Search

Most solid organ transplant recipients did not develop an appreciable serologic response after 2 doses of the mRNA SARS-CoV-2 vaccine.We analyzed the humoral response after a third dose of the BNT162b2 vaccine in 130 kidney transplant recipients, compared to 48 health care workers, and associated factors, including prevaccine cellular immune response, by evaluating intracellular cytokine production after stimulation of donor's peripheral blood mononuclear cells.After 2 doses, most of the controls (47 out of 48, 98%) and only 40% of kidney recipients (52 of 130) kidney recipients were seropositive (P.001). Most seronegative recipients developed a serologic response after the booster (47 out 78, 60%), thus bringing the total number of seropositive recipients to 99 out of 130 (76%). After the third dose, there was a significant increase in antibodies titers in both groups. Decreased humoral response was significantly associated with an older age, lower lymphocyte count, and a lower level of antibodies before booster administration. CD4A third dose of the BNT162b2 mRNA vaccine in kidney recipients is safe and effectively results in increased IgG anti-S levels, including in individuals who were seronegative after 2 doses. Long-term studies of the length of the immune response and protection are required.

Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) are often co-transmitted. Viral coinfection results in worse outcomes. Persons who inject drugs (PWIDs) face barriers to medical treatment, but HCV treatment is indicated and effective even with ongoing active drug use. We aimed to assess access to HCV care and treatment results in patients coinfected with HIV-HCV. This is a real-world retrospective single-center study of patients followed in the HIV clinic between 2002 and 2018. Linkage to care was defined as achieving care cascade steps: (1) hepatology clinic visit, (2) receiving prescription of anti-HCV treatment, and (3) documentation of sustained virologic response (SVR). Of 1660 patients with HIV, 254 with HIV-HCV coinfection were included. Only 39% of them achieved SVR. The rate limiting step was the engagement into hepatology care. Being a PWID was associated with ~50% reduced odds of achieving study outcomes, active drug use was associated with ~90% reduced odds. Older age was found to facilitate treatment success. Once treated, the rate of SVR was high in all populations. HCV is undertreated in coinfected young PWIDs. Further efforts should be directed to improve access to care in this marginalized population.

Background Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease worldwide. New treatments for HCV revolutionized management and prompted the world health organization to set the goal of viral elimination by 2030. These developments strengthen the need for HCV screening in order to identify asymptomatic carriers prior to development of chronic liver disease and its complications. Different screening strategies have been attempted, most targeting high-risk populations. Previous studies focusing on patients arriving at emergency departments showed a higher prevalence of HCV compared to the general population. Aim To identify previously undiagnosed HCV carriers among high risk emergency room attendees and link them to care for anti-viral treatment. Methods In this single center prospective study, persons visiting the emergency department in an urban hospital were screened by a risk factor-specific questionnaire. The risk factors screened for were exposure to blood products or organ transplantation before 1992; origins from countries with high prevalence of HCV; intravenous drug use; human immunodeficiency virus carriers; men who have sex with men; those born to HCV-infected mothers; prior prison time; and chronic kidney disease. Those with at least one risk factor were tested for HCV by serum for HCV antibodies, a novel oral test from saliva (OraQuick®) or both. Results Five hundred and forty-one participants had at least one risk factor and were tested for HCV. Eighty four percent of all study participants had only one risk factor. Eighty five percent of participants underwent OraQuick® testing, 34% were tested for serum anti-HCV antibodies, and 25% had both tests. 3.1% of patients (17/541) had a positive result, compared to local population incidence of 1.96%. Of these, 82% were people who inject drugs (current or former), and 64% served time in prison. One patient had a negative HCV-RNA, and two patients died from non-HCV related reasons. On review of past medical records, 12 patients were found to have been previously diagnosed with HCV but were unaware of their carrier state. At 1-year follow-up none of the remaining 14 patients had completed HCV-RNA testing, visited a hepatology clinic or received anti-viral treatment. Conclusion Targeted high-risk screening in the emergency department identified undiagnosed and untreated HCV carriers, but did not improve treatment rates. Other strategies need to be developed to improve linkage to care in high risk populations.

