Serum Hepatitis B Virus DNA Levels Research Articles

Hepatitis B Virus Increases SphK1-S1P Synthesis by Promoting the Availability of the Transcription Factor USF1.

Hepatitis B virus (HBV) is the most common chronic viral infection globally, affecting ∼360 million people and causing about 1 million deaths annually due to end-stage liver disease or hepatocellular carcinoma. Current antiviral treatments rarely achieve a functional cure for chronic hepatitis B, highlighting the need for improved monitoring and intervention strategies. This study explores the role of the sphingosine kinase 1 (SphK1)-sphingosine-1-phosphate (S1P) axis in HBV-related liver injury. We investigated the association between serum S1P concentration and HBV DNA levels in chronic hepatitis B patients, finding a significant positive correlation. Additionally, SphK1 was elevated in liver tissues of HBV-positive hepatocellular carcinoma patients, particularly in HBsAg-positive regions. HBV infection models in HepG2-sodium taurocholate cotransporting polypeptide cells confirmed that HBV enhances SphK1 expression and S1P production. Inhibition of HBV replication through antiviral agents and the CRISPR-Cas9 system reduced SphK1 and S1P levels. Further, we identified the transcription factor USF1 as a key regulator of SphK1 expression during HBV infection. USF1 binds to the SphK1 promoter, increasing its transcriptional activity, and is upregulated in response to HBV infection. In vivo studies in mice demonstrated that HBV exposure promotes the expression of USF1 and SphK1-S1P. These findings suggest that the SphK1-S1P axis, regulated by HBV-induced USF1, could serve as a potential biomarker and therapeutic target for HBV-related liver injury.

Elevated Hepatitis B virus RNA levels in hepatocellular carcinoma patients compared to cirrhotic individuals: A propensity score matched analysis.

To delineate the levels of serum Hepatitis B virus (HBV) RNA in patients with HBV-related hepatocellular carcinoma (HCC) and study comparisons with those of individuals afflicted with cirrhosis. Adult patients diagnosed with HBV-related cirrhosis or HCC (initial diagnosis) were enrolled in the cross-sectional study. Serum HBV DNA level was quantified through a real-time polymerase chain reaction assay with a lower limit of quantification (LLQ) of 20 IU/ml. Additionally, serum HBV RNA was quantified employing RNA real-time fluorescence thermostatic amplification detection technology with LLQ of 100 copies/ml. Propensity score matching (PSM) was conducted to ensure balance in between-group confounders. A total of 187 patients (47 with HCC and 140 with cirrhosis) were recruited, among whom 140 (74.9%) had undergone antiviral therapy prior to their inclusion, with varying durations. Serum HBV RNA was detectable in 89.4% of HCC patients at the time of carcinoma diagnosis. After PSM, individuals with HCC exhibited significantly elevated levels of serum HBV DNA and HBV RNA compared to those with cirrhosis (median lgHBV RNA 3.1 vs 2.0 copies/ml, P = 0.001). Subgroup analysis, including 38 patients who exhibited ultrasensitive HBV DNA negativity, revealed similar results (median lgHBV RNA 3.0 vs 0.0 copies/ml, P < 0.001). Serum HBV RNA levels were significantly higher in HBV-related HCC patients compared to cirrhotic patients. The presence of serum HBV RNA positivity or elevated levels was associated with the onset of HCC.

An Experimental Animal Study: Electroacupuncture Facilitates Antiviral Immunity Against Hepatitis B Virus Through the IFN-γ/JAK/STAT Axis.

