Daclatasvir, sofosbuvir, and ribavirin for hepatitis C virus genotype 3 and advanced liver disease: A randomized phase III study (ALLY-3+).

Patients with hepatitis C virus (HCV) genotype 3 infection, especially those with advanced liver disease, are a challenging population in urgent need of optimally effective therapies. The combination of daclatasvir (DCV; pangenotypic nonstructural protein 5A inhibitor) and sofosbuvir (SOF; nucleotide nonstructural protein 5B inhibitor) for 12 weeks previously showed high efficacy (96%) in noncirrhotic genotype 3 infection. The phase III ALLY-3+ study (N = 50) evaluated DCV-SOF with ribavirin (RBV) in treatment-naïve (n = 13) or treatment-experienced (n = 37) genotype 3-infected patients with advanced fibrosis (n = 14) or compensated cirrhosis (n = 36). Patients were randomized 1:1 to receive open-label DCV-SOF (60 + 400 mg daily) with weight-based RBV for 12 or 16 weeks. The primary endpoint was sustained virological response at post-treatment week 12 (SVR12). SVR12 (intention-to-treat) was 90% overall (45 of 50): 88% (21 of 24) in the 12-week (91% observed) and 92% (24 of 26) in the 16-week group. All patients with advanced fibrosis achieved SVR12. SVR12 in patients with cirrhosis was 86% overall (31 of 36): 83% (15 of 18) in the 12-week (88% observed) and 89% (16 of 18) in the 16-week group; for treatment-experienced patients with cirrhosis, these values were 87% (26 of 30), 88% (14 of 16; 93% observed), and 86% (12 of 14), respectively. One patient (12-week group) did not enter post-treatment follow-up (death unrelated to treatment). There were 4 relapses (2 per group) and no virological breakthroughs. The most common adverse events (AEs) were insomnia, fatigue, and headache. There were no discontinuations for AEs and no treatment-related serious AEs. The all-oral regimen of DCV-SOF-RBV was well tolerated and resulted in high and similar SVR12 after 12 or 16 weeks of treatment among genotype 3-infected patients with advanced liver disease, irrespective of past HCV treatment experience.

Leroy V ，Angus P ，Bronowicki JP ，Dore GJ ，Hezode C ，Pianko S ，Pol S ，Stuart K ，Tse E ，McPhee F ，Bhore R ，Jimenez-Exposito MJ ，Thompson AJ ... -  《-》

High Efficacy and Safety of Flat-Dose Ribavirin Plus Sofosbuvir/Daclatasvir in Genotype 3 Cirrhotic Patients.

Pellicelli A ，Messina V ，Giannelli V ，Distefano M ，Palitti VP ，Vignally P ，Tarquini P ，Izzi A ，Moretti A ，Babudieri S ，Dell'Isola S ，Marignani M ，Scifo G ，Iovinella V ，Cariti G ，Pompili M ，Candilo FD ，Fontanella L ，Ettorre GM ，Vennarecci G ，Ippolito AM ，Barbarini G ... -  《-》

Comparative efficacy of sofosbuvir-ribavirin versus sofosbuvir-daclatasvir for treatment of chronic hepatitis C in an area with limited NS5A inhibitor availability.

Kurniawan J ，Gani RA ，Hasan I ，Sulaiman AS ，Lesmana CRA ，Jasirwan COM ，Kalista KF ，Nababan SHH ，Zulkifly S ... -  《-》

Daclatasvir plus sofosbuvir, with or without ribavirin, achieved high sustained virological response rates in patients with HCV infection and advanced liver disease in a real-world cohort.

