Liver stiffness measurements predict Sinusoidal Obstructive Syndrome after hematopoietic stem cell transplantation.

Sinusoidal Obstructive Syndrome (SOS) is a life-threatening complication after hematopoietic stem-cell transplantation (HSCT), characterized by post-sinusoidal portal hypertension. FibroScan is used to assess portal hypertension non-invasively. We assessed transient elastography (TE) applicability in diagnosing SOS. The study included 27 adult patients, 11 underwent TE for high SOS risk pre-HSCT, 17 underwent TE post-HSCT due to bilirubin ≥2 mg/dl with no definite diagnosis of SOS. The first group had median Liver Stiffness Measurement (LSM) of 7.4 kPa (range, 3.3-22.5). Based on LSM results, conditioning regimen was modified for six patients and two of them developed SOS. Only one patient who did not have protocol adjustment experienced SOS. No patient with LSM < 7 kPa developed SOS. The second group had median LSM of 7.7 kPa (4.4-31.5). Median LSM after HSCT was significantly higher in patients who subsequently developed established SOS (n = 10) compared to patients who did not (n = 8), with values of 10.7 kPa (5.6-31.5) and 5.9 kPa (4.4-13.8), respectively (p = 0.02). An LSM cut-off of 7.5 kPa had a sensitivity and specificity of 75 and 80% for diagnosing SOS. In conclusion, pre-HSCT LSM can help adjustment of conditioning regimen in patients with high-risk for SOS. Post-HSCT LSM can help in early diagnosis of SOS.

Hepatitis B virus infection and risk of colorectal cancer: a large, population-based cohort study from Israel.

BACKGROUND: Recent population-based studies have suggested a possible link between hepatitis B (HBV) infection and extra-hepatic malignancies. We aimed to evaluate the association between HBV and colorectal cancer (CRC) using a large, population-based cohort study utilizing data from a large health maintenance organization (HMO). METHODS: The study included patients with non-cirrhotic HBV based on relevant ICD-9-CM codes and supportive serology identified from the HMO's database. Age-, sex-, ethnicity-, and BMI-matched non-HBV patients in a 1:10 ratio were included in the control group. We assessed the overall diagnosis rate of CRC and hepatocellular carcinoma (HCC) during the study period and calculated the diagnosis rate of CRC in each age category (≤50, 51-70, and ≥70) in both groups. RESULTS: A total of 3430 HBV patients and 34,300 controls were included in the study. The mean age, sex, BMI, and ethnic composition were similar, and the rates of family history of CRC did not differ between both groups. The overall follow-up period was 134±16 months. The diagnosis rate of HCC (1.6% vs. 0.1%; P<0.0001) was significantly higher in the HBV patients. However, the proportion of CRC was comparable for both groups (0.6% vs. 0.8%, P=0.404), which was evident in all age subgroups. CONCLUSIONS: Our findings suggest that HBV infection is associated with an increased risk of HCC diagnosis but is not linked to an elevated risk of CRC. These findings may inform future clinical practice and research regarding the relationship between HBV and extrahepatic malignancies.

