Future anti-HDV treatment strategies, including those aimed at HBV functional cure.

HDV is a defective virus that uses the HBV surface antigen to enter hepatocytes. It is associated with an accelerated course of liver fibrosis progression and an increased risk of hepatocellular carcinoma. Negative HDV RNA 24 weeks after the end of therapy has been proposed as an endpoint but late relapses make this endpoint suboptimal, hence HBsAg loss appears to be more appropriate. Current HBV antiviral agents have poor activity against HDV hence the search for improved therapy. Drugs only active against HDV, such as lonafarnib, have shown efficacy in combination with nucleoside analogues and peginterferon, but do not lead to HBsAg loss. HBsAg loss sustained 24 weeks after the end of therapy with negative HBV DNA is termed functional cure. Agents that are being investigated for functional cure include those that inhibit replication such as entry inhibitors, polymerase inhibitors and capsid assembly modulators but seldom lead to functional cure. Agents that reduce HBV antigen load such as RNA interference and inhibitors of HBsAg secretion are promising. Immunomodulators on their own seldom achieve functional cure, hence these agents in combination to assess the optimal combination are being investigated. Consequently, agents leading to functional cure of HBV are ideal for both HBV and HDV.

Switching to or Add-on Peginterferon in Patients on Nucleos(t)ide Analogues for Chronic Hepatitis B: The SWAP RCT.

BACKGROUND & AIMS: The optimal therapeutic strategy in nucleoside analogue (NA) experienced chronic hepatitis B (CHB) using peginterferon is still unclear; hence we explored a switch to or add-on peginterferon strategy versus continued NA. METHODS: We conducted a randomized controlled trial of CHB patients on NA >12 months with HBV DNA(-) randomized to switch or add-on peginterferon-alpha2b (1.5 µg/kg/weekly) for 48 weeks versus continuing NA (controls) (allocation 2:2:1; Clinicaltrial.gov: NCT01928511) in tertiary Singapore hospitals. The primary composite endpoint at week 72 was hepatitis B e antigen (HBeAg) loss or quantitative HBsAg (qHBsAg) >1 log IU/mL reduction, and secondary endpoints were HBsAg loss, HBsAg seroconversion, qHBsAg <200 IU/mL, qHBsAg <100 IU/mL, HBV DNA(-), viral relapse, and safety. Analysis was by intention-to-treat (ITT). RESULTS: A total of 253 patients (controls 51, switch 103, add-on 99) were randomized. The primary ITT endpoint was achieved in 3.9% of controls, 33.3% of switch, and 26.7% of add-on (P < .0001, switch/add-on versus controls). HBsAg loss occurred in 0% of controls, 7.8% of switch, and 10.1% of add-on (ITT, P < .001, switch/add-on versus controls). HBeAg(+) patients on peginterferon had higher HBeAg loss than controls but poor HBsAg responses, whereas HBeAg(-) patients on peginterferon achieved better HBsAg responses than controls. Reduction in qHBsAg in HBeAg(+) was 0.14 log IU/mL versus 0.51 log IU/mL in HBeAg(-) (P < .0001) in peginterferon-treated patients. Clinical relapse was higher in switch (13.6% overall, 27% in HBeAg(+)) versus 1% add-on and 0% controls. Adverse events were typically interferon-related symptoms, with one death (myocardial infarction unrelated to therapy). CONCLUSIONS: ITT analysis showed that either peginterferon strategies were superior to NA for the primary endpoint and HBsAg loss, but add-on peginterferon is preferred to switch due to improved safety and similar efficacy. ClincialTrials.gov number: NCT01928511.

Robust antiviral responses in severe hepatitis flare persist after early retreatment cessation and lead toward hepatitis B surface antigen loss: A proof-of-concept study.

