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We describe a rare case of polyserositis with chylous ascites following nivolumab therapy, highlighting the challenges in recognising and managing immune-related adverse events (irAEs) associated with immune checkpoint inhibitors (ICPIs). Induced polyserositis and chylous ascites are very rare and require immunosuppressive treatment, with a variable response of high-dose IV steroids. LEARNING POINTS: Oncological therapy with immune checkpoint inhibitors (ICPIs) is frequently associated with immune-related adverse events (irAEs) most involving cutaneous, gastrointestinal and pulmonary sites.
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The development of steatotic liver disease after liver transplant (LT) is widely described, and epidemiological data have revealed an increased incidence in recent times. Its evolution runs from simple steatosis to steatohepatitis and, in a small proportion of patients, to significant fibrosis and cirrhosis. Apparently, post-LT steatotic disease has no impact on the recipient's overall survival; however, a higher cardiovascular and malignancy burden has been reported. Many donors' and recipients' risk factors have been associated with this occurrence, although the recipient-related ones seem of greater impact. Particularly, pre- and post-LT metabolic alterations are strictly associated with steatotic graft disease, sharing common pathophysiologic mechanisms that converge on insulin resistance. Other relevant risk factors include genetic variants, sex, age, baseline liver diseases, and immunosuppressive drugs. Diagnostic evaluation relies on liver biopsy, although non-invasive methods are being increasingly used to detect and monitor both steatosis and fibrosis stages. Management requires a multifaceted approach focusing on lifestyle modifications, the optimization of immunosuppressive therapy, and the management of metabolic complications. This review aims to synthesize the current knowledge of post-LT steatotic liver disease, focusing on the recent definition of metabolic-dysfunction-associated steatotic liver disease (MASLD) and its metabolic and multisystemic concerns.
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BACKGROUND & AIMS: In chronic HBV infection, elevated reactive oxygen species levels derived from dysfunctional mitochondria can cause increased protein oxidation and DNA damage in exhausted virus-specific CD8 T cells. The aim of this study was to understand how these defects are mechanistically interconnected to further elucidate T cell exhaustion pathogenesis and, doing so, to devise novel T cell-based therapies. METHODS: DNA damage and repair mechanisms, including parylation, CD38 expression, and telomere length were studied in HBV-specific CD8 T cells from chronic HBV patients. Correction of intracellular signalling alterations and improvement of antiviral T cell functions by the NAD precursor nicotinamide mononucleotide and by CD38 inhibition was assessed. RESULTS: Elevated DNA damage was associated with defective DNA repair processes, including NAD-dependent parylation, in HBV-specific CD8 cells of chronic HBV patients. NAD depletion was indicated by the overexpression of CD38, the major NAD consumer, and by the significant improvement of DNA repair mechanisms, and mitochondrial and proteostasis functions by NAD supplementation, which could also improve the HBV-specific antiviral CD8 T cell function. CONCLUSIONS: Our study delineates a model of CD8 T cell exhaustion whereby multiple interconnected intracellular defects, including telomere shortening, are causally related to NAD depletion suggesting similarities between T cell exhaustion and cell senescence. Correction of these deregulated intracellular functions by NAD supplementation can also restore antiviral CD8 T cell activity and thus represents a promising potential therapeutic strategy for chronic HBV infection. IMPACT AND IMPLICATIONS: Correction of HBV-specific CD8 T cell dysfunction is believed to represent a rational strategy to cure chronic HBV infection, which however requires a deep understanding of HBV immune pathogenesis to identify the most important targets for functional T cell reconstitution strategies. This study identifies a central role played by NAD depletion in the intracellular vicious circle that maintains CD8 T cell exhaustion, showing that its replenishment can correct impaired intracellular mechanisms and reconstitute efficient antiviral CD8 T cell function, with implications for the design of novel immune anti-HBV therapies. As these intracellular defects are likely shared with other chronic virus infections where CD8 exhaustion can affect virus clearance, these results can likely also be of pathogenetic relevance for other infection models.
