NUC Treatment Research Articles

Comparison of HBV-specific T cell reactivity across the pregnant, postpartum and non-pregnant women with chronic HBV infection.

To investigate the features of HBV-specific T cell reactivity across the pregnant, postpartum or non-pregnant women with chronic HBV infection. A total of 283 patients with chronic HBV infection were enrolled in this study, including 129 patients during pregnancy, 58 patients during postpartum less than 6 months and 96 non-pregnant patients at childbearing age. A universal ELISpot assay was set up using a broad-spectrum T-cell epitope peptide library which containing 103 functionally validated CD8+ T-cell epitopes derived from overall HBsAg, HBc/eAg, HBx and HBpol proteins and fitting to the human leukocyte antigen polymorphisms of Chinese population. Then, The functional HBV-specific T cells in peripheral blood were detected. The spot-forming units (SFUs) of HBV-specific T cells in the pregnant group showed no statistical difference from the postpartum group, but significantly less than that in the non-pregnant group (p = 0.046). In the untreated patients, the pregnant group displayed HBe/cAg-specific T cells (SFUs) less than the non-pregnant group (P = 0.025) and the postpartum group (P = 0.045). Meanwhile, in the NUCs-treated patients, the three groups presented similar HBV-specific T cell reactivity. Furthermore, the SFUs in the NUCs-treated pregnant group were similar to that in the NUCs-untreated pregnant group. Importantly, ROC analysis demonstrated that the HBV-specific T cells (SFUs) (AUC = 0.742) and combined with HBsAg levels (AUC = 0.775) or with HBeAg level (AUC = 0.78) had a good predictive performance for hepatitis progression during pregnancy group. Pregnancy can reduce HBV-specific T cell reactivity in the women with chronic HBV infection, and NUCs treatment cannot improve their HBV-specific T cells reactivity. Routine monitoring of HBV-specific T cells during pregnant and postpartum period can provide precise evaluation for immune function and valuable guidance for treatments.

Longterm Outcome of Therapeutic Vaccination with a Third Generation Pre-S/S HBV Vaccine (PreHevbrioR) of Chronically HBV Infected Patients.

Several antiviral treatment regimens for chronic hepatitis B (CHB) virus infection have been shown to be effective in suppressing viral load and reducing the risk of hepatocellular injury and its complications. It has been hypothesized that high levels of circulating HBV surface antigen(s) may lead to immune tolerance against HBV and contribute to chronic carriership. Conversely, low-level HBsAg may create a window for the reconstitution of an HBV-specific immune response through vaccination and control of infection. Previous studies in non-responders to yeast-derived HBV vaccines, using a third-generation pre-S/S vaccine, have led to up to 95% anti-HBs seroconversion. This report evaluates the long-term outcome after experimental vaccination with a pre-S/S HBV vaccine intended as a therapeutic intervention in chronic HBV carriers. Four low-level HBsAg carriers (<500 IU/mL) were vaccinated three to seven times with 20 μg PreHevbrioR. Three out of four carriers eliminated HBsAg completely and seroconverted to anti-HBs. One patient seroconverted to anti-HBs but remained with a borderline HBsAg titer (10 IU/mL). Serum anti-HBs levels following repeated vaccination varied between 27 and >1000 IU/L, respectively. Long-term observation (>6 years) showed that after discontinuing NUC treatment for at least two years, HBsAg and HBV DNA remained negative with anti-HBs positive titers ranging between 80 and >1000 IU/L. Based on our preliminary observations, there is a rationale to further evaluate the role of this vaccine as a therapeutic agent.

Longitudinal changes in renal function in patients with chronic hepatitis B on antiviral treatment.

