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Chronic hepatitis B (CHB) was, and still is, a prevalent liver disease in the world, especially high in the Asia‐Pacific areas. With the advent of preventive vaccines and effective viral suppression drugs and active implementations, CHB has gradually become under control. The world‐wide prevalence reduces from 4.2% in 1980 to 3.2% in 2020 study. CHB patients receiving long‐term antiviral therapies significantly improve the clinical outcomes, saving from end‐stage liver diseases. Despite of these impressive progresses, to meet the WHO sustained development goals (SDG) for CHB control, a 90% reduction of incidence and a 65% reduction of mortality in year 2030, there is still a long way to go. In this review, four ongoing approaches have been proposed: (i) A continuous monitoring of long‐term vaccine efficacy in vaccinated populations; (ii) consolidating the hepatitis B virus vaccination program against vaccine hesitancy and limited resources; (iii) rolling‐out current oral antivirals to more CHB patients not only for diseases treatment but also for infection preventions; and (iv) development of curative therapies, both friendly‐to‐dispense and affordable. A coherent and persevere efforts by the society may succeed and achieve the SDG for CHB in the future. [ABSTRACT FROM AUTHOR]

Transmission of hepatitis B virus (HBV) and hepatitis C virus (HCV) is similar regarding the mode of transmission and related risk factors. Therefore, it is not rare to encounter dual HBV/HCV infection in populations at risk of parenteral exposure to hepatitis viruses. Besides, in HBV endemic countries before the era of global HBV vaccination, dual HBV/HCV infection was clinically significant likely because of HCV superinfection over pre‐existing HBsAg carriage. Universal childhood HBV vaccination was implemented worldwide since 1992. Public education programs for prevention of new hepatitis viral infections have been actively promoted recently by World Health Organization. Apart from preventive measures, potent anti‐HBV agents effective in the control of viral replication have been introduced gradually in the past three decades. Direct acting antiviral agents capable of curing HCV infection in more than 97% of patients with chronic hepatitis C have also been widely implemented in the past decade. These interventions will change the epidemiology of new HBV or HCV mono‐infection and dual HBV/HCV infection. Understanding the evolution in the epidemiology of dual HBV/HCV infection is important for evaluation of current public health policy towards infectious disease control in different countries. The changing prevalence of dual HBV/HCV infection in certain Asia‐Pacific countries will be re‐visited based on endemicity of HBV or HCV, as well as in populations at risk of parenteral viral infection. [ABSTRACT FROM AUTHOR]

Background and Aims: Patients with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection are at risk of developing adverse outcomes. Coinfection with both viruses may further increase the risk. Currently, little is known about the role of fibrosis‐4 (FIB‐4) index, a simple liver fibrosis stage biomarker, in predicting the clinical outcomes. Methods: We retrospectively enrolled 152 non‐cirrhotic patients with dual chronic HCV and HBV infection: 56 patients received pegylated interferon/ribavirin therapy, while 96 patients remained untreated. The association between the FIB‐4 index and the incidence of liver cirrhosis and hepatocellular carcinoma (HCC) was explored. Results: After a 9.88‐year follow‐up, the incidence of hepatitis B surface antigen seroclearance was 4.97 (95% confidence interval: 3.13–7.89) per 100 person‐years in the treated group and was 1.77 (1.10–2.85) in the untreated group. Of the treated group, only three and six patients developed HCC and liver cirrhosis, respectively, while 17 and 23 patients developed HCC and liver cirrhosis, respectively, in untreated group. Baseline FIB‐4 index correlated with the development of liver cirrhosis in multivariable analysis of all subjects. High baseline FIB‐4 index (per 1 point increase) in the treated groups was associated with a higher risk of developing liver cirrhosis (P = 0.001) and HCC (P = 0.038) in univariable analysis. FIB‐4 index decreased only in the treated group who achieved sustained virological response (n = 34, FIB‐4 index decreasing from 1.84 to 1.55). Conclusions: In Taiwanese patients coinfected with HCV and HBV, FIB‐4 index helps identify patients at risk of developing adverse events, even in patients receiving pegylated interferon/ribavirin therapy. [ABSTRACT FROM AUTHOR]

Hepatitis B virus ( HBV) is a common human pathogen transmitted worldwide, and its chronic infection is a well-known risk factor for hepatocellular carcinoma ( HCC). The sex disparity of HBV-related liver diseases has been noticed for a long time, which could be attributed to sex hormone effects, other than gender behaviors or environmental impact. This difference is experimentally confirmed in HBV transgenic mice, as well as in immunocompetent mice receiving hydrodynamic delivery of HBV. Androgen and estrogen pathways were identified to play opposite regulations of HBV transcription by targeting viral enhancer I at molecular level. In addition to the direct effects on HBV life cycle, sex hormones may be also involved in the immune response to HBV infection and the progression of associated liver diseases, although the detailed mechanisms are still unclear. Besides, several unaddressed issues such as HBV entry, micro RNA profiles, viral integration, and adaptability in which androgen and estrogen axes might be involved are warranted to be delineated. The comprehensive understanding of the sex disparity in HBV virology and pathogenesis will be helpful to provide newly biomarkers for clinical diagnosis and develop novel drugs to manage HBV-related HCC patients. [ABSTRACT FROM AUTHOR]

BACKGROUND: The efficacy and safety of linifanib (ABT-869), a selective inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptor tyrosine kinases, were assessed in this phase 2, single-arm, open-label, multicenter trial. METHODS: Eligible patients had unresectable or metastatic hepatocellular carcinoma and had received ≤ 1 prior systemic therapy. Patients received oral linifanib at a fasting dose of 0.25 mg/kg,. The primary endpoint was the progression-free rate at 16 weeks. Tumor response was assessed every 8 weeks. Secondary endpoints included the time to disease progression, overall survival, and objective response rate. Safety was also assessed. RESULTS: Of the 44 patients enrolled, the majority were Asian (89%), had received no prior systemic therapy (82%), had Child-Pugh class A hepatic function (86%), and had hepatitis B virus infection (61%). The estimated progression-free rate at 16 weeks was 31.8% (34.2% for patients with Child-Pugh class A hepatic function), the estimated objective response rate was 9.1% (10.5% for patients with Child-Pugh class A hepatic function), the median time to disease progression was 3.7 months (3.7 months for patients with Child-Pugh class A hepatic function), and the median overall survival was 9.7 months (10.4 months for patients with Child-Pugh class A hepatic function). The most common linifanib-related adverse events were diarrhea (55%) and fatigue (52%). The most common linifanib-related grade 3/4 adverse events were hypertension (25%) and fatigue (14%). Serum levels of biomarkers cancer antigen (CA) 125, cytokeratin fragment (CYFRA)21.1, and protein induced by vitamin K absence or antagonist II (PIVKA) demonstrated potential as prognostic indicators of patient response or outcome. CONCLUSIONS: Single-agent linifanib was found to be clinically active in patients with advanced hepatocellular carcinoma, with an acceptable safety profile. Cancer 2013. © 2012 American Cancer Society. [ABSTRACT FROM AUTHOR]

Objective: Mothers sero-positive for hepatitis B are slightly more likely to have a son. It is not known whether it is ever having HBV (HBsAg[+]) or currently active HBV (HBeAg[+]) which is associated with having a son. Method: Multivariable linear regression was used to assess the adjusted association of HBeAg(+) with offspring sex in all (90%) births (∼3 million) in Taiwan from 1988 to 1999. Results: Totally, 5% of mothers were HBeAg(+). HBeAg(+) mothers were slightly more likely to have a son (sex ratio 108 rather than 106) adjusted for HBsAg, birth order, mother's age, birth year, and area of residence. Conclusion: At a population level HBV status makes little difference to the sex ratio at birth. Am. J. Hum. Biol. 2012. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Abstract: Development of Micro-Electro-Mechanical Systems (MEMS) technology has recently allowed the migration of real-time polymerase chain reaction (PCR) machines to lab-on-a-chip systems. The miniaturization of biological instruments has been studied extensively, with several prototypes constructed and tested. In this study, the lab-on-a-chip system is evaluated; its DNA quantification is estimated by theorems, and the specifications of proposed chip prototypes are compared with the original machines. The analysis results suggest five hypotheses. Using experiments and the data collected from published papers, these hypotheses were either verified or rejected, and the advantages and shortcomings of real-time PCR chips were identified. The proven advantages of the lab-on-a-chip system are its compact size, low sample volume to nano-liter, and short analysis time—less than 10s to complete one PCR cycle and 370s for completing the whole quantification process. However, the detection limits, quantification uncertainties, and melting analysis ability of the chip prototypes are at best comparable to, and perhaps worse than, those of commercial instruments. Real-time PCR chips are not perfectly accurate diagnostic tools for a laboratory but they have advantages over traditional techniques for point-of-care testing. [Copyright &y& Elsevier]

