Prevalence of hepatitis B, hepatitis C, and tuberculosis among people living with HIV in Iran: a systematic review and meta-analysis.

BACKGROUND: Up to now several studies estimate the prevalence of HBV, HCV, and TB among people living with HIV (PLWH) in Iran; however, their results are inconsistent. This study aimed to estimate the overall prevalence of HBV, HVC, and TB among Iranian PLWH. METHODS: In this systematic review and meta-analysis six databases including Medline, Web of Science, Scopus, MagIran, Scientific Information Database (SID), and Barakat Knowledge network system were searched up to October 2023 with no language restriction. All studies estimated the prevalence of HBV, HCV, and TB among PLWH in Iran were included. The random-effects model was used to report the study estimates. Results were reported at a 95% confidence interval (CI). RESULTS: Out of 1050 retrieved references, 58 articles met the eligibility criteria. Overall among PLWH, HBV prevalence was 13.0% (95% CI: 11.0, 15.0), HCV prevalence was 54% (95% CI: 45.0, 64.0), and TB prevalence was 19% (95% CI: 13.0, 24.0). The results from multivariate meta-regression analysis showed no statistically significant association between HBV and TB prevalence with the year of study, quality of studies, age, gender, and persons who inject drugs (PWID). HCV prevalence was significantly associated with PWID. CONCLUSION: We found HBV, HCV, and TB infections are common among PLWH in Iran and required to be screened and treated with effective and timely services.

Revisiting Mac-2-Binding Protein Glycosylation Isomer (M2BPGi) for Diagnosing High-Risk Liver Fibrosis in Chronic Hepatitis B Patients: A Stepwise Diagnostic Analysis.

Background: The level of liver fibrosis is the basis for the treatment of chronic hepatitis B (CHB), and it is necessary to adapt non-invasive liver fibrosis modalities. We aimed to investigate the use of M2BPGi as a single or combined diagnostic modality for liver fibrosis in CHB patients through a stepwise diagnostic analysis. Methods: Cross-sectional data were taken from patients between October 2021 and August 2022. Demographic data, blood profile, liver function, and liver stiffness were measured in CHB patients over 18 years old, willing to take part in the research, and had complete data. APRI, FIB-4, and AAR were calculated using the well-known formulas. Serum M2BPGi-levels were converted into a cut-off index (COI). The patients were divided into low-risk (LR) and high-risk fibrosis (HR) groups. A cut-off for each predictor variable to differentiate between the LR and HR groups was determined. The obtained cut-off was assessed for its association with the grouping of liver elastography results. Models to diagnose the liver stiffness measurement (LSM) ≥8 kPa were created and compared through multivariate and ROC analyses. Results: The number of patients that met the inclusion and exclusion criteria was 143 (HR = 65, LR = 78). The cut-off for diagnosing LSM ≥8kPa was 0.311, 0.742, 0.635, and 1.434 for APRI, FIB-4, AAR, and M2BPGi, respectively. This cut-off was significantly associated with the results of the HR and LR groupings. A multivariate analysis found that FIB4, AAR, and M2BPGi added significantly to the model. Statistically, the most optimal use of M2BPGi was combined with FIB-4, with an AUC of 0.835. Conclusions: The optimal cut-off of M2BPGi for diagnosing high-risk liver fibrosis in this study was 1.434. M2BPGi should be used with FIB-4 as a diagnostic tool for diagnosing liver fibrosis, especially in the absence of a liver biopsy or elastography.

A Rare Presentation of Glucose-6-Phosphate Dehydrogenase Deficiency.

Approximately 400 million individuals globally experience glucose-6-phosphate dehydrogenase (G6PD) insufficiency, an enzymatic condition that may be hazardous. Because of mutations in the G6PD gene, which result in functional variants alongside a variety of biochemical and clinical symptoms, this condition is an X-linked hereditary genetic disorder. Our case is that of a 12-year-old male child who presented with acute liver failure and later on, exhibited signs of hemolysis as well. We had to rule out the possibilities of acetaminophen toxicity and hepatitis A before reaching the conclusion that an underlying G6PD deficiency was being exacerbated by viral infection and simultaneous ingestion of non-steroidal anti-inflammatory drugs (NSAIDs).

Current updates on the molecular and genetic signals as diagnostic and therapeutic targets for hepatitis B virus-associated hepatic malignancy.