Patients with chronic hepatitis B (CHB) on nucleos(t)ide analogues (NUCs) often experience renal function decline. Conflicting results regarding the impact of NUC use and renal function have recently been reported. To examine longitudinal changes in renal function according to the NUC treatment type compared with untreated patients METHODS: From 2014 to 2022, we retrospectively analysed 10,642 patients with CHB. The primary outcome was chronic kidney disease (CKD) progression, which was defined as a minimum one-stage elevation. We applied propensity score (PS) matching for outcome comparisons. In the PS-matched cohort of 1996 pairs, the NUC-treated group (7.6/100 person-years [PYs]) had a significantly higher CKD progression risk than the untreated group (4.4/100 PYs), with a hazard ratio (HR) of 1.70 (p < 0.001). The tenofovir disoproxil fumarate (TDF)-treated group (7.9/100 PYs) showed a 1.76-fold increased CKD progression risk compared with the untreated group (4.5/100 PYs) in the PS-matched cohort (p < 0.001). Both the entecavir- and tenofovir alafenamide (TAF)-treated groups showed CKD progression risks comparable to those of the untreated group in the PS-matched cohorts of 755 and 426 pairs, respectively (p = 0.132 and p = 0.120, respectively). No significant CKD progression risk was found between the entecavir- (6.0/100 PYs) and TAF-treated (5.2/100 PYs) groups in the PS-matched cohort of 510 pairs (p = 0.118). NUC-treated patients, especially those on TDF, faced a higher CKD progression risk than untreated patients. Entecavir- and TAF-treated patients had comparable CKD progression risks to untreated patients. No difference was observed between entecavir and TAF in the risk of CKD progression.

Hepatocellular carcinoma reduced, HBsAg loss increased, and survival improved after finite therapy in hepatitis B patients with cirrhosis.

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. 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). 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.

Lower pretreatment HBV DNA levels are associated with better off-treatment outcomes after nucleo(s)tide analogue withdrawal in patients with HBeAg-negative chronic hepatitis B: A multicentre cohort study

Background & AimsPretreatment predictors of finite nucleo(s)tide analogue (NUC) therapy remain elusive. We studied the association between pretreatment HBV DNA levels and outcomes after therapy cessation. MethodsPatients with chronic hepatitis B who were HBeAg negative at the start of NUC treatment were enrolled from sites in Asia and Europe. We studied the association between pretreatment HBV DNA levels and (1) clinical relapse (defined as HBV DNA >2,000 IU/ml + alanine aminotransferase >2 × the upper limit of normal or retreatment) and (2) HBsAg loss after NUC withdrawal. ResultsWe enrolled 757 patients, 88% Asian, 57% treated with entecavir, with a median duration of treatment of 159 (IQR 156–262) weeks. Mean pretreatment HBV DNA levels were 5.70 (SD 1.5) log IU/ml and were low (<20,000 IU/ml) in 150 (20%) and high (>20,000 IU/ml) in 607 (80%). The cumulative risk of clinical relapse at 144 weeks after therapy cessation was 22% among patients with pretreatment HBV DNA levels <20,000 IU/ml vs. 60% among patients with pretreatment HBV DNA levels >20,000 IU/ml, whereas the cumulative probabilities of HBsAg loss were 17.5% vs. 5% (p <0.001). In multivariable analysis, pretreatment HBV DNA levels <20,000 IU/ml were independently associated with a reduced likelihood of clinical relapse (adjusted hazard ratio 0.379, p <0.001) and with an increased chance of HBsAg loss (adjusted hazard ratio 2.872, p <0.001). ConclusionsLower pretreatment HBV DNA levels are associated with a lower risk of clinical relapse and a higher chance of HBsAg loss after cessation of NUC therapy, independent of end-of-treatment viral antigen levels. Further studies are needed to confirm these findings in non-Asian populations. Impact and ImplicationsA subgroup of patients with chronic hepatitis B may not require retreatment after stopping antiviral therapy. In this study, comprising 757 patients with chronic hepatitis B from Europe and Asia, we found that higher viral load before initiation of treatment was a risk factor for relapse after stopping treatment. Patients with a low HBV DNA level before starting antiviral therapy had the lowest risk of relapse, and a high chance of HBsAg loss, after stopping treatment. These findings can help select patients for treatment withdrawal and guide intensity of off-treatment monitoring.