Predictors of advanced liver fibrosis and the performance of fibrosis scores: lean compared to non-lean metabolic dysfunction-associated steatotic liver disease (MASLD) patients.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) in lean patients differs from that of NAFLD in non-lean patients. However, current data regarding predictors of advanced fibrosis and the performance of fibrosis-4 index (FIB-4) and NAFLD fibrosis score (NFS) in lean compared to non-lean metabolic dysfunction-associated steatotic liver disease (MASLD) patients is insufficient. METHODS: This was a cross-sectional study. Lean was defined as Body Mass Index <25 kg/m2. Advanced fibrosis (F3-F4) was detected by liver biopsy or two-dimension shear wave elastography (2D-SWE). Predictors of advanced fibrosis were identified using logistic regression and area under ROC curves (AUROC) were derived for FIB-4 and NFS. RESULTS: Lean patients (N.=153) comprised 19.2% of the MASLD cohort. Advanced fibrosis was associated with the number of cardiometabolic risk factors (CMRF) in lean (OR=2.06, P=0.011) and non-lean (OR=1.58, P<0.001) patients, however, hypertension and diabetes or impaired fasting glucose were significant only among non-lean. Age was associated with advanced fibrosis in both subgroups with age ≥65 showing higher odds in lean compared to non-lean patients (P=0.016). Non-lean patients had higher odds for advanced fibrosis relative to lean patients (OR=4.8, P=0.048). FIB-4 and NFS predicted advanced fibrosis among lean (AUROC=0.79 and AUROC=0.85, respectively) and non-lean (AUROC=0.79 and AUROC=0.76, respectively) patients. NFS ≥-1.445 showed higher specificity among lean compared to non-lean (P<0.001) and compared to that of FIB-4 ≥1.3 in lean patients (P<0.001). CONCLUSIONS: The number of CMRF was predictive of advanced fibrosis in both subgroups while age ≥65 showed higher odds among lean patients. NFS ≥-1.445 is more specific than FIB-4 ≥1.3 for advanced fibrosis prediction in lean patients. These findings may help identify high-risk lean MASLD patients for further liver fibrosis stage assessment.

Toxicity mechanisms of biomass burning aerosols in in vitro hepatic steatosis models.

Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease that contributes to the global rise in liver-related morbidity and mortality. Wood tar (WT) aerosols are a significant fraction of carbonaceous aerosol originating from biomass smoldering, contributing to air pollution particles smaller than 2.5 mm (PM2.5). Mechanistic biological associations exist between exposure to PM2.5 and increased NAFLD phenotypes in both cell and animal models. Therefore, this study examines whether an existing NAFLD-like condition can enhance the biological susceptibility of liver cells exposed to air pollution in the form of WT material. Liver cells were incubated with lauric or oleic acid (LA, OA, respectively) for 24 h to accumulate lipids and served as an in vitro hepatic steatosis model. When exposed to 0.02 or 0.2 g/L water-soluble WT aerosols, both steatosis model cells showed increased cell death compared to the control cells (blank-treated cells with or without pre-incubation with LA or OA) or compared to WT-treated cells without pre-incubation with LA or OA. Furthermore, alterations in oxidative status included variations in reactive oxygen species (ROS) levels, elevated levels of lipid peroxidation adducts, and decreased expression of antioxidant genes associated with the NRF2 transcription factor. In addition, steatosis model cells exposed to WT had a higher degree of DNA damage than the control cells (blank-treated cells with or without pre-incubation with LA or OA). These results support a possible systemic effect through the direct inflammatory and oxidative stress response following exposure to water-soluble WT on liver cells, especially those predisposed to fatty liver. Furthermore, the liver steatosis model can be influenced by the type of fatty acid used; increased adverse effects of WT on metabolic dysregulation were observed in the LA model to a higher extent compared to the OA model.

Hepatitis D double reflex testing of all hepatitis B carriers in low-HBV- and high-HBV/HDV-prevalence countries.

Hepatitis D virus (HDV) infection occurs as a coinfection with hepatitis B and increases the risk of hepatocellular carcinoma, decompensated cirrhosis, and mortality compared to hepatitis B virus (HBV) monoinfection. Reliable estimates of the prevalence of HDV infection and disease burden are essential to formulate strategies to find coinfected individuals more effectively and efficiently. The global prevalence of HBV infections was estimated to be 262,240,000 in 2021. Only 1,994,000 of the HBV infections were newly diagnosed in 2021, with more than half of the new diagnoses made in China. Our initial estimates indicated a much lower prevalence of HDV antibody (anti-HDV) and HDV RNA positivity than previously reported in published studies. Accurate estimates of HDV prevalence are needed. The most effective method to generate estimates of the prevalence of anti-HDV and HDV RNA positivity and to find undiagnosed individuals at the national level is to implement double reflex testing. This requires anti-HDV testing of all hepatitis B surface antigen-positive individuals and HDV RNA testing of all anti-HDV-positive individuals. This strategy is manageable for healthcare systems since the number of newly diagnosed HBV cases is low. At the global level, a comprehensive HDV screening strategy would require only 1,994,000 HDV antibody tests and less than 89,000 HDV PCR tests. Double reflex testing is the preferred strategy in countries with a low prevalence of HBV and those with a high prevalence of both HBV and HDV. For example, in the European Union and North America only 35,000 and 22,000 cases, respectively, will require anti-HDV testing annually.