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Hepatite B Crônica , Hepatite B , Humanos , NAD/metabolismo , Linfócitos T CD8-Positivos , Espécies Reativas de Oxigênio/metabolismo , Antivirais/uso terapêutico , Antivirais/metabolismo , Vírus da Hepatite B , Hepatite B/patologiaRESUMO
BACKGROUND: Long-term administration of TDF/ETV in patients with HBV-related compensated cirrhosis reduces HCC and decompensation events but the effect of this regimen on development/regression of oesophageal varices (EV) is currently unknown. AIM: To assess the risk of EV development/progression in this population. METHODS: A total of 186 Caucasian HBV-monoinfected compensated cirrhotics were enrolled in a long-term cohort study from TDF/ETV introduction. Upper GI endoscopies were performed according to Baveno recommendations. Primary endpoint was development/progression of oesophageal/gastric varices over time. RESULTS: At TDF/ETV start, median age was 61 years, 80% males, 60% HBV-DNA undetectable, 63% NUCs previously exposed, 73% normal ALT, 40% platelets <150,000/mmc and 25 (13%) with low-risk varices (LRV). During 11 years of antiviral therapy and 666 endoscopies performed, 9 patients either developed or had a progression of oesophageal or gastric varices with an 11-year cumulative probability of 5.1% (95% CI 3-10%); no patient bled. Out of 161 patients without EV at baseline, the 11-year probably was 4.5% with all varices developing within the first six years of treatment. In 25 patients with LRV at baseline, the 11-year probability of progression or regression was 9.3% and 58%, respectively. Only baseline platelet count (HR 0.96, p = 0.028) was associated with LRV development at multivariate analysis: platelet ≤90,000/mmc (AUROC 0.70) had 98.1% specificity, 42.9% sensitivity, 50% PPV for LRV onset. CONCLUSIONS: In compensated cirrhotic patients under long-term effective TDF/ETV treatment, the 11-year risk of developing/progressing EV is negligible, thus challenging the current endoscopic surveillance recommendations in patients without EV at baseline.
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Carcinoma Hepatocelular , Varizes Esofágicas e Gástricas , Neoplasias Hepáticas , Varizes , Masculino , Humanos , Pessoa de Meia-Idade , Feminino , Tenofovir , Antivirais , Vírus da Hepatite B/genética , Estudos de Coortes , Carcinoma Hepatocelular/complicações , Varizes Esofágicas e Gástricas/etiologia , Varizes Esofágicas e Gástricas/complicações , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/complicações , Cirrose Hepática/diagnóstico , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/complicações , Varizes/complicações , Resultado do TratamentoRESUMO
OBJECTIVE: Exhausted hepatitis B virus (HBV)-specific CD8 T cells in chronic HBV infection are broadly heterogeneous. Characterisation of their functional impairment may allow to distinguish patients with different capacity to control infection and reconstitute antiviral function. DESIGN: HBV dextramer+CD8 T cells were analysed ex vivo for coexpression of checkpoint/differentiation markers, transcription factors and cytokines in 35 patients with HLA-A2+chronic hepatitis B (CHB) and in 29 control HBsAg negative CHB patients who seroconverted after NUC treatment or spontaneously. Cytokine production was also evaluated in HBV peptide-stimulated T cell cultures, in the presence or absence of antioxidant, polyphenolic, PD-1/PD-L1 inhibitor and TLR-8 agonist compounds and the effect on HBV-specific responses was further validated on additional 24 HLA-A2 negative CHB patients. RESULTS: Severely exhausted HBV-specific CD8 T cell subsets with high expression of inhibitory receptors, such as PD-1, TOX and CD39, were detected only in a subgroup of chronic viraemic patients. Conversely, a large predominance of functionally more efficient HBV-specific CD8 T cell subsets with lower expression of coinhibitory molecules and better response to in vitro immune modulation, typically detected after resolution of infection, was also observed in a proportion of chronic viraemic HBV patients. Importantly, the same subset of patients who responded more efficiently to in vitro immune modulation identified by HBV-specific CD8 T cell analysis were also identified by staining total CD8 T cells with PD-1, TOX, CD127 and Bcl-2. CONCLUSIONS: The possibility to distinguish patient cohorts with different capacity to respond to immune modulatory compounds in vitro by a simple analysis of the phenotypic CD8 T cell exhaustion profile deserves evaluation of its clinical applicability.
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Hepatite B Crônica , Hepatite B , Humanos , Hepatite B Crônica/tratamento farmacológico , Vírus da Hepatite B , Antígeno HLA-A2/metabolismo , Antígeno HLA-A2/farmacologia , Antígeno HLA-A2/uso terapêutico , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T CD8-PositivosRESUMO
BACKGROUND AND AIMS: COVID-19 mRNA vaccines were approved to prevent severe forms of the disease, but their immunogenicity and safety in cirrhosis is poorly known. METHOD: In this prospective single-center study enrolling patients with cirrhosis undergoing COVID-19 vaccination (BNT162b2 and mRNA-1273), we assessed humoral and cellular responses vs healthy controls, the incidence of breakthrough infections and adverse events (AEs). Antibodies against spike- and nucleocapsid-protein (anti-S and anti-N) and Spike-specific T-cells responses were quantified at baseline, 21 days after the first and second doses and during follow-up. RESULTS: 182 cirrhotics (85% SARS-CoV-2-naïve) and 38 controls were enrolled. After 2 doses of vaccine, anti-S titres were significantly lower in cirrhotics vs controls [1,751 (0.4-25,000) U/mL vs 4,523 (259-25,000) U/mL, p=0.012] and in SARS-CoV-2-naïve vs previously infected cirrhotics [999 (0.4-17,329) U/mL vs 7,500 (12.5-25,000) U/mL, (p<0.001)]. T-cell responses in cirrhotics were similar to controls, although with different kinetics. In SARS-CoV-2-naïve cirrhotics, HCC, Child-Pugh B/C and BNT162b2 were independent predictors of low response. Neither unexpected nor severe AEs emerged. During follow-up, 2% turned SARS-CoV-2 positive, all asymptomatic. CONCLUSION: Humoral response to COVID-19 vaccines appeared suboptimal in patients with cirrhosis, particularly in SARS-CoV-2-naïve decompensated cirrhotics, although cellular response appeared preserved, and low breakthrough infections rate was registered.