Pathogenesis of flares in liver inflammation in hepatitis B virus-infected women during and after pregnancy

Abstract Women with chronic hepatitis B (CHB) are at risk of increased liver inflammation during pregnancy. To investigate the pathogenesis of these hepatic flares we studied immune responses and gut microbiota in 19 women with CHB (12 without and 7 with antiviral (NUC) treatment) and 3 uninfected controls in each trimester and at two and six months postpartum. Increased serum alanine aminotransferase (ALT) activity as a liver inflammation marker was defined as a value greater than the upper limit of normal and twice the baseline value. While increased plasma levels of soluble CD163, inflammatory cytokines and chemokines generally occurred during episodes of liver inflammation, increases of IL-22 and IFN-γ levels during pregnancy preceded a postpartum ALT increase. In contrast, levels of IL-27, a cytokine produced by the trophoblast, increased also in women with normal ALT levels. The fecal microbiota of HBV-infected patients with and without NUC treatment had lower α-diversity (inverse Simpson index) than those of uninfected controls. 16srRNA amplicon analysis and PCA showed patient-specific clustering of microbiota. To identify factors predictive of a postpartum ALT increase, we compared 16srRNA DNA data from patients with a postpartum ALT increase to those with normal postpartum ALT levels (four patients per group). Combining all time points, the gut microbiota of those with postpartum ALT increase differed significantly from those with normal ALT activities (UMAP, PERMANOVA p&amp;lt;0.003). In conclusion, the composition of the fecal microbiota was patient-rather than time point-specific and differed between patients with and without postpartum ALT increase. Supported by NIH Bench-to-Bedside Award (B.R. and D.T.Y.L.)

A multicenter randomized-controlled trial of nucleos(t)ide analogue cessation in HBeAg-negative chronic hepatitis B

Nucleos(t)ide analogues (NUCs) are the standard and mostly lifelong treatment for chronic HBeAg-negative hepatitis B, as functional cure (loss of HBsAg) is rarely achieved. Discontinuation of NUC treatment may lead to functional cure; however, to date, the evidence for this has been based on small or non-randomized clinical trials. The STOP-NUC trial was designed with the aim of increasing the HBsAg loss rate using a NUC treatment interruption approach. In this multicenter, randomized-controlled trial, 166 HBeAg-negative patients with chronic hepatitis B on continuous long-term NUC treatment, with HBV DNA <172 IU/ml (1,000 copies/ml) for ≥4 years, were randomized to either stop (Arm A) or continue NUC treatment (Arm B) for a 96-week observation period. In total, 158 patients were available for final analysis, 79 per arm. The primary endpoint was sustained HBsAg loss up to week96. Our study met its primary objective by demonstrating HBsAg loss in eight patients (10.1%, 95% CI 4.8%-19.5%) in Arm A and in no patient in Arm B (p=0.006). Among patients with baseline HBsAg levels <1,000 IU/ml, seven (28%) achieved HBsAg loss. In Arm A, re-therapy was initiated in 11 (13.9%) patients, whereas 32 (40.5%) patients achieved sustained remission. A decrease of HBsAg >1 log IU/ml was observed in 16 patients (20.3%) in Arm A and in one patient (1.3%) in Arm B. No serious adverse events related to treatment cessation occurred. Cessation of NUC treatment was associated with a significantly higher rate of HBsAg loss than continued NUC treatment, which was largely restricted to patients with end of treatment HBsAg levels <1,000 IU/ml. As HBeAg-negative patients with chronic hepatitis B on nucleos(t)ide analogues (NUCs) rarely achieve functional cure, treatment is almost always lifelong. The STOP-NUC trial was conducted to investigate whether discontinuing long-term NUC treatment can increase the cure rate. We found that some patients achieved functional cure after stopping NUCs, which was especially pronounced in patients with HBsAg levels <1,000at the end of NUC treatment, and that many did not need to resume therapy. The results of the Stop-NUC trial provide evidence for the concept of stopping NUC treatment as a therapeutic option that can induce functional cure.

Phenotypic CD8 T cell profiling in chronic hepatitis B to predict HBV-specific CD8 T cell susceptibility to functional restoration in vitro

ObjectiveExhausted hepatitis B virus (HBV)-specific CD8 T cells in chronic HBV infection are broadly heterogeneous. Characterisation of their functional impairment may allow to distinguish patients with different capacity to control...

Ascites re-compensation in HBV-related first decompensated cirrhosis after anti-viral therapy.