Purpose: Hepatitis B virus (HBV) reactivation can occur after radiotherapy (RT) for hepatobiliary malignancies. Our previous in vitro culture study identified interleukin-6 (IL-6) as the main bystander mediator of RT-induced HBV replication. We attempted to examine the molecular mechanism in HBV-transgenic mice. Methods and materials: HBV transgenic mice were treated with whole liver RT (4 Gy daily for 5 days) with or without administration of IL-6 (400 ng twice daily for 15 days). The serum level of HBV DNA was measured using real-time polymerase chain reaction, and the IL-6 concentration was measured using enzyme-linked immunosorbent assay. The intensity of immunostaining with antibodies to HBV core protein and phosphorylated signal transducer and activator of transcription (STAT)3 in the mouse liver was qualitatively analyzed. HepG2.2.15 cells (a human hepatoblastoma cell line that persistently produces HBV DNA) were used to investigate the molecular role of IL-6 plus RT in HBV reactivation. Results: HBV reactivation was induced in vivo with IL-6 plus RT (5.58-fold) compared with RT alone (1.31-fold, p = .005), IL-6 alone (1.31-fold, p = .005), or sham treatment (1.22-fold, p = .004). HBV core protein staining confirmed augmentation of intrahepatic HBV replication. IL-6 plus RT-induced HBV DNA replication in HepG2.2.15 cells was suppressed by the STAT3 inhibitor AG490 and by transfection with dominant-negative STAT3 plasmid. Phosphorylated STAT3 staining was strongest in liver tissue from mice treated with IL-6 plus RT. The mobility shift assay demonstrated that reactivation was mediated through the interaction of phosphorylated STAT3/hepatocyte nuclear factor-3 complex with HBV enhancer 1. Conclusion: RT to the liver and longer sustained IL-6 induced HBV reactivation through the STAT3 signal transduction pathway. [Copyright &y& Elsevier]

Accurate epidemiological data on common deafness genes are essential to improve the efficiency and to reduce the cost of molecular diagnosis. They may depend on several factors, including a clear delineation of the source of patients being studied. In the present study, we hypothesize that patients with idiopathic sensorineural hearing loss recruited from different sources might reveal discrepancies in the epidemiological results of genetic screening, because patients from different sources might demonstrate distinct clinical or audiologic features and thus result in biased selection of subjects. To elucidate the relative importance of common deafness genes in Taiwanese and to verify our hypothesis, we conducted a prospective project screening mutations in GJB2, SLC26A4 and mitochondrial 12S rRNA gene in a total of 420 Taiwanese families with idiopathic bilateral sensorineural hearing loss, of which 325 families were recruited from hospitals and 95 from hearing rehabilitation facilities. Allele frequencies of common mutations in these three genes and distributions of the corresponding genotypes were then compared between the two groups. The allele frequencies of mutations in SLC26A4, GJB2 and mitochondrial 12S rRNA in the probands of the 420 families were 14.4, 21.7 and 3.8%, respectively. The allele frequency of SLC26A4 mutations in the hospital group was significantly higher than that in the rehabilitation facility group (16.2 vs. 8.4%, χ2-test, p < 0.05), whereas no difference in the frequencies of GJB2 mutations and mitochondrial 12S rRNA mutations was found between the two groups. Distributions of probands classified by SLC26A4 genotypes were also different between the two groups (χ2-test, p < 0.05). Accordingly, a discrepancy in the genetic screening results might exist between different sources of idiopathic hearing-impaired patients. Further analysis of audiological results and construction of a logistic regression model showed that different audiological features, namely hearing levels and hearing loss patterns, might be responsible for the unequal distributions of mutations and probands between the hospital and rehabilitation facility groups. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background/Aims: Adiponectin induces insulin sensitivity and modulates inflammatory responses. We thus studied the implications of adiponectin in patients with chronic hepatitis C virus (HCV) infection inherently linked to insulin resistance. Methods: We analyzed the association of serum adiponectin levels with clinical, virologic, and histologic findings in 95 naı̈ve Taiwanese patients with chronic hepatitis C before and after antiviral therapy. Results: At baseline, 14 (15%) of the 95 patients were obese and 26 (27%) had type 2 diabetes mellitus. Fifty-seven patients were infected with HCV genotype 1 and 38 with genotype 2. Steatosis and periportal fibrosis was present in 44 (46%) and 69 (73%), respectively. In multivariate analysis, male gender, insulin resistance, high HCV load and genotype 2 were significantly associated with a lower serum adiponectin level. In contrast, intrahepatic gene expression of adiponectin receptors was higher in genotype 2 compared with genotype 1. Serum adiponectin level did not correlate with other clinical or histologic parameters. After treatment, change of steatosis also did not correlate with the change of adiponectin level (P=0.61). Conclusions: Adiponectin correlated with hepatitis C viral factors at both serum and liver tissue levels. The interactions among adiponectin, insulin resistance and chronic HCV infection merit further studies. [Copyright &y& Elsevier]

Background/Aims: The optimal strategy to prescribe highly active antiretroviral therapy (HAART) in patients infected with both hepatitis B virus (HBV) and human immunodeficiency virus (HIV) remains unsettled. This study aimed to compare the HBV dynamics between HBeAg-positive and HBeAg-negative coinfected patients treated with lamivudine-containing HAART.Methods: We retrospectively analyzed the serial changes of plasma HBV DNA levels in 24 HBsAg-positive HIV-infected patients who entered the HAART program. A polymerase chain reaction-based assay, capable of quantifying as few as 400 HBV copies/ml, was used. The median follow-up time was 18 months.Results: HAART containing lamivudine 300 mg/day effectively suppressed plasma HBV-DNA to 10−3–10−5-fold of the baseline levels, but a multi-phasic decay of HBV DNA was observed. The later phases became flat, as a persistent residual HBV viremia, in eight of the studied 10 HBeAg-positive patients; in contrast, residual HBV viremia was not observed in the 10 HBeAg-negative patients studied (8/10 vs. 0/10, P=0.0007, Fisher''s exact test). HAART without lamivudine did not suppress plasma HBV DNA levels in the remaining four patients.Conclusions: HAART containing lamivudine 300 mg/day effectively suppress HBV replication in HBeAg-negative HIV/HBV-coinfected patients. Nevertheless, residual HBV replication persisted in most HBeAg-positive coinfected patients. [Copyright &y& Elsevier]

Background/Aim: The natural history of hepatitis-C virus (HCV) infection has been explored in volunteer blood donors, but not yet in hepatitis-B endemic areas. Whether previous or concurrent hepatitis-B virus (HBV) infection influences the natural history of HCV infection remains unknown. Thus, we followed the anti-HCV-positive blood donors who had past or concurrent HBV infection in Taiwan. Methods: From 1992 to 1993, 1588 anti-HCV reactive volunteer blood donors were referred to us from the Taipei Blood Center and 879 (55%) repeatedly reactive for anti-HCV were enrolled. Two hundred and forty-three donors (HCV RNA seropositive rate 49% by polymerase chain reaction (PCR)) received regular follow-ups (mean period: 4.9 years) with their liver disease status determined mainly by clinical and biochemical parameters, serum alpha-fetoprotein level and imaging studies. Hepatitis-C virus genotype and occult HBV infection were determined by PCR-based assays. Results: Of the initial 879 subjects, 250 (28%) had chronic hepatitis, nine (1%) had liver cirrhosis (LC) and two (0.2%) had hepatocellular carcinoma (HCC) already. In the 243 regularly followed donors, 30% had repeatedly normal serum alanine aminotransferase (ALT) and 70% had more than once elevated ALT. Cirrhosis developed in four (1.6%; follow-up period range: 2–6 years) and HCC in two (0.8%; follow-up period: 3 and 4 years, respectively). Distribution of HCV genotype and hepatitis-B surface antigen (HBsAg) did not differ between those with and those without elevation of ALT. Of the 15 donors with LC and/or HCC, only 1(7%) was positive for both HBsAg and HBV DNA and the other 14 were negative for both HBsAg and serum HBV DNA. Conclusions: Incidentally detected hepatitis-C was progressive in a small proportion of anti-HCV-positive volunteer blood donors in Taiwan. Occult HBV infection played a minimal role in the development of LC in this donor population. [ABSTRACT FROM AUTHOR]