Chronic hepatitis B (CHB) remains a global health challenge, necessitating innovative therapeutic strategies. Enhancing the body's immune response against the hepatitis B virus (HBV) emerges as a fundamental strategy for achieving a functional cure. While acupuncture has shown potential in immune modulation, its specific anti-HBV effects are not well understood. This study evaluates the potential of electroacupuncture (EA) in HBV infection and explores its underlying immunological mechanisms using a mouse model. HBV-infected mice were established using the high-pressure hydrodynamic method and divided into four groups: normal saline (NS), EA, sham EA (SE), and tenofovir disoproxil fumarate (TF), with n = 6 per group. During treatment, blood was collected every Sunday via the orbital sinus to monitor HBV DNA, HBsAg, and HBeAg levels. Transcriptomics and metabolomics analyses were employed to unearth clues regarding EA's anti-HBV mechanism. Validation of these mechanisms included splenic T-cell flow analysis, Western blotting, RT-qPCR, immunofluorescence, and ELISA. Serum HBV DNA levels decreased by 1.10, 0.19, and 1.98 log10 IU/mL in the EA, SE, and TF-treated mice, respectively, compared to the NS. Concurrently, the hepatic HBV DNA levels decreased by 1.09, 0.24, and 2.03 log10 IU/mL. EA also demonstrated superior inhibition of HBV antigens, with serum HBeAg levels decreasing by 43.86%, 8.74%, and 8.03%, and serum HBsAg levels decreasing by 28.01%, 0.26%, and 9.39% in the EA, SE, and TF groups, respectively. Further analysis through transcriptomics and metabolomics revealed that EA's anti-HBV effects primarily hinge on immune modulation, particularly the IFN-γ/JAK/STAT pathway and taurine metabolism. EA also increased the ratio of splenic CD8+ CD69+ and CD8+ IFN-γ+ T-cells while upregulating key proteins in the JAK/STAT pathway and cytokines associated with antiviral immunity. EA manifests inhibitory effects on HBV, particularly in antigen suppression, with its mode of action intricately linked to the regulation of IFN-γ/JAK/STAT.

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.

Clinical and virological characteristics of coexistent hepatitis B surface antigen and antibody in treatment-naive children with chronic hepatitis B virus infection.

Serological pattern of simultaneous positivity for hepatitis B surface antigen (HBsAg) and antibody against HBsAg (anti-HBs) is considered a specific and atypical phenomenon among patients with chronic hepatitis B virus (HBV) infection, especially in pediatric patients. Unfortunately, there is limited understanding of the clinical and virological characteristics among children having chronic HBV infection and the coexistence of HBsAg and anti-HBs. Hence, our objective was to determine the prevalence of coexistent HBsAg and anti-HBs and to explore the associated clinical and virological features in this patient population. The researchers conducted a retrospective cohort study on the 413 pediatric patients with chronic HBV infection from December 2011 to June 2022. The patients were stratified into two groups based on their anti-HBs status. Demographic, serum biochemical and virological parameters of two group were compared. Of the total 413 enrolled subjects, 94 (22.8%) were tested positive for both HBsAg and anti-HBs. Patients with anti-HBs were younger and demonstrated significantly higher ratio of albumin to globulin (A/G), elevated serum levels of alanine transaminase (ALT), lower ratio of aspartate transaminase (AST)/ALT (AST/ALT) and reduced serum levels of globulin, HBsAg and HBV DNA, Additionally, these patients were more likely to show coexistent HBeAg and anti-HBe when compared to patients without anti-HBs. The results of multivariate logistical analysis revealed that AST/ALT, serum levels of globulin and HBsAg were negatively associated with coexistence of HBsAg and anti-HBs. Our data demonstrated a considerable prevalence of coexisting HBsAg and anti-HBs in pediatric patients. Children with this specific serological pattern were commonly of a younger age, seemly predisposing them to early liver impairment and lower HBV replication activity.

Long-term antiviral therapy is associated with changes in the profile of transcriptionally active HBV integration in the livers of patients with CHB.

Hepatitis B virus (HBV) integration exists throughout the clinical course of chronic hepatitis B (CHB). This study investigated the effects of long-term antiviral therapy on the level and profiles of transcriptionally active HBV integration. Serial liver biopsies and paired blood samples were obtained from 16, 16, and 22 patients with CHB at baseline, 78, and 260 weeks of entecavir monotherapy or combined with pegylated interferon alfa, respectively. Serum HBV biomarkers were longitudinally assessed. RNA-seq and HIVID2 program was used to identify HBV-host chimeric RNAs transcribed from integrated DNA. The counts of HBV integration reads were positively related to both serum HBV DNA levels (r = 0.695, p = 0.004) and HBeAg titers (r = 0.724, p = 0.021) at baseline, but the positive correlation exited only to the serum HBsAg levels after 260 weeks of antiviral therapy (r = 0.662, p = 0.001). After 78 weeks of antiviral therapy, the levels of HBV integration expression decreased by 12.25 folds from baseline. The viral junction points were enriched at the S and HBx genes after the long-term antiviral therapy. HBs-FN1 became one of the main transcripts, with the mean proportion of HBs-FN1 in all integrated expression increased from 2.79% at baseline to 10.54% at Week 260 of antiviral treatment. Antiviral therapy may reduce but not eliminate the HBV integration events and integration expression. Certain integration events, such as HBs-FN1 can persist in long-term antiviral treatment.

