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The chr12q24.13 locus encoding OAS1–OAS3 antiviral proteins has been associated with coronavirus disease 2019 (COVID-19) susceptibility. Here, we report genetic, functional and clinical insights into this locus in relation to COVID-19 severity. In our analysis of patients of European (n = 2,249) and African (n = 835) ancestries with hospitalized versus nonhospitalized COVID-19, the risk of hospitalized disease was associated with a common OAS1 haplotype, which was also associated with reduced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) clearance in a clinical trial with pegIFN-λ1. Bioinformatic analyses and in vitro studies reveal the functional contribution of two associated OAS1 exonic variants comprising the risk haplotype. Derived human-specific alleles rs10774671-A and rs1131454-A decrease OAS1 protein abundance through allele-specific regulation of splicing and nonsense-mediated decay (NMD). We conclude that decreased OAS1 expression due to a common haplotype contributes to COVID-19 severity. Our results provide insight into molecular mechanisms through which early treatment with interferons could accelerate SARS-CoV-2 clearance and mitigate against severe COVID-19.

To compare biliary stricture severity on magnetic resonance cholangiopancreatography (MRCP), magnetic resonance elastography (MRE), and vibration-controlled transient elastography (VCTE) liver stiffness (LS) for evaluation of risk stratification and prognostication in primary sclerosing cholangitis (PSC). Eighty-seven patients (31–61 years; 34 female/53 male) prospectively underwent biochemical testing, VCTE, MRCP, and MRE between January 2014 and July 2016. Correlation between the MRCP grading of PSC based on biliary stricture severity, LS on MRE and VCTE, and the Mayo Risk Score as well as the Amsterdam Oxford Prognostic Index (AOPI) were evaluated and compared. Stricture severity was classified according to previous classification systems based on ERCP. Spearman’s correlation and Kruskal-Wallis tests were performed. MRE-LS and intrahepatic stricture severity combined demonstrated higher discriminatory ability among risk categories based on Mayo Risk Score (AUROC = 0.8). MRE-LS alone demonstrated excellent discriminatory ability among risk categories based on AOPI using cutoffs of 1 and 2.7 and was superior to intrahepatic stricture severity (AUROC = 0.9, AUROC = 0.6–0.7). There was a weak correlation between intrahepatic stricture severity and MRE-LS (rho = 0.3; p = 0.011). VCTE-LS values were not correlated with stricture severity and were noncontributory to differentiate patients across risk groups. Intrahepatic stricture severity alone was a poor discriminator of advanced liver fibrosis on MRE (AUROC = 0.7); however, combining intra- and extrahepatic stricture severity and controlling for cholestasis and disease duration improved results (AUROC = 0.9). This study demonstrates a significant discriminatory ability of LS values on MRE to distinguish between early to moderate and advanced liver fibrosis. LS values on MRE may add value to risk prognostication and further studies including clinical outcomes are needed. • Risk stratification was excellent for liver stiffness measurements on MRE and poor for VCTE and biliary stricture severity. • Risk stratification was further improved when liver stiffness measured on MRE was combined with intrahepatic and extrahepatic stricture severity and indicators of cholestasis were controlled for. • Liver stiffness measurements on MRE correlated with prognostic scores better than measurements performed on VCTE.

Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection are the most important underlying causes for the development of hepatocellular carcinoma (HCC) worldwide. Determining the optimal approach for management of the viral infection and the HCC depends on the virus and the stage of the cancer. In patients with HCV-associated HCC, there are multiple reasons to first treat the HCC. Firstly, in case of a curable HCC, the urgency for HCC treatment is important to avoid progression during HCV treatment. Secondly, the presence of HCC itself appears to reduce the rates of sustained virological response (SVR) achieved with direct-acting antivirals (DAAs). And finally, the evidence does not support the concept of an increase in HCC recurrence due to DAAs, so a patient can safely be treated after HCC cure. For patients with very advanced HCC, the benefits of HCV therapy are questionable. In contrast, those who develop HCC in the setting of chronic HBV infection, treatment with nucleoside analogues (NAs) is recommended prior to treating HCC, to prevent further liver injury and reduce the risk for HCC recurrence. Ultimately, earlier diagnosis and treatment of HBV and HCV will hopefully reduce the incidence of HCC worldwide.

