Successful hepatitis B and C screening in the health check-up in the German primary care setting.

Background & Aims: A goal of the World Health Organization's global hepatitis strategy is the elimination of chronic hepatitis C virus (HCV) infection by 2030. As part of its strategy, the Federal Joint Committee (Germany) decided to include hepatitis B and C screening in a preventive medical examination, which is performed at the primary care level in Germany. We investigated the results 1 year after implementation of screening between October 2021 and September 2022. Methods: HBsAg/HBV DNA and anti-HCV/HCV RNA screenings were identified by billing categories in 286,192 individuals of 11 ambulatory healthcare centers. Results: Compared to 30,106 HBsAg and 31,266 anti-HCV laboratory requisitions in the year 2018, the number of tests increased to 286,192 during the screening period. Compared to routine care, additional anti-HCV positive tests age dependently increased the tally by 98% (177 plus 170 positive cases in males) and 123% (96 plus 118 positive cases in females) in those aged 35-44 years up to 518% (17 plus 88 positive cases in males) and 514% (29 plus 149 positive cases in females) in those aged 75-84 years. Similar results were observed for HBsAg. Prevalences of HBsAg, anti-HCV and HCV RNA were 0.54%, 0.79% and 0.13%, respectively. Conclusions: A structured hepatitis screening program at the primary care level has been successfully established and leads to age- and-sex-dependent large additional effects compared to routine care. Impact and implications: Strategies to eliminate chronic hepatitis B and C virus infection are country specific and vary between clinical scenarios. Our analysis proves the efficacy of a screening program by primary care physicians compared to routine care in a low-prevalence country. This program should be accompanied by additional efforts in risk populations like people who inject drugs who are under-represented in the current screening approach.

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.

Infectivity of Hepatitis B Virus Surface Antigen-Positive Plasma With Undetectable HBV-DNA: Can HBsAg Screening Be Discontinued in Egyptian Blood Donors?

Hepatitis B Virus (HBV) infectivity data were reviewed and the 50% infectious dose (ID50) was reassessed in different HBsAg-positive infection stages enabling modelling of transfusion-transmitted (TT)-HBV infection risk if HBsAg donor screening was replaced by individual donation nucleic acid amplification technology (ID-NAT). Quantitative HBsAg and HBV-DNA assays were performed against international standards to compare the ratio between potential infectious HBV virions and subviral HBsAg particles in Egyptian HBsAg-positive blood donors as well as in Japanese chimpanzee samples of known infectivity. HBV-DNA load below the quantification limit of detection was estimated against a reference standard by replicate NAT testing (n = 25). Infectivity of chimpanzee samples collected during ramp-up and declining viremic phase were tested in a human liver chimeric mice (HLCM) model and compared with published infectivity data from different HBsAg-positive infection stages. Lowest estimates of ID50 in HBsAg-positive plasma were 3-6 HBV virions in chimpanzee studies. Infectivity decreased approximately 10-100-fold in the declining viremic phase using HLCM. In acute phase samples, HBV to HBsAg particle ratios varied between 1:102-104 but in HBsAg-positive blood donors this particle ratio reached 1:106-1012 when viral load was below 100 HBV-DNA copies/mL. Modelled TT-HBV risk of an HBsAg-positive/ID-NAT nonreactive blood transfusion was estimated at 5.5%-27% for components containing 20-200 mL of plasma when assuming an ID50 of 316 (point estimate between 100 and 1000) virions. It cannot be ensured that discontinuation of HBsAg donor screening and reliance on ID-NAT alone is safe.

Interferon alpha induces a stronger antiviral effect than interferon lambda in HBV/HDV infected humanized mice.