The interleukin-1 (IL-1) gene complex consists of the IL-1α, IL-1β and IL-1 receptor antagonist genes. Single-nucleotide polymorphisms (SNP) in all three genes have been associated with human diseases. In this study, primers containing mismatches at 1–3 nucleotide positions were designed to incorporate a restriction site for endonuclease AlwNI or XcmI in the presence of allele-specific nucleotides at the polymorphic positions. Based on this technique, a simple and robust multiplex polymerase chain reaction/restriction fragment length polymorphism (multiplex PCR/RFLP) assay was developed to determine simultaneously three to four informative SNPs (IL-1β/+3954, IL-1β/−511 and IL-1Ra/9261 or IL-1α/−889, IL-1β/−31, IL-1β/5810 and IL-1Ra/11100 SNPs) in the IL-1 gene complex. [Copyright &y& Elsevier]

HBV expresses more than 10 spliced RNAs from the viral pregenomic RNA, but their functions remain elusive and controversial. To address the function of HBV spliced RNAs, we generated splicing-deficient HBV mutants and conducted experiments to assess the impact of these mutants on HBV infection. HepG2-NTCP cells, human hepatocyte chimeric FRG mice (hu-FRG mice), and serum from patients with chronic hepatitis B were used for experiments on HBV infection. Additionally, SHifter assays and cryo-electron microscopy were performed. We found the infectivity of splicing-deficient HBV was decreased 100-1,000-fold compared with that of wild-type HBV in hu-FRG mice. Another mutant, A487C, which loses the most abundant spliced RNA (SP1), also exhibits severely impaired infectivity. SP1 hypothetically encodes a novel protein HBcSP1 (HBc-Cys) that lacks the C-terminal cysteine from full-length HBc. In the SHifter assay, HBcSP1 was detected in wild-type viral particles at a ratio of about 20-100% vs. conventional HBc, as well as in the serum of patients with chronic hepatitis B, but not in A487C particles. When infection was conducted with a shorter incubation time of 4-8 h at lower PEG concentrations in HepG2-NTCP cells, the entry of the A487C mutant was significantly slower. SP1 cDNA complementation of the A487C mutant succeeded in rescuing its infectivity in hu-FRG mice and HepG2-NTCP cells. Moreover, cryo-electron microscopy revealed a disulfide bond between HBc cysteine 183 and 48 in the HBc intradimer of the A487C capsid, leading to a locked conformation that disfavored viral entry in contrast to the wild-type capsid. Prior studies unveiled the potential integration of the HBc-Cys protein into the HBV capsid. We confirmed the proposal and validated its identity and function during infection. HBV SP1 RNA encodes a novel HBc protein (HBcSP1) that lacks the C-terminal cysteine from conventional HBc (HBc-Cys). HBcSP1 was detected in cell culture-derived HBV and confirmed in patients with chronic infection by both immunological and chemical modification assays at 10-50% of capsid. The splicing-deficient mutant HBV (A487C) impaired infectivity in human hepatocyte chimeric mice and viral entry in the HepG2-NTCP cell line. Furthermore, these deficiencies of the splicing-deficient mutant could be rescued by complementation with the SP1-encoded protein HBcSP1. We confirmed and validated the identity and function of HBcSP1 during infection, building on the current model of HBV particles. [Display omitted] • The infectivity of splicing-deficient HBV was significantly decreased compared to WT HBV in hu-FRG mice. • SP1 RNA encodes HBcSP1, which is found in 10 to 50% of nucleocapsids in patients with CHB and cell line-derived WT HBV. • The splicing-deficient mutant A487C, lacking HBcSP1, reduces the efficiency of viral entry kinetics. • Disulfide bonds between Cys48 and Cys183 in the A487C capsid led to a locked conformation that disfavored viral entry. [ABSTRACT FROM AUTHOR]

Persons with chronic HBV infection coinfected with HIV experience accelerated progression of liver fibrosis compared to those with HBV monoinfection. We aimed to determine whether HIV and its proteins promote HBV-induced liver fibrosis in HIV/HBV-coinfected cell culture models through HIF-1α and TGF-β1 signaling. The HBV-positive supernatant, purified HBV viral particles, HIV-positive supernatant, or HIV viral particles were directly incubated with cell lines or primary hepatocytes, hepatic stellate cells, and macrophages in mono or 3D spheroid coculture models. Cells were incubated with recombinant cytokines and HIV proteins including gp120. HBV sub-genomic constructs were transfected into NTCP-HepG2 cells. We also evaluated the effects of inhibitor of HIF-1α and HIV gp120 in a HBV carrier mouse model that was generated via hydrodynamic injection of the pAAV/HBV1.2 plasmid into the tail vein of wild-type C57BL/6 mice. We found that HIV and HIV gp120, through engagement with CCR5 and CXCR4 coreceptors, activate AKT and ERK signaling and subsequently upregulate hypoxia-inducible factor-1α (HIF-1α) to increase HBV-induced transforming growth factor-β1 (TGF-β1) and profibrogenic gene expression in hepatocytes and hepatic stellate cells. HIV gp120 exacerbates HBV X protein-mediated HIF-1α expression and liver fibrogenesis, which can be alleviated by inhibiting HIF-1α. Conversely, TGF-β1 upregulates HIF-1α expression and HBV-induced liver fibrogenesis through the SMAD signaling pathway. HIF-1α small-interfering RNA transfection or the HIF-1α inhibitor (acriflavine) blocked HIV-, HBV-, and TGF-β1-induced fibrogenesis. Our findings suggest that HIV coinfection exacerbates HBV-induced liver fibrogenesis through enhancement of the positive feedback between HIF-1α and TGF-β1 via CCR5/CXCR4. HIF-1α represents a novel target for antifibrotic therapeutic development in HBV/HIV coinfection. HIV coinfection accelerates the progression of liver fibrosis compared to HBV monoinfection, even among patients with successful suppression of viral load, and there is no sufficient treatment for this disease process. In this study, we found that HIV viral particles and specifically HIV gp120 promote HBV-induced hepatic fibrogenesis via enhancement of the positive feedback between HIF-1α and TGF-β1, which can be ameliorated by inhibition of HIF-1α. These findings suggest that targeting the HIF-1α pathway can reduce liver fibrogenesis in patients with HIV and HBV coinfection. [Display omitted] • HIV and HIV gp120 increase HBV-induced profibrogenic gene expression in hepatocytes and hepatic stellate cells. • HIV coinfection increases HBV-induced liver fibrogenesis through upregulation of the HIF-1α and TGF-β1 pathway. • The HIF-1α inhibitor (acriflavine) can block HIV-, HBV- and TGF-β1-induced liver fibrogenesis. • HIF-1α represents a novel target for antifibrotic therapy in patients with HIV/HBV coinfection. [ABSTRACT FROM AUTHOR]

Simple Summary: Cell-free tumor DNA (ctDNA), the DNA released into circulation from tumors, is a promising tumor marker with versatile applications. The associations of the amount, somatic mutation frequency, and epigenetic modifications of ctDNA with the tumor burden, tumor behavior, and prognosis have been widely investigated in different types of tumors. However, there are still some challenging issues to be resolved before ctDNA can complement or even replace current serum tumor markers. We propose employing exogenous viral DNA integration that produces unique virus–host chimera DNA (vh-DNA) at junction sites. Cell-free vh-DNA may become a new biomarker because it overcomes background interference detection problems, takes advantage of virus tropism to localize the tumor, and acts as a universal marker for monitoring clonal expansion or tumor loads in tumors related to oncogenic viruses. The idea of using tumor-specific cell-free DNA (ctDNA) as a tumor biomarker has been widely tested and validated in various types of human cancers and different clinical settings. ctDNA can reflect the presence or size of tumors in a real-time manner and can enable longitudinal monitoring with minimal invasiveness, allowing it to be applied in treatment response assessment and recurrence monitoring for cancer therapies. However, tumor detection by ctDNA remains a great challenge due to the difficulty in enriching ctDNA from a large amount of homologous non-tumor cell-free DNA (cfDNA). Only ctDNA with nonhuman sequences (or rearrangements) can be selected from the background of cfDNA from nontumor DNAs. This is possible for several virus-related cancers, such as hepatitis B virus (HBV)-related HCC or human papillomavirus (HPV)-related cervical or head and neck cancers, which frequently harbor randomly integrated viral DNA. The junction fragments of the integrations, namely virus–host chimera DNA (vh-DNA), can represent the signatures of individual tumors and are released into the blood. Such ctDNA can be enriched by capture with virus-specific probes and therefore exploited as a circulating biomarker to track virus-related cancers in clinical settings. Here, we review virus integrations in virus-related cancers to evaluate the feasibility of vh-DNA as a cell-free tumor marker and update studies on the development of detection and applications. vh-DNA may be a solution to the development of specific markers to manage virus-related cancers in the future. [ABSTRACT FROM AUTHOR]