AIM: Hepatitis B flare has been interpreted as result of immune response against upsurging hepatitis B virus (HBV) and its antigen(s) that may lead to HBV decline/clearance spontaneously. It has been speculated that antiviral therapy could halt the effective immune response with viral persistent as a consequence. A proof-of-concept study was conducted to investigate this issue. METHODS: Serial biochemical, quantitative hepatitis B surface antigen (HBsAg), interferon-γ (IFN-γ) and tumor-necrosis factor-α (TNF-α) assays were performed in four patients with severe hepatitis flare who had achieved precipitous HBsAg decline within 4 weeks of antiviral therapy. RESULTS: TNF-α and IFN-γ were found to be elevated in parallel to upsurging HBV DNA and HBsAg levels in all patients. Higher levels of TNF-α and IFN-γ and levels relative to qHBsAg were observed during and after early termination of therapy within 4 weeks in two patients and were followed by further HBsAg decline to <5 IU/ml and even achieved HBsAg loss in one patient. The patient who had stopped therapy on day 44 showed minimal HBsAg decline afterward and the patient who continued therapy showed a 10-fold rebound of qHBsAg from its nadir. The subsequent IFN-γ and TNF-α activity of these two patients was minimal. CONCLUSIONS: The results suggest that patients with severe hepatitis flare who achieved precipitous HBsAg decline may have robust immune response to clear the virus, and early termination of antiviral therapy may allow the protective immune response to continue and accelerate HBV decline toward HBsAg loss.

Kinetics of quantitative hepatitis B surface antigen in patients with rheumatic disease and chronic hepatitis B receiving biologic agents.

The effect of biologic treatment on quantitative Hepatitis B surface Antigen (qHBsAg) levels and HBsAg clearance in rheumatic patients with chronic HBV infection has not been well studied. We prospectively followed rheumatic patients with HBeAg-negative chronic HBV infection (n = 28) treated with biologics and oral antivirals, categorized into patients with chronic hepatitis B (CHB, group A n = 13) and chronic HBV infection (group B n = 15) and matched them to appropriate non-rheumatic controls. qHBsAg kinetics were serially measured and compared between groups. No HBV reactivation (HBVr) was recorded during the 108.25 patient-year follow-up. Among patients with CHB, the annual rapid qHBsAg decline (i.e. decline >0.5 log10  IU/mL/year) as well as HBsAg clearance did not differ between rheumatic patients [n = 4 (32.7%), n = 1 (7.7%)] and controls [n = 6 (28.4%), p = .726 and n = 2 (7.7%), p = .818, respectively]. In contrast, there was a slower annual qHBsAg decline in rheumatic patients with chronic HBV compared to non-rheumatic controls (-0.04 vs -0.13 log10  IU/mL at year 1, p = .019) with no cases of rapid qHBsAg decline or HBsAg clearance in rheumatic patients (0%) compared to a cumulative incidence of 24% and a rate of 20%, respectively in controls. In biologic-treated rheumatic patients with HBeAg-negative HBV receiving antiviral prophylaxis, there was slower qHBsAg decline, lower cumulative rates of rapid qHBsAg decline and HBsAg clearance compared to non-rheumatic controls.

Long-term hepatitis B surface antigen (HBsAg) kinetics during entecavir treatment in Korean patients-Functional cure unlikely.

The aim of this study was to investigate the on-treatment kinetics of quantitative HBsAg during entecavir therapy to predict the treatment period needed to achieve functional cure. From a cohort of 1009 CHB treatment-naïve patients who were started on entecavir, the kinetics of quantitative HBsAg decline was assessed in 410 patients by a linear mixed model. The difference in the kinetics of quantitative HBsAg was determined based on the HBeAg positivity, HBeAg seroclearance and presence of baseline liver cirrhosis. Among the 410 patients, 213 patients (52.0%) were HBeAg-positive and 217 patients (66.1%) were male with a median age of 48 years. During a median follow-up of 53.5 months, the quantitative HBsAg level showed a slow but consistent decrease. The expected log qHBsAg levels as a function of time during entecavir treatment in HBeAg(+) and HBeAg(-) patients were 3.4773-0.0039 × Months and 3.1853-0.0036 × Months, respectively. The estimated time to clearance of quantitative HBsAg in our study was greater than 74.1 years in HBeAg-positive patients and 73.5 years in HBeAg-negative patients. The calculated time to achieve functional cure is lifelong without regard to HBeAg seroclearance or presence of liver cirrhosis. The mathematical modelling from a long-term follow-up of chronic hepatitis B patients on entecavir shows that HBsAg clearance requires decades of treatment. Thus, lifelong therapy is inevitable in entecavir-treated patients to achieve functional cure.

The association of vitamin D with hepatitis B virus replication: Bystander rather than offender.

