Impact of pre-transplant immune checkpoint inhibitor use on post-transplant outcomes in HCC: A systematic review and individual patient data meta-analysis.

BACKGROUND & AIMS: Treatment with immune checkpoint inhibitors (ICIs) for hepatocellular carcinoma (HCC) prior to liver transplantation (LT) has been reported; however, ICIs may elevate the risk of allograft rejection and impact other clinical outcomes. This study aims to summarize the impact of ICI use on post-LT outcomes. METHODS: In this individual patient data meta-analysis, we searched databases to identify HCC cases treated with ICIs before LT, detailing allograft rejection, HCC recurrence, and overall survival. We performed Cox regression analysis to identify risk factors for allograft rejection. RESULTS: Among 91 eligible patients, with a median (IQR) follow-up of 690.0 (654.5) days, there were 24 (26.4%) allograft rejections, 9 (9.9%) HCC recurrences, and 9 (9.9%) deaths. Age (adjusted hazard ratio [aHR] per 10 years 0.72, 95% CI 0.53-0.99, p = 0.044) and ICI washout time (aHR per 1 week 0.92, 95% CI 0.86-0.99, p = 0.022) were associated with allograft rejection. The median (IQR) washout period for patients with ≤20% probability of allograft rejection was 94 (196) days. Overall survival did not differ between cases with and without allograft rejection (log-rank test, p = 0.2). Individuals with HCC recurrence had fewer median (IQR) ICI cycles than those without recurrence (4.0 [1.8] vs. 8.0 [9.0]; p = 0.025). The proportion of patients within Milan post-ICI was lower for those with recurrence vs. without (16.7% vs. 65.3%, p = 0.032). CONCLUSION: Patients have acceptable post-LT outcomes after ICI therapy. Age and ICI washout length relate to the allograft rejection risk, and a 3-month washout may reduce it to that of patients without ICI exposure. Number of ICI cycles and tumor burden may affect recurrence risk. Large prospective studies are necessary to confirm these associations. IMPACT AND IMPLICATIONS: This systematic review and individual patient data meta-analysis of 91 patients with hepatocellular carcinoma and immune checkpoint inhibitor use prior to liver transplantation suggest acceptable overall post-transplant outcomes. Older age and longer immune checkpoint inhibitor washout period have a significant inverse association with the risk of allograft rejection. A 3-month washout may reduce it to that of patients without immune checkpoint inhibitor exposure. Additionally, a higher number of immune checkpoint inhibitor cycles and tumor burden within Milan criteria at the completion of immunotherapy may predict a decreased risk of hepatocellular carcinoma recurrence, but this observation requires further validation in larger prospective studies.

Dosing of Rifaximin Soluble Solid Dispersion Tablets in Adults With Cirrhosis: 2 Randomized, Placebo-controlled Trials.

BACKGROUND & AIMS: Cirrhosis-related complications are a major burden. Rifaximin soluble solid dispersion (SSD) tablets (immediate-release [IR]; sustained extended-release [SER]) were designed to increase rifaximin water solubility. These analyses evaluate dosing for prevention of cirrhosis complication-related hospitalizations/mortality and overt hepatic encephalopathy (OHE) treatment. METHODS: Two phase II, randomized, double-blind, placebo-controlled trials were conducted. Trial 1: outpatients with early decompensated cirrhosis randomized to placebo or rifaximin SSD once-nightly: IR 40 or 80 mg, SER 40 or 80 mg, or IR 80 mg plus SER 80 mg, for 24 weeks. Trial 2: inpatients with OHE randomized to lactulose plus placebo or rifaximin SSD: IR 40 mg once or twice daily or SER 80 mg once or twice daily for ≤14 days. Primary efficacy endpoint: time to cirrhosis complication-related hospitalization/all-cause mortality (Trial 1) or time to OHE resolution (Trial 2). RESULTS: In Trial 1 (n = 516), no significant difference in time to cirrhosis complication-related hospitalization/all-cause mortality vs placebo. In a post hoc analysis, time to all-cause hospitalization/all-cause mortality was improved with IR 40 mg vs placebo (15.4% [12/78] vs 27.7% [26/94]; P = .03). A Trial 2 prespecified interim analysis (n = 71) showed lactulose plus rifaximin SSD IR 40 mg bid significantly reduced median time to OHE resolution (21.1 hours) vs lactulose plus placebo (62.7 hours; P = .02). Trial 2 was subsequently terminated. CONCLUSION: Rifaximin SSD IR 40 mg may reduce hospitalizations in patients with cirrhosis and shorten duration of OHE during hospitalization-considered a negative finding, yet also hypothesis-generating. (ClinicalTrials.govNCT01904409; NCT03515044).

