the following 116 articles about Hepatitis.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4 · 5
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 Comparison of the efficacy of sofosbuvir plus ribavirin in Chinese patients with genotype 3a or 3b HCV infection. 2019

Huang, Rui / Rao, Huiying / Xie, Qing / Gao, Zhiliang / Li, Wu / Jiang, Deyuan / Mo, Hongmei / Massetto, Benedetta / Stamm, Luisa M / Brainard, Diana M / Wei, Lai. ·Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory for Hepatitis C and Immunotherapy for Liver Disease, Beijing, China. · Department of Infectious Disease, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. · Infectious Disease Department, The Third Affiliated Hospital, Sun Yet-Sen University, Guangzhou, China. · First Affiliated Hospital of Kunming Medical University, Kunming, China. · Biostatistics, Gilead Sciences, Inc, Foster City, California. · Virology, Gilead Sciences, Inc, Foster City, California. · Clinical Research, Gilead Sciences, Inc, Foster City, California. ·J Med Virol · Pubmed #30861150.

ABSTRACT: BACKGROUND AND AIM: Genotype 3b hepatitis C virus (HCV) infection represents approximately 50% of patients with genotype 3 in China. We compared the efficacy of sofosbuvir (SOF) plus ribavirin (RBV) in Chinese patients with genotype 3a and 3b HCV. METHODS: The analyzed data are from a phase 3, open-label study of SOF plus RBV for 24 weeks conducted in China. The primary endpoint for the trial was sustained virologic response at 12 weeks after the end of therapy (SVR12). RESULTS: Of 126 patients included in this analysis, 58 (46%) had genotype 3a and 68 (54%) had genotype 3b. Both the subtypes were similar in age, sex, body mass index, IL28B, and baseline HCV RNA. However, more treatment-experienced and cirrhotic patients were in the genotype 3b group. All 100% of patients with genotype 3a (95% confidence interval [CI], 94-100), and 91% (95% CI, 82-97) of patients with genotype 3b achieved SVR12 (P = 0.030). For treatment-experienced patients with genotype 3b, the SVR12 rate was 73% (95% CI, 39-94) and 88% (95% CI, 64-99) among patients with and without cirrhosis (P = 1.00), respectively. CONCLUSION: SOF plus RBV for 24 weeks in patients with HCV genotype 3 infection resulted in high rates of SVR. However, the SVR12 rate among patients with genotype 3b was lower than that observed in patients with genotype 3a infection, particularly among treatment-experienced patients with cirrhosis.

4 Clinical Trial Sofosbuvir-velpatasvir single-tablet regimen administered for 12 weeks in a phase 3 study with minimal monitoring in India. 2019

Sood, Ajit / Duseja, Ajay / Kabrawala, Mayank / Amrose, Pradeep / Goswami, Bhadadev / Chowdhury, Abhijit / Sarin, Shiv Kumar / Koshy, Abraham / Hyland, Robert H / Lu, Sophia / Camus, Gregory / Stamm, Luisa M / Brainard, Diana M / Subramanian, G Mani / Prasad, Madhura / Bhatia, Shobna / Shah, Samir R / Kapoor, Dharmesh / Shalimar, ? / Saraswat, Vivek. ·Head of Department of Gastroenterology, Dayanand Medical College and Hospital, 6-E, Tagore Nagar, Ludhiana, 141001, India. ajitsood10@gmail.com. · Post-graduate Institute of Medical Education and Research, Chandigarh, India. · Surat Institute of Digestive Sciences, Surat, India. · YRG CARE, Taramani, Chennai, India. · Institute of Digestive and Liver Disease, Ganeshguri, India. · Institute of Post Graduate Medical Education and Research, Kolkata, India. · Institute of Liver and Biliary Sciences, New Delhi, India. · Lakeshore Hospital, Kochi, India. · Gilead Sciences, Inc, Foster City, CA, USA. · VGM Hospital, Coimbatore, India. · King Edward Memorial Hospital, Mumbai, India. · Global Hospital, Mumbai, India. · Global Hospital, Hyderabad, India. · All India Institute of Medical Science, Delhi, India. · Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India. ·Hepatol Int · Pubmed #30790229.

ABSTRACT: BACKGROUND AND AIMS: In clinical studies, sofosbuvir-velpatasvir has demonstrated high cure rates and favorable tolerability in patients chronically infected with chronic hepatitis C virus (HCV) of any genotype. We evaluated the effectiveness and safety of sofosbuvir-velpatasvir administered with minimal medical monitoring to patients in India. METHODS: At 16 sites in India, 129 adult patients with chronic HCV infection of any genotype initiated 12 weeks of once-daily sofosbuvir-velpatasvir (400-100 mg). Patients with compensated cirrhosis or prior treatment experience could be included in the study. Study drug was dispensed monthly, but there were no on-treatment study assessments. The primary efficacy endpoint was rate of sustained virologic response (HCV RNA < 15 IU/mL) 12 weeks after treatment (SVR12), which was compared to a pre-specified performance goal of 85%. RESULTS: The majority of patients had HCV genotype 3 infection (70%), followed by HCV genotype 1 (22%). The SVR12 rate was 93% (120/129; 95% CI, 87% to 97%) (p = 0.009 compared with the 85% performance goal). Of the nine patients who did not achieve SVR12, 1 experienced virologic failure, 2 relapsed after treatment, 1 withdrew consent after treatment, and 5 were lost to follow-up (1 during and 4 after treatment). Sofosbuvir-velpatasvir was well-tolerated, and no patients discontinued treatment because of an adverse event. The most frequently reported adverse events were headache (3% of patients), upper abdominal pain (2%), and pyrexia (2%). CONCLUSIONS: In this study conducted at multiple sites in India, sofosbuvir-velpatasvir administered without genotype restriction or on-treatment safety assessments was well-tolerated and highly effective.

