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

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

Taurine-conjugated bile acids and their link to hepatic S1PR2 play a significant role in hepatitis C-related liver disease.

BACKGROUND: Bile acids mediate gut-liver cross-talk through bile acid receptors. Serum, hepatic, and microbial bile acid metabolism was evaluated in HCV-compensated chronic liver disease. METHODS: Patients underwent liver biopsy; portal and peripheral blood were obtained before (HCVi), and 6 months after sustained virologic response (SVR), splenic blood was obtained only after SVR. The fecal microbiome and liver transcriptome were evaluated using RNA-Seq. Twenty-four bile acids were measured in serum, summed as free, taurine-conjugated bile acids (Tau-BAs), and glycine-conjugated bile acids. RESULTS: Compared to SVR, HCVi showed elevated conjugated bile acids, predominantly Tau-BA, compounded in HCVi cirrhosis. In the liver, transcription of bile acids uptake, synthesis, and conjugation was decreased with increased hepatic spillover into systemic circulation in HCVi. There was no difference in the transcription of microbial bile acid metabolizing genes in HCVi. Despite an overall decrease, Tau-BA remained elevated in SVR cirrhosis, mainly in splenic circulation. Only conjugated bile acids, predominantly Tau-BA, correlated with serum proinflammatory markers and hepatic proinflammatory pathways, including NLRP3 and NFKB. Among hepatic bile acid receptors, disease-associated conjugated bile acids showed the strongest association with hepatic spingosine-1-phosphate receptor 2 (S1PR2). CONCLUSIONS: Enhanced expression of hepatic S1PR2 in HCVi and HCVi-cirrhosis and strong associations of S1PR2 with Tau-BAs suggest pathological relevance of Tau-BA-hepatic S1PR2 signaling in chronic liver disease. These findings have therapeutic implications in chronic liver diseases.

Nonalcoholic Fatty Liver Disease and Ethnicity: Lessons Learned from the Arab Population in Israel.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease. We aimed to investigate the potential similarities and differences regarding the disease among Arabs and Jews. Retrospective study included all patients older than 18 years with NAFLD diagnosis according to ICD-10 codes. Data regarding demographics, comorbidities, and outcomes were retrieved using the MdClone platform from "Clalit" in Israel. Data concerning 34,090 Arab patients and 173,500 Jewish patients with NAFLD were included. Arab patients were significantly younger at diagnosis (35.0 ± 13 years vs. 43.6 ± 15 years, p < 0.001) and had higher rates of obesity and diabetes mellitus (69.5% vs. 56.5% and 27.0% vs. 22.7%, p < 0.001, respectively). Arab patients had higher rates of cirrhosis and portal hypertension-related complications (2.5% vs. 2.0%, p < 0.001), esophageal varices (0.9% vs. 0.5%, p < 0.001), spontaneous bacterial peritonitis (0.3% vs. 0.1%, p < 0.001), and hepatorenal syndrome (0.3% vs. 0.1%, p < 0.001). There was no significant difference in the prevalence of hepatocellular carcinoma between study groups (0.4% vs. 0.5%, p = 0.156). Liver transplantation was performed in 0.2% of Arab NAFLD patients compared to 0.07% of Jewish NAFLD patients (p < 0.001). Lower rates of all-cause mortality were found among the Arab NAFLD patients versus Jewish NAFLD patients (7.7% versus 11.5%, p < 0.001). According to the Cox regression model, Arab ethnicity is a risk factor for death with OR of 1.36. Significant differences regarding comorbidities, complications, liver transplantations rates, and all-cause mortality were found among NAFLD patients of different ethnicities, hence specific population need specific consideration in prevention, early diagnosis and follow up.

Namodenoson at the Crossroad of Metabolic Dysfunction-Associated Steatohepatitis and Hepatocellular Carcinoma.