Recent studies indicate that treatment of chronic hepatitis D virus (HDV) with either pegylated interferon (IFN)λ or pegylated IFNα monotherapy leads to a dramatic decline in HDV RNA. Herein, we investigated the innate antiviral efficacy of IFNλ and IFNα in humanized mice that lack an adaptive immune response. Humanized mice were either co-infected with hepatitis B virus (HBV) and HDV simultaneously, or HDV infection was performed subsequent to HBV infection (i.e., superinfected). After steady viral replication was achieved, mice received either IFNλ (n=6) or IFNα (n=7) for 12 (or 13) weeks. Pretreatment median levels of serum HBV DNA (8.8 [IQR:0.2] log IU/ml), HDV RNA (9.8 [0.5] log IU/ml), HBsAg (4.0 [0.4] log IU/ml) and human albumin, hAlb (6.9 [0.1] log ng/mL) were similar between mice treated with IFNα or IFNλ and between those coinfected versus superinfected. Compared to mice treated with IFNλ, mice treated with IFNα had a significantly greater decline in HBV, HDV, and HBsAg levels. In conclusion, IFNα induces stronger inhibition of HBV and HDV than IFNλ in humanized mice that lack an adaptive immune response. Further studies are needed to assess the respective role of the combined innate-and adaptive-immune systems in the treatment of HBV and HDV with IFNα and IFNλ.

Association Between Serum Levels of Anti-heat Shock Protein 27 Antibody and Liver Cell Injury in Chronic Hepatitis B.

Heat Shock Protein 27 (HSP27), an anti-HBV factor, exists in the intracellular and extracellular spaces. As an inflammatory modulator, serum HSP27 (sHSP27) is associated with elevated pro-inflammatory cytokines and a higher likelihood of hepatocellular carcinoma in chronic hepatitis. SHSP27 results in natural antibody production (anti-HSP27-Ab) that is more stable and easily detectable compared to sHSP27. We aimed to investigate any potential association between anti-HSP27-Ab level and chronic hepatitis B (CHB) progression and inflammation indicated by liver cell injury and HBV replication. This cross-sectional study was conducted on 91 patients with CHB and 92 individuals without CHB. Following demographic data collection, anti-HSP27-Ab, serum lipids including total cholesterol, triglyceride, LDL-C, HDL-C, and aminotransferase levels were measured using enzymatic assays in participants' serum samples. HBV DNA was also measured by quantitative PCR in CHB patients. Bivariate and multivariate analyses showed a significantly higher mean level of anti-HSP27-Ab in CHB than in healthy individuals (0.304 vs. 0.256AU/ml, P value = 0.015). These levels held significant differences in the CHB subgroups of male patients, at the age of 50 years and above, with non-smoking status, elevated aminotransferase levels, and hypotriglyceridemia (P value < 0.05). However, no difference was found between the antibody levels and HBV DNA copies (P value > 0.05). This study provides evidence that anti-HSP27 antibody levels can reflect the degree of liver necrosis indicated by aminotransferase levels. Regarding the higher incidence rate of HBV-associated complications in 50 to 60-year-old men, monitoring the antibody can be beneficial in managing this group of CHB patients, which deserves further investigation.

A pilot integrated model nurse clinic increases the uptake of antiviral treatment for the prevention of mother-to-child transmission of HBV.

BACKGROUND AND AIMS: Mother-to-child-transmission (MTCT) of hepatitis B virus (HBV) may still occur despite birth-dose HBV vaccinations when pregnant women are positive for hepatitis B surface antigen (HBsAg) with high viral loads (HBV DNA ≥ 200 000 IU/mL). A pilot integrated model nurse clinic (IMNC) was started in 2020 to implement the pre-emptive antiviral therapy with tenofovir disoproxil fumarate (TDF). We aimed to evaluate the performance of IMNC on uptake of TDF. METHODS: This was a territory-wide retrospective cohort of all consecutive HBsAg-positive women of child-bearing age with pregnancy records in public hospitals 2019-2022. Demographic characteristics, liver biochemistries and virologic parameters, and TDF use were collected. Concurrently, data from a prospective audit in Union Hospital, the private hospital with the highest number of deliveries in Hong Kong, from June 2022 to May 2023 were compared. RESULTS: The prevalence rate of HBV DNA ≥ 200 000 IU/mL in pregnant women with available HBV DNA records was 29.2% (66/226) in 2019, 27.3% (99/363) in 2020, 15.9% (125/784) in 2021 and 17.2% (117/679) in 2022 (p < .001), out of 2052 pregnant women who had their HBV DNA checked within 1 year prior to delivery. An increasing uptake rate of TDF by highly viraemic pregnant women (i.e. ≥ 200 000 IU/mL) was noted after the commencement of IMNC in public hospitals, with 67% (45/67) in 2019, 83% (88/106) in 2020, 91% (117/128) in 2021 and 89% (149/167) in 2022. Moreover, all highly viraemic pregnant women from Union Hospital received TDF. Continuous use of TDF was associated with a reduced risk of postpartum biochemical flare. CONCLUSIONS: IMNC increases the uptake of antiviral treatment in pregnant women at risk of MTCT of HBV. IMNC contributes to hepatitis elimination through a structured care plan to prevent MTCT of HBV.