Liver cancer caused by the hepatitis B virus (HBV) is the third most common cancer-related cause of death worldwide. Early detection of HBV-caused hepatic tumors increases the likelihood of a successful cure. Molecular and genetic signals are becoming more and more recognized as possible indicators of HBV-associated hepatic malignancy and of how well a treatment is working. As a result, we have discussed the current literature on molecular and genetic sensors, including extracellular vesicle microRNAs (EV-miRNAs), long non-coding circulating RNAs (lncRNAs), extracellular vesicles (EVs), and cell free circulating DNA (cfDNA), for the diagnosis and forecasting of HBV-related hepatic cancer. Extracellular vesicle microRNAs such as miR-335-5p, miR-172-5p, miR-1285-5p, miR-497-5p, miR-636, miR-187-5p, miR-223-3p, miR-21, miR-324-3p, miR-210-3p, miR-718, miR-122, miR-522, miR-0308-3p, and miR-375 are essential for the posttranscriptional regulation of oncogenes in hepatic cells as well as the epigenetic modulation of many internal and external signaling pathways in HBV-induced hepatic carcinogenesis. LncRNAs like lnc01977, HULC (highly up-regulated in liver cancer), MALAT1 (metastasis-associated lung adenocarcinoma transcript 1), and HOTAIR (hox transcript antisense intergenic RNA) have been demonstrated to control hepatic-tumors cell growth, relocation, encroachment, and cell death resiliency. They are also becoming more and more involved in immune tracking, hepatic shifting, vasculature oversight, and genomic destabilization. EVs are critical mediators involved in multiple aspects of liver-tumors like angiogenesis, immunology, tumor formation, and the dissemination of malignant hepatocytes. Furthermore, cfDNA contributes to signals associated with tumors, including mutations and abnormal epigenetic changes during HBV-related hepatic tumorigenesis.

Effect of Peg-IFN on the viral kinetics of patients with HDV infection treated with bulevirtide.

Background & Aims: Bulevirtide is a first-in-class entry inhibitor antiviral treatment for chronic hepatitis D. The viral kinetics during bulevirtide therapy and the effect of combining bulevirtide with pegylated-interferon (Peg-IFN) are unknown. Methods: We used mathematical modelling to analyze the viral kinetics in two French observational cohorts of 183 patients receiving bulevirtide with or without Peg-IFN for 48 weeks. Results: The efficacy of bulevirtide in blocking cell infection was estimated to 90.3%, whereas Peg-IFN blocked viral production with an efficacy of 92.4%, albeit with large inter-individual variabilities. The addition of Peg-IFN to bulevirtide was associated with a more rapid virological decline, with a rate of virological response (>2 log of decline or undetectability) at week 48 of 86.9% (95% prediction interval [PI] = [79.7-95.0]), compared with 56.1% (95% PI = [46.4-66.7]) with bulevirtide only. The model was also used to predict the probability to achieve a cure of viral infection, with a rate of 8.8% (95% PI = [3.5-13.2]) with bulevirtide compared with 18.8% (95% PI = [11.6-29.0]) with bulevirtide + Peg-IFN. Mathematical modelling suggests that after 144 weeks of treatment, the rates of viral cure could be 42.1% (95% PI = [33.3-52.6]) with bulevirtide and 66.7% (95% PI = [56.5-76.8]) with bulevirtide + Peg-IFN. Conclusions: In this analysis of real-world data, Peg-IFN strongly enhanced the kinetics of viral decline in patients treated with bulevirtide. Randomized clinical trials are warranted to assess the virological and clinical benefit of this combination, and to identify predictors of poor response to treatment. Impact and implications: Bulevirtide has been approved for chronic HDV infection by regulatory agencies in Europe based on its good safety profile and rapid virological response after treatment initiation, but the optimal duration of treatment and the chance to achieve a sustained virological response remain unknown. The results presented in this study have a high impact for clinicians and investigators as they provide important knowledge on the long-term virological benefits of a combination of Peg-IFN and bulevirtide in patients with CHD. Clinical trials are now warranted to confirm those predictions.

Modelling hepatitis C infection acquired from blood transfusions in the UK between 1970 and 1991 for the Infected Blood Inquiry.

The Statistics Expert Group was convened at the request of the Infected Blood Inquiry to provide estimates of the number of infections and deaths from blood-borne infections including hepatitis B virus, human immunodeficiency virus, hepatitis C virus (HCV) and variant Creutzfeldt Jakob disease, as a direct result of contaminated blood and blood products administered in the United Kingdom of Great Britain and Northern Ireland (UK). In the absence of databases of HCV infections and related deaths for all nations of the UK, a statistical model was required to estimate the number of infections and subsequent deaths from HCV acquired from blood transfusions from January 1970 to August 1991. We present this statistical model in detail alongside the results of its application to each of the four nations in the UK. We estimated that 26 800 people (95% uncertainty interval 21 300-38 800) throughout the UK were chronically infected with HCV because of contaminated blood transfusions between January 1970 and August 1991. The number of deaths up to the end of 2019 that occurred as a result of this chronic infection is estimated to be 1820 (95% uncertainty interval 650-3320).