Hepatitis B virus (HBV) infection and its related liver diseases are important health problems worldwide, particularly in the Asia-Pacific region. For the past 4–5 decades, Taiwan's government and scientists have cooperated together to control this virus infection and its related liver diseases. These efforts and achievements have made progress toward the elimination of HBV. Taiwan's government initiated the Viral Hepatitis Control Program (VHCP) in the1970s, and then launched the national vaccination program in 1984. This universal vaccination program effectively decreased the rate of hepatitis B carriage and the development of hepatocellular carcinoma (HCC) in the younger generation. Since 2003, approved anti-HBV treatments were reimbursed nationwide. This reimbursement program resulted in a higher uptake of anti-HBV treatments, which contributed to a decrease in liver-related disease progression and subsequently reduced attributable mortality in Taiwan. This experience can be shared by countries in other parts of the world regarding the control of chronic viral hepatitis B. [ABSTRACT FROM AUTHOR]

Regular hepatocellular carcinoma (HCC) surveillance by ultrasonography in combination with the α-fetoprotein (AFP) examination is unsatisfactory in diagnostic sensitivity for early-stage HCC especially in cirrhotic patients. We conducted a prospective study in a tertiary medical center in Taiwan and consecutively collected serum samples from patients with chronic hepatitis, liver cirrhosis (LC), or HCC for new biomarker discovery. Overall, 166 patients were enrolled, including 40 hepatitis, 30 LC, and 96 HCC. Four acute-phase serum amyloid A (A-SAA) derived biomarkers including total A-SAA, A-SAA monomer and oligomer, and protein misfolding cyclic amplification (PMCA) signal were measured and compared between patients with and without HCC. A-SAA biomarkers significantly increased in the HCC group when compared to the hepatitis and LC groups, and generally increased in more advanced tumor stages. Among A-SAA biomarkers, the area under the receiver operator characteristic curves (AUROCs) for PMCA signal in discrimination of all-stage and early-stage HCC were 0.86 and 0.9 in cirrhotic patients, which is comparable to AFP. For cirrhotic patients with low AFP (< 7 ng/mL), PMCA signal maintained good capacity in prediction of early-stage HCC (AUROC: 0.94). Serum A-SAA and its prion-like property showed a potential to complement AFP in detection of early-stage HCC. [ABSTRACT FROM AUTHOR]

Background/Aims: Chronic hepatitis B virus (HBV) infection still poses a major threat to global health. Oligoadenylate synthetase–ribonuclease L (RNase L) antiviral pathway is one of interferon‐induced antiviral effectors. The relationship between RNase L and HBV has never been investigated and we aim to examine the serum RNase L levels in patients with different stages of chronic HBV infection. Methods: The patients were enrolled from 1985 to 2000, who had been HBsAg positive for longer than 6 months, at the National Taiwan University Hospital. In total, 426 patients with chronic HBV infection were included in this study, including 135 inactive carriers, 148 cirrhosis, and 143 hepatocellular carcinoma (HCC) cases. Results: The RNase L levels increase as the disease severity increases. Higher RNase L levels were associated with higher HBV viral load, and the HBV‐RNase L relationship was replaced by the disease severity status when adding disease status into the model. Compared with inactive carriers, the risk of liver cirrhosis was 60‐fold (odds ratio = 60.8, 95% confidence interval = 3.49–1061) with the highest quintile of RNase L levels, after the adjustment of HBV DNA. The dose–response trend was statistically significant with quintiles and one increment of RNase L level in relation to liver cirrhosis. Similar results were found when HCC was compared with inactive carriers, while there was no association when compared between liver cirrhosis and HCC. Conclusions: A positive relationship between serum RNase L and HBV viral titers or advanced disease status is uncovered in this study. Further investigation in this area may provide more details of an innate immune response for HBV and opportunity for novel therapeutic strategy. [ABSTRACT FROM AUTHOR]

Summary: Background: Lipid‐lowering effect was observed during treatment with tenofovir disoproxil fumarate (TDF) for chronic hepatitis B (CHB). However, the metabolic features in patients switching from TDF to tenofovir alafenamide (TAF) remain unclear. Aims: To compare the impacts of switching from TDF to TAF or from entecavir to TAF on body weight and metabolic features in patients with CHB. Methods: This was a multi‐centre, prospective, observational study in patients with CHB on TDF or entecavir who switched to TAF. Baseline characteristics, lipid profile and sugar profile were determined. This study received IRB approval from each hospital. Results: We enrolled 177 patients on TDF (99) or entecavir (78) and followed them for 48 weeks after the switch to TAF. At baseline, TDF‐experienced patients had lower serum triglyceride, total cholesterol, high‐density lipoprotein (HDL) cholesterol and low‐density lipoprotein (LDL) cholesterol than entecavir‐experienced patients. The switch from TDF to TAF significantly increased body weight, triglyceride, total cholesterol, HDL, LDL, fasting glucose, glycaemic haemoglobin, insulin and insulin resistance. The switch from entecavir to TAF did not affect these measures. There was no significant difference in atherosclerotic cardiovascular disease risk scores between groups. Conclusions: The switch from TDF to TAF was associated with weight gain, derangements of lipid profile, and increased insulin resistance in patients with CHB. Long‐term effects on these metabolic features need further investigation. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) usually recurs after curative surgical resection. Currently, no approved adjuvant therapy has been shown to reduce HCC recurrence rates. In this study, the in vivo effect of sequential combination treatment with recombinant mouse interferon-alpha (rmIFN-α) and an anti-mouse-PD1 antibody on hepatitis B virus (HBV) clearance in mice was evaluated. A Phase I clinical trial was then conducted to assess the safety, tolerability, and inhibitory activity of sequential therapy with ropeginterferon alfa-2b and nivolumab in patients with HCC recurrence who underwent curative surgery for HBV-related HCC. The animal modeling study showed that HBV suppression was significantly greater with the rmIFN-α and anti-PD1 sequential combination treatment in comparison with sole treatment with rmIFN-α or anti-PD1. In the Phase I study, eleven patients completed the sequential therapy with ropeginterferon alfa-2b every two weeks for six doses at 450 µg, followed by three doses of nivolumab every two weeks up to 0.75 mg/kg. A notable decrease in or clearance of HBV surface antigen was observed in two patients. The dose-limiting toxicity of grade 3 alanine transaminase and aspartate aminotransferase increases was observed in one patient. The maximum tolerated dose was then determined. To date, no HCC recurrence has been observed. The treatment modality was well tolerated. These data support the further clinical development of sequential combination therapy as a post-surgery prophylactic measure against the recurrence of HBV-related HCC. [ABSTRACT FROM AUTHOR]

On March 11, 2020, the World Health Organization declared the worldwide spread of the infectious disease COVID-19, caused by a new strain of coronavirus, SARS-CoV-2, as a pandemic. Like in all other infectious diseases, the host immune system plays a key role in our defense against SARS-CoV-2 infection. However, viruses are able to evade the immune attack and proliferate and, in susceptible individuals, cause severe inflammatory response known as cytokine storm, particularly in the lungs. The advancement in our understanding of the mechanisms underlying the host immune responses promises to facilitate the development of approaches for prevention or treatment of diseases. Components of immune system, such as antibodies, can also be used to develop sensitive and specific diagnostic methods as well as novel therapeutic agents. In this review, we summarize our knowledge about how the host mounts immune responses to infection by SARS-CoV-2. We also describe the diagnostic methods being used for COVID-19 identification and summarize the current status of various therapeutic strategies, including vaccination, being considered for treatment of the disease. [ABSTRACT FROM AUTHOR]

