Abstract:
BACKGROUND & AIMS:To evaluate the hypothesis that increasing T cell frequency and activity may provide durable control of hepatitis B virus (HBV), we administered nivolumab, a programmed death receptor 1 (PD-1) inhibitor, with or without GS-4774, an HBV therapeutic vaccine, in virally suppressed patients with HBV e antigen (HBeAg)-negative chronic HBV. METHODS:In a phase Ib study, patients received either a single dose of nivolumab at 0.1 mg/kg (n = 2) or 0.3 mg/kg (n = 12), or 40 yeast units of GS-4774 at baseline and week 4 and 0.3 mg/kg of nivolumab at week 4 (n = 10). The primary efficacy endpoint was mean change in HBV surface antigen (HBsAg) 12 weeks after nivolumab. Safety and immunologic changes were assessed through week 24. RESULTS:There were no grade 3 or 4 adverse events or serious adverse events. All assessed patients retained T cell PD-1 receptor occupancy 6-12 weeks post-infusion, with a mean total across 0.1 and 0.3 mg/kg cohorts of 76% (95% CI 75-77), and no significant differences were observed between cohorts (p = 0.839). Patients receiving 0.3 mg/kg nivolumab without and with GS-4774 had mean declines of -0.30 (95% CI -0.46 to -0.14) and -0.16 (95% CI -0.33 to 0.01) log10 IU/ml, respectively. Patients showed significant HBsAg declines from baseline (p = 0.035) with 3 patients experiencing declines of >0.5 log10 by the end of study. One patient, whose HBsAg went from baseline 1,173 IU/ml to undetectable at week 20, experienced an alanine aminotransferase flare (grade 3) at week 4 that resolved by week 8 and was accompanied by a significant increase in peripheral HBsAg-specific T cells at week 24. CONCLUSIONS:In virally suppressed HBeAg-negative patients, checkpoint blockade was well-tolerated and led to HBsAg decline in most patients and sustained HBsAg loss in 1 patient. LAY SUMMARY:Chronic hepatitis B virus infection (CHB) is characterized by a dysfunctional immune response. In patients with CHB, inhibitory receptors, such as programmed death receptor 1 (PD-1) are overexpressed on T cells, leading to an ineffective immune response in the liver. Herein, we show that the PD-1 inhibitor, nivolumab, is safe and effective for the treatment of virally suppressed patients with CHB. Australian New Zealand Clinical Trials Registry (http://www.anzctr.org.au/) number: ACTRN12615001133527.
journal_name
J Hepatoljournal_title
Journal of hepatologyauthors
Gane E,Verdon DJ,Brooks AE,Gaggar A,Nguyen AH,Subramanian GM,Schwabe C,Dunbar PRdoi
10.1016/j.jhep.2019.06.028subject
Has Abstractpub_date
2019-11-01 00:00:00pages
900-907issue
5eissn
0168-8278issn
1600-0641pii
S0168-8278(19)30400-3journal_volume
71pub_type
杂志文章abstract:BACKGROUND & AIMS:Current techniques for predicting outcome and requirement for emergency liver transplantation (ELT) in acute liver failure (ALF) are imperfect, though The Kings College Criteria (KCC) are the most commonly applied tools for this purpose. Their performance in identification of patients with non-paracet...
journal_title:Journal of hepatology
pub_type: 杂志文章,meta分析
doi:10.1016/j.jhep.2010.03.023
更新日期:2010-09-01 00:00:00
abstract::Guinea pig Kupffer cells were obtained by partial digestion of the liver with pronase and collagenase and purified by centrifugal elutriation. Cells were kept in monolayer culture and their capacity to secrete superoxide anion in response to phagocytosis of zymosan was determined by the cytochrome c method. Compared t...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(88)80006-0
更新日期:1988-12-01 00:00:00
abstract::Recently, GBV-C and HGV-two isolates of the same new flavivirus-were identified in serum samples of patients with indeterminate hepatitis and posttransfusion hepatitis, respectively. The pathogenic relevance of these viruses is still uncertain. As viral infections are presumed to trigger autoimmune processes, we inves...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(96)80306-0
更新日期:1996-12-01 00:00:00
abstract:BACKGROUND/AIMS:Type 2 autoimmune hepatitis (AIH) is characterized by the presence of anti-liver kidney microsome (anti-LKM-1) and/or anti-liver cytosol type 1 (anti-LC1) autoantibodies. However, the correlation between these autoantibodies and the genetic background has not been studied. METHODS:Frequencies of HLA cl...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2006.07.034
更新日期:2006-12-01 00:00:00
abstract::Because of the tremendous success of clinical transplantation of the liver and other organs in the last three decades, the demand for organs for transplantation has risen sharply and there is now a substantial shortage. The utilization of organs from other species, xenotransplantation, is increasingly viewed as a pote...