BACKGROUND/PURPOSE: Low vitamin D is frequent in hepatitis B virus (HBV)-infected patients and several studies show an inverse association of serum vitamin D level with HBV viral load. However, the causal relationship remains unclear. METHODS: HBV carriers receiving regular 6-month surveillance without current antiviral treatment or cirrhosis were invited to participate into this trial. The markers of HBV replication included serum HBV DNA and quantitative HBsAg (qHBsAg) levels. Those with undetectable HBV DNA or sufficient vitamin D levels, cancer or electrolyte imbalance were excluded. The eligible subjects were randomized to receive either vitamin D supplement 2000 IU per day for 2 months (vitamin D group) or none (control group). RESULTS: A total of 196 HBV carriers (93 males and 103 females; mean age 51.9 ± 10.0 years) were screened. Of them, 28 patients had undetectable serum HBV DNA levels, which is defined as spontaneous viral clearance. The vitamin D levels were not different between patients with detectable HBV DNA and those without (p = 0.18). After exclusion, 149 patients were randomized to two groups: 75 in vitamin D group and 74 in control group. After 2 months vitamin D supplement, the serum vitamin D levels were significantly higher in the vitamin D group than the control group (p < 0.001). However, the serum qHBsAg and HBV DNA levels were comparable between these two groups. CONCLUSION: There is no causal relationship between vitamin D and HBV replication. The role of liver reserve on serum vitamin D levels in patients with chronic HBV infection needs further investigation.

Mother-to-child transmission of hepatitis B: Examining viral cut-offs, maternal HBsAg serology and infant testing.

BACKGROUND & AIMS: Antipartum antiviral therapy in the setting of high viral load is recommended to prevent mother-to-child transmission of hepatitis B although recommended viral load cut-offs vary. Quantitative HBsAg has been proposed as an alternative screening strategy to identify high viral load in this setting. Guidelines suggest testing all infants for vaccine response and infection. We set out to re-examine viral load cut-offs; the predictive value of quantitative HBsAg and the need for follow-up infant testing in our cohort. METHODS: A retrospective cohort study of 469 HBsAg positive mother-baby pairs from 2 tertiary hospitals in Sydney was performed. Antiviral therapy (lamivudine or tenofovir disoproxil fumarate) was offered to women with viral load ≥6 log10  IU/mL (high) from 32 weeks gestation. Transmission and vaccine response was analysed according to viral load. The utility of quantitative HBsAg in identifying high viral load was examined. RESULTS: Mother-to-child transmission only occurred in setting of high viral load, in 0.85% (1/117) of those who received antiviral therapy and in 8.66% (2/23) of those who chose not to. Quantitative HBsAg did not accurately identify high-risk mothers HBV DNA ≥6 log10  IU/mL. Successful infant vaccine response was 98.7% overall, and 99.4% when viral load was <6 log10  IU/mL. CONCLUSION: Antiviral therapy initiated at 32 weeks when maternal viral load is ≥6 log10  IU/mL almost completely abrogates transmission. Quantitative HBsAg does not reliably predict high viral load. When maternal viral load is <6 log10  IU/mL, high vaccine efficacy and zero transmission suggests testing infants is of little value.

HBsAg loss after peginterferon-nucleotide combination treatment in chronic hepatitis B patients: 5 years of follow-up.

Combining peginterferon-alfa-2a (pegIFN) with a nucleotide analogue can result in higher rates of HBsAg loss than either therapy given alone. Here, we investigated the durability of the response to combination therapy in chronic hepatitis B (CHB) patients after 5 years of follow-up. In the initial study, 92 CHB patients (44 HBeAg-positive, 48 HBeAg-negative) with HBV DNA >100 000 c/mL (~20 000 IU/mL) and active hepatitis were treated for 48 weeks with pegIFN 180 µg/week and 10 mg adefovir dipivoxil daily. For the long-term follow-up (LTFU) study, patients were followed up for 5 years after the end of treatment. At year 5, 70 (32 HBeAg-positive, 38 HBeAg-negative) patients remained in the study. At year 5, 19% (6/32) of HBeAg-positive patients and 16% (6/38) of HBeAg-negative patients lost HBsAg, and no HBsAg seroreversion was observed. The 5-year cumulative Kaplan-Meier estimate for HBsAg loss was 17.2% for HBeAg-positive patients and 19.3% for HBeAg-negative patients. Fourteen of sixteen patients who lost HBsAg at any time point during follow-up developed anti-HBs antibodies (>10 IU/L). At year 5, in total 63% (20/32) of HBeAg-positive and 71% (27/38) of HBeAg-negative patients were retreated with nucleos(t)ide analogues during follow-up. The cumulative Kaplan-Meier estimate for retreatment was 60% of patients at year 5. At year 5 of follow-up, 18% of CHB patients treated with pegIFN/nucleotide analogue combination therapy had durable HBsAg loss and 88% of these had developed anti-HBs antibodies.

