Efficacy and Safety of All-oral,12-week Ravidasvir Plus Ritonavir-boosted Danoprevir and Ribavirin in Treatment-naive Noncirrhotic HCV Genotype 1 Patients:Results from a Phase 2/3 Clinical Trial in China

Background and Aims:Ravidasvir(RDV)is a new generation pangenotypic hepatitis C virus(HCV)NS5A inhibitor,with high barrier to baseline resistance-associated species.This is the first phase 2/3 study conducted in China's Mainland confirming the efficacy and safety of RDV+ritonavir-boosted danoprevir+ribavirin for 12 weeks in treatment-naive noncirrhotic patients with genotype 1 infection in a large population.Methods:In this multicenter,randomized,doubleblinded,placebo-controlled phase 2/3 trial(NCT03362814),we enrolled 424 treatment-nafve,noncirrhotic adult HCV genotype 1 patients.All patients were randomized at 3∶1 ratio to receive a combination of RDV 200mg once daily plus ritonavir-boosted danoprevir 100mg/100mg twice daily and oral ribavirin 1000/1200mg/day(body weight<75/≥75 kg)(n=318)or placebo(n=106)for 12 weeks.The primary end-point was the rate of sustained virologic response 12 weeks after the end of treatment,and the safety was evaluated and compared between treatment and placebo groups.Results:The overall rate of sustained virological response at 12 weeks after treatment is 99%(306/309,95%,CI:97%-100%)under per protocol set analysis.All patients harboring baseline NS5A resistance-associated species in the treatment group(76/76,per protocol set)achieved sustained virological response at 12 weeks after treatment.No treatment-related serious adverse events were reported.Laboratory abnormalities showed mild or moderate severity(grade 1 and grade 2)in liver function tests.Conclusions:In treatment-na(i)ve,noncirrhotic HCV Chinese patients infected with HCV genotype 1,all-oral regimen of RDV+ritonavir-boosted danoprevir+ribavirin for 12 weeks was highly efficacious,safe,and well tolerated.

Efficacy and Safety of All-oral Emitasvir and Sofosbuvir in Patients with Genotype 1b HCV Infections without Cirrhosis

Publications>Journals>Journal of Clinical and Translational Hepatology>Article Full Text ORIGINAL ARTICLE OPEN ACCESS Efficacy and Safety of All-oral Emitasvir and Sofosbuvir in Patients with Genotype 1b HCV Infections without Cirrhosis Huiying Rao1,Xingxiang Yang2,Youwen Tan3,Qin Ning4,Daokun Yang5,Jiefei Wang6,Yongfeng Yang7,Sujun Zheng8,Dongliang Yang9,Jinlin Hou10,Qing Xie11,Caiyan Zhao12,Lunli Zhang13,Xiaorong Mao14,Tong Sun15,Lang Bai16,Fuchun Zhang17,Jinglan Jin18,Yingren Zhao19,Maorong Wang20,Wen Xie21,Yingjie Ma22,Jun Quan23,Xuebing Yan24,Ping An25,Feng Lin26,Jidong Jia27,Xiaoxuan Hu28,Zuojiong Gong29,Jie Wu30,Yongping Chen31,Zhansheng Jia32,Minghua Lin33,Guiqiang Wang34,Yueyong Zhu35,Yingjun Zhang*,36,Hongming Xie36,Lin Luo36,Qingyun Ren36,Rui Huang1 and Lai Wei*,37 Author information Journal of Clinical and Translational Hepatology 2020;8(3):255-261DOI:10.14218/JCTH.2020.00031 Abstract Background and Aims:Emitasvir is a new type of hepatitis C virus(HCV)nonstructural protein 5A(NS5A)inhibitor,and the data of phase 2 trial has shown emitasvir-sofosbuvir to have good safety and tolerance.We conducted this phase 3 trial to further verify the efficacy and safety.Methods:We evaluated the antiviral activity and safety of a 12-week regimen of emitasvir phosphate(100 mg)combined with sofosbuvir(400 mg)once daily in non-cirrhotic patients with genotype 1 HCV infection.The primary endpoint was a sustained virological response at 12 weeks(SVR12)after the end of treatment.Results:Of the 362 patients enrolled in the trial,39.8%were male,99.2%had HCV genotype 1b,0.8%had genotype 1a and 79.8%were treatment-naïve.The average age was 47.2 years.All patients completed the treatment and follow-up.All 3 patients with genotype 1a achieved SVR.Two genotype 1b treatment-naïve patients experienced virologic relapse.The rate of SVR12 was 99.7%(358/359),and SVR24 was 99.4%(357/359)in genotype 1b.Overall,36.2%had resistance-associated substitutions(RASs)in NS5A and 98.3%had RASs in NS5B at baseline.The RASs at baseline had no effect on the rates of response.Serious adverse events were reported in 16 patients and were not related to emitasvir-sofosbuvir.Most adverse events did not require therapy.Conclusions:The 12 weeks of treatment with emitasvir-sofosbuvir was a highly efficient and safe treatment for a wide range of patients with HCV genotype 1b infection without cirrhosis,who had not been treated or who had been treated with interferon-based regimen previously.

Hepatitis B Virus Induces Microtubule Stabilization to Promote Productive Infection through Upregulating Microtubule-associated Protein 1S

Background and Aims:Continuous release and transmission of hepatitis B virus(HBV)is one of the main factors leading to chronic hepatitis B(CHB)infection.However,the mechanism of HBV-host interaction for optimal viral transport is unclear.Hence,we aimed to explore how HBV manipulates microtubule-associated protein 1S(MAP1S)and microtubule(MT)to facilitate its transport and release.Methods:The expression of MAP1S or acetylated MT was investigated by immunofluorescence,RT-PCR,immunoblotting,and plasmid transfection.MAP1S overexpression or knockdown was performed by lentiviral infection or shRNA transfection,respectively.HBV DNA was quantified using q-PCR.Results:Significantly higher level of MAP1S in HepG2215 cells compared with HepG2 cells was detected using RT-PCR(p<0.01)and immunoblotting(p<0.001).Notably,stronger MAP1S expression was observed in the liver tissues of patients with CHB than in healthy controls.MAP1S overexpression or knockdown demonstrated that MAP1S promoted MT acetylation and reduced the ratio of HBV DNA copies inside to outside cells.Further,transfection with the hepatitis B virus X protein(HBx)-expressing plasmids induced significantly higher level of MAP1S than that in controls(p<0.0001),whereas HBVX−mutant-encoding HBV proteins(surface antigen,core protein,and viral DNA polymerase)hardly affected its expression.Conclusions:These results demonstrate that HBx induces the forma tion of stable MTs to promote the release of HBV particles through upregulating MAP1S.Thus,our studies delineate a unique molecular pathway through which HBV manipulates the cytoskeleton to facilitate its own transportation,and indicate the possibility of targeting MAP1S pathway for treatment of patients with CHB.