Immune Mechanisms Underlying Hepatitis B Surface Antigen Seroclearance in Chronic Hepatitis B Patients With Viral Coinfection

Wu, Shuling; Yi, Wei; Gao, Yumei; Deng, Wen; Bi, Xiaoping; Lin, Yanjie; Yang, Liu; Lu, Yao; Liu, Ruyu; Chang, Min; Shen, Ge; Hu, Leiping; Zhang, Lu; Li, Minghui; Xie, Yao

doi:10.3389/fimmu.2022.893512

Cited by 9 publications

(6 citation statements)

References 170 publications

(139 reference statements)

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“…Therefore, pursuing a better endpoint, HBsAg seroclearance, is important. HBsAg seroclearance, also called "functional cure", can effectively improve the long-term prognosis of patients and greatly reduce the risk of cirrhosis and liver cancer (18)(19)(20). Pegylated interferon a-2a (PEG-IFN a-2a) have a unique advantage over nucleoside (acid) analogues (NAs) in achieving HBsAg seroclearance (21)(22)(23).…”

Section: Discussionmentioning

confidence: 99%

Study on pathological and clinical characteristics of chronic HBV infected patients with HBsAg positive, HBV DNA negative, HBeAg negative

et al. 2023

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AimsStudy of clinical characteristics of hepatitis B virus deoxyribonucleic acid (HBV DNA)-negative, hepatitis B surface antigen (HBsAg)-positive, hepatitis B e antigen (HBeAg)-negative patients based on liver histopathology.MethodsWe retrospectively enrolled patients with chronic HBV infection diagnosis at Beijing Ditan Hospital from May 2008 to November 2020. To study the differences between patients with significant hepatic histopathology and those without significant hepatic histopathology. And to study the independent factors of significant hepatic histopathology.Results85 HBV DNA-negative and HBeAg-negative patients were 37.90 ± 10.30 years old, 23.50% of patients with grade of inflammation (G) >1, 35.30% of patients with liver fibrosis stage (S) >1, 44.70% patients were diagnosed with significant hepatic histopathology. Compared to the no significant hepatic histopathology group, another group had older age (41.70 ± 10.70 vs 34.80 ± 8.87 years, t=-3.28, P=0.002), higher total bilirubin (TBIL) [14.9(10.3, 22.4) vs 11(8.9, 14.4) μmol/L, z=-2.26, P=0.024], lower cholinesterase (CHE) (t=-2.86, P=0.005, 7388.00 ± 2156.00 vs 8988.00 ± 2823.00 U/L) and lower platelet (PLT) (t=2.75, P=0.007, 157.00 ± 61.40 vs 194.00 ± 61.00 10^9/L). Abnormal ALT patients are more likely to have significant hepatic histopathology (z=5.44, P=0.020, 66.70% vs 337.50%). G had significant correlation with CHE (P=0.008, r=-0.23), alanine aminotransferase (ALT) (P=0.041, r=0.18), aspartate aminotransferase (AST) (P=0.001, r=0.29). S had significant correlation with TBIL (P = 0.008, r = 0.23), age (P < 0.001, r = 0.32), international normalized ratio (INR) (P = 0.04, r = 0.23), CHE (P < 0.001, r = -0.30), PLT (P < 0.001, r = -0.40) and prothrombin time activity (PTA) (P = 0.046, r = -0.22). Multivariate logistic analysis indicated only age (95%CI=1.014~1.130, OR=1.069, P=0.013) was an impact factor for significant hepatic histopathology. The cutoff point of age was 34.30 years.ConclusionsA large proportion of chronic HBV infection patients with HBeAg-negative and HBV DNA-negative still have chronic hepatitis. Age is an independent factor for significant hepatic histopathology

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Section: Discussionmentioning

confidence: 99%

Study on pathological and clinical characteristics of chronic HBV infected patients with HBsAg positive, HBV DNA negative, HBeAg negative

et al. 2023

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“…Therefore, the expression of RANTES and MIP-1α in HBsAg negative group is higher than that in HBsAg positive group, which may contribute to the restoration and activation of immune function in HBsAg negative and HBV DNA positive patients. Existing studies have shown that HBsAg induces depletion phenotypes and dysfunction of T and B cells by leading to innate and adaptive immune deficiencies, so lowering serum HBsAg levels contributes to the recovery of host immune responses [57]. The decrease of HBsAg level can promote the reconstruction of host immune system: the antigen presentation ability of dendritic cells (DC) is restored, NK cell killing is restored, cytotoxic granules and IFN-γ secretion are increased, T cell activation is promoted, the proliferation ability of depleted T cells is restored, and the function of HBsAg specific plasma cells secreting anti-HBs is restored [58].…”

Section: Discussionmentioning

confidence: 99%

Serological, molecular characteristics and cytokines profile of HBsAg negative/HBV DNA positive patients in clinic