Proportion of pregnant women with HBV infection eligible for antiviral prophylaxis to prevent vertical transmission: A systematic review and meta-analysis.

Background & Aims: In 2020, the World Health Organization (WHO) recommended peripartum antiviral prophylaxis (PAP) for pregnant women infected with hepatitis B virus (HBV) with high viremia (≥200,000 IU/ml). Hepatitis B e antigen (HBeAg) was also recommended as an alternative when HBV DNA is unavailable. To inform policymaking and guide the implementation of prevention of mother-to-child transmission strategies, we conducted a systematic review and meta-analysis to estimate the proportion of HBV-infected pregnant women eligible for PAP at global and regional levels. Methods: We searched PubMed, EMBASE, Scopus, and CENTRAL for studies involving HBV-infected pregnant women. We extracted proportions of women with high viremia (≥200,000 IU/ml), proportions of women with positive HBeAg, proportions of women cross-stratified based on HBV DNA and HBeAg, and the risk of child infection in these maternal groups. Proportions were pooled using random-effects meta-analysis. Results: Of 6,999 articles, 131 studies involving 71,712 HBV-infected pregnant women were included. The number of studies per WHO region was 66 (Western Pacific), 21 (Europe), 17 (Africa), 11 (Americas), nine (Eastern Mediterranean), and seven (South-East Asia). The overall pooled proportion of high viremia was 21.27% (95% CI 17.77-25.26%), with significant regional variation: Western Pacific (31.56%), Americas (23.06%), Southeast Asia (15.62%), Africa (12.45%), Europe (9.98%), and Eastern Mediterranean (7.81%). HBeAg positivity showed similar regional variation. After cross-stratification, the proportions of high viremia and positive HBeAg, high viremia and negative HBeAg, low viremia and positive HBeAg, and low viremia and negative HBeAg were 15.24% (95% CI 11.12-20.53%), 2.70% (95% CI 1.88-3.86%), 3.69% (95% CI 2.86-4.75%), and 75.59% (95% CI 69.15-81.05%), respectively. The corresponding risks of child infection following birth dose vaccination without immune globulin and PAP were 14.86% (95% CI 8.43-24.88%), 6.94% (95% CI 2.92-15.62%), 7.14% (95% CI 1.00-37.03%), and 0.14% (95% CI 0.02-1.00%). Conclusions: Approximately 20% of HBV-infected pregnant women are eligible for PAP. Given significant regional variations, each country should tailor strategies for HBsAg screening, risk stratification, and PAP in routine antenatal care. Impact and implications: In 2020, the WHO recommended that pregnant women who test positive for the hepatitis B surface antigen (HBsAg) undergo HBV DNA testing or HBeAg and those with high viremia (≥200,000 IU/ml) or positive HBeAg receive PAP. To effectively implement new HBV PMTCT interventions and integrate HBV screening, risk stratification, and antiviral prophylaxis into routine antenatal care services, estimating the proportion of HBV-infected pregnant women eligible for PAP is critical. In this systematic review and meta-analysis, we found that approximately one-fifth of HBV-infected pregnant women are eligible for PAP based on HBV DNA testing, and a similar proportion is eligible based on HBeAg testing. Owing to substantial regional variations in eligibility proportions and the availability and costs of different tests, it is vital for each country to optimize strategies that integrate HBV screening, risk stratification, and PAP into routine antenatal care services. Systematic review registration: This study was registered with PROSPERO (Protocol No: CRD42021266545).

Significant liver histological change is common in HBeAg-positive chronic hepatitis B with normal ALT.

