Mycophenolate Interruption Restores Anti-SARS-CoV-2 Vaccine Immunogenicity in Unresponsive Liver Transplant Recipients

Background & aims: The fourth dose of anti-SARS-CoV-2 vaccine slightly improved the humoral response among previously seronegative liver transplant (LT) recipients. Mycophenolate (MMF) treatment worsens the vaccination response. This study aimed to evaluate whether temporary MMF interruption might improve the immunogenicity of the fourth anti-SARS-CoV-2 BNT16b2 vaccine dose in nonresponsive LT recipients. Methods: LT recipients negative for anti-spike glycoprotein-specific immunoglobulin G receptor-binding domain (s-RBD) antibodies after the third vaccine dose were enrolled. Anti-SARS-CoV-2 spike-specific T-cell responses were measured before and 2 months following the fourth vaccine dose, and anti-SARS-CoV-2 s-RBD antibodies also 6 months thereafter. MMF was suspended two weeks before and after vaccination. Results: Five LT recipients were enrolled. After a mean of 78 days after vaccination, all patients tested positive for anti-SARS-CoV-2 s-RBD antibodies. The mean antibody titer was 8944 UI/mL. The positive antibody response was maintained during a mean of 193 days of follow-up. Three patients developed a positive T-cell response. Two patients (one positive for T-cell response) developed a self-limited SARS-CoV-2 infection. Conclusions: Suspending MMF prior to the fourth dose of the anti-SARS-CoV-2 mRNA vaccine seems feasible and safe. This procedure could restore vaccine-induced immunogenicity in a large portion of previously nonresponsive LT recipients

Baseline Predictors of the Long-Term Insufficient Biochemical Response in Patients with Autoimmune Hepatitis: A Single Center Experience

The treatment response criteria in autoimmune hepatitis (AIH) have been recently updated. This study aimed to assess treatment responses in 39 (16 males) patients with AIH confirmed by histology. Prednisone added to azathioprine or mycophenolate was the most frequent first-line treatment. Serum alanine aminotransferase (ALT) levels were periodically checked for a median of 45 months. Eight (20.5%) patients presented 4 weeks non-response (NR). Baseline lower multiples of ALT above the upper normal limit (UNL) (p = 0.005), Ishak liver fibrosis score > 3 (p = 0.029), and less frequent confluent necrosis > 2 (p 100 strongly predicted CBR failure (p = 0.003) at a follow-up greater than 12 months. In conclusion, the absence of cirrhosis and a ≥50% UNL decrease in serum ALT levels were independent predictors for CBR. A baseline GLUCRE score may help identify patients maintaining longer CBR

Vitamin D binding protein gene polymorphisms and baseline vitamin D levels as predictors of antiviral response in chronic hepatitis C

Vitamin D deficiency seems to predict the unsuccessful achievement of sustained viral response (SVR) after anti-viral treatment in hepatitis C virus (HCV) difficult to treat genotypes. Vitamin D binding protein (GC) gene polymorphisms are known to influence vitamin D levels. This study was performed to assess whether the interaction between basal circulating vitamin D and the GC polymorphism plays a role in influencing the rate of anti viral responses in patients affected by chronic hepatitis C. Two hundred six HCV patients treated with a combination therapy of PEGinterferon plus ribavirin were retrospectively evaluated. GC rs7041 G>T, GC rs4588 C>A and IL- 28B rs12979860 C>T polymorphisms were genotyped. Frequencies of GC rs7041 G>T and rs4588 C>A polymorphisms were: G/G=64 (31.1%), G/T=100 (48.5%), T/T=42 (20.4%) and C/C=108 (52.4%), C/A=84 (40.8%), A/A=14 (6.8%). Patients were divided into those carrying 653 major alleles (WT+: G-C/G-C, G-C/T-C, G-C/G-A, N=100) and the remaining (WT-: G-C/T-A, T-A/T-C, T-A/T-A, T-C/T-C, N=106). Four groups were identified: vitamin D 6420 ng/mL and WT-, vitamin D 6420 and WT+, vitamin D>20 and WT-, vitamin D>20 and WT+. In difficult to treat HCV genotypes the proportion of patients achieving SVR significantly increased with a linear trend from the first to the last group: 6/25 (24.0%), 9/24 (37.5%), 12/29 (41.4%), 19/29 (65.5%) (p=0.003). At multivariate analysis having basal vitamin D >20 ng/mL plus the carriage of GC WT+ was found to be an independent predictor of SVR (O.R. 4.52, p=0.015). Conclusions: in difficult to treat HCV genotypes, simultaneous pre treatment normal serum vitamin D levels and the carriage of GCglobulin wild type isoform strongly predicts the achievement of SVR after PEG-interferon plus ribavirin antiviral therapy. Page 3 of 28 Hepatolog

