High HBV DNA Levels Research Articles

Real-world clinical data-driven modelling on the initiation time of antiviral prophylaxis among pregnant women with chronic hepatitis B infection

Background & AimsThe risk of mother-to-child transmission (MTCT) for pregnant women with chronic hepatitis B (CHB) infection still exists, especially for those with high HBV DNA level. The guidelines for initiating prophylaxis for pregnant women with CHB vary across countries. We aimed to explore the latest prophylaxis initiation time for these women. MethodsWe collected the real-world clinical data of 328 pregnant women with CHB infection aged 20-49 treated by telbivudine (LdT) or tenofovir disoproxil fumarate (TDF) from July 2010 to December 2020 in China. A mathematical model was developed to describe the viral kinetics of HBV after prophylaxis. We calculated the time required to reduce viral load below the threshold value of 5.3 log10 IU/mL. We derived the prophylaxis initiation time by subtracting the required time to threshold from the childbirth gestational week. ResultsThe median time for 328 women to reduce HBV DNA levels below the threshold of 5.3 log10 IU/mL was 4.2 (range: 0.2-12.8) weeks, corresponding to prophylaxis initiation time of no later than 35.1 (25.2-41.4) weeks. Specifically, for women with viral loads > 8.0 log10 IU/mL, prophylaxis should be initiated before 33.9 (25.2-39.5) weeks, and particularly before the lower bound of 25.2 weeks, to maximize clinical safety. For women with viral load >7.0 to 8.0 log10 IU/mL, prophylaxis should be initiated before 35.5 (28.6-39.8) weeks, and for women with viral load >5.3 to 7.0 log10 IU/mL, prophylaxis should be initiated before 36.2 (28.3-41.4) weeks. ConclusionPregnant women with HBV DNA levels >5.3 to 8.0 log10 IU/mL can initiate prophylaxis before 28 gestational weeks. However, women with HBV DNA >8.0 log10 IU/mL could consider initiating prophylaxis before 25 weeks. Impact and implicationsThis study investigates how long it takes to decrease maternal viral load below a threshold·(5.3 log10 IU/mL) after receiving antiviral prophylaxis in pregnant women with different HBV DNA levels based on real-world clinical data and mathematical modelling, which provides quantitative evidence on the initiation time of antiviral prophylaxis. The results show that pregnant women with CHB infection at high HBV DNA levels (>8 log10 IU/mL) should initiate antiviral prophylaxis earlier to decrease the risk of mother-to-child transmission of HBV. Physicians can determine when to begin antiviral prophylaxis for those women according to their maternal HBV DNA levels. Our findings justify the initiation time of antiviral prophylaxis recommended by the Chinese guidelines and will offer new insights for other international guidelines.

HBV integrations reshaping genomic structures promote hepatocellular carcinoma

ObjectiveHepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), mostly characterised by HBV integrations, is prevalent worldwide. Previous HBV studies mainly focused on a few hotspot integrations. However, the oncogenic role of...

Preoperative Antiviral Therapy and Long-Term Outcomes for Hepatitis B Virus-Related Hepatocellular Carcinoma After Curative Liver Resection: A Multicenter Analysis.

To examine the association of the history of preoperative antiviral therapy (AVT) with the tumor recurrence and overall survival in HBV-related HCC patients undergoing curative-intent hepatectomy. Patients who underwent curative-intent hepatectomy for HBV-related HCC between 2014 and 2019 at 4 Chinese hospitals were analyzed. Patients were categorized as having undergone preoperative antiviral therapy (AVT) > 1 year or without antiviral therapy (non-AVT). Patient clinical features, short-term outcomes, overall survival (OS), and time-to-recurrence (TTR) were also compared. Multivariate Cox regression analysis was performed to identify the impact of preoperative AVT on the OS and TTR. Among the 565 patients, 190 (33.6%) underwent continuous AVT > 1 year before surgery. Patients in the non-AVT group were more likely to have worse liver function and more advanced tumor pathological characteristics than those in the AVT group. Postoperative morbidity and mortality rates were comparable between the two groups. Multivariate analyses revealed that a preoperative HBV viral level ≥ 2000 IU/mL was independently associated with poorer TTR (hazard ratio, 1.328; 95% CI, 1.049-1.682) and preoperative AVT was a protective factor for OS (hazard ratio, 0.691; 95% CI, 0.484-0.986). A high preoperative HBV DNA level was an independent risk factor for tumor recurrence. Preoperative AVT > 1 year was associated with better OS and a reduced incidence of tumor recurrence by inhibiting the preoperative level of HBV DNA.

