Faculty Bibliography

The utility of thromboelastography/thromboelastometry currently has unvalidated clinical benefit in the assessment and reversal of coagulopathy among cirrhotic patients as compared to standard coagulation testing. A novel systematic review and meta-analysis was conducted in order to assess pooled outcome data among patients receiving thromboelastography/thromboelastometry as compared to standard coagulation testing. As compared to standard coagulation testing, there was a significant reduction in the number of patients requiring pRBC, platelet, and fresh frozen plasma transfusions among thromboelastography/thromboelastometry group with pooled OR 0.53 (95% CI 0.32-0.85; P = 0.009), 0.29 (95% CI 0.12-0.74; P = 0.009), and 0.19 (95% CI 0.12-0.31; P < 0.00001), respectively. Similarly, there was a significant reduction in number of pRBC, platelet, and fresh frozen plasma units transfused in the thromboelastography/thromboelastometry group with pooled MD -1.53 (95% CI -2.86 to -0.21; P = 0.02), -0.57 (95% CI -1.06 to -0.09; P = 0.02), and -2.71 (95% CI -4.34 to -1.07; P = 0.001), respectively. There were significantly decreased total bleeding events with pooled OR 0.54 (95% CI 0.31-0.94; P = 0.03) and amount of intraoperative bleeding during liver transplantation with pooled MD -1.46 (95% CI -2.49 to -0.44; P = 0.005) in the thromboelastography/thromboelastometry group. Overall, there was no significant difference in mortality between groups with pooled OR 0.91 (95% CI 0.63-1.30; P = 0.60). As compared to standard coagulation testing, a thromboelastography/thromboelastometry-guided approach to the assessment and reversal of cirrhotic coagulopathy improves overall number of patients exposed to blood product transfusions, quantity of transfusions, and bleeding events.

BACKGROUND AND AIM/OBJECTIVE:Morbid obesity is considered a relative contraindication for LT (Liver Transplant). We investigated if BMI (lean vs. obese) is a risk factor for post-LT graft and overall survival in NASH and non-NASH patients. METHODS:Using the UNOS database, LT recipients from 01/2002 to 06/2013 (age ≥18 yrs.) with follow up until 2017 were included. The association of BMI categories calculated at LT with graft and overall survival after LT were examined. RESULTS:After adjusting for confounders, all obesity cohorts (Overweight, Class I, Class II, and Class III obesity) among LT recipients for NASH had significantly reduced risk of graft and patient loss at 10 years follow up compared to the lean BMI cohort. In contrast, non-NASH group of LT recipients had no increased risk for graft and patient loss for overweight, Class I, Class II obesity groups, but had significantly increased the risk for graft (p<0.001) and patient loss (p=0.005) in the Class III obesity group. CONCLUSION/CONCLUSIONS:In this retrospective analysis of UNOS database, adult recipients selected for first LT, NASH patients with the lowest BMI have the worse long-term graft and patient survival as opposed to non-NASH patients where the survival was worse with higher BMI.

BACKGROUND: Many patients with primary biliary cholangitis have an inadequate response to first-line therapy with ursodeoxycholic acid. Seladelpar is a potent, selective agonist for the peroxisome proliferator-activated receptor-delta (PPAR-delta), which is implicated in bile acid homoeostasis. This first-in-class study evaluated the anti-cholestatic effects and safety of seladelpar in patients with an inadequate response to ursodeoxycholic acid. METHODS: The study was a 12-week, double-blind, placebo-controlled, phase 2 trial of patients with alkaline phosphatase of at least 1.67 times the upper limit of normal (ULN) despite treatment with ursodeoxycholic acid. Patients, recruited at 29 sites in North America and Europe, were randomly assigned to placebo, seladelpar 50 mg/day, or seladelpar 200 mg/day while ursodeoxycholic acid was continued. Randomisation was done centrally (1:1:1) by a computerised system using an interactive voice-web response system with a block size of three. Randomisation was stratified by region (North America and Europe). The primary outcome was the percentage change from baseline in alkaline phosphatase over 12 weeks, analysed in the modified intention-to-treat (ITT) population (any randomised patient who received at least one dose of medication and had at least one post-baseline alkaline phosphatase evaluation). This study is registered with ClinicalTrials.gov (NCT02609048) and the EU Clinical Trials Registry (EudraCT2015-002698-39). FINDINGS: Between Nov 4, 2015, and May 26, 2016, 70 patients were screened at 29 sites in North America and Europe. During recruitment, three patients treated with seladelpar developed fully reversible, asymptomatic grade 3 alanine aminotransferase increases (one on 50 mg, two on 200 mg), ranging from just over five to 20 times the ULN; as a result, the study was terminated after 41 patients were randomly assigned. The modified ITT population consisted of 12 patients in the placebo group, 13 in the seladelpar 50 mg group, and 10 in the seladelpar 200 mg group. Mean changes from baseline in alkaline phosphatase were -2% (SD 16) in the placebo group, -53% (14) in the seladelpar 50 mg group, and -63% (8) in the seladelpar 200 mg group. Changes in both seladelpar groups versus placebo were significant (p<0.0001 for both groups vs placebo), with no significant difference between the two seladelpar groups (p=0.1729). All five patients who received seladelpar for 12 weeks had normal alkaline phosphatase values at the end of treatment, based on a central laboratory ULN for alkaline phosphatase of 116 U/L. The most frequently reported adverse events were pruritus (16%; one patient on placebo, four on seladelpar 50 mg, and one on seladelpar 200 mg), nausea (13%; one patient on placebo, three on seladelpar 50 mg, and one on seladelpar 200 mg), diarrhoea (10%; two patients on placebo, one on seladelpar 50 mg, and one on seladelpar 200 mg), dyspepsia (8%; two patients on seladelpar 50 mg and one on seladelpar 200 mg), muscle spasms (8%; three patients on seladelpar 200 mg), myalgia (8%; one patient on placebo and two on seladelpar 200 mg), and dizziness (8%; one patient on placebo and two on seladelpar 50 mg). INTERPRETATION: Seladelpar normalised alkaline phosphatase levels in patients who completed 12 weeks of treatment. However, treatment was associated with grade 3 increases in aminotransferases and the study was stopped early. The effects of seladelpar should be explored at lower doses. FUNDING: CymaBay Therapeutics.

