Role Of Hepatitis Research Articles

Deleterious role of hepatitis B virus infection in therapeutic response among patients with rheumatoid arthritis in a clinical practice setting: a case-control study

BackgroundPrevious studies have revealed that hepatitis B virus (HBV) infection may be associated with rheumatoid arthritis (RA), while there are no further clinical studies regarding the role of HBV infection in RA progression during disease-modifying anti-rheumatic drug (DMARD) therapy. Here, we aimed to explore the influence of HBV infection on radiographic and clinical outcomes among patients with RA in a clinical practice setting.MethodsThirty-two consecutive patients with RA (Disease Activity Score 28-joint assessment based on C-reactive protein (DAS28-CRP) ≥2.6) with chronic HBV infection (CHB) were retrospectively recruited as the CHB group and 128 age-matched, sex-matched, and disease activity-matched contemporary patients with RA without CHB were included in the non-CHB group. Clinical data were collected at baseline and visits at month 1, 3, 6, and 12. The therapeutic target was defined as DAS28-CRP <2.6 in all patients or <3.2 in patients with long disease duration (>24 months). The primary outcome was the percentage of patients with one-year radiographic progression (a change in modified total Sharp score ≥0.5).ResultsCompared with the non-CHB group, a significantly higher percentage of patients with one-year radiographic progression was observed in the CHB group (53% vs. 17%, p < 0.001), with smaller proportions of patients achieving therapeutic target at month 6 and month 12 (53% vs. 82% and 53% vs. 75%, both p < 0.05), remission at month 6 (DAS28-CRP <2.6, 50% vs. 72%, p = 0.039), and American College of Rheumatology (ACR)20/50 responses and good or moderate European League Against Rheumatism (EULAR) responses mainly at month 6 and 12 (all p < 0.05). Multivariate logistic regression analysis revealed that CHB status was significantly associated with one-year radiographic progression and failure to achieve therapeutic target within 6 months. HBV reactivation occurred in 34% of patients with CHB during one-year follow up, with two patients suffering hepatitis flare.ConclusionsHBV infection may play a deleterious role in radiographic and clinical outcomes in patients with RA, and HBV reactivation should be paid close attention during immunosuppressive therapy.

Association Between Hepatitis C Virus and Chronic Kidney Disease: A Systematic Review and Meta-Analysis

Introduction and aim. The role of hepatitis C virus infection as a risk factor for the development and progression of chronic kidney disease in the general population remains unclear.Material and methods. A systematic review of the published medical literature was performed to assess whether positive anti-HCV serologic status is associated with higher frequency of chronic kidney disease in the adult general population. We used a random-effects model to generate a summary estimate of the relative risk of chronic kidney disease (defined by lowered glomerular filtration rate or detectable proteinuria) with HCV across the published studies. Meta-regression and stratified analysis were also carried out.Results. Forty studies were eligible (n = 4,072,867 patients), and separate meta-analyses were conducted according to the outcome. Pooling results of longitudinal studies (n = 15 studies, n = 2,299,134 unique patients) demonstrated an association between positive anti-HCV serologic status and increased incidence of CKD, the summary estimate for adjusted HR with HCV across the surveys, 1.54 (95% CI, 1.26; 1.87) (P < 0.001). Between-study heterogeneity was observed (Q value by Chi-squared [χ2] test 500.3, P < 0.0001). The risk of chronic kidney disease related to HCV, in the subset of surveys from Asia was 1.45 (1.27; 1.65) (P < 0.001) (no heterogeneity). According to our meta-regression, ageing (P < 0.0001) and duration of follow-up (P < 0.0001) increased the risk of chronic kidney disease among HCV-positive subjects. We observed a relationship between anti-HCV positive serologic status and frequency of proteinuria, adjusted effect estimate of proteinuria with HCV among surveys was 1.633 (95% CI, 1,29; 2.05) (P < 0.001) (n = 10 studies; 315,404 unique patients). However, between-studies heterogeneity was noted (P value by Q test < 0.0001).Conclusion. An association between HCV infection and increased risk of chronic kidney disease in the general population exists. The mechanisms underlying such association are currently under active investigation.

Role of hepatitis B surface antigen in hepatitis B virus relapse after entecavir or tenofovir prophylaxis in patients undergoing cancer chemotherapy.