Efficacy of Vaccination and Revaccination Against Hepatitis B Virus Using 2 Different Strategies in Patients With Inflammatory Bowel Disease.

BACKGROUND: Patients with inflammatory bowel disease (IBD) exhibit an increased risk for acquiring hepatitis B virus (HBV), thus they should be vaccinated preferably, if not already infected or immunized. We assessed the efficacy of HBV vaccination in IBD patients and impact of different factors on the immune response. We also evaluated the success rate of 2 different revaccination strategies in the nonresponders. METHODS: This was a retrospective observational cohort study carried out in 5 tertiary centers. All patients were tested for hepatitis B surface antigen, antibodies against hepatitis B surface antigen (anti-HBs), and antibodies against hepatitis B core antigen. Patients tested negative and underwent the standard schedule with 20 µg at 0, 1, and 6 months. Nonresponders (anti-HBs <10 IU/L) were offered a revaccination scheme with either 3 doses of 40 µg at 0, 1, and 6 months or an accelerated scheme with 20 µg at 0, 1, and 2 months. RESULTS: A total of 409 patients were included, and 273 (66.7%) of those (females: 49.5%; Crohn's disease [CD]: 56.7%) responded to baseline vaccination. A total of 189 (69.2%) of 273 (females: 48.1%; CD: 60.3%) developed anti-HBs >100 IU/L. Body mass index <30 kg/m2 (P = .017) was positively associated, while diagnosis of CD (P = .013), extensive UC (P <.0001), extraintestinal manifestations (P = .001), and treatment with immunomodulators/anti-tumor necrosis factor (P < .00) negatively affected the response. Revaccination was offered to 103 patients, and 58.3% of them achieved anti-HBs >10 IU/L. Both revaccination strategies were equally effective. CONCLUSIONS: IBD patients demonstrate lower response to HBV vaccination compared with the general population. Age, body mass index, type, disease activity, and immunosuppression negatively affect the response. Half of nonresponders may benefit from an enhanced revaccination attempt.

In this retrospective study, we addressed the impact of several factors on the immune response postvaccination against hepatitis B virus in a large cohort of >400 inflammatory bowel disease patients and compared the effectiveness of 2 different revaccination strategies on nonresponders.

Hepatitis B clinical care provision in pregnancy: A whole-of-population linkage study in Victoria, Australia.

BACKGROUND AND AIM: Pregnancy is a key setting for engagement in chronic hepatitis B (CHB) care, due to the implications for transmission to the infant and antenatal diagnosis representing an opportunity for ongoing follow-up. This study aimed to identify the coverage and predictors of clinical care for women with CHB during and after pregnancy in a population-level cohort. METHODS: Notified CHB cases in Victoria, Australia, were linked with hospitalizations, medical services, and prescribing data, covering the period 1991-2018. Women with an admission for a live birth were identified and services provided during pregnancy were assessed, including general practitioner (GP) or specialist visits, viral load and serology testing, and antiviral treatment. Viral load and serology testing coverage ware also assessed for the 2-year period following pregnancy. Demographic and clinical predictors of viral load testing during pregnancy were assessed. RESULTS: A total of 11 015 birth events occurred for 6090 women with CHB. During pregnancy most had a GP consultation (91.6%); however, only 39.5% had viral load testing and 41.4% had a gastroenterology or infectious diseases specialist consultation. Viral load testing and serology testing in the 2 years after pregnancy occurred in approximately half (47.9% and 52.2%, respectively) with increases over time. Viral load testing was more likely in those born overseas, those with more than one previous birth, and those living in Melbourne. CONCLUSIONS: Despite improvements over time, key gaps were identified in the provision of CHB clinical care during and after pregnancy, with implications for ongoing transmission and adverse outcomes.

Diagnostic accuracy of an uncorrected native T1 mapping sequence for liver fibrosis and inflammation in autoimmune hepatitis: a prospective study using histopathology as reference standard.