High antigen burden during chronic hepatitis B (CHB) results in a low frequency HBV-specific T cell response with restricted functionality. However, this observation is based on limited data because low T cell frequencies have hindered effective ex vivo analysis. We adapted the ELISpot assay to overcome this obstacle to measure ex vivo T cell responses in CHB patients. We modified the key variables of cell number and the peptide pulsing method to improve ex vivo detection of HBV-specific T cells. We detected IFN-γ responses in 10/15 vaccinated controls and 20/30 CHB patients, averaging 195 and 84 SFUs/2 × 106 PBMCs respectively. Multi-analyte FluoroSpots improved functional characterization of T cells. We detected IFN-γ responses in all tested vaccinated controls (n = 10) and CHB patients (n = 13). IL-2 responses were detectable in 9/10 controls and 10/13 patients. TNF-α displayed less sensitivity, detectable in only 7/10 controls and 7/13 patients. Antigen-specific analysis demonstrated that IFN-γ responses were dominated by polymerase and core, with weak responses to envelope and X. IL-2 responses were found in 3/5 patients and equally directed towards polymerase and core. While their ex vivo frequency is extremely low, a fraction of HBV-specific T cells are detectable and display multi-functionality ex vivo.

The US Food and Drug Administration recently issued a black box warning regarding the risk of hepatitis B virus (HBV) reactivation with direct-acting antiviral (DAA) treatment in hepatitis C virus (HCV)-coinfected individuals. The warning included all HBV infection, active and resolved, which, along with the lack of consensus among the gastroenterology and hepatology guidelines, have left clinicians unsure on how to proceed. Recent data have filled some knowledge gaps regarding the true risk of HBV reactivation in HCV treatment. The clinical data pertaining to the risk of reactivation in active and resolved HBV infection are reviewed, and potential prevention and management strategies are proposed, noting there are still some knowledge gaps remaining. Recent large prospective studies of HBV/HCV-coinfected patients, along with the largest meta-analysis of such patients to date, provide additional insight into the risk of HBV reactivation with HCV antiviral treatment. Subclinical HBV reactivation is not uncommon, occurring in about 25% of patients, but the risk of clinically significant events such as hepatitis remains low in HBsAg-positive individuals, and even lower in isolated HBcAb-positive patients. However, recent case reports have brought to light particular situations, such as concomitant immunosuppression, as potential pitfalls to the previous low risk of reactivation attributed to resolved infection. Recent prospective data and a large meta-analysis confirm that clinically significant HBV reactivation remains an uncommon event with the use of DAAs in HBsAg-positive patients, and even rarer in isolated HBcAb-positive cases.

To develop and internally validate MR elastography (MRE) quantified liver stiffness (LS) cut-off values for distinguishing early/moderate fibrosis from cirrhosis in primary sclerosing cholangitis (PSC) against non-invasive fibrosis test of vibration-controlled transient elastography (VCTE). Sixty-seven patients were enrolled prospectively at a tertiary care centre to undergo MRE and VCTE. MRE-quantified LS was calculated using three region-of-interest (ROI) methods: Trace, Average and Maximum. Each ROI method was compared with the reference standard of VCTE. Internal validation was performed with bootstrapping. Univariable and multivariable linear regression determined independent predictors for MRE-quantified LS and final Mayo Risk Score (MRS). MRE-quantified LS by Trace ROI method had the highest sensitivity [87.5%; 95% confidence interval (CI), 66.0-96.8] and specificity (96.1%; 95%CI, 89.6-99.0) for distinguishing cirrhosis; and was the strongest predictor of final MRS (β, 0.44; 95% CI, 0.27-0.61). Alkaline phosphatase twice the normal upper limit (β, 1.55; 95% CI, 0.95-2.17), abnormal bilirubin (β, 1.27; 95% CI, 0.41-2.14) and thrombocytopaenia (β, 0.79; 95% CI, 0.12-1.46) were independent predictors of LS. MRE has a higher correlation with MRS than VCTE; and though MRE is possibly influenced by severe cholestasis and portal hypertension, MRE-quantified LS is an independent predictor of worse MRS. • MRE is valid and reliable in assessing cirrhosis in PSC, and MRE-quantified Liver stiffness (LS) score was the strongest predictor of final Mayo Risk Score (MRS). • Trace ROI performs best for distinguishing moderate fibrosis from cirrhosis and has the highest correlation with Mayo Risk Score (MRS). • Cholestasis, hyperbilirubinaemia and portal hypertension may influence MRE LS score.