Safety, pharmacokinetics and antiviral activity of ABI-H2158, a hepatitis B virus core inhibitor: A randomized, placebo-controlled phase 1 study.

Treatment for chronic hepatitis B virus infection (cHBV) is mostly indefinite, with new finite-duration therapies needed. We report safety, pharmacokinetics and antiviral activity of the investigational HBV core inhibitor ABI-H2158. This Phase 1a/b study (NCT03714152) had three parts: Part A, participants received a single ascending oral dose of ABI-H2158 (5-500 mg) or placebo; Part B, participants received multiple doses of ABI-H2158 300 mg once (QD) or twice (BID) daily or placebo, for 10 days; Part C, cHBV patients received ABI-H2158 (100, 300, or 500 mg QD or 300 mg BID) or placebo, for 14 days. Ninety-three participants enrolled. In Parts A/B, there were no serious adverse events (SAEs) or deaths, and all treatment-emergent AEs (TEAEs) were Grade 1. In Part C, two patients had Grade 3 TEAEs unrelated to ABI-H2158; there were no deaths, SAEs or Grade 4 TEAEs. In Part A, median time to maximum ABI-H2158 plasma concentration (Tmax ) and mean terminal elimination half-life (t½ ) were 1-4 and 9.8-20.7 h, and area under the plasma concentration-time curve increased dose proportionally. In Part B, Day 10 Tmax was 2 h, mean t½ was 15.5-18.4 h, and exposure accumulated 1.7- to 3.1-fold. In Part C, Day 14 Tmax was 1 h, exposure accumulated 1.4- to 1.8-fold, and ABI-H2158 was associated with >2 log10 declines in HBV nucleic acids. In conclusion, ABI-H2158 in cHBV patients following 14 days of dosing was well tolerated and demonstrated potent antiviral activity. Safety and pharmacokinetics supported future QD dosing.

Variability and Lability of Ammonia Levels in Healthy Volunteers and Patients With Cirrhosis: Implications for Trial Design and Clinical Practice.

INTRODUCTION: Ammonia levels are used to assess hepatic encephalopathy, but their levels are highly variable in clinical practice. METHODS: We studied factors associated with variation in ammonia values in cirrhotic patients without previous hepatic encephalopathy and healthy volunteers (HVs). RESULTS: Ammonia increased by 12% and 18% at 1 and 2 hour, respectively, after a protein meal in 64 cirrhotic patients (P < 0.001). In 237 HVs, ammonia levels varied significantly between sites (P < 0.0001). New site-specific ammonia upper limits based on HV levels using a strict analysis protocol differed from routinely used values. Correlation between paired fresh samples was high (r = 0.83) but modest between fresh and frozen samples (r = 0.62). DISCUSSION: Sample handling, processing, and protein intake impact ammonia levels across sites.

The Effects of Hepatic Steatosis on the Natural History of HBV Infection.

Fatty liver prevalence is increasing and becoming a global health burden. Chronic hepatitis B infection (CHB) is one of the most common chronic viral infections. Steatosis in CHB patients increases risk of cirrhosis and hepatocellular carcinoma. Data from studies on the interaction between CHB and nonalcoholic fatty liver disease are not conclusive. Liver biopsy is the gold standard for diagnosis of fatty liver; however, noninvasive diagnostic tests have been developed to diagnose and predict fibrosis in CHB/NAFLD. Treatment guidelines are not clear.

Safety and efficacy of a fixed-dose combination regimen of grazoprevir, ruzasvir, and uprifosbuvir with or without ribavirin in participants with and without cirrhosis with chronic hepatitis C virus genotype 1, 2, or 3 infection (C-CREST-1 and C-CREST-2, part B): two randomised, phase 2, open-label trials.