Hepatitis B and hepatitis C are common predisposing factors leading to cirrhosis and liver cancer. Therapies for hepatitis B suppress viral replication and improve morbidity and mortality. Treatment and evaluation of hepatitis B should be similar in all age groups. This article discusses special topics related to hepatitis B and the elderly. Hepatitis C is a treatable disease whose treatment can lead to viral eradication. This article discusses key points regarding hepatitis C diagnosis and treatment in the context of new advances in disease staging and treatment, with special attention on hepatitis C infection in the elderly.

BACKGROUND: An association of Coronary artery disease (CAD) with hepatitis C (HCV) has been suggested, but definitive data are still lacking. AIM: Our study sought to estimate the prevalence and severity of CAD in HCV patients compared to with age-, sex-, and race-matched controls without HCV infection. SUBJECTS AND METHODS: 63 HCV-infected patients were compared with 63 age, race, and sex-matched controls without HCV infection undergoing coronary angiography for evaluation of CAD. CAD was defined as more than a 50% blockage in any of the proximal coronary arteries on angiogram. The severity of the stenosis was defined by the modified Reardon severity scoring system: <50% stenosis of the luminal diameter, 1 point; 50-74%, 2 points; 75-99%, 3 points; 100% or total obstruction, 4 points. The points for each lesion in the proximal coronary circulation were summed to give the score for severity. RESULTS: A significantly higher prevalence of CAD was noted in the HCV population (69.8% vs. 47.6%, = 0.01). The combined Reardon's severity score in the HCV group was significantly higher compared to the controls (6.26 +/- 5.39 vs. 2.6 +/- 3.03, P < 0.0005). Additionally, significant multivessel CAD (>50% stenosis and >/=2 vessels involved) was also noted significantly more commonly in the HCV group compared to controls (57.1% vs. 15.9%, P < 0.0005). CONCLUSION: In this retrospective study the prevalence and severity of CAD was higher in HCV patients who were evaluated for CAD by angiogram compared with matched non-HCV patients. HCV-positive status is potentially a risk factor for CAD.

BACKGROUND: The uridine nucleotide analogue sofosbuvir is a selective inhibitor of hepatitis C virus (HCV) NS5B polymerase. We assessed the safety and efficacy of sofosbuvir in combination with pegylated interferon alfa-2a (peginterferon) and ribavirin in non-cirrhotic treatment-naive, patients with HCV. METHODS: For this open-label, randomised phase 2 trial, we recruited patients from 42 centres in the USA and Puerto Rico between March 23, 2011, and Sept 21, 2011. Patients were eligible for inclusion if they had chronic HCV infection (genotypes 1, 4, 5, or 6), were aged 18 years or older, and had not previously received treatment for HCV infection. Using a computer-generated randomisation sequence, we randomly assigned patients with HCV genotype-1 to one of three cohorts (A, B, and C; in a 1:2:3 ratio), with randomisation stratified by IL28B (CC vs non-CC allele) and HCV RNA (<800,000 IU/mL vs >/=800,000 IU/mL). Patients received sofosbuvir 400 mg plus peginterferon and ribavirin for 12 weeks (cohort A) or for 24 weeks (cohort B), or 12 weeks of sofosbuvir plus peginterferon and ribavirin followed by 12 weeks of either sofosbuvir monotherapy or sofosbuvir plus ribavirin (cohort C). We enrolled patients with all other eligible genotypes in cohort B. The primary efficacy endpoint was sustained virological response at post-treatment week 24 (SVR24) by intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, number NCT01329978. RESULTS: We enrolled 316 patients with HCV genotype-1: 52 to cohort A, 109 to cohort B, and 155 to cohort C. We assigned 11 patients with HCV genotype-4 and five patients with genotype-6 to cohort B (we detected no patients with genotype 5). In patients with HCVgenotype-1, SVR24 was achieved by 46 patients (89%, 95% CI 77-96) in cohort A, 97 patients (89%, 82-94) in cohort B, and by 135 (87%, 81-92) in cohort C. We detected no difference in the proportion of patients achieving SVR24 in cohort A compared with cohort B (p=0.94), or in cohort C (p=0.78). Nine (82%) of 11 patients with genotype-4 and all five with genotype-6 achieved SVR24. Seven patients, all with genotype-1 infection, relapsed after completion of assigned treatment. The most common adverse events that led to the discontinuation of any study drug--anaemia and neutropenia--were associated with peginterferon and ribavirin treatment. Three (6%) patients in cohort A, 18 (14%) patients in cohort B, and three (2%) patients in cohort C discontinued treatment because of an adverse event. INTERPRETATION: Our findings suggest that sofosbuvir is well tolerated and that there is no additional benefit of extending treatment beyond 12 weeks, but these finding will have to be substantiated in phase 3 trials. These results lend support to the further assessment of a 12 week sofosbuvir regimen in a broader population of patients with chronic HCV genotype-1 infection, including those with cirrhosis. FUNDING: Gilead Sciences.