Serological response and breakthrough infection after COVID-19 vaccination in patients with cirrhosis and post-liver transplant

Background: Vaccine hesitancy and lack of access remain major issues in disseminating COVID-19 vaccination to liver patients globally. Factors predicting poor response to vaccination and risk of breakthrough infection are important data to target booster vaccine programs. The primary aim of the current study was to measure humoral responses to 2 doses of COVID-19 vaccine. Secondary aims included the determination of factors predicting breakthrough infection.Methods: COVID-19 vaccination and Biomarkers in cirrhosis And post-Liver Transplantation is a prospective, multicenter, observational case-control study. Participants were recruited at 4–10 weeks following first and second vaccine doses in cirrhosis [n = 325; 94% messenger RNA (mRNA) and 6% viral vaccine], autoimmune liver disease (AILD) (n = 120; 77% mRNA and 23% viral vaccine), post-liver transplant (LT) (n = 146; 96% mRNA and 3% viral vaccine), and healthy controls (n = 51; 72% mRNA, 24% viral and 4% heterologous combination). Serological end points were measured, and data regarding breakthrough SARS-CoV-2 infection were collected.Results: After adjusting by age, sex, and time of sample collection, anti-Spike IgG levels were the lowest in post-LT patients compared to cirrhosis (p < 0.0001), AILD (p < 0.0001), and control (p = 0.002). Factors predicting reduced responses included older age, Child-Turcotte-Pugh B/C, and elevated IL-6 in cirrhosis; non-mRNA vaccine in AILD; and coronary artery disease, use of mycophenolate and dysregulated B-call activating factor, and lymphotoxin-α levels in LT. Incident infection occurred in 6.6%, 10.6%, 7.4%, and 15.6% of cirrhosis, AILD, post-LT, and control, respectively. The only independent factor predicting infection in cirrhosis was low albumin level.Conclusions: LT patients present the lowest response to the SARS-CoV-2 vaccine. In cirrhosis, the reduced response is associated with older age, stage of liver disease and systemic inflammation, and breakthrough infection with low albumin level

Serological response and breakthrough infection after COVID-19 vaccination in patients with cirrhosis and post-liver transplant

Background: Vaccine hesitancy and lack of access remain major issues in disseminating COVID-19 vaccination to liver patients globally. Factors predicting poor response to vaccination and risk of breakthrough infection are important data to target booster vaccine programs. The primary aim of the current study was to measure humoral responses to 2 doses of COVID-19 vaccine. Secondary aims included the determination of factors predicting breakthrough infection. Methods: COVID-19 vaccination and Biomarkers in cirrhosis And post-Liver Transplantation is a prospective, multicenter, observational case-control study. Participants were recruited at 4-10 weeks following first and second vaccine doses in cirrhosis [n = 325; 94% messenger RNA (mRNA) and 6% viral vaccine], autoimmune liver disease (AILD) (n = 120; 77% mRNA and 23% viral vaccine), post-liver transplant (LT) (n = 146; 96% mRNA and 3% viral vaccine), and healthy controls (n = 51; 72% mRNA, 24% viral and 4% heterologous combination). Serological end points were measured, and data regarding breakthrough SARS-CoV-2 infection were collected. Results: After adjusting by age, sex, and time of sample collection, anti-Spike IgG levels were the lowest in post-LT patients compared to cirrhosis (p < 0.0001), AILD (p < 0.0001), and control (p = 0.002). Factors predicting reduced responses included older age, Child-Turcotte-Pugh B/C, and elevated IL-6 in cirrhosis; non-mRNA vaccine in AILD; and coronary artery disease, use of mycophenolate and dysregulated B-call activating factor, and lymphotoxin-α levels in LT. Incident infection occurred in 6.6%, 10.6%, 7.4%, and 15.6% of cirrhosis, AILD, post-LT, and control, respectively. The only independent factor predicting infection in cirrhosis was low albumin level. Conclusions: LT patients present the lowest response to the SARS-CoV-2 vaccine. In cirrhosis, the reduced response is associated with older age, stage of liver disease and systemic inflammation, and breakthrough infection with low albumin level

Toll Like Receptor 4 D299G Associates with Disease Progression in Caucasian Patients with Chronic HBV Infection: Relationship with Gender.