Chronic hepatitis B infection and diabetes mellitus: a double liver trouble?

BACKGROUND: Concomitant Diabetes mellitus (DM) is commonly recognized in patients with chronic hepatitis B (CHB) infection, although its impact on liver-related outcomes remains controversial. We aimed to evaluate the effect of DM on the course, management and outcome of patients with CHB. METHODS: We performed a large retrospective cohort study utilizing the Leumit-Health-Service (LHS) database. We reviewed electronic reports of 692106 LHS members from different ethnicities and districts in Israel from 2000-2019 and included patients with CHB diagnosis based on ICD-9-CM codes and supportive serology results. These were divided into two cohorts of patients with CHB and DM (CHD-DM) (N.=252) and those with CHB without DM (N.=964). Clinical parameters, treatment figures and patients' outcomes were compared and multiple regression models and Cox regression analysis were performed to investigate the association between DM and cirrhosis/HCC risk in CHB patients. RESULTS: CHD-DM patients were significantly older (49.2±10.9 vs. 37.9±14, P<0.001), and had higher rates of obesity (BMI>30) and NAFLD (47.2% vs. 23.1%, and 27% vs. 12.6%, P<0.001, respectively). Both groups had a predominance of inactive carrier (HBeAg negative infection) state, but the HBeAg seroconversion rate was significantly lower in the CHB-DM group (25% vs. 45.7%; P<0.01). Multivariable Cox regression analysis showed that DM was independently associated with increased cirrhosis risk (HR 2.63; P=0.002). Older age, advanced fibrosis and DM were associated with HCC, but DM did not reach significance (HR 1.4; P=0.12) possibly due to the small number of HCC cases. CONCLUSIONS: Concomitant DM in CHB patients was significantly and independently associated with cirrhosis and possibly with increased risk of HCC.

Acquired Hepatocerebral Degeneration: A Case Series of a Rare Condition.

BACKGROUND: Acquired hepatocerebral degeneration (AHD) is a neurologic complication of severe chronic liver disease (CLD) with portosystemic shunts. The proposed etiology is manganese accumulation in the brain tissue, especially in the basal ganglia. Combination of clinical manifestation, mostly extrapyramidal movement disorders, and hyperintensities on T1-weighted brain magnetic resonance imaging (MRI) is diagnostic. Although liver transplantation controversial, it is suggested for AHD. OBJECTIVES: To depict clinical and neuroimaging characteristics and response to treatments in patients diagnosed with AHD at Sheba Medical Center. METHODS: Review of patients with AHD diagnosis at the Liver Diseases Center at Sheba Medical Center between 2012 and 2017, data of clinical and neuroimaging, follow-up, and response to treatments, including liver transplantation were recorded. RESULTS: Five patients with diagnosis of AHD were identified, median age at diagnosis 55 years (range 45-64 years). Four patients had cirrhosis at the time of AHD diagnosis. The main risk factor for AHD was the presence of portosystemic shunts. The most prevalent clinical manifestations were movement disorders, specifically a combination of extrapyramidal and cerebellar signs including instability, rigidity, tremor, bradykinesia, and cognitive impairment. Brain MRI revealed hyperintensities on T1-weighted images in the basal ganglia in all patients. Administration of antiparkinsonian drugs showed clinical improvement, whereas liver transplantation performed in two patients was not associated to neurological improvement. CONCLUSIONS: AHD is related to portosystemic shunts. The combination of Parkinsonism and cerebellar signs and MRI pallidal lesions should alert physicians to the diagnosis. The role of liver transplantation in AHD is still controversial.

Reduced Neutralization Efficacy against Omicron Variant after Third Boost of BNT162b2 Vaccine among Liver Transplant Recipients.