BACKGROUND AND AIMS: Numerous HBeAg-positive chronic hepatitis B (CHB) patients with persistently normal ALT have significant liver histopathology. It is imperative to identify true "immune tolerant" patients. We aimed to evaluate the liver histopathology features of HBeAg-positive CHB patients with normal ALT and the incidence of liver cirrhosis and HCC in CHB patients during follow-up. METHODS: 179 HBeAg-positive CHB patients with normal ALT who performed liver biopsy from 2009 to 2018 were retrospectively analyzed. Liver necroinflammation ≥ G2 and/or liver fibrosis ≥ S2 was defined as significant liver histopathological change. RESULTS: 57.5% patients were in the indeterminate phase with significant liver histological changes. The proportion of the patients with evident liver necroinflammation was higher in the high-normal ALT group (21-40U/L) when compared with the low-normal ALT group (≤ 20 U/L) (51.3% vs. 30.0%, p < 0.05), and patients aged ≥ 40 years had a higher proportion of significant fibrosis than those aged < 40 years (64.5% vs. 39.9%, p < 0.05). The percentages of patients with ≥ S2 and ≥ G2/S2 in the HBV DNA < 107 IU/mL group were higher than those in the HBV DNA ≥ 107 IU/mL group (72.7% vs. 40.1%, p < 0.01; 81.8% vs. 54.1%, p < 0.05). During follow-up, two of immune tolerant patients and four of indeterminate patients developed into cirrhosis, and one of immune tolerant patients and one of indeterminate patients developed into HCC, respectively. CONCLUSIONS: HBeAg-positive CHB patients with high-normal ALT or HBV DNA < 107 IU/mL were tend to be indeterminate. Liver biopsy or noninvasive approaches are recommended to evaluate liver histopathology, and antiviral therapy is recommended for patients with significant liver histopathology.

Quantitative PCR-based high-sensitivity detection of HBV-DNA levels reflects liver function deterioration in patients with hepatitis B virus-related cirrhosis.

OBJECTIVES: To investigate the clinical implication of quantitative polymerase chain reaction (PCR)-based high-sensitivity detection of hepatitis B virus (HBV)-DNA levels in patients with HBV-related liver cirrhosis (LC). METHODS: From January 2020 to December 2022, 100 fasting serum samples were collected and retrospectively analyzed from patients with treated HBV-related LC attending the Suzhou Hospital of Integrated Traditional Chinese and Western Medicine and Suzhou Guangci Cancer Hospital. Patients were divided into a negative group (HBV-DNA < 20 IU/mL) and a positive group (HBV-DNA ≥ 20 IU/mL) according to their high-sensitivity HBV-DNA test results. The clinical characteristics and serological indicators of the two groups were compared, mainly including gender, age, liver function [total protein (TP), albumin (ALB), alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), total bilirubin (TBIL), direct bilirubin (DBIL), and indirect bilirubin (IBIL)], lipids [total cholesterol (TC) and triglycerides (TG)], platelets (PLT), five serum liver fibrosis markers [cholyglycine (CG), hyaluronic acid (HA), laminin (LN), precollagen type III (PCIII), and type IV collagen (IV-C)], serum gastrointestinal tumor markers [α-fetoprotein (AFP) and carcinoembryonic antigen (CEA)], and hepatitis B surface antigen (HBsAg). The differences between the two groups in terms of liver function Child-Pugh grades and the incidence of hepatocellular carcinoma (HCC) were also compared. RESULTS: There were 39 patients in the positive group, including 29 males and 10 females, and 61 patients in the negative group, including 38 males and 23 females, with no statistically significant differences in gender and age distribution between the two groups (P > 0.05). The levels of serological indicators (TP, ALB, AST, GGT, ALP, TBIL, DBIL, IBIL, TC, TG, PLT, CG, HA, LN, PCIII, IV-C, AFP, CEA, and HBsAg) in both groups showed no significant differences (P > 0.05), but the ALT level in the positive group was higher than that in the negative group (P < 0.0001). The positive group had worse Child-Pugh grades and higher HCC incidence compared to the negative group (P < 0.0001, P = 0.028). CONCLUSIONS: Patients with HBV-related LC and HBV-DNA ≥ 20 IU/mL have higher serum ALT levels, worse liver function Child-Pugh grades, and higher HCC incidence than those with HBV-DNA < 20 IU/mL. High-sensitivity HBV-DNA quantification can reflect the deterioration of liver function in patients with HBV-related LC to some extent.