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Vacinas contra COVID-19 , COVID-19 , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Anticorpos , Anticorpos Antivirais , Vacina BNT162 , Infecções Irruptivas , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Imunidade Celular , Cirrose Hepática , Estudos Prospectivos , RNA Mensageiro , SARS-CoV-2 , VacinaçãoRESUMO
BACKGROUND & AIMS: Bulevirtide (BLV) has recently been conditionally approved for the treatment of chronic hepatitis delta (CHD) in Europe, but its effectiveness and safety in patients with compensated cirrhosis and clinically significant portal hypertension (CSPH) are unknown. METHODS: Consecutive patients with HDV-related compensated cirrhosis and CSPH who started BLV 2 mg/day were enrolled in this single-center study. Clinical/virological characteristics were collected at baseline, weeks 4, 8 and every 8 weeks thereafter. HDV RNA was quantified by Robogene 2.0 (lower limit of detection 6 IU/ml). RESULTS: Eighteen Caucasian patients with compensated cirrhosis and CSPH under nucleos(t)ide analogue treatment were enrolled: median (IQR) age was 48 (29-77) years, and 67% were male. Median (IQR) platelet count was 70 (37-227) x103/µl, liver stiffness measurement (LSM) 16.4 (7.8-57.8) kPa, alanine aminotransferase (ALT) 106 (32-222) U/L, HBsAg 3.7 (2.5-4.3) log IU/ml, HDV RNA 4.9 (3.3-6.6) log IU/ml. During 48 weeks of BLV monotherapy, HDV RNA declined by 3.1 (0.2-4.3) log IU/ml (p <0.001 vs. baseline), becoming undetectable in 5 patients (23%). A virological response was observed in 14 (78%) patients while a non-response was observed in 2 (11%). ALT decreased to 35 (15-86) U/L (p <0.001 vs. baseline), normalizing in 83% of patients. A combined response was observed in 67% of patients. Aspartate aminotransferase and gamma-glutamyltransferase levels significantly improved. Concerning liver function parameters, albumin values significantly increased and bilirubin remained stable. LSM significantly improved in patients with virological response, while platelet count was unchanged. None of the patients developed decompensating events or hepatocellular carcinoma. BLV was well tolerated, no patient discontinued treatment and the increase in bile acids was fully asymptomatic. CONCLUSIONS: A 48-week course of BLV 2 mg/day monotherapy is safe and effective even for difficult-to treat patients with HDV-related compensated cirrhosis and CSPH. LAY SUMMARY: Hepatitis delta virus (HDV) is associated with the most severe form of viral hepatitis. A new treatment for HDV called bulevirtide has recently received conditional approval for patients with chronic HDV infection. However, its safety and effectiveness in patients with more advanced liver disease is not known. Herein, we show that it is safe and effective in patients with HDV-related cirrhosis and clinically significant portal hypertension.
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Antivirais , Hepatite D , Hipertensão Portal , Lipopeptídeos , Neoplasias Hepáticas , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antivirais/uso terapêutico , Hepatite D/complicações , Hepatite D/tratamento farmacológico , Vírus Delta da Hepatite/genética , Hipertensão Portal/complicações , Hipertensão Portal/tratamento farmacológico , Cirrose Hepática/complicações , Cirrose Hepática/tratamento farmacológico , Adulto , Lipopeptídeos/uso terapêuticoRESUMO
The entry inhibitor bulevirtide (BLV) received conditional approval from the EMA in July 2020 for the treatment of adult patients with compensated chronic hepatitis delta. However, the effectiveness and safety of BLV administered as monotherapy beyond 48 weeks in difficult-to-treat patients with HDV-related cirrhosis is presently unknown. Herein, we describe the first patients with HDV-related compensated cirrhosis who were treated with BLV (10 mg/day as a starting dose) for up to 3 years on a compassionate use program. Patients were also monitored for HBcrAg and HBV RNA levels, and HDV- and HBV-specific T-cell markers. In the patient who stopped BLV at week 48, after achieving a virological and biochemical response, the initial virological and biochemical rebound was followed by alanine aminotransferase normalization coupled with low HDV RNA and HBsAg levels. In the 2 patients treated continuously for 3 years, virological and biochemical responses were maintained throughout the treatment period even after dose reduction. In a patient with advanced compensated cirrhosis, liver function tests significantly improved, esophageal varices disappeared, and histological/laboratory features of autoimmune hepatitis resolved. Overall, no safety issues were recorded, as bile salt increase was asymptomatic. While serum HBV RNA levels remained undetectable in all patients, HBV core-related antigen levels showed a progressive, yet modest decline during long-term BLV treatment. No HDV-specific interferon-γ-producing T cells were detected, neither after HDV reactivation (after BLV withdrawn in Patient 1) nor during 3 years of BLV treatment. In conclusion, this report shows that continuous administration of BLV monotherapy for 3 years leads to excellent virological and clinical responses in patients with HDV-related cirrhosis who had contraindications to interferon-based therapies.
