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Background and Aims: RO7062931 is an N-acetylgalactosamine (GalNAc)-conjugated single-stranded locked nucleic acid oligonucleotide complementary to HBV RNA. GalNAc conjugation targets the liver through the asialoglycoprotein receptor (ASGPR). This two-part phase 1 study evaluated the safety, pharmacokinetics, and pharmacodynamics of RO7062931 in healthy volunteers and patients with chronic hepatitis B (CHB) who were virologically suppressed., Approach and Results: Part 1 was a single ascending dose study in healthy volunteers randomized to receive a single RO7062931 dose (0.1-4.0 mg/kg), or placebo. Part 2 was a multiple ascending dose study in patients with CHB randomized to receive RO7062931 at 0.5, 1.5, or 3.0 mg/kg or placebo every month for a total of 2 doses (Part 2a) or RO7062931 at 3.0 mg/kg every 2 weeks, 3.0 mg/kg every week (QW), or 4.0 mg/kg QW or placebo for a total of 3-5 doses (Part 2b). Sixty healthy volunteers and 59 patients received RO7062931 or placebo. The majority of adverse events (AEs) reported were mild in intensity. Common AEs included self-limiting injection site reactions and influenza-like illness. Supradose-proportional increases in RO7062931 plasma exposure and urinary excretion occurred at doses ≥3.0 mg/kg. In patients with CHB, RO7062931 resulted in dose-dependent and time-dependent reduction in HBsAg versus placebo. The greatest HBsAg declines from baseline were achieved with the 3.0 mg/kg QW dose regimen (mean nadir ~0.5 log 10  IU/mL) independent of HBeAg status., Conclusions: RO7062931 is safe and well tolerated at doses up to 4.0 mg/kg QW. Supradose-proportional exposure at doses of 3.0-4.0 mg/kg was indicative of partial saturation of the ASGPR-mediated liver uptake system. Dose-dependent declines in HBsAg demonstrated target engagement with RO7062931., (© 2021 Roche Products Ltd. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Unlabelled: Transarterial chemoembolization (TACE) is the current standard of treatment for unresectable intermediate-stage hepatocellular carcinoma (HCC). Brivanib, a selective dual inhibitor of vascular endothelial growth factor and fibroblast growth factor signaling, may improve the effectiveness of TACE when given as an adjuvant to TACE. In this multinational, randomized, double-blind, placebo-controlled, phase III study, 870 patients with TACE-eligible HCC were planned to be randomly assigned (1:1) after the first TACE to receive either brivanib 800 mg or placebo orally once-daily. The primary endpoint was overall survival (OS). Secondary endpoints included time to disease progression (TTDP; a composite endpoint based on development of extrahepatic spread or vascular invasion, deterioration of liver function or performance status, or death), time to extrahepatic spread or vascular invasion (TTES/VI), rate of TACE, and safety. Time to radiographic progression (TTP) and objective response rate were exploratory endpoints. The trial was terminated after randomization of 502 patients (brivanib, 249; placebo, 253) when two other phase III studies of brivanib in advanced HCC patients failed to meet OS objectives. At termination, median follow-up was approximately 16 months. Intention-to-treat analysis showed no improvement in OS with brivanib versus placebo (median, 26.4 [95% confidence interval {CI}: 19.1 to not reached] vs. 26.1 months [19.0-30.9]; hazard ratio [HR]: 0.90 [95% CI: 0.66-1.23]; log-rank P=0.5280). Brivanib improved TTES/VI (HR, 0.64 [95% CI: 0.45-0.90]), TTP (0.61 [0.48-0.77]), and rate of TACE (0.72 [0.61-0.86]), but not TTDP (0.94 [0.72-1.22]) versus placebo. Most frequent grade 3-4 adverse events included hyponatremia (brivanib, 18% vs. placebo, 5%) and hypertension (13% vs. 3%)., Conclusions: In this study, brivanib as adjuvant therapy to TACE did not improve OS., (© 2014 by the American Association for the Study of Liver Diseases.)

Unlabelled: As there is currently a lack of consensus on the most appropriate dose and duration of peginterferon alfa-2a (PEG-IFNα-2a) therapy in hepatitis B e antigen (HBeAg)-positive patients, the efficacy and safety of either 24 or 48 weeks' duration and 90 μg/week or 180 μg/week doses were compared. HBeAg-positive patients (n = 544; 34% genotype B, 51% genotype C) were randomized to receive PEG-IFNα-2a (2 × 2 factorial design) for 24 or 48 weeks and at 90 μg/week or 180 μg/week and included in the per-protocol population. The primary efficacy endpoint of the noninferiority study was HBeAg seroconversion 6 months posttreatment. The prespecified odds ratio (OR) noninferiority margin was 1.88 with a one-sided significance level of 0.025. The highest rates of HBeAg seroconversion 6 months posttreatment were in the 180/48 arm (36.2% versus 14.1%-25.8% in the other arms). When the dose and duration arms were pooled, the OR for noninferiority of 24 weeks versus 48 weeks was 2.17 (95% confidence interval [CI] 1.43, 3.31; P = 0.749) and for 90 μg versus 180 μg was 1.79 (95% CI 1.18, 2.72; P = 0.410). As the upper limit of the 95% CI of the ORs were >1.88, 24 weeks were inferior to 48 weeks and 90 μg/week was inferior to 180 μg/week. The highest rates of response in the 180/48 arm were achieved by patients with HBsAg <1,500 IU/mL at Week 12 (58%) or Week 24 (57%), whereas patients with HBsAg >20,000 IU/mL did not respond. Adverse events were typical of those associated with PEG-IFNα-2a., Conclusion: Compared with lower doses and shorter durations, the licensed PEG-IFNα-2a treatment regimen (180 μg/48 weeks) was the most efficacious and beneficial for HBeAg-positive patients predominantly infected with hepatitis B virus genotypes B or C., (Copyright © 2011 American Association for the Study of Liver Diseases.)