Hepatitis C virus (HCV) therapy has improved dramatically in recent years; however, small clinical gaps remained. The recent approval of the final two antiviral regimens likely to come to clinical use addresses most unmet medical needs. The clinical trial data supporting the approval of these regimens is reviewed, highlighting how they address outstanding clinical needs and noting the very few gaps that still remain. The approval of sofosbuvir/velpatasvir/voxilaprevir provides an excellent salvage regimen for patients who have failed prior treatment with direct antiviral agents. A 12-week course of therapy leads to sustained virological response in almost all retreatment settings. In addition, the approval of glecaprevir/pibrentasvir offers an 8-week treatment option for all non-cirrhotic treatment-naive patients and also provides a much needed therapy for patients with chronic kidney disease and HCV genotypes other than 1 and 4. Two newly approved regimens have been approved for HCV patients who previously failed direct antiviral therapy and patients with chronic kidney disease with genotypes other than 1 and 4.

The treatment of HCV infection has evolved at an extremely rapid pace over the past few years. The development of direct-acting antiviral agents, which potently inhibit different stages in the viral life cycle, has led to the replacement of interferon with well-tolerated oral therapies with cure rates of >90% in most patient populations. Understanding the mechanisms of action of the various agents as well as related issues, including the molecular basis for resistance, helps to guide drug development and clinical use. In this Review, we provide a mechanistic description of NS3/4A protease inhibitors, nucleotide and non-nucleotide inhibitors of the NS5B viral polymerase and inhibitors of the NS5A protein, followed by a summary of clinical data from studies of each drug class alone and in combination. Remaining challenges in drug development efforts are also discussed.

Introduction: Epidemiologic and modeling studies suggest that between 45 and 70% of individuals with chronic hepatitis C virus (HCV) infection in Canada remain undiagnosed. The Canadian Association for the Study of the Liver (CASL) recommends one-time screening of baby boomers (1945-1975). Screening programs in the US have shown a very high prevalence of previously undiagnosed HCV among patients seen in the emergency department (ED). We sought to assess the feasibility of implementing a targeted birth-cohort HCV screening program in a Canadian ED setting. Methods: Patients born from 1945 to 1975 presenting to the ED of a downtown Toronto hospital were offered HCV testing. Patients with life-threatening conditions, unable to provide verbal consent in English or intoxication were excluded. Blood samples were collected by finger prick on Dried Blood Spot (DBS) collection cards and tested for anti-HCV antibody with reflex to HCV RNA. Patients with positive HCV RNA were referred to a liver specialist. Results: During a 27-month period (July 2017 - Sept 2019), 8363 patients in the birth cohort presented to the ED during daytime hours. 80% (6714) met eligibility criteria, and 48.4% (3247) were offered testing. Screening was performed by non-medical staff (mean 8/day, median spots on DBS 4). 345 (10.6%) had been previously tested, and 639 (19.7%) declined. 2136 (65.8%) patients underwent testing: median age 58.4 years (40-82), 1117 male (52.3%). Of these, 45 patients (2.1%; 95% CI 1.5%-2.7%) were anti-HCV positive: 32 (76.2%) were HCV RNA positive, 10 (23.8%) negative and 3 not done due to inadequate DBS sample. 26 patients (81.3%) were linked to care and 3 (9.4%) lost to follow-up. HCV prevalence in the ED was significantly higher than the general Canadian population (2.1% vs 0.7%; p Conclusion: Acceptance of HCV screening in the ED birth cohort was high and easily performed using DBS to ensure the majority of positive samples were tested for HCV RNA. Challenges included implementation that limited number of people tested, and linkage to care for HCV positive patients. HCV prevalence among this ED birth cohort was higher than the general population but lower than seen in the ED in the US. This may in part be due to exclusion of individuals with more severe medical issues, refusal by higher risk subgroups, or population and healthcare system differences between countries.