Treatment decisions based on HBV DNA.

The most common cause of hepatocellular carcinoma (HCC) worldwide is chronic hepatitis B virus (HBV) infection (CHB). Long-term suppression of HBV replication by antiviral treatment reduces the risk of HCC and mortality. Nonetheless, only 2.2% of CHB patients globally received the treatment in 2019. Current international CHB guidelines recommend antiviral treatment only in subsets of patients with clear evidence of liver damage as evidenced by elevation of alanine aminotransferase (ALT). This review aims to provide existing evidence that the risk of HCC is significantly associated with serum levels of HBV DNA, and the association is non-linear parabolic, in both untreated and treated CHB patients, regardless of HBeAg status or ALT levels. Therefore, the decision for the antiviral treatment should be based on serum HBV DNA levels and age, rather than ALT levels or liver biopsy, to reduce or prevent the risk of HCC in CHB patients. The potential impact and cost-effectiveness data on early antiviral treatment initiation were also collated.

#2336 Hepatitis-B virus related membranous nephropathy presenting as nephrotic syndrome treated with tenofovir

Abstract Background The prevalence of Hepatitis B virus (HBV) related nephropathy particularly membranous nephropathy follows geographic HBV prevalence patterns. Hepatitis B virus infection occurs throughout the world and is endemic in developing countries such as Africa, Eastern Europe, the Middle East, Central Asia, China, Southeast Asia, the Pacific islands and the Amazon basin of South America. Vertical transmission from mother to child often predominates in endemic areas. Membranous glomerulonephritis is the most common histological renal lesion associated with hepatitis B virus infection. Treatment options for renal patients with chronic HBV infection are complex, being dictated by the overall clinical picture and best conducted by multidisciplinary approach and thorough renal monitoring. Therapeutic guidelines are very limited, mostly case series are available in this setting. Anti-viral treatment is indicated in hepatitis B surface antigen (HBsAg)-positive patients with evidence of active liver disease based on aminotransferases and serum HBV DNA levels of 2000-20 000 IU/ml have been proposed as the threshold to start treatment Aim To present a case of young healthy male with chronic HBV infection with nephrotic syndrome and Membranous Nephropathy who developed reactivation after discontinuation of Tenofovir. Case A 32-year old man presented with generalized edema 5 months ago associated with dipstick proteinuria. The swelling has progressed and now associated with walking difficulty thus sought consult and was then admitted. His mother had been hypertensive for more than a decade and work up revealed that she is positive for anti-HBS and negative for HBsAg. His father is negative for HBsAg. His childhood and past medical history is unremarkable. He is a non-smoker, non alcoholic and no history of illicit drug use. He is monogamous and not promiscuous. He has 6 siblings and two of his brothers are hypertensives and found to have chronic Hepatitis B infection. His complement levels were low, ANA and ASO titers were negative. His creatinine was 1.06 mg/dl, BUN- 11.77 mg/dl, SGPT-161 U/L (NV: &amp;lt; 42 U/L), albumin- 1.50 g/dl (NV: 3.5-5.0 g/dl). Total cholesterol- 443.30 mg/dl, Triglycerides 330.46 mg/dl. Urine PCR-4,369 mg/g. Hepatitis profile revealed reactive for HBsAg and HBeAg. His HBV viral load was 170 000 000 IU/ml (989 400 000 copies/ml). His HIV screening was negative. A kidney biopsy was performed which revealed Membranous Glomerulonephritis. He was given Tenofovir 300 mg daily for 6 months. His repeat HBV viral load was &amp;lt; 20 IU/ml (&amp;lt; 116 copies/ml) and his 24 h urinary protein was 1,891 mg/24H. His albumin was 4.57 g/dl and his creatinine remained stable at 0.96 mg/dl while his SGPT went back to normal at 40 U/L. A repeat HBeAg revealed 0.55 which could be a possible seroconversion. Tenofovir was discontinued for 6 months however patient came back with persistent proteinuria associated with high HBV DNA titer. A repeat 24H-urine protein showed 1,182 mg/24H. Tenofovir was resumed and Enalapril was continued. Follow up check up 3 months after revealed urine PCR was 850 mg/g and his kidney function remained stable. He is advised to continue Tenofovir with frequent follow up until he becomes HBsAg-negative. Recommendation We recommend that antiviral treatment in this subset of population requires prolong treatment until persistent seroconversion of HBeAg and persistent undetectable HBV DNA level or have lost HBsAg even if the patient does not develop hepatitis B surface antibody. This recommendation of prolong treatment are still developing and requires further investigation.