This study investigated whether hepatitis B surface antigen (HBsAg) could predict hepatitis B virus (HBV) relapse after cessation of entecavir or tenofovir disoproxil fumarate (TDF) prophylaxis for chronic hepatitis B cancer patients who are undergoing chemotherapy. The study enrolled 122 hepatitis B e-antigen-negative cancer patients who underwent chemotherapy with entecavir or TDF for antiviral prophylaxis and posttreatment follow-up for at least 6months. Of the 122 patients, 52 and 18 experienced virological and clinical relapse, which had 3-year cumulative incidences of 46.6% and 18.6%, respectively. Multivariate analysis showed that end-of-treatment HBsAg levels and baseline HBV-DNA≥2000IU/mL were independent predictors of virological relapse. The best HBsAg cutoff value was 500IU/mL. An end-of-treatment HBsAg of 500IU/mL was useful for predicting virological relapse in patients with baseline HBV-DNA<2000IU/mL (3-year rate: 21.3% vs 46.4%, P=0.038, in patients with HBsAg <500 and ≥500IU/mL, respectively), but not in patients with baseline HBV-DNA≥2000IU/mL. Of the 52 patients who experienced virological relapse, 13 experienced transient virological relapse. Patients with baseline HBV-DNA level<2000IU/mL experienced a higher rate of transient virological relapse (42.1% vs 15.2%, P=0.031). Three patients experienced hepatic decompensation upon alanine aminotransferase flares, and no patient died after timely retreatment. Ten patients experienced posttreatment HBsAg loss, and the 3-year HBsAg loss rate was 30.7% in patients with end-of-treatment HBsAg<100IU/mL. The baseline HBV-DNA and end-of-treatment HBsAg levels could predict virological relapse after withdrawal of entecavir and TDF prophylaxis for chemotherapy.

NKT cells in liver diseases.

Natural killer T cells are innate-like and tissue-resident lymphocytes, which recognize lipid antigens and are enriched in the liver. Natural killer T cells play important roles in infections, tumors, autoimmune diseases, and metabolic diseases. In this study, we summarize recent findings on biology of natural killer T cells and their roles in hepatitis B virus and hepatitis C virus infection, autoimmune liver diseases, alcoholic liver disease, nonalcoholic fatty liver disease, and hepatocellular carcinoma. Controversial results from previous studies are discussed, and indicate the dynamic alteration in the role of natural killer T cells during the progression of liver diseases, which might be caused by changes in natural killer T subsets, factors skewing cytokine responses, and intercellular crosstalk between natural killer T cells and CD1d-expressing cells or bystander cells.

Hepatitis B virus X protein activates proteasomal activator 28 gamma expression via upregulation of p53 levels to stimulate virus replication.

Proteasomal activator gamma (PA28γ), frequently overexpressed in hepatocellular carcinoma, is believed to play important roles in tumourigenesis. However, the underlying mechanism of PA28γ overexpression and its possible roles in hepatitis B virus (HBV) replication are largely unknown. In the present study, we found that hepatitis B virus X protein (HBx) activates PA28γ expression by upregulating p53 levels in human hepatoma cells. The elevated PA28γ levels in turn repressed seven in absentia homologue 1 expression via downregulation of p53 levels, thereby inhibiting ubiquitin-dependent proteasomal degradation of HBx, which ultimately led to upregulation of HBx levels. The correlation among HBx, p53 and PA28γ was exactly reproduced in a 1.2-mer HBV replicon system, mimicking the natural course of HBV infection. In particular, knockdown of either p53 or PA28γ in HepG2 cells downregulated HBx levels and thereby inhibited HBV replication, whereas overexpression of p53 or PA28γ in Hep3B cells upregulated HBx levels, which stimulated HBV replication, indicating that p53 and PA28γ act as activators of HBV replication. In conclusion, HBx levels are upregulated via a positive feedback loop involving p53 and PA28γ to stimulate HBV propagation.