5 Clinical Trial Sofosbuvir-velpatasvir for treatment of chronic hepatitis C virus infection in Asia: a single-arm, open-label, phase 3 trial. 2019

Wei, Lai / Lim, Seng Gee / Xie, Qing / Văn, Kính Nguyen / Piratvisuth, Teerha / Huang, Yan / Wu, Shanming / Xu, Ming / Tang, Hong / Cheng, Jun / Le Manh, Hung / Gao, Yanhang / Mou, Zhuangbo / Sobhonslidsuk, Abhasnee / Dou, Xiaguang / Thongsawat, Satawat / Nan, Yuemin / Tan, Chee Kiat / Ning, Qin / Tee, Hoi Poh / Mao, Yimin / Stamm, Luisa M / Lu, Sophia / Dvory-Sobol, Hadas / Mo, Hongmei / Brainard, Diana M / Yang, Yong-Feng / Dao, Long / Wang, Gui-Qiang / Tanwandee, Tawesak / Hu, Peng / Tangkijvanich, Pisit / Zhang, Lunli / Gao, Zhi Liang / Lin, Feng / Le, Thi Tuyet Phuong / Shang, Jia / Gong, Guozhong / Li, Jun / Su, Minghua / Duan, Zhongping / Mohamed, Rosmawati / Hou, Jin Lin / Jia, Jidong. ·Peking University People's Hospital, Beijing, China. · National University Hospital, Singapore. Electronic address: mdclimsg@nus.edu.sg. · Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. · National Hospital for Tropical Diseases, Hanoi, Vietnam. · Songklanagarind Hospital, Songkla, Thailand. · Xiangya Hospital, Central South University, Changsha, Hunan, China. · Shanghai Public Health Clinical Centre, Shanghai, China. · Guangzhou No 8 People's Hospital, Guangzhou, Guangdong, China. · West China Hospital, Sichuan University, Chengdu, Sichuan, China. · Beijing Ditan Hospital, Beijing, China. · Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam. · The First Hospital of Jilin University, Changchun, Jilin, China. · Jinan Infectious Disease Hospital, Jinan, Shandong, China. · Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. · Shengjing Hospital of China Medical University, Shenyang, Liaoning, China. · Maharaj Nakorn Chiang Mai Hospital, Chiang Mai, Thailand. · The 3rd Hospital of Hebei Medical University, Shijiazhuang, Hebei, China. · Singapore General Hospital, Singapore. · Tongji Hospital Affiliated to Tongji Medicine College, Huazhong University of Science and Technology, Wuhan, Hubei, China. · Hospital Tengku Ampuan Afzan, Kuantan, Pahang, Malaysia. · Gilead Sciences, Foster City, CA, USA. · The Second Hospital of Nanjing, Affiliated to South East University, Nanjing, Jiangsu, China. · Bach Mai Hospital, Hanoi, Vietnam. · Peking University First Hospital, Beijing, China. · Siriraj Hospital, Mahidol University, Bangkok, Thailand. · The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China. · King Chulalongkorn Memorial Hospital, Bangkok, Thailand. · The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China. · The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China. · The People's Hospital of Hainan Province, Haikou, Hainan, China. · People's Hospital 115, Ho Chi Minh City, Vietnam. · Henan Province People's Hospital, Zhengzhou, Henan, China. · The Second Xiangya Hospital of Central South University, Changsha, China. · Jiangsu Province People's Hospital, Nanjing, Jiangsu, China. · The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China. · Beijing You-An Hospital, Capital Medical University, Beijing, China. · University Malaya Medical Centre, Kuala Lumpur, Malaysia. · Nanfang Hospital of Southern Medical University, Guangzhou, Guangdong, China. · Beijing Friendship Hospital Affiliate of Capital, Beijing, China. ·Lancet Gastroenterol Hepatol · Pubmed #30555048.