Treatment with bulevirtide in HIV-infected patients with chronic hepatitis D: ANRS HD EP01 BuleDelta and compassionate cohort.

Background & Aims: In France, bulevirtide (BLV) became available in September 2019 through an early access program to treat patients with HDV. The aim of this analysis was to evaluate the efficacy and safety of BLV in patients with HIV and HDV coinfection. Methods: Patients received BLV 2 mg ± pegylated interferon-α (pegIFNα) according to the physician's decision. The primary endpoint (per-protocol analysis) was the virological response rate at Week 48, defined as the proportion of patients with undetectable serum HDV RNA or a HDV RNA decline >2 log10 IU/ml from baseline. Results: The characteristics of the 38 patients were as follows: 28 male, mean age 47.7 years, and mean baseline HDV RNA viral load 5.7 ± 1.2 log10 IU/ml. Median HIV viral load and mean CD4 count were 32 (30-65) copies/ml and 566 ± 307/mm3, respectively. Eight patients stopped treatment before Week 48. At Week 48, 10 of 19 patients (52.6%) in the 2 mg BLV group and five of seven patients (71.4%) in the 2 mg BLV + pegIFNɑ group had reached virological response (no HDV RNA available in four patients). At Week 48, seven of 19 patients in the 2 mg BLV group and three of six patients in the 2 mg BLV + pegIFNɑ group had a combined response (virological response and normal alanine aminotransferase level). Conclusions: Adults living with HIV coinfected with HDV can be treated by BLV with a virological response in more than 50% of patients. The combination of BLV and pegIFNɑ showed a strong virological response. Impact and implications: Bulevirtide is the only EMA-approved drug for HDV treatment, and we showed that it can be used in adults living with HIV, with an overall good tolerability. Bulevirtide induces a virological response in more than 50% of patients, suggesting that bulevirtide should be considered as a first-line therapy in this specific population. Bulevirtide in combination with pegIFNα could be used in patients without pegIFNα contraindication. No specific drug-drug interaction is reported. Bulevirtide is the only EMA-approved drug for HDV treatment, and we showed that it can be used in adults living with HIV, with an overall good tolerability. Bulevirtide induces a virological response in more than 50% of patients, suggesting that bulevirtide should be considered as a first-line therapy in this specific population. Bulevirtide in combination with pegIFNα could be used in patients without pegIFNα contraindication. No specific drug-drug interaction is reported. Bulevirtide is the only EMA-approved drug for HDV treatment, and we showed that it can be used in adults living with HIV, with an overall good tolerability. Bulevirtide induces a virological response in more than 50% of patients, suggesting that bulevirtide should be considered as a first-line therapy in this specific population. Bulevirtide in combination with pegIFNα could be used in patients without pegIFNα contraindication. No specific drug-drug interaction is reported.

Understanding the influence of cytokines in intrauterine hepatitis B transmission: A cross-sectional study in China.

Cytokines may related to intrauterine Hepatitis B virus (HBV) transmission. 205 HBsAg(+) pregnant cases and 74 HBsAg(-) women were included. Neonatal blood samples were taken within 24 h of delivery and before HBV vaccinations. Serological HBV biomarkers and cytokines were detected. 21.9 % of the newborns from HBsAg(+) women were intrauterinally transmitted, including 7.3 % with dominant transmission (DBT) and 14.6 % occult transmission (OBT). HBV DNA load (odd ratio [OR], 1.44; 95 % confidence interval [CI], 1.05-1.98), interferon-γ (IFN-γ) (OR, 1.01; 95 %CI, 1.00-1.02) and toll-like receptor 9 (TLR9) (OR, 1.27; 95 %CI, 1.06-1.52) positively correlated with DBT. Only IFN-γ (OR, 1.01; 95 %CI, 1.00-1.01) positively associated with OBT. According to the generated restricted cubic spline, TLR9 was positively correlates with rise of DBT in a log-shape. It may be possible to develop a nomogram which intercalates these factors to predict intrauterine HBV transmissions. Further research should consider immune processes involved in chorioamnionitis.

