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.

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.

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.

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.

Clinical Outcomes and Quantitative HBV Surface Antigen Levels in Diverse Chronic Hepatitis B Patients in Canada: A Retrospective Real-World Study of CHB in Canada (REVEAL-CANADA).

BACKGROUND: Hepatitis B surface antigen (HBsAg) loss is associated with improved clinical outcomes for individuals with chronic hepatitis B (CHB); however, the effects of varying HBsAg levels on clinical outcomes in diverse cohorts are understudied. METHODS: In this cross-sectional, multicentre, retrospective study, the data on adult subjects enrolled in the Canadian HBV Network with CHB seen from 1 January 2012 to 30 January 2021 with the treatment and virologic data within 1 year of HBsAg testing were analyzed. Patients were tested for HBsAg using qualitative (for HBsAg-negative samples) and/or commercial quantitative assays. Fibrosis or hepatic necroinflammation was determined by the liver stiffness measurement (LSM). The baseline data were summarized using descriptive statistics and compared by using univariable/multivariable analyses. RESULTS: This study included 844 CHB patients, with a median age of 49.6 years (IQR 40.1-60.5), and 37% were female. In total, 751 patients (78.6%) had known ethnicity data, and 76.7% self-reported as Asian, 11.4% as Black, 6.8% as White, and 4.8% as other. Among the 844 patients, 237 (28.0%) were HBsAg (-) (1000 IU/mL. Overall, 80% (682) had known HBeAg status at the last follow-up, and the majority (87.0%) were HBeAg-negative. In addition, 54% (461/844) had prior antiviral therapy, 19.7% of which (16.3, 23.7, n = 91) were HBsAg (-). The treated patients had a lower risk of cirrhosis (16.46, 95% CI 1.89-143.39, p = 0.01) or HCC (8.23, 95% CI 1.01-67.39, p = 0.05) than the untreated patients. A lower proportion of the HBsAg-loss group had cirrhosis (5.7% vs. 10.9%, p = 0.021) and HCC (0.9% vs. 6.2%, p = 0.001). CONCLUSION: In this retrospective, ethnically diverse cohort study, CHB patients who received antiviral therapy and/or had HBsAg loss were less likely to develop cirrhosis and HCC, confirming the results of the studies in less diverse cohorts. No association was found between the qHBsAg level and fibrosis determined with LSM. Individuals who achieved HBsAg loss had low-level qHBsAg within 1 year of seroclearance.

ACE Score Identifies HBeAg-negative Inactive Carriers at a Single-point Evaluation, Regardless of HBV Genotype.

Background and Aims: Hepatitis B virus (HBV) biomarkers have been used for a better categorization of patients, even though the lack of simple algorithms and the impact of genotypes limit their application. Our aim was to assess the usefulness of noninvasive markers for the identification of HBV inactive carriers (ICs) in a single-point evaluation and to design a predictive model for their identification. Methods: This retrospective-prospective study included 343 consecutive HBeAg-negative individuals. Clinical, analytical, and virological data were collected, and a liver biopsy was performed if needed. Subjects were classified at the end of follow-up as ICs, chronic hepatitis B and gray zone.A predictive model was constructed, and validated by 1000-bootstrap samples. Results: After 39 months of follow-up, 298 subjects were ICs, 36 were chronic hepatitis B CHB, and nine were gray zone. Eighty-nine (25.9%) individuals required a liver biopsy. Baseline HBV DNA hazard ratio (HR) 6.0, p<0.001), HBV core-related antigen (HBcrAg) (HR 6.5, p<0.001), and elastography (HR 4.6, p<0.001) were independently associated with the IC stage. The ACE score (HBV DNA, HBcrAg, elastography), obtained by bootstrapping, yielded an area under the receiver operating characteristics (AUROC) of 0.925 (95% CI: 0.880-0.970, p<0.001) for identification of ICs. The AUROC for genotype D was 0.95, 0.96 for A, 0.90 for E, and 0.88 for H/F. An ACE score of <1 had a positive predictive value of 99.5%, and a score ≤12 points had a diagnostic accuracy of 93.8%. Conclusions: Low baseline HBV DNA, HBcrAg, and liver stiffness were independently associated with the IC phase. A score including those variables identified ICs at a single-point evaluation, and might be applied to implement less intensive follow-up strategies.

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.

Molecular epidemiology and clinical characteristics of hepatitis D virus infection in Canada.

Background & Aims: HDV affects 4.5-13% of chronic hepatitis B (CHB) patients globally, yet the prevalence of HDV infection in Canada is unknown. To investigate the prevalence, genotype, demographics, and clinical characteristics of HDV in Canada, we conducted a retrospective analysis of (1) HDV antibody and RNA positivity among referred specimens, and (2) a cross-sectional subset study of 135 HDV seropositive +/-RNA (HDV+) patients compared with 5,132 HBV mono-infected patients in the Canadian HBV Network. Methods: Anti-HDV IgG-positive specimens collected between 2012 and 2019 were RNA tested and the genotype determined. Patients enrolled in the Canadian HBV Network were >18 years of age and HBsAg-positive. Clinical data collected included risk factors, demographics, comorbidities, treatment, fibrosis assessment, and hepatic complications. Results: Of the referred patients, 338/7,080 (4.8%, 95% CI 4.3-5.3) were HDV seropositive, with 219/338 RNA-positive (64.8%, 95% CI 59.6-69.7). The HDV+ cohort were more likely to be born in Canada, to be White or Black/African/Caribbean than Asian, and reporting high-risk behaviours, compared with HBV mono-infected patients. Cirrhosis, complications of end-stage liver disease, and liver transplantation were significantly more frequent in the HDV+ cohort. HDV viraemia was significantly associated with elevated liver transaminases and cirrhosis. Five HDV genotypes were observed among referred patients but no association between genotype and clinical outcome was detected within the HDV+ cohort. Conclusions: Nearly 5% of the Canadian HBV referral population is HDV seropositive. HDV infection is highly associated with risk behaviours and both domestic and foreign-born patients with CHB. HDV was significantly associated with progressive liver disease highlighting the need for increased screening and surveillance of HDV in Canada. Lay summary: Evidence of HDV infection was observed in approximately 5% of Canadians who were infected with HBV referred to medical specialists. HDV-positive patients were more likely to be male, born in Canada, or White or Black/African/Caribbean compared to Asian, and to have reported high-risk activities such as injection or intranasal drug use or high-risk sexual contact compared with patients infected with only HBV. Patients infected with HDV were also more likely to suffer severe liver disease, including liver cancer, compared with HBV mono-infected 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.