ABSTRACT: BACKGROUND: Treatment with combined sofosbuvir and velpatasvir has resulted in high sustained virological response rates in patients chronically infected with hepatitis C virus (HCV) with genotypes 1-6 in clinical trials and real-world settings, but its efficacy and safety has not been assessed in Asia, a region with diverse HCV genotypes. METHODS: In this single-arm, open-label, phase 3 trial, we recruited patients from 38 sites across China, Thailand, Vietnam, Singapore, and Malaysia, who were chronically infected with HCV genotypes 1-6, and were HCV treatment-naive or treatment-experienced, either without cirrhosis or with compensated cirrhosis. Patients self-administered a combined sofosbuvir (400 mg) and velpatasvir (100 mg) tablet once daily for 12 weeks. The primary efficacy endpoint was sustained virological response, defined as HCV RNA less than 15 IU/mL at 12 weeks after completion of treatment (SVR12), assessed in all patients who received at least one dose of study drug. The primary safety endpoint was the proportion of adverse events leading to premature discontinuation of study drug. This trial is registered with ClinicalTrials.gov, number NCT02671500, and is completed. FINDINGS: Between April 14, 2016, and June 30, 2017, 375 patients were enrolled in the study, of whom 374 completed the full treatment course and one discontinued treatment. Overall, 362 (97% [95% CI 94-98]) of 375 patients achieved SVR12. Among 42 patients with HCV genotype 3b, all of whom had baseline resistance-associated substitutions in NS5A, 25 (89% [95% CI 72-98]) of 28 patients without cirrhosis and seven (50% [23-77]) of 14 patients with cirrhosis achieved SVR12. The most common adverse events were upper respiratory tract infection (36 [10%] patients) and headache (18 [5%] patients). There were no discontinuations due to adverse events. Serious adverse events were reported in three (1%) patients, none of which was judged to be related to sofosbuvir-velpatasvir treatment. INTERPRETATION: Consistent with data from other phase 3 studies, single-tablet sofosbuvir-velpatasvir for 12 weeks is an efficacious and safe treatment for Asian patients with chronic HCV infection, but might have lower efficacy in those infected with HCV genotype 3b and with cirrhosis. FUNDING: Gilead Sciences.

6 Clinical Trial Sofosbuvir/velpatasvir for the treatment of HCV: excellent results from a phase-3, open-label study in Russia and Sweden. 2019

Isakov, Vasily / Chulanov, Vladimir / Abdurakhmanov, Dzhamal / Burnevich, Eduard / Nurmukhametova, Elena / Kozhevnikova, Galina / Gankina, Natalya / Zhuravel, Sergey / Romanova, Svetlana / Hyland, Robert H / Lu, Sophia / Svarovskaia, Evguenia S / McNally, John / Brainard, Diana M / Ivashkin, Vladimir / Morozov, Vyacheslav / Bakulin, Igor / Lagging, Martin / Zhdanov, Konstantin / Weiland, Ola. ·a 1 Department of Gastroenterology and Hepatology , Institute of Nutrition , Moscow , Russia. · b 2 Central Research Institute of Epidemiology , Moscow , Russia. · c 3 Hepatology Unit, Sechenov First State Medical University , Moscow , Russia. · d 4 City Clinical Hospital #24 of Moscow Healthcare Department , Moscow , Russia. · e 5 Clinic Tour LLC , Moscow , Russia. · f 6 Central Scientific and Research Institute of Epidemiology , Moscow , Russia. · g 7 Krasnoyarsk Regional Center of AIDS Prevention , Krasnoyarsk , Russia. · h 8 Sklifosovsky Scientific Research Institution of Emergency Care of Moscow Healthcare Department , Moscow , Russia. · i 9 Center for Prevention and Control AIDS and Infectious Diseases , Saint Petersburg , Russia. · j 10 Gilead Sciences , Foster City , CA, USA. · k 11 Hepatolog LLC , Samara , Russia. · l 12 Propedeutics of Internal Diseases, Gastroenterology and Dietology, I.I. Mechnikov North-West State Medical University , Saint Petersburg , Russia. · m 13 Department of Infectious Diseases/Virology , Institute of Biomedicine Sahlgrenska Academy University of Gothenburg , Gothenburg , Sweden. · n 14 Kirov Medical Military Academy , Saint Petersburg , Russia. · o 15 Department of Internaö Medicine Division of Infectious Diseases , Karolinska Institutet, Karolinska University Hospital Huddinge , Stockholm , Sweden. ·Infect Dis (Lond) · Pubmed #30499360.

ABSTRACT: BACKGROUND: In both Russia and Sweden, the dominant hepatitis C virus (HCV) is genotype 1, but around one-third of patients have genotype 3 infection. For such countries, HCV genotype testing is recommended prior to therapy. An effective pangenotypic therapy may potentially eliminate the need for genotyping. In this study, we evaluated the efficacy and safety of sofosbuvir/velpatasvir for 12 weeks in patients from Russia and Sweden. METHODS: In an open-label, single-arm phase-3 study, patients could have HCV genotype 1-6 infection and were treatment-naïve or interferon treatment-experienced. All patients received sofosbuvir/velpatasvir, once daily for 12 weeks. The primary endpoint was sustained virologic response 12 weeks post-treatment (SVR12). RESULTS: Of 122 patients screened, 119 were enrolled and treated. Overall, half (50%) were male, 18% had cirrhosis, and 24% had failed prior interferon-based therapy. In total, 66% of patients were infected with HCV genotype 1 (59% 1b and 7% 1a), 6% with genotype 2, and 29% with genotype 3. The overall SVR12 rate was 99% (118/119, 95% confidence interval 95-100%). One treatment-experienced patient infected with HCV genotype 3 experienced virologic relapse after completing treatment. The most common adverse events were headache (16%) and fatigue (7%). Serious adverse events were observed in four patients, but none were related to treatment. No patients discontinued treatment due to adverse events. CONCLUSION: Sofosbuvir/velpatasvir as a pangenotypic treatment for 12 weeks was highly effective in patients from Russia and Sweden infected with HCV genotypes 1, 2, or 3. Sofosbuvir/velpatasvir was safe and well-tolerated. Clinical trial number: ClinicalTrials.gov NCT02722837.