PURPOSE: There is an unmet clinical need for non-invasive imaging biomarkers that could replace liver biopsy in the management of patients with autoimmune hepatitis (AIH). In this study, we sought to evaluate the diagnostic accuracy of a simple uncorrected, non-contrast T1 mapping for detecting fibrosis and inflammation in AIH patients using histopathology as a reference standard. MATERIAL AND METHODS: Over 3 years, 33 patients with AIH were prospectively studied using a multiparametric liver MRI protocol which included T1 mapping. Biopsies were performed up to 3 months before imaging, and a standardized histopathological score for fibrosis (F0-F4) and inflammatory activity (PPA0-4) was used as a reference. Statistical analysis included independent t test, Mann-Whitney U-test, and ROC (receiver operating characteristic) analysis. RESULTS: T1 mapping values were significantly higher in patients with advanced fibrosis (F0-2 vs. F3-4; p < 0.015), significant fibrosis (F0-1 vs. F2-4; p < 0.005), and significant inflammatory activity (PPA 0-1 vs. PPA 2-4 p = 0.048). Moreover, the technique demonstrated a good diagnostic performance in detecting significant (AUC 0.856) and advanced fibrosis (AUC 0.835), as well as significant inflammatory activity (AUC 0.763). CONCLUSION: A rapid, simple, uncorrected, non-contrast T1 mapping sequence showed satisfactory diagnostic performance in comparison with histopathology for detecting significant tissue inflammation and fibrosis in AIH patients, being a potential non-invasive imaging biomarker for monitoring disease activity in such individuals.

Causal mediation analyses for the natural course of hepatitis C: a prospective cohort study.

BackgroundHepatitis C virus (HCV) infection is a systemic disease. However, the relative contribution of intrahepatic and extrahepatic diseases to mediating HCV-induced mortality is unclear, albeit critical in resource allocation for reducing preventable deaths. To this end, this study comprehensively quantified the extent to which intrahepatic and extrahepatic diseases mediate HCV-induced mortality.MethodsA community-based cohort study with >25 years of follow-up was conducted in Taiwan. HCV infection was profiled by antibodies against HCV and HCV RNA in participants' serum samples. The cohort data were linked to Taiwan's National Health Insurance Research Database to determine the incidences of potential mediating diseases and mortality. We employed causal mediation analyses to estimate the mediation effects of HCV on mortality in relation to the incidences of 34 candidate diseases.ResultsIn 18,972 participants with 934 HCV infection, we observed that 54.1% of HCV-induced mortality was mediated by intrahepatic diseases, such as liver cirrhosis and liver cancer, and 45.9% of mortality was mediated by extrahepatic diseases. The major extrahepatic mediating diseases included septicemia (estimated proportion of HCV-induced mortality mediated through the disease: 25.2%), renal disease (16.7%), blood/immune diseases (12.2%), gallbladder diseases (9.7%), and endocrine diseases (9.6%). In women, hypertension (20.0%), metabolic syndrome (18.9%), and type 2 diabetes (17.0%) also mediated HCV-induced mortality. A dose-response relationship of HCV viral load was further demonstrated for the mediation effect.ConclusionBoth intrahepatic and extrahepatic manifestations mediated approximately a half of HCV-induced mortality. The mediation mechanisms are supported by a dose-response relationship of HCV viral load.

Center and Individual Willingness to Consider Heart and Lung Offers From Donors With Hepatitis C.

INTRODUCTION: Transplants with hearts and lungs from donors with hepatitis C virus (HCV D+) have been proven safe and effective since development of direct-acting antivirals, yet the presence of HCV + persists as a reason to decline organs. METHODS: We identified adult candidates listed January 1, 2015-March 8, 2023 for heart or lung transplant using the Scientific Registry of Transplant Recipients. We identified individual-level and center-level characteristics associated with listing to consider HCV D+ offers using multilevel logistic regression in a multivariable framework. RESULTS: Over the study period, the annual percentage of candidates willing to consider HCV D+ offers increased for both heart (9.5%-74.3%) and lung (7.8%-59.5%), as did the percentage of centers listing candidates for HCV D+ heart (52.9%-91.1%) and lung (32.8%-82.8%) offers. Candidates at centers with more experience with HCV D+ transplants were more likely to consider HCV D+ organ offers. After adjustment, listing center explained 70% and 78% of the residual variance in willingness to consider HCV D+ hearts and lungs, respectively. CONCLUSIONS: Although listing for consideration of HCV D+ offers has increased, it varies by transplant center. Center-level barriers to consideration of HCV D+ organs reduce recipients' transplant access.

Diagnostic Overshadowing of Chronic Hepatitis C in People With Mental Health Conditions Who Inject Drugs: A Scoping Review.