Predictors of Significant Histological Hepatic Abnormality in Treatment-Naive Patients Infected with HBeAg-Negative Chronic Hepatitis B.

This study aimed to determine the predictors for significant hepatic abnormality (SHA), a treatment indication, by assessing demographic, laboratory, and radiological results of chronic hepatitis B (CHB) patients who underwent liver biopsy. In this retrospective study, individuals with untreated hepatitis B e-antigen (HBeAg)-negative CHB infection were enrolled. Multivariate analysis modeling was conducted with parameters identified as predictors for SHA in univariate analysis. Optimal threshold levels for variables to predict SHA in patients with chronic hepatitis B were determined based on receiver operating characteristic (ROC) curve analysis. A total of 566 patients with untreated chronic hepatitis B were included in the cohort; 61% (345/566) were male, and the median age was 41 years (interquartile range [IQR]=34-50). Notably, 36.9% (209/566) had SHA. In the multivariate analysis, utilizing different models, age, gender, HBV-DNA, LDL, ALT, and platelet count were identified as the most reliable predictors for SHA in CHB patients. For predicting SHA, the area under the ROC curve values of HBV-DNA, AST, and ALT were 0.704 (sensitivity=62.8%, specificity=76.2%; p<0.0001), 0.747 (sensitivity=51.9%, specificity=88.9%; p<0.0001), and 0.737 (sensitivity=68.6%, specificity=68.4%; p<0.0001), respectively. In our study, age, male gender, ALT, AST, HBV-DNA, LDL cholesterol, platelet count, and FIB-4 score were independent predictors of SHA in HBeAg-negative chronic hepatitis B. The most sensitive parameters for SHA were LDL and ALT. The most specific parameters were age, AST, and APRI score. SHA may occur in patients with high HBV-DNA levels, even if ALT values are normal in HBeAg-negative patients.

Factors affecting HBV DNA suppression in chronic hepatitis B patients treated with tenofovir disoproxil fumarate.

Background: This study aims to determine the factors affecting HBV DNA suppression in chronic hepatitis B patients with tenofovir disoproxil fumarate (TDF). Methods: A case-control was carried out from October 2021 to August 2022 on 182 chronic hepatitis B patients who had TDF therapy regularly for 24 weeks at H. Adam Malik and USU Hospitals in Medan, Indonesia. The history of the samples was obtained, followed by physical examination, and blood collection. CTLA-4 polymorphism examination was carried out using real-time PCR, while the serum CTLA-4 levels were assessed with ELISA. Results:The CTLA-4 -1661G>A polymorphism, genotype GG+AG, increased 1.52 times risk of not achieving HBV DNA suppression to TDF compared to genotype AA (p=0.041). High CTLA-4 levels increased 2.28 times risk, high HBV DNA levels increased 2.09 times risk, low ALT levels increased 1.95 times risk of not achieving HBV DNA suppression (p= 0.009, 0.026, 0.036, respectively). There was no relationship between gender, age, ethnicity, obesity, baseline AST, HBeAg, genotype, liver fibrosis and HBV DNA suppression after 24 weeks of treatment (p>0.05). Conclusions: The levels of CTLA-4, HBV DNA, ALT, and CTLA-4 -1661G>A polymorphism have a potential relationship with the suppression of HBV DNA in chronic hepatitis B patients with TDF.

Hepatitis B virus-related intrahepatic cholangiocarcinoma originates from hepatocytes

