RESUMEN
Reversing CD8+ T cell dysfunction is crucial in treating chronic hepatitis B virus (HBV) infection, yet specific molecular targets remain unclear. Our study analyzed co-signaling receptors during hepatocellular priming and traced the trajectory and fate of dysfunctional HBV-specific CD8+ T cells. Early on, these cells upregulate PD-1, CTLA-4, LAG-3, OX40, 4-1BB, and ICOS. While blocking co-inhibitory receptors had minimal effect, activating 4-1BB and OX40 converted them into antiviral effectors. Prolonged stimulation led to a self-renewing, long-lived, heterogeneous population with a unique transcriptional profile. This includes dysfunctional progenitor/stem-like (TSL) cells and two distinct dysfunctional tissue-resident memory (TRM) populations. While 4-1BB expression is ubiquitously maintained, OX40 expression is limited to TSL. In chronic settings, only 4-1BB stimulation conferred antiviral activity. In HBeAg+ chronic patients, 4-1BB activation showed the highest potential to rejuvenate dysfunctional CD8+ T cells. Targeting all dysfunctional T cells, rather than only stem-like precursors, holds promise for treating chronic HBV infection.
Asunto(s)
Linfocitos T CD8-positivos , Virus de la Hepatitis B , Hepatitis B Crónica , Humanos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/virología , Hepatitis B Crónica/metabolismo , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/metabolismo , Transducción de Señal , Animales , Receptores OX40/metabolismo , Ratones , Receptor de Muerte Celular Programada 1/metabolismo , Antígenos CD/metabolismoRESUMEN
BACKGROUND: Coinfection with hepatitis D virus (HDV) accelerates the progression of liver disease associated with chronic hepatitis B. Bulevirtide inhibits the entry of HDV into hepatocytes. METHODS: In this ongoing phase 3 trial, patients with chronic hepatitis D, with or without compensated cirrhosis, were randomly assigned, in a 1:1:1 ratio, to receive bulevirtide subcutaneously at 2 mg per day (2-mg group) or 10 mg per day (10-mg group) for 144 weeks or to receive no treatment for 48 weeks followed by bulevirtide subcutaneously at 10 mg per day for 96 weeks (control group). Patients will complete 96 weeks of additional follow-up after the end of treatment. The primary end point was a combined response at week 48 of an undetectable HDV RNA level, or a level that decreased by at least 2 log10 IU per milliliter from baseline, and normalization of the alanine aminotransferase (ALT) level. The key secondary end point was an undetectable HDV RNA level at week 48, in a comparison between the 2-mg group and the 10-mg group. RESULTS: A total of 49 patients were assigned to the 2-mg group, 50 to the 10-mg group, and 51 to the control group. A primary end-point response occurred in 45% of patients in the 2-mg group, 48% in the 10-mg group, and 2% in the control group (P<0.001 for the comparison of each dose group with the control group). The HDV RNA level at week 48 was undetectable in 12% of patients in the 2-mg group and in 20% in the 10-mg group (P = 0.41). The ALT level normalized in 12% of patients in the control group, 51% in the 2-mg group (difference from control, 39 percentage points [95% confidence interval {CI}, 20 to 56]), and 56% in the 10-mg group (difference from control, 44 percentage points [95% CI, 26 to 60]). Loss of hepatitis B virus surface antigen (HBsAg) or an HBsAg level that decreased by at least 1 log10 IU per milliliter did not occur in the bulevirtide groups by week 48. Headache, pruritus, fatigue, eosinophilia, injection-site reactions, upper abdominal pain, arthralgia, and asthenia were more common in the 2-mg and 10-mg groups combined than in the control group. No treatment-related serious adverse events occurred. Dose-dependent increases in bile acid levels were noted in the 2-mg and 10-mg groups. CONCLUSIONS: After 48 weeks of bulevirtide treatment, HDV RNA and ALT levels were reduced in patients with chronic hepatitis D. (Funded by Gilead Sciences; MYR 301 ClinicalTrials.gov number, NCT03852719.).
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Antivirales , Hepatitis B Crónica , Hepatitis D Crónica , Humanos , Antivirales/administración & dosificación , Antivirales/efectos adversos , Antivirales/uso terapéutico , Antígenos de Superficie de la Hepatitis B , Virus de la Hepatitis B/genética , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis D Crónica/tratamiento farmacológico , Virus de la Hepatitis Delta/genética , ARN , Coinfección/tratamiento farmacológico , Coinfección/virologíaRESUMEN
BACKGROUND: Bepirovirsen is an antisense oligonucleotide that targets all hepatitis B virus (HBV) messenger RNAs and acts to decrease levels of viral proteins. METHODS: We conducted a phase 2b, randomized, investigator-unblinded trial involving participants with chronic HBV infection who were receiving or not receiving nucleoside or nucleotide analogue (NA) therapy. Participants were randomly assigned (in a 3:3:3:1 ratio) to receive weekly subcutaneous injections of bepirovirsen at a dose of 300 mg for 24 weeks (group 1), bepirovirsen at a dose of 300 mg for 12 weeks then 150 mg for 12 weeks (group 2), bepirovirsen at a dose of 300 mg for 12 weeks then placebo for 12 weeks (group 3), or placebo for 12 weeks then bepirovirsen at a dose of 300 mg for 12 weeks (group 4). Groups 1, 2, and 3 received loading doses of bepirovirsen. The composite primary outcome was a hepatitis B surface antigen (HBsAg) level below the limit of detection and an HBV DNA level below the limit of quantification maintained for 24 weeks after the planned end of bepirovirsen treatment, without newly initiated antiviral medication. RESULTS: The intention-to-treat population comprised 457 participants (227 receiving NA therapy and 230 not receiving NA therapy). Among those receiving NA therapy, a primary-outcome event occurred in 6 participants (9%; 95% credible interval, 0 to 31) in group 1, in 6 (9%; 95% credible interval, 0 to 43) in group 2, in 2 (3%; 95% credible interval, 0 to 16) in group 3, and 0 (0%; post hoc credible interval, 0 to 8) in group 4. Among participants not receiving NA therapy, a primary-outcome event occurred in 7 participants (10%; 95% credible interval, 0 to 38), 4 (6%; 95% credible interval, 0 to 25), 1 (1%; post hoc credible interval, 0 to 6), and 0 (0%; post hoc credible interval, 0 to 8), respectively. During weeks 1 through 12, adverse events, including injection-site reactions, pyrexia, fatigue, and increased alanine aminotransferase levels, were more common with bepirovirsen (groups 1, 2, and 3) than with placebo (group 4). CONCLUSIONS: In this phase 2b trial, bepirovirsen at a dose of 300 mg per week for 24 weeks resulted in sustained HBsAg and HBV DNA loss in 9 to 10% of participants with chronic HBV infection. Larger and longer trials are required to assess the efficacy and safety of bepirovirsen. (Funded by GSK; B-Clear ClinicalTrials.gov number, NCT04449029.).