Diagnostic overshadowing refers to a phenomenon whereby people with mental health conditions encounter inadequate or delayed medical attention and misdiagnosis. This occurs when physical symptoms are mistakenly attributed to their mental health condition. This paper presents a scoping review focusing on direct causes and background factors of diagnostic overshadowing in the context of hepatitis C infection in people who inject drugs and have concurrent mental health conditions. Despite significant strides in hepatitis C treatment with direct-acting antiviral drugs, the complex interplay of mental health conditions and physical symptoms necessitates a nuanced approach for accurate diagnosis and effective screening. This review was conducted using Joanna Briggs Institute's methodology for scoping reviews. The databases searched included Medline, Embase, PsycInfo, Global Health, CINAHL and Scopus. This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR). The search strategies identified 1995 records. Overall, 166 studies were excluded. Forty-two (42) studies met the inclusion criteria. Three (n = 3) studies represented direct causes, and 39 (n = 39) with background factors related to diagnostic overshadowing. Studies highlighted six key themes encompassing diagnostic overshadowing, with communication barriers, stigma and knowledge deficiencies being the most prominent. Recognising and addressing diagnostic overshadowing in chronic hepatitis C will lead to increased screening, diagnosis and timely administration of life-saving antiviral therapy, resulting in profound enhancements in well-being and health outcomes. Moreover, this proactive approach will play a pivotal role in advancing the global effort towards eliminating hepatitis C by 2030.

Outcomes of a 1-Year Pilot Study Implementing Universal Hepatitis Delta Virus Testing Among Veterans With Chronic Hepatitis B.

Current US guidelines recommend risk-based testing for hepatitis delta virus (HDV) in persons with chronic hepatitis B (CHB). While there is debate as to whether a risk-based or universal testing approach is most effective, limited data exist on universal HDV testing programs in the United States. We performed a 1-year pilot study evaluating the outcomes of a universal HDV testing approach among US veterans with CHB. All consecutive adults with CHB receiving care at hepatology clinics at a single-centre Veterans Affairs Health System from 1 October 2022 to 30 September 2023 were prospectively tested for anti-HDV antibody (anti-HDV). Patients who were anti-HDV Ab-positive were subsequently tested for HDV RNA. Comparison of HDV testing between groups utilised chi-square testing. A total of 91 consecutive CHB patients (90.0% male, mean age 60.9 ± 14.1 years, 73.9% Asian, 26.1% non-Asia, 16.5% cirrhosis and 17.1% with active or past history of drug use) had anti-HDV ordered. Overall, 76.9% (n = 70) completed anti-HDV testing; 4.3% (n = 3) were positive. HDV RNA testing was ordered in all three patients; two patients completed HDV RNA testing and one had detectable HDV RNA. No significant differences in completion of anti-HDV testing was observed by age, sex, race/ethnicity, cirrhosis status or drug use history. Among a single-centre prospective cohort study piloting a universal HDV testing approach, one patient with viremic HDV was identified. Implementing true reflex testing of all CHB patients with anti-HDV, followed by automated HDV RNA testing for anti-HDV-positive patients would improve the HDV testing cascade and timely diagnosis of HDV.

Social Determinants of Hepatitis C Virus Infection in the United States, 2016-2021.

This cross-sectional study assessed hepatitis C virus (HCV) antibody and RNA test results performed from 2016 to 2021 at a large US clinical reference laboratory. When individual patient factors (ie, income, education, and race/ethnicity) were not available, estimates from the US Census were linked to the residential zip code. The final analytic cohort comprised 19,543,908 individuals with 23,233,827 HCV antibody and RNA test results. An analysis of progressively increasing poverty quintiles demonstrated an increasing trend in both HCV antibody positivity (from 2.6% in the lowest quintile to 6.9% in the highest, P < 0.001 for trend) and HCV RNA positivity (from 1.0% to 3.6%, P < 0.001 for trend). Increasing levels of education were associated with a decreasing trend in both HCV antibody positivity (from 8.4% in the least educated quintile to 3.0% in the most, P < 0.001 for trend) and HCV RNA positivity (from 4.7% to 1.2%, P < 0.001 for trend). Persistent differences in positivity rates by these social determinants were observed over time. HCV antibody and RNA positivity rates were nearly identical in predominantly Black non-Hispanic, Hispanic, and White non-Hispanic zip codes. However, after adjustment for all other factors in the study, residents of predominantly Black non-Hispanic and Hispanic zip codes were significantly less likely to test positive for HCV RNA (adjusted odds ratios [AOR]: 0.51, 95% confidence interval [CI]: 0.51-0.52; AOR: 0.46, 95% CI: 0.46-0.46, respectively). These findings may benefit targeted intervention initiatives by public health agencies.