BACKGROUND: There is a need for hepatitis C virus (HCV) therapies with excellent efficacy across genotypes and in diverse populations. Part A of the C-CREST-1 and C-CREST-2 trials led to the selection of a three-drug regimen of grazoprevir (MK-5172; an HCV NS3/4A protease inhibitor; 100 mg/day) plus ruzasvir (MK-8408; an NS5A inhibitor; 60 mg/day) plus uprifosbuvir (MK-3682; an HCV NS5B polymerase inhibitor; 450 mg/day). Part B of the studies tested this combination as a single formulation in different treatment durations in a broader population. METHODS: Part B of these randomised, phase 2, open-label clinical trials enrolled individuals from 15 countries who were chronically infected with HCV genotypes 1-6 (HCV RNA ≥10 000 IU/mL) with or without compensated cirrhosis. Those with genotype 1, genotype 2, genotype 4, or genotype 6 were treatment-naive; those with genotype 3 could be treatment-naive or treatment-experienced with pegylated interferon and ribavirin. Randomisation occurred centrally using an interactive voice response system and integrated web response system. Participants were randomly assigned to receive treatment for 8, 12, or 16 weeks with a fixed-dose combination of grazoprevir, ruzasvir, and uprifosbuvir with or without ribavirin. The primary endpoint was the proportion of participants achieving sustained virological response 12 weeks after the end of all study therapy (SVR12), defined as HCV RNA less than the lower limit of quantification (either target detected unquantifiable or target not detected [<15 IU/mL]). The trials are registered at ClinicalTrials.gov, numbers NCT02332707 and NCT02332720. FINDINGS: 676 participants were randomly assigned between Feb 18, 2015, and Aug 16, 2016. In all 675 participants who received at least one dose of study drug (full analysis set), SVR12 for the 8-week regimen of grazoprevir, ruzasvir, and uprifosbuvir with and without ribavirin was achieved in 39 (93% [95% CI 81-99]) of 42 participants with genotype 1a, 45 (98% [88-100]) of 46 with genotype 1b, 54 (86% [75-93]) of 63 with genotype 2, 98 (95% [89-98]) of 103 with genotype 3, and seven (100% [59-100]) of seven participants with genotype 4. SVR12 for the 12-week regimen with and without ribavirin was achieved in 87 (99% [95% CI 94-100]) of 88 participants with genotype 1, 61 (98% [91-100]) of 62 with genotype 2, and four (100% [40-100]) of four with genotype 6. Among participants with cirrhosis who were infected with genotype 3, SVR12 for the 12-week regimen with and without ribavirin was achieved in 28 (97% [95% CI 82-100]) of 29 of those who were treatment-naive and 29 (100% [88-100]) of 29 who were treatment-experienced. SVR12 for the 16-week regimen with and without ribavirin was achieved in 26 (100% [95% CI 87-100]) of 26 participants with genotype 2 infection and 72 (96% [89-99]) of 75 participants with genotype 3 infection. The most common adverse events were headache (143 [22%] of 664), fatigue (129 [19%] of 664), and nausea (83 [13%] of 664). 16 (2%) of 664 participants had serious adverse events. INTERPRETATION: The combined regimen of grazoprevir (100 mg/day), ruzasvir (60 mg/day), and uprifosbuvir (450 mg/day) has the potential to provide a simplified treatment for HCV that is effective and well tolerated in most individuals infected with HCV, as well as a shorter duration of treatment in many individuals. FUNDING: Merck & Co, Inc.

Hepatitis B Virus Infection and Liver Decompensation.

The goal in patients with immune active hepatitis B virus (HBV) infection is to significantly suppress viral replication and prevent progression of fibrosis to cirrhosis and liver decompensation and decrease the incidence of hepatocellular carcinoma. This is achievable by the highly active antivirals, entecavir and tenofovir, which are considered first-line therapy in most patients with immune active hepatitis C virus and after liver transplantation to prevent HBV recurrence. Patients with decompensated cirrhosis should be referred for liver transplantation and treated with first-line antivirals as early as possible, with the goal of achieving complete viral suppression in the shortest time possible.

Management of the patient with SVR.