BackgroundHepatitis B virus (HBV) infection is one of the most common risk factors for intrahepatic cholangiocarcinoma (ICC). However, there is no direct evidence of a causal relationship between HBV infection and ICC. In this study, we attempted to prove that ICC may originate from hepatocytes through a pathological study involving ICC tissue-derived organoids.MethodThe medical records and tumor tissue samples of 182 patients with ICC after hepatectomy were collected. The medical records of 182 patients with ICC were retrospectively analyzed to explore the prognostic factors. A microarray of 182 cases of ICC tumor tissue and 6 cases of normal liver tissue was made, and HBsAg was stained by immunohistochemistry (IHC) to explore the factors closely related to HBV infection. Fresh ICC tissues and corresponding adjacent tissues were collected to make paraffin sections and organoids. Immunofluorescence (IF) staining of factors including HBsAg, CK19, CK7, Hep-Par1 and Albumin (ALB) was performed on both fresh tissues and organoids. In addition, we collected adjacent nontumor tissues of 6 patients with HBV (+) ICC, from which biliary duct tissue and normal liver tissue were isolated and RNA was extracted respectively for quantitative PCR assay. In addition, the expression of HBV-DNA in organoid culture medium was detected by quantitative PCR and PCR electrophoresis.ResultsA total of 74 of 182 ICC patients were HBsAg positive (40.66%, 74/182). The disease-free survival (DFS) rate of HBsAg (+) ICC patients was significantly lower than that of HBsAg (−) ICC patients (p = 0.0137). IF and IHC showed that HBsAg staining was only visible in HBV (+) ICC fresh tissues and organoids, HBsAg expression was negative in bile duct cells in the portal area. Quantitative PCR assay has shown that the expression of HBs antigen and HBx in normal hepatocytes were significantly higher than that in bile duct epithelial cells. Combined with the IF and IHC staining, it was confirmed that HBV does not infect normal bile duct epithelial cells. In addition, IF also showed that the staining of bile duct markers CK19 and CK7 were only visible in ICC fresh tissue and organoids, and the staining of hepatocyte markers Hep-Par1 and ALB was only visible in normal liver tissue fresh tissue. Real-time PCR and WB had the same results. High levels of HBV-DNA were detected in the culture medium of HBV (+) organoids but not in the culture medium of HBV (−) organoids.ConclusionHBV-related ICC might be derived from hepatocytes. HBV (+) ICC patients had shorter DFS than HBV (−) ICC patients.

Primary non-response to antiviral therapy affects the prognosis of hepatitis B virus-related hepatocellular carcinoma

Background and aimAlthough antiviral treatments have been shown to affect the recurrence and long-term survival of patients with hepatocellular carcinoma (HCC) who have high viral loads, the effect of different responses to antiviral therapy on the clinical outcomes remains unclear. This study aimed to assess the effect of primary non-response (no-PR) to antiviral therapy on the survival or prognosis of patients with HCC with a high load of hepatitis B virus (HBV) DNA.MethodsA total of 493 HBV-HCC patients hospitalized at Beijing Ditan Hospital of Capital Medical University were admitted to this retrospective study. Patients were divided into two groups based on viral response (no-PR and primary response). Kaplan–Meier (KM) curves were used to compare the overall survival of the two cohorts. Serum viral load comparison and subgroup analysis were performed. Additionally, risk factors were screened and the risk score chart was created.ResultsThis study consisted of 101 patients with no-PR and 392 patients with primary response. In the different categories based on hepatitis B e antigen and HBV DNA, no-PR group had a poor 1-year overall survival (OS). In addition, in the alanine aminotransferase < 50 IU/L and cirrhosis groups, primary nonresponse was related to poor overall survival and progression-free survival. Based on multivariate risk analysis, primary non-response (hazard ratio (HR) = 1.883, 95% CI 1.289–2.751, P = 0.001), tumor multiplicity (HR = 1.488, 95% CI 1.036–2.136, P = 0.031), portal vein tumor thrombus (HR = 2.732, 95% CI 1.859–4.015, P < 0.001), hemoglobin < 120 g/L (HR = 2.211, 95% CI 1.548–3.158, P < 0.001) and tumor size ≥ 5 cm (HR = 2.202, 95% CI 1.533–3.163, P < 0.001) were independent risk factors for 1-year OS. According to the scoring chart, patients were divided into three risk groups (high-, medium-, and low-risk groups) with mortality rates of 61.7%, 30.5%, and 14.1%, respectively.ConclusionsThe level of viral decline at 3 months post-antiviral treatment may predict the OS of patients with HBV-related HCC, and primary non-response may shorten the median survival time of patients with high HBV-DNA levels.

Inadequate Hospital Practices to Prevent Mother-to-Child Transmission of Hepatitis B Virus Infection: A European Survey.