Community-Based Screening for Hepatitis B and C Infectivity Using Two Quantitative Antigens to Identify Endemic Townships.

Screening and linkage to care are essential to achieve viral hepatitis elimination before 2030. The accurate identification of endemic areas is important for controlling diseases with geographic aggregation. Viral activity drives prognosis of chronic hepatitis B and hepatitis C virus infection. This screening was conducted in Chiayi County from 2018-2019. All residents aged 30 years or older were invited to participate in quantitative HBsAg (qHBsAg) and HCV Ag screening. Among the 4010 participants (male:female = 1630:2380), the prevalence of qHBsAg and HCV Ag was 9.9% (396/4010) and 4.1% (163/4010), respectively. High-prevalence townships were identified, three for qHBsAg > 15% and two for HCV Ag > 10%. The age-specific prevalence of qHBsAg was distributed in an inverse U-shape with a peak (16.0%, 68/424) for subjects in their 40 s; for HCV, prevalence increased with age. Concentrations of qHBsAg < 200 IU/mL were found in 54% (214/396) of carriers. The rate of oral antiviral treatment for HCV was 75.5% (114/151), with subjects younger than 75 years tending to undergo treatment (85.6% vs. 57.4%, p < 0.001). QHBsAg and HCV Ag core antigens can reflect the concentration of the viral load, which serves as a feasible screening tool. Using quantitative antigen screening for hepatitis B and C in community-based screening, two hyperendemic townships were identified from an endemic county.

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.

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.

Perspectives on stopping nucleos(t)ide analogues therapy in patients with chronic hepatitis B.

Long-term treatment with nucleos(t)ide analogs (NAs) is the current first line therapy for patients with chronic hepatitis B (CHB), recommended by most of the current guidelines. NAs prevent disease progression, liver failure, decrease the risk of hepatocellular carcinoma (HCC), and have favorable safety profiles. However, low rates of on-therapy functional cure (hepatitis B surface antigen [HBsAg] loss), which is regarded as the optimal end point, prevent many patients from stopping NA therapy with the need for a lifelong treatment. The higher likelihood of HBsAg loss associated with stopping as compared to continuing NAs has got a lot of attention recently. Recommendations regarding endpoints allowing for safely stopping NA therapy differ between international guidelines. Whereas in HBeAg-positive patients, HBeAg seroconversion with at least one year of consolidation therapy is an acceptable endpoint of treatment, the recommendations for HBeAg-negative ones differ. Some guidelines propose ≥3 years of HBV DNA undetectability to stop NA while others regard HBsAg loss as the only acceptable endpoint. Stopping NA can lead to substantial rates of virologic relapses and consequent ALT flares in some cases. Moreover, no reliable predictor(s) of post-NA relapses have been identified so far. Quantitative HBsAg is becoming an increasingly promising marker to predict safe NA cessation. On the other hand, investigating the role of the immune system in mediating sustained virologic responses after NA withdrawal is needed to suggest immunological biomarkers to safely stop NA. In this article, we will review relevant literature regarding NA stopping strategy and discuss promising viral and immunological biomarkers to predict antiviral responses and thus to help identify patients who are more likely to achieve HBsAg seroclearance.

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.

Characteristics of an Outpatient Cohort with HBeAg-Negative Chronic Hepatitis B.

BACKGROUND: Patients with hepatitis Be antigen-negative chronic hepatitis B (HBeAg-negative CHB), and patients' inactive carriers (IC) have similar laboratory and serologic characteristics and are not always easy to distinguish. AIM: To characterise hepatitis Be antigen (HBeAg) negative chronic hepatitis B cohort based on their laboratory and virology evaluations at one point of time. METHODS: A prospective non-randomized study was conducted on 109 patients with HBeAg negative chronic hepatitis B treated as outpatients at the Clinic for Infectious Diseases and Febrile Conditions. All patients underwent laboratory and serology testing, quantification of HBV DNA and HBs antigen (qHBsAg). RESULTS: A group of 56 patients were inactive carriers (IC), and 53 patients had HBeAg-negative CHB (AH). The mean values of ALT, HBV DNA and qHBsAg in IC were 29.13 U/L; 727.95 IU/ml and 2753.73 IU/ml respectively. In the AH group, the mean values of ALT, HBV DNA and quantitative HBsAg were 50.45 U/L; 7237363.98 IU/ml and 12556.06 IU/ml respectively. The serum value of ALT was more influenced by qHBsAg than HBV DNA in both IC and AH groups (R = 0.22 vs R = 0.15) (p > 0.05). CONCLUSION: patients with inactive and active HBeAg-negative CHB have similar laboratory and serology profile. It is necessary to combine analysis of ALT, HBV DNA and qHBsAg for better discrimination between patient's IC and patient with HBeAg-negative CHB.