Asunto(s)
Antivirales , Hepatitis B Crónica , Oligonucleótidos Antisentido , ARN Viral , Humanos , Antivirales/efectos adversos , Antivirales/uso terapéutico , ADN Viral/sangre , Antígenos e de la Hepatitis B/sangre , Antígenos de Superficie de la Hepatitis B/sangre , Virus de la Hepatitis B/genética , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/virología , Oligonucleótidos Antisentido/administración & dosificación , Oligonucleótidos Antisentido/efectos adversos , Oligonucleótidos Antisentido/uso terapéutico , Resultado del Tratamiento , ARN Viral/efectos de los fármacos , ARN Mensajero/efectos de los fármacos , Inyecciones SubcutáneasRESUMEN
BACKGROUND & AIMS: Patients who discontinue nucleo(s)tide analogue therapy are at risk of viral rebound and severe hepatitis flares, necessitating intensive off-treatment follow-up. METHODS: We studied the association between hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA levels at off-treatment follow-up week 24 (FU W24), with subsequent clinical relapse, and HBsAg loss in a multicenter cohort of hepatitis B e antigen (HBeAg)-negative patients with chronic hepatitis B who discontinued nucleo(s)tide analogue therapy. RESULTS: We studied 475 patients, 82% Asian, and 55% treated with entecavir. Patients with higher HBV DNA levels at FU W24 had a higher risk of clinical relapse (hazard ratio [HR], 1.576; P < .001) and a lower chance of HBsAg loss (HR, 0.454; P < .001). Similarly, patients with higher HBsAg levels at FU W24 had a higher risk of clinical relapse (HR, 1.579; P < .001) and a lower chance of HBsAg loss (HR, 0.263; P < .001). A combination of both HBsAg <100 IU/mL and HBV DNA <100 IU/mL at FU W24 identified patients with excellent outcomes (9.9% clinical relapse and 58% HBsAg loss at 216 weeks of follow-up). Conversely, relapse rates were high and HBsAg loss rates negligible among patients with both HBsAg >100 IU/mL and HBV DNA >100 IU/mL (P < .001). CONCLUSIONS: Among HBeAg-negative patients with chronic hepatitis B who discontinued antiviral therapy and who did not experience clinical relapse before FU W24, serum levels of HBV DNA and HBsAg at FU W24 can be used to predict subsequent clinical relapse and HBsAg clearance. A combination of HBsAg <100 IU/mL with HBV DNA <100 IU/mL identifies patients with a low risk of relapse and excellent chances of HBsAg loss and could potentially be used as an early surrogate end point for studies aiming at finite therapy in HBV.
Asunto(s)
Antígenos de Superficie de la Hepatitis B , Hepatitis B Crónica , Humanos , Antígenos e de la Hepatitis B , Hepatitis B Crónica/diagnóstico , Hepatitis B Crónica/tratamiento farmacológico , ADN Viral , Antivirales/uso terapéutico , Estudios de Seguimiento , Virus de la Hepatitis B/genética , Recurrencia , Resultado del TratamientoRESUMEN
Chronic hepatitis B (CHB) virus infection, which can be divided into immune-tolerant (IT), immune-active (IA), inactive carrier (IC) phases, and HBeAg-negative hepatitis (ENEG), can induce liver cirrhosis and eventually hepatocellular carcinoma (HCC). CD3+CD56+ NKT-like cells play an important role in antiviral immune response. However, the mechanism of NKT-like cells to mediate immune tolerance remains largely elusive. In this study, we observed circulating NKT-like cells from IC and IT CHB patients were phenotypically and functionally impaired, manifested by increased expression of inhibitory receptor TIGIT and decreased capacity of secreting antiviral cytokines. Besides, TIGIT+ NKT-like cells of IC and IT CHB patients expressed lower levels of cytotoxic cytokines than the TIGIT- subset. Furthermore, increased expression of CD155, the ligand of TIGIT, on plasmacytoid dendritic cells (pDCs) was detected in IC and IT CHB patients. Importantly, the co-culture of NKT-like cells and pDCs showed that NKT-like cells restored their antiviral ability after TIGIT blockade upon HBV peptide stimulation in IC and IT CHB patients. In conclusion, our findings suggest that the TIGIT pathway may mediate immune tolerance in IT CHB patients and lead to functional impairment in IC patients, indicating that TIGIT may be a potential therapeutic checkpoint for immunotherapy of CHB patients.