Juveniles, young adults, and infants with hepatitis B virus infection: A genomic study.

Integration of hepatitis B virus (HBV) DNA into the human genome is recognized as an oncogenic factor and a barrier to hepatitis B cure. In the study, biopsy liver tissues were collected from adolescents and young adults with acute HBV infection younger than or equal to 35 years of age and from HBV-infected infant patients younger than or equal to 6 months of age. A high-throughput sequencing method was used to detect HBV DNA integration. Totally, 12 adolescents, young adults, and 6 infants were included. Among the 12 patients with acute HBV infection, immunohistochemical staining of intrahepatic hepatitis B surface antigen for all displayed negative results, and no HBV DNA integrants in the hepatocyte DNA were confirmed. All infant patients had elevated levels of alanine aminotransferase and high levels of serum HBV DNA. Numerous gene sites of hepatocyte DNA were integrated by HBV DNA for each infant patient, ranging from 120 to 430 integration sites. The fragile histidine triad gene was the high-frequency integrated site in the intragenic region for infant patients. In conclusion, hepatocyte DNA is integrated by HBV DNA in babies with active hepatitis B but seems seldom affected among adolescents and young adults with acute HBV infection. Infantile hepatitis B should be taken seriously considering abundant HBV DNA integration events.

Short-Term Efficacy of Tenofovir Alafenamide in Acute-On-Chronic Liver Failure: A Single Center Experience.

Patients with acute-on-chronic liver failure (ACLF) who take entecavir (ETV) and tenofovir disoproxil fumarate (TDF) experience a reduction in hepatic events and mortality. The effectiveness of tenofovir alafenamide (TAF) was not well investigated. This study was aim to compare the antiviral efficacy and mortality between TAF and ETV in patients with ACLF caused by the hepatitis B virus (HBV). One hundred and six patients with HBV-ACLF who received TAF (25 mg/day) and ETV (0.5 mg/day) for 12 weeks were analyzed. The primary endpoints were overall mortality and liver transplantation (LT) at week 12. Biochemical responses, virologic responses, mortality, drug safety, and side effects were evaluated. At 4 and 12 weeks of TAF treatment, patients showed significantly higher HBV-DNA reduction (P < .001), higher HBV-DNA undetectability rates (P < .001), and lower HBV DNA levels (P < .001) in serum. Lower Child-Turcotte-Pugh (CTP) scores (P = .003) were observed at 4 weeks in the TAF group, although the CTP scores showed no difference between TAF group and ETV group at 12 weeks (P = 1.143). Lower alanine aminotransferase (ALT) levels of patients in the TAF group at week 4 and 12 were observed (P = .023 and P < .0001, separately). The mortality of TAF group was lower after 4 weeks of treatment (P = .038); however, the 2 groups had similar mortality rates at week 8 and 12. Among the causes of death in HBV-ACLF patients, we found the same incidence of liver-related problems in both groups (P > .05). This study showed that ACLF patients with chronic HBV infection treated with TAF had a rapid decline in HBV DNA, a higher rate of ALT reduction and improved CTP scores compared to the ETV group, thereby improving patient survival.

The performance of hepatitis B surface antigen quantification as a noninvasive biomarker predicting liver injury and serum hepatitis B virus DNA level.