A combination of different diagnostic tools allows identification of inactive hepatitis B virus carriers at a single time point evaluation.

BACKGROUND & AIMS: Serial evaluation of hepatitis B virus (HBV) DNA and aminotransferase values is required for identification of inactive HBV carriers (ICs). Recently, HBV surface antigen quantification (qHBsAg) and liver stiffness measurement (LSM) have been proposed as diagnostic tools in chronic HBV infection. The aim of this study was to evaluate the efficacy of HBV DNA quantification, qHBsAg and LSM in diagnosing ICs at a single time point. METHODS: Fifty-seven previously characterized ICs and 90 untreated HBsAg-/anti-HBe-positive patients [49 chronic hepatitis (CH), 41 cirrhosis] were enrolled. HBV DNA ≤2000 IU/mL, LSM ≤6.2 kPa and qHBsAg ≤1000 IU/mL were used as cut-offs to evaluate sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and diagnostic accuracy (DA). RESULTS: Combined HBV DNA quantification and qHBsAg correctly identified 30/57 (52.6%) ICs showing 94% sensitivity, 96% specificity, 98% PPV, 87% NPV and 95% DA. HBV DNA coupled with LSM identified 40/57 (70.2%) ICs showing 97% sensitivity, 97% specificity, 98% PPV, 95% NPV and 97% DA. Combined LSM and qHBsAg identified 33/57 (57.9%) ICs showing 95% sensitivity, 78% specificity, 89% PPV, 89% NPV and 89% DA. The evaluation of the three parameters altogether allowed the identification of 23/57 (40.3%) ICs showing 100% specificity, 96% sensitivity, 100% PPV, 92% NPV and 97% DA. Similar results were obtained when either CH or cirrhotic patients were excluded from the analysis. CONCLUSIONS: Combined evaluation of HBV DNA amount with LSM and/or qHBsAg is a highly reliable tool allowing the identification of a considerable number of HBV ICs at a single time point evaluation.

Long-term outcome of inactive and active, low viraemic HBeAg-negative-hepatitis B virus infection: Benign course towards HBsAg clearance.

BACKGROUND & AIMS: The difference between the long-term outcome of low-viraemic (HBV-DNA≤20 000-IU/mL, LV-AC) and inactive HBsAg carriers (HBV-DNA≤2000-IU/mL, IC) remains to be defined. We studied prospectively 153 HBeAg-negative HBsAg-carriers with baseline HBV-DNA≤20 000-IU/mL and normal transaminases. METHODS: IC, LV-AC or chronic hepatitis B (CHB) (HBV-DNA persistently ≤2000-IU/mL, ≤20 000-IU/mL or >20 000-IU/mL respectively) were diagnosed after 1-year, 3-monthly monitoring. Thereafter IC and LV-AC were followed-up for additional 57.2 (8.5-158.3) months. HBV-DNA, HBsAg, HBV"core-related"Antigen (HBcrAg) and total-anti-HBc were quantified at baseline. RESULTS: After the 1st year diagnostic follow-up CHB [higher HBV-DNA (P=.005), total-anti-HBc (P=.012), ALT (P=.007) and liver-stiffness (P=.021)] was identified in 20 (13.1%) carriers; baseline HBsAg≤1000IU/HBV-DNA≤2000IU/mL excluded the presence of CHB (NPV-100%). Thereafter, during the long-term follow-up none of 87 IC reactivated, 19 (21.8%) cleared HBsAg [older-age (P=.004), lower HBsAg (P<.001), higher yearly HBsAg decline (P<.001)]. Twenty-five of 46 (54.3%) LV-AC remained stable, 20 (43.5%) became IC and 1 (2.2%) developed CHB. The best single-point CHB and IC diagnostic-accuracies were total-anti-HBc (84.2%, NPV-98.2%) and HBV-DNA/total-anti-HBc/HBcrAg combination (89.5%, 93%-sensitivity, 84.8%-specificity) respectively. CONCLUSIONS: Viraemia persistently ≤20 000-IU/mL predicts a benign clinical outcome: it was associated with transition to IC in 43% of LV-AC and to Occult HBV Infection in 20% of IC within 5-years. Nevertheless, 13.1% of individuals with low viraemia at presentation develops CHB within 1 year: 1-year HBV-DNA monitoring resulted the most accurate diagnostic approach that can be limited to at least a half of cases by the single point HBV-DNA/HBsAg quantification. The IC-diagnostic-accuracy combining HBV-DNA/total-anti-HBc/HBcrAg needs to be confirmed in further studies.