Prevention of vertical transmission of Hepatitis B virus (HBV) infection is crucial to eliminate viral hepatitis as a major public health threat by 2030. We aimed to assess the current hospital policies and practices implemented before, at, and after birth, and to evaluate potential barriers to the full application of international guidelines. A web-based survey was supported by Penta Foundation and distributed across Europe from October to December 2021. Overall, 76 centers with delivery departments completed the survey. HBsAg maternal screening is performed in the first trimester of pregnancy in 53% of the centers and in the third in 46%. HBsAg positive pregnant women are tested for serologic HBV markers and HBV-DNA in 78% and 63% of the departments; 38% of the HBeAg positive women with high HBV-DNA levels are treated during the last trimester of pregnancy. At birth, 91% of the departments administer HBV vaccine to infants born to HBsAg positive mothers within 12 hours of birth; 74% test women with unknown HBsAg status and 78% of them wait for the maternal testing results before administering HBV vaccine to their newborns. After birth, 47% of the departments provide post-vaccination serological testing for infants born to HBsAg positive mothers. The timing of the HBV vaccine schedule varies greatly. There is significant heterogeneity in the hospital policies and correlated procedures. The implementation of a multidisciplinary clinical pathway is a must if a stronger connection between the prenatal, perinatal, and postnatal phases is to be established.

HBV with precore and basal core promoter mutations exhibits a high replication phenotype and causes ER stress-mediated cell death in humanized liver chimeric mice.

Mutations within the precore (PC) and basal core promoter (BCP) regions of the HBV genome are associated with fulminant hepatitis and HBV reactivation. These mutations may enhance viral replication, but little is known about whether they directly induce damage to the liver. We investigated mechanisms of direct cytopathic effects induced by the infection with PC/BCP mutants in the absence of immune response in vitro and in vivo . Mice with humanized livers and hepatocytes derived from humanized mice were infected with either wild-type or mutant-type PC/BCP HBV, and the HBV replication and human hepatocyte damage were evaluated. HBV proliferated vigorously in mice with PC/BCP-mutant infection, and the severe loss of human hepatocytes with a slight human ALT elevation subsequently occurred only in PC/BCP mutant mice. In PC/BCP mutant infection, the accumulation of HBsAg in humanized livers colocalized with the endoplasmic reticulum, leading to apoptosis through unfolded protein response in HBV-infected hepatocytes. RNA-sequencing revealed the molecular characteristics of the phenotype of PC/BCP mutant infection in a humanized mouse model. Reduced ALT elevation and higher HBV DNA levels in this model are consistent with characteristics of HBV reactivation, indicating that the hepatocyte damage in this model might mimic HBV reactivation followed by hepatocyte damage under immunosuppressive conditions. PC and BCP mutations were associated with enhanced viral replication and cell death induced by ER stress using HBV infection models. These mutations might be associated with liver damage in patients with fulminant hepatitis or HBV reactivation.

Acute Hepatitis B Virus Infection in North American Adults

Acute hepatitis B virus (aHBV) is thought to be self-limited with clearance of hepatitis B surface antigen (HBsAg) within 6 months. There are limited reports of the presenting features and outcomes of adults with symptomatic aHBV in the United States. Demographics, clinical features, and 12-month outcomes of patients with adjudicated aHBV were captured prospectively and compared with a contemporaneous cohort of chronic HBV (cHBV) patients enrolled in the Hepatitis B Research Network. Between 2011 and 2018, 60 adjudicated patients with aHBV were compared with 1534 cHBV untreated controls. Although similar in age, other features were dissimilar: aHBV patients were more often male (72% vs 51%), single (72% vs 30%), and non-Hispanic whites or blacks (75% vs 24%). They also were frequently genotype A2 (65% vs 9%), having different risk factors: sexual exposure (75% vs 16%) or injection drug use (10% vs 2%), compared with the cHBV controls. In addition to higher serum aminotransferase and bilirubin levels, acute patients had higher HBV DNA levels (4.8 vs 3.6 log10 IU/mL), whereas quantitative hepatitis B e antigen (HBeAg) levels were lower (1.4 vs 3.0 log10 IU/mL), despite higher rates of HBeAg (73% vs 25%). The median time to HBsAg clearance was 27 weeks and to anti-HBs appearance, 41 weeks. In the current era, caucasian men infected with genotype A2 as a result of sexual exposure or injection drug use were the predominant group in aHBV, suggesting a potential strategy for adult vaccination in North America. Strikingly, only an estimated 36% of subjects cleared HBsAg by month 6; the definition of resolution in acute hepatitis B may need to be modified. ClinicalTirals.gov number NCT01263587.

A Predictive Model to Evaluate the HbeAg Positivity of Chronic Hepatitis B Virus Patients in Clinics: A Cross-Sectional Study.