7 Clinical Trial Efficacy and safety of sofosbuvir-velpatasvir with or without ribavirin in HCV-infected Japanese patients with decompensated cirrhosis: an open-label phase 3 trial. 2019

Takehara, Tetsuo / Sakamoto, Naoya / Nishiguchi, Shuhei / Ikeda, Fusao / Tatsumi, Tomohide / Ueno, Yoshiyuki / Yatsuhashi, Hiroshi / Takikawa, Yasuhiro / Kanda, Tatsuo / Sakamoto, Minoru / Tamori, Akihiro / Mita, Eiji / Chayama, Kazuaki / Zhang, Gulan / De-Oertel, Shampa / Dvory-Sobol, Hadas / Matsuda, Takuma / Stamm, Luisa M / Brainard, Diana M / Tanaka, Yasuhito / Kurosaki, Masayuki. ·Osaka University, 2-15 Yamadaoka, Suita, Osaka, 565-0871, Japan. takehara@gh.med.osaka-u.ac.jp. · Hokkaido University, Sapporo, Hokkaido, Japan. · Hyogo College of Medicine, Nishinomiya, Hyogo, Japan. · Okayama University, Okayama, Japan. · Osaka University, 2-15 Yamadaoka, Suita, Osaka, 565-0871, Japan. · Yamagata University, Yamagata, Japan. · Nagasaki Medical Center, Nagasaki, Japan. · Iwate Medical University, Iwate, Japan. · Chiba University, Chiba, Japan. · University of Yamanashi, Yamanashi, Japan. · Osaka City University, Osaka, Japan. · National Hospital Organization Osaka National Hospital, Osaka, Japan. · Hiroshima University, Hiroshima, Japan. · Gilead Sciences, Inc, Foster City, CA, USA. · Gilead Sciences K.K, Tokyo, Japan. · Nagoya City University, Nagoya, Aichi, Japan. · Musashino Red Cross Hospital, Tokyo, Japan. ·J Gastroenterol · Pubmed #30203225.

ABSTRACT: BACKGROUND: In Japan, hepatitis C virus (HCV)-infected patients with decompensated cirrhosis currently have no treatment options. In this Phase 3 study, we evaluated sofosbuvir-velpatasvir with or without ribavirin for 12 weeks in patients with any HCV genotype and decompensated cirrhosis [Child-Pugh-Turcotte (CPT) class B or C] in Japan. METHODS: Patients were randomized 1:1 to receive sofosbuvir-velpatasvir with or without ribavirin for 12 weeks. Randomization was stratified by CPT class and genotype. Sustained virologic response 12 weeks following completion of treatment (SVR12) was the primary efficacy endpoint. RESULTS: Of the 102 patients enrolled, 57% were treatment naive, 78% and 20% had genotype 1 and 2 HCV infection, respectively, and 77% and 20% had CPT class B and C cirrhosis, respectively, at baseline. Overall, 61% of patients were female and the mean age was 66 years (range 41-83). SVR12 rates were 92% (47/51) in each group. Among patients who achieved SVR12, 26% had improved CPT class from baseline to posttreatment week 12. Most adverse events (AEs) were consistent with clinical sequelae of advanced liver disease or known toxicities of ribavirin. Four patients (8%) who received sofosbuvir-velpatasvir and seven (14%) who received sofosbuvir-velpatasvir plus ribavirin experienced a serious AE. The 3 deaths (bacterial sepsis, gastric varices hemorrhage, hepatocellular carcinoma) were attributed to liver disease progression. CONCLUSION: Sofosbuvir-velpatasvir for 12 weeks provides a highly effective and well-tolerated therapy for Japanese patients with HCV and decompensated cirrhosis. Ribavirin did not improve efficacy but increased toxicity.

8 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.

9 Clinical Trial Pharmacokinetics, Safety, and Tolerability of the Direct-acting Hepatitis C Antiviral Sofosbuvir in HealthyChineseSubjects. 2018

Li, Xiaojiao / Chen, Hong / Niu, Junqi / Chen, Guiling / Shen, Gong / Massetto, Benedetta / Brainard, Diana M / Zhu, Xiaoxue / Zhang, Hong / Ding, Yanhua. ·Phase I Clinical Trial Unit, First Hospital, Jilin University, Changchun, Jilin, China. · Department of Hepatology, First Hospital, Jilin University, Changchun, Jilin, China. · Gilead Sciences Inc, Foster City, California. · Phase I Clinical Trial Unit, First Hospital, Jilin University, Changchun, Jilin, China. Electronic address: dingyanhua2003@126.com. ·Clin Ther · Pubmed #30185395.