Namodenoson (CF102) is a small, orally available, anti-inflammatory, and anti-cancer drug candidate currently in phase 2B trial for the treatment of metabolic dysfunction-associated steatohepatitis (MASH; formerly known as non-alcoholic steatohepatitis (NASH)) and in phase 3 pivotal clinical trial for the treatment of hepatocellular carcinoma (HCC). In both MASH and HCC, the mechanism-of-action of namodenoson involves targeting the A3 adenosine receptor (A3AR), resulting in deregulation of downstream signaling pathways and leading to inhibition of inflammatory cytokines (TNF-α, IL-1, IL-6, and IL-8) and stimulation of positive cytokines (G-CSF and adiponectin). Subsequently, inhibition of liver inflammation, steatosis, and fibrosis were documented in MASH experimental models, and inhibition of HCC growth was observed in vitro, in vivo, and in clinical studies. This review discusses the evidence related to the multifaceted mechanism of action of namodenoson, and how this mechanism is reflected in the available clinical data in MASH and HCC.

Novel proteomic signatures may indicate MRI-assessed intrahepatic fat state and changes: The DIRECT PLUS clinical trial.

BACKGROUND AND AIMS: We demonstrated in the randomized 18-month DIRECT PLUS trial (n = 294) that a Mediterranean (MED) diet, supplemented with polyphenol-rich Mankai duckweed, green tea, and walnuts and restricted in red/processed meat, caused substantial intrahepatic fat (IHF%) loss compared with 2 other healthy diets, reducing NAFLD by half, regardless of similar weight loss. Here, we investigated the baseline proteomic profile associated with IHF% and the changes in proteomics associated with IHF% changes induced by lifestyle intervention. APPROACH AND RESULTS: We calculated IHF% by proton magnetic resonance spectroscopy (normal IHF% <5% and abnormal IHF% ≥5%). We assayed baseline and 18-month samples for 95 proteomic biomarkers.Participants (age = 51.3 ± 10.8 y; 89% men; and body mass index = 31.3 ± 3.9 kg/m 2 ) had an 89.8% 18-month retention rate; 83% had eligible follow-up proteomics measurements, and 78% had follow-up proton magnetic resonance spectroscopy. At baseline, 39 candidate proteins were significantly associated with IHF% (false discovery rate <0.05), mostly related to immune function pathways (eg, hydroxyacid oxidase 1). An IHF% prediction based on the DIRECT PLUS by combined model ( R2 = 0.47, root mean square error = 1.05) successfully predicted IHF% ( R2 = 0.53) during testing and was stronger than separately inputting proteins/traditional markers ( R2 = 0.43/0.44). The 18-month lifestyle intervention induced changes in 18 of the 39 candidate proteins, which were significantly associated with IHF% change, with proteins related to metabolism, extracellular matrix remodeling, and immune function pathways. Thrombospondin-2 protein change was higher in the green-MED compared to the MED group, beyond weight and IHF% loss ( p = 0.01). Protein principal component analysis revealed differences in the third principal component time distinct interactions across abnormal/normal IHF% trajectory combinations; p < 0.05 for all). CONCLUSIONS: Our findings suggest novel proteomic signatures that may indicate MRI-assessed IHF state and changes during lifestyle intervention. Specifically, carbonic anhydrase 5A, hydroxyacid oxidase 1, and thrombospondin-2 protein changes are independently associated with IHF% change, and thrombospondin-2 protein change is greater in the green-MED/high polyphenols diet.

Circulating isomiRs May Be Superior Biomarkers Compared to Their Corresponding miRNAs: A Pilot Biomarker Study of Using isomiR-Ome to Detect Coronary Calcium-Based Cardiovascular Risk in Patients with NAFLD.