Background and Objective: The study aims to investigate the correlation between Hepatitis B ‘e’ antigen (HBeAg) and HBV DNA levels, and to find a convenient tool to estimate the HBV DNA level for clinicians. Materials and Methods: We enrolled 1020 patients in this cross-sectional study and divided them into four groups: an HbeAg-positive and -negative group, and high and low HBV DNA levels groups. Results: Alanine aminotransferase (ALT), Albumin (ALB) and HBeAg are independent risk factors for CHB patients. When the level of HBeAg is higher than 16.15 S/CO, it is four times more likely that the patients will have high levels of HBV DNA than those who do not. The ALT and TB are independent risk factors in HBeAg-negative patients with a high HBV DNA level. We have drawn three predictive models to estimate the HBV DNA levels for those with the chronic hepatitis B virus (CHB), and those that are HBeAg-positive and HBeAg-negative (Y1 = 0.004 × ALT(IU/L) + 1.412 × HBeAg (S/CO) − 0.029 × ALB (g/L) + 0.779, the AUC is 0.672, and the cutoff value is −0.072, there the sensitivity is 0.615, the specificity is 0.648, PPV is 65.182% and NPV is 60.837%; Y2 = 0.007 × HBeAg (S/CO) − 0.016 × HGB (g/L) + 3.070, the AUC is 0.724, and the cutoff value is 1.216, where the sensitivity is 0.626, the specificity is 0.897, PPV is 94.118% and NPV is 34.437%; Y3 = −0.005 × ALT(IU/L) + 0.006 × TB (umol/L) + 0.385, the AUC is 0.661, and the cutoff value is 0.263, where the sensitivity is 0.677, the specificity is 0.587, PPV is 66.820% and NPV is 40.774%, respectively). We propose that HBeAg is the most important risk factor for the patient with a high HBV DNA level, however, it is not as important in the HBeAg-positive group. Conclusions: HBeAg is an independent risk factor that reflects the level of HBV DNA with a strong correlation. Patient with HBeAg (−) should combine TB and ALT to estimate the level of HBV DNA.

Definition and Management of the Immune Tolerance Phase in Chronic Hepatitis B

In the natural course of chronic hepatitis B, the immune tolerance phase is characterized by HBeAg positivity, very high levels of HBV DNA, and persistent normal alanine aminotransferase. The international guideline recommendation for patients in this phase is observation without antiviral treatment because of the low risk of disease progression and the lack of effective antiviral agents. However, recent retrospective studies have shown that progression to hepatic fibrosis and hepatocellular carcinoma may occur in patients who are in the immune tolerance phase. Despite the conceptual definition and clinical diagnostic criteria for this phase, it is difficult to accurately diagnose the true immune tolerance phase. Therefore, we should pay attention to the clinical evaluation and interpretation of the immune tolerance phase and understand the clinical situations in which antiviral treatments should be considered.

A study of the effectiveness of nucleos(t)ide analogues in the treatment of HBeAg- positive chronic hepatitis B with normal alanine aminotransferase and high level of HBV DNA

Objective: To investigate the effectiveness of nucleos(t)ide analogues in the treatment of HBeAg-positive chronic hepatitis B with normal alanine aminotransferase and high level of HBV DNA. Methods: Treatment-naïve chronic hepatitis B patients who were followed up at the Center of Infectious Diseases, West China Hospital of Sichuan University from January 2019 to January 2020 were selected as subjects. Demographic characteristics, the results of laboratory examination before treatment and one year after treatment were retrospectively collected. Patients were divided into tenofovir dipivoxil (TDF) and propofol fumurate tenofovir (TAF) treatment group according to different types of medication. The changes of serum HBV DNA level, HBeAg serological conversion and HBsAg quantitative level were analyzed and compared between the two groups. Results: A total of 38 cases were enrolled. Among them, there were 16 and 22 cases in the TDF and TAF group, respectively. There was no statistically significant difference in demographic characteristics, baseline HBV DNA levels and HBsAg quantitative levels between the two groups. Virological response was achieved in 60.5% (23/38) of patients after one year of antiviral therapy. Serum HBV DNA levels below the lower limit of detection [68.2% (15/22) vs. 50.0% (8/16), P=0.258] and higher HBeAg seroconversion rate [18.2%] (4/22) vs. 6.3% (1/16), P=0.374] was obtained in TAF than TDF group; however, there was no statistically significant differences between the two. Serum HBsAg quantitative level was significantly reduced with TDF and TAF treatment. In addition, alanine aminotransferase elevation was reduced in TAF than TDF treated group. Multivariate logistic regression analysis showed that patient age was an independent predictor of a virological response to antiviral therapy. Conclusion: HBeAg-positive CHB patients with normal alanine aminotransferase, and high HBV DNA level can obtain better curative effect after TDF and TAF treatment.