Asunto(s)
Complejo CD3 , Antígeno CD56 , Células Dendríticas , Virus de la Hepatitis B , Hepatitis B Crónica , Tolerancia Inmunológica , Células T Asesinas Naturales , Receptores Inmunológicos , Humanos , Receptores Inmunológicos/metabolismo , Hepatitis B Crónica/inmunología , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/virología , Antígeno CD56/metabolismo , Masculino , Virus de la Hepatitis B/inmunología , Femenino , Células T Asesinas Naturales/inmunología , Adulto , Células Dendríticas/inmunología , Tolerancia Inmunológica/inmunología , Complejo CD3/inmunología , Complejo CD3/metabolismo , Persona de Mediana Edad , Receptores Virales/metabolismo , Receptores Virales/inmunología , Citocinas/metabolismo , Citocinas/inmunologíaRESUMEN
BACKGROUND AND AIMS: The predominantly progressive, indeterminate, and predominantly regressive (P-I-R) classification extends beyond staging and provides information on dynamic changes of liver fibrosis. However, the prognostic implication of P-I-R classification is not elucidated. Therefore, in the present research, we investigated the utility of P-I-R classification in predicting the on-treatment clinical outcomes. APPROACH AND RESULTS: In an extension study on a randomized controlled trial, we originally enrolled 1000 patients with chronic hepatitis B and biopsy-proven histological significant fibrosis, and treated them for more than 7 years with entecavir-based therapy. Among the 727 patients with a second biopsy at treatment week 72, we compared P-I-R classification and Ishak score changes in 646 patients with adequate liver sections for the histological evaluation. Progressive, indeterminate, and regressive cases were observed in 70%, 17%, and 13% of patients before treatments and 20%, 14%, and 64% after 72-week treatment, respectively, which could further differentiate the histological outcomes of patients with stable Ishak scores. The 7-year cumulative incidence of HCC was 1.5% for the regressive cases, 4.3% for the indeterminate cases, and 22.8% for the progressive cases ( p <0.001). After adjusting for age, treatment regimen, platelet counts, cirrhosis, Ishak fibrosis score changes, and Laennec staging, the posttreatment progressive had a HR of 17.77 (vs. posttreatment regressive; 95% CI: 5.55-56.88) for the incidence of liver-related events (decompensation, HCC, and death/liver transplantation). CONCLUSIONS: The P-I-R classification can be a meaningful complement to the Ishak fibrosis score not only in evaluating the histological changes but also in predicting the clinical outcomes.
Asunto(s)
Carcinoma Hepatocelular , Hepatitis B Crónica , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patología , Antivirales/uso terapéutico , Neoplasias Hepáticas/patología , Cirrosis Hepática/patología , Hígado/patología , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/patología , Fibrosis , Biopsia/efectos adversosRESUMEN
BACKGROUND AND AIMS: Long-term nucleos(t)ide analog (Nuc) treatment can reduce HCC in patients with HBV-related liver cirrhosis (HBV-LC). Earlier small cohort studies showed a comparable 5-year incidence of HCC in HBeAg-negative patients with HBV-LC who stopped and those continued Nuc therapy. This study aimed to validate these findings using a large cohort with 10-year follow-up. APPROACH AND RESULTS: From 2 centers, 494 HBeAg-negative patients with HBV-LC who stopped (finite group) and 593 who continued (continuous group) Nuc therapy were recruited. HCC, HBsAg loss, liver-related mortality/transplantation, and overall survival rates were compared between 2 groups with 1:1 propensity score matching of sex, treatment history, types of Nuc, age, transaminases, platelet count, and HBsAg levels at end of therapy in finite group or 3-year on-therapy in continuous groups. During a median follow-up of 6.2 (3.4-8.9) years, the annual and 10-year HCC incidence were lower in finite group (1.6 vs. 3.3%/y and 10-y 15.7% vs. 26.8%, respectively; log-rank test, p <0.0001). The finite group showed greater HBsAg decline/year (-0.116 vs. -0.095 log 10 IU/mL, p =0.0026) and 7.6 times higher 10-year incidence of HBsAg loss (22.7% vs. 3%, p <0.0001). Multivariate Cox regression showed finite therapy an independent factor for HBsAg loss (adjusted HR: 11.79) but protective against HCC (adjusted HR: 0.593), liver-related mortality/transplantation (adjusted HR: 0.312), and overall mortality (adjusted HR: 0.382). CONCLUSIONS: Finite Nuc therapy in HBeAg-negative HBV-LC may reduce HCC incidence, increase HBsAg loss, and improve survival. Greater HBsAg decline/loss may reflect enhanced immunity and contribute to the reduction of hepatic carcinogenesis.
Asunto(s)
Carcinoma Hepatocelular , Hepatitis B Crónica , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Antígenos de Superficie de la Hepatitis B , Virus de la Hepatitis B/genética , Antígenos e de la Hepatitis B , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/epidemiología , Neoplasias Hepáticas/tratamiento farmacológico , Antivirales/uso terapéutico , Cirrosis Hepática/complicaciones , Cirrosis Hepática/tratamiento farmacológico , ADN ViralRESUMEN
BACKGROUND AND AIMS: A single-nation study reported that pretreatment HBV viral load is associated with on-treatment risk of HCC in patients who are HBeAg-positive without cirrhosis and with chronic hepatitis B initiating antiviral treatment. We aimed to validate the association between baseline HBV viral load and on-treatment HCC risk in a larger, multinational cohort. APPROACH AND RESULTS: Using a multinational cohort from Korea, Hong Kong, and Taiwan involving 7545 adult patients with HBeAg-positive, without cirrhosis and with chronic hepatitis B who started entecavir or tenofovir treatment with baseline HBV viral load ≥5.00 log 10 IU/mL, HCC risk was estimated by baseline viral load. HBV viral load was analyzed as a categorical variable. During continuous antiviral treatment (median, 4.28 y), HCC developed in 200 patients (incidence rate, 0.61 per 100 person-years). Baseline HBV DNA level was independently associated with on-treatment HCC risk in a nonlinear pattern. HCC risk was lowest with the highest baseline viral load (≥8.00 log 10 IU/mL; incidence rate, 0.10 per 100 person-years), but increased sharply as baseline viral load decreased. The adjusted HCC risk was 8.05 times higher (95% CI, 3.34-19.35) with baseline viral load ≥6.00 and <7.00 log 10 IU/mL (incidence rate, 1.38 per 100 person-years) compared with high (≥8.00 log 10 IU/mL) baseline viral load ( p <0.001). CONCLUSIONS: In a multinational cohort of adult patients with HBeAg-positive without cirrhosis and with chronic hepatitis B, baseline HBV viral load was significantly associated with HCC risk despite antiviral treatment. Patients with the highest viral load who initiated treatment had the lowest long-term risk of HCC development.