Circulating miRNAs are increasingly being considered as biomarkers in various medical contexts, but the value of analyzing isomiRs (isoforms of canonical miRNA sequences) has not frequently been assessed. Here we hypothesize that an in-depth analysis of the full circulating miRNA landscape could identify specific isomiRs that are stronger biomarkers, compared to their corresponding miRNA, for identifying increased CV risk in patients with non-alcoholic fatty liver disease (NAFLD)-a clinical unmet need. Plasma miRNAs were sequenced with next-generation sequencing (NGS). Liver fat content was measured with magnetic-resonance spectrometry (MRS); CV risk was determined, beyond using traditional biomarkers, by a CT-based measurement of coronary artery calcium (CAC) score and the calculation of a CAC score-based CV-risk percentile (CAC-CV%). This pilot study included n = 13 patients, age > 45 years, with an MRS-measured liver fat content of ≥5% (wt/wt), and free of overt CVD. NGS identified 1103 miRNAs and 404,022 different isomiRs, of which 280 (25%) and 1418 (0.35%), respectively, passed an abundance threshold. Eighteen (sixteen/two) circulating miRNAs correlated positively/negatively, respectively, with CAC-CV%, nine of which also significantly discriminated between high/low CV risk through ROC-AUC analysis. IsomiR-ome analyses uncovered 67 isomiRs highly correlated (R ≥ 0.55) with CAC-CV%. Specific isomiRs of miRNAs 101-3p, 144-3p, 421, and 484 exhibited stronger associations with CAC-CV% compared to their corresponding miRNA. Additionally, while miRNAs 140-3p, 223-3p, 30e-5p, and 342-3p did not correlate with CAC-CV%, specific isomiRs with altered seed sequences exhibited a strong correlation with coronary atherosclerosis burden. Their predicted isomiRs-specific targets were uniquely enriched (compared to their canonical miRNA sequence) in CV Disease (CVD)-related pathways. Two of the isomiRs exhibited discriminative ROC-AUC, and another two showed a correlation with reverse cholesterol transport from cholesterol-loaded macrophages to ApoB-depleted plasma. In summary, we propose a pipeline for exploring circulating isomiR-ome as an approach to uncover novel and strong CVD biomarkers.

Dynamic Elevation of Aromatic Amino Acids in Hepatitis C Virus-Induced Cirrhosis After a Standard Meal.

INTRODUCTION: Perturbations in aromatic (AAAs) and branched-chain amino acids (BCAAs) are seen in decompensated liver disease. The aim of this study was to evaluate the dynamic, postprandial relationship between hepatitis C virus-induced liver disease and amino acid concentrations in patients with compensated liver disease. METHODS: Patients infected with hepatitis C virus underwent a baseline liver biopsy to determine Ishak Fibrosis Score and evaluate the liver transcriptome. Patients ate a standard meal and underwent peripheral vein sampling at defined intervals. Quantitative analysis of amino acids was performed using liquid chromatography-tandem mass spectrometry. RESULTS: At baseline, there was no difference in AAA and BCAA concentrations between patients with cirrhosis and non-cirrhotic patients. After a standard meal, AAAs, but not BCAAs, were elevated in patients with cirrhosis compared with non-cirrhotic patients at every time point. The HepQuant SHUNT fraction was significantly higher in patients with cirrhosis and positively correlated with AAA concentration at all time points, but not BCAA. Analysis of the hepatic transcriptome demonstrated greater downregulation of the AAA degradation pathways than the BCAA degradation pathways. DISCUSSION: At baseline, cirrhotic patients with compensated liver disease have adequate reserve liver function to metabolize AAAs and BCAAs. When faced with a metabolic stressor, such as a standard meal, patients with cirrhosis are less able to metabolize the increased load of AAAs. This impairment correlates with portosystemic shunting. Further evaluation of AAA levels in compensated liver disease might further the understanding of the liver-muscle axis and the role it may play in the development of sarcopenia in liver disease.

MELD-Na score may underestimate disease severity and risk of death in patients with metabolic dysfunction-associated steatotic liver disease (MASLD).

Portal hypertension often precedes the development of advanced fibrosis in patients with Metabolic dysfunction-associated steatotic liver disease (MASLD) and may accelerate disease progression to cirrhosis. We aimed to evaluate whether prioritization tools accurately predict survival in patients with MASLD and clinically significant portal hypertension (CSPH). We retrospectively identified patients diagnosed with esophageal or gastric varices (EGV). Laboratory results, endoscopy reports and outcomes of patients with MASLD were compared to patients with advanced stage chronic liver disease (CLD) of other etiologies. During the study period 326 patients were diagnosed with EGV. 88 (26.9%) had MASLD, 113 (34.6%) viral hepatitis (VH), 63 (19.3%) alcoholic liver disease (ALD) and 62 (19%) both VH and ALD (VHALD). EGV bleeding events were significantly more frequent in patients with MASLD (36.3%), compared to VH (28.3%), ALD (30.1%) and VHALD (25.8%), respectively (p < 0.01). Mean Model for End-Stage Liver Disease (MELD)-Na score surrounding 1 year of first event of EGV bleeding was significantly lower in MASLD patients compared to all other etiologies (p = 0.02). At a MELD-Na score of 11-20, cumulative survival rate was significantly lower in MASLD patients compared to all other etiologies (log rank p < 0.01). MASLD patients present with EGV bleeding at lower MELD-Na scores compared to other etiologies of CLD. MELD-Na score may therefore underestimate disease severity and risk of death in patients with MASLD and CSPH.