Most patients with hepatitis B virus (HBV) have no symptoms, and many are unaware of the infection. However, HBV can reactivate with immunosuppression; chemotherapy causes reactivation in 22 % of hepatitis B surface antigen-positive patients. HBV reactivation can be fatal. HBV reactivation can be prevented, provided that HBV is recognized prior to chemotherapy. The objective of this study is to estimate the health and economic effects of HBV screening strategies in patients receiving adjuvant chemotherapy for breast cancer. We developed a state-transition microsimulation model to examine the cost-effectiveness of three HBV screening strategies: (1) "No screening"; (2) "Screen-and-Treat to prevent reactivation" (screen-all) with either lamivudine/tenofovir (LAM/TDF) or entecavir (ETV); and (3) "Screen-and-Treat high-risk only" (screen-HR) and treat with either LAM/TDF or ETV. Model data were obtained from the published literature. We used a payer's perspective, a lifetime horizon, and a 5 % discount rate for the analysis. "Screen-all" would prevent at least 38 severe reactivations per 100,000 persons screened over the lifetime of the cohort. "Screen-all" was associated with an increase of 0.0034-0.0035 QALYs and an additional cost of C$164-C$266 per person, which translated into an incremental cost-effectiveness ratio of C$47,808/QALY-C$76,527/QALY gained compared with "No screening" depending on the antiviral therapy received. "Screen-all" was the most cost-effective strategy, while "Screen-HR" was inferior in all scenarios tested. HBV screening before adjuvant chemotherapy for breast cancer patients would prevent a significant number of reactivations, would likely be moderately cost-effective, and may extend the lives of breast cancer patients.

HBV and HCV infections continue to be major global health problems, causing over 1 million deaths annually. Key studies this year investigated the innate and adaptive immune responses in different clinical scenarios in HBV infection, whereas others evaluated the merits of transplanting HCV-infected organs into uninfected recipients.

Molecular analysis of liver biopsy samples from patients requires ideal tissue preservation and handling to yield suitable material for laboratory analysis. Biopsy size, tissue handling and preservation method all may affect the quality and quantity of DNA, RNA and protein that can be extracted from liver biopsy samples. In the present study, murine liver biopsies were performed and stored under various conditions: snap-freezing, RNAlater and Allprotect. Yield was compared to fresh biopsy tissue. Fresh tissue generated the highest yield of RNA while samples subjected to the snap-freezing generated the lowest yield of RNA. Preservation in RNAlater yielded higher quantities of RNA than storage in Allprotect, particularly with larger biopsy samples. There was a non-significant trend toward improved RNA quality with RNAlater (p = 0.35). DNA and protein yield were similar with RNAlater and Allprotect under a number of handling condition. Errors in tissue handling such as delays in tissue submersion or freezing did not significantly affect tissue yields in either preservation solution. Tissue yield was unchanged with up to three freeze-thaw cycles in both solutions. Biopsy size (5 vs 2 mm) and width (15 vs 18 g) had a marked effect on tissue yield. Ideally 5-mm biopsies with 15-gauge needles should be used to maximize yield. RNAlater provided higher RNA yield with similar yields of DNA and protein and was notably cheaper and easier to handle.

Approval of Ledipasvir/Sofosbuvir for the treatment of chronic hepatitis C (HCV) includes the truncation of therapy from 12 to 8 weeks in treatment naïve, non-cirrhotic patients with baseline HCV RNA levels

Chronic hepatitis B is a dynamic disease with a very variable outcome ranging from mild, asymptomatic, nonprogressive disease to end-stage liver disease and/or hepatocellular carcinoma. Clinically significant endpoints take years or decades to develop and thus various biomarkers—ranging from clinical data to sophisticated virologic diagnostics—are used as surrogates for disease progression. Liver biopsy remains a robust indicator of disease severity; however, noninvasive markers may offer a useful alternative with some advantages. Clinical decisions are often made using alanine transaminase; however, it lacks adequate specificity to be used in isolation. Serologic markers (hepatitis B early antigen and hepatitis B surface antigen) provide information about the degree of immune control of viral replication, and thus remain important therapeutic indices. Sensitive measurement of serum hepatitis B virus DNA level is an indispensable biomarker. Its suppression is important, but only because it represents a bridge to more permanent stages of disease resolution. Newer assays, including hepatitis B surface antigen titers and hepatitis B genotyping, have therapeutic implications and are becoming more widely available. Clinicians caring for patients with chronic hepatitis B must be aware of the utility and limitations of available surrogate biomarkers.