In the current era of therapy with direct-acting antiviral (DAAs) drugs, achievement of a sustained virological response (SVR) is achievable in ⩾90% of hepatitis C-infected patients. SVR benefits are well-recognized with reductions in rates of liver complications, hepatocellular carcinoma and mortality. Additional benefits include reduced morbidity related to extrahepatic and systemic manifestations of hepatitis C such as renal, dermatologic, and metabolic complications. However, not all patients will derive all of these benefits and monitoring for progression is necessary, especially in those with more advanced fibrosis. To maximize the health benefits of SVR, counseling patients on best means to maintain good liver health and prevent reinfection are also important.

Acute-on-chronic liver failure: extracorporeal liver assist devices.

PURPOSE OF REVIEW: Acute-on-chronic liver failure (ACLF), a syndrome precipitated by acute liver injury in patients with advanced cirrhosis, is associated with multiorgan dysfunction and high rates of mortality. Liver support systems have been developed in an attempt to improve survival of patients with ACLF by providing a bridge until recovery of the native liver function. RECENT FINDINGS: Nonbiological devices such as molecular adsorbent recirculating system (MARS) and fractionated plasma separation and adsorption (Prometheus) are effective in improving severe hepatic encephalopathy and cholestasis, have good safety and tolerability profiles and are frequently employed in patients with ACLD; however, randomized controlled trials (RCTs) failed to show improvement in survival. Biologic devices that incorporate hepatic cells in bioreactors are also under development. Recent data from pilot studies suggested improvement in survival rates in some groups of patients with ACLF; however, their effect on patient survival in RCT is still unknown. SUMMARY: Liver support systems are safe and well tolerated when used in management of patients with ACLF. Their use should continue in controlled clinical trials to explore their role in bridging patients to liver transplantation or recovery in well defined patient groups.

Implications of hepatitis C virus infection for behavioral symptoms and activities of daily living.

Hepatitis C virus (HCV) is neurovirulent and has been shown to be associated with neuropsychological (NP) deficits in a subset of infected individuals. Despite these previous findings, little work has been done to examine neurobehavioral symptoms associated with HCV infection. We examined 34 HCV seropositive (HCV+) individuals and 35 healthy comparison participants (HCV-) with the self-rating form of the Frontal Systems Behavior Scale (FrSBe). Results showed that at the group level, only the FrSBe apathy subscale mean was clinically elevated (T score >65) among HCV+ persons; executive dysfunction, disinhibition, and total subscale means were not clinically elevated. At the individual level, a significantly higher proportion of HCV+ individuals than of HCV- individuals reported clinically elevated FrSBe T scores . Moreover, HCV+ individuals were nearly 3 times as likely to report clinically elevated FrSBe T scores of apathy, executive dysfunction, and disinhibition as compared to HCV- participants. A multiple regression that included substance use disorders, neuropsychological impairment, and age indicated that HCV status was an independent predictor of self-reported FrSBe total T scores. Across all participants, small, yet significant, correlations were found between elevated self-reported FrsBe T scores and dependence in activities of daily living. These results show that a subset of HCV-infected individuals report clinically elevated behavioral symptoms. Clinical implications for the assessment and management of elevated behavioral symptoms in HCV are discussed.

Treatment persistence in and cost of therapy for patients with chronic hepatitis C: Peginterferon alfa-2a plus ribavirin versus peginterferon alfa-2b plus ribavirin.

PURPOSE: Treatment persistence and cost of therapy for patients with chronic hepatitis C (CHC) treated with peginterferon alfa-2a plus ribavirin and peginterferon alfa-2b plus ribavirin were evaluated. METHODS: This retrospective database analysis used eligibility, pharmacy, and medical claims data from a large U.S. health plan for patients with CHC treated with peginterferon alfa-2a plus ribavirin and peginterferon alfa-2b plus ribavirin from January 2002 through June 2006. For the purposes of this analysis, the study population included all hepatitis C virus (HCV) genotypes. Comparable groups for assessment of outcomes were constructed using propensity score matching to reduce the effect of known sources of bias. Outcome variables included treatment persistence and annualized overall and HCV-attributable health care costs. RESULTS: A total of 1783 matched pairs were analyzed. Compared with patients receiving peginterferon alfa-2a plus ribavirin, patients receiving peginterferon alfa-2b plus ribavirin were 18% less likely to be persistent with therapy at week 48 (p = 0.013). During the first six months of follow-up, mean all-cause costs (p = 0.0368) and HCV-attributable costs (p < 0.0001) were significantly lower for peginterferon alfa-2a plus ribavirin than for peginterferon alfa-2b plus ribavirin. Mean annualized all-cause costs (p = 0.0060) and HCV-attributable costs (p = 0.0167) over the entire follow-up period were significantly lower for patients treated with peginterferon alfa-2a plus ribavirin versus peginterferon alfa-2b plus ribavirin. CONCLUSION: Analysis of information from a health care claims database suggests that treating CHC with peginterferon alfa-2a plus ribavirin may improve treatment persistence and help reduce the health care costs imposed by CHC compared with treatment with peginterferon alfa-2b plus ribavirin.