A Simple, Rapid, and Effective Heparinase Protocol to Enable Nucleic Acid Study from Frozen Heparinized Plasma.

Cell-free RNAs (cfRNAs) are promising analytes as non-invasive biomarkers and have even greater potential if tied in with metabolomics. Plasma is an optimal source for cfRNAs but is often derived from a variety of anticoagulants. Plasma obtained in heparin is suitable for metabolomics but is difficult to utilize for qPCR-based downstream analysis. In the present study, we aimed to develop a simple, time-efficient, and cost-effective heparinase protocol, followed by library preparation and sequencing of human plasma cfRNAs drawn and stored in heparin at -80 °C for several years. Blood was collected in CPT™ sodium heparin tubes from patients with chronic HCV infection (NCT02400216) at the National Institutes of Health (NIH) Clinical Center. Plasma cfRNAs were treated with heparinase I and used for library preparation and next-generation sequencing (NGS). Heparinase treatment maintained RNA integrity and allowed for successful library preparation for all the study subjects even with 7 ng of cfRNAs as starting material. The classification report derived from Pavian R package v1.2.0 showed no artificial reads. The abundance of chordate over microbial reads suggests no addition of experimental error through heparinase I treatment. We report a novel and practical approach to heparinase treatment for human plasma collected and frozen in sodium heparin for several years. This is an effective demonstration of utilizing heparin plasma for NGS and downstream transcriptomic research, which could then be integrated with metabolomics from the same samples, maximizing efficiency and minimizing blood draws.

Hepatitis D Virus and HBsAg Dynamics in the era of new Antiviral Treatments.

PURPOSE OF REVIEW: Hepatitis D virus (HDV) infection is the most severe form of chronic viral hepatitis, with no FDA-approved therapy. Progress in the development of effective HDV treatments is accelerating. This review highlights how mathematical modeling is improving understanding of HDV-HBsAg-host dynamics during antiviral therapy and generating insights into the efficacy and modes of action (MOA) of new antiviral agents. RECENT FINDINGS: Clinical trials with pegylated-interferon-λ, bulevertide, nucleic acid polymers, and/or lonafarnib against various steps of the HDV-life cycle have revealed new viral-kinetic patterns that were not observed under standard treatment with pegylated-interferon-α. Modeling indicated that the half-lives of circulating HDV and HBsAg are ~ 1.7 d and ~ 1.3 d, respectively, estimated the relative response of HDV and HBsAg during different antiviral therapies, and provided insights into the efficacy and MOA of drugs in development for treating HDV, which can inform response-guided therapy to individualize treatment duration. Mathematical modeling of HDV and HBsAg kinetics provides a window into the HDV virus lifecycle, HDV-HBsAg-host dynamics during antiviral therapy, and the MOA of new drugs for HDV.

Liver Fibrosis Regression and Associated Factors in HCV Patients Treated with Direct-Acting Antiviral Agents.

There is accumulating evidence that treatment of chronic hepatitis C (HCV) leads to improvements in liver fibrosis. We aimed to investigate the improvement in fibrosis stage following treatment with direct-acting antivirals (DAAs) and factors associated with fibrosis regression. Fibroscan® was performed for patients treated with DAAs, at least 3 years post-HCV eradication. The fibrosis stage at the onset of treatment was compared with the current fibrosis stage. A total of 209 patients were enrolled in this study (56% males; age 58.8 ± 13.3 years; age at treatment 54 ± 10.9 years). Genotype subgrouping was as follows: 1a (16%), 1b (58%), 2a (4%), 3 (18%), and 4a (2%). Overall, 71% of patients were considered treatment-naïve, with a mean follow-up time of 4.5 ± 1.3 years. Fibrosis improvement was observed among 57% of patients; fibrosis progression was seen among 7% of patients and no change was seen in 36% of patients. Moreover, 28% of these patients regressed from F3/F4 to F2 or less. In our multivariable analysis, the age at treatment and advanced fibrosis stage were found to be factors significantly associated with fibrosis regression. In conclusion, fibrosis improvement was observed among 57% of HCV patients after treatment with DAAs. Age and advanced fibrosis at baseline were found to be factors associated with fibrosis regression.