Aim: Alpha‐fetoprotein (AFP) checkup with abdominal ultrasonography for hepatocellular carcinoma (HCC) surveillance remains controversial. We evaluated a serial AFP‐increase and high AFP levels in the prediction of HCC. Methods: At‐risk patients with chronic liver disease underwent HCC surveillance with trimonthly AFP measurement were included and categorized into HCC and non‐HCC groups. Their AFP levels at 12, 9, and 6 months (−6M) before the outcome date were evaluated. Group‐based trajectory analysis and multivariable regression analysis were performed to identify AFP trajectories as risk predictors for HCC. Results: Overall, 2776 patients were included in the HCC (n = 326) and non‐HCC (n = 2450) groups. Serial AFP levels were significantly higher in the HCC than the non‐HCC groups. Trajectory analysis identified AFP‐increase group (11%) increased 24‐fold risks of HCC compared with the AFP‐stable (89%) group. Compared with patients without the AFP‐increase, a serial 3‐month AFP‐increase ≥10% elevated HCC risk by 12.1‐fold (95% CI: 6.5–22.4) in 6 months, and the HCC risks increased 13–60 fold in patients with cirrhosis, hepatitis B, or C receiving antiviral therapy, or AFP levels <20 ng/ml. Combining serial AFP‐increase ≥10% and AFP ≥20 ng/ml at −6M significantly increased 41.7‐fold (95% CI: 13.8–126.2) HCC risks. In patients who underwent biannual AFP checkups, those with both 6‐month AFP‐increase ≥10% and AFP ≥20 ng/ml increased 22.1‐fold (95% CI: 12.52–39.16) HCC risks in 6 months. Most HCCs were detected at an early stage. Conclusions: Serial 3–6‐month AFP‐increase of ≥10% previously and AFP level of ≥20 ng/ml significantly increased HCC risks in 6 months. [ABSTRACT FROM AUTHOR]

The clinical utility of the splenic arterial pulsatility index (SAPI), a duplex Doppler ultrasonographic index, to predict the stage of hepatic fibrosis in hemodialysis patients with chronic hepatitis C virus (HCV) infection remains elusive. We conducted a retrospective, cross-sectional study to include 296 hemodialysis patients with HCV who underwent SAPI assessment and liver stiffness measurements (LSMs). The levels of SAPI were significantly associated with LSMs (Pearson correlation coefficient: 0.413, p < 0.001) and different stages of hepatic fibrosis as determined using LSMs (Spearman's rank correlation coefficient: 0.529, p < 0.001). The areas under receiver operating characteristics (AUROCs) of SAPI to predict the severity of hepatic fibrosis were 0.730 (95% CI: 0.671–0.789) for ≥F1, 0.782 (95% CI: 0.730–0.834) for ≥F2, 0.838 (95% CI: 0.781–0.894) for ≥F3, and 0.851 (95% CI: 0.771–0.931) for F4. Furthermore, the AUROCs of SAPI were comparable to those of the fibrosis index based on four parameters (FIB-4) and superior to those of the aspartate transaminase (AST)-to-platelet ratio index (APRI). The positive predictive value (PPV) for ≥F1 was 79.5% when the Youden index was set at 1.04, and the negative predictive values (NPVs) for ≥F2, ≥F3, and F4 were 79.8%, 92,6%, and 96.9%, respectively, when the maximal Youden indices were set at 1.06, 1.19, and 1.30. The diagnostic accuracies of SAPI with the maximal Youden index for a fibrosis stage of ≥F1, ≥F2, ≥F3, and F4 were 69.6%, 67.2%, 75.0%, and 85.1%, respectively. In conclusion, SAPI can serve as a good noninvasive index in predicting the severity of hepatic fibrosis in hemodialysis patients with chronic HCV infection. [ABSTRACT FROM AUTHOR]

Background Data on hepatitis C virus (HCV) reinfection in East Asian people with HIV after treatment-induced sustained virologic response (SVR) are limited. Methods HIV/HCV-coinfected patients in Taiwan who achieved SVR12 with interferon (IFN) or direct-acting antivirals (DAAs) between 2005 and 2021 underwent HCV RNA measurements at SVR24 and then biannually. HCV reinfection was defined as the detection of different HCV strains beyond SVR12. HIV-negative, low-risk individuals with SVR12 served as reference patients. Crude reinfection rates and secular trends were assessed. Multivariate Cox regression analysis was performed to identify baseline factors associated with HCV reinfection. Results A total of 216 HIV-positive and 1589 reference patients were recruited, with median follow-up durations of 3.0 and 6.0 years, respectively. During a total of 772 person-years of follow-up (PYFU), the HCV reinfection rate in HIV-positive patients was 4.02 per 100 PYFU (95% CI, 2.85–5.65), while the HCV reinfection rate in reference patients was 0.14 per 100 PYFU (95% CI, 0.09–0.23) during 10 862 PYFU. HIV-positive patients had a higher risk of HCV reinfection than reference patients (hazard ratio [HR], 17.63; 95% CI, 7.10–43.80; P  < .001). No baseline factors were predictive of HCV reinfection in HIV-positive patients. The incidence of HCV reinfection in HIV-positive patients increased after 2015, when DAAs were made available in Taiwan. Conclusions The risk of HCV reinfection remains high in HIV/HCV-coinfected patients with treatment-induced SVR12. In addition to mass screening and treatment scale-up, strategies to reduce reinfection are needed for HCV microelimination in HIV-positive patients in Taiwan. [ABSTRACT FROM AUTHOR]

The letter to the editor comments on an article by Dr. Lee about HBV infection and hepatitis D virus.

A letter to the editor is presented in response to the article "Allelic Loss of Chromosome 18q and Prognosis in Colorectal Cancer," by J. Jen, H. Kim and S. Piantadosi in the July 28, 1994 issue.

Ropeginterferon alfa-2b is a novel mono-pegylated and extra-long-acting interferon, being developed for the treatment of myeloproliferative neoplasm (MPN) and chronic viral hepatitis. It has a favorable pharmacokinetic profile and less frequent dosing schedule, i.e., once every two to four weeks, compared to conventional pegylated interferon products, which have multiple isomers and are administered weekly. It was approved for the long-term treatment of polycythemia vera, an MPN, and has been included in the NCCN clinical practice guidelines for this indication. Ropeginterferon alfa-2b has demonstrated efficacy and showed a favorable safety profile for the treatment of chronic viral hepatitis in several clinical studies. In this article, we review its pharmacokinetics and available clinical data and suggest that ropeginterferon alfa-2b administered once every two weeks can serve as a new treatment option for patients with chronic viral hepatitis, including chronic hepatitis B, C, and D. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Many patients with chronic hepatitis B (CHB) are classified as indeterminate patients because they fall outside the defined CHB phases. We aimed to explore hepatocellular carcinoma (HCC) risk in hepatitis B e antigen (HBeAg)-negative patients with indeterminate phase and investigated whether the risk could be stratified by serum levels of hepatitis B core-related antigen (HBcrAg). METHODS: Two retrospective cohorts enrolling HBeAg-negative, treatment-naïve CHB patients without cirrhosis were constructed (N = 2,150 in Taiwanese discovery cohort and N = 1,312 in Japanese validation cohort with a mean follow-up period of 15.88 and 12.07 years, respectively). The primary end point was HCC development. RESULTS: According to the American Association for the Study of Liver Disease guidelines, 990 (46%) HBeAg-negative patients had indeterminate CHB phase at baseline in the Taiwanese cohort. Compared with the patients with inactive CHB and those with immune-active CHB, the indeterminate patients exhibited intermediate but diverse risk of HCC. When HCC risk was stratified by a HBcrAg level of 10,000 U/mL, 10-year HCC cumulative incidence was 0.51% and 5.33% for low HBcrAg and high HBcrAg groups, respectively, with a hazard ratio of 4.47 (95% confidence interval: 2.62–7.63). This cutoff was validated to stratify HCC risk not only in different subgroup analyses but also in an independent Japanese cohort. Finally, the overall HBeAg-negative CHB patients could be simply reclassified into high-risk and low-risk groups by combining ALT, hepatitis B virus DNA, and HBcrAg levels in both cohorts. DISCUSSION: Serum HBcrAg level of 10,000 U/mL stratifies HCC risk in HBeAg-negative patients with indeterminate phase, which is useful for optimizing their clinical management. [ABSTRACT FROM AUTHOR]