ABSTRACT: PURPOSE: The purpose of this study was to investigate the safety, tolerability, and pharmacokinetic profile of sofosbuvir and its metabolites after a single dose of sofosbuvir 400mg and once daily dosing of sofosbuvir 400mg for 7days in healthy Chinese subjects. METHODS: This Phase I, open-label, single- and multiple-dose study enrolled 14 Chinese subjects aged 18 to 45years with an approximately even distribution of healthy male (n = 9) and nonpregnant, nonlactating female subjects (n = 5). Subjects received a single oral dose of sofosbuvir 400mg (one tablet) (morning, fasted conditions; single-dose treatment). After a 3-day washout, subjects received oral sofosbuvir 400mg (one tablet) (morning, fasted) for 7days (multiple dose treatment). FINDINGS: No significant accumulation of sofosbuvir, GS-566500, or GS-331007 was observed. Steady state of the major metabolite GS-331007 was achieved after 4days of consecutive dosing with sofosbuvir 400mg once daily. Sofosbuvir was generally well tolerated. IMPLICATIONS: Overall, this study supports the further evaluation of sofosbuvir 400mg in the Chinese population. The pharmacokinetic properties of sofosbuvir, GS-556500, and GS-311007 were found to be broadly similar in healthy Chinese subjects compared with non-Chinese subjects in previous sofosbuvir studies. ChinaDrugTrials.org.cn identifier: CTR20150249.

10 Clinical Trial No impact of resistance-associated substitutions on the efficacy of sofosbuvir, velpatasvir, and voxilaprevir for 12 weeks in HCV DAA-experienced patients. 2018

Sarrazin, Christoph / Cooper, Curtis L / Manns, Michael P / Reddy, K Rajender / Kowdley, Kris V / Roberts, Stuart K / Dvory-Sobol, Hadas / Svarovskia, Evguenia / Martin, Ross / Camus, Gregory / Doehle, Brian P / Stamm, Luisa M / Hyland, Robert H / Brainard, Diana M / Mo, Hongmei / Gordon, Stuart C / Bourliere, Marc / Zeuzem, Stefan / Flamm, Steven L. ·Medizinische Klinik 1, Goethe University Hospital, Frankfurt, Germany; St. Josefs-Hospital, Wiesbaden, Germany. · University of Ottawa, Ottawa, Ontario, Canada. · Hannover Medical School, Hannover, Germany. · University of Pennsylvania, Philadelphia, PA, USA. · Swedish Medical Center, Seattle, WA, USA. · Alfred Health Gastroenterology Department and Monash University Melbourne, Australia. · Gilead Sciences, Inc, Foster City, CA, USA. Electronic address: Hadas.Dvory-Sobol@Gilead.com. · Gilead Sciences, Inc, Foster City, CA, USA. · Henry Ford Health System, Detroit, MI, USA. · Hôpital Saint Joseph, Marseilles, France. · Medizinische Klinik 1, Goethe University Hospital, Frankfurt, Germany. · Northwestern Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. ·J Hepatol · Pubmed #30098373.

ABSTRACT: BACKGROUND & AIMS: In phase III studies, the fixed dose combination of sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) administered for 12 weeks led to a sustained virologic response at 12 weeks (SVR12) in 96% of NS5A inhibitor-experienced patients, and an SVR12 rate of 98% in DAA-experienced patients who had not previously received an NS5A inhibitor. Herein, we evaluate the relationship between the presence of detectable resistance-associated substitutions (RASs) at baseline and treatment outcome, and whether RASs were selected for in cases of virologic failure. METHODS: NS3, NS5A, and NS5B deep sequencing analyses were performed at baseline for all patients and at the time of virologic failure. Results are reported using a 15% cut-off. RESULTS: A total of 82.7% of NS5A inhibitor-experienced patients (205/248) had baseline NS3 and/or NS5A RASs; 79% had baseline NS5A RASs. SVR12 rates were similar in patients with or without NS3 and/or NS5A RASs, and with or without VOX- or VEL-specific RASs. RASs at NS5A position Y93 were present in 37.3% of patients and 95% achieved SVR12. All patients with ≥2 NS5A RASs achieved SVR12. Baseline NS3 and/or NS5A RASs were present in 46.6% (83/178) of non-NS5A inhibitor DAA-experienced patients, all of whom achieved SVR12. All patients with baseline NS5B nucleoside inhibitor RASs, including two patients with S282T, achieved SVR12. Treatment-selected resistance was seen in one of seven patients who relapsed. CONCLUSIONS: Baseline RASs had no impact on virologic response in DAA-experienced patients following treatment with SOF/VEL/VOX for 12 weeks. Selection of viral resistance with virologic relapse was uncommon. LAY SUMMARY: In phase III studies, 12 weeks of treatment with the combination of sofosbuvir, velpatasvir and voxilaprevir (SOF/VEL/VOX) cured 97% of patients with hepatitis C virus who failed prior treatment with direct-acting antiviral drugs. Herein, we show that the presence of pretreatment drug resistance did not affect treatment outcome in these patients who had previously received direct-acting antivirals. We also showed that new drug resistance was rare in patients who failed treatment with SOF/VEL/VOX for 12 weeks. This has important implications for the selection of best retreatment strategies for these patients.