journal_title:Journal of hepatology
pub_type: 杂志文章,评审
doi:10.1016/s0168-8278(96)80082-1
更新日期:1996-08-01 00:00:00
abstract:BACKGROUND/AIMS:Bacillus Calmette Guerin (BCG) infection causes hepatic injury following granuloma formation and secretion of cytokines which render mice highly sensitive to endotoxin-mediated hepatotoxicity. This work investigates the role of inducible nitric oxide synthase (iNOS) in liver damage induced by BCG and en...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2004.07.031
更新日期:2004-11-01 00:00:00
abstract:BACKGROUND/AIMS:Norfloxacin is useful to prevent infections in hospitalized cirrhotic patients with low ascitic fluid protein concentrations. It is also effective in preventing the recurrence of spontaneous bacterial peritonitis. The aim of our study was to determine the efficacy of norfloxacin in the primary prophylax...
journal_title:Journal of hepatology
pub_type: 临床试验,杂志文章,多中心研究,随机对照试验
doi:10.1016/s0168-8278(98)80061-5
更新日期:1998-09-01 00:00:00
abstract:BACKGROUND & AIMS:Patients listed with exception points for hepatocellular carcinoma (HCC) have been more likely to be transplanted than those listed for chronic liver failure (LF) based on the model for end-stage liver disease (MELD) score. The aim of this study was to determine outcomes in the 5-year experience of a ...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2016.10.008
更新日期:2017-02-01 00:00:00
abstract:BACKGROUND & AIMS:Autophagy plays a crucial role in hepatic homeostasis and its deregulation has been associated with chronic liver disease. However, the effect of autophagy on the release of fibrogenic extracellular vesicles (EVs) by platelet-derived growth factor (PDGF)-stimulated hepatic stellate cells (HSCs) remain...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2020.04.044
更新日期:2020-11-01 00:00:00
abstract::A substantial production of prostaglandin E2 (PGE2) was induced in primary cultures of rat Kupffer cells by zymosan, calcium ionophore A23187, phorbol ester and arachidonic acid, whereas contact with latex particles, glucan or immunocomplexes led to a minor PGE2 release only. Superoxide generation, on the other hand, ...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(88)80028-x
更新日期:1988-04-01 00:00:00
abstract:BACKGROUND:Chronic liver disease and liver transplantation (LT) can delay both timing and ability of women to conceive. With increased awareness and availability of in vitro fertilisation (IVF), the need for accurate counselling is paramount. To date, minimal data exists to inform outcomes of IVF in patients with chron...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2020.12.022
更新日期:2021-01-15 00:00:00
abstract:BACKGROUND/AIMS:Although matrix metalloproteinases (MMPs) and their specific inhibitors (TIMPs) play an essential role in liver injury associated with tissue remodeling, the cellular origin of MMPs/TMPs within the liver remains to be clarified. METHODS:Different liver cell populations were analysed with respect to the...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(99)80007-5
更新日期:1999-01-01 00:00:00
abstract:BACKGROUND & AIMS:Hepatitis B virus (HBV) and D virus (HDV) co-infections cause the most severe form of viral hepatitis. HDV induces an innate immune response, but it is unknown how the host cell senses HDV and if this defense affects HDV replication. We aim to characterize interferon (IFN) activation by HDV, identify ...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2018.02.021
更新日期:2018-07-01 00:00:00
abstract::Ten patients with non-alcoholic cirrhosis and ten control subjects were studied in basal conditions and after ingestion of a standard mixed test meal. Plasma somatostatin, blood glucose, plasma insulin, C-peptide and glucagon were determined before and 15, 30, 45, 60, 90, 120 and 180 min after the start of the meal. B...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/0168-8278(91)90906-r
更新日期:1991-01-01 00:00:00
abstract:BACKGROUND/AIMS:IgM antibodies to hepatitis C virus have been found in a variable proportion of patients with chronic hepatitis C. We have evaluated whether IgM anti-core antibodies correlate with viraemia or hepatic injury in chronic hepatitis C. METHODS:Serum from 106 patients with chronic hepatitis C with varying s...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(96)80181-4
更新日期:1996-01-01 00:00:00
abstract:BACKGROUND & AIMS:Biliary atresia represents obstructive cholangiopathy in infants progressing rapidly to cirrhosis and end-stage liver disease. Activated NK cells expressing Nkg2d have been linked to bile duct injury and obstruction by establishing contact with cholangiocytes. To define the mechanisms used by cytotoxi...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2013.09.021
更新日期:2014-02-01 00:00:00
abstract::Liver disease is common in patients with cystic fibrosis, but the pathogenesis is poorly understood. The chronic colonization of bacteria in the lower airways leads to repeated treatments with antibiotics, especially aminoglycosides in high dosages. To investigate the possible role of aminoglycoside treatment in the n...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(05)80058-3
更新日期:1994-02-01 00:00:00
abstract:BACKGROUND & AIMS:Non-selective beta blockers (NSBBs) have been shown to have deleterious outcomes in patients with refractory ascites, alcoholic hepatitis and spontaneous bacterial peritonitis leading many physicians to stop the drug in these cases. Acute-on-chronic liver failure (ACLF) is characterized by systemic in...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2015.10.018
更新日期:2016-03-01 00:00:00
abstract:BACKGROUND & AIMS:The pathogenesis of autoimmune hepatitis (AIH) is not understood, but it was suggested that AIH may be related to a numerical or functional impairment of CD4+CD25+FOXP3+ regulatory T cells (Treg), which are important mediators of immune tolerance to self-antigens. However, the role of Treg in AIH is n...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2012.02.029
更新日期:2012-07-01 00:00:00
abstract::Interferon-alpha therapy has a beneficial effect in 30-40% of selected patients with chronic hepatitis B who respond by clearing hepatitis B e antigen (HBeAg) and hepatitis B viral (HBV) DNA from serum. This is usually associated with normalization of serum aminotransferase activities. On long-term follow-up of treate...