Effective antiviral therapy can significantly improve the long-term prognosis of HBV-related decompensated patients, and re-compensation may be achieved in part of the patients. To explore the re-compensation of ascites after HBV suppression and the risk factors, the clinical outcomes of 196 consecutive patients with HBV-related first decompensated cirrhosis of ascites treated with nucleos(t)ide analogue (NUC) were analyzed retrospectively. Among these patients, the median serum HBV DNA level was 5.0 (IQR, 3.0-6.0) log10 IU/mL before treatment. Most patients were given NUC with high barrier to resistance including ETV (152), TDF (1) and TAF (1). Initial combination of LAM plus ADV and LdT plus ADV was used in 41 patients and 1 patients, respectively. After NUC treatment, the percentage of patients with ascites regression was 77.6%, 81.4%, 70.5%, 93.8%, 80.8% at 12, 24, 36, 48, 60 months, respectively (P<0.001). The distribution of ascites severity showed that the patients' ascites improved, with the proportion of no ascites and mild ascites gradually increased. The proportion of re-compensation of ascites defined as negative HBV DNA, improved liver function and ascites regression (off diuretics) was 59.7%, 70.0%, 52.3%, 59.4%, 46.2% at 12, 24, 36, 48, 60 months (P<0.001). The rate of ascites regression was higher in viral response (VR) cohort when compared with that in non-VR cohort. Univariate and multivariable analysis showed that level of serum ALT (OR:0.988, 95%CI, p=0.029) and load of serum HBV DNA (OR:0.78895%CI, p=0.044) at baseline were risk factors of re-compensation of ascites. This study demonstrated that antiviral therapy could reverse decompensation of ascites in HBV-related first decompensated cirrhosis and the level of ALT and HBV DNA were risk factors of ascites re-compensation.

Intrahepatic quantification of HBV antigens in chronic hepatitis B reveals heterogeneity and treatment-mediated reductions in HBV core-positive cells

Patterns of liver HBV antigen expression have been described but not quantified at single-cell resolution. We applied quantitative techniques to liver biopsies from individuals with chronic hepatitis B and evaluated sampling heterogeneity, effects of disease stage, and nucleos(t)ide (NUC) treatment, and correlations between liver and peripheral viral biomarkers. Hepatocytes positive for HBV core and HBsAg were quantified using a novel four-plex immunofluorescence assay and image analysis. Biopsies were analysed from HBeAg-positive (n= 39) and HBeAg-negative (n= 75) participants before and after NUC treatment. To evaluate sampling effects, duplicate biopsies collected at the same time point were compared. Serum or plasma samples were evaluated for levels of HBV DNA, HBsAg, hepatitis B core-related antigen (HBcrAg), and HBV RNA. Diffusely distributed individual HBV core+ cells and foci of HBsAg+ cells were the most common staining patterns. Hepatocytes positive for both HBV core and HBsAg were rare. Paired biopsies revealed large local variation in HBV staining within participants, which was confirmed in a large liver resection. NUC treatment was associated with a >100-fold lower median frequency of HBV core+ cells in HBeAg-positive and HBeAg-negative participants, whereas reductions in HBsAg+ cells were not statistically significant. The frequency of HBV core+ hepatocytes was lower in HBeAg-negative participants than in HBeAg-positive participants at all time points evaluated. Total HBV+ hepatocyte burden correlated with HBcrAg, HBV DNA, and HBV RNA only in baseline HBeAg-positive samples. Reductions in HBV core+ hepatocytes were associated with HBeAg-negative status and NUC treatment. Variation in HBV positivity within individual livers was extensive. Correlations between the liver and the periphery were found only between biomarkers likely indicative of cccDNA (HBV core+ and HBcrAg, HBV DNA, and RNA). HBV infects liver hepatocyte cells, and its genome can exist in two forms that express different sets of viral proteins: a circular genome called cccDNA that can express all viral proteins, including the HBV core and HBsAg proteins, or a linear fragment that inserts into the host genome typically to express HBsAg, but not HBV core. We used new techniques to determine the percentage of hepatocytes expressing the HBV core and HBsAg proteins in a large set of liver biopsies. We find that abundance and patterns of expression differ across patient groups and even within a single liver and that NUC treatment greatly reduces the number of core-expressing hepatocytes.