11 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.

12 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.

13 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.

14 Clinical Trial Sofosbuvir/velpatasvir for 12 weeks in genotype 1-4 HCV-infected liver transplant recipients. 2018

Agarwal, Kosh / Castells, Lluís / Müllhaupt, Beat / Rosenberg, William M C / McNabb, Brian / Arterburn, Sarah / Camus, Gregory / McNally, John / Stamm, Luisa M / Brainard, Diana M / Mani Subramanian, G / Mariño, Zoe / Dufour, Jean-François / Forns, Xavier. ·Institute of Liver Studies, King's College Hospital NHS Trust Foundation, London, UK. · Liver Unit, Internal Medicine Department, Hospital Universitari Vall d'Hebron, CIBEREHD, Univerisitat Autònoma de Barcelona, Barcelona, Spain. · Department for Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland. · Institute for Liver and Digestive Health, University College London, London, UK. · Gilead Sciences Inc., Foster City, CA, USA. · Liver Unit, Hospital Clinic, CIBEREHD and IDIBAPS, University of Barcelona, Barcelona, Spain. · Department of Hepatology, University of Bern, Bern, Switzerland. · Liver Unit, Hospital Clinic, CIBEREHD and IDIBAPS, University of Barcelona, Barcelona, Spain. Electronic address: XFORNS@clinic.cat. ·J Hepatol · Pubmed #29886154.

ABSTRACT: BACKGROUND & AIMS: Sofosbuvir, an NS5B inhibitor, combined with velpatasvir, an NS5A inhibitor (SOF/VEL), produces high sustained virologic response rates 12 weeks after treatment (SVR12) in patients with genotype 1-6 HCV infection, and has no anticipated clinically relevant drug-drug interactions with immunosuppressants. This study evaluated the safety and efficacy of SOF/VEL in adults with recurrent chronic genotype 1-4 HCV infection after liver transplant. METHODS: Patients received SOF/VEL 400/100 mg daily for 12 weeks. Patients could be treatment experienced or treatment naïve with no cirrhosis or with compensated cirrhosis. The primary endpoints were SVR12 and discontinuations due to adverse events. RESULTS: A total of 79 patients were enrolled and treated in this study (37 [47%] had genotype 1, 3 [4%] genotype 2, 35 [44%] genotype 3, and 4 [5%] genotype 4 HCV). Of these, 81% were male, 82% were white, 18% had compensated cirrhosis, and 59% were treatment experienced. The most commonly used immunosuppressants were tacrolimus (71%), mycophenolic acid (24%), cyclosporine (14%), and azathioprine (11%). Median (range) time from liver transplantation was 7.5 (0.3, 23.9) years. The SVR12 rate was 96%. By genotype, SVR12 rates were 95% (genotype 1), 100% (genotype 2), 97% (genotype 3), and 100% (genotype 4). Two patients experienced virologic relapse: one with genotype 1a infection was non-cirrhotic and treatment naïve, and one with genotype 3 infection was non-cirrhotic and treatment experienced. One patient discontinued SOF/VEL due to hyperglycemia. No serious or severe adverse events were deemed SOF/VEL-related by the investigator, and no liver transplant rejection episodes or deaths occurred during the study period. CONCLUSIONS: Treatment with SOF/VEL for 12 weeks was highly effective and well tolerated in genotype 1-4 HCV-infected liver transplant recipients with and without cirrhosis. LAY SUMMARY: Sofosbuvir/velpatasvir is a combination of two drugs in one tablet that is approved for the treatment of patients with chronic hepatitis C virus (HCV) infection. When patients with chronic HCV infection receive a liver transplant, the HCV infection usually recurs, and damages the transplanted liver. This study tested the effects of 12 weeks of sofosbuvir/velpatasvir treatment in patients who had HCV recurrence after a liver transplant. Three months following the end of treatment, 96% of patients were cured of HCV infection. Clinical trial number: NCT02781571.

15 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.

16 Clinical Trial Effects of sofosbuvir-based hepatitis C treatment on the pharmacokinetics of tenofovir in HIV/HCV-coinfected individuals receiving tenofovir disoproxil fumarate. 2018

MacBrayne, Christine E / Marks, Kristen M / Fierer, Daniel S / Naggie, Susanna / Chung, Raymond T / Hughes, Michael D / Kim, Arthur Y / Peters, Marion G / Brainard, Diana M / Seifert, Sharon M / Castillo-Mancilla, Jose R / Bushman, Lane R / Anderson, Peter L / Kiser, Jennifer J. ·University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA. · New York Presbyterian Hospital, New York, NY, USA. · Icahn School of Medicine at Mount Sinai, New York, NY, USA. · Duke Clinical Research Institute, Durham, NC, USA. · Massachusetts General Hospital, Boston, MA, USA. · Harvard T. H. Chan School of Public Health, Boston, MA, USA. · University of California, San Francisco, CA, USA. · Gilead Sciences, Foster City, CA, USA. · University of Colorado Department of Medicine, Aurora, CO, USA. ·J Antimicrob Chemother · Pubmed #29746648.