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Antivirales , Carcinoma Hepatocelular , Antígenos e de la Hepatitis B , Hepatitis B Crónica , Neoplasias Hepáticas , Carga Viral , Humanos , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/virología , Masculino , Neoplasias Hepáticas/virología , Neoplasias Hepáticas/epidemiología , Neoplasias Hepáticas/etiología , Femenino , Persona de Mediana Edad , Antígenos e de la Hepatitis B/sangre , Antivirales/uso terapéutico , Carcinoma Hepatocelular/virología , Carcinoma Hepatocelular/epidemiología , Carcinoma Hepatocelular/etiología , Adulto , Taiwán/epidemiología , Virus de la Hepatitis B , Hong Kong/epidemiología , República de Corea/epidemiología , Estudios de Cohortes , Tenofovir/uso terapéutico , Guanina/análogos & derivados , Guanina/uso terapéutico , ADN Viral/sangre , Incidencia , Factores de RiesgoRESUMEN
The question of whether patients in the immune-tolerant (IT) phase of chronic hepatitis B virus (HBV) infection should undergo antiviral therapy and determine the optimal regimen remains unclear. A comprehensive search of PubMed, Embase, MEDLINE, Cochrane Library, and Wanfang Data from inception to 5 December 2023, was conducted. Studies reporting on key outcomes such as HBV DNA undetectability, HBeAg loss or seroconversion, HBsAg loss or seroconversion, and hepatocellular carcinoma (HCC) incidence in patients in the IT phase of chronic HBV infection were included. In total, 23 studies were incorporated. Approximately 4% of patients in the IT phase achieved spontaneous HBeAg loss over 48 weeks of follow-up. Antiviral therapy demonstrated a favourable impact on HBV DNA negative conversion (Children: risk ratios [RR] = 6.83, 95% CI: 2.90-16.05; Adults: RR = 25.84, 95% CI: 6.47-103.31) and HBsAg loss rates (Children: RR = 9.49, 95% CI: 1.74-51.76; Adults: RR = 7.35, 95% CI: 1.41-38.27) for patients in the IT phase. Subgroup analysis revealed that in adult patients in the IT phase, interferon plus nucleos(t)ide analogues (NA)-treated patients exhibited a higher pooled rate of HBsAg loss or seroconversion than those treated with NA monotherapy (9% vs. 0%). Additionally, the pooled annual HCC incidence for patients in the IT phase was 3.03 cases per 1000 person-years (95% CI: 0.99-5.88). Adult patients in the IT phase had a significantly lower HCC incidence risk than HBeAg-positive indeterminate phase patients (RR = 0.46, 95% CI: 0.32-0.66), with no significant differences observed between IT and immune-active phases. Presently, there is insufficient evidence solely based on reducing the risk of HCC incidence, to recommend treating patients in the IT phase of chronic HBV infection. However, both adult and paediatric patients in the IT phase responded well to antiviral therapy, showing favourable rates of HBsAg loss or seroconversion.
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Antivirales , Carcinoma Hepatocelular , Antígenos e de la Hepatitis B , Hepatitis B Crónica , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/epidemiología , Carcinoma Hepatocelular/virología , Carcinoma Hepatocelular/inmunología , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/virología , Hepatitis B Crónica/epidemiología , Hepatitis B Crónica/inmunología , Neoplasias Hepáticas/epidemiología , Neoplasias Hepáticas/virología , Neoplasias Hepáticas/inmunología , Antivirales/uso terapéutico , Antígenos e de la Hepatitis B/sangre , Antígenos e de la Hepatitis B/inmunología , Virus de la Hepatitis B/inmunología , Incidencia , Antígenos de Superficie de la Hepatitis B/sangre , Antígenos de Superficie de la Hepatitis B/inmunología , ADN Viral/sangre , Tolerancia Inmunológica , Resultado del Tratamiento , SeroconversiónRESUMEN
OBJECTIVE: A convenient, reproducible biomarker of hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) transcriptional activity is lacking. We measured circulating HBV RNA (cirB-RNA) in untreated and nucleos(t)ide analogues (NUC) treated chronic hepatitis B (CHB) patients to define its correlation with intrahepatic viral markers and HBV core-related antigen (HBcrAg). DESIGN: Paired liver biopsy and serum samples were collected from 122 untreated and 30 NUC-treated CHB patients. We measured cirB-RNA, HBV DNA, hepatitis B surface antigen (HBsAg), HBcrAg and alanine aminotransferase levels. cirB-RNA was quantified using an investigational HBV RNA assay for use on the cobas 6800 system. The test detects a region spanning the HBV canonical polyadenylation site. cccDNA and 3.5 kb RNA in liver tissue were assessed by quantitative PCR and droplet digital PCR. RESULTS: cirB-RNA was detectable in 100% of HBeAg(+) chronic hepatitis (CH), 57% and 14% of HBeAg(-) CH and chronic infection untreated patients and 47% of NUC-treated patients. cirB-RNA undetectability was associated with lower intrahepatic cccDNA transcriptional activity, as well as serum HBcrAg, but no significant differences in HBsAg, in both untreated and treated patients. In untreated HBeAg(-) patients, cirB-RNA correlated with intrahepatic 3.5 kb RNA and cccDNA transcriptional activity, serum HBV DNA and HBcrAg, but not with HBsAg or total cccDNA levels. Combined undetectability of both cirB-RNA and HBcrAg detection in untreated HBeAg(-) patients identified a subgroup with the lowest levels of intrahepatic transcriptionally active cccDNA. CONCLUSION: Our results support the usefulness of quantification of circulating HBV RNA expressed from cccDNA as an indicator of intrahepatic active viral reservoir in both untreated and NUC-treated CHB patients. TRIAL REGISTRATION NUMBER: NCT02602847.