Background Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease and hepatocellular carcinoma. Treatment with first generation protease inhibitors (PI) + peg-interferon (pegIFN) and ribavirin (RBV) achieved sustained virologic response (SVR) rates of 65–75% but was associated with multiple side effects. The aim of this study was to evaluate safety and efficacy of Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir (3D) ± RBV in HCV genotype 1 patients that failed previous treatment with first generation PIs. Methods An investigator-initiated, open-label, multi-centre clinical trial. HCV Genotype 1 patients who were previously null/partial responders or relapsers to telaprevir, boceprevir or simepravir+pegIFN/RBV and met eligibility criteria were included. 3D ± RBV were administrated for 12 or 24 weeks according to label. The primary outcome was antiviral response (SVR12); Secondary outcomes were patient reported outcomes, adverse events and resistance associated variants. Results Thirty-nine patients initiated treatment according to study protocol (59% men, age 54.0 ± 8.7 years, BMI 28.7 ± 4.5 kg/m2). Thirty-seven (94.9%) completed the study. Thirty-five patients had genotype 1b (9 cirrhotics) and 4 had genotype 1a (2 cirrhotics). Intention-to-treat SVR12 was 92.3% and per-protocol SVR12 was 97.3%. The rate of advanced fibrosis (FibroScan® score F3–4) declined from 46.2 to 25.7% (P = 0.045). Abnormal ALT levels declined from 84.6 to 8.6% (P Conclusion 3D ± RBV is safe and effective in achieving SVR among patients with HCV genotype 1 who failed previous first-generation PI treatment. Trial registration NCT02646111 (submitted to ClinicalTrials.gov, December 28, 2015).

Majority of transplant recipients did not develop an appreciable humoral response following SARS‐CoV‐2 vaccine, in contrast to dialysis patients and healthy individuals. We analyzed the serologic response to BNT162b2 (Pfizer‐BioNTech) vaccine in a cohort of 19 kidney transplant recipients, vaccinated prior to transplantation, compare to 109 recipients vaccinated after transplantation, and to 39 healthcare workers, by determining the level of anti‐spike antibodies after transplantation. All controls and 17 of 19 (90%) of recipients vaccinated before transplant were seropositive, while only 49 of 109 (45%) recipients vaccinated post‐transplant had positive serology (P

Drug-induced liver injury is an emerging form of acute and chronic liver disease that may manifest as fatty liver. Amiodarone (AMD), a widely used antiarrhythmic drug, can cause hepatic injury and steatosis by a variety of mechanisms, not all completely understood. We hypothesized that repetitive AMD administration may induce hepatic lipotoxicity not only via effects on the liver but also via effects on adipose tissue. Indeed, repetitive AMD administration induced endoplasmic reticulum (ER) stress in both liver and adipose tissue. In adipose tissue, AMD reduced lipogenesis and increased lipolysis. Moreover, AMD treatment induced ER stress and ER stress-dependent lipolysis in 3T3L1 adipocytes in vitro. In the liver, AMD caused increased expression of genes encoding proteins involved in fatty acid (FA) uptake and transfer (Cd36, Fabp1, and Fabp4), and resulted in increased hepatic accumulation of free FAs, but not of triacylglycerols. In line with this, there was increased expression of hepatic de novo FA synthesis genes. However, AMD significantly reduced the expression of the desaturase Scd1 and elongase Elovl6, detected at mRNA and protein levels. Accordingly, the FA profile of hepatic total lipids revealed increased accumulation of palmitate, an SCD1 and ELOVL6 substrate, and reduced levels of palmitoleate and cis-vaccenate, products of the enzymes. In addition, AMDtreated mice displayed increased hepatic apoptosis. The studies show that repetitive AMD induces ER stress and aggravates lipolysis in adipose tissue while inducing a lipotoxic hepatic lipid environment, suggesting that AMD-induced liver damage is due to compound insult to liver and adipose tissue. NEW & NOTEWORTHY AMD chronic administration induces hepatic lipid accumulation by several mechanisms, including induction of hepatic ER stress, impairment of b-oxidation, and inhibition of triacylglycerol secretion. Our study shows that repetitive AMD treatment induces not only hepatic ER stress but also adipose tissue ER stress and lipolysis and hepatic accumulation of free fatty acids and enrichment of palmitate in the total lipids. Understanding the toxicity mechanisms of AMD would help devise ways to limit liver damage.