Differential methylation patterns in paternally imprinted gene promoter regions in sperm from hepatitis B virus infected individuals.

BACKGROUND: Hepatitis B virus (HBV) infection poses a substantial threat to human health, impacting not only infected individuals but also potentially exerting adverse effects on the health of their offspring. The underlying mechanisms driving this phenomenon remain elusive. This study aims to shed light on this issue by examining alterations in paternally imprinted genes within sperm. METHODS: A cohort of 35 individuals with normal semen analysis, comprising 17 hepatitis B surface antigen (HBsAg)-positive and 18 negative individuals, was recruited. Based on the previous research and the Online Mendelian Inheritance in Man database (OMIM, https://www.omim.org/ ), targeted promoter methylation sequencing was employed to investigate 28 paternally imprinted genes associated with various diseases. RESULTS: Bioinformatic analyses revealed 42 differentially methylated sites across 29 CpG islands within 19 genes and four differentially methylated CpG islands within four genes. At the gene level, an increase in methylation of DNMT1 and a decrease in methylation of CUL7, PRKAG2, and TP53 were observed. DNA methylation haplotype analysis identified 51 differentially methylated haplotypes within 36 CpG islands across 22 genes. CONCLUSIONS: This is the first study to explore the effects of HBV infection on sperm DNA methylation and the potential underlying mechanisms of intergenerational influence of paternal HBV infection.

Analysis of host factor networks during hepatitis B virus infection in primary human hepatocytes.

BACKGROUND: Chronic hepatitis B virus (HBV) infection affects around 250 million people worldwide, causing approximately 887,000 deaths annually, primarily owing to cirrhosis and hepatocellular carcinoma (HCC). The current approved treatments for chronic HBV infection, such as interferon and nucleos(t)ide analogs, have certain limitations as they cannot completely eradicate covalently closed circular DNA (cccDNA). Considering that HBV replication relies on host transcription factors, focusing on host factors in the HBV genome may provide insights into new therapeutic targets against HBV. Therefore, understanding the mechanisms underlying viral persistence and hepatocyte pathogenesis, along with the associated host factors, is crucial. In this study, we investigated novel therapeutic targets for HBV infection by identifying gene and pathway networks involved in HBV replication in primary human hepatocytes (PHHs). Importantly, our study utilized cultured primary hepatocytes, allowing transcriptomic profiling in a biologically relevant context and enabling the investigation of early HBV-mediated effects. METHODS: PHHs were infected with HBV virion particles derived from HepAD38 cells at 80 HBV genome equivalents per cell (Geq/cell). For transcriptomic sequencing, PHHs were harvested 1, 2-, 3-, 5-, and 7 days post-infection (dpi). After preparing the libraries, clustering and sequencing were conducted to generate RNA-sequencing data. This data was processed using Bioinformatics tools and software to analyze DEGs and obtain statistically significant results. Furthermore, qRT-PCR was performed to validate the RNA-sequencing results, ensuring consistent findings. RESULTS: We observed significant alterations in the expression patterns of 149 genes from days 1 to 7 following HBV infection (R2 > 0.7, q < 0.05). Functional analysis of these genes identified RNA-binding proteins involved in mRNA metabolism and the regulation of alternative splicing during HBV infection. Results from qRT-PCR experiments and the analysis of two validation datasets suggest that RBM14 and RPL28 may serve as potential biomarkers for HBV-associated HCC. CONCLUSIONS: Transcriptome analysis of gene expression changes during HBV infection in PHHs provided valuable insights into chronic HBV infection. Additionally, understanding the functional involvement of host factor networks in the molecular mechanisms of HBV replication and transcription may facilitate the development of novel strategies for HBV treatment.

A comprehensive model to better screen out antiviral treatment candidates for chronic hepatitis B patients.