The immune responses of liver transplant (LT) recipients after the third boost of the BNT162b2mRNA vaccine improved. This study evaluates the durability of the immune response of LT recipients after the third boost, its predictors, and the impact of emerging variants. The receptor-binding domain IgG was determined at median times of 22 (first test) and 133 days (second test) after the administration of the third boost. IgG antibody titers > 21.4 BAU/mL were defined as a positive response. The neutralization efficacies of the vaccine against the wild-type, Omicron, and Delta variants were compared in the first test. The 59 LT recipients were of a median age of 61 years (range 25−82); 53.5% were male. Following administration of the third dose, the positive immune response decreased from 81.4% to 76.3% between the first and second tests, respectively, (p < 0.0001). The multivariate analysis identified CNI monotherapy (p = 0.02) and hemoglobin > 12 g/dL (p = 0.02) as independent predictors of a maintained positive immune response 133 days after the third dose. The geometric mean titers of Omicron neutralization were significantly lower than the wild-type and Delta virus (21, 137, 128, respectively; p < 0.0001). The immune response after the third BNT162b2mRNA vaccine dose decreased significantly in LT recipients. Further studies are required to evaluate the efficacy of the fourth vaccine dose and the durability of the immune response.

The impact of ethnicity on chronic hepatitis B infection course and outcome: big data analysis from Israel.

OBJECTIVES: The effect of ethnicity on chronic hepatitis B virus (CHB) infection's course and outcome has attracted little research. We aimed to compare different aspects of ethnic disparities in CHB patients, including prevalence, phenotypes, management, and outcome between two major ethnic groups in Israel. DESIGN: We conducted a large retrospective cohort study utilizing the Leumit-Health-Service database. Electronic reports of almost 700,000 members from different ethnicities and districts throughout Israel from 2000 to 2019 were reviewed. Patients' ethnicity was categorized based on the classification of the Israeli Central Bureau of Statistics into two main groups, Arabs and Jews. CHB diagnosis was based on ICD-9-CM codes and supportive serology results. Prevalence, clinical backgrounds, disease course, and patients' outcomes were compared between both groups. RESULTS: The prevalence of CHB in the Arab minority group was almost twice and a half-higher when compared to their Jewish counterparts (4.3% vs. 1.8%), but they had a lower rate of referral for HBsAg testing (7% vs. 7.9%). The Arab CHB patients were significantly younger at the time of diagnosis (37.6± 13.5 vs. 45.3± 15; P < 0.001). Male predominance was noted in both groups. The Arab patients had a higher rate of active hepatitis (HBeAg-positive and/or negative hepatitis) phase (36.4% vs. 29.8%; P = 0.01), as well as a significantly higher rate of HBeAg seroconversion (45.2% vs. 35.4%; P = 0.033). Nucleos/tide analogue treatment figures were similar, with most patients in both groups receiving a high barrier to resistance treatment. Patients' outcome was similar in both groups as the rate of hepatocellular carcinoma, cirrhosis, and advanced fibrosis (after stratification analysis) were comparable between both groups. CONCLUSION: Marked by a prominently higher prevalence of HBV infection, patients in the Arab ethnic group had a lower rate of referral for HBsAg testing but received comparable management and had a similar outcome compared to their Jewish counterparts.

Real-world hepatitis B antiviral treatment trends and adherence to practice guidelines: a large cohort study.

BACKGROUND: Epidemiologic data regarding chronic hepatitis B virus infections in Israel is limited as extensive population-based studies have not been performed. OBJECTIVE: This work aimed to evaluate the current characteristics of hepatitis B infection among Israeli adults and evaluate adherence to the European Association for the Study of the Liver practice guidelines for antiviral treatment. METHODS: Clinical and demographic data of HBsAg-positive patients registered in the Leumit-Health-Service database (one of the four major health maintenance organizations in Israel) between 2000 and 2019 were retrieved. Patients were compared according to eligibility to antiviral treatment and type of nucleos(t)ide analogue (NA) treatment. RESULTS: In total, 1216 patients had documented HBsAg positivity (males 58.6%, mean age 40.2 ± 14.2 years), 90.6% of whom were HBeAg negative. Antiviral therapy eligibility was met by 37% of patients, among whom 89% received antiviral therapy. Antiviral therapies include NA with a high barrier to resistance (HBR) (64.5%) and NA with a low barrier to resistance (LBR) (35.5%). Compared to patients who received LBR NA, patients receiving HBR NA had shorter treatment (68.7 ± 50 vs. 161.5 ± 42.6 months, p < .001) and follow-up duration (125 ± 68 vs. 188 ± 48 months, p < .001); at the end of follow-up, ALT levels and APRI score were higher among patients on LBR NA compared to patients on HBR NA. CONCLUSION: Most patients received antiviral treatment according to the international practice guidelines. However, one-third of them were treated with a less potent NA, probably due to their lower cost. These findings should encourage the optimization of HBV care and full compliance with the professional practice guideline recommendations.