Viruses are efficient metabolic engineers that actively rewire host metabolic pathways to support their lifecycle, presenting attractive metabolic targets for intervention. Here we chart the metabolic response of lung epithelial cells to SARS-CoV-2 infection in primary cultures and COVID-19 patient samples. Bulk and single-cell analyses show that viral replication induces endoplasmic stress and lipid accumulation. Protein expression screen suggests a role for viral proteins in mediating this metabolic response even in the absence of replication. Metabolism-focused drug screen showed that fenofibrate reversed lipid accumulation and blocked SARS-CoV-2 replication. Analysis of 3,233 Israeli patients hospitalized due to COVID-19 supported in vitro findings. Patients taking fibrates showed significantly lower markers of immunoinflammation and faster recovery. Additional corroboration was received by comparative epidemiological analysis from cohorts in Europe and the United States. A subsequent prospective interventional open-label study was carried out in 15 patients hospitalized with severe COVID-19. The patients were treated with 145 mg/day of nanocrystallized fenofibrate (TriCor®) in addition to standard-of-care. Patients receiving fenofibrate demonstrated a rapid reduction in inflammation and a significantly faster recovery compared to control patients admitted during the same period and treated with the standard-of-care. Taken together, our data show that elevated lipid metabolism underlies critical aspects of COVID-19 pathogenesis, suggesting that pharmacological modulation of lipid metabolism should be strongly considered for the treatment of coronavirus infection.

COVID-19 is associated with increased morbidity and mortality in transplant recipients. There are no efficacy data available regarding these patients with any of the available SARS-CoV-2 vaccines. We analyzed the humoral response following full vaccination with the BNT162b2 (Pfizer-BioNTech) in 136 kidney transplant recipients, and compared it to 25 controls. In order to exclude prior exposure to the virus, only participants with negative serology to SARS-CoV-2 nucleocapsid protein were included. All controls developed a positive response to spike protein, while only 51 of 136 transplant recipients (37.5%) had positive serology (p

Background and aims Two SARS-CoV-2 mRNA vaccines were approved to prevent COVID-19 infection, with reported vaccine efficacy of 95%. Liver transplant (LT) recipients are at risk for lower vaccine immunogenicity and were not included in the registration trials. We assessed vaccine immunogenicity and safety in this special population. Methods LT recipients followed at the Tel-Aviv Sourasky Medical Center and healthy volunteers were tested for SARS-CoV-2 IgG antibodies directed against the Spike-protein (S) and Nucleocapsid-protein (N) 10-20 days after receiving the second Pfizer-BioNTech BNT162b2 SARS-CoV-2 vaccine dose. Information regarding vaccine side effects and clinical data was collected from patients and medical records. Results Eighty LT recipients were enrolled. Mean age was 60 years and 30% were female. Twenty-five healthy volunteer controls were younger (mean age 52.7 years, p=0.013) and mostly female (68%, p=0.002). All participants were negative for IgG N-protein serology, indicating immunity did not result from prior COVID-19 infection. All controls were positive for IgG S-protein serology. Immunogenicity among LT recipients was significantly lower with positive serology in only 47.5% (p, Graphical abstract

Background and Purpose: Drug induced liver injury is an emerging form of acute and chronic liver disease that may manifest as fatty liver. Amiodarone (AMD), a widely used anti-arrhythmic drug, can cause hepatic injury and steatosis by a variety of mechanisms, which are not completely understood. Experimental Approach: Chronic damage was induced by daily gavage of 180mg/kg body weight AMD for four consecutive days to C57Bl/6OlaHsd male mice. Key Results: Chronic AMD administration induced endoplasmic reticulum (ER) stress in both liver and adipose tissue. In adipose tissue, AMD reduced lipogenesis and increased lipolysis. Moreover, AMD treatment induced ER stress and ER stress-dependent lipolysis in 3T3L1 adipocytes in vitro. In the liver, AMD caused increased expression of genes encoding proteins involved in fatty acid (FA) uptake and transfer (Cd36, Fabp1 and Fabp4) and resulted in increased hepatic accumulation of free FAs, but not of triacylglycerols. In line with this, there was increased expression of hepatic de novo FA synthesis genes (Srebp1 and FA synthase encoded by Fasn). However, AMD significantly reduced the expression of the desaturase Scd1 and elongase Elovl6, detected at mRNA and protein levels. Accordingly, the FA profile of hepatic total lipids revealed increased accumulation of palmitate, a SCD1 and ELOVL6 substrate, and reduced levels of palmitoleate and cis-vaccenate, products of the enzymes. In addition, AMD-treated mice displayed increased hepatic apoptosis, known to be induced by lipotoxic palmitate. Conclusions and Implications: Chronic AMD induced ER stress and aggravated lipolysis in adipose tissue, while inducing a lipotoxic hepatic lipid environment.