A long-term study of liver-related events in Caucasian hepatitis B patients with normal ALT values and high viremia.

There is ongoing debate whether antiviral therapy should be initiated in hepatitis B e antigen (HBeAg)-negative patients with normal alanine aminotransferase (ALT) levels but high HBV DNA levels >2,000 IU/mL. Since the need for antiviral therapy might be different between Asian and Caucasian patients, we studied the long-term disease outcome in Caucasian patients living in Western Europe. One hundred sixteen patients with high HBV DNA levels (>2,000 IU/mL) at diagnosis were included in the high viremia group, while those with HBV DNA <2,000 IU/mL were used as controls (n = 327). All patients were Caucasian, HBeAg negative, had normal ALT levels and had no significant liver disease at diagnosis. Median follow-up was 7 + 9.8 years in the high viremia group and this was 10 + 12.5 years in controls. The cumulative probability of a liver-related event over 10 years was 4.8% vs 0.0% in the control group (p=.008). In multivariable analysis, high viremia group was associated with the occurrence of a liver-related event (hazards ratio (HR) 95% confidence interval (CI): 1.20-11.98, p=.023). In this subgroup, older age at diagnosis (HR 95% CI: 1.01-1.16, p=.023) predicted a higher risk of liver-related event. In the high viremia group, liver-related mortality was 0.9% and none of the patients developed hepatocellular carcinoma. HBV DNA >2,000 IU/mL influences the long-term disease outcome in Caucasian HBeAg-negative patients living in Western Europe. Nevertheless, the risk of liver-related events is low.

Acute-Phase Serum Amyloid A May Predict Microvascular Invasion and Early Tumor Recurrence in Patients with Hepatitis B Virus-Related Hepatocellular Carcinoma Undergoing Liver Resection

Objective To elucidate the impact of acute-phase protein serum amyloid A (aSAA) on microvascular invasion (MVI) and early recurrence in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Methods HBV-related HCC patients (n = 192) undergoing liver resection were included in the study. The protein levels of aSAA were analyzed by immunohistochemical staining in 172 tumor specimens, and further detected via western blotting in HCC and their corresponding portal vein tumor thrombus (PVTT) (n = 20). Cox and logit regression analysis was performed. Exploratory subgroup analysis was used to balance the potential confounders. Results HBV-related HCC patients with high aSAA levels tended to have high HBV-DNA loads. Logit and Cox regression analyses revealed high expression of aSAA is an independent risk factor not only for MVI (OR 5.384, 95% CI 2.286–13.301, P < 0.001) but also for early recurrence (HR 6.040, 95% CI 1.970–18.540, P = 0.002), overall recurrence (HR 3.720, 95% CI 2.140–6.450, P < 0.001), and overall survival (HR 4.15, 95% CI 2.380–7.230, P < 0.001). Subgroup analysis showed that the effects of aSAA were consistent across all subgroups examined. Additionally, the aSAA protein level was significantly higher in PVTT than that in its corresponding tumor specimen. A high HBV-DNA level and large tumor size were the independent risk factors for early HCC recurrence in patients with high levels of aSAA. Conclusions High expression of aSAA was an independent risk factor for MVI and early tumor recurrence in HBV-related HCC patients after liver resection. The aSAA protein level could thus be a promising biomarker for predicting MVI and early recurrence in these patients.

Programmed death 1 expressing CD8+ CXCR5+ follicular T cells constitute effector rather than exhaustive phenotype in patients with chronic hepatitis B.