ABSTRACT: Background: The nucleotide analogues tenofovir and sofosbuvir are considered to have low potential for drug interactions. Objectives: To determine the effect of sofosbuvir-based HCV treatment on plasma concentrations of tenofovir and cellular concentrations of tenofovir diphosphate. Methods: HIV-infected participants with acute HCV were treated for 12 weeks with sofosbuvir + ribavirin in Cohort 1 or 8 weeks with ledipasvir/sofosbuvir in Cohort 2 of AIDS Clinical Trials Group study 5327. Only participants taking tenofovir disoproxil fumarate were included in this analysis. Tenofovir in plasma, tenofovir diphosphate in dried blood spots and tenofovir diphosphate in PBMCs were measured pre-HCV therapy and longitudinally during the study using validated LC/MS-MS. Results: Fifteen and 22 men completed Cohorts 1 and 2, respectively. In Cohort 1, tenofovir diphosphate was 4.3-fold higher (95% CI geometric mean ratio 2.46-7.67; P = 0.0001) in dried blood spots and 2.3-fold higher (95% CI 1.09-4.92; P = 0.03) in PBMCs following 12 weeks of sofosbuvir + ribavirin versus study entry. Tenofovir in the plasma was unchanged. In Cohort 2, tenofovir diphosphate was 17.8-fold higher (95% CI 12.77-24.86; P < 0.0001) in dried blood spots after 8 weeks of ledipasvir/sofosbuvir versus study entry. Tenofovir plasma concentrations were 2.1-fold higher (95% CI 1.44-2.91; P = 0.0005). Despite the increase in cellular tenofovir diphosphate concentrations, only a small decline in CLCR (6%-7%) was observed in both cohorts between study entry and end of treatment. Conclusions: These data indicate an unexpected drug interaction with tenofovir disoproxil fumarate and sofosbuvir at the cellular level. Additional studies are needed to determine the mechanism and clinical significance.

17 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.

18 Clinical Trial Pharmacokinetics and Safety of Velpatasvir and Sofosbuvir/Velpatasvir in Subjects with Hepatic Impairment. 2018

Mogalian, Erik / Brainard, Diana M / Osinusi, Anu / Moorehead, Lisa / Murray, Bernard / Ling, Kah Hiing John / Perry, Robert / Curtis, Craig / Lawitz, Eric / Lasseter, Kenneth / Marbury, Thomas / Mathias, Anita. ·Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA, 94404, USA. Erik.Mogalian@gilead.com. · Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA, 94404, USA. · Elite Research Institute, Miami, FL, USA. · Compass Research, Orlando, FL, USA. · Texas Liver Institute, University of Texas Health San Antonio, San Antonio, TX, USA. · Clinical Pharmacology of Miami, Miami, FL, USA. · Orlando Clinical Research Center, Orlando, FL, USA. ·Clin Pharmacokinet · Pubmed #29520729.

ABSTRACT: BACKGROUND: The pharmacokinetics and safety of velpatasvir, a potent pangenotypic hepatitis C virus NS5A inhibitor, were evaluated in two hepatic impairment studies: a phase I study in hepatitis C virus-uninfected subjects and a phase III study (ASTRAL-4) in hepatitis C virus-infected patients. METHODS: In the phase I study, subjects with moderate or severe hepatic impairment (Child-Pugh-Turcotte Class B or C), and demographically matched subjects with normal hepatic function received a single dose of velpatasvir 100 mg. Pharmacokinetics and safety assessments were performed, and pharmacokinetic parameters were calculated using non-compartmental methods and summarized using descriptive statistics and compared statistically by geometric least-squares mean ratios and 90% confidence intervals. In ASTRAL-4, subjects with decompensated cirrhosis (Child-Pugh-Turcotte Class B) were randomized to receive treatment with either sofosbuvir/velpatasvir ± ribavirin for 12 weeks or sofosbuvir/velpatasvir for 24 weeks. Pharmacokinetic and safety assessments were performed and pharmacokinetic parameters were calculated using a non-compartmental analysis and summarized using descriptive statistics and were compared to pharmacokinetics from ASTRAL-1 [subjects without cirrhosis or with compensated (Child-Pugh-Turcotte Class A) cirrhosis]. RESULTS: In the phase I study, plasma exposures (area under the concentration-time curve) were similar in subjects with Child-Pugh-Turcotte Class B (n = 10) or Child-Pugh-Turcotte Class C hepatic impairment (n = 10) compared with normal hepatic function (n = 13). Percent free velpatasvir was similar in subjects without or with any degree of hepatic impairment. In the phase III study, velpatasvir overall exposure (area under the concentration-time curve over the 24-h dosing interval; AUC CONCLUSIONS: No sofosbuvir/velpatasvir dose modification is warranted for patients with any degree of hepatic impairment.

19 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.

20 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.