Non-selective dampening of the host immune response after hepatitis C clearance and its association with circulating chemokine and endotoxin levels.

BACKGROUND & AIMS: Direct-acting antiviral (DAA) therapy has revolutionized treatment for the hepatitis C virus (HCV). While DAA therapy is common, little is known about the intrahepatic immunological changes after sustained virologic response (SVR). We aim to describe transcriptional alterations of the gut microbiome and the liver after SVR. METHODS: Twenty-two HCV patients were evaluated before and 9 months after 12 weeks of sofosbuvir/velpatasvir treatment. All achieved SVR. A liver biopsy, portal blood (direct portal vein cannulation), peripheral blood and stool samples were obtained. RNA-seq and immunofluorescent staining were performed on liver biopsies. RNA-seq and 16S rRNA metagenomics were performed on stool. RESULTS: Differential expression within liver transcription showed 514 downregulated genes (FDR q < .05; foldchange > 2) enriched in inflammatory pathways; of note, GO:0060337, type 1 IFN signalling (p = 8e-23) and GO:0042742, defence response to bacterium (p = 8e-3). Interestingly, microbial products increased in the portal blood and liver after SVR. Due to the increase in microbial products, the gut microbiome was investigated. There was no dysbiosis by Shannon diversity index or Bacteroides/Firmicutes ratio. There was a differential increase in genes responsible for bacterial lipopolysaccharide production after SVR. CONCLUSIONS: The decrease in the antiviral interferon pathway expression was expected after SVR; however, there was an unanticipated decrease in the transcription of genes involved in recognition and response to bacteria, which was associated with increased levels of microbial products. Finally, the alterations in the function of the gut microbiome are a promising avenue for further investigation of the gut-liver axis, especially in the context of the significant immunological changes noted after SVR.

Comorbidities and Malignancy among NAFLD Patients Compared to the General Population, A Nation-Based Study.

(1) Background: Non-alcoholic fatty liver disease (NAFLD) is a common liver disease. Aims: We aimed to investigate the frequency of comorbidities and malignancies among NAFLD patients compared to the general population. (2) Methods: A retrospective study included adult patients with a NAFLD diagnosis. A control group was matched for age and gender. Demographics, comorbidities, malignancies, and mortality were collected and compared. (3) Results: 211,955 NAFLD patients were analyzed in comparison to 452,012 matched general population controls. Significantly higher rates of diabetes mellitus (23.2% vs. 13.3%), obesity (58.8% vs. 27.8%), hypertension (57.2% vs. 39.9%), chronic ischemic heart disease (24.7% vs. 17.3%), and CVA (3.2% vs. 2.8%) were found among NAFLD patients. Patients with NAFLD had significantly higher rates of the following malignancies: prostate cancer (1.6% vs. 1.2%), breast cancer (2.6% vs. 1.9%), colorectal cancer (1.8% vs. 1.4%), uterine cancer (0.4 vs. 0.2%), kidney cancer (0.8% vs. 0.5%), but a lower rate of lung cancer (0.9% vs. 1.2%) and stomach cancer (0.3% vs. 0.4%). The all-cause mortality rate among NAFLD patients was significantly lower in comparison to the general population (10.8% vs. 14.7%, p < 0.001). (4) Conclusions: Higher rates of comorbidities and malignancies among NAFLD patients were observed, but a lower rate of all-cause mortality was found.

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.

Modeling-Based Response-Guided Hepatitis C Treatment During Pregnancy and Postpartum.

Treating hepatitis C virus (HCV) in pregnancy would address HCV during prenatal care and potentially reduce the risk of vertical transmission. Response-guided therapy could provide a means to individualize and the reduce duration of HCV treatment during pregnancy. Data from a 27-year-old woman indicated that, pretreatment, HCV was stable and that it dropped in a biphasic manner during sofosbuvir/velpatasvir therapy, reaching target not detected at time of delivery-16 days post-initiation of therapy. Mathematical modeling of measured HCV at days 0, 7, and 14 predicted that cure could have been achieved after 7 weeks of sofosbuvir/velpatasvir, reducing the duration of therapy by 5 weeks.