Classical CD8 T cells are implicated for protective and pathogenic roles in chronic hepatitis B (CHB) infection. Recently, a subset of CD8 T cells expressing C-X-C chemokine receptor type 5 (CXCR5) and exhibiting features of TFH cells has been identified during chronic viral infections. However, in CHB, knowledge of their roles is limited. We characterized circulating CD8+ CXCR5+/- cells and investigated their association with clinical and viral factors. We found that CHB infection did not influence the overall frequencies of CD8+ CXCR5+ cells whereas CD8+ CXCR5- cells were increased. However, among CHB, CD8+ CXCR5+ cells were higher in patients with low HBsAg and HBV-DNA levels, patients who were HBeAg negative and had high fibrosis scores, and these cells exhibited a significant association with HBsAg and HBV-DNA reduction. Contrarily, CD8+ CXCR5- cells were expanded and positively correlated with patients having high HBsAg, HBV-DNA, and alanine aminotransferase levels. CD8+ CXCR5+ cells express costimulatory molecules ICOS, OX40, CD40 ligand, inhibitory molecule programmed death 1, transcription factors B-cell lymphoma (BCL)-2, BCL-6, and signal transducer and activator of transcription 3, and are enriched in effector and central memory phenotype. Moreover, these cells are heterogeneous in nature given that they constitute different subsets of cytotoxic follicular T cells (TCF), including TCF1, TCF2, TCF17, and TCF22. Despite expressing high PD-1, CD8+ CXCR5+ cells are activated, proliferating, secreting more IFN-γ, IL-21, and IL-22, and have better cytolytic potential than CD8+ CXCR5- cells, which were inhibited after PD-1/PD-L1 blockade. CD8+ CXCR5+ cells are efficient in helping B cells in terms of plasmablasts and plasma cell generation. In conclusion, CD8+ CXCR5+ cells are enriched in effector phenotypes, produce HBV-specific cytokines despite increased PD-1, and are associated with HBsAg and HBV-DNA reduction. These cells competently support B-cell function, required for viral clearance, which may serve as potential therapeutic targets for CHB.

Antiviral Therapy Reduces Mortality in Hepatocellular Carcinoma Patients with Low-Level Hepatitis B Viremia.

Background and AimsAlthough antiviral treatment has been shown to reduce mortality in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients with high HBV-DNA levels, it is still unclear whether it is useful in reducing mortality in patients with low HBV-DNA levels.MethodsA retrospective analysis of 756 HBV-associated HCC patients at the Beijing Ditan Hospital with HBV-DNA levels < 500 IU/mL was conducted between January 2008 and June 2017. Patients were divided into antiviral and non-antiviral groups based on whether they received nucleos(t)ide analogue (NA) treatment when they were diagnosed with HCC in our hospital for the first time. We used 1:4 frequency matching by age, gender, tumor size, Barcelona Clinic Liver Cancer (BCLC) staging, anti-tumor therapy, cirrhosis, diabetes, and hyperlipoidemia to compare the antiviral (n = 366) and non-antiviral (n = 100) groups. A Cox multivariate regression analysis was employed to evaluate the effects of NA therapy on the hazard ratio (HR), and the Kaplan–Meier survival curve was used to determine the mortality risk in patients with HCC. A Log rank test was performed to analyze the effects of NA therapy on the survival rate of patients with HCC.ResultsAfter propensity score matching, the 1-, 3-, and 5-year overall survival (OS) rates for the antiviral and non-antiviral groups were 82.5%, 68.6%, and 52.2%, and 61.0%, 51.0%, and 38.0%, respectively. The l-year progression-free survival (PFS) rates for the two groups were 68.0% and 47.0%, respectively. The OS of the antiviral group was significantly higher than that of the control group (P < 0.001, P = 0.001, and P = 0.013, respectively). The 1-year PFS for the antiviral group was also significantly better than that for the non-antiviral groups (P = 0.005). After adjusting for confounding prognostic factors in the Cox model, the HR of 5-year death after antiviral treatment was 0.721 (95% confidence interval [CI], 0.530–0.980, P = 0.037). Antiviral therapy is an independent protective factor for 5-year mortality in patients with HCC and low-level viremia.ConclusionAntiviral therapy significantly reduced mortality in HCC patients with low HBV-DNA levels.

The Impact of Nucleos(t)ide Analogs Off-Therapy Among Chronic Hepatitis B Patients: A Systematic Review and Meta-Analysis.