Chronic hepatitis B (CHB) is still a major public health problem worldwide. Recently, evidence indicating that serum hepatitis B surface antigen (HBsAg) quantification can be used for monitorization of hepatitis B virus (HBV) infection has been increased. In this study, we evaluated HBsAg levels during the natural course of CHB and identified correlations between HBsAg, HBV DNA levels and liver histopathology. From 6 August 2016 to 7 June 2017, naive patients, who are ≥18 years old, fulfilled the criteria for the diagnosis of CHB and had a liver biopsy within a year before or after admission, were included. HBsAg levels in serum samples were investigated by electrochemiluminescence immunoassay. Results were correlated with serum HBV DNA levels, histologic activity index (HAI) and fibrosis scores. In this study 66 patients were included. There was a moderate and significant correlation between HBsAg levels and fibrosis scores (r = 0.386, P = 0.001), but no correlation with HAI. Serum HBsAg levels showed a positive, strong and significant (r = 0.740, P < 0.001) correlation with HBV DNA levels. In hepatitis B e antigen-negative patients, serum HBsAg levels were perfectly correlated with HBV DNA levels (r = 0.992, P < 0.001) and moderately correlated with fibrosis scores (r = 0.360, P = 0.006). We found a positive correlation between serum HBsAg levels and the severity of fibrosis scores and serum HBV DNA levels. These findings suggest that serum HBsAg quantification might be a useful noninvasive diagnostic test for the prediction of fibrosis severity and HBV DNA level.

Hepatitis B Virus DNA-Level Change is Associated With Tumor Recurrence in Patients With Resected Hepatitis B Virus Hepatocellular Carcinoma

IntroductionTo investigate the significance of perioperative hepatitis B virus (HBV) DNA changes for predicting recurrence in patients with HBV-related hepatocellular carcinoma (HCC) undergoing liver resection (LR). MethodsFrom 2013 to 2020, 241 patients with HBV-related HCC who underwent LR in five Hallym university-affiliated hospitals were enrolled. The serum HBV DNA level, together with other clinicopathological variables, was analyzed for association with HCC recurrence. ResultsPreoperatively, 99 patients had undetectable HBV DNA and 142 had detectable viral levels. Of those with detectable viral levels, 72 rapidly progressed to undetectable levels within 3 mo after LR (Rapid group), and 70 showed persistently detectable levels (Nonrapid group). The Rapid group had a better recurrence-free survival (RFS) rate than the Nonrapid group (1-y, 3-y RFS = 75.4%, 57.3%, versus 54.7%, 39.9%, respectively, P = 0.012). In the subgroup analysis, the Rapid group had a better RFS rate in early stages (1-y, 3-y RFS = 82.6%, 68.5%, versus 62.8%, 45.8%, respectively, P = 0.005); however, the RFS rates between the two groups were comparable in the advanced stage (1-y, 3-y RFS = 61.1%, 16.7% versus 45.5%, 22.7%, respectively, P = 0.994). Among the 142 patients with preoperatively detectable HBV DNA, persistently detectable HBV DNA within 3 mo postoperatively (hazard ratio [HR] = 1.7, P = 0.022), large tumor size (HR = 2.7, P < 0.001), multiple tumors (HR = 3.2, P < 0.001), and microvascular invasion (HR = 1.7, P = 0.028) were independent risk factors for RFS in multivariate analysis. ConclusionsRapidly undetectable HBV DNA after LR is associated with a better prognosis for recurrence in patients with HCC. Therefore, appropriate treatment and/or screening may be necessary for patients who do not return to undetectable HBV DNA after LR.

Two genetic variants in the SRD5A2 gene are found to be associated with sex differences in the disease characteristics of patients with chronic hepatitis B virus infection

BackgroundTo examine the expression characteristics of single nucleotide polymorphisms (SNPs) in the SRD5A2 gene and investigate their potential association with differences in the clinical characteristics between sexes in patients with chronic hepatitis B virus (HBV) infection.MethodsA total of 30 loci in six genes primarily involved in the metabolism and signaling of sex hormones/sex hormone receptors, namely AKR1C2, AKR1C3, HSD17B6, SRD5A1, SRD5A2, and ESR1, were genotyped in 1007 patients from eight counties (cities) in Northeastern China with chronic HBV infection and 1040 healthy controls, and their association with viral replication characteristics and the differences in disease severity between sexes was assessed. Western blotting was conducted to determine the hepatic SRD5A2 protein level and its relationship with the inflammatory activity and fibrosis degree in male and female patients.ResultsTwo SNP loci in the SRD5A2 gene (rs12470143 and rs7594951) exhibited significant differences in genotype and allele frequencies between sexes, with the proportion of T alleles significantly higher in males than in females. It was found that the incidence and severity of HBV-related liver fibrosis were significantly higher in patients with the T/T genotype in SRD5A2 rs12470143 and rs7594951 than those with the non-T/T genotype. Additionally, serum HBV DNA levels were significantly elevated in T/T patients compared to non-T/T patients. Female patients exhibited significantly lower serum DNA levels compared to male patients. Western blot analysis indicated that greater hepatic SRD5A2 protein levels were associated with higher METAVIR inflammation and fibrosis scores. Furthermore, multivariate analysis showed that the two genetic variants in the SRD5A2 gene (rs12470143 C > T, r7594951 C > T), together with the male sex, age > 50 years old, HBeAg positive status, elevated serum HBsAg load, high serum HBV DNA load, and HBV genotype C, were independent risk factors for HBV-related liver fibrosis.ConclusionsThis study demonstrated that two genetic variants in the SRD5A2 gene (rs12470143 C > T, r7594951 C > T) are associated with sex differences in the clinical characteristics of patients with chronic HBV infection.