Impairments in fine-motor coordination and speed of information processing predict declines in everyday functioning in hepatitis C infection.

Research increasingly supports the neurovirulence of chronic infection with the hepatitis C virus (HCV). For example, HCV infection has been associated with neuropsychological impairment in several ability areas, including psychomotor skills. This study aimed to examine whether HCV-associated neuropsychological impairment is predictive of declines in the independent performance of physical (PADLs) and instrumental (IADLs) activities of daily living. A total of 106 volunteers with HCV infection completed a comprehensive neuropsychological, medical, and psychiatric research evaluation. As compared to 30 HCV-seronegative comparison participants, the HCV-infected group reported significantly greater declines in both PADLs and IADLs. Within the HCV cohort, individuals with impaired speed of information processing reported significantly greater IADL declines, whereas impaired fine-motor coordination was associated with declines in both IADLs and PADLs. In a series of regression analyses, impaired speed of information processing and depressive symptoms (as measured by the Beck Depression Inventory) were the only independent predictors of IADL declines, whereas general affective distress (as measured by the Profile of Mood States), sex, and fine-motor coordination impairment were predictive of declines in PADLs. Although the clinical assessment of HCV typically emphasizes both affective (e.g., depression) and physical factors, findings from the present study suggest that cognitive impairment is an important contributor to everyday functioning in persons living with HCV infection and therefore warrants consideration in clinical and research evaluations.

Introduction to the Hepatic Encephalopathy Scoring Algorithm (HESA).

A primary obstacle to early diagnosis and treatment of hepatic encephalopathy (HE) is the lack of a well-validated, standardized assessment method. The purpose of this study was to present preliminary validity data on a new method of grading HE, the Hepatic Encephalopathy Scoring Algorithm (HESA), which combines clinical impressions with neuropsychological performances to characterize HE. Participants were 49 inpatients admitted for complications of end stage liver disease. Each participant's level of HE was graded using HESA and the West Haven Criteria (WHC) by independent raters blinded to each other's rating. A moderately strong association was found between the two grading methods (r = 0.60), and individual HESA clinical and neuropsychological indicators were good discriminators among grades. The results also suggest HESA may be more sensitive to mental status impairment in the middle grades of HE than WHC. These findings suggest HESA holds promise as a multi-method approach to grading all levels of HE.

Cognitive dysfunction in chronic hepatitis C: a review.

The hepatitis C virus (HCV) is a common blood-borne illness that affects up to 2% of the world's population and almost 4 million Americans. Cognitive impairment, or difficulty with thinking, has become a well-established symptom in persons with end stage liver disease. It was previously assumed that cognitive impairment was a consequence of cirrhosis-associated hepatic encephalopathy. Recent evidence, however, suggests that approximately one-third of people with chronic HCV experience cognitive impairment even in the absence of cirrhosis and that its occurrence is unrelated to other indices of liver function, such as laboratory values, viral load, and genotype. In the present review, evidence outlining the presence of cognitive deficits associated with HCV, possible etiological factors, effects of antiviral therapy, and co-infection with human immunodeficiency virus (HIV) is presented. Implications of these findings and directions for future work are discussed.

Randomized controlled study of extracorporeal albumin dialysis for hepatic encephalopathy in advanced cirrhosis.