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Lipopeptídeos/farmacologia , Cirrose Hepática/tratamento farmacológico , Adulto , Antivirais/farmacologia , Antivirais/uso terapêutico , Feminino , Hepatite D/complicações , Hepatite D/tratamento farmacológico , Humanos , Lipopeptídeos/uso terapêutico , Cirrose Hepática/etiologia , Testes de Função Hepática/métodos , Testes de Função Hepática/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Segurança do Paciente/normas , Segurança do Paciente/estatística & dados numéricos , Resultado do TratamentoRESUMO
The hepatitis B virus (HBV) is a member of the Hepadnaviridae family, which includes small DNA enveloped viruses that infect primates, rodents, and birds and is the causative factor of chronic hepatitis B. A common feature of all these viruses is their great specificity by species and cell type, as well as a peculiar genomic and replication organization similar to that of retroviruses. The HBV virion consists of an external lipid envelope and an internal icosahedral protein capsid containing the viral genome and a DNA polymerase, which also functions as a reverse transcriptase.
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Vírus da Hepatite B , Hepatite B Crônica , Animais , DNA Viral/genética , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Humanos , Vírion , Replicação ViralRESUMO
BACKGROUND & AIMS: Recently, several risk scores for prediction of hepatocellular carcinoma (HCC) were developed in cohorts of treated Asian patients with chronic hepatitis B (CHB), but they have not been assessed in non-Asian patients. We evaluated the predictability and comparative utility of our PAGE-B and recent Asian HCC risk scores in nucleos(t)ide analogue (NA)-treated adult Caucasian patients with CHB, with or without well-documented compensated cirrhosis but not previous diagnosis of HCC. METHODS: We included 1,951 patients treated with entecavir/tenofovir and followed up for a median of 7.6 years. The c-statistic was used to estimate the predictability of PAGE-B, HCC-Rescue, CAMD, mPAGE-B, and AASL score for HCC development within 5 or 10 years. The low- and high-risk group cut-offs were used for estimation of negative (NPV) and positive predictive values (PPV), respectively. RESULTS: HCC developed in 103/1,951 (5.3%) patients during the first 5 years and in another 39/1,428 (2.7%) patients between years 5 and 10. The 3-, 5-, and 10-year cumulative HCC rates were 3.3%, 5.9%, and 9.6%, respectively. All scores offered good 5- and 10-year HCC prediction (c-statistic: 0.78-0.82). NPVs were always >99% (99.3-100%), whereas PPV ranged between 13% and 24%. CONCLUSIONS: In NA-treated Caucasian patients with CHB including compensated cirrhosis, HCC risk scores developed in NA-treated Asian patients offer good 5- and 10-year HCC predictability, similar to that of PAGE-B. PAGE-B and mPAGE-B scores are simpler in clinical practice, as they do not require an accurate diagnosis of cirrhosis, but the addition of albumin in mPAGE-B score does not seem to offer an advantage in patients with well compensated liver disease. LAY SUMMARY: Several risk scores for prediction of hepatocellular carcinoma (HCC) were recently developed in cohorts of treated Asian patients with chronic hepatitis B (CHB). In Caucasian patients with CHB treated with oral antivirals, newer Asian HCC risk scores offer good 5- and 10-year HCC predictability, similar to that of PAGE-B. For clinical practice, PAGE-B and mPAGE-B scores are simpler, as they do not require an accurate diagnosis of cirrhosis.