HBV DNA and HBsAg Levels at 24 Weeks Off-Treatment Predict Clinical Relapse and HBsAg Loss in HBeAg-Negative Patients Who Discontinued Antiviral Therapy

Patients who discontinue nucleo(s)tide analogue therapy are at risk of viral rebound and severe hepatitis flares, necessitating intensive off-treatment follow-up. We studied the association between hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) DNA levels at off-treatment follow-up week 24 (FU W24), with subsequent clinical relapse, and HBsAg loss in a multicenter cohort of hepatitis B e antigen (HBeAg)-negative patients with chronic hepatitis B who discontinued nucleo(s)tide analogue therapy. We studied 475 patients, 82% Asian, and 55% treated with entecavir. Patients with higher HBV DNA levels at FU W24 had a higher risk of clinical relapse (hazard ratio [HR], 1.576; P < .001) and a lower chance of HBsAg loss (HR, 0.454; P < .001). Similarly, patients with higher HBsAg levels at FU W24 had a higher risk of clinical relapse (HR, 1.579; P < .001) and a lower chance of HBsAg loss (HR, 0.263; P < .001). A combination of both HBsAg <100 IU/mL and HBV DNA <100 IU/mL at FU W24 identified patients with excellent outcomes (9.9% clinical relapse and 58% HBsAg loss at 216 weeks of follow-up). Conversely, relapse rates were high and HBsAg loss rates negligible among patients with both HBsAg>100 IU/mL and HBV DNA >100 IU/mL (P < .001). Among HBeAg-negative patients with chronic hepatitis B who discontinued antiviral therapy and who did not experience clinical relapse before FU W24, serum levels of HBV DNA and HBsAg at FU W24 can be used to predict subsequent clinical relapse and HBsAg clearance. A combination of HBsAg <100 IU/mL with HBV DNA <100 IU/mL identifies patients with a low risk of relapse and excellent chances of HBsAg loss and could potentially be used as an early surrogate end point for studies aiming at finite therapy in HBV.

Liver histological reversibility of lamivudine in treatment-naïve children with chronic hepatitis B: a retrospective cohort study from a single center Shanghai China.

Low viral load of hepatitis B virus (HBV) infection may also result in serious liver complications. Whether long-term suppression of HBV replication has beneficial effects on the reversibility of the liver histology associated with chronic hepatitis B (CHB) in children is unclear. This study assessed the histological response of lamivudine (LAM) in CHB children. Treatment-naïve CHB patients who 1≤ aged <18 years, indicating the immune-active phase, and receiving LAM were enrolled. Demographics, biochemical value, virology and histology, and safety were retrospectively analysed. Patients visit the hospital at baseline, every 12 weeks during treatment, and every 24 or 48 weeks after treatment withdrawal. Histological inflammatory improvement was defined as a ≥1-point decrease in the inflammatory score. Fibrosis regression was defined as a decrease of ≥1 point or no worsening of the fibrosis score. Total 35 children enrolled, 13 of them were lost, and 22 patients remained in the study up to 10 years after treatment. Liver biopsy results both at baseline and before treatment withdrawal were available for 14 of the 22 patients. Of the 14 children, 78.6% were male and 78.6% were HBeAg-positive. At baseline, the mean age was 7.3±5.2 years. The serum HBV DNA level of 13 subjects was 7.3±1.3 log10 IU/m. and alanine aminotransferase (ALT) was 142±102 U/L. The mean inflammation score was 2.9±0.7. The mean fibrosis score was 3.7±0.8. The mean duration was 96.0±23.6 weeks (median 96 weeks). All patients (100%) had a normal ALT after a median 12-week treatment; after 24-week, HBV DNA were <1,000 IU/mL in 92.9%. At a median of 30-week, 100% of the HBeAg-positive patients showed HBeAg seroconversion; 7.1% exhibited HBsAg seroconversion after 24-week treatment. After a mean of 96-week, the 14 patients (100%) exhibited a mean 2.2-point inflammatory improvement from baseline (P<0.001), and 92.9% exhibited a mean 2.1-point fibrosis reduction (P<0.001). No virological breakthroughs or serious adverse events occurred. This study showed that 96-week mean duration of LAM may reverse advanced inflammation and fibrosis/cirrhosis in young CHB children.