SAT-328 - The role of hepatitis E in acute non-traumatic neuropathy in China: a prospective case-control study

SAT-328 - The role of hepatitis E in acute non-traumatic neuropathy in China: a prospective case-control study

FRI-382 - The role of hepatitis C virus eradication with DAA on insulin resistence regulation

FRI-382 - The role of hepatitis C virus eradication with DAA on insulin resistence regulation

FRI-275 - Role of hepatitis B core-related antigen and antibodies to hepatitis B core antigen level in the natural history of chronic HBV infection

FRI-275 - Role of hepatitis B core-related antigen and antibodies to hepatitis B core antigen level in the natural history of chronic HBV infection

Pachydermoperiostosis in a patient with chronic hepatitis B virus infection referred as acromegaly: a case report

BackgroundPrimary hypertrophic osteoarthropathy also known as pachydermoperiostosis is a rare genetic disorder that has often been confused with acromegaly because of similar clinical features. Vascular endothelial growth factors which have been implicated in the clinical features of pachydermoperiostosis, have also been shown to be present in chronic hepatitis and implicated in the malignant transformation of hepatitis B infection to hepatocellular carcinoma. To the best of our knowledge there is one reported case of pachydermoperiostosis with chronic hepatitis B infection. We do not imply a causal relationship between pachydermoperiostosis and hepatitis B infection because pachydermoperiostosis is a genetic disorder; however, the question is raised whether hypertrophic osteoarthropathy is one of the many extrahepatic manifestations of chronic hepatitis B infection.Case presentationA 21-year-old African (Ghanaian) man with chronic hepatitis B infection was referred to our Endocrine unit as having acromegaly with changing facial features, enlarging hands and feet, and large knee joint effusions which affected activities of daily living. He was finally diagnosed as having pachydermoperiostosis when acromegaly, rheumatological disorders, as well as cardiopulmonary disorders were ruled out. He improved with arthrocentesis, a tapering regime of steroids, non-steroidal anti-inflammatory drugs, and proton pump inhibitors.ConclusionsThe possible role of hepatitis B in hypertrophic osteoarthropathy, that is, secondary hypertrophic osteoarthropathy, needs to be explored; however, with digital clubbing in his father our patient is likely to have pachydermoperiostosis.

Hepatitis B virus X protein represses LKB1 expression to promote tumor progression and poor postoperative outcome in hepatocellular carcinoma

BackgroundHepatitis B virus X (HBx) protein plays critical roles in hepatitis B virus (HBV)-associated hepatocellular tumorigenesis through different molecular mechanisms, including inactivation of p53, a key transcription factor of liver kinase B1 (LKB1). We hypothesized that p53 inactivation by HBx protein could decrease LKB1 expression, thereby promoting tumor progression and poor outcomes in patients with HBV-associated hepatocellular carcinoma. MethodsManipulation strategies for HBx protein and/or p53 were used to verify that loss of LKB1 could promote colony formation and invasiveness in HepG2 and Hep3B cells. The expressions of HBx protein and LKB1 in 93 hepatocellular carcinomas (HCC) were also evaluated by immunohistochemistry. Kaplan-Meier and Cox regression models were used to assess the prognostic value of both HBx protein and LKB1 proteins in patients with hepatocellular carcinoma. ResultsMechanistically, LKB1 expression was decreased at the transcriptional level after inactivation of p53 by HBx protein. Decreases in LKB1 expression were also associated with HBx protein-mediated colony formation and invasive capabilities. HBx protein, LKB1, and a combination of both proteins had prognostic significance for overall survival and relapse-free survival in our study population. ConclusionThe results from cell line experiments and evaluation of patient prognosis according to expression of HBx protein and LKB1 in their HCC strongly support the hypothesis that decreases in LKB1 expression by HBx protein-mediated p53 inactivation may play an important role in HBV-associated hepatocellular tumorigenesis.

Role of hepatitis B core-related antigen and antibodies to hepatitis B core antigen levels in the natural history of chronic HBV infection

Introduction: A reliable identification of chronic hepatitis B (CHB) patients requiring antiviral treatment could be challenging when chronic hepatitis (CH) is in a biochemical remission simulating a chronic infection (CI) profile.

MiR-29c inhibits HCV replication via activation of type I IFN response by targeting STAT3 in JFH-1-infected Huh7 cells.