1236. Baseline liver stiffness and alanine transaminase predicts reduction in liver stiffness in people with chronic hepatitis B on tenofovir alafenamide

Abstract Background Globally, 296 million people are infected with chronic hepatitis B (CHB) and at risk for cirrhosis and hepatocellular carcinoma. Suppressive therapy with a nucleos(t)ide analogue (NUC) such as tenofovir alafenamide (TAF) reduces risk of cirrhosis and cancer. Transient elastography measures liver stiffness and is used to monitor liver fibrosis in CHB. This study evaluates liver stiffness change among people taking NUC and determines correlates with improvement in liver stiffness. Methods Participants enrolled at the University of Maryland, Baltimore were treated with TAF 25mg daily for 2 years. Liver stiffness (FibroScan©) was measured at baseline and year 2. Mild (F0/F1) and advanced (≥ F2) fibrosis, was defined as ≤ 7.4kPa and ≥ 7.5kPa, respectively. Correlates of liver stiffness change from baseline to year 2 was evaluated with multiple linear regression. P-value of &amp;lt; 0.05 was considered statistically significant. Results Since 2017, 60 have completed the study. Twenty-nine were switched from another NUC to TAF and 31 were off NUC treatment at baseline (“No NUC”: 17 treatment naïve, 14 prior NUC). Baseline alanine transaminase (ALT) was higher in the "No NUC" group (53.5 IU/ml ± 42.7 versus 30.2 IU/ml ± 15.5, p = &amp;lt; 0.007). Most (67.2%) participants had mild fibrosis at baseline. Nineteen had advanced fibrosis. Among those with advanced fibrosis, fibrosis stage improved by at least 1 stage in 14 with no change in 5. Liver stiffness improved in the No NUC group (mean change in stiffness -1.2161 kPa, p = 0.02), but not in the switch group. Subgroup analysis of those with advanced fibrosis also showed reduction in liver stiffness in the No NUC group only. Increased baseline ALT and baseline liver stiffness were predictive of reduction in liver stiffness (rho= - 0.3, p= 0.005 and rho= - 0.7, p &amp;lt; 0.0001, respectively). Baseline liver stiffness predicts change in liver stiffness with NUC therapy Increased liver stiffness, and therefore fibrosis, at baseline was associated with greater reductions in liver stiffness, and therefore liver stiffness, after 2 years of NUC therapy (rho = -0.7, p&amp;lt; 0.0001). Conclusion Liver stiffness improved with 2 years of NUC treatment in people with CHB, including those with advanced liver fibrosis. Either baseline ALT or liver stiffness can predict reduction in liver stiffness. This may reflect an overestimation of fibrosis stage in the presence of liver inflammation at NUC initiation. Repeating FibroScan after initiation of NUC treatment would therefore be useful, especially in people with elevated ALT, for guiding CHB care. Disclosures Lydia Tang, MBChB, Gilead Sciences: Grant/Research Support Shyam Kottilil, MD, PhD, Arbutus Pharmaceuticals: Grant/Research Support|Gilead: Grant/Research Support|Merck: Grant/Research Support|Regeneron Pharmaceuticals: Advisor/Consultant|Silverback Therapeutics: Advisor/Consultant|The Liver Company: Advisor/Consultant|Yufan Biotechnologies: Advisor/Consultant.

Towards a Functional Cure for Hepatitis B Virus: A 2022 Update on New Antiviral Strategies.

Chronic infection with hepatitis B virus (HBV) represents one of the main causes of the development of cirrhosis and its complications. Treatment with potent third-generation nucleos(t)ide analogues (NUCs) results in >99% HBV DNA undetectability, and prevents fibrosis progression and liver-related complications. However, NUCs are not able to induce the so-called functional cure, which is hepatitis B surface antigen (HBsAg) loss and anti-HBs seroconversion. Consequently, NUC treatment is currently intended as being long-term or lifelong, resulting in the need for clinical monitoring and potentially suffering from compliance issues. Consequently, drug development in HBV has the goal of developing new agents in order to achieve a functional cure for HBV. Currently, the three main strategies include the following: inhibition of viral replication, inhibition of viral antigens, and immune modulation. This review summarizes the most recent updates concerning HBV compounds among these three main classes.

Hepatitis C Virus Reactivation in Anti-HCV Antibody-Positive Patients with Chronic Hepatitis B Following Anti-HBV Therapies.