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Hepatitis B Crónica , Humanos , Hepatitis B Crónica/diagnóstico , Hepatitis B Crónica/tratamiento farmacológico , Virus de la Hepatitis B/genética , Antígenos de Superficie de la Hepatitis B , Antígenos e de la Hepatitis B , ADN Circular , ADN Viral , Antivirales/uso terapéutico , Hígado/patología , Antígenos del Núcleo de la Hepatitis B , ARN , BiomarcadoresRESUMEN
OBJECTIVE: Hepatitis B virus (HBV) can integrate into the chromosomes of infected hepatocytes, contributing to the production of hepatitis B surface antigen (HBsAg) and to hepatocarcinogenesis. In this study, we aimed to explore whether transcriptionally active HBV integration events spread throughout the liver tissue in different phases of chronic HBV infection, especially in patients with HBsAg loss. DESIGN: We constructed high-resolution spatial transcriptomes of liver biopsies containing 13 059 tissue spots from 18 patients with chronic HBV infection to analyse the occurrence and relative distribution of transcriptionally active viral integration events. Immunohistochemistry was performed to evaluate the expression of HBsAg and HBV core antigen. Intrahepatic covalently closed circular DNA (cccDNA) levels were quantified by real-time qPCR. RESULTS: Spatial transcriptome sequencing identified the presence of 13 154 virus-host chimeric reads in 7.86% (1026 of 13 059) of liver tissue spots in all patients, including three patients with HBsAg loss. These HBV integration sites were randomly distributed on chromosomes and can localise in host genes involved in hepatocarcinogenesis, such as ALB, CLU and APOB. Patients who were receiving or had received antiviral treatment had a significantly lower percentage of viral integration-containing spots and significantly fewer chimeric reads than treatment-naïve patients. Intrahepatic cccDNA levels correlated well with viral integration events. CONCLUSION: Transcriptionally active HBV integration occurred in chronically HBV-infected patients at different phases, including in patients with HBsAg loss. Antiviral treatment was associated with a decreased number and extent of transcriptionally active viral integrations, implying that early treatment intervention may further reduce the number of viral integration events.
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Hepatitis B Crónica , Hepatitis B , Humanos , Virus de la Hepatitis B/genética , Antígenos de Superficie de la Hepatitis B/genética , Antígenos de Superficie de la Hepatitis B/análisis , Hepatitis B Crónica/tratamiento farmacológico , Hígado/patología , Antivirales/uso terapéutico , Perfilación de la Expresión Génica , ADN Viral/genética , ADN Viral/análisis , ADN Circular/genéticaRESUMEN
OBJECTIVE: The association between baseline pretreatment serum HBV DNA levels and on-treatment hepatocellular carcinoma (HCC) risk remains controversial in patients with chronic hepatitis B (CHB). We aimed to investigate the association between baseline HBV viral load and on-treatment HCC risk in CHB patients without cirrhosis. DESIGN: Using a multicentre historical cohort study including 4693 hepatitis B e antigen (HBeAg)-negative and HBeAg-positive, adult CHB patients without cirrhosis who initiated antiviral treatment, HCC risk was estimated by baseline HBV viral load as a categorical variable. RESULTS: During a median of 7.6 years of antiviral treatment, 193 patients developed HCC (0.53 per 100 person- years). Baseline HBV DNA level was independently associated with on-treatment HCC risk in a non-linear, parabolic pattern. Patients with moderate baseline viral loads (5.00-7.99 log10 IU/mL) exhibited the highest HCC risk (HR, 2.60; p<0.001), followed by those with low viral loads (3.30-4.99 log10 IU/mL; HR, 1.66; p=0.11). Patients with high viral loads (≥8.00 log10 IU/mL) presented the lowest HCC risk. Particularly, patients with baseline HBV DNA levels 6.00-6.99 log10 IU/mL had the highest on-treatment HCC risk (HR, 3.36; p<0.001) compared with those with baseline HBV DNA levels≥8.00 log10 IU/mL. These findings were more prominent among HBeAg-positive patients, younger patients, or those with less advanced hepatic fibrosis. CONCLUSION: Patients with moderate baseline viral load, particularly around 6 log10 IU/mL, demonstrated the highest on-treatment HCC risk, despite long-term antiviral treatment. Early initiation of antiviral treatment, tailored to viral load, should be considered to minimise HCC risk in adult CHB patients without cirrhosis.
Asunto(s)
Carcinoma Hepatocelular , Hepatitis B Crónica , Neoplasias Hepáticas , Adulto , Humanos , Carcinoma Hepatocelular/epidemiología , Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/prevención & control , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/tratamiento farmacológico , Neoplasias Hepáticas/epidemiología , Neoplasias Hepáticas/etiología , Virus de la Hepatitis B/genética , Estudios de Cohortes , Antígenos e de la Hepatitis B , ADN Viral , Carga Viral , Cirrosis Hepática/tratamiento farmacológico , Antivirales/uso terapéuticoRESUMEN
The hepatitis B elimination is a goal proposed by the WHO to be achieved by 2030 through the adoption of synergistic measures for the prevention and chronic HBV infection treatment. Complete cure is characterized by the HBV elimination from the body and is the goal of the chronic hepatitis B treatment, which once achieved, will enable the hepatitis B elimination. This, today, has been a scientific challenge. The difficulty in achieving a complete cure is due to the indefinite maintenance of a covalently closed episomal circular DNA (cccDNA) reservoir and the maintenance and persistence of an insufficient and dysfunctional immune response in chronically infected patients. Among the measures adopted to eliminate hepatitis B, two have the potential to directly interfere with the virus cycle, but with limited effect on HBV control. These are conventional vaccines-blocking transmission and antiviral therapy-inhibiting replication. Vaccines, despite their effectiveness in protecting against horizontal transmission and preventing mother-to-child vertical transmission, have no effect on chronic infection or potential to eliminate the virus. Treatment with antivirals suppresses viral replication, but has no curative effect, as it has no action against cccDNA. Therapeutic vaccines comprise an additional approach in the chronic infection treatment, however, they have only a modest effect on the immune system, enhancing it temporarily. This manuscript aims to address (1) the cccDNA persistence in the hepatocyte nucleus and the immune response dysfunction in chronically infected individuals as two primary factors that have hampered the treatment and HBV elimination from the human body; (2) the limitations of antiviral therapy and therapeutic vaccines, as strategies to control hepatitis B; and (3) the possibly promising therapeutic approaches for the complete cure and elimination of hepatitis B.