Treatment of chronic hepatitis D with peginterferon lambda-the phase 2 LIMT-1 clinical trial.

BACKGROUND AND AIMS: HDV infection leads to the most aggressive form of human viral hepatitis for which there is no FDA-approved therapy. PEG IFN-lambda-1a (Lambda) has previously demonstrated a good tolerability profile in HBV and HCV patients compared to PEG IFN-alfa. The goal of Phase 2 LIMT-1 trial was to evaluate the safety and efficacy of Lambda monotherapy in patients with HDV. APPROACH AND RESULTS: An open-label study of Lambda 120 or 180 mcg, administered once weekly by subcutaneous injections for 48 weeks, followed by 24 weeks of posttreatment follow-up. Thirty-three patients were allocated to Lambda 180 mcg (n=14) or 120 mcg (n=19). Baseline mean values: HDV RNA 4.1 log10 IU/mL (SD±1.4); ALT 106 IU/L (35-364); and bilirubin 0.5 mg/dL (0.2-1.2). Intention-to-treat rates of virologic response to Lambda 180 mcg and 120 mcg, 24 weeks following treatment cessation were 5 of 14(36%) and 3 of 19 (16%), respectively. The posttreatment response rate of 50% was seen in low BL viral load (≤4 log10) on 180 mcg. Common on-treatment adverse events included flu-like symptoms and elevated transaminase levels. Eight (24%) cases of hyperbilirubinemia with or without liver enzyme elevation, leading to drug discontinuation, were mainly observed in the Pakistani cohort. The clinical course was uneventful, and all responded favorably to dose reduction or discontinuation. CONCLUSIONS: Treatment with Lambda in patients with chronic HDV may result in virologic response during and following treatment cessation. Clinical phase 3 development of Lambda for this rare and serious disease is ongoing.

Longitudinal multi-omics analyses of the gut-liver axis reveals metabolic dysregulation in hepatitis C infection and cirrhosis.

The gut and liver are connected via the portal vein, and this relationship, which includes the gut microbiome, is described as the gut-liver axis. Hepatitis C virus (HCV) can infect the liver and cause fibrosis with chronic infection. HCV has been associated with an altered gut microbiome; however, how these changes impact metabolism across the gut-liver axis and how this varies with disease severity and time is unclear. Here we used multi-omics analysis of portal and peripheral blood, faeces and liver tissue to characterize the gut-liver axis of patients with HCV across a fibrosis severity gradient before (n = 29) and 6 months after (n = 23) sustained virologic response, that is, no detection of the virus. Fatty acids were the major metabolites perturbed across the liver, portal vein and gut microbiome in HCV, especially in patients with cirrhosis. Decreased fatty acid degradation by hepatic peroxisomes and mitochondria was coupled with increased free fatty acid (FFA) influx to the liver via the portal vein. Metatranscriptomics indicated that Anaerostipes hadrus-mediated fatty acid synthesis influences portal FFAs. Both microbial fatty acid synthesis and portal FFAs were associated with enhanced hepatic fibrosis. Bacteroides vulgatus-mediated intestinal glycan breakdown was linked to portal glycan products, which in turn correlated with enhanced portal inflammation in HCV. Paired comparison of patient samples at both timepoints showed that hepatic metabolism, especially in peroxisomes, is persistently dysregulated in cirrhosis independently of the virus. Sustained virologic response was associated with a potential beneficial role for Methanobrevibacter smithii, which correlated with liver disease severity markers. These results develop our understanding of the gut-liver axis in HCV and non-HCV liver disease aetiologies and provide a foundation for future therapies.

Modeling the Interplay between HDV and HBV in Chronic HDV/HBV Patients.

Hepatitis D virus is an infectious subviral agent that can only propagate in people infected with hepatitis B virus. In this study, we modified and further developed a recent model for early hepatitis D virus and hepatitis B virus kinetics to better reproduce hepatitis D virus and hepatitis B virus kinetics measured in infected patients during anti-hepatitis D virus treatment. The analytical solutions were provided to highlight the new features of the modified model. The improved model offered significantly better prospects for modeling hepatitis D virus and hepatitis B virus interactions.

The impact of the COVID-19 pandemic on colorectal and gastric cancer diagnosis, disease stage and mortality.