Background and Aims: Whether hepatitis C virus (HCV) reactivation occurs and how the viral load evolves in anti-HCV antibody-positive chronic hepatitis B (CHB) patients who underwent nucleos(t)ide analogue (Nuc) therapies remain unsolved. Methods: A cohort of 66 such patients was studied. Results: At the start of Nuc treatment (baseline), all patients had detectable hepatitis B virus (HBV) DNA levels (6.05 ± 1.88 log IU/mL), while HCV RNA levels (3.79 ± 1.43 log IU/mL) were detected (i.e., chronic hepatitis C (CHC)) in only 13 patients (19.7%). Following Nuc therapies, HBV DNA levels reached the nadirs at end of therapy (EOT) (6.05 ± 1.88 vs. 0.25 ± 0.99 log IU/mL, p < 0.0001) and relapsed at 6 months after EOT (6mEOT) at a level of 3.45 ± 2.64 log IU/mL compared with EOT (p < 0.0001). Among the 13 CHC patients, a non-significant decrease in HCV RNA was noted at EOT (3.52 ± 1.71 vs. 2.77 ± 2.63 log IU/mL, p = 0.166) but tended to decrease further at 6mEOT (2.77 ± 2.63 vs. 1.89 ± 2.06 log IU/mL, p = 0.063). Two of the thirteen CHC patients showed an increase in HCV-RNA ≥ 1 log10 IU/mL at EOT, and one of the fifty-three patients with undetectable HCV RNA at baseline (i.e., resolved past HCV infection) showed detectable HCV RNA at year 1 (3200 IU/mL) and year 2 (1240 IU/mL) following entecavir therapy. Conclusions: HCV reactivation did occur during HBV suppression, and the rate was 4.5% (3/66), 15.4% (2/13), and 1.9% (1/53), for all patients, CHC patients, and patients with resolved past HCV infection, respectively. The reverse HBV and HCV viral evolutions at 6mEOT indicate that HBV relapse may suppress HCV replication again.

Effect of Antiviral Treatment on Hepatitis B Virus Integration and Hepatocyte Clonal Expansion.

This study investigated the effect of nucleos(t)ide analogue (NUC) treatment on hepatitis B virus (HBV) DNA integration and hepatocyte clonal expansion, both of which are implicated in hepatocellular carcinoma (HCC) in chronic hepatitis B. Twenty-eight patients receiving NUCs (11 lamivudine, 7 telbivudine, 10 entecavir) were included. All had liver biopsies at baseline and year 1, and 7 had a third biopsy at year 10. HBV DNA integration and hepatocyte clone size were assessed by inverse polymerase chain reaction. All patients had detectable HBV integration at baseline, with a median integration frequency of 1.01 × 109 per liver and hepatocyte clone size of 2.41 × 105. Neither integration frequency nor hepatocyte clone size correlated with age and HBV virologic parameters. After 1 year of treatment, HBV integration was still detectable in all patients, with a median of 5.74 × 108 integration per liver (0.22 log reduction; P = .008) and hepatocyte clone size of 1.22 × 105 (0.40 log reduction; P = .002). HBV integration remained detectable at year 10 of treatment, with a median integration frequency of 4.84 × 107 integration per liver (0.93 log reduction from baseline) and hepatocyte clone size of 2.55 × 104 (1.02 log reduction from baseline). From baseline through year 1 to year 10, there was a decreasing trend in both integration frequency and hepatocyte clone size (P = .066 and.018, respectively). NUCs reduced both HBV DNA integration and hepatocyte clonal expansion, suggesting another alternative pathway besides direct viral suppression to reduce HCC risk. Our findings supported the notion for a long-term NUC treatment to prevent HCC.

Model to predict on-treatment restoration of functional HBV-specific CD8+ cell response foresees off-treatment HBV control in eAg-negative chronic hepatitis B.