Lower HBV DNA level is associated with more severe liver fibrosis in HBeAg-positive chronic hepatitis B with normal alanine transaminase.

BACKGROUND: The association of hepatitis B virus (HBV) DNA levels and liver fibrosis in chronic hepatitis B (CHB) patients with immune-tolerant phase remains unclear. We explored the association between liver fibrosis and HBV DNA levels in HBeAg-positive CHB patients with normal alanine transaminase (ALT) with relatively high HBV DNA. METHODS: Six hundred and twenty-two HBeAg-positive CHB patients with normal ALT were included. Patients were divided into three categories: low (6 log10 IU/mL ≤ HBV DNA < 7 log10 IU/mL), moderate (7 log10 IU/mL ≤ HBV DNA < 8 log10 IU/mL), and high (HBV DNA ≥ 8 log10 IU/mL). APRI, FIB-4, transient elastography, or liver biopsy were used to assess liver fibrosis. RESULTS: The median age of patients was 33.0 years and 57.9% patients were male. 18.8%, 52.1%, and 29.1% of patients had low, moderate, and high HBV DNA levels, respectively. The APRI (0.33 vs. 0.26 vs. 0.26, P < 0.001), FIB-4 (1.03 vs. 0.71 vs. 0.68, P < 0.001), and LSM values (7.6 kPa vs. 5.6 kPa vs. 5.5 kPa, P = 0.086) were higher in low HBV DNA group than other two groups. Low HBV DNA group had higher proportions of significant fibrosis (24.8% vs. 9.9% vs. 3.3%, P < 0.001) and cirrhosis (7.7% vs. 2.5% vs. 1.1%, P = 0.004) than moderate and high HBV DNA groups. Moderate (OR 3.095, P = 0.023) and low (OR 4.968, P = 0.003) HBV DNA were independent risk factors of significant fibrosis. CONCLUSION: Lower HBV DNA level was associated with more severe liver fibrosis in HBeAg-positive CHB patients with ALT.

Factors influencing pathological changes in the liver tissue in hepatitis B virus carriers with low-level viremia.

OBJECTIVES: To investigate the optimal timing for initiating antiviral therapy in hepatitis B virus (HBV) carriers with low-level viremia (LLV). METHODS: We retrospectively enrolled 126 HBV carriers with LLV who underwent liver biopsy. Patients' clinical data, routine blood test results, portal vein diameter, splenic vein diameter and thickness, and measurements (LSM) within 1 week before liver biopsy were obtained. Single-factor and multifactor statistical methods were used to analyze factors that affected inflammation and fibrosis in pathological liver tissues. The receiver operating characteristic curve was used to analyze liver stiffness and HBV DNA levels to determine liver tissue inflammation and fibrosis. R -Studio software was used to draw nomograms, calibration plots, and model decision curves. RESULTS: Infection duration and HBV DNA levels affected liver tissue inflammation. Albumin(ALB), aspartate aminotransferase (AST), HBV DNA, liver stiffness, age, and splenic thickness affected liver fibrosis. The best cutoff value of the LSM for diagnosing liver inflammation and fibrosis was 7.45 (specificity, 92%). The best cutoff value of HBV DNA for diagnosing liver inflammation and fibrosis was 39.5 (specificity, 96%). HBV DNA,and splenic thickness affected the treatment decision in naive chronic hepatitis Bpatients with LLV CONCLUSIONS: HBV carriers with LLV have high incidences of liver tissue inflammation and fibrosis. The infection duration and HBV DNA levels affected liver inflammation whereas the ALB, AST levels, HBV DNA, LSM, age, and splenic thickness affected liver fibrosis. Eligible expansion of antiviral treatment indications is necessary, however, a universal treatment approach may be inefficient. HBV DNA can be a reference for initiating antiviral therapy.

Comparison of the NeuMoDx™ HBV quant assay and artus QS-RGQ® kit for HBV DNA quantitation in plasma samples.

