Aims:Previous studies have shown that hepatitis B virus(HBV)–related disease progression involves gut microbiota dysbiosis linked to inflammation,endotoxin translocation,and immune imbalance.While the artificial live...Aims:Previous studies have shown that hepatitis B virus(HBV)–related disease progression involves gut microbiota dysbiosis linked to inflammation,endotoxin translocation,and immune imbalance.While the artificial liver support system(ALSS)improves liver function and inflammation,its impact on the gut microbiome remains unclear.This study aimed to investigate changes in the gut microbiota of healthy individuals(healthy control[HC]group),patients with chronic hepatitis B(CHB group),patients with HBV-related acute-on-chronic liver failure(HBV-ACLF group),and patients after ALSS treatment.Methods:This single-center,prospective study enrolled 89 participants from the Infectious Disease Center of West China Hospital,Sichuan University,between October 2019 and December 2021,comprising the HC(n=11),CHB(n=24),HBV-ACLF(n=54),and ALSS(n=39 patients from the HBV-ACLF group who received three sessions of ALSS treatment)groups.We analyzed the diversity,composition,and characteristic microbial taxa of the gut microbiota under different disease con-ditions and evaluated the impact of ALSS treatment on gut microbiota dysbiosis.Fecal microbiota was analyzed by 16S ribosomal RNA sequencing.Microbial characteristics were assessed throughα-diversity(Chao1,Shannon,and Simpson indices)andβ-diversity(principal coordinate analysis).Statistical analysis was performed using the Kruskal–Wallis test,and the linear discriminant analysis(LDA)effect size(LEfSe)analysis was used to identify the characteristic microbial taxa among the different groups.Results:ALSS treatment significantly reduced serum total bilirubin(HBV-ACLF:370.64±113.13 vs.ALSS:203.08±118.70µmol/L,t=7.45,p<0.001),decreased creatinine levels(HBV-ACLF:107.14±55.45 vs.ALSS:82.43±57.16µmol/L,t=2.11,p=0.039),and modestly decreased albumin levels(HBV-ACLF:31.68±3.62 vs.ALSS:29.88±4.01 g/L,t=2.27,p=0.026).Microbial richness was significantly lower in the CHB group compared with HC(Chao1 index:W=198,p=0.018).Microbial diversity also declined,with Shannon and Simpson indices significantly reduced in the HBV-ACLF group compared with CHB(Shannon:W=898,p=0.007;Simpson:W=883,p=0.011),and similar reductions observed in the ALSS group(Shannon:W=643,p=0.013;Simpson:W=660,p=0.006).β-diversity analysis revealed distinct microbial community structures among groups(Adonis R2=0.98576,p=0.042).LEfSe analysis showed enrichment of Escherichia–Shigella and Enterococcus in HBV-ACLF,while ALSS reduced their relative abundance,suggesting a partial restoration of gut microbial balance.展开更多
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...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.展开更多
Background and Aims:Genotype(GT)1 remains the predominant hepatitis c virus(HCV)GT in Chinese patients.Over 80%of those Chinese patients harbor the interferon-sensitive CC allele of IFNL4rs12979860,which is favorable ...Background and Aims:Genotype(GT)1 remains the predominant hepatitis c virus(HCV)GT in Chinese patients.Over 80%of those Chinese patients harbor the interferon-sensitive CC allele of IFNL4rs12979860,which is favorable for interferon-based treatment regimens.This phaseⅢclinical trial aimed to evaluate the efficacy and safety of the ritonavirboosted danoprevir plus pegylated-interferonα-2a and ribavirin regimen for 12 weeks in treatment-na(i)ve mainland Chinese patients infected with HCV GT1 without cirrhosis.Methods:One hundred and forty-one treatment-na(i)ve,non-cirrhotic HCV GT1 Chinese patients(age≥18 years)were enrolled for this single-arm,multicenter,phaseⅢMANASA study(NCT03020082).Patients received a combination of ritonavir-boosted danoprevir(100 mg/100 mg)twice a day plus subcutaneous injection of weekly pegylated-interferonα-2a(180μg)and oral ribavirin(1000/1200 mg/day body weight<75/≥75 kg)for 12 weeks.The primary end-point was sustained virologic response rate at 12 weeks after the end of treatment.The secondary end-points were safety outcomes,tolerability,virologic response over time and relapse rate.Results:All enrolled patients were HCV GT1-infected,and most among them(97.9%,123/141)had the HCV GT1b subtype.Single-nucleotide polymorphism test showed that the majority of patients were of the IFNL4 rs12979860 CC genotype(87.2%,123/141).Overall,140 patients completed the 12-week treatment,and 97.1%(136/140)patients achieved sustained virologic response at 12 weeks(per protocol population group,95%confidence interval:92.9-99.2%).Only drug-related serious adverse event occurred.Most of the adverse events were grade 1 and grade 2 alanine aminotransferase elevation or liver dysfunction.One patient discontinued treatment because of severe head injury in a car accident.Conclusions:The triple regimen of ritonavir-boosted danoprevir plus pegylated-interferonα-2a and ribavirin produced a sustained virologic response rate of 97.1%after 12 weeks treatment in noncirrhotic HCV GT1-infected Chinese patients,and was safe and well tolerated.展开更多
基金supported by the National Key Research and Development Program of China(No.2022YFC2304800)1.3.5 project for disciplines of excellence,West China Hospital,Sichuan University(No.ZYJC21014).