UNLABELLED: Extracorporeal albumin dialysis (ECAD) may improve severe hepatic encephalopathy (HE) in patients with advanced cirrhosis via the removal of protein or non-protein-bound toxins. A prospective, randomized, controlled, multicenter trial of the efficacy, safety, and tolerability of ECAD using molecular adsorbent recirculating system (MARS) was conducted in such patients. Patients were randomized to ECAD and standard medical therapy (SMT) or SMT alone. ECAD was provided daily for 6 hours for 5 days or until the patient had a 2-grade improvement in HE. HE grades (West Haven criteria) were evaluated every 12 hours using a scoring algorithm. The primary endpoint was the difference in improvement proportion of HE between the 2 groups. A total of 70 subjects [median age, 53; 56% male; 56% HE grade 3; 44% HE grade 4; median model for end-stage liver disease (MELD) 32 (11-50) and CPT 13 (10-15)] were enrolled in 8 tertiary centers. Patients were randomized to ECAD + SMT (n = 39) or SMT alone (n = 31). Groups were matched in demographics and clinical variables. The improvement proportion of HE was higher in ECAD (mean, 34%; median, 30%) versus the SMT group (mean, 18.9%; median, 0%) (P = 0.044) and was reached faster and more frequently than in the SMT group (P = 0.045). Subjects receiving ECAD tolerated treatment well with no unexpected adverse events. CONCLUSION: The use of ECAD may be associated with an earlier and more frequent improvement of HE (grade 3/4). Because this 5-day study was not designed to examine the impact of MARS on survival, a full assessment of the role of albumin dialysis awaits the results of additional controlled trials.

Contrast-enhanced ultrasound as a predictor of treatment efficacy within 2 weeks after transarterial chemoembolization of hepatocellular carcinoma.

PURPOSE: To determine whether contrast-enhanced ultrasound (CEUS) can aid in assessing treatment efficacy within the first 2 weeks after transarterial chemoembolization for hepatocellular carcinoma. MATERIALS AND METHODS: Contrast-enhanced ultrasound was performed to detect residual tumor blood flow after 42 transarterial chemoembolization procedures in 33 patients who had hepatocellular carcinomas, and the results were compared with final tumor outcome. Twenty-nine CEUS studies were performed within 2 weeks after treatment and the remainder within 1 month. Phase-inversion low-mechanical-index real-time and intermittent imaging were performed after the intravenous injection of 0.5-2 mL US contrast medium by experienced radiologists blind to all other imaging findings. RESULTS: Nine tumors did not reach final outcome--patients were lost to follow-up or died without autopsy (n = 6) or tumors were retreated before final outcome was established (n = 3). Of the remaining 33 tumors, outcome was established by histology (n = 9), angiography (n = 14), tumor growth (n = 2), or by computed tomography and/or magnetic resonance imaging performed more than 6 months after treatment (n = 8). Twenty-three tumors were studied by CEUS within 2 weeks and 10 within 1 month after treatment. Of these 33 tumors, there were no false-negative results and one false-positive result. The only error occurred when the CEUS study was performed within 1 day after treatment. CONCLUSIONS: Residual tumor blood flow on CEUS performed at 2 or more days after transarterial chemoembolization may be predictive of tumor outcome that currently requires 3 months to be reliably detected by computed tomography and/or magnetic resonance imaging.

Liver fibrosis: noninvasive diagnosis with double contrast material-enhanced MR imaging.

PURPOSE: To retrospectively evaluate the accuracy of double contrast material-enhanced (hereafter double-enhanced) magnetic resonance (MR) imaging depiction of hepatic fibrosis, with histopathologic analysis findings as the reference standard. MATERIALS AND METHODS: The institutional review board approved this HIPAA-compliant study and waived the requirement for informed consent. One hundred one patients (58 men, 43 women; mean age +/- standard deviation, 52 years +/- 10) who underwent double-enhanced MR imaging with superparamagnetic iron oxide (SPIO)-enhanced and double-enhanced spoiled gradient-echo (SPGR) sequences between 2001 and 2004 and had a reliable reference standard for the diagnosis of liver fibrosis were included. Two blinded MR radiologists retrospectively scored qualitative (reticulation, nodularity, and total scores) and quantitative (contrast-to-noise ratio between hyperintense and hypointense liver regions, coefficient of variation, and noise-corrected coefficient of variation) liver texture features on MR images in consensus. The image scores for patients with advanced (METAVIR fibrosis score >/= 3) versus those for patients with mild (METAVIR score