Background This study assessed the association of alanine-aminotransferase (ALT) and hepatitis C virus (HCV) RNA levels with pro-inflammatory and pro-fibrogenic cytokines and chemokines during acute HCV infection to provide further insight into the potential HCV immunopathogenesis. Methods Participants in the ATAHC study, a prospective study of recent HCV infection, with detectable HCV RNA at the time of HCV detection were included. Plasma levels of 27 cytokines and chemokines were measured and their correlation with ALT and HCV RNA levels were assessed. Log10 transformed cytokines and ALT values were used in the analysis. Results Among 117 individuals, the plasma levels of interferon-gamma inducible protein-10 (IP-10) and macrophage inflammatory protein-1beta (MIP-1β) were positively correlated with ALT levels (IP-10: r = 0.42, P 400,000 IU/mL (vs. 400,000 IU/mL (vs.

Despite the rapid progress in treatment, chronic hepatitis C virus (HCV) infection remains a growing cause of liver-related mortality globally. Patients who have been infected for decades are now presenting with advanced liver disease with the complications of cirrhosis and liver cancer. Early attempts at treatment with peginterferon and ribavirin were limited by toxicity, long treatment duration, and limited efficacy. This was especially relevant for patients with cirrhosis, where exposure to peginterferon-based therapy was relatively ineffective and led to high rates of toxicity. However, the recent development of multiple novel direct-acting antivirals (DAAs) has revolutionized the treatment of HCV. The majority of patients can now be cured with short courses of extremely well-tolerated all-oral regimens. However, the real test of these regimens comes in patients with more advanced liver disease, both in terms of safety and efficacy. Patients with cirrhosis have the greatest need for therapy and have traditionally been the most difficult to cure. The new therapies are rapidly changing this paradigm. Accumulating data suggest that high cure rates are achievable in patients with compensated cirrhosis and may even be possible in patients with signs of liver failure. This review will focus on the treatment of HCV in patients with cirrhosis, with an emphasis on the challenges that remain and strategies to deal with this important population.

Antimitochondrial antibodies (AMAs) found in patients with primary biliary cirrhosis (PBC) cross-react with bacterial proteins and hence molecular mimicry has been proposed as a mechanism for AMA development. Alterations in gastrointestinal permeability would provide a potential route for increased exposure of gut flora to the immune system. In this study we aimed to compare the measured gastrointestinal permeability in patients with PBC to that in patients with liver disease (hepatitis C) and healthy control populations. Subjects drank a mixture of sucrose, lactulose, and mannitol dissolved in water. Eight-hour urinary excretion of the sugars was measured to assess intestinal permeability. Antiendomysial antibody testing was performed to exclude subclinical celiac disease. Eighty-six patients with PBC were evaluated and compared to 69 hepatitis C patients and 155 healthy controls. The mean urinary excretion of sucrose in the PBC patients (133.89 +/- 72.56 mg) was significantly higher than that in hepatitis C patients (101.07+/-63.35) or healthy controls (89.46+/-41.76) (P=0.0001), suggesting abnormal gastric or proximal small intestinal permeability. Sucrose excretion was not increased among patients with hepatitis C compared to healthy controls. The ratio of lactulose:mannitol excretion, reflecting small bowel permeability, was also elevated in the PBC group (0.017+/-0.012) compared to healthy controls (0.012+/-0.007) (P=0.0001) but was equal to that found among patients with hepatitis C (0.016+/-0.011) (P=NS). We conclude that the permeability of both the stomach and the small bowel is increased in patients with PBC, however, it is unclear if it is a cause, consequence, or manifestation of the disease.

The acute phase of hepatitis C (HCV) infection is typically defined as the initial 6 months following exposure to the virus; however, in some individuals, the acute phase of the infection can last much longer (Orland et al. Hepatology 33:321–27, 2001). Although some patients have symptoms of acute hepatitis, most infected individuals are entirely asymptomatic. As a result, many patients are unaware of the infection until it progresses to chronic infection, and may not develop symptoms until decades later with the onset of decompensated cirrhosis or hepatocellular carcinoma (HCC). A substantial proportion (20–40 %) of infected patients clear the virus during the acute phase. Interferon-based treatment is also much more likely to be successful in the acute phase of infection but is relatively poorly tolerated. Therefore, recognition of acute HCV infection is critical to prioritize those patients who do not spontaneously clear the infection for immediate therapy. However, the promise of highly effective well-tolerated all-oral therapies in development may alter the management approach. This review will focus on the epidemiology, natural history, diagnosis, and treatment of acute HCV infection.