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Protein accumulation is the hallmark of various neuronal, muscular, and other human disorders. It is also often seen in the liver as a major protein-secretory organ. For example, aggregation of mutated alpha1-antitrypsin (AAT), referred to as PiZ, is a characteristic feature of AAT deficiency, whereas retention of hepatitis B surface protein (HBs) is found in chronic hepatitis B (CHB) infection. We investigated the interaction of both proteotoxic stresses in humans and mice. Animals overexpressing both PiZ and HBs (HBs-PiZ mice) had greater liver injury, steatosis, and fibrosis. Later they exhibited higher hepatocellular carcinoma load and a more aggressive tumor subtype. Although PiZ and HBs displayed differing solubility properties and distinct distribution patterns, HBs-PiZ animals manifested retention of AAT/HBs in the degradatory pathway and a marked accumulation of the autophagy adaptor p62. Isolation of p62-containing particles revealed retained HBs/AAT and the lipophagy adapter perilipin-2. p62 build-up led to activation of the p62-Nrf2 axis and emergence of reactive oxygen species. Our results demonstrate that the simultaneous presence of two prevalent proteotoxic stresses promotes the development of liver injury due to protein retention and activation of the p62-Nrf2 axis. In humans, the PiZ variant was over-represented in CHB patients with advanced liver fibrosis (unadjusted odds ratio = 9.92 [1.15-85.39]). Current siRNA approaches targeting HBs/AAT should be considered for these individuals. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
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Antígenos de Superfície da Hepatite B/metabolismo , Hepatopatias/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Proteína Sequestossoma-1/metabolismo , alfa 1-Antitripsina/metabolismo , Animais , Antígenos de Superfície da Hepatite B/toxicidade , Humanos , Hepatopatias/patologia , Camundongos , Estresse Fisiológico/fisiologia , alfa 1-Antitripsina/toxicidadeRESUMO
BACKGROUND: An accurate, single-point differential diagnosis between HBeAg-negative infection (ENI) and chronic hepatitis B (CHB) is an unmet need. AIMS: To assess the diagnostic value of the new hepatitis B core-related antigen (HBcrAg) assay. METHODS: A retrospective anonymised data analysis was performed in a multicentre European (nine centres and six countries) cohort of 1582 consecutive HBsAg-positive/HBeAg-negative subjects classified according to EASL guidelines as: 550-CHB, 710-ENI and 322-GZ (grey-zone, HBV-DNA <20 000 IU/mL). RESULTS: Mean age was 44 (±13.2 y), 59% were men; HBV genotypes were 15% A, 2% B, 2% C, 45% D, 9% E, 1% F and 26% unknown. Median HBV-DNA serum levels were 2.2 (1.5-2.7), 3.5 (3.2-3.8) and 5.6 (4.8-6.6) logIU/mL in ENI, GZ and CHB, P < 0.0001. HBsAg serum levels (HBsAgsl) were comparable in CHB and GZ, but lower in ENI (2.9 [2.1-3.6] logIU/mL), P < 0.0001. HBcrAg serum levels (HBcrAgsl) were <3 logU/mL in 90.7% (644/710) ENI, 75.2% (242/322) GZ and 4.7% (26/550) CHB (P < 0.0001). Median HBcrAgsl were 4.8 (3.9-5.7), 2.5 (2.0-2.9) and 2.0 (2.0-2.5) logU/mL in CHB, GZ and ENI, (P < 0.0001). ROC-AUCs for HBcrAg and HBsAg were 0.968 (95% CI, 0.958-0.977) and 0.732 (95% CI, 0.704-0.760) respectively. The optimal HBcrAgsl cut-off to distinguish CHB from ENI was 3.14 logU/mL (95% CI, 3.02-3.25, 91% SE, 93% SP and 92.4% DA). HBcrAgsl were associated with HBV genotypes (P < 0.001, one-way ANOVA) but using genotype-specific cut-offs, HBcrAg DA remained unchanged with overlapping 95% CI. CONCLUSION: The HBcrAg assay showed high diagnostic performance in the accurate single-point identification of patients with HBeAg-negative CHB, independently of HBV genotype. This should prompt future prospective studies to confirm its diagnostic role in clinical practice.
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Antígenos E da Hepatite B , Hepatite B Crônica , Adulto , DNA Viral/genética , Feminino , Antígenos de Superfície da Hepatite B , Vírus da Hepatite B/genética , Hepatite B Crônica/diagnóstico , Humanos , Masculino , Estudos Prospectivos , Estudos RetrospectivosRESUMO
Hepatocellular carcinoma (HCC) may still develop in chronic hepatitis B (CHB) patients even under effective long-term oral antiviral therapy, but its pathogenesis in the setting of long-standing inhibition of viral replication has not been completely elucidated. We investigated whether species of circulating cell-free DNA (cfDNA) may be involved in the process of hepatocarcinogenesis in treated CHB patients. Serum samples were obtained from HBeAg-negative CHB patients with (HCC cases, n = 37) or without HCC development during the first 5 years of oral antiviral therapy (controls, n = 74). HCC cases and controls were matched 1:2 for age, sex and platelets. Determination of different circulating cfDNA species (before HCC diagnosis in HCC cases) including total cfDNA quantity, levels of Alu repeat DNA and RNase P coding DNA, copies of mitochondrial DNA and levels of 5-methyl-2'-deoxycytidine as an indicator of DNA methylation was performed. HCC cases compared with controls had higher median levels of Alu247 (123 vs 69 genomic equivalent, p = .042) and RNase P coding DNA (68 vs 15 genomic equivalent, p < .001). In contrast, median cfDNA concentration, Alu115 levels, Alu247/Alu115 ratio as an index of DNA integrity and mitochondrial DNA copies did not differ significantly between HCC cases and controls. Receiver operating characteristic curve analysis showed that levels RNase P coding DNA offered good prediction of subsequent HCC development (c-statistic: 0.80, p < .001). In conclusion, serum levels of RNase P coding DNA are increased years before HCC diagnosis and could be potentially helpful in the prediction of the HCC risk in treated HBeAg-negative CHB patients.