Background: Primary biliary cholangitis (PBC) is a rare autoimmune liver disease with variation in prevalence, phenotype and prognosis across different geographical regions. Little is known about PBC in Israel. Our aim was to characterize the demography, clinical presentation, treatment patterns and prognosis in a cohort of PBC patients followed in a referral center in central Israel. Methods: Clinical, demographic and laboratory data were collected from the medical records of PBC patients followed at Tel Aviv Medical Center in the years 2003–2020. Results: We have identified 189 patients with a confirmed diagnosis of PBC, 92.6% were female and the mean age at diagnosis was 54.7 years. Thirty-nine percent were diagnosed with another autoimmune disease and 5.9% were diagnosed with a PBC-AIH (autoimmune hepatitis) variant syndrome. Ninety-six percent were treated with ursodeoxycholic acid (UDCA) at a mean dose of 13.3 mg/kg. A total of 28.1% were found with inadequate response to UDCA according to the Toronto criteria, and 53% of the UDCA non-responders were treated with bezafibrate. Younger age at diagnosis, higher baseline levels of alkaline phosphatase (ALP) and gamma-glutamyltransferase (GGT), AIH-PBC variant and positive anti-smooth muscle antibodies (ASMA) were associated with an inadequate UDCA response. In a multivariable analysis, higher ALP at diagnosis (OR = 1.92 CI 1.11–3.20 per 50-unit change, p = 0.018) and ASMA (OR = 27.6 CI 2.58–295, p = 0.006) independently predicted inadequate UDCA response. Higher alanine transaminase (ALT), ALP and GGT, lower albumin, younger age at diagnosis and pruritus conferred an increased risk for disease progression. Conclusions: Disease characteristics, treatment patterns, response to therapy and prognosis of a PBC patient cohort in a tertiary center in central Israel were revealed. The results highlight the importance of risk stratification in PBC, specifically in younger patients, those presenting with a high level of liver enzymes and in ASMA-positive patients with an assumed diagnosis of the AIH-PBC variant.

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third cause of cancer-related mortality. Globally, approximately 80 % of HCCs are associated with chronic hepatitis B virus (HBV) infection. HCC is the most prevalent cancer in Southeast Asia and Sub-Saharan Africa where HBV infection is endemic. Although HBV-associated HCC is relatively uncommon in developed countries, its incidence is rising, partially due to immigration waves from endemic areas. Since it is recognised as an oncogenic virus, much has been learned about the molecular pathways leading to HBV-induced hepatic carcinogenesis. HBV promotes carcinogenesis in direct and indirect ways. Directly, viral DNA integrates into the host genome causing multiple mutations. Indirect mechanisms include induction of fibrosis and immune activation causing chronic inflammation. For over three decades, a highly effective and safe vaccine for HBV is available. Currently, over 180 counties have adopted a universal vaccination program to all newborn infants, a policy that is already impacting the prevalence of HBV-related HCC in children and adolescents. Secondary prevention of HCC focuses on the 350–400 million persons who are chronically infected. The most important risk factors for HCC in these individuals are increased baseline and persistently elevated HBV DNA levels. Recently, we have seen the development of antiviral medications that are highly effective in viral suppression. Studies demonstrate that antiviral treatment delays liver disease progression and reduces the incidence of HCC. For those patients that have already developed cirrhosis, a careful surveillance schedule should be initiated to detect early HCC in order to apply curative interventions. For HBV carriers with HCC, tertiary prevention by antiviral therapy aims to reduce recurrence and prolong survival. In this chapter, we aim to comprehensively review aspects of HBV-associated HCC including epidemiology, pathogenesis, molecular pathways, and treatments.

Background Cardiovascular disease is a leading cause of death among kidney transplant recipients. Metabolic syndrome increases the risk for cardiovascular events and decreases graft survival. Lately, guidelines for management of the metabolic syndrome, primarily hypertension, diabetes mellitus (DM) and hypercholesterolemia have dramatically changed in an attempt to decrease cardiovascular risks among kidney transplant recipients. In the present study we examined whether these guideline changes had impact on our management of post-transplantation patients and the subsequent treatment outcomes for these diseases. Methods Data were obtained from kidney transplant clinic files from two follow-up (FU) periods—between 1994–1997 and between 2008–2011. Demographic data, monitoring and screening frequency for cardiovascular risk factors, immunosuppression regimen, treatment for hypertension, diabetes and hyperlipidemia, treatment outcomes and graft function changes were compared between the two follow-up periods. Results There was a significant increase in the percentage of patients undergoing transplantation due to renal failure secondary to diabetes and/or hypertension. Patient monitoring and screening during the second FU period were less frequent, but more targeted, reflecting changes in clinic routines. Blood pressure was better controlled in the second FU period (p