journal_title:Journal of hepatology
pub_type: 杂志文章,评审
doi:
更新日期:1995-01-01 00:00:00
abstract::Worldwide, the increasingly dominant model of laboratory testing is the centralised laboratory, in which automation of analytical processes increases, enabling the analysis of large numbers of samples at a relatively low cost. However, this trend does not fulfil the requirements for care of patients with chronic hepat...
journal_title:Journal of hepatology
pub_type: 杂志文章,评审
doi:10.1016/j.jhep.2018.05.017
更新日期:2018-10-01 00:00:00
abstract::Intravascular coagulation is involved in the development of certain types of liver injury, including that induced by dimethylnitrosamine. Nitric oxide inhibits platelet aggregation and adhesion; however, its role in protecting against intravascular coagulation has not been clarified. We therefore investigated the effe...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/0168-8278(95)80068-9
更新日期:1995-11-01 00:00:00
abstract:BACKGROUND/AIMS:A 4977-base pair deletion has been detected in the hepatic mitochondrial DNA of alcoholic patients with microvesicular steatosis, a lesion ascribed to impaired mitochondrial beta-oxidation. However, only a single deletion had been looked for in this previous study, and it could not be determined whether...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(97)80286-3
更新日期:1997-07-01 00:00:00
abstract:BACKGROUND & AIMS:Hepatic steatosis is an important factor in pathogenesis, progression and response to treatment in hepatitis C. We aimed to investigate differences in hepatic lipid composition in liver biopsies from patients with chronic hepatitis C using proton magnetic resonance spectroscopy ((1)H MRS) and to trans...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2009.10.006
更新日期:2010-01-01 00:00:00
abstract:BACKGROUND/AIMS:Selective cyclooxygenase (COX)-2 inhibitors do not adversely affect renal function in experimental cirrhosis. In the current study, we investigated the molecular mechanisms underlying the effects of the selective COX-2 inhibitor, celecoxib, and assessed the influence of albumin on its actions. METHODS:...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2004.09.011
更新日期:2005-01-01 00:00:00
abstract::This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. ...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2015.01.037
更新日期:2015-02-10 00:00:00
abstract:BACKGROUND/AIMS:The tropical parasite Schistosoma mansoni causes granulomatous inflammation following lodging of eggs in portal capillaries. In vitro studies indicated that the host reaction should involve reactive oxygen intermediates; however, it is not known what occurs in vivo at the site of the disease. Moreover, ...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/s0168-8278(99)80189-5
更新日期:1999-04-01 00:00:00
abstract:BACKGROUND & AIMS:Number-needed-to-treat is used in assessing the effectiveness of a health-care intervention, and reports the number of patients who need to be treated to prevent one additional bad outcome. Although largely used in medical literature, there are no studies measuring the benefit of liver transplantation...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2014.01.022
更新日期:2014-06-01 00:00:00
abstract:BACKGROUND & AIMS:Hepatocellular carcinoma (HCC) is an aggressive cancer with a poor prognosis mainly due to metastasis. MicroRNAs are endogenous small noncoding RNAs that regulate cellular gene expression and are functionally linked to tumourigenesis. Using microarray analysis, we recently identified 20 miRNAs associa...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2009.12.025
更新日期:2010-05-01 00:00:00
abstract:BACKGROUND & AIMS:Chronic hepatitis C virus (HCV)-infected patients with cirrhosis are a high-priority population for treatment. To help inform the benefit-risk profile of the all-oral direct-acting antiviral (DAA) combination regimen of ombitasvir, paritaprevir, and ritonavir, with or without dasabuvir (OBV/PTV/r±DSV)...
journal_title:Journal of hepatology
pub_type: 杂志文章,评审
doi:10.1016/j.jhep.2017.06.011
更新日期:2017-10-01 00:00:00