Background and Aim: Although most chronic hepatitis B (CHB) patients achieve effective virological suppression after receiving long-term nucleos(t)ide analogs (Nucs) therapy, the safety of off-therapy is controversial under the monitor.Methods: We identified studies through searching PubMed, Embase, Cochrane Library, and Web of Science from January 1990 to February 2021. The eligible studies compare the long outcomes between discontinued and continued Nucs treatments groups among CHB patients. This study was conducted to investigate long-term outcomes, including biochemical, serological, and virological outcomes, as well as hepatocellular carcinoma (HCC) development rate between discontinued and maintained Nucs therapy groups among CHB patients.Results: Five eligible studies covering 1,425 patients were selected for meta-analysis. Our result exhibits that patients with Nucs off-treatment have a higher risk of alanine aminotransferase (ALT) flares-up than those who continued Nucs therapy under the monitor (OR = 9.39, 95%CI = 3.87–22.78). Nucs off-therapy patients have a higher virological bound incidence (OR = 617.96, 95%CI = 112.48–3,395.14) and a higher HBV DNA level (OR = 9.39, 95%CI = 3.87–22.78) than those who continued Nucs therapy. There was no statistically significant difference in the risk of hyperbilirubinaemia, hepatic decompensation, and HCC development between both two groups. Patients in Nucs off-therapy group demonstrate a higher HBsAg loss rate than those in the continued group (OR = 7.10, 95%CI = 6.68–13.69).Conclusions: Nucs off-therapy patients may exhibit a higher chance of achieving HBsAg loss than those who continue Nucs therapy. It requires close monitoring after Nucs off-therapy and timely restarting of Nucs therapy when ALT concentrations increase.

Predictors of Virological Suppression After Clinical Relapse in Patients Who Discontinued Entecavir or Tenofovir.

The predictors of persistent virological suppression after clinical relapse remain unclear. To investigate the predictors of retreatment or persistent virological suppression after clinical relapse in chronic hepatitis B (CHB) patients who discontinued entecavir or tenofovir disoproxil fumarate (TDF). A total of 243 hepatitis B e antigen-negative CHB patients without cirrhosis who experienced clinical relapse after entecavir or TDF cessation were enrolled. Of the 243 CHB patients, 192 received retreatment and 51 did not receive retreatment after clinical relapse. Of the 51 patients without retreatment, 23 achieved persistent virological suppression (persistent HBV DNA < 2000IU/mL at least 2years) and 10 experienced hepatitis B surface antigen (HBsAg) loss. The Cox regression analysis showed that short consolidation duration, short duration of the first clinical relapse from the end of treatment (EOT), and high bilirubin and HBV DNA levels at the first clinical relapse were independent predictors of retreatment. Long duration of the first clinical relapse from the EOT and low HBsAg levels at the first clinical relapse were independent factors of patients with persistent virological suppression. The rates of persistent virological suppression at the first clinical relapse among patients with HBsAg < 100 and ≥ 100IU/mL were 44.4% (12/27) and 5.1% (11/216) (P < 0.001), respectively. Baseline HBsAg levels and no retreatment requirement were independent factors associated with HBsAg loss. The HBsAg of 100IU/mL at the first clinical relapse could predict persistent virological suppression after clinical relapse in patients who discontinued entecavir or TDF therapy.

Predictive factors for hepatocellular carcinoma in chronic hepatitis B using structural equation modeling: a prospective cohort study

Background & AimsThe factors predicting hepatocellular carcinoma (HCC) occurrence in chronic hepatitis B need to be precisely known to improve its detection. We identified pathways and individual predictive factors associated with HCC in the ANRS CO22 HEPATHER cohort. MethodsThe study analyzed HBV-infected patients recruited at 32 French expert hepatology centers from August 6, 2012, to December 31, 2015. We excluded patients with chronic HCV, HDV and a history of HCC, decompensated cirrhosis or liver transplantation. Structural equation models were developed to characterize the causal pathways leading to HCC occurrence. The association between clinical characteristics (age, gender, body-mass index, liver fibrosis, alcohol consumption, smoking status, diabetes, hypertension, dyslipidemia, alpha-fetoprotein, HBV DNA levels, antiviral therapy) and incident HCC was quantified. ResultsAmong the 4489 patients included, 33 patients reported incident HCC. The median follow-up was 45.5 months. Age (β = 0.18 by decade, 95% CI 0.14−0.23), male gender (β = 0.23, 95% CI 0.18−0.29), metabolic syndrome (β = 0.28, 95% CI 0.22−0.33), alcohol consumption (β = 0.09, 95% CI 0.05−0.14) and HBV DNA (β = 0.25, 95% CI 0.170.34) had a significant and direct effect on the occurrence of advanced liver fibrosis. Liver fibrosis (β = 0.71, 95% CI 0.55−0.87) predicted, in turn, the occurrence of HCC. ConclusionsLiver fibrosis mediates the effects of age, gender, alcohol, metabolic syndrome and HBV DNA on the occurrence of HCC. Elderly men with chronic hepatitis B, risky alcohol use, advanced liver fibrosis, metabolic syndrome and high HBV DNA levels should be monitored closely to detect the development of HCC.