When can we stop nucleoside analogues in patients with chronic hepatitis B?

Treatment with nucleoside analogue (NAs) is now the most common treatment for chronic hepatitis B (CHB) and is recommended by all guidelines. Stopping NAs is a controversial issue in these patients, unless the clinical endpoints of HBeAg seroconversion or HBsAg seroclearance are achieved. While HBeAg seroconversion can occur in a significant number of patients, HBsAg seroclearance rates are low. HBsAg seroclearance is increasingly accepted as the ideal end of treatment, representing a functional cure. Treatment withdrawal leads to relapse in 50% of patients who achieve HBeAg seroconversion and complete at least 12 months of consolidation therapy. In HBeAg negative CHB, the Asian Pacific Association for the Study of the Liver (APASL) stopping rules show that although clinical relapse occurs in approximately 43% and virological relapse occurs in 70%, very few patients experience flare or decompensation. NAs treatment for >2 years was associated with a lower rate of relapse. Recently, stopping NA therapy was shown to be associated with HBsAg in 20%-39% of HBeAg negative patients and more frequently in those with low quantitative HBsAg (qHBsAg). However, the most optimal level is unclear. Quantitative HBsAg is becoming a useful tool to predict a sustained response or relapse before stopping therapy. In conclusion, stopping NA therapy is generally safe and can be an option in specific situations such as HBeAg seroconversion. However, it is associated with disease relapse. Thus, patient selection based on qHBsAg may help identify patients who are more likely to achieve HBsAg seroclearance or a sustained response.

Treatment outcomes and validation of the stopping rule for response to peginterferon in chronic hepatitis B: A Thai nationwide cohort study.

BACKGROUND AND AIMS: Peginterferon has demonstrated effectiveness in clinical trials in patients with chronic hepatitis B (CHB). However, its efficacy in real-life settings remains unclear. We investigated the efficacy of peginterferon for CHB and validated the performance of previously identified response predictors in clinical practice. METHODS: We analyzed prospectively collected data from a Thai nationwide cohort of CHB patients treated with peginterferon alfa-2a (180 µg/week, 48 weeks). RESULTS: Among a total of 233 patients, mostly with genotype B or C, sustained response was observed in 23% of 135 hepatitis B e antigen (HBeAg)-positive patients (HBeAg seroconversion with hepatitis B virus [HBV] DNA < 2000 IU/mL) and 42% of 98 HBeAg-negative patients (HBV DNA < 2000 IU/mL with aminotransferase normalization) at 24 weeks after treatment. Age, sex, presence of cirrhosis, genotype, and pretreatment levels of aminotransferase, HBV DNA, and hepatitis B surface antigen (HBsAg) were not identified as significant predictors of sustained response. In HBeAg-positive patients, HBsAg > 20 000 IU/mL at week 12 provided a good stopping rule, with a negative predictive value of 96%. In HBeAg-negative patients, the performance of 12-week stopping rules of no decline in HBsAg with a < 2log10 decline in HBV DNA and a < 10% log10 decline in HBsAg showed modest negative predictive values of 80% and 66%, respectively, for achieving sustained response. CONCLUSION: Outcomes in CHB patients treated with peginterferon in a clinical setting are similar to those demonstrated in clinical trials. Application of the early stopping rule based on HBsAg quantification may allow individualization of therapy, particularly in HBeAg-positive patients.

New insights in the management of chronic hepatitis B.

Chronic hepatitis B (CHB) remains a global healthcare challenge, complicated by the development of cirrhosis and hepatocellular carcinoma, accounting for approximately 600,000 deaths per year. Hepatitis B is a DNA virus, which utilises a covalently closed circular (ccc) DNA to act as a transcriptional template for the virus. The persistence of cccDNA in the nucleus of infected hepatocytes accounts for HBV chronicity. Quantitative hepatitis B surface antigen (qHBsAg) acts as a surrogate for the level of cccDNA and therefore may provide useful information around treatment response and viral immune control. Current antiviral therapies are limited in their ability to achieve HBsAg loss, which is considered the 'gold-standard' treatment endpoint. This article focuses on the unmet needs in CHB today; a better definition of disease phase, the timing of therapeutic intervention, optimising treatment strategies with current therapies and the development of novel agents; all with HBsAg loss as the therapeutic goal.