Background: Evidence for mitigation of transfusion-transmitted dengue informed by surveillance data is lacking. In this study, we evaluated the risk of positive dengue viral (DENV) ribonucleic acid (RNA) from blood transfusions during a large outbreak in Taiwan.Methods: Serum collected from blood donors living in districts experiencing the dengue epidemic were tested for DENV RNA using a qualitative transcription-mediated nucleic acid amplification assay (TMA). The TMA-reactive specimens were further tested for immunoglobulin (Ig)M and IgG antibodies, nonstructural protein 1 (NS1) antigen, and viral RNA by reverse-transcription polymerase chain reaction. We estimated DENV RNA prevalence and the number of DENV infections among blood donors.Results: A total of 4976 specimens were tested for DENV RNA, and 21 were TMA-reactive. The detection rate was 0.84 (95% confidence interval [CI], 0.15-4.73), 3.36 (95% CI, 1.31-8.60), and 6.19 (95% CI, 3.14-12.17) per 1000 donors in districts where the weekly dengue incidence was 5-50, 50-200, and 200 or more per 100 000 residents, respectively. Alanine aminotransferase screening only detected 4.4% of TMA-reactive donations. A total of 143 transfusion-transmitted DENV infections probably occurred during this outbreak, accounting for 9.2 in 10 000 dengue infections.Conclusions: Approximately 0.5%-1% of blood donations were DENV RNA positive in epidemic districts. The correlation of DENV RNA rates with dengue incidence may inform the design of effective control measures. [ABSTRACT FROM AUTHOR]

Background and Aim Patients with hepatitis B virus ( HBV) genotype B infection experience hepatitis B e-antigen ( HBeAg) seroconversion at an earlier stage than do patients with genotype C infection. Therefore, this study investigated whether the differential phenotypes are related to HBV genomic evolution. Methods Thirty-three HBeAg-positive patients with a mean follow-up of 3.1 years were enrolled: 16 at the immune tolerance stage (group I) and 17 at the immune clearance stage (group II). The evolution rates of paired viral genomes at enrollment and at the final follow-up in the full-length genome (μf), nonoverlapping regions (synonymous [μs] and nonsynonymous [μa]), and overlapping regions (μ) were calculated. The evolution rates were then compared according to serum alanine aminotransferase ( ALT) levels and HBV genotype. Results The overall μf evolution rate was lower in group I than in group II (1.4 × 10−5 ± 3.3 × 10−5 vs 1.2 × 10−3 ± 1.2 × 10−3 nucleotide substitution/site/year, P < 0.001). We observed similar results for the μs, μa, and μ evolution rates. All evolution parameters were comparable between genotypes B and C. We determined a positive correlation between μa/y and the area under the average ALT time curve in genotype B (R2 = 0.6935, P < 0.0001), but not in genotype C (R2 = 0.1606, P = 0.124). Conclusion The evolution rate of the HBV genome is higher at the immune clearance stage than at the immune tolerance stage. Host immune selection might play a role in triggering evolution of genotype B. [ABSTRACT FROM AUTHOR]

Summary: Background: Data are limited regarding the risk of hepatitis C virus (HCV) reinfection after treatment‐induced sustained virologic response (SVR) in patients on haemodialysis. Aims: To assess the risk of HCV reinfection among patients on haemodialysis with treatment‐induced SVR. Methods: Patients on haemodialysis patients who achieved SVR12 with interferon (IFN) or direct‐acting antiviral (DAA)‐based treatment received follow‐up at SVR24 and then biannually with HCV RNA measurements. HCV reinfection was defined as the resurgence of viremia by different viral strains beyond SVR12. The low‐risk general population who achieved SVR12 and who underwent the same post‐SVR12 surveillance served as the reference group. Crude reinfection rates per 100 person‐years (PYs) were calculated. Multivariate Cox regression analysis was performed to estimate the relative risk of HCV reinfection between the two groups. Results: We recruited 374 patients on haemodialysis and 1571 reference patients with a mean post‐SVR12 follow‐up of 4.7 and 6.1 years. All haemodialysis patients who achieved SVR12 also achieved SVR24. The incidence rates of HCV reinfection were 0.23 per 100 PYs (95% confidence interval [CI]: 0.09‐0.59) in haemodialysis patients and 0.16 per 100 PYs (95% CI: 0.10‐0.26) in the reference group. The risk of HCV reinfection in patients on haemodialysis was comparable to that in the reference patients (hazard ratio [HR]: 1.39; 95% CI: 0.44‐4.38, P = 0.57). Conclusions: The risk of HCV reinfection in patients on haemodialysis who achieve SVR12 is low and comparable to that in the low‐risk general population. HCV microelimination in this special population is feasible once universal screening and scaled‐up treatment are implemented. [ABSTRACT FROM AUTHOR]

A review of the article "Immunocompetent Nontransgenic Mouse Models for Studying Hepatitis B Virus Immune Responses" by Horng-Tay Tzeng, Ping-Ning Hsu, and Pei-Jer Chen, which appeared in the "Journal of Gastroenterology and Hepatology" on March 10, 2013, is presented.

Background: Information on the dynamics of metabolic dysfunction-associated steatotic liver disease (MASLD) among hepatitis C virus patients achieving sustained virologic response (SVR12) with direct-acting antivirals (DAAs) is limited.We enrolled 1512 eligible participants in this prospective study. MASLD was defined by a controlled attenuation parameter (CAP) of ≥248 dB/m utilizing vibration-controlled transient elastography in conjunction with presence of  ≥1 cardiometabolic risk factor. The distribution of MASLD and the changes in CAP were evaluated before treatment and at SVR12. Forward stepwise logistic regression analyses were performed to determine factors significantly associated with the regression or emergence of MASLD.The prevalence of MASLD decreased from 45.0% before treatment to 36.1% at SVR12. Among 681 participants with MASLD before treatment, 144 (21%) exhibited MASLD regression at SVR12. Conversely, among 831 participants without MASLD before treatment, 9 (1.1%) developed MASLD at SVR12. Absence of type 2 diabetes (T2D) [odds ratio (OR): 1.73, 95% confidence interval (CI): 1.13–2.65, p = 0.011], age > 50 years (OR: 1.73, 95% CI: 1.11–2.68, p = 0.015), and alanine transaminase (ALT) ≤ 2 times the upper limit of normal (ULN) (OR: 1.56; 95% CI: 1.03–2.37, p = 0.035) were associated with the regression of MASLD. Presence of T2D was associated with the emergence of MASLD (OR: 5.83, 95% CI: 1.51–22.56, p = 0.011).The prevalence of MASLD decreased after achieving SVR12 with DAAs. Patients with pre-existing T2D showed a diminished probability of MASLD regression and a heightened risk of MASLD emergence post-SVR12.Methods: Information on the dynamics of metabolic dysfunction-associated steatotic liver disease (MASLD) among hepatitis C virus patients achieving sustained virologic response (SVR12) with direct-acting antivirals (DAAs) is limited.We enrolled 1512 eligible participants in this prospective study. MASLD was defined by a controlled attenuation parameter (CAP) of ≥248 dB/m utilizing vibration-controlled transient elastography in conjunction with presence of  ≥1 cardiometabolic risk factor. The distribution of MASLD and the changes in CAP were evaluated before treatment and at SVR12. Forward stepwise logistic regression analyses were performed to determine factors significantly associated with the regression or emergence of MASLD.The prevalence of MASLD decreased from 45.0% before treatment to 36.1% at SVR12. Among 681 participants with MASLD before treatment, 144 (21%) exhibited MASLD regression at SVR12. Conversely, among 831 participants without MASLD before treatment, 9 (1.1%) developed MASLD at SVR12. Absence of type 2 diabetes (T2D) [odds ratio (OR): 1.73, 95% confidence interval (CI): 1.13–2.65, p = 0.011], age > 50 years (OR: 1.73, 95% CI: 1.11–2.68, p = 0.015), and alanine transaminase (ALT) ≤ 2 times the upper limit of normal (ULN) (OR: 1.56; 95% CI: 1.03–2.37, p = 0.035) were associated with the regression of MASLD. Presence of T2D was associated with the emergence of MASLD (OR: 5.83, 95% CI: 1.51–22.56, p = 0.011).The prevalence of MASLD decreased after achieving SVR12 with DAAs. Patients with pre-existing T2D showed a diminished probability of MASLD regression and a heightened risk of MASLD emergence post-SVR12.Results: Information on the dynamics of metabolic dysfunction-associated steatotic liver disease (MASLD) among hepatitis C virus patients achieving sustained virologic response (SVR12) with direct-acting antivirals (DAAs) is limited.We enrolled 1512 eligible participants in this prospective study. MASLD was defined by a controlled attenuation parameter (CAP) of ≥248 dB/m utilizing vibration-controlled transient elastography in conjunction with presence of  ≥1 cardiometabolic risk factor. The distribution of MASLD and the changes in CAP were evaluated before treatment and at SVR12. Forward stepwise logistic regression analyses were performed to determine factors significantly associated with the regression or emergence of MASLD.The prevalence of MASLD decreased from 45.0% before treatment to 36.1% at SVR12. Among 681 participants with MASLD before treatment, 144 (21%) exhibited MASLD regression at SVR12. Conversely, among 831 participants without MASLD before treatment, 9 (1.1%) developed MASLD at SVR12. Absence of type 2 diabetes (T2D) [odds ratio (OR): 1.73, 95% confidence interval (CI): 1.13–2.65, p = 0.011], age > 50 years (OR: 1.73, 95% CI: 1.11–2.68, p = 0.015), and alanine transaminase (ALT) ≤ 2 times the upper limit of normal (ULN) (OR: 1.56; 95% CI: 1.03–2.37, p = 0.035) were associated with the regression of MASLD. Presence of T2D was associated with the emergence of MASLD (OR: 5.83, 95% CI: 1.51–22.56, p = 0.011).The prevalence of MASLD decreased after achieving SVR12 with DAAs. Patients with pre-existing T2D showed a diminished probability of MASLD regression and a heightened risk of MASLD emergence post-SVR12.Conclusions: Information on the dynamics of metabolic dysfunction-associated steatotic liver disease (MASLD) among hepatitis C virus patients achieving sustained virologic response (SVR12) with direct-acting antivirals (DAAs) is limited.We enrolled 1512 eligible participants in this prospective study. MASLD was defined by a controlled attenuation parameter (CAP) of ≥248 dB/m utilizing vibration-controlled transient elastography in conjunction with presence of  ≥1 cardiometabolic risk factor. The distribution of MASLD and the changes in CAP were evaluated before treatment and at SVR12. Forward stepwise logistic regression analyses were performed to determine factors significantly associated with the regression or emergence of MASLD.The prevalence of MASLD decreased from 45.0% before treatment to 36.1% at SVR12. Among 681 participants with MASLD before treatment, 144 (21%) exhibited MASLD regression at SVR12. Conversely, among 831 participants without MASLD before treatment, 9 (1.1%) developed MASLD at SVR12. Absence of type 2 diabetes (T2D) [odds ratio (OR): 1.73, 95% confidence interval (CI): 1.13–2.65, p = 0.011], age > 50 years (OR: 1.73, 95% CI: 1.11–2.68, p = 0.015), and alanine transaminase (ALT) ≤ 2 times the upper limit of normal (ULN) (OR: 1.56; 95% CI: 1.03–2.37, p = 0.035) were associated with the regression of MASLD. Presence of T2D was associated with the emergence of MASLD (OR: 5.83, 95% CI: 1.51–22.56, p = 0.011).The prevalence of MASLD decreased after achieving SVR12 with DAAs. Patients with pre-existing T2D showed a diminished probability of MASLD regression and a heightened risk of MASLD emergence post-SVR12. [ABSTRACT FROM AUTHOR]

Focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA) are benign hepatocellular tumors. The risk of bleeding and malignant transformation of HCA are strong arguments to differentiate HCA from FNH. Despite great progress that has been made in the differential radiological diagnosis of the 2 types of nodules, liver biopsy is sometimes necessary to separate the 2 entities. Identification of HCA subtypes using immunohistochemical techniques, namely, HNF1A-inactivated HCA (35-40%), inflammatory HCA (IHCA), and beta-catenin-mutated inflammatory HCA (b-IHCA) (50-55%), beta-catenin-activated HCA (5- 10%), and unclassifiedHCA(10%) has greatly improved the diagnostic accuracy of benign hepatocellular nodules. IfHCAmalignant transformation occurs in all HCA subgroups, the risk is by far the highest in the ??-catenin-mutated subgroups (b-HCA, b-IHCA). In the coming decade the management of HCA will be more dependent on the identification of HCA subtypes, particularly for smaller nodules (<5 cm) in terms of imaging, follow-up, and resection. [ABSTRACT FROM AUTHOR]

Background & Aims: This study aimed at investigating mutations in the hepatitis B surface protein (HBsAg) in occult hepatitis B virus (HBV) infection (OBI) and their influence on viral antigenicity and phenotype. Methods: The characteristics of 61 carriers with OBI (OBI group), 153 HBsAg(+) carriers with serum HBsAg ⩽100IU/ml (HBsAg-L group) and 54 carriers with serum HBsAg >100IU/ml (HBsAg-H group) from 38,499 blood donors were investigated. Mutations in the major hydrophilic region (MHR) of the viral sequences were determined. Thirteen representative MHR mutations observed in OBI sequences were antigenically characterized with a panel of monoclonal antibodies (MAbs) and commercial HBsAg immunoassays and functionally characterized in HuH7 cells and hydrodynamically injected mice. Results: Of 61 OBI sequences, 34 (55.7%) harbored MHR mutations, which was significantly higher than the frequency in either the HBsAg-L (34.0%, p =0.003) or the HBsAg-H group (17.1%, p <0.001). Alterations in antigenicity induced by the 13 representative MHR mutations identified in the OBI group were assessed by reacting recombinant HBV mutants with 30 different MAbs targeting various epitopes. Four out of the 13 mutations (C124R, C124Y, K141E, and D144A) strongly decreased the analytical sensitivity of seven commercial HBsAg immunoassays, and 10 (G119R, C124Y, I126S, Q129R, S136P, C139R, T140I, K141E, D144A, and G145R) significantly impaired virion and/or S protein secretion in both HuH7 cells and mice. Conclusions: MHR mutations alter antigenicity and impair virion secretion, both of which may contribute to HBsAg detection failure in individuals with OBI. [Copyright &y& Elsevier]

Background: Peginterferon alfa-2a (40KD), a new treatment option for patients with chronic hepatitis B (CHB), offers improved efficacy with a defined treatment duration compared with lamivudine, but at a higher cost. We undertook an economic evaluation of peginterferon alfa-2a from the perspective of the Taiwan Bureau of National Health Insurance to assess the clinical outcomes and costs of 48 weeks of peginterferon alfa-2a for the treatment of patients with hepatitis B e antigen (HBeAg)-positive CHB, compared to lamivudine treatment for 48 weeks. Methods: We performed a cost-effectiveness analysis using a state-transition Markov model simulating the natural history of HBeAg-positive CHB. Efficacy data were obtained from a randomized clinical trial of 820 patients (87% were Asian) comparing peginterferon alfa-2a to lamivudine. We modeled a hypothetical cohort of 32-year-old patients with HBeAg-positive CHB. Life expectancy, quality-adjusted life expectancy, lifetime costs ($NTD) and incremental cost-effectiveness ratios (ICER) were estimated. One-way sensitivity analyses were performed on all parameters in the model to evaluate uncertainty. Results: Treatment with peginterferon alfa-2a compared to lamivudine resulted in higher total costs, but longer quality-adjusted life expectancy, yielding an ICER of $NTD 381 000 ($US 12 000) per quality-adjusted life year (QALY) gained. Although there is uncertainty associated with the prognosis of HBeAg-positive CHB, the ICER did not exceed $NTD 485 000 ($US 15 000) per QALY gained despite variation in the parameters used in the analysis. Conclusions: Our analysis suggests that 48-week treatment with peginterferon alfa-2a compared to 48-week treatment with lamivudine in HBeAg-positive patients offers life expectancy and quality of life benefits at a favorable cost-effectiveness ratio. [ABSTRACT FROM AUTHOR]

The authors mentioned the previously reported high chronicity rate of up to 90% in infants infected with HBV.[2] The high chronicity rate was from those infants acquiring HBV infection from their HBeAg-positive mothers. Our previous study found that 65% (13/20) of the infants with non-fulminant hepatitis B and 73% (8/11) of patients with fulminant hepatitis B spontaneously cleared HBsAg.[4] Therefore, the spontaneous HBsAg and HBeAg seroconversion rate was inherently higher in infants with elevated ALT, compared with infants with normal ALT. 1 S. Zhu, Y. Dong, L. Wang, W. Liu, P. Zhao, Early initiation of antiviral therapy contributes to a rapid and significant loss of serum HBsAg in infantile-onset hepatitis B. J Hepatol. [Extracted from the article]