Background: MiR-29c, a member of the miR-29 family, has been recognized to play an important role in hepatitis C virus (HCV) infection. However, the underlying molecular mechanism of miR-29c involved in HCV replication is not fully understood. Methods: RT-qPCR assay was used to detect the expression pattern of miR-29c and signal transducer and activator of transcription 3 (STAT3) mRNA in JFH-1-infected Huh7 cells. HCV replication was evaluated by the expression of HCV RNA, non-structural protein 5A (NS5A) and non-structural protein 3 (NS3). Dual-Luciferase Reporter assay was applied to search for the candidate target mRNAs of miR-29c. Western blot assay was performed to detect the protein level of double-stranded RNA-dependent protein kinase R (PKR), (2′-5′)-oligoadenylate synthetase (OAS) and interferon regulatory transcription factor 1 (IRF1). Results: miR-29c expression was down-regulated, and STAT3 mRNA and protein expressions were up-regulated in JFH-1-infected Huh7 cells. MiR-29c overexpression or STAT3 knockdown repressed HCV replication, while miR-29c depletion or STAT3 upregulation promoted HCV replication. Additionally, STAT3 was a direct target of miR-29c, and miR-29c suppressed STAT3 protein expression in Huh7 cells. Moreover, STAT3 overexpression reversed miR-29c-mediated suppression on HCV replication. Furthermore, the anti-miR-29c-mediated inhibitory effect on type I IFN response was abated following STAT3 knockdown. Conclusions: miR-29c might repress HCV infection via promoting type I IFN response by targeting STAT3 in JFH-1-infected Huh7 cells, offering a promising avenue for HCV treatment.

HBxAg suppresses cell apoptosis and promotes the secretion of placental hormones in human placental trophoblasts via activation of the EGFR/Akt pathway.

The aim of this study is to investigate the role of Hepatitis B virus x (HBx) in the growth and secretion of human placental trophoblasts. Firstly, placenta tissues were collected from pregnant HBV carriers with various viral loads. The results of immunohistochemical technique showed that the HBx protein and pEGFR protein levels were both markedly increased with the viral load elevation. Then, a placental trophoblast cell strain (JEG-3-HBx), which stably expressed HBx mRNA and protein, was established with the pcDNA-HBx transfection followed by the G418 selection. The JEG-3-HBx strain displayed distinct activation of the EGFR/AKT pathway, a lower level of cell apoptosis, and higher secretion levels of placental hormones, including human chorionic gonadotropin (hCG), progesterone, estrogen and β-endorphin. Subsequently, HBx siRNA was used to silence the HBx gene in the JEG-3-HBx strain. Our data showed that the HBx siRNA transfection markedly suppressed the activation of the EGFR/AKT pathway, promoted cell apoptosis, and reduced the secretion of the placental hormones. Finally, EGF was applied to simulate the JEG-3-HBx strain with or without the HBx siRNA transfection. EGF treatment counteracted the reduction of cell apoptosis and the suppression of hormone secretion caused by HBx siRNA in the cell strain. In conclusion, the pEGFR protein was robustly upregulated in HBx-infected human placenta tissues and trophoblast cells. HBx reduces cell apoptosis and promotes the secretion of placental hormones in human placental trophoblast cells via activation of the EGFR/Akt pathway.

Social Norm, Family Communication, and HBV Screening among Asian Americans

Individuals’ behaviors are influenced by those of others in their social environment (i.e., descriptive norms), as well as by how individuals perceive they should behave in that environment (e.g., injunctive norms). Although social norms are thought to play an important role in hepatitis B virus (HBV) screening, limited theoretical or empirical guidance exists on how the underlying process works. In addition, norms are social phenomena that are spread through family discussion about the importance of getting HBV screening. Using the theory of normative social behavior (TNSB), this study examined the roles of injunctive norms (IN), descriptive norms (DN), and family discussion in HBV screening behavior among Asian Americans. Data from a survey of Asian Americans in the Baltimore Washington metropolitan area (N = 877) were used to test underlying theoretical propositions. DN and family discussion emerged as key factors in HBV screening behavior among all Asian Americans. IN were associated with HBV screening among Chinese and Korean Americans, but not for Vietnamese Americans. Family discussion moderated the influence of DN on behavior among Chinese and Vietnamese Americans. However, the main effect of DN on screening behavior was not modified by IN (no interactions between DN and IN). The results indicate that family discussion and social norms are integral in enabling Asian Americans to undergo HBV screening and warrant sensitivity in the design and implementation of a liver cancer prevention program in this high-risk group of Asian Americans.

HBV reactivation in allogeneic stem cell transplant recipients: Risk factors, outcome, and role of hepatitis B virus mutations.