文摘Aims:Previous studies have shown that hepatitis B virus(HBV)–related disease progression involves gut microbiota dysbiosis linked to inflammation,endotoxin translocation,and immune imbalance.While the artificial liver support system(ALSS)improves liver function and inflammation,its impact on the gut microbiome remains unclear.This study aimed to investigate changes in the gut microbiota of healthy individuals(healthy control[HC]group),patients with chronic hepatitis B(CHB group),patients with HBV-related acute-on-chronic liver failure(HBV-ACLF group),and patients after ALSS treatment.Methods:This single-center,prospective study enrolled 89 participants from the Infectious Disease Center of West China Hospital,Sichuan University,between October 2019 and December 2021,comprising the HC(n=11),CHB(n=24),HBV-ACLF(n=54),and ALSS(n=39 patients from the HBV-ACLF group who received three sessions of ALSS treatment)groups.We analyzed the diversity,composition,and characteristic microbial taxa of the gut microbiota under different disease con-ditions and evaluated the impact of ALSS treatment on gut microbiota dysbiosis.Fecal microbiota was analyzed by 16S ribosomal RNA sequencing.Microbial characteristics were assessed throughα-diversity(Chao1,Shannon,and Simpson indices)andβ-diversity(principal coordinate analysis).Statistical analysis was performed using the Kruskal–Wallis test,and the linear discriminant analysis(LDA)effect size(LEfSe)analysis was used to identify the characteristic microbial taxa among the different groups.Results:ALSS treatment significantly reduced serum total bilirubin(HBV-ACLF:370.64±113.13 vs.ALSS:203.08±118.70µmol/L,t=7.45,p<0.001),decreased creatinine levels(HBV-ACLF:107.14±55.45 vs.ALSS:82.43±57.16µmol/L,t=2.11,p=0.039),and modestly decreased albumin levels(HBV-ACLF:31.68±3.62 vs.ALSS:29.88±4.01 g/L,t=2.27,p=0.026).Microbial richness was significantly lower in the CHB group compared with HC(Chao1 index:W=198,p=0.018).Microbial diversity also declined,with Shannon and Simpson indices significantly reduced in the HBV-ACLF group compared with CHB(Shannon:W=898,p=0.007;Simpson:W=883,p=0.011),and similar reductions observed in the ALSS group(Shannon:W=643,p=0.013;Simpson:W=660,p=0.006).β-diversity analysis revealed distinct microbial community structures among groups(Adonis R2=0.98576,p=0.042).LEfSe analysis showed enrichment of Escherichia–Shigella and Enterococcus in HBV-ACLF,while ALSS reduced their relative abundance,suggesting a partial restoration of gut microbial balance.
基金Ascletis BioScience Co.,Ltd.provided financial support for this study
文摘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.
基金Ascletis Pharmaceuticals Co.,Ltd.provided financial support for this study(MANASA)
文摘Background and Aims:Genotype(GT)1 remains the predominant hepatitis c virus(HCV)GT in Chinese patients.Over 80%of those Chinese patients harbor the interferon-sensitive CC allele of IFNL4rs12979860,which is favorable for interferon-based treatment regimens.This phaseⅢclinical trial aimed to evaluate the efficacy and safety of the ritonavirboosted danoprevir plus pegylated-interferonα-2a and ribavirin regimen for 12 weeks in treatment-na(i)ve mainland Chinese patients infected with HCV GT1 without cirrhosis.Methods:One hundred and forty-one treatment-na(i)ve,non-cirrhotic HCV GT1 Chinese patients(age≥18 years)were enrolled for this single-arm,multicenter,phaseⅢMANASA study(NCT03020082).Patients received a combination of ritonavir-boosted danoprevir(100 mg/100 mg)twice a day plus subcutaneous injection of weekly pegylated-interferonα-2a(180μg)and oral ribavirin(1000/1200 mg/day body weight<75/≥75 kg)for 12 weeks.The primary end-point was sustained virologic response rate at 12 weeks after the end of treatment.The secondary end-points were safety outcomes,tolerability,virologic response over time and relapse rate.Results:All enrolled patients were HCV GT1-infected,and most among them(97.9%,123/141)had the HCV GT1b subtype.Single-nucleotide polymorphism test showed that the majority of patients were of the IFNL4 rs12979860 CC genotype(87.2%,123/141).Overall,140 patients completed the 12-week treatment,and 97.1%(136/140)patients achieved sustained virologic response at 12 weeks(per protocol population group,95%confidence interval:92.9-99.2%).Only drug-related serious adverse event occurred.Most of the adverse events were grade 1 and grade 2 alanine aminotransferase elevation or liver dysfunction.One patient discontinued treatment because of severe head injury in a car accident.Conclusions:The triple regimen of ritonavir-boosted danoprevir plus pegylated-interferonα-2a and ribavirin produced a sustained virologic response rate of 97.1%after 12 weeks treatment in noncirrhotic HCV GT1-infected Chinese patients,and was safe and well tolerated.