High Immune Response Rate to the Fourth Boost of the BNT162b2 Vaccine against the Omicron Variants of Concern among Liver Transplant Recipients.

The immune response of liver transplant (LT) recipients to a third dose of the BNT162b2 mRNA vaccine significantly waned after four months. We aimed to evaluate the immune response and breakthrough infection rates of a fourth dose against the Omicron variants among LT recipients. LT recipients who had no past or active SARS-CoV-2 infection and received three doses of the BNT162b2mRNA vaccine were included. Of the 73 LT recipients, 50 (68.5%) received a fourth dose. The fourth dose was associated with a significantly higher positive immune response than the third dose. Receptor-binding domain (RBD) IgG and Omicron BA.1 and BA.2 neutralizing antibodies were determined at a median of 132 and 29 days after the third and fourth vaccines. They were 345 binding antibody units per milliliter (BAU/mL) vs. 2118 BAU/mL (p < 0.0001), 10 vs. 87 (p < 0.0001), and 15 vs. 149 (p = 0.001), respectively. Breakthrough infections were documented among nine (18%) LT recipients after the fourth dose and among seven (30.4%) patients following the third dose (p = 0.2); 93.5% of breakthrough infections were mild. The infection rate after the fourth dose was higher among diabetic vs. nondiabetic recipients (33.3% vs. 6.9%, respectively; p = 0.02). Further studies are needed to evaluate additional factors influencing the breakthrough infection rate among LT recipients.

Research trends analysis of chronic hepatitis C versus nonalcoholic fatty liver disease: A literature review text-mining analysis of publications.

Background: Hepatits C virus (HCV) rates have lowered due to direct-acting antiviral treatment. Nonalcoholic steatohepatitis (NASH)/nonalcoholic fatty liver disease (NAFLD) is rising with no available therapy. We employed text-mining to analyze trends in HCV and NAFLD research from the past two decades. Materials and Methods: We queried PubMed for all HCV and NASH/NAFLD entries published between 2000 and 2020. We compared the total number of publications on both etiologies. We performed subanalyses for different terms of interest and for geographic origin. Results: Overall, 75,934 HCV-related entries and 24,987 NASH/NAFLD-related entries were published during the study period. Up to 2015, there was a linear upward slope in the number of annual HCV publications (154.9 publications/year, p < 0.001). In 2015, the yearly number of HCV publications started showing a downward slope (-242.2 publications/year, p < 0.001). The number of NASH/NAFLD publications showed a continuous upward slope during the study period. The NASH/NAFLD field lacks publications on screening and treatment methods. Conclusion: Trends in publications varied between both etiologies. They reflect the success of antiviral treatment for HCV. The growing rates of NAFLD/NASH and the lack of a targeted cure explain the rise in related publications.

Licogliflozin for nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled, phase 2a study.