Diagnostic Utility of Pre-Genomic Hepatitis B RNA in the Evaluation of HBV/HIV Coinfection.

Background: Newer biomarkers of Hepatitis B virus (HBV) infection and treatment response have not been well-characterized in individuals with HBV/HIV coinfection. Methods: Pre-genomic RNA (pgRNA) and quantitative HBsAg (qHBsAg) were used to evaluate the associations with baseline characteristics. Participants included two separate groups - 236 with HBV/HIV coinfection enrolled in a cross-sectional cohort in Ghana and 47 from an HBV nucleoside/nucleotide treatment trial comparing tenofovir to adefovir in the United States. Results: In both cohorts, HBe antigenemia was highly associated with pgRNA and HBV DNA levels. In the treatment cohort, pre-treatment pgRNA serum concentration was 7.0 log10 U/mL, and mean qHBsAg was 201,297 IU/mL. The observed treatment-associated decrease in pgRNA was consistent with a biphasic decline curve that reached second-phase kinetics following treatment week 12. Changes from baseline were significantly correlated with changes in serum ALT (r = - 0.518; P = 0.023) but not with changes in HBV DNA (r = 0.132, P = NS). qHBsAg also correlated with ALT change (r = - 0.488, P = 0.034). Conclusion: pgRNA and qHBsAg represent newer biomarkers of HBV replication that may help monitor response and treatment outcomes. HBV pgRNA is highly associated with both HBeAg and ALT and may predict both active replication from the closed circular DNA (cccDNA) template as well as hepatic injury.

Evaluating the relationship between hepatitis B viral activity and gestational diabetes mellitus: A prospective cohort study.

BACKGROUND: Hepatitis B infection has been associated with the development of gestational diabetes but the underlying mechanism is not known. OBJECTIVE: To examine associations between viral activity, gestational diabetes mellitus (GDM), and insulin resistance in pregnant people with chronic hepatitis B infection (HBV). DESIGN: Prospective cohort study across three tertiary maternity centres in Melbourne, Australia, between May 2021 and April 2023. METHODS: Participants were followed prospectively through pregnancy to evaluate subsequent GDM diagnosis. Demographics, pregnancy outcomes, and markers of viral activity were compared between those with GDM versus those without. Logistic regression analysis was performed pre- and post-adjustment for known confounders. Sub-group analysis of participants from South East Asia (SEA) was performed. Outcome measures included GDM diagnosis, insulin resistance (Homeostatic Model Assessment Insulin Resistance score (HOMA-IR) score), HBV activity as measured by liver function tests, HBV viral load, hepatitis B e antigen, and quantitative hepatitis B surface antigen (quantHBsAg). RESULTS: A total of 113 women were recruited. One third (38/112, 33.9%) developed GDM, mostly diagnosed on isolated postprandial hyperglycaemia (25/38, 65.8%). Over half were born in SEA (66/113, 58.4%). Mean quantHBsAg was significantly lower in those with GDM (p = 0.044). No other associations were identified between GDM or HOMA-IR and markers of hepatic activity on multivariate logistic regression analysis and on sub-group analysis of those born in SEA. CONCLUSIONS: QuantHBsAg was significantly lower in those with GDM; otherwise, no association between GDM and measures of HBV viral activity was found. QuantHBsAg may be useful as an early pregnancy marker for GDM risk and warrants further research.

Prevalence, characteristics, and virologic correlations of hepatitis delta (D) among patients with hepatitis B surface antigen in Mongolia.