21 Clinical Trial Resistance analysis in patients with genotype 1-6 HCV infection treated with sofosbuvir/velpatasvir in the phase III studies. 2018

Hezode, Christophe / Reau, Nancy / Svarovskaia, Evguenia S / Doehle, Brian P / Shanmugam, Ragavi / Dvory-Sobol, Hadas / Hedskog, Charlotte / McNally, John / Osinusi, Anu / Brainard, Diana M / Miller, Michael D / Mo, Hongmei / Roberts, Stuart K / O'Leary, Jacqueline G / Shafran, Stephen D / Zeuzem, Stefan. ·Service d'Hépatologie, Hôpital Henri-Mondor, AP-HP, Université Paris-Est, INSERM U955, Créteil, France. · Rush University Medical Center, Chicago, IL, USA. · Gilead Sciences, Inc., Foster City, CA, USA. Electronic address: jenny.svarovskaia@gilead.com. · Gilead Sciences, Inc., Foster City, CA, USA. · Alfred Health and Monash University, Melbourne, Victoria, Australia. · Baylor University Medical Center at Dallas, TX, USA. · University of Alberta, Edmonton, Canada. · Johann Wolfgang Goethe University Medical Center, Frankfurt am Main, Germany. ·J Hepatol · Pubmed #29221887.

ABSTRACT: BACKGROUND & AIMS: The fixed-dose combination of sofosbuvir/velpatasvir was highly efficacious in patients infected with genotype (GT)1-6 hepatitis C virus (HCV) in the ASTRAL studies. This analysis evaluated the impact of baseline resistance-associated substitutions (RASs) on treatment outcome and emergence of RASs in patients infected with HCV GT1-6 who were treated with sofosbuvir/velpatasvir. METHODS: Non-structural protein 5A and 5B (NS5A and NS5B) deep sequencing was performed at baseline and at the time of relapse for all patients treated with sofosbuvir/velpatasvir for 12 weeks (n = 1,778) in the ASTRAL-1-3, ASTRAL-5 and POLARIS-2-3 studies. RESULTS: Patients with 37 known and 19 novel HCV subtypes were included in these analyses. Overall, 28% (range 9% to 61% depending on genotype) had detectable NS5A class RASs at baseline, using a 15% sequencing assay cut-off. There was no significant effect of baseline NS5A class RASs on sustained virologic response at week 12 (SVR12) with sofosbuvir/velpatasvir; the SVR12 rate in the presence of NS5A class RASs was 100% and 97%, in patients with GT1a and GT1b infection, respectively, and 100% in patients with GT2 and GT4-6 infections. In GT3 infection, the SVR rate was 93% and 98% in patients with and without baseline NS5A class RASs, respectively. The overall virologic failure rate was low (20/1,778 = 1.1%) in patients treated with sofosbuvir/velpatasvir. Single NS5A class resistance was observed at virologic failure in 17 of the 20 patients. CONCLUSIONS: Sofosbuvir/velpatasvir taken for 12 weeks once daily resulted in high SVR rates in patients infected with GT1-6 HCV, irrespective of baseline NS5A RASs. NS5A inhibitor resistance, but not sofosbuvir resistance, was detected in the few patients with virologic failure. These data highlight the high barrier to resistance of this regimen for the treatment of chronic HCV across all genotypes in the vast majority of patients. LAY SUMMARY: Sofosbuvir/velpatasvir taken once daily for 12 weeks resulted in high sustained virologic response rates in patients infected with HCV, irrespective of the presence of NS5A resistance-associated variants prior to treatment. Single class NS5A inhibitor resistance, but not sofosbuvir resistance, was detected in the few patients with virologic failure. These data highlight the high barrier to resistance of this regimen for the treatment of chronic HCV across all genotypes in the vast majority of patients.

22 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.

23 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.

24 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.

25 Clinical Trial Characterization of HCV resistance from a 3-day monotherapy study of voxilaprevir, a novel pangenotypic NS3/4A protease inhibitor. 2018

Lawitz, Eric / Yang, Jenny C / Stamm, Luisa M / Taylor, James G / Cheng, Guofeng / Brainard, Diana M / Miller, Michael D / Mo, Hongmei / Dvory-Sobol, Hadas. ·Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, USA. · Gilead Sciences, Inc., Foster City, CA, USA. ·Antivir Ther · Pubmed #29063860.

ABSTRACT: BACKGROUND: Voxilaprevir (VOX; GS-9857) is a pangenotypic HCV NS3/4A protease inhibitor (PI) with potent antiviral activity against HCV genotypes (GTs) 1-6 and improved coverage of GT1 NS3 resistance-associated substitutions (RAS) associated with other HCV PIs. In a 3-day Phase Ib monotherapy study in patients infected with HCV GT1a, 1b, 2, 3 and 4, VOX was well-tolerated and resulted in maximal mean viral load reduction >3 log METHODS: The NS3 gene was amplified and successfully deep sequenced using MiSeq for 66 patients at baseline and 61 patients post-baseline using 15% and 1% assay cutoffs. RESULTS: With a 15% assay cutoff, pretreatment HCV NS3 RAS were present in the HCV of 38% (9/24) of patients with GT1a and 5% (1/19) with GT3a; there were no pretreatment NS3 RAS present in patients with GT1b (n=6), GT2 (n=7) or GT4 (n=4). In patients with and without pretreatment NS3 RAS, ≥3.4 log CONCLUSIONS: The lack of selection of NS3 RAS in the majority of patients demonstrates a high resistance barrier for VOX. ClinicalTrails.gov identifier NCT02185794.

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