Nonalcoholic steatohepatitis (NASH) is a common chronic liver disease that may advance to fibrosis and lead to mortality; however, no pharmacotherapy is currently available. We tested the hypothesis that inhibition of both the sodium-glucose cotransporters 1 and 2 with licogliflozin would lead to improvement in NASH. A total of 107 patients with phenotypic or histologic NASH were randomized (1:2:2) to receive oral administration of either placebo (n = 21), licogliflozin 30 mg (n = 43) or 150 mg (n = 43) once daily for 12 weeks. Licogliflozin 150 mg showed a significant 32% (80% confidence interval (CI): 21-43%; P = 0.002) placebo-adjusted reduction in serum alanine aminotransferase after 12 weeks of treatment, the primary endpoint of the study. However, the 30 mg dose of licogliflozin did not meet the primary endpoint (placebo-adjusted reduction 21% (80% CI: 7-32%; P = 0.061)). Diarrhea occurred in 77% (33 of 43), 49% (21 of 43) and 43% (9 of 21) of patients treated with licogliflozin 150 mg, 30 mg and placebo, respectively, which was mostly mild in severity. No other major safety concerns were identified. Treatment with 150 mg licogliflozin led to reductions in serum alanine aminotransferase in patients with NASH. Studies of longer duration and in combination with drugs that have different mechanisms of action are needed to validate these findings and to define a role of licogliflozin as a therapeutic option for NASH. ClinicalTrials.gov identifier: NCT03205150.

Extracellular Vesicular Transmission of miR-423-5p from HepG2 Cells Inhibits the Differentiation of Hepatic Stellate Cells.

Liver fibrosis (LF) is a major cause of morbidity and mortality worldwide. Hepatic stellate cells (HSCs) are the primary source of extracellular matrix in the liver and their activation is a central event in LF development. Extracellular vesicles (EVs) are intercellular communication agents, which play important roles in physiological processes in chronic liver diseases. The aim of this study was to examine the crosstalk between hepatocytes and HSCs mediated by hepatocyte-secreted EVs. EVs were purified from primary mouse hepatocytes, HepG2 cell lines, under normal or stressed conditions. The effect of EVs on primary HSCs (pHSCs) differentiation was evaluated by measuring of differentiation markers. In addition, their impact on the carbon tetrachloride (CCl4)-induced fibrosis mouse model was evaluated. The results demonstrated that HepG2-EVs regulate HSC differentiation and that under stress conditions, promoted pHSCs differentiation into the myofibroblast phenotype. The evaluation of miRNA sequences in the HepG2 secreted EVs demonstrated high levels of miR-423-5p. The examination of EV cargo following stress conditions identified a significant reduction of miR-423-5p in HepG2-EVs relative to HepG2-EVs under normal conditions. In addition, pHSCs transfected with miR-423-5p mimic and exhibit lower mRNA levels of alpha smooth muscle actin and Collagen type 1 alpha, and the mRNA expression level of genes targeted the family with sequence-similarity-3 (FAM3) and Monoacylglycerol lipase (Mgll). This study strengthened the hypothesis that EVs are involved in LF and that their cargo changes in stress conditions. In addition, miR-423-5p was shown to be involved in HSCs differentiation and hence, fibrosis development.

A third dose of the BNT162b2 mRNA vaccine significantly improves immune responses among liver transplant recipients.

BACKGROUND & AIMS: Immune responses of solid organ transplant recipients to 2 doses of the BNT162b2 mRNA anti-SARS-CoV-2 vaccine are impaired. The immunogenicity and safety of a third dose among liver transplant (LT) recipients are unknown. This work aimed to evaluate the immune response of LT recipients to a third dose of the BNT162b2 mRNA vaccine. METHODS: Consecutive LT recipients (n = 61) in follow-up at Sheba Medical Center were included. Receptor binding domain (RBD) IgG, neutralizing antibody (NA) titers, and T-cell levels before and 21-28 days after a third vaccine dose were determined. Adverse effects after the third dose were monitored. RESULTS: The median age of LT recipients was 65 years and 57.4% were male. The humoral immune response rate improved significantly, with 56% of patients showing a response before the third vaccine dose compared to 98% after the third dose. The cellular response in 12 evaluated patients improved significantly (p = 0.008). The geometric mean of anti-RBD IgG levels, NA levels, and T-cell count also increased significantly after the third dose. NA titers after the third dose negatively correlated with age (p = 0.03), mycophenolate mofetil treatment (p = 0.005), and combined immunosuppression as opposed to calcineurin inhibitor monotherapy (p = 0.001). After the third dose, adverse effects were reported by 37% of recipients and were mostly mild (local pain and fatigue). CONCLUSION: After a third BNT162b2 mRNA vaccine, the immune response improved significantly among LT recipients, without serious adverse effects. Further studies are needed to evaluate immune response durability and to determine the optimal number and schedule of booster vaccine doses. LAY SUMMARY: The Pfizer-Biotech BNT162b2SARS-CoV-2 vaccine induced significant immunity among liver transplant recipients after a third dose. The majority of the patients developed sufficient levels of both humoral and cellular immune responses. Factors that predict non-response were older age and immunosuppressive medications.