Association of vitamin D and polymorphisms of its receptor with antiviral therapy in pregnant women with hepatitis B.

The interruption of mother-to-child transmission (MTCT) is considered important to decrease the individual and population morbidity of hepatitis B virus (HBV) infection as well as the global burden of hepatitis B. Serum vitamin D (VD) is associated with hepatitis B. To assess whether baseline VD levels and single nucleotide polymorphisms of the VD receptor gene (VDR SNPs) are associated with the efficacy of tenofovir disoproxil fumarate (TDF) in the prevention of MTCT in pregnant women with high HBV viral loads. Thirty-eight pregnant women who were at high risk for MTCT of HBV (those with an HBV DNA level ≥ 2 × 105 IU/mL during 12-24 wk of gestation) receiving antiviral therapy of TDF between June 1, 2019 and June 30, 2021 in Mianyang were included in this retrospective study. The women received 300 mg TDF once daily from gestational weeks 24-28 until 3 mo after delivery. To further characterize the clinical relevance of maternal serum HBV DNA levels, we stratified patients according to HBV DNA level as follows: Those with levels < 2 × 105 (full responder group) vs those levels ≥ 2 × 105 IU/mL (partial responder group) at delivery. Serum levels of 25-hydroxyvitamin D [25(OH)D], liver function markers, virological parameters, VDR SNPs and other clinical parameters were collected to analyze their association with the efficacy of TDF. The Mann-Whitney U test or t test was used to analyze the serum levels of 25(OH)D in different groups. Multiple linear regressions were utilized to analyze the determinants of the maternal HBV DNA level at delivery. Univariate and multivariate logistic regression analyses were employed to explore the association of targeted antiviral effects with various characteristics at baseline and delivery. A total of 38 pregnant women in Mianyang City at high risk for MTCT of HBV were enrolled in the study. The MTCT rate was 0%. No mother achieved hepatitis B e antigen or hepatitis B surface antigen (HBsAg) clearance at delivery. Twenty-three (60.5%) participants were full responders, and 15 (39.5%) participants were partial responders according to antiviral efficacy. The present study showed that a high percentage (76.3%) of pregnant women with high HBV viral loads had deficient (< 20 ng/mL) or insufficient (≥ 20 but < 31 ng/mL) VD levels. Serum 25(OH)D levels in partial responders appeared to be significantly lower than those in full responders both at baseline (25.44 ± 9.42 vs 17.66 ± 5.34 ng/mL, P = 0.006) and delivery (26.76 ± 8.59 vs 21.24 ± 6.88 ng/mL, P = 0.044). Serum 25(OH)D levels were negatively correlated with maternal HBV DNA levels [log(10) IU/mL] at delivery after TDF therapy (r = -0.345, P = 0.034). In a multiple linear regression analysis, maternal HBV DNA levels were associated with baseline maternal serum 25(OH)D levels (P < 0.0001, β = -0.446), BMI (P = 0.03, β = -0.245), baseline maternal log10 HBsAg levels (P = 0.05, β = 0.285) and cholesterol levels at delivery (P = 0.015, β = 0.341). Multivariate logistic regression analysis showed that baseline serum 25(OH)D levels (OR = 1.23, 95%CI: 1.04-1.44), maternal VDR Cdx2 TT (OR = 0.09, 95%CI: 0.01-0.88) and cholesterol levels at delivery (OR = 0.39, 95%CI: 0.17-0.87) were associated with targeted antiviral effects (maternal HBV DNA levels < 2 × 105 at delivery). Maternal VD levels and VDR SNPs may be associated with the efficacy of antiviral therapy in pregnant women with high HBV viral loads. Future studies to evaluate the therapeutic value of VD and its analogs in reducing the MTCT of HBV may be justified.