Hepatitis B virus (HBV) reactivation (HBVr) in recipients of allogeneic hematopoetic stem cells (aHSCs) appears heterogeneously with respect to its frequency, manifestation, and outcome. The aim of this study was to present data from a large German cohort of recipients of aHSC transplantation (aHSCT), focusing on the incidence of HBVr in antibody to hepatitis B core antigen (anti‐HBc)‐positive aHSCT recipients, its clinical outcome, and the role of mutations in HBV. Between 2005 and 2015, 1,871 patients received aHSCT at University Hospital Essen. A follow‐up of at least 6 months after transplant was available in 55 patients who were anti‐HBc‐positive; clinical and virologic data were analyzed. The HBV genome was sequenced with next generation technology from serum samples of 8 patients with HBVr. Thirteen out of 55 (23.6%) patients developed HBVr at a median of 26 months after aHSCT. After initiation of antiviral treatment, complete HBV DNA suppression was achieved in 7/10 (70%) patients 1 to 40 months after HBVr. Nine of 13 patients had increased alanine aminotransferase; 3 patients had compromised coagulation and model for end‐stage liver disease scores of 18‐27, and 1 of these patients died due to liver failure 5 weeks after HBVr. As a risk factor for HBVr, we identified anti‐HBc signal to cut‐off ration (S/CO) ≥7.5 before transplantation. Complete HBV DNA suppression was achieved in 7/10 patients; therapy‐relevant mutations were found in 1 patient. In 4/8 patients, immune escape mutations were detected either as majority or minority variants. Conclusion: HBVr is common in anti‐HBc‐positive aHRCT recipients and can lead to severe hepatitis with compromised coagulation. The level of anti‐HBc S/CO before transplantation is a risk factor for HBVr. Complete virologic response under adequate antiviral treatment could not be achieved in all patients. (Hepatology Communications 2017;1:1014–1023)

Direct-Acting Antivirals in Kidney Transplant Patients: Successful Hepatitis C Treatment and Short-Term Reduction in Urinary Protein/Creatinine Ratios.

Background:The role of Hepatitis C Virus (HCV) clearance in kidney graft survival is unknown. We examined short-term trends of protein/creatinine (P/C) ratios in HCV-infected kidney transplant recipients treated with direct-acting antivirals (DAAs).Methods:This is a retrospective study of 19 kidney transplant patients with HCV infection treated with DAAs at the University of Alabama at Birmingham between January 2013 and June 2016. Markers of glomerular damage were assessed using average urinary protein/creatinine (P/C) ratios measured pretreatment and posttreatment. Treatment efficacy was defined as sustained virologic response at 12 weeks post-HCV treatment (SVR12).Results:The median age of the 19 patients included was 59 years (Q1 = 58, Q3 = 64). Of these patients, 68% were African American, 32% were White and 63% were male. The median time between kidney transplant and initiation of DAA therapy was 2.25 years (Q1 = 0.79, Q3 = 3.79). Posttreatment P/C ratios (median = 0.127, Q1=0.090, Q3 = 0.220) were significantly lower (P = 0.01) than pretreatment ratios (median = 0.168, Q1 = 0.118, Q3 = 0.385). P/C ratios decreased in 14 of 19 patients (74%) with a median change of -0.072 (median percent change = -40%). Post-treatment estimated glomerular filtration rates (median = 58.9, Q1 = 48.9, Q3 = 72.3) were not significantly different (P = 0.82) than the pretreatment values (median = 57.0, Q1 = 48.8, Q3 = 67.8). All patients achieved SVR12.Conclusions:In this preliminary study, there was a statistically significant decrease in P/C ratios associated with HCV clearance, suggesting a potential role for DAAs in improving kidney graft survival. Larger cohort studies will be needed to assess the clinical and long-term benefits of DAAs in this population.

Application of specialized nursing quality management in the hepatitis B liver cirrhosis patient in decompensated period