SummaryBackgroundHepatitis B virus (HBV)‐specific CD8+ cell response restoration during nucleos(t)ide analogue (NUC) treatment could lead to off‐treatment HBV control in e‐antigen‐negative chronic hepatitis B (CHBe(−)).AimTo predict this response with variables involved in T‐cell exhaustion for use as a treatment stopping tool.MethodsIn NUC‐treated CHBe(−) patients, we considered a functional response in cases with HBV‐specific CD8+ cells against core and polymerase HBV epitopes able to proliferate and secrete type I cytokines after antigen encounter. We performed a logistic regression model (LRM) to predict the likelihood of developing this response, based on patient age (subrogate of infection length), HBsAg level, NUC therapy starting point and duration (antigenic pressure). We discontinued treatment and assessed HBV DNA dynamics, HBsAg decline and loss during off‐treatment follow‐up according to LRM likelihood.ResultsWe developed an LRM that predicted the presence of a proliferative type I cytokine‐secreting CD8+ cell response, which correlated positively with treatment duration and negatively with treatment initiation after the age of 40 years and with age adjusted by HBsAg level. We observed a positive correlation between LRM probability and intensity of proliferation, number of epitopes with the functional proliferating response and type I cytokine secretion level. Off‐treatment, HBsAg loss, HBsAg decline >50% and HBV control were more frequent in the group with >90% LRM probability.ConclusionsShort‐term low‐level antigen exposure and early long‐term NUC treatment influence the restoration of a functional HBV‐specific CD8+ cell response. Based on these predictors, a high likelihood of detecting this response at treatment withdrawal is associated with off‐treatment HBV control and HBsAg decline and loss.

Finite Antiviral Therapy in Chronic Hepatitis B Patients with Cirrhosis.

Antiviral therapy has greatly improved the survival and reduced the incidence of adverse liver events such as hepatic decompensation and hepatocellular carcinoma in chronic hepatitis B patients with cirrhosis (hepatitis B virus [HBV]-cirrhosis). However, hepatitis B surface antigen loss, regarded as the ultimate goal of therapy or functional cure, was rarely achieved during long-term indefinite nucleos(t)ide analogues (Nuc) treatment. Emerging issues such as medication adherence and loss-to-follow-up may lead to increased risk of hepatic decompensation, even catastrophic life-threatening events. Studies have shown that finite therapy is feasible and reasonably safe, even in patients with HBV-cirrhosis. This review critically assesses the scientific evidence of the pros and cons for finite Nuc therapy in HBV-cirrhosis and proposes how to stop Nuc therapy and monitor the off-therapy patients. It also proposes the perspective and unsolved issues to be investigated in the future.

What Should Be Done to Re-evaluate Cessation of Nucleos(t)ide Analog Therapy for Chronic Hepatitis B Infection?

Abstract Anti-viral therapy with nucleos(t)ide analogs (NUCs) for chronic hepatitis B (CHB) is generally considered to be a long-term treatment. Relevant guidelines issued by Asian Pacific Association for the Study of the Liver, European Association for the Study of the Liver, and American Association for the Study of Liver Diseases have recently proposed requirements and standards for cessation of NUCs, but it remains unclear which proportion of CHB patients on long-term or prolonged treatment of NUCs will relapse after NUCs cessation. Recently, paradoxical increase in loss of hepatitis B surface antigen (HBsAg) with or without the development of anti-hepatitis B surface antibody has been observed in NUCs’ treated CHB patients with cessation of therapy. Hence, it is of great clinical relevance to identify CHB who might have been over-treated with NUCs and might even benefit HBsAg loss or seroconversion with cessation of therapy. To address these issues, our review comprehensively analyzed the data from recent clinical trials in which the antiviral efficacy in the long-term or prolonged treatment of NUCs and/or interferon-α for CHB patients were evaluated. Furthermore, the relevant problems and deficiencies existing in the study design of previous clinical studies were also described. To solve the unmet issues in the field, a prospective study with a large-enough sample size would be required to understand the related virologic and immunological markers that can accurately predict the outcome and prognosis of the CHB patients who stop the NUCs treatment. With the rapid advancement of antiviral drug development for CHB patients, the future ideal regimens should include multiple targets for antiviral drug therapy combined with efficient immune-modulatory therapy, which will help more CHB patients to obtain functional cure with NUCs cessation.