We aimed to compare the NeuMoDx HBV Assay with the artus HBV Assay using residual plasma samples and to evaluate the discordant results. The study included 200 patient samples analyzed with the NMD assay and stored at -80 °C. Samples were analyzed by artus in 2023. Discordant results were evaluated by cobas 6800 HBV DNA Test. Excellent agreement was found between both tests. Of the 100 samples that were HBV DNA negative by NMD, 93 were negative and 7 were positive by artus. With the Cobas test, 5 samples were positive. Of the100 HBV DNA positive samples detected by NMD, 99 were positive with the artus assay. This sample was also HBV DNA negative by the Cobas test. The sensitivity and specificity of NeuMoDx were found 93 % and 99 %, respectively. There was excellent qualitative agreement and strong quantitative correlation between the NeuMoDx and artus assays for HBV DNA detection and quantitation.

Hepatitis B virus DNA and RNA persist in liver after serologic recovery in persons with hepatitis C virus.

After recovery from a hepatitis B virus (HBV) infection, reactivation can occur with immunosuppression; thus, it is assumed that replication competent HBV persists in the liver. We sought to detect persistent HBV from 13 people with spontaneous recovery. We quantified HBV DNA and RNA in core liver biopsies (median 1.72x106 cells) from people who inject drugs (PWID). Among 13 biopsies, 8 (61%) had evidence of HBV DNA or RNA and 5 (38%) had both HBV DNA and RNA. mRNAs derived from cccDNA and integrated HBV DNA. Here, we show prevalent HBV DNA and RNA despite clinical recovery in PWID.

We used a sensitive method to determine the amount of hepatitis B virus DNA or RNA in the livers of 13 individuals who recovered from hepatitis B virus infection. We found viral DNA or RNA in the liver in 61% of individuals despite no detectable virus in blood. Our findings support that eliminating all hepatitis B from the liver is a difficult treatment goal.

The Effect of Low HBV-DNA Viral Load on Recurrence in Hepatocellular Carcinoma Patients Who Underwent Primary Locoregional Treatment and the Development of a Nomogram Prediction Model.

(1) Background: HBV-DNA is an essential clinical indicator of primary hepatocellular carcinoma (HCC) prognosis. Our study aimed to investigate the prognostic implication of a low load of HBV-DNA in HCC patients who underwent local treatment. Additionally, we developed and validated a nomogram to predict the recurrence of patients with low (20-100 IU/mL) viral loads (L-VL). (2) Methods: A total of 475 HBV-HCC patients were enrolled, including 403 L-VL patients and 72 patients with very low (<20 IU/mL) viral loads (VL-VL). L-VL HCC patients were randomly divided into a training set (N = 282) and a validation set (N = 121) at a ratio of 7:3. Utilizing the Lasso-Cox regression analysis, we identified independent risk factors for constructing a nomogram. (3) Results: L-VL patients had significantly shorter RFS than VL-VL patients (38.2 m vs. 23.4 m, p = 0.024). The content of the nomogram included gender, BCLC stage, Glob, and MLR. The C-index (0.682 vs. 0.609); 1-, 3-, and 5-year AUCs (0.729, 0.784, and 0.783, vs. 0.631, 0.634, the 0.665); calibration curves; and decision curve analysis (DCA) curves of the training and validation cohorts proved the excellent predictive performance of the nomogram. There was a statistically significant difference in RFS between the low-, immediate-, and high-risk groups both in the training and validation cohorts (p < 0.001); (4) Conclusions: Patients with L-VL had a worse prognosis. The nomogram developed and validated in this study has the advantage of predicting patients with L-VL.

Inverse relationship between HBV DNA levels and liver histopathological changes in immune-tolerant CHB patients.

Limited data exist regarding the association between hepatitis B virus (HBV) DNA levels and liver histopathological changes in patients with chronic hepatitis B (CHB) during the immune tolerant (IT) phase. In this study, we retrospectively analysed liver biopsy results from 150 adult IT-CHB patients. The liver tissue necroinflammation and fibrosis were evaluated by the Scheuer scoring system. Multivariate logistic regression, smooth curve fitting, and segmented regression models were used to examine the association between HBV DNA levels and liver histopathological changes. A total of 26%, 30.67% and 42% of IT patients had significant necroinflammation (≥G2), significant fibrosis (≥S2) and significant histopathological changes (≥G2 and/or ≥S2), respectively. HBV DNA levels were independently and non-linear inversely associated with significant necroinflammation and histopathological changes in IT-CHB patients. Patients with HBV DNA levels <107 IU/mL had a higher risk of significant histopathological changes compared to those with levels >107 IU/mL. The findings were further confirmed by smooth curve fitting analyses, subgroup and sensitivity analyses. In segmented regression model analyses, the optimal DNA value for the lowest odds ratio of significant histopathological changes was 7.26 log10 IU/mL. A non-linear inverse association between HBV DNA levels and significant histopathological changes in IT-CHB patients. DNA 7.26 log10 IU/mL may serve as a potential cut-off point to define a 'true immune tolerant phase' with minimal liver histopathological changes.