Objective To study the specialized nursing quality management of infectious diseases in the role of hepatitis B liver cirrhosis patient care in liver disease internal medicine during decompensated period. Methods For 180 patients with decompensated period of hepatitis B cirrhosis, quality of care was carried out in of the liver specialized subject index management to ensure decubitus standardized rate, gastrointestinal bleeding predictive rate, hepatic encephalopathy predictive nursing accuracy for the corresponding nursing quality monitoring indicators. The comparisons were conducted in the nurse's core competence evaluation results, patient's satisfaction during hospitalization for nursing and common complications for specialized quality indicators before and after implementations. Results After the introduction of specialized nursing quality indicators, nurse's disease clinical core competency assessment qualified rate increased significantly in nurse's ability of disease observation and assessment increasing from 64.71% to 88.24%, professional knowledge master inclining from 61.76% to 94.12%, strain capacity increasing from 55.88% to 85.29%, and patient care satisfaction improving from 85.56% to 97.78% (χ2=5.230 8, 10.349 7, 7.083 3, 8.800 0; P< 0.05) . Conclusions Specialized nurse quality index is applied to manage patients with hepatitis B cirrhosis in decompensated period for nursing quality control management, which can improve the core competence of nurses and patient satisfaction on nursing service, and decrease complications, as well as enrich the connotation of the nurse quality. Key words: Liver cirrhosis; Hepatitis B; Specialized quality indicator; In decompensated period; Quality of care

Lack of Association between Hepatitis C Virus core Gene Variation 70/91aa and Insulin Resistance.

The role of hepatitis C virus (HCV) in insulin resistance (IR) is not fully understood. The aim of this study was to determine the impact of amino acid (aa) substitutions in the core region of HCV according to IR and to identify clinical and laboratory associations. Ninety-two treatment-naive HCV patients were recruited to determine laboratory data and blood cell count. IR was determined using Homeostasis Model Assessment (HOMA) index where IR was defined as HOMA ≥2. HCV RNA load and genotype were determined by Abbott Real time HCV. HCV core region was determined by direct nucleotide sequencing. Bivariate analysis was conducted using HOMA IR ≥2 as a dependent factor. IR prevalence was 43.5% (n = 40), vitamin D sufficiency was found in 76.1% (n = 70) and 72.8% (n = 67) had advanced liver fibrosis. In the bivariate analyses, elevated values of γGT (p = 0.024) and fibrosis staging (p = 0.004) were associated with IR, but IR was not related to core mutations. The presence of glutamine in position 70 was associated with low vitamin D concentration (p = 0.005). In the multivariate analysis, no variable was independently associated with HOMA-IR. In conclusion, lack of association between IR and HCV core mutations in positions 70 and 91 suggests that genetic variability of this region has little impact on IR.

Report from European Association for the Study of the Liver: HCC Summit, Geneva, Switzerland, 2-5 February 2017.

The European Association for the Study of the Liver Hepatocellular Carcinoma (HCC) international meeting held in Geneva in February 2017 focused on the state of the art of HCC management, from diagnosis to treatment and the potential development of clinical research in this field. This report reviews some of the most interesting topics discussed at the meeting such as the role of hepatitis C viral infection treatment with direct-acting antivirals in enhancing HCC risk, current prognostic systems, early diagnosis techniques, curative therapies for early HCC and the systemic treatments for advanced disease with a look into future perspectives.

Role of hepatitis B core protein in HBV transcription and recruitment of histone acetyltransferases to cccDNA minichromosome

The hepatitis B core protein (HBc) has been suggested to interact with covalently closed circular DNA (cccDNA) and regulate hepatitis B virus (HBV) transcription. However, direct evidence is lacking. We aimed to identify the specific HBc region(s) responsible for transcription regulation and its interaction with cccDNA. Seventeen mutants with mutations at the four arginine-rich clusters of the HBc carboxyl-terminal domain (CTD) were created. The effect of HBc mutations on the levels of HBV DNA, RNA, and hepatitis B surface antigen (HBsAg) were measured. The association of cccDNA with mutant HBc and histone acetyltransferases (HATs) was assessed by chromatin immunoprecipitation (ChIP). Compared with wild-type HBc, HBc mutants with mutations in clusters III and IV resulted in a significant reduction in HBV RNA levels (all P < 0.05). HBc arginine clusters III and IV mutants also had a significantly lower levels of intracellular HBV DNA (<5% of wild-type; P < 0.001) and HBsAg (<10% of wild-type; P < 0.0001). cccDNA-ChIP assay demonstrated that HBc clusters III and IV mutants had a smaller degree of association with cccDNA (P < 0.001). In the HBc mutants, the association between HATs with cccDNA were reduced. In conclusion, HBc-CTD arginine residues at clusters III and IV play an important role in the regulation of HBV transcription as well as subsequent replication steps, likely through the reduced interaction of HBc with cccDNA and reduced acetylation of cccDNA-bound histones. These findings may provide clues to the identification of novel therapeutic targets against HBV.