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Vacunas contra Hepatitis B , Virus de la Hepatitis B , Hepatitis B , Humanos , Virus de la Hepatitis B/efectos de los fármacos , Vacunas contra Hepatitis B/uso terapéutico , Hepatitis B/tratamiento farmacológico , Hepatitis B/prevención & control , Antivirales/uso terapéutico , Animales , ADN Circular , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/virologíaRESUMEN
Chronic hepatitis B, a major cause of liver disease and cancer, affects >250 million people worldwide. Currently there is no cure, only suppressive therapies. Efforts to develop finite curative hepatitis B virus (HBV) therapies are underway, consisting of combinations of multiple novel agents with or without nucleos(t)ide reverse-transcriptase inhibitors. The HBV Forum convened a webinar in July 2021, along with subsequent working group discussions to address how and when to stop finite therapy for demonstration of sustained off-treatment efficacy and safety responses. Participants included leading experts in academia, clinical practice, pharmaceutical companies, patient representatives, and regulatory agencies. This Viewpoints article outlines areas of consensus within our multistakeholder group for stopping finite therapies in chronic hepatitis B investigational studies, including trial design, patient selection, outcomes, biomarkers, predefined stopping criteria, predefined retreatment criteria, duration of investigational therapies, and follow-up after stopping therapy. Future research of unmet needs are discussed.
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Hepatitis B Crónica , Hepatitis B , Humanos , Hepatitis B Crónica/tratamiento farmacológico , Antivirales/uso terapéutico , Virus de la Hepatitis B/genética , Resultado del Tratamiento , Biomarcadores , Antígenos de Superficie de la Hepatitis B , ADN Viral , Hepatitis B/tratamiento farmacológicoRESUMEN
BACKGROUND: Improved epidemiologic and treatment data for active tuberculosis (TB) with chronic hepatitis B virus (cHBV) infection might inform and encourage screening and vaccination programs focused on persons at risk of having both conditions. METHODS: We matched the California Department of Public Health TB registry during 2016-2020 to the cHBV registry using probabilistic matching algorithms. We used chi-square analysis to compare the characteristics of persons with TB and cHBV with those with TB only. We compared TB treatment outcomes between these groups using modified Poisson regression models. We calculated the time between reporting of TB and cHBV diagnoses for those with both conditions. RESULTS: We identified 8435 persons with TB, including 316 (3.7%) with cHBV. Among persons with TB and cHBV, 256 (81.0%) were non-US-born Asian versus 4186 (51.6%) with TB only (P < .0001). End-stage renal disease (26 [8.2%] vs 322 [4.0%]; P < .001) and HIV (21 [6.7%] vs 247 [3.0%]; P = .02) were more frequent among those with TB and cHBV compared with those with TB only. Among those with both conditions, 35 (11.1%) had TB diagnosed >60 days before cHBV (median, 363 days) and 220 (69.6%) had TB diagnosed >60 days after cHBV (median, 3411 days). CONCLUSIONS: Persons with TB and cHBV were found more frequently in certain groups compared with TB only, and infrequently had their conditions diagnosed together. This highlights an opportunity to improve screening and treatment of TB and cHBV in those at high risk for coinfection.
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Hepatitis B Crónica , Tuberculosis , Humanos , Masculino , Femenino , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/epidemiología , Hepatitis B Crónica/tratamiento farmacológico , California/epidemiología , Persona de Mediana Edad , Adulto , Tuberculosis/epidemiología , Tuberculosis/tratamiento farmacológico , Resultado del Tratamiento , Coinfección/epidemiología , Antituberculosos/uso terapéutico , Adulto Joven , Anciano , Sistema de Registros , Infecciones por VIH/complicaciones , Infecciones por VIH/epidemiología , AdolescenteRESUMEN
BACKGROUND: The safety of immune-checkpoint inhibitors (ICIs) has not been thoroughly investigated in non-small cell lung cancer (NSCLC) patients with chronic hepatitis B (CHB) or occult hepatitis B infection (OBI). The authors analyzed the incidence of hepatitis B virus (HBV) reactivation, immune-related hepatitis and jaundice in NSCLC patients in a real-world setting. METHODS: A total of 1277 NSCLC patients treated with ICIs were analyzed. Among them, 52 patients were hepatitis B surface antigen (HBsAg) (+) (group A, CHB), 759 patients were HBsAg (-)/hepatitis B core antibody immunoglobulin G (anti-HBc IgG) (+) (group B, OBI), and 466 patients were HBsAg (-)/anti-HBc IgG (-) (group C). Among the 52 patients with CHB, 38 (73.1%) were receiving antiviral therapy. The primary end point was HBV reactivation, immune-related hepatitis, and jaundice. The secondary end points included other immune-related adverse events and efficacy. RESULTS: HBV reactivation was observed in two patients (0.2%) who were both in group A (CHB). Among CHB patients who were not receiving antiviral therapy, HBV reactivation was observed in 14.3% (2 of 14 patients). The incidences of immune-related hepatitis and jaundice were comparable among the three groups. The incidence of ≥grade 3 other immune-related adverse events and efficacy were all comparable among the three groups (p > .05 for all comparisons). CONCLUSIONS: In this large, real-world cohort study, the safety and efficacy of ICIs were comparable in patients with CHB and OBI. HBV reactivation was observed in patients with CHB without antiviral therapy indicating antiviral prophylaxis should be required for them. For patients with OBI, the risk of HBV reactivation was minimal.