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Carcinoma Hepatocelular , DNA Tumoral Circulante , Hepatite B Crônica , Neoplasias Hepáticas , Antivirais/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/epidemiologia , Metilação de DNA , Vírus da Hepatite B/genética , Hepatite B Crônica/complicações , Hepatite B Crônica/tratamento farmacológico , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/epidemiologiaRESUMO
BACKGROUND & AIMS: In chronic HBV infection, mitochondrial functions and proteostasis are dysregulated in exhausted HBV-specific CD8 T cells. To better characterise the potential involvement of deregulated protein degradation mechanisms in T cell exhaustion, we analysed lysosome-mediated autophagy in HBV-specific CD8 T cells. Bioactive compounds able to simultaneously target both mitochondrial functions and proteostasis were tested to identify optimal combination strategies to reconstitute efficient antiviral CD8 T cell responses in patients with chronic HBV infection. METHODS: Lysosome-mediated degradation pathways were analysed by flow cytometry in virus-specific CD8 T cells from patients with chronic HBV infection. Mitochondrial function, intracellular proteostasis, and cytokine production were evaluated in HBV-peptide-stimulated T cell cultures, in the presence or absence of the polyphenols resveratrol (RSV) and oleuropein (OLE) and their metabolites, either alone or in combination with other bioactive compounds. RESULTS: HBV-specific CD8 T cells from patients with CHB showed impaired autophagic flux. RSV and OLE elicited a significant improvement in mitochondrial, proteostasis and antiviral functions in CD8 T cells. Cytokine production was also enhanced by synthetic metabolites, which correspond to those generated by RSV and OLE metabolism in vivo, suggesting that these polyphenols may also display an effect after transformation in vivo. Moreover, polyphenolic compounds improved the T cell revitalising effect of mitochondria-targeted antioxidants and of programmed cell death protein 1/programmed cell death ligand 1 blockade. CONCLUSIONS: Simultaneously targeting multiple altered intracellular pathways with the combination of mitochondria-targeted antioxidants and natural polyphenols may represent a promising immune reconstitution strategy for the treatment of chronic HBV infection. LAY SUMMARY: In chronic hepatitis B, antiviral T lymphocytes are deeply impaired, with many altered intracellular functions. In vitro exposure to polyphenols, such as resveratrol and oleuropein, can correct some of the deregulated intracellular pathways and improve antiviral T cell function. This effect can be further strengthened by the association of polyphenols with antioxidant compounds in a significant proportion of patients. Thus, the combination of antioxidants and natural polyphenols represents a promising strategy for chronic hepatitis B therapy.
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Linfócitos T CD8-Positivos/imunologia , Hepatite B Crônica , Compostos Fitoquímicos/farmacologia , Resveratrol/farmacologia , Antioxidantes/farmacologia , Células Cultivadas , Citocinas/biossíntese , Vírus da Hepatite B/patogenicidade , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/metabolismo , Hepatite B Crônica/patologia , Humanos , Fatores Imunológicos , Glucosídeos Iridoides/farmacologia , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Mitocôndrias Hepáticas/fisiologia , Polifenóis/farmacologia , Proteólise/efeitos dos fármacos , Deficiências na ProteostaseRESUMO
Hepatitis delta virus (HDV) requires hepatitis B virus (HBV) to complete its infection cycle and causes severe hepatitis, with limited therapeutic options. To determine the prospect of T cell therapy in HBV/HDV co-infection, we study the impact of HDV on viral antigen processing and presentation. Using in vitro models of HBV/HDV co-infection, we demonstrate that HDV boosts HBV epitope presentation, both in HBV/HDV co-infected and neighboring mono-HBV-infected cells through the upregulation of the antigen processing pathway mediated by IFN-ß/λ. Liver biopsies of HBV/HDV patients confirm this upregulation. We then validate in vitro and in a HBV/HDV preclinical mouse model that HDV infection increases the anti-HBV efficacy of T cells with engineered T cell receptors. Thus, by unveiling the effect of HDV on HBV antigen presentation, we provide a framework to better understand HBV/HDV immune pathology, and advocate the utilization of engineered HBV-specific T cells as a potential treatment for HBV/HDV co-infection.