The Relationship between Viral Replication and the Severity of Hepatic Necroinflammatory Damage Changed before HBeAg Loss in Patients with Chronic Hepatitis B Virus Infection.

Background and Aims: Disease progression of chronic hepatitis B virus (HBV) infection is driven by the interactions between viral replication and the host immune response against the infection. This study aimed to clarify the relationship between HBV replication and hepatic inflammation during disease progression. Methods: Two cross-sectional, one validation cohort, and meta-analyses were used to explore the relationship between HBV replication and liver inflammation. Spearman analysis, multiple linear regression, and logistic regression were used to explore the relationship between variables. Results: In the cross-sectional cohorts A and B including 1,350 chronic hepatitis B patients, Spearman analysis revealed a negative relationship between HBV replication (such as HBV DNA) and liver inflammation (such as ALT) in HBeAg-positive patients with higher HBV DNA >2×106 IU/mL (rho=-0.160 and -0.042) which turned to be positive in HBeAg-positive patients with HBV DNA ≤2×106 IU/mL (rho=0.278 and 0.260) and HBeAg-negative patients (rho=0.450 and 0.363). After adjustment for sex, age, and anti-HBe, results from logistic regression and multiple linear regression showed the opposite relationship still existed in HBeAg-positive patients with different DNA levels; the opposite relationship in HBeAg-positive patients with different DNA levels was validated in a third cohort; the opposite relationship in patients with different HBeAg status was partially confirmed by meta-analysis (overall R: -0.004 vs 0.481). Conclusions: These results suggested a negative relationship between viral replication and liver inflammation in HBeAg-positive patients with high HBV DNA, which changed to a positive relationship for those HBeAg-positive patients with DNA less than 2×106 IU/mL and HBeAg-negative patients.

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

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

HBV DNA polymerase upregulates the transcription of PD-L1 and suppresses T cell activity in hepatocellular carcinoma.

BACKGROUND: In HBV-associated HCC, T cells often exhibit a state of functional exhaustion, which prevents the immune response from rejecting the tumor and allows HCC to progress. Moreover, polymerase-specific T cells exhibit more severe T-cell exhaustion compared to core-specific T cells. However, whether HBV DNA polymerase drives HBV-specific CD8+ T cell exhaustion in HBV-related HCC remains unclear. METHODS: We constructed a Huh7 cell line stably expressing HA-HBV-DNA-Pol and applied co-culture systems to clarify its effect on immune cell function. We also examined how HBV-DNA-Pol modulated PD-L1 expression in HCC cells. In addition, HBV-DNA-Pol transgenic mice were used to elucidate the underlying mechanism of HBV-DNA-Pol/PD-L1 axis-induced T cell exhaustion. RESULTS: Biochemical analysis showed that Huh7 cells overexpressing HBV-DNA-Pol inhibited the proliferation, activation, and cytokine secretion of Jurkat cells and that this effect was dependent on their direct contact. A similar inhibitory effect was observed in an HCC mouse model. PD-L1 was brought to our attention during screening. Our results showed that the overexpression of HBV-DNA-Pol upregulated PD-L1 mRNA and protein expression. PD-L1 antibody blockade reversed the inhibitory effect of Huh7 cells overexpressing HBV-DNA-Pol on Jurkat cells. Mechanistically, HBV-DNA-Pol interacts with PARP1, thereby inhibiting the nuclear translocation of PARP1 and further upregulating PD-L1 expression. CONCLUSIONS: Our findings suggest that HBV-DNA-Pol can act as a regulator of PD-L1 in HCC, thereby directing anti-cancer immune evasion, which further provides a new idea for the clinical treatment of liver cancer.