We assessed the effectiveness and safety of daclatasvir (DCV) plus sofosbuvir (SOF), with or without ribavirin (RBV), in a large real-world cohort, including patients with advanced liver disease. Adults with chronic HCV infection at high risk of decompensation or death within 12 months and with no available treatment options were treated in a European compassionate use programme. The recommended regimen was DCV 60 mg plus SOF 400 mg for 24 weeks; RBV addition or shorter duration was allowed at physicians' discretion. The primary endpoint was sustained virological response at post-treatment week 12 (SVR12). Of the 485 evaluable patients, 359 received DCV+SOF and 126 DCV+SOF+RBV. Most patients were men (66%), white (93%) and treatment-experienced (70%). The most frequent HCV genotypes were 1b (36%), 1a (33%) and 3 (21%), and 80% of patients had cirrhosis (42% Child-Pugh B/C; 46% Model for End-Stage Liver Disease score >10). SVR12 (modified intention-to-treat) was achieved by 91% of patients (419/460); 1 patient had virological breakthrough and 13 patients relapsed. Virological failure was not associated with treatment group (adjusted risk difference DCV+SOF minus DCV+SOF+RBV: 1.06%; 95% CI -2.22% to 4.35%). High SVR12 was observed regardless of HCV genotype or cirrhosis, liver transplant or HIV/HCV coinfection status. Twenty eight patients discontinued treatment due to adverse events (n=18) or death (n=10) and 18 died during follow-up. Deaths and most safety events were associated with advanced liver disease and not considered treatment related. DCV+SOF with or without RBV achieved high SVR12 and was well tolerated in a diverse cohort of patients with severe liver disease. NCT02097966.

Welzel TM ，Petersen J ，Herzer K ，Ferenci P ，Gschwantler M ，Wedemeyer H ，Berg T ，Spengler U ，Weiland O ，van der Valk M ，Rockstroh J ，Peck-Radosavljevic M ，Zhao Y ，Jimenez-Exposito MJ ，Zeuzem S ... -  《-》

Daclatasvir plus sofosbuvir, with or without ribavirin, for hepatitis C virus genotype 3 in a French early access programme.

Optimally effective treatment for hepatitis C virus genotype 3 (GT3) is urgently needed, particularly in advanced liver disease. Daclatasvir plus sofosbuvir was efficacious in phase 3 studies. Real-world data for daclatasvir+sofosbuvir in advanced GT3 infection are presented from the French Temporary Authorisation for Use programme, which allowed patients in need without other treatment options access to daclatasvir ahead of its market authorization. Patients with F3/F4 fibrosis and/or extrahepatic hepatitis C virus manifestations, post-liver transplant hepatitis C virus recurrence and/or indication for liver/kidney transplant, were treated with daclatasvir+sofosbuvir (60+400 mg daily) for a recommended duration of 24 weeks. Addition of ribavirin and/or shorter treatment was at physician's discretion. The primary efficacy analysis was sustained virological response at post-treatment week 12 (SVR12; modified intention-to-treat). Safety was assessed by spontaneous adverse event reporting. The efficacy population comprised 333 patients, mostly cirrhotic (77%, of whom 18% were decompensated) and treatment experienced (72%). After 24 weeks of daclatasvir+sofosbuvir, SVR12 was 89% (174/196) overall (95% CI 83.6-92.5%), 98% (43/44) without cirrhosis (95% CI 88.2-99.6%) and 86% (129/150) with any degree of cirrhosis (95% CI 79.5-90.7%), without SVR12 increase in those who received additional ribavirin for 24 weeks (SVR12 82% [50/61; 95% CI 70.5-89.6%]). Among 516 GT3-infected patients with safety data, 5 discontinued for adverse events and 11 died. Daclatasvir+sofosbuvir achieved high SVR12 rates and was well tolerated in this large real-world cohort of GT3-infected patients with advanced liver disease, without benefit of ribavirin in those treated 24 weeks.

Hézode C ，Lebray P ，De Ledinghen V ，Zoulim F ，Di Martino V ，Boyer N ，Larrey D ，Botta-Fridlund D ，Silvain C ，Fontaine H ，D'Alteroche L ，Leroy V ，Bourliere M ，Hubert-Fouchard I ，Guyader D ，Rosa I ，Nguyen-Khac E ，Fedchuk L ，Akremi R ，Bennai Y ，Filipovics A ，Zhao Y ，Bronowicki JP ... -  《-》