Liver damage favors the eliminations of HBV integration and clonal hepatocytes in chronic hepatitis B

BackgroundHBV integration is suspected to be an obstinate risk factor for hepatocellular carcinoma (HCC) in the era of antiviral therapy. Integration events start to occur in the immunotolerance phase, but their fates in the immune clearance phase have not yet been clarified. Here, we report the influences of liver damage on HBV integration and clonal hepatocyte expansion in patients with chronic hepatitis B (CHB).MethodsHBV integration breakpoints in liver biopsy samples from 54 CHB patients were detected using a modified next-generation sequencing assay.ResultsA total of 3729 (69 per sample) integration breakpoints were found in the human genome, including some hotspot genes and KEGG pathways, especially in patients with abnormal transaminases. The number of breakpoint types, an integration risk parameter, was negatively correlated with HBV DNA load and transaminase levels. The average, maximum and total frequencies of given breakpoint types, parameters of clonal hepatocyte expansion, were negatively correlated with HBV DNA load, transaminase levels and liver inflammation activity grade score. The HBV DNA load and inflammation activity grade score were further found to be positively correlated with transaminase levels. Moreover, nucleos(t)ide analog (NUC) treatment that normalized transaminases nonsignificantly reduced the types, but significantly increased the average frequency and negated the enrichments of integration breakpoints.ConclusionLiver damage mainly removed the inventories of viral integration and clonal hepatocytes in CHB. NUC treatment may have reduced HBV integration but clearly increased clonal hepatocyte expansion, which may explain why HCC risk cannot be ruled out by NUC treatment.

Are nucleos(t)ide analogues effective against severe outcomes in COVID-19 and hepatitis B virus coinfection?

Background and Aim:The impact of chronic hepatitis B virus (HBV) infection and nucleos(t)ide analogue (NUC) treatment on disease severity and clinical outcomes in patients with coronavirus 2019 (COVID-19) is unknown. The objective of this study was to determine whether HBV infection and the use of NUCs impacts mortality in patients with COVID-19.Materials and Methods:A total of 231 adult patients (77 with COVID-19 and HBV coinfection) with a laboratory-confirmed diagnosis of COVID-19 were enrolled in this retrospective study. Univariate and binary logistic regression analysis were performed to evaluate the risk factors for mortality from COVID-19.Results:Patients with COVID-19 and HBV coinfection had a similar rate of mortality to those without HBV coinfection (7.8% vs 9.7%; p=0.627). Cardiovascular disease (odds ratio [OR]: 8.22, 95% confidence interval [CI]: 1.52-44.2; p=0.014) and a high basal aspartate transaminase level (OR: 7.94, 95% CI: 1.81-34.8; p=0.006) were independent predictors of mortality due to COVID-19. In the COVID-19 and HBV coinfection group, the patients who died had a significantly higher median level of HBV DNA than patients who survived (378 IU/mL vs 0 IU/mL; p=0.048). Thirty (39%) patients with HBV coinfection received NUC treatment, and none of these patients died.Conclusion:HBV infection was not associated with mortality in patients with COVID-19, and it seems that NUC treatment for HBV infection might have an antiviral effect on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

The impact of hepatitis flare on HBeAg loss was effective mainly in the first year of Nucleot(s)ide therapy in chronic hepatitis B.

HBeAg loss during nucleos(t)ide analogue (Nuc) therapy is significantly higher in patients with hepatitis flare (ALT≥5-times upper limited of normal). It is not clear whether ALT level higher above the hepatitis flare leads to greater HBeAg loss rate nor its durability. This study aimed to investigate the impact of pretherapy ALT level on HBeAg loss in each year of Nuc treatment. Entecavir or Tenofovir treated HBeAg-positive chronic hepatitis B (CHB) patients were recruited consecutively. Patients with prior treatment history that experienced HBeAg seroconversion and reversion were excluded. Pretherapy age, gender, cirrhosis, genotype, ALT, HBsAg and HBV DNA levels were analysed. The hazard function was calculated for the probability of HBeAg loss in each year. Of the 290 patients, the 3-year cumulative HBeAg loss rate was 58.1%, higher in patients with hepatitis flare than those without (67.6% vs. 39.6%, P<0.001). The HBeAg loss rate in the first year correlated positively with higher ALT levels at a stepwise fashion. The hazard function in patients with hepatitis flare was 0.74 at half year, then dropped to 0.33 by the first year and was lower thereafter to a rate closer to that of the patients without hepatitis flare. In conclusion, the impact of pretherapy ALT levels on HBeAg loss rate was not long-lasting and was effective mainly in the first year of Nuc therapy. Strategies such as adding an immune-modulating agent may help enhance HBeAg loss rate after the first year of Nuc therapy for those who remained HBeAg positive. Word count: 249 (<250).