HBV-RNA, Quantitative HBsAg, Levels of HBV in Peripheral Lymphocytes and HBV Mutation Profiles in Chronic Hepatitis B.

A comprehensive characterization of chronic HBV (CHB) patients is required to guide therapeutic decisions. The cumulative impact of classical and novel biomarkers on the clinical categorization of these patients has not been rigorously assessed. We determined plasma HBV-RNA and HBsAg levels, HBV in peripheral lymphocytes (PBMCs) and HBV mutation profiles in CHB patients. Patient demographics (n = 139) and classical HBV biomarkers were determined during a clinical routine. HBV-RNA in plasma and HBV-DNA in PBMCs were determined by RT-PCR. HBsAg levels were determined using Architect. In samples with HBV-DNA viral load >1000 IU/mL, genotype mutations in precore (PC), basal core promoter (BCP), HBsAg and Pol regions were determined by sequencing. Most patients (n = 126) were HBeAg-negative (HBeAgNeg) with significantly lower levels of HBV-RNA, HBV-DNA and HBsAg compared to HBeAg-positive (HBeAgPos) patients (p < 0.05). HBV genotype D prevailed (61/68), and >95% had BCP/PC mutations. Escape mutations were identified in 22.6% (13/63). HBeAgNeg patients with low levels of HBsAg (log IU ≤ 3) were older and were characterized by undetectable plasma HBV-DNA and undetectable HBV-RNA but not undetectable HBV-DNA in PBMCs compared to those with high HBsAg levels. In >50% of the studied HBeAgNeg patients (66/126), the quantitation of HBsAg and HBV-RNA may impact clinical decisions. In conclusion, the combined assessment of classical and novel serum biomarkers, especially in HBeAgNeg patients, which is the largest group of CHB patients in many regions, may assist in clinical decisions. Prospective studies are required to determine the real-time additive clinical advantage of these biomarkers.

Immunogenicity and Adverse Effects of the 2-Dose BNT162b2 Messenger RNA Vaccine Among Liver Transplantation Recipients.

The BNT162b2 messenger RNA (mRNA) vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been shown to be safe and effective in immunocompetent patients. The safety and efficacy of this vaccine in liver transplantation (LT) recipients is still under evaluation. The objective of this study was to assess the safety and efficacy of the BNT162b2 vaccine among transplant recipients. The immune responses of 76 LT recipients receiving 2 doses of the vaccine were compared with those of 174 age-matched immunocompetent controls. Postvaccination immunoglobulin G (IgG) antibodies against the receptor-binding domain (RBD) of SARS-CoV-2 and neutralizing antibodies (NA) to the BNT162b2 mRNA vaccine were determined at least 14 days after the second dose of the vaccine. IgG antibody titers ≥1.1 were defined as positive antibodies. Adverse effects were monitored during the study period. Following administration of the second dose, transplant recipients showed reduced immune responses compared with controls (72% versus 94.2%; P < 0.001). At a median time of 38 days after the second vaccination, the geometric mean of RBD IgG and NA titers were 2.1 (95% confidence interval [CI], 1.6-2.6) and 150 (95% CI, 96-234) among transplant recipients and 4.6 (95% CI, 4.1-5.1) and 429 (95% CI, 350-528) in the control group, respectively (P < 0.001). Antibody responses were lower in transplant recipients who were receiving combined immunosuppression therapy and in those with impaired renal function. Among the LT recipients with negative antibody responses, 1 became infected with SARS-CoV-2, but no recipients with positive antibody responses became infected. Overall, most (n = 39 [51%]) adverse effects self-reported by transplant recipients were mild and occurred more often in women than in men. Compared with patients who were immunocompetent, LT recipients had lower immune responses. The durability of immune responses to the BNT162b2 vaccine among LT recipients requires further investigation.