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Hepatite B/tratamento farmacológico , Vírus Delta da Hepatite/imunologia , Vírus Delta da Hepatite/fisiologia , Adulto , Idoso , Animais , Linhagem Celular , Quimioterapia Adjuvante/métodos , Coinfecção/tratamento farmacológico , Modelos Animais de Doenças , Feminino , Células Hep G2 , Hepatite B/metabolismo , Vírus da Hepatite B/patogenicidade , Vírus da Hepatite B/fisiologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Imunidade Inata , Fenômenos Imunogenéticos/genética , Interferon beta/metabolismo , Masculino , Camundongos , Camundongos SCID , Pessoa de Meia-Idade , Cultura Primária de Células , Replicação Viral/efeitos dos fármacosRESUMO
Many mutation analyses of the HBV genome have been performed in the search for new prognostic markers. However, the Kozak sequence preceding precore was covered only infrequently in these analyses. In this study, the HBV core promoter/precore region was sequenced in serum samples from European inactive HBV carriers. Quadruple mutation GCAC1809-1812TTCT was found with a high prevalence of 42% in the Kozak sequence preceding precore among all HBV genotypes. GCAC1809-1812TTCT was strongly associated with coexistence of basal core promoter (BCP) double mutation A1762T/G1764A and lower HBV DNA levels. In vitro GCAC1809-1812TTCT lead to drastically diminished synthesis of pregenomic RNA (pgRNA), precore mRNA, core, HBsAg, and HBeAg. Calculation of the pgRNA secondary structure suggests a destabilization of the pgRNA structure by A1762T/G1764A that was compensated by GCAC1809-1812TTCT. In 125 patients with HBV-related cirrhosis, GCAC1809-1812TTCT was not detected. While a strong association of GCAC1809-1812TTCT with inactive carrier status was observed, BCP double mutation was strongly correlated with cirrhosis, but this was only observed in absence of GCAC1809-1812TTCT. In conclusion, our data reveal that GCAC1809-1812TTCT is highly prevalent in inactive carriers and acts as a compensatory mutation for BCP double mutation. GCAC1809-1812TTCT seems to be a biomarker of good prognosis in HBV infection.
Assuntos
Biomarcadores/análise , DNA Viral/genética , Antígenos de Superfície da Hepatite B/genética , Vírus da Hepatite B/genética , Hepatite B/complicações , Cirrose Hepática/epidemiologia , Mutação , Adulto , DNA Viral/análise , Europa (Continente)/epidemiologia , Feminino , Genótipo , Hepatite B/genética , Hepatite B/virologia , Vírus da Hepatite B/isolamento & purificação , Heterozigoto , Humanos , Cirrose Hepática/diagnóstico , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , Regiões Promotoras GenéticasRESUMO
BACKGROUND: To overcome safety limitations of tenofovir-disoproxil, EASL guidelines proposed switching chronic hepatitis B patients older than 60 years or with bone or renal disease to tenofovir-alafenamide or entecavir. AIMS: To estimate the number of patients who would benefit from a treatment switch in a real-life setting. METHODS: Consecutive hepatitis B patients receiving tenofovir-disoproxil before 31 December 2017 were enrolled in a cross-sectional study in two European hospitals. Clinical and virological data were recorded; renal function was assessed by estimated glomerular filtrate rate, serum phosphate and creatinine, proteinuria, and albuminuria; bone involvement by spine and femur DEXA scan. RESULTS: In total, 565 patients included: 62 (18-91) years, 75% males, 92% Caucasian, 92% HBeAg-negative, 40% cirrhotic. Fifty-five percent of patients fulfilled age criterion (>60 years). Older patients had higher rates of cirrhosis (51% vs 26%, p<0.001), cardiovascular disease, and renal impairment. Thirty-six percent of patients met renal criteria, more commonly NA-experienced individuals (35% vs 21%, p=0.001); 17% had bone disease. Overall, 66% of patients had at least one criterion (71% if NA-experienced), 8% all three criteria, 28% age and renal criteria. CONCLUSIONS: Approximately two-thirds of patients receiving long-term tenofovir-disoproxil are candidates for an entecavir or tenofovir-alafenamide switch according to EASL recommendations.