BACKGROUND: Chronic hepatitis B virus (HBV) infection is a serious human health threat given its high morbidity and mortality. Timely and effective antiviral treatment can postpone liver disease progression and reduce the occurrence of HBV-related end-stage liver disease. At present, the antiviral treatment criteria are mainly based on alanine transaminase (ALT) levels, HBV DNA levels and HBV e antigen levels according to the American Association for the Study of Liver Diseases treatment guidelines. However, some chronic hepatitis B (CHB) patients not meeting the above criteria still experience liver disease progression without antiviral treatment. It is urgent to identify a more comprehensive tool to screen out more antiviral treatment candidates as soon as possible. METHODS: Considering the vital role of the immune response in the development of HBV infection and CHB cure, we collected data from 335 treatment-naïve CHB patients and comprehensively analysed their clinical and immune traits (including innate and adaptive responses). The immune parameters were obtained by flow cytometry. Finally, we established a model that can better distinguished CHB patients who need treatment through machine learning and LASSO regression of serological and immune parameters. RESULTS: Through a series of analyses, we selected four important clinical parameters (ALT, HBV DNA, the Fibroscan value, and the A/G ratio) and four immune indicators (NKbright + NKp44+, NKbright + NKG2A+, NKT+GranzymeB+, and CD3 + CD107a + ) from more than 200 variables and then successfully established a mathematical model with high sensitivity and specificity to better screen out antiviral treatment candidates from all CHB patients. CONCLUSIONS: Our results developed a refined model to better screen out antiviral treatment candidates from all CHB patients by combining common clinical parameters and important immune indicators, including innate and adaptive immunity. These findings provide more information for improving treatment guidelines and have potential implications for the timing of antiviral therapy to achieve better virus control and reduce the occurrence of end-stage liver disease.

Healthcare resource utilization and costs associated with hepatitis A in the United States: a retrospective database analysis.

AIM: To investigate hepatitis A-related healthcare resource use and costs in the US. METHODS: The Merative Marketscan Commercial Claims and Encounters database was retrospectively analyzed for hepatitis A-related inpatient, outpatient, and emergency department (ED) claims from January 1, 2012 to December 31, 2018. We calculated the hepatitis A incidence proportion per 100,000 enrollees, healthcare resource utilization, and costs (in 2020 USD). Results were stratified by age, gender, and select comorbidities. RESULTS: The overall hepatitis A incidence proportion was 6.1 per 100,000 enrollees. Among individuals with ≥1 hepatitis A-related claim, the majority (92.6%) had ≥1 outpatient visit related to hepatitis A; 9.1% were hospitalized and 4.2% had ≥1 ED visit. The mean (standard deviation [SD]) length of hospital stay was 5.2 (8.1) days; the mean (SD) number of outpatient and ED visits were 1.3 (1.3) and 1.1 (0.6), respectively. The incidence proportion per 100,000 was higher among adults than children (7.5 vs. 1.5), individuals with HIV than those without (126.7 vs. 5.9), and individuals with chronic liver disease than those without (143.6 vs. 3.8). The total mean (SD)/median (interquartile range, IQR) per-patient cost for hepatitis A-related care was $2,520 ($10,899)/$156 ($74-$529) and the mean cost of hospitalization was 18.7 times higher than that of outpatient care ($17,373 vs. $928). LIMITATIONS: The study data included only a commercially insured population and may not be representative of all individuals. CONCLUSIONS: In conclusion, hepatitis A is associated with a substantial economic burden among privately insured individuals in the US.

Hepatitis A is an acute liver infection caused by the hepatitis A virus. In the US, safe and effective vaccines for hepatitis A have been available since 1996. Vaccination recommendations include children (all children aged 12­23 months and previously unvaccinated children aged 2­18 years old) and adults at risk of infection or severe disease (e.g. international travelers, men who have sex with men, persons experiencing homelessness, persons with chronic liver disease or persons with HIV infection). Since 2016, the US has experienced person-to-person outbreaks of hepatitis A, primarily affecting unvaccinated individuals who use drugs or are experiencing homelessness. To better understand the impact of hepatitis A in the US, we assessed healthcare resource use and costs in 15,435 patients with hepatitis A from 2012 to 2018 in the Merative Marketscan Commercial Claims and Encounters database. We found that slightly more than 6 per 100,000 enrollees had hepatitis A from 2012 to 2018 and the number of people treated for hepatitis A per 100,000 was highest for people living with HIV or with chronic liver disease. The majority (92.6%) of people reported at least an outpatient visit, 9.1% were hospitalized, and 4.2% had an emergency department visit. The average cost for hepatitis A-related care was $2,520 per patient and was 18.7 times higher for hospitalized patients ($17,373) than for patients treated in outpatient care ($928). Our results are limited by the generalizability of the dataset, which is a convenience sample of private insurance claims, and are therefore unlikely to capture groups at high-risk for hepatitis A, such as individuals experiencing homelessness. In conclusion, hepatitis A leads to considerable healthcare costs for privately insured individuals in the US.

Development of the first officially licensed live attenuated duck hepatitis A virus type 3 vaccine strain HB80 in China and its protective efficacy against DHAV-3 infection in ducks.