Noninvasive Assessment of Fibrosis Regression after Direct-acting Antiviral Treatment in Hepatitis C Virus Patients.

BACKGROUND: New direct acting antiviral agent (DAA) therapies are associated with a high sustained virological response rate (SVR) in hepatitis C virus (HCV) patients. The understanding of the impact of SVR on fibrosis stage is limited. OBJECTIVES: To determine the effect of treatment with the DAAs on long-term liver fibrosis stages, as determined by shear-wave elastography (SWE) or FibroTest. METHODS: Fibrosis stage was determined at baseline and at 6-month intervals after end of treatment (EOT), using two-dimensional SWE or FibroTest©; APRI and FIB-4 scores. RESULTS: The study comprised 133 SVR12 patients. After a median follow-up of 15 months (range 6-33), liver fibrosis stage decreased by at least 1 stage in 75/133 patients (56%). Cirrhosis reversal was observed in 24/82 (29%). Repeated median liver stiffness SWE values in cirrhotic patients were 15.1 kPa at baseline (range 10.5-100), 13.4 kPa (range 5.5-51) at 6 months, and 11.4 kPa (range 6.1-35.8) at 12 months after EOT, P = 0.01. During the second year after EOT, no statistically significant differences in liver fibrosis stage in 12, 18, and 24 months were found. Splenomegaly was the only significant negative predictor of liver fibrosis regression during all time points of repetitive noninvasive assessment. CONCLUSIONS: Following successful DAA treatment, the majority of our HCV patients with advanced fibrosis demonstrated significant improvement, as assessed by non-invasive methods. Advanced fibrosis stage was a negative predictor of fibrosis regression. Longer follow-up periods are required to further establish the impact of DAAs treatment in HCV patients with advanced fibrosis.

Evaluation of a universal hepatitis B vaccination program and antenatal screening for hepatitis B surface antigen: Results from a real-world study 2015-2016.

BACKGROUND AND AIMS: Universal vaccination against hepatitis B virus (HBV) in infancy was implemented in Israel in 1992. This population-based study aimed to evaluate the coverage rate and cost-benefit of the HBV vaccination program among infants in Israel and the Hepatitis B surface antigen (HBsAg) status in their mothers. METHODS: Using the database of a health maintenance organization with 2 million members, we retrospectively identified, all the infants born in 2015-2016 and their mothers. Maternal data collected included age, ethnicity, country of birth and HBsAg status during pregnancy. HBV vaccination coverage among infants was calculated. A cost-benefit analysis of the HBV vaccination program was conducted based on the actual costs of HBV infection treatments in all HBsAg positive mothers. RESULTS: Our cohort included 72,792 mothers who gave birth to 77,572 live infants. A total of 71,107 (97.7%) mothers were screened for HBV during pregnancy, of them 124 (0.2%), who gave birth to 132 infants were HBsAg positive. HBV vaccination coverage rates were 94%, 93% and 89%, for the first, second and third dose, respectively. Birth dose coverage of 95% among infants born to HBsAg positive mothers was significantly higher compared to HBsAg negative or unscreened mothers (p < 0.001). The percentage of HBsAg positivity among mothers who were born in Israel, the Former Soviet Union or Ethiopia, were 0.1%, 0.8% and 5%, respectively (p < 0.001). Ethnic differences were not found between HBsAg positive and HBsAg negative mothers. Calculated benefit-to-cost ratios were 1.24:1 and 4.15:1, with and without antenatal HBsAg screening, respectively. CONCLUSIONS: The Israeli vaccination program against HBV infection is epidemiologically and economically justified. High coverage rates among infants born to HBsAg positive mothers reflect very good adherence to the vaccination program and antenatal screening. Higher HBsAg positivity rates among immigrant mothers identify a high-risk population for HBV infection.