Assuntos
Antivirais/uso terapêutico , Guanina/análogos & derivados , Hepatite B Crônica/tratamento farmacológico , Tenofovir/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Comorbidade , Farmacorresistência Viral , Feminino , Guanina/uso terapêutico , Hepatite B Crônica/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto , Estudos RetrospectivosRESUMO
BACKGROUND & AIMS: A recent study in Asian patients with chronic hepatitis B (CHB) reported that the incidence of hepatocellular carcinoma (HCC) was lower in patients treated with tenofovir disoproxil fumarate (TDF) than entecavir (ETV), but this finding remains controversial. We aimed to identify any differences in HCC incidence, or other patient outcomes, between patients receiving TDF or ETV in the well monitored, multicenter European PAGE-B cohort. METHODS: We included 1,935 Caucasians with CHB, with or without compensated cirrhosis, treated with ETV (n = 772) or TDF (n = 1,163) monotherapy. Mean follow-up was 7.1 ± 3.0 years from ETV/TDF onset. RESULTS: The 5-year cumulative HCC incidence was 5.4% in ETV- and 6.0% in TDF-treated patients (log-rank, p = 0.321), with no significant difference in any patient subgroup (with or without cirrhosis, naïve or experienced to oral antiviral(s) [total, with or without cirrhosis]). In multivariable Cox regression analyses, the hazard of HCC was similar between ETV- and TDF-treated patients after adjustment for several HCC risk factors. ETV- and TDF-treated patients had similar rates of on-therapy biochemical and virological remission, HBsAg loss, liver transplantation and/or death. Elastographic reversion of cirrhosis at year 5 (liver stiffness <12 kPa) was observed in 245/347 (70.6%) patients with pretreatment cirrhosis, being more frequent in TDF- than ETV- treated patients (73.8% vs. 61.5%, p = 0.038). CONCLUSION: In Caucasian patients with CHB, with or without cirrhosis, long-term ETV or TDF monotherapy is associated with similar HCC risk, rates of biochemical/virological remission, HBsAg loss and liver transplantation or death, but elastographic reversion of cirrhosis at year 5 was more frequent with TDF. LAY SUMMARY: In a large cohort of Caucasians with chronic hepatitis B treated with entecavir (ETV) or tenofovir disoproxil fumarate (TDF) monotherapy, cumulative rates of hepatocellular carcinoma did not differ (up to 12 years). Nor did rates of biochemical/virological remission, HBsAg loss and liver transplantation or death. However, elastographic reversion of cirrhosis at year 5 was more frequent in TDF- than ETV-treated patients with pretreatment cirrhosis.
Assuntos
Carcinoma Hepatocelular , Guanina/análogos & derivados , Cirrose Hepática , Neoplasias Hepáticas , Tenofovir/uso terapêutico , Antivirais/uso terapêutico , Carcinoma Hepatocelular/epidemiologia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , Técnicas de Imagem por Elasticidade/métodos , Técnicas de Imagem por Elasticidade/estatística & dados numéricos , Feminino , Seguimentos , Guanina/uso terapêutico , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/isolamento & purificação , Hepatite B Crônica/complicações , Hepatite B Crônica/diagnóstico , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/etnologia , Humanos , Incidência , Cirrose Hepática/diagnóstico por imagem , Cirrose Hepática/etiologia , Cirrose Hepática/terapia , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Transplante de Fígado/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Medição de Risco , População Branca/estatística & dados numéricosRESUMO
BACKGROUND & AIMS: Protein induced by vitamin K absence or antagonist-II (PIVKA-II) has been suggested as a serum biomarker for hepatocellular carcinoma (HCC) in Asian hepatitis B virus (HBV)-treated subjects but no studies tested it in Caucasian cirrhotics long-term nucleos(t)ide analogues (NUCs)-treated. We assessed the detection accuracy of PIVKA-II alone or in combination with alpha-foetoprotein (AFP) in patients under surveillance. METHODS: This cross-sectional, single centre case-control study was conducted in 212 NUC-treated cirrhotics: 64 HCC and 148 HCC-free controls for 84 (60-107) months. PIVKA-II was determined by a CMIA immunoassay (Abbott; limit of quantification: 8.2 mAU/mL). RESULTS: Protein induced by vitamin K absence or agonist II (PIVKA-II) and AFP levels were significantly higher in HCC patients [Barcelona Clinic Liver Cancer staging system stage 0/A in 91%, diameter 20 (6-50) mm] compared to controls: 109 (17-12 157) vs 31 (13-82) mAU/mL and 5 (1-1163) vs 2 (1-7) ng/mL (P < .001 for both markers), with a cut-off of 48 mAU/mL and 4.2 ng/mL by AUROC analysis. The PIVKA-II 82 mAU/mL and AFP 7 ng/mL cut-offs showed 100% specificity, with the former more sensitive (54% vs 42%), accurate (86% vs 83%), with higher negative predictive value (80% vs 76%) compared to AFP for HCC detection. PIVKA-II more frequently than AFP levels exceeded the cut-off 6-18 months before HCC diagnosis. Combining PIVKA-II with AFP increased sensitivity, accuracy and negative predictive values to 67%, 90% and 85%, preserving 100% specificity. PIVKA-II was associated with lesions >20 mm or neoplastic thrombosis. CONCLUSIONS: Combination of PIVKA-II and AFP increases the detection rate for HCC in NUC-treated HBV Caucasian cirrhotics, a potential new approach for surveillance.