Duck hepatitis A virus type 3 (DHAV-3) is an infectious virus that is highly fatal to ducklings and causes significant economic losses in the duck industry worldwide. Biosecurity and vaccination are required to control the pathogen. In the present study, we attenuated a lowly pathogenic DHAV-3 clinical isolate, named as HB, by serial passaging in duck embryos, and followed by several adaptive proliferations in specific-pathogen-free (SPF) chicken embryos. The virulence of DHAV-3 at different passages was assessed by infecting 3-day-old ducklings. We found that the HB strain lost pathogenicity to ducklings from the 55th passage onwards. The 80th passage strain (HB80), which achieved good growth capacity in duck embryos with a viral titer of 108.17 50% egg lethal dose per milliliter (ELD50/mL), was selected as a live attenuated vaccine candidate. The HB80 strain did not induce clinical symptoms or pathological lesions in 3-day-old ducklings and showed no virulence reversion after 5 rounds of in vivo back-passage. The minimum effective dose of HB80 was determined to be 104.5 ELD50 by hypodermic inoculation of the neck. Importantly, a single dose of HB80 elicited good immune responses and provided complete protection against challenge with the lethal DHAV-3 strain. Compared with the genomic sequence of the parental HB strain, HB80 had 7 amino acid substitutions, two of them are in the hypervariable region of the VP1 and polymerase-encoding 3D regions, which may play a role in virulence attenuation. Our data suggest that the attenuated HB80 strain is a promising vaccine candidate for the prevention of DHAV-3 infections in China. HB80 has been registered as a New Veterinary Drug Registration Certificate by the Chinese Ministry of Agriculture and Rural Affairs (MARA), and is the first live attenuated DHAV-3 vaccine strain to be officially licensed in China.

PegIFN alpha-2a reduces relapse in HBeAg-negative patients after nucleo(s)tide analogue cessation: A randomized-controlled trial.

BACKGROUND & AIMS: Nucleo(s)tide analogue (NUC) cessation can lead to HBsAg clearance but also a high rate of virological relapse. However, the effect of pegylated interferon alpha-2a (PegIFN-α-2a) on virological relapse after NUC cessation is unknown. Therefore, this study aimed to evaluate the effect of switching from NUC to PegIFN-α-2a treatment for 48 weeks on virological relapse until week 96. METHODS: In this multicentre randomized controlled clinical trial, 180 non-cirrhotic HBeAg-negative chronic hepatitis B patients on continuous NUC therapy for ≥ 2.5 years with HBV DNA levels < 60 IU/mL were randomized to discontinue NUC (n=90) or receive 48 weeks of PegIFN-α-2a treatment (n=90) and followed up till 96 weeks. The primary endpoint was the virological relapse rate until week 96. RESULTS: Intention-to-treat analysis revealed patients in the interferon monotherapy group had significantly lower cumulative virological relapse rates than the NUC cessation group until week 96 (20.8% vs. 53.6%, P < 0.0001). Consistently, a significantly lower proportion of patients in the interferon monotherapy group had virological relapse than those in the NUC cessation group at 48 weeks off treatment (17.8% vs. 36.7%, P = 0.007). The virological relapse rate positively correlated with HBsAg levels in the NUC cessation group. The interferon monotherapy group had a lower cumulative clinical relapse rate (7.8% vs. 20.9%, P = 0.008) and a higher HBsAg loss rate (21.5% vs. 9.0%, P = 0.03) than the NUC cessation group. CONCLUSIONS: Switching from NUC to PegIFN-α-2a treatment for 48 weeks significantly reduces virological relapse rates and achieves higher HBsAg loss rates than NUC treatment cessation alone in HBeAg-negative chronic hepatitis B patients. IMPACT AND IMPLICATIONS: Nucleo(s)tide analogue (NUC) cessation can lead to HBsAg clearance but also a high rate of virological relapse, but an optimised scheme to reduce the virological relapse rate after NUC withdrawal is yet to be reported. This randomized controlled trial investigated the effect of switching from NUC to PegIFN-α-2a treatment for 48 weeks on virological relapse until week 96 in HBeAg-negative chronic hepatitis B patients. The interferon monotherapy group had a significantly lower cumulative virological relapse rate (20.8% vs. 53.6%, P < 0.0001) and higher HBsAg loss rate (21.5% vs. 9.0%, P= 0.03) than the NUC cessation group until week 96. This provides an optimized strategy for NUC cessation in HBeAg-negative patients. TRIAL REGISTRATION NUMBER: NCT02594293.