A randomized, open-label comparative study of entecavir versus adefovir therapy was performed in subjects with chronic hepatitis B who had hepatic decompensation (Child-Turcotte-Pugh score ≥7). Adult subjects were randomized and treated (n = 191) with entecavir 1.0 mg or adefovir 10 mg daily for up to 96 weeks from the date of last subject randomization. Subjects were positive or negative for hepatitis B e antigen and experienced or naive for treatment with nucleos(t)ide analogues. The primary efficacy endpoint was the mean reduction in serum hepatitis B virus (HBV) DNA, as determined by polymerase chain reaction, at week 24, adjusted for baseline HBV DNA and lamivudine resistance status by linear regression analysis. Entecavir demonstrated superiority to adefovir for this endpoint (treatment difference 1.74 log(10) copies/mL [95% confidence interval -2.30, -1.18]; P < 0.0001). The entecavir group showed a greater change from baseline in HBV DNA at all time points through week 48 and a higher proportion of subjects who achieved HBV DNA < 300 copies/mL at weeks 24 (entecavir 49%; adefovir 16%; P < 0.0001) and 48 (entecavir 57%; adefovir 20%; P < 0.0001). Approximately two-thirds of subjects in both groups showed improvement/stabilization in Child-Turcotte-Pugh status. Model for End-Stage Liver Disease score change at week 48 was -2.6 for entecavir and -1.7 for adefovir. Adverse event rates were comparable between groups. Cumulative hepatocellular carcinoma rates were 12% for entecavir and 20% for adefovir. Cumulative death rates were 23% for entecavir and 33% for adefovir. Week 24 mortality rates were 12% for both groups. conclusion: Entecavir demonstrated superior virologic efficacy to adefovir in a population of patients with chronic hepatitis B who had hepatic decompensation. Biochemical and clinical benefits were also demonstrated. Entecavir was well tolerated, and early mortality rates were consistent with rates observed in similar populations treated with lamivudine., (Copyright © 2011 American Association for the Study of Liver Diseases.)

Unlabelled: Current guidelines for management of chronic hepatitis B recommend treatment for patients presenting with elevated hepatitis B virus (HBV) DNA and alanine aminotransferase (ALT) >2 x upper limit of normal (ULN) or histological evidence of liver disease. Retrospective analyses have demonstrated that significant hepatic necroinflammation and fibrosis were present in a substantial proportion of patients with ALT 1 to 2 x ULN. To assess therapeutic efficacy in this clinical setting, we retrospectively examined treatment endpoints among the subset of nucleoside-naïve chronic hepatitis B (CHB) patients treated in phase 3 clinical trials of entecavir who had both screening and baseline serum ALT 1.3 to 2 x ULN. A total of 1347 patients were randomized to treatment with entecavir or lamivudine. Three hundred thirty-six patients, constituting 25% of the total study population, had screening and baseline ALT 1.3 to 2 x ULN. Clinically significant necroinflammation (Knodell necroinflammation score > or =7) was observed in 60% and 72% of hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients, respectively, whereas marked fibrosis (Ishak fibrosis score > or =4) was observed in 8% and 15% of HBeAg-positive and HBeAg-negative patients, respectively. Among entecavir-treated HBeAg-negative patients, the proportions of patients achieving histological improvement, HBV DNA <300 copies/mL, and ALT normalization were similar between patients with mildly elevated ALT and those with ALT >2 x ULN. However, entecavir-treated HBeAg-positive patients with mildly elevated ALT had lower response rates for histological improvement, HBV DNA less than 300 copies/mL, ALT normalization, and HBeAg seroconversion than those with ALT greater than 2 x ULN., Conclusion: This retrospective analysis demonstrated that HBeAg-negative CHB patients treated with entecavir responded similarly irrespective of baseline ALT level. However, HBeAg-positive patients with mildly elevated ALT responded less well to treatment with entecavir than did those with ALT greater than 2 x ULN.

Persons with non-A, non-B hepatitis (cases) identified in 5 transfusion studies in the early 1970s have been followed ever since and compared for outcome with matched, transfused, non-hepatitis controls from the same studies. Previously, we reported no difference in all-cause mortality but slightly increased liver-related mortality between these cohorts after 18 years follow-up. We now present mortality and morbidity data after approximately 25 years of follow-up, restricted to the 3 studies with archived original sera. All-cause mortality was 67% among 222 hepatitis C-related cases and 65% among 377 controls (P = NS). Liver-related mortality was 4.1% and 1.3%, respectively (P =.05). Of 129 living persons with previously diagnosed transfusion-associated hepatitis (TAH), 90 (70%) had proven TAH-C, and 39 (30%), non-A-G hepatitis. Follow-up of the 90 TAH-C cases revealed viremia with chronic hepatitis in 38%, viremia without chronic hepatitis in 39%, anti-HCV without viremia in 17%, and no residual HCV markers in 7%. Thirty-five percent of 20 TAH-C patients biopsied for biochemically defined chronic hepatitis displayed cirrhosis, representing 17% of all those originally HCV-infected. Clinically evident liver disease was observed in 86% with cirrhosis but in only 23% with chronic hepatitis alone. Thirty percent of non-A, non-B hepatitis cases were unrelated to hepatitis viruses A,B,C, and G, suggesting another unidentified agent. In conclusion, all-cause mortality approximately 25 years after acute TAH-C is high but is no different between cases and controls. Liver-related mortality attributable to chronic hepatitis C, though low (<3%), is significantly higher among the cases. Among living patients originally HCV-infected, 23% have spontaneously lost HCV RNA.