Abstract Background and Aims Consensus interferon (CIFN) is a newly developed type I interferon. The aim of this study was to investigate the safety and efficacy of CIFN in the treatment of patients with chronic hepatitis C and to determine the predictors for sustained response. Methods Patients were randomized to receive 3 μg or 9 μg CIFN three times a week for 24 weeks, followed by 24 weeks of observation. Efficacy was assessed by normalization of serum transaminase levels and disappearance of serum hepatitis C virus (HCV)-RNA at the end of treatment and at 24 weeks after stopping treatment. Histologic response was defined as a decrease of at least two points in the Knodell necroinflammatory score at week 48 and was compared with baseline. Results There were no serious adverse effects related to CIFN therapy. Overall, 44% of patients receiving 3 μg and 48% of patients receiving 9 μg had normalization of serum transaminase levels and disappearance of HCV viremia at the end of treatment. At 24 weeks after stopping treatment, 16% of patients in receiving 9 μg and 12% of patients receiving 3 μg had sustained responses. The histologic responses in patients receiving 9 μg and those receiving 3 μg were 60% and 36%, respectively. The necroinflammatory score was significantly reduced from baseline to week 48 in both groups. In addition, bodyweight < 60 kg and pretreatment serum HCV-RNA level < 0.5 MEq/mL can serve as predictors for sustained response to CIFN treatment. Conclusions These findings suggest that 9 μg CIFN is safe and effective in the treatment of patients with chronic hepatitis C. [ABSTRACT FROM AUTHOR]

AbstractBackground: Interspousal transmission of hepatitis C virus (HCV) has been documented; however, the annual risk of interspousal transmission remains unclear. Methods: A long-term prospective study to define the risk of interspousal transmission of HCV was conducted. One hundred and twelve index patients with chronic hepatitis C and their anti-HCV seronegative spouses were enrolled. Results: The mean follow-up period was 45.9 months. Antibodies to HCV (anti-HCV) and HCV-RNA were tested for in each seronegative spouse every year. Seroconversion of anti-HCV occurred in only one spouse, 2 years after enrolment, with a concomitant acute hepatitis. This subject and his spouse were infected with HCV genotype 1b. Nucleotide sequence comparison of the hypervariable region of their HCV genomes showed a homology of 98%. Further phylogenetic analysis suggested that they had virtually the same isolate. Accordingly, the annual risk of interspousal transmission of HCV infection was 0.23% per year. Conclusions: These findings suggest a low incidence of interspousal transmission of HCV; however, the risk may be cumulative and such couples should be educated to avoid HCV infection from their spouses. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatitis B virus (HBV) infection is the major risk factor for hepatocellular carcinoma (HCC). Understanding the unique features for HBV-induced HCC can shed new light on the unmet needs in its early diagnosis and effective therapy. During decades of chronic hepatitis B, hepatocytes undergoing repeated damage and regeneration accumulate genetic changes predisposing to HCC development. In addition to traditional mutations in viral and cellular oncogenes, HBV integration into the cell chromosomes is an alternative genetic change contributing to hepatocarcinogenesis. A striking male dominance in HBV-related HCC further highlights an interaction between androgen sex hormone and viral factors, which contributes to the gender difference via stimulating viral replication and activation of oncogenes preferentially in male patients. Meanwhile, a novel circulating tumor biomarker generated by HBV integration shows great potential for the early diagnosis of HCC. These unique HBV-induced hepatocarcinogenic mechanisms provide new insights for the future development of superior diagnosis and treatment strategies. Hepatitis B virus (HBV) infection is one of the important risk factors for hepatocellular carcinoma (HCC) worldwide, accounting for around 50% of cases. Chronic hepatitis B infection generates an inflammatory microenvironment, in which hepatocytes undergoing repeated cycles of damage and regeneration accumulate genetic mutations predisposing them to cancer. A striking male dominance in HBV-related HCC highlights the influence of sex hormones which interact with viral factors to influence carcinogenesis. HBV is also considered an oncogenic virus since its X and surface mutant proteins showed tumorigenic activity in mouse models. The other unique mechanism is the insertional mutagenesis by integration of HBV genome into hepatocyte chromosomes to activate oncogenes. HCC survival largely depends on tumor stages at diagnosis and effective treatment. However, early diagnosis by the conventional protein biomarkers achieves limited success. A new biomarker, the circulating virus–host chimera DNA from HBV integration sites in HCC, provides a liquid biopsy approach for monitoring the tumor load in the majority of HBV–HCC patients. To maximize the efficacy of new immunotherapies or molecular target therapies, it requires better classification of HCC based on the tumor microenvironment and specific carcinogenic pathways. An in-depth study may benefit both the diagnosis and treatment of HBV-related HCC. [ABSTRACT FROM AUTHOR]

Taiwan has launched a series of population-wide interventions to prevent hepatocellular carcinoma (HCC) related to hepatitis B and C virus infection since 1984. We took this opportunity to investigate the impact of each intervention on the incidence and case-fatality rate of HCC, and assessed their relative contributions to the overall reduction in mortality during this period. Population-based registry data on HCC mortality and incidence from individuals aged 0 to 84 years between 1979 and 2016 were collected before (Period 1) and after universal hepatitis B vaccination from 1984 (Period 2), universal health care from 1995 (Period 3), and viral hepatitis therapy from 2003 (Period 4). A Bayesian Poisson regression model was used for mortality decomposition analysis to estimate the respective contributions of these interventions to the reduction in age-specific incidence and case-fatality rates. Mortality declined substantially in children, young- and middle-aged groups, but only slightly decreased in the elderly group. The declining trends in mortality were in part explained by incidence reduction and in part by a remarkable decline in case-fatality rate attributed to universal health care. Hepatitis B vaccination led to a 35.9% (26.8% to 44.4%) reduction in incidence for individuals aged 30 years or below, whereas antiviral therapy reduced the incidence of HCC by 14.9% (11.8% to 17.9%) and 15.4% (14.1% to 16.6%) for individuals aged 30–49 years and 50–69 years, respectively. Vaccination and antiviral therapy were effective in reducing HCC incidence and mortality for the young and middle-aged groups, while the case-fatality rate was improved by universal health care for all age groups. Since 1984, a series of population-wide interventions have been launched in Taiwan to prevent viral hepatitis-related hepatocellular carcinoma, including a universal hepatitis B vaccination program (from 1984), universal health care (from 1995), and a national viral hepatitis therapy program (from 2004). Vaccination and antiviral therapy were effective in reducing HCC incidence and mortality for the young and middle-aged groups, while the case-fatality rate was improved by universal health care for all age groups. [Display omitted] • We assessed the impact of serial population-wide prevention programs on HCC mortality (incidence and case-fatality rates). • Hepatitis B vaccination was associated with a 35.9% reduction in incidence in the young age group. • Antiviral therapy was associated with a ~15% decline in incidence in the middle-aged group. • Surveillance resulted in a remarkable decline in the case-fatality rate across the whole population. [ABSTRACT FROM AUTHOR]

The nephrotoxicity of sofosbuvir (SOF) on human immunodeficiency virus and hepatitis C virus (HIV/HCV)‐coinfected patients receiving antiretroviral therapy (ART) remains controversial. We prospectively compared the estimated glomerular filtration rate (eGFR) changes in 167 patients receiving SOF‐based direct‐acting antivirals (DAAs) who also received tenofovir disoproxil fumarate (TFV)‐based (n = 116) and TFV‐free ART (n = 51). The eGFR was assessed by the Chronic Kidney Disease Epidemiology Collaboration (CKD‐EPI) equation, and the eGFR changes between ART regimens were compared by the generalized estimated equation. During DAA treatment, participants on TFV‐based ART had a higher eGFR decline than those on TFV‐free ART (slope coefficient difference: −0.82 ml/min/1.73 m2/month [95% CI: −1.21 to −0.43]; p < 0.001), whereas the eGFR changes did not differ between groups (slope coefficient difference: 0.13 ml/min/1.73 m2/month [95% CI: −0.32 to 0.58]; p = 0.42) after discontinuing DAAs. Participants on TFV TDF‐based ART had a higher eGFR decline than those on TFV alafenamide fumarate (TAF)‐based ART (slope coefficient difference: −0.31 ml/min/1.73 m2/month [95% CI: −0.50 to −0.12]; p = 0.01). After discontinuing DAAs, the eGFR changes did not differ between groups (slope coefficient difference: 0.06 ml/min/1.73 m2/month [95% CI: −0.98 to 1.10]; p = 0.91). In conclusion, HIV/HCV‐coinfected patients on TFV‐based ART had a slight eGFR decline compared to those on TFV‐free ART during SOF‐based DAA therapy. A similar trend between TDF‐based and TAF‐based ART was also observed. Because the differences of eGFR changes are limited, the physicians should not discourage the use of SOF‐based DAAs in HIV‐positive patients on TFV‐based ART. [ABSTRACT FROM AUTHOR]