Clinical and biochemical features of hepatitis delta virus (HDV) infections in Mongolia remain largely unknown. We aimed to investigate the clinical characteristics of HDV patients in Mongolia using several markers. The 143 hepatitis B surface antigen (HBsAg)-positive patients were divided into 122 HDV-positive and 21 HDV-negative patients by HDV RNA positivity. Subgroup analysis was performed between hepatitis B e antigen (HBeAg)-positive and -negative HDV-positive patients. Liver function, quantitative HBsAg (qHBsAg), anti-HDV Immunoglobulin (Ig) M, Mac-2 binding protein glycosylation isomer (M2BPGi), hepatitis B virus (HBV) DNA level, and HDV RNA level were tested. HDV RNA was positive in 85.3% (122/143) of patients showing anti-HDV IgG. Liver disease activity was higher in HDV-positive patients than in HDV-negative patients. The HDV-positive group included a higher proportion of patients with high qHBsAg and M2BPGi levels (p < 0.001). The positivity rate for anti-HDV IgM was significantly higher in the HDV-positive group (p < 0.001). HDV RNA levels showed an inverse correlation with qHBsAg levels in HBeAg-positive-HDV-positive patients (r = -0.49, p = 0.034), and a positive correlation with qHBsAg levels in HBeAg-negative patients (r = 0.35, p < 0.001). Hepatitis B virus (HBV) DNA and HDV RNA levels did not show any correlation. M2BPGi levels likewise did not correlate with HDV RNA levels. A high positivity rate for HDV RNA was observed for HBV patients in Mongolia using the highly sensitive HDV RNA assay. The positivity rate for anti-HDV IgM was high in HDV RNA-positive patients. Severity of liver disease and M2BPGi levels were both high in the HDV RNA-positive group.

Serum hepatitis B surface antigen quantification as a useful assessment for significant fibrosis in hepatitis B e antigen-positive hepatitis B virus carriers.

BACKGROUND AND AIMS: The role of serum quantitative hepatitis B surface antigen (qHBsAg) in identifying hepatitis B virus (HBV) carriers with significant fibrosis is unknown. This study aims to evaluate the diagnostic value of qHBsAg for hepatic fibrosis in hepatitis B e antigen (HBeAg)-positive HBV carriers. METHODS: Consecutive biopsy-proven HBeAg-positive HBV carriers were prospectively recruited in our center from 2009 to 2011 and were randomly divided into training and validation set. Area under receiver-operator curve (AUC) was used to determine the diagnostic accuracy of simple tests for significant fibrosis (Scheuer stage, F ≥ 2). RESULTS: Overall, a total of 197 eligible patients (median age 31 years; 149 males) were enrolled. The median qHBsAg was 4.20 (log10 IU/mL). Significant fibrosis was confirmed in 112 (56.9%) patients. By logistical regression analysis, qHBsAg and γ-glutamyl transpeptidase were identified as predictors for significant fibrosis in training set (n = 124). Thus, qHBsAg index and γ-glutamyl transpeptidase to qHBsAg ratio (GqHBsR) were selected for the subsequent analysis. In the training set, an AUC of 0.762, 0.826, 0.749, and 0.771 was observed for qHBsAg index, GqHBsR, FIB-4, and aspartate aminotransferase to platelet ratio index, respectively (all P < 0.05). GqHBsR yielded a higher AUC than aspartate aminotransferase to platelet ratio index and FIB-4 (both P < 0.05). Using the optimal cut-off of 7.78, GqHBsR showed a sensitivity of 78.9% and a specificity of 73.6%. About 80% of liver biopsy could be avoided in the entire cohort. CONCLUSIONS: Serum qHBsAg-based simple tests, especially GqHBsR, can accurately and specifically identify significant fibrosis in treatment-naïve HBeAg-positive HBV carriers.

HDV RNA Levels and Progression of Hepatitis Delta Infection: A 14 Year Follow Up Experience in Italy.

BACKGROUND: Identification of outcome predictors is one of the unmet needs in chronic HDV infection. Until recently, no reliable quantitative assays for HDV RNA were available. AIMS: To evaluate the impact of baseline viremia on natural history of HDV infection in a cohort of patients whose serum samples were stored at their first visit 15 years ago. METHODS: Quantitative HBsAg, HBeAg, HBeAb, HBV DNA, HDV RNA, genotypes, and liver disease severity were assessed at baseline. Patients who were no longer on active follow-up were recalled and re-evaluated in August 2022. RESULTS: The majority of patients were male (64.9%); the median age was 50.1 years; and all patients were Italian, with only three born in Romania. All were HBeAg negative with HBV genotype D infection. Patients were subdivided three groups: 23 were in active follow-up (Group 1), 21 were recalled due to no longer being in follow-up (Group 2), and 11 died (Group 3). Liver cirrhosis was diagnosed in 28 subjects at the first visit; 39.3% of diagnosed patients were in Group 3, 32.1% were in Group 1 and 28.6% were in Group 2 (p = 0.001). Baseline HBV DNA IU/mL Log10 were 1.6 (1.0-5.9) in Group 1, 1.3 (1.0-4.5) in Group 2, and 4.1 (1.5-4.5) in Group 3; median baseline HDV RNA Log10 levels were 4.1 (0.7-6.7) in Group 1, 3.2 (0.7-6.2) in Group 2, and 5.2 (0.7-6.7) in Group 3, resulting significantly higher rates among patients in Group 3 compared to the other groups (p = 0.038). Eighteen patients in Group 2, as compared to 7 in Group 1, had undetectable HDV RNA at the follow-up evaluation (p = 0.001). CONCLUSIONS: HDV chronic infection is a heterogeneous disease. It may not only progress but also improve over time in patients, who eventually become HDV RNA-undetectable. HDV RNA levels may help identify the subgroup of patients with less progressive liver disease.