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Carcinoma de Pulmón de Células no Pequeñas , Hepatitis B Crónica , Hepatitis B , Ictericia , Neoplasias Pulmonares , Humanos , Virus de la Hepatitis B , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/epidemiología , Antígenos de Superficie de la Hepatitis B/farmacología , Antígenos de Superficie de la Hepatitis B/uso terapéutico , Incidencia , Carcinoma de Pulmón de Células no Pequeñas/complicaciones , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/epidemiología , Estudios de Cohortes , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/inducido químicamente , Antivirales/efectos adversos , Inmunoglobulina G/farmacología , Inmunoglobulina G/uso terapéutico , Ictericia/inducido químicamente , Ictericia/complicaciones , Ictericia/tratamiento farmacológico , Hepatitis B/complicaciones , Activación Viral , ADN ViralRESUMEN
BACKGROUND & AIMS: Immunotherapy for chronic hepatitis B virus (HBV) infection has not yet demonstrated sufficient efficacy. We developed a non-integrative lentiviral-vectored therapeutic vaccine for chronic hepatitis B and tested its antiviral effects in HBV-persistent mice and two inactive HBsAg carriers. METHODS: Lentiviral vectors (LVs) encoding the core, preS1, or large HBsAg (LHBs) proteins of HBV were evaluated for immunogenicity in HBV-naïve mice and therapeutic efficacy in a murine model of chronic HBV infection. In addition, two inactive HBsAg carriers each received two doses of 5×107 transduction units (TU) or 1×108 TU of lentiviral-vectored LHBs (LV-LHBs), respectively. The endpoints were safety, LHBs-specific T-cell responses, and serum HBsAg levels during a 24-week follow-up. RESULTS: In the mouse models, LV-LHBs was the most promising in eliciting robust antigen-specific T cells and in reducing the levels of serum HBsAg and viral load. By the end of the 34-week observation period, six out of ten (60%) HBV-persistent mice vaccinated with LV-LHBs achieved serum HBsAg loss and significant depletion of HBV-positive hepatocytes in the liver. In the two inactive HBsAg carriers, vaccination with LV-LHBs induced a considerable increase in the number of peripheral LHBs-specific T cells in one patient, and a weak but detectable response in the other, accompanied by a sustained reduction of HBsAg (-0.31 log10 IU/ml and -0.46 log10 IU/ml, respectively) from baseline to nadir. CONCLUSIONS: A lentiviral-vectored therapeutic vaccine for chronic HBV infection demonstrated the potential to improve HBV-specific T-cell responses and deplete HBV-positive hepatocytes, leading to a sustained loss or reduction of serum HBsAg. IMPACT AND IMPLICATIONS: Chronic HBV infection is characterized by an extremely low number and profound hypo-responsiveness of HBV-specific T cells. Therapeutic vaccines are designed to improve HBV-specific T-cell responses. We show that immunization with a lentiviral-vectored therapeutic HBV vaccine was able to expand HBV-specific T cells in vivo, leading to reductions of HBV-positive hepatocytes and serum HBsAg.
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Hepatitis B Crónica , Humanos , Ratones , Animales , Hepatitis B Crónica/prevención & control , Hepatitis B Crónica/tratamiento farmacológico , Virus de la Hepatitis B , Antígenos de Superficie de la Hepatitis B , Lentivirus/genética , Vacunas contra Hepatitis B/uso terapéutico , VacunaciónRESUMEN
BACKGROUND & AIMS: Oral antiviral therapy with nucleos(t)ide analogues (NAs) for chronic hepatitis B (CHB) is well-tolerated and lifesaving, but real-world data on utilization are limited. We examined rates of evaluation and treatment in patients from the REAL-B consortium. METHODS: This was a cross-sectional study nested within our retrospective multinational clinical consortium (2000-2021). We determined the proportions of patients receiving adequate evaluation, meeting AASLD treatment criteria, and initiating treatment at any time during the study period. We also identified factors associated with receiving adequate evaluation and treatment using multivariable logistic regression analyses. RESULTS: We analyzed 12,566 adult treatment-naïve patients with CHB from 25 centers in 9 countries (mean age 47.1 years, 41.7% female, 96.1% Asian, 49.6% Western region, 8.7% cirrhosis). Overall, 73.3% (9,206 patients) received adequate evaluation. Among the adequately evaluated, 32.6% (3,001 patients) were treatment eligible by AASLD criteria, 83.3% (2,500 patients) of whom were initiated on NAs, with consistent findings in analyses using EASL criteria. On multivariable logistic regression adjusting for age, sex, cirrhosis, and ethnicity plus region, female sex was associated with adequate evaluation (adjusted odds ratio [aOR] 1.13, p = 0.004), but female treatment-eligible patients were about 50% less likely to initiate NAs (aOR 0.54, p <0.001). Additionally, the lowest evaluation and treatment rates were among Asian patients from the West, but no difference was observed between non-Asian patients and Asian patients from the East. Asian patients from the West (vs. East) were about 40-50% less likely to undergo adequate evaluation (aOR 0.60) and initiate NAs (aOR 0.54) (both p <0.001). CONCLUSIONS: Evaluation and treatment rates were suboptimal for patients with CHB in both the East and West, with significant sex and ethnic disparities. Improved linkage to care with linguistically competent and culturally sensitive approaches is needed. IMPACT AND IMPLICATIONS: Significant sex and ethnic disparities exist in hepatitis B evaluation and treatment, with female treatment-eligible patients about 50% less likely to receive antiviral treatment and Asian patients from Western regions also about 50% less likely to receive adequate evaluation or treatment compared to Asians from the East (there was no significant difference between Asian patients from the East and non-Asian patients). Improved linkage to care with linguistically competent and culturally sensitive approaches is needed.