Discovery, optimization and biological evaluation of novel HBsAg production inhibitors

Hepatitis B virus (HBV) infection is a major global health problem. HBsAg inhibitors are expected to reduce the production of HBsAg via inhibiting host proteins PAPD5 & PAPD7 and finally achieve the ideal goal of “functional cure”. In this work, a series of tetrahydropyridine (THP) derivatives with a bridged ring were synthesized and evaluated for their inhibiting HBsAg production and HBV DNA activity. Among them, compound 17i was identified as potent HBsAg production inhibitor with excellent in vitro anti-HBV potency (HBV DNA EC50 = 0.018 μM, HBsAg EC50 = 0.044 μM) and low toxicity (CC50 > 100 μM). Moreover, 17i exhibited favorable in vitro/in vivo DMPK properties in mice. 17i could also significantly reduce serum HBsAg and HBV DNA levels (1.08 and 1.04 log units, respectively) in HBV transgenic mice.

Does hepatic steatosis impact chronic hepatitis B?

Does hepatic steatosis impact chronic hepatitis B?

Functional Cure of Chronic Hepatitis B with Antiviral Treatment in Children having High-level Viremia and Normal or Mildly Elevated Serum Aminotransferase.

There is a lack of data supporting the notion that antiviral treatments can benefit children with chronic hepatitis B (CHB) having high viremia and normal or mildly elevated serum alanine aminotransferase (ALT) levels. We aimed to analyze the efficacy of antiviral treatments in children with CHB and explore the factors associated with functional cure. Forty-eight children with CHB having high viremia and normal or mildly elevated serum ALT levels were screened in this real-world study. Thirty-two children received either interferon-alpha (IFN-α) monotherapy, IFN-α therapy with a nucleoside analog (NA) add-on, or IFN-α and NA combination therapy. The 16 children in the control group did not receive antiviral treatment. All 48 children were available for follow-up assessments for the entire 36-month study period. We identified a functional cure with respect to hepatitis B virus (HBV) DNA loss, loss /seroconversion of circulating hepatitis B e antigen (HBeAg), and loss of hepatitis B surface antigen (HBsAg) with or without seroconversion. Cox regression analysis was employed to evaluate the factors that may have influenced the functional cure. After 36 months, the cumulative functional cure rate was 56.25% (18/32) in the treated group and 0% (0/16) in the control group (p<0.001). In the treated group, the serum HBV DNA levels declined rapidly at the end of a 6-month visit and the cured children achieved a loss rate of 100% (18/18) within 16 months of beginning treatment, compared with 64.29% (9/14) of the uncured children (p<0.001). The rates of HBeAg seroconversion were significantly higher among the cured children than among the uncured children (p<0.001). All 16 children in the control group maintained high levels of serum HBV DNA and were positive for both serum HBeAg and HBsAg during the entire 36 months of the study period. Functional cure was associated with younger ages (1-6 vs. 7-14 years, p=0.013), CD8+ T lymphocyte counts (p=0.013), and B lymphocyte counts (p=0.003). No serious adverse events were observed. Antiviral treatment achieved a functional cure of CHB in a high proportion of children having high-level viremia and normal or mildly elevated ALT levels. Younger age and high peripheral lymphocyte counts were associated with this functional cure.

Lack of geographical and ethnic distribution of Hepatitis B virus genotypes in Hainan Island, China.

Recent studies showed that the distribution of hepatitis B virus (HBV) genotype exhibited geographical and ethnic characteristics. Haikou city is the largest city on Hainan Island that geographically isolated from mainland of China, and is the home of multiple ethnic groups. The aim of the study was to investigate the characteristics of the HBV genotype/subgenotype distribution in Haikou city. HBV DNA was isolated from180 serum samples derived from the Han and Li groups. The HBV genotype was detected by polymerase chain reaction using genotype-specific primers and was further determined by full-length genome sequences. The results revealed that the genotype B (37.2%) and C (62.8%) were the predominant HBV genotypes in Haikou, regardless of ethnic background., Additionally, the genotype distribution was not significantly different regarding ethnicity, sex or level of serum HBV DNA. Moreover, there were multiple subgenotypes circulating in the region. In conclusion, our study revealed the diverse HBV genotypes/subgenotypes in Haikou. These findings provide a preliminary study of the distribution of HBV genotypes circulating on Hainan Island.