Large spontaneous HBV DNA fluctuations and potential usefulness of a single-point measurement of combined HBV DNA and quantitative HBsAg for the exclusion of HBeAg-negative chronic hepatitis B: A prospective Tunisian cohort study.

BACKGROUND AND STUDY AIM: During the natural course of HBeAg-negative chronic hepatitis B (CHB), fluctuations in hepatitis B virus (HBV) DNA and alanine aminotransferase (ALT) levels are often observed, making the classification of patients difficult. We aimed to describe spontaneous short-term HBV DNA level fluctuations and to assess the usefulness of qHBsAg in Tunisian patients with HBeAg-negative chronic HBV infection. PATIENTS AND METHODS: We included 174 treatment-naive Tunisian patients with HBeAg-negative chronic HBeAg-negative HBV infection. A prospective 1-year follow-up was conducted with serial determinations of HBV DNA, ALT levels, and qHBsAg. The patients were classified into three groups: inactive carriers (G1), patients with negative HBeAg CHB (G2), and patients with an "indeterminate state" (G3). For the latter group, a liver biopsy was indicated. RESULTS: Only genotype D was detected. During follow-up, 21.6% and 19.5% of patients with a low initial (<2,000 IU/ml) and intermediate viral load (2,000-20,000 IU/ml) experienced a subsequent increase in their HBV DNA levels above 2,000 and 20,000 IU/ml, respectively. Significant variations in viral load were observed in 61.1% of patients at 6-month intervals. Among the 174 patients, 89 (51.1%) belonged to G1, 33 (19%) to G2, and 52 (29.9%) to G3. Fourteen patients have undergone a liver biopsy, of whom seven showed moderate to severe liver disease. Combination of HBV DNA < 2,000 IU/ml and qHBsAg < 832 IU/ml excluded CHB in 98.4% of cases. A cutoff point for qHBsAg < 100 IU/ml associated with an annual decline of > 0.5 log 10 IU/ml is a good predictor marker of functional cure for hepatitis B. CONCLUSIONS: This study highlights the large short-term fluctuations in HBV DNA in patients with HBeAg-negative chronic HBeAg-negative HBV infection with genotype D. Thus, using the cutoff value of 832 for qHBsAg combined with that of 2,000 for HBV DNA makes it possible to exclude CHB for most patients.

Control of HBV infection in HIV/HBV co-infected patients treated with antiretroviral therapy - experience of Lodz Centre.

Aim of the study: To analyse the impact of combined antiretroviral therapy (cART) on selected markers of hepatitis B virus (HBV) infection, as well as assessment of the degree of fibrosis in antiretroviral patients who had HIV/HBV co-infection. Material and methods: Analysis of HBs antigen (HBsAg), anti-HBs, HBsAg levels, anti-HDV, anti-HCV, as well as assessment of HBV DNA viraemia and liver fibrosis by elastography in people with HIV/HBV co-infection. Results: Among 515 people under the care of the Lodz Centre at the time of treatment initiation 28 people (5.4%) HBsAg was detected. In HIV/HBV coinfected patients 14 people (50%) had anti-HCV and 6 (21.6%) had anti-HDV. In the group of 23 people treated with antiretroviral therapy for more than 12 months, all but one patient achieved HBV viraemia below the detection threshold. Six (26.1%) eliminated HBsAg, 3 (13%) produced anti-HBs. In the group we examined, four patients has fibrosis at level F4 on the Metavir scale - 3 patients were treated for more than 12 months and one patient was treated for less than 12 months. Conclusions: Antiretroviral treatment of patients co-infected with HIV/HBV based on tenofovir (in the form of disoproxil or alafenamide) with emtricitabine or lamivudine leads to virological control of HBV infection.