Abstract This study aimed to verify whether rs4986790 A >G single nucleotide polymorphism of toll like receptor 4 (TLR-4) associates with a more severe course of hepatitis B virus (HBV) chronic infection. A cross-sectional study enrolled 191 Caucasian HBV-positive patients: 28 HBsAg+ inactive carriers, 121 chronic hepatitis B, 42 HBsAg+transplant candidates. A longitudinal study included 94 patients followed-up for a median time of 19.3 years. TLR-4 rs4986790 A/A genotype was carried less frequently in male HBsAg+inactive carriers than in males with HBsAg+active chronic infection (12/17 Vs 109/121, p00.022). At stepwise logistic regression analysis, the carriage of TLR-4 rs4986790 A/A genotype was found to be and independent predictor of liver fibrosis (O.R. 14.8, p00.019). In conclusion, in HBV-positive Caucasian patients, the A/A genotype of the rs4986790 polymorphism may influence a worse outcome of chronic HBV infection, mainly through a synergistic interaction with male gender

Toll like receptor 4 D299G associates with disease progression in caucasian patients with chronic HBV infection: relationship with gender

This study aimed to verify whether rs4986790 A >G single nucleotide polymorphism of toll like receptor 4 (TLR-4) associates with a more severe course of hepatitis B virus (HBV) chronic infection. A cross-sectional study enrolled 191 Caucasian HBV-positive patients: 28 HBsAg+ inactive carriers, 121 chronic hepatitis B, 42 HBsAg+transplant candidates. A longitudinal study included 94 patients followed-up for a median time of 19.3 years. TLR-4 rs4986790 A/A genotype was carried less frequently in male HBsAg+inactive carriers than in males with HBsAg+active chronic infection (12/17 Vs 109/121, p00.022). At stepwise logistic regression analysis, the carriage of TLR-4 rs4986790 A/A genotype was found to be and independent predictor of liver fibrosis (O.R. 14.8, p00.019). In conclusion, in HBV-positive Caucasian patients, the A/A genotype of the rs4986790 polymorphism may influence a worse outcome of chronic HBV infection, mainly through a synergistic interaction with male gender

Morbidity and mortality after transjugular intrahepatic portosystemic shunt placement in patients with cirrhosis

Objectives Transjugular intrahepatic portosystemic shunt (TIPS) is adopted to treat refractory complications of portal hypertension, such as variceal bleeding and ascites. This study aimed to assess predictors of hepatic encephalopathy (HE) development and cumulative transplant-free survival after TIPS placement in patients with cirrhosis complicated by refractory ascites and major gastroesophageal bleeding. Materials and methods Sixty-three cirrhotic patients who underwent TIPS positioning as a secondary prophylaxis of major upper gastroesophageal bleeding (N=30) or to control refractory ascites (N=33) were enrolled. Results After a median follow-up of 26 months following TIPS insertion, only 1/30 (3.3%) patients developed reoccurrence of bleeding. Complete control of refractory ascites was recorded in 19/23 (82.6%) patients. Within the first month after TIPS placement, 34/63 (53.9%) patients developed clinically significant HE, which was associated with the baseline presence of type 2 hepatorenal syndrome (P=0.022). At the end of 90 months of follow-up, 35 (55.6%) patients were alive, 12 (19.0%) patients underwent liver transplantation, and 16 (25.4%) patients died. Independent predictors of transplant-free survival were a model for end-stage liver disease score up to 15 (P<0.001), the absence of a history of spontaneous bacterial peritonitis (P=0.010) pre-TIPS, and no HE within 1 month post-TIPS (P=0.040). Conclusion TIPS insertion can be considered a safe and effective treatment in patients with cirrhosis and severe complications of portal hypertension that are not manageable with standard treatments. Interestingly, if confirmed in future studies, the history of spontaneous bacterial peritonitis pre-TIPS could be added to the model for end-stage liver disease score as a strong baseline predictor of post-TIPS mortality