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Antivirales , Disparidades en Atención de Salud , Hepatitis B Crónica , Humanos , Femenino , Masculino , Antivirales/uso terapéutico , Estudios Transversales , Persona de Mediana Edad , Estudios Retrospectivos , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/etnología , Adulto , Disparidades en Atención de Salud/estadística & datos numéricos , Disparidades en Atención de Salud/etnología , Factores Sexuales , Etnicidad/estadística & datos numéricos , Salud GlobalRESUMEN
BACKGROUND & AIMS: The use of tenofovir disoproxil fumarate (TDF) is associated with a reduction in bone mineral density and an increase in bone metabolism biomarkers. However, data on clinical bone fractures remain limited. We evaluated the impact of TDF compared to entecavir on the risk of fracture in elderly patients with chronic hepatitis B (CHB). METHODS: Patients with CHB aged ≥60 years receiving entecavir or TDF between January 2008 and December 2022 were identified using a territory-wide database in Hong Kong. The risk of incident fracture in entecavir- and TDF-treated patients before and after month 24 were compared after propensity score matching. RESULTS: A total of 41,531 patients with CHB (mean age 69.8±7.8 years, 61.6% male) receiving entecavir (n = 39,897 [96.1%]) and TDF (n = 1,634 [3.9%]) were analysed. At a median follow-up of 25.3 (9.1-58.5) months, 1,733 (4.2%) patients developed incident fracture. Patients with incident fracture were more likely to have diabetes, hypertension, congestive heart failure, rheumatoid arthritis, osteoporosis, and a history of fracture. Compared with propensity score-matched entecavir-treated patients, the risk of incident fracture in TDF-treated patients was comparable in the first 24 months (weighted subdistribution hazard ratio [sHR] 0.99, 95% CI 0.56-1.73, p = 0.960) but increased after month 24 (weighted sHR 1.80, 95% CI 1.11-2.93, p = 0.019). The 24-, 60-, and 96-month cumulative incidences (95% CI) of fracture in TDF-treated and entecavir-treated patients were 2.3% (1.6%-3.4%) vs. 2.6% (1.9%-3.5%), 6.4% (5.0%-8.2%) vs. 4.7% (3.8%-6.0%), and 10.2% (8.3%-12.6%) vs. 6.8% (5.4%-8.5%), respectively. CONCLUSIONS: The risk of fracture increased with TDF treatment for ≥24 months in elderly patients with CHB. Selection of nucleos(t)ide analogues should be individualised based on age and comorbidities. IMPACT AND IMPLICATIONS: Previous literature suggested that the use of tenofovir disoproxil fumarate (TDF) is associated with a decrease in bone mineral density. However, data on the impact of TDF on long-term incident clinical fracture remains scarce. In this real-world territory-wide study of 41,531 treated patients with chronic hepatitis B in Hong Kong, patients who received TDF were at a higher risk of fracture after 2 years of treatment than those who received entecavir. Given the ageing population of patients with chronic hepatitis B and the rising prevalence of comorbidities, our findings support the current treatment guidelines that recommend selecting antiviral treatment based on age and comorbidities.
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Fracturas Óseas , Hepatitis B Crónica , Anciano , Humanos , Masculino , Persona de Mediana Edad , Femenino , Tenofovir/efectos adversos , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/tratamiento farmacológico , Antivirales/efectos adversos , Estudios Retrospectivos , Resultado del Tratamiento , Fracturas Óseas/inducido químicamente , Fracturas Óseas/epidemiología , Fracturas Óseas/complicacionesRESUMEN
BACKGROUND & AIMS: HBsAg loss is only observed in a small proportion of patients with chronic hepatitis B (CHB) who undergo interferon treatment. Investigating the host factors crucial for functional cure of CHB can aid in identifying individuals who would benefit from peginterferon-α (Peg-IFNα) therapy. METHODS: We conducted a genome-wide association study (GWAS) by enrolling 48 patients with CHB who achieved HBsAg loss after Peg-IFNα treatment and 47 patients who didn't. In the validation stage, we included 224 patients, of whom 90 had achieved HBsAg loss, to validate the identified significant single nucleotide polymorphisms. To verify the functional involvement of the candidate genes identified, we performed a series of in vitro and in vivo experiments. RESULTS: GWAS results indicated a significant association between the rs7519753 C allele and serum HBsAg loss in patients with CHB after Peg-IFNα treatment (p = 4.85 × 10-8, odds ratio = 14.47). This association was also observed in two independent validation cohorts. Expression quantitative trait locus analysis revealed higher hepatic TP53BP2 expression in individuals carrying the rs7519753 C allele (p = 2.90 × 10-6). RNA-sequencing of liver biopsies from patients with CHB after Peg-IFNα treatment revealed that hepatic TP53BP2 levels were significantly higher in the HBsAg loss group compared to the HBsAg persistence group (p = 0.035). In vitro and in vivo experiments demonstrated that loss of TP53BP2 decreased interferon-stimulated gene levels and the anti-HBV effect of IFN-α. Mechanistically, TP53BP2 was found to downregulate SOCS2, thereby facilitating JAK/STAT signaling. CONCLUSION: The rs7519753 C allele is associated with elevated hepatic TP53BP2 expression and an increased probability of serum HBsAg loss post-Peg-IFNα treatment in patients with CHB. TP53BP2 enhances the response of the hepatocyte to IFN-α by suppressing SOCS2 expression. IMPACT AND IMPLICATIONS: Chronic hepatitis B (CHB) remains a global public health issue. Although current antiviral therapies are more effective in halting disease progression, only a few patients achieve functional cure for hepatitis B with HBsAg loss, highlighting the urgent need for a cure for CHB. This study revealed that the rs7519753 C allele, which is associated with high expression of hepatic TP53BP2, significantly increases the likelihood of serum HBsAg loss in patients with CHB undergoing Peg-IFNα treatment. This finding not only provides a promising predictor for HBsAg loss but identifies a potential therapeutic target for Peg-IFNα treatment. We believe our results are of great interest to a wide range of stakeholders based on their potential clinical implications.