Chen

Liu

et al. 2023

Preprint

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Background In this study, the serological characteristics, sequencing analysis and cytokine levels of HBsAg negative and HBV DNA positive patients were analyzed to preliminarily determine whether being HBsAg clearance was related to immune function. Methods Evaluate the basic medical records and laboratory data of 279 HBsAg negative and HBV DNA positive patients. Serum samples from 30 HBsAg negative and HBV DNA positive patients, 20 matched HBsAg persistently positive patients and 16 healthy people were tested for 48 cytokines, chemokines and growth factors. Sanger sequencing was used to analyze the HBV S region sequences of HBsAg negative and HBV DNA positive patients samples. Results Of the 76428 HBV-infected patients enrolled, 358 (0.47%) were defined as HBsAg negative and HBV DNA positive patients. The main serological patterns of HBsAg negative and HBV DNA positive patients were anti-HBe and anti-HBc positive, accounting for 47.67%. HBV DNA load<200IU/ml was found in 94.98%. Serum sCD40L, G-CSF, IFN-γ, MIP-1α, RANTES and Eotaxin levels were significantly higher in the HBsAg negative group than in the HBsAg positive group(P＜0.05), but IL-4, IL-6, IL-8, IL-13, IL-17A, PDGF-AA, TGF-α and TNF-β levels were lower in the HBsAg negative group(P<0.05). Between the HBsAg negative group and the healthy control group, there were also differences in the levels of several serum cytokines, chemokines, and growth factors. The levels of AST/ALT were positively correlated with IL-15(P=0.040/0.009) and IL-18(P=0.031/P=0.003). Nine HBsAg negative samples were sequenced, revealing amino acid substitutions in the HBV S protein, including immune escape mutations(Y100C, S114T, C124Y, P127L, G130R, T131N, M133T) and affecting HBsAg secretion mutations(E2R/K/D). Conclusions The levels of HBV DNA replication and transcription are low in most HBsAg negative and HBV DNA positive patients. Since there were fewer HBsAg negative and HBV DNA positive patients in this study with significant and meaningful HBV mutations, viral factors might not be the primary causes. Therefore, it is more valuable to proceed from the host factor. By inducing a slightly stronger host immune response and controlling liver inflammation, several cytokines and chemokines, including G-CSF, IFN-γ, MIP-1α, RANTES and Eotaxin, may promote in the clearance of HBsAg.

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“…The HBeAg -positive status could be suggested as a surrogate marker for HBV viral load usually accompanied by high HBV DNA in patients with HIV/HBV coinfection ( Li et al., 2016 ), which ultimately results in immune activation and restoration. The HBeAg -positive stage generates less HBsAg than the HBeAg -negative stage because the chromosome integration level caused by HBV double -stranded linear DNA (dslDNA) becomes low ( Bill and Summers, 2004 ; Wu et al., 2022 ). Mutations in the precore region that occur over time in chronic untreated HBV infection lead to viral mutants that do not produce HBeAg and therefore HBeAg-negative disease, which is associated with periods of high viral replication and necro-inflammatory activity in the liver.…”

Section: Discussionmentioning

confidence: 99%

Incidence and predictors of HBV functional cure in patients with HIV/HBV coinfection: A retrospective cohort study

Zhang

Wang²,

Jiang³

et al. 2023

Front. Cell. Infect. Microbiol.

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BackgroundThis study was the first to examine the association of baseline clinical factors with the rate of HBsAg clearance in a large retrospective cohort of Chinese patients with HIV/HBV coinfection treated with combination antiretroviral therapy (ART).MethodsOur retrospective cohort included 431 patients with HIV/HBV coinfection treated with TDF-containing ART. The median follow-up was 6.26 years. Logistic regression was used to investigate the association of baseline variables with HBsAg clearance, and Cox regression was used to investigate the association of baseline variables with time to HBsAg clearance.ResultsThe clearance rate of HBsAg in our study was 0.072 (95% CI 0.049~0.101). In the multivariate logistic regression, advanced age (OR=1.1, P=0.007), high CD4 cell count (OR=2.06, P=0.05), and HBeAg positivity (OR=8.00, P=0.009) were significantly associated with the rate of HBsAg clearance. The AUC of the model integrating the above three predictors was 0.811. Similar results were found in the multivariate Cox regression (HR = 1.09, P = 0.038 for age, HR = 1.05, P = 0.012 for CD4 count and HR = 7.00, P = 0.007 for HBeAg).ConclusionsLong-term TDF-containing ART can lead to HBsAg clearance of 7.2% in Chinese patients with HIV/HBV coinfection. Advanced age, high CD4 cell count, and positive HBeAg at baseline could be regarded as potential predictors and biological markers for HBsAg clearance in patients with HIV/HBV coinfection.

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Immune Mechanisms Underlying Hepatitis B Surface Antigen Seroclearance in Chronic Hepatitis B Patients With Viral Coinfection

Cited by 9 publications

References 170 publications

Study on pathological and clinical characteristics of chronic HBV infected patients with HBsAg positive, HBV DNA negative, HBeAg negative

Study on pathological and clinical characteristics of chronic HBV infected patients with HBsAg positive, HBV DNA negative, HBeAg negative

Serological, molecular characteristics and cytokines profile of HBsAg negative/HBV DNA positive patients in clinic

Incidence and predictors of HBV functional cure in patients with HIV/HBV coinfection: A retrospective cohort study

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