Background: Since the outbreak of COVID-19, a significant decline in endoscopic procedures has been observed. Aims: We investigated the change of incidence, clinical characteristics, disease stage and mortality of patients with gastric cancer (GC) or colorectal cancer (CRC) diagnosed in 2020 compared to the pre-pandemic year 2019. Methods: Demographic, clinical and laboratory data on all patients diagnosed with GC or CRC at the Soroka University Medical Center were retrospectively collected and compared. Number of cases, time of diagnosis, clinical presentation, staging at diagnosis and mortality rates were compared. Results: Two hundred sixteen patients were diagnosed with CRC in 2019, whereas only 162 were diagnosed in 2020 (25% reduction), while 36 GC diagnoses were made in 2019 compared to 24 in 2020 (33% reduction). The age-adjusted incidence was calculated to be 24.28 for CRC and 5.0 for GC in 2020 compared to 29.93 and 5.32 in 2019, respectively. CRC patients had a significantly lower rate of rectal bleeding as their presenting symptom in 2020 compared with 2019, 8.1 vs. 19% (p = 0.003), but higher rate of diarrhea as their presenting symptom, 4.3 vs. 1% (p = 0.044). No significant differences regarding other presenting symptoms, comorbidities, surgery or mortality rates were found between the groups diagnosed in 2019 or 2020. Conclusion: A decrease in GC and CRC incidence was observed during the year 2020; lower rate of rectal bleeding and higher rate of diarrhea as presenting symptoms were noted in 2020, but no significant difference was found regarding other presenting symptoms, disease stage, surgery or mortality.

Characterization of Hepatic Dysfunction in Subjects Diagnosed With Chronic GVHD by NIH Consensus Criteria.

Hepatic chronic graft-versus-host disease (cGVHD) causes morbidity and current diagnostic criteria are nonspecific. An accurate diagnosis is imperative because overdiagnosis can lead to unnecessary treatment with immunosuppressive agents and raising the risk of opportunistic infections. We aim to characterize different patterns of liver injury and cytokine profiles associated with hepatic dysfunction in cGVHD, to evaluate the accuracy of the NIH Consensus Criteria (NCC) for hepatic cGVHD and to explore predictors for hepatic cGHVD. Patients were evaluated in this prospective cross-sectional study of patients with cGVHD recruited under a natural history protocol. Laboratory tests and cytokines were measured. The cGVHD were diagnosed and scored based on NCC. Clinically indicated liver biopsy specimens or autopsies were reviewed by an expert hepatopathologist (D.E.K.). Comparisons were made between groups, and univariable and multivariable logistic regression were calculated. Of the 302 patients enrolled, 151 fulfilled hepatic cGVHD based on NCC; however, 69% had at least 1 abnormal liver test result. Abnormal alanine aminotransferase (ALT) and aspartate aminotransferase were associated with lower platelets, higher total bilirubin (TB), total cholesterol, serum amyloid A, and IL 15. Abnormal ALP and gamma-glutamyl transpeptidase were associated with higher cholesterol, and IL7. Lower platelet count was associated with higher ALT, TB, and triglycerides and lower albumin. Of the 27 with liver tissue, 16 had histologic features of GVHD, only eight met clinical criteria for hepatic GVHD. Sensitivity and specificity of NCC in identifying hepatic GVHD were 50% and 27% (Kappa = -0.23). Only 6 had only hepatic GVHD, whereas 10 had hepatic GVHD with either iron overload, nodular regenerative hyperplasia, or steatosis. Multivariable logistic regression showed that ALP and total cholesterol were associated with hepatic GVHD and total cholesterol >220 mg/dL increased the sensitivity for histologic hepatic GVHD. In conclusion, abnormal liver enzymes in cGVHD are nonspecific and have poor correlation with histologic evidence for hepatic GVHD, highlighting the importance of histology. Cytokines provide insight into the pathogenesis of hepatic cGVHD. Decreased platelet count was associated with factors associated with liver disease including portal vein diameter, which may suggest progression of liver disease. This highlights the need of incorporating these factors in natural history study and using liver biopsy to understand the development of liver dysfunction in hematopoietic stem cell transplantation and to develop better instruments to decreased hepatic cGVHD related morbidity and mortality. The study was registered with a ClinicalTrials.gov identifier NCT00092235.