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.

Persistent neurocognitive decline in a clinic sample of hepatitis C virus-infected persons receiving interferon and ribavirin treatment.

Treatment of hepatitis C virus (HCV) with pegylated interferon and ribavirin (IFN/RBV) can be associated with neuropsychiatric side effects, which may necessitate dose reductions or treatment discontinuation. This study aimed to characterize the time course and predictors of cognitive and affective/mood symptoms after IFN/RBV treatment initiation. Forty individuals enrolled in a longitudinal project underwent comprehensive cognitive, medical, and psychiatric assessment at baseline and 10 weeks, 6 months, 12 months, and 18 months after treatment initiation. Analyses were conducted to determine the prevalence of neurocognitive impairment over time; explicate the relationship between neurocognitive impairment, neuropsychiatric symptoms, and liver disease at each time point; and identify predictors of neurocognitive decline as well as cognitive effects of viral clearance. By 10 weeks after initiating IFN/RBV, the prevalence of neurocognitive impairment rose from 22.5 to 47.4% (p < 0.05). Infection with genotype 1 and premorbid depression were associated with more severe declines (p < 0.05). After 18 months, 42.5% remained neurocognitively impaired, independent of viral clearance, severity of liver disease, and current depressive symptoms. Undetectable viral load was not associated with improvement 18 months after initiating treatment (p > 0.10). Results of the current study indicate that IFN/RBV treatment-emergent neurocognitive declines are significant, prevalent, and may persist long after treatment cessation. Clinicians should monitor cognition throughout the course of treatment for HCV, noting that early declines may indicate individuals at elevated risk for persistent neurocognitive impairment. Longer-term studies are needed to determine whether lasting declines may remit over longer intervals or with newer direct acting agents.

Noninvasive classification of hepatic fibrosis based on texture parameters from double contrast-enhanced magnetic resonance images.

PURPOSE: To demonstrate a proof of concept that quantitative texture feature analysis of double contrast-enhanced magnetic resonance imaging (MRI) can classify fibrosis noninvasively, using histology as a reference standard. MATERIALS AND METHODS: A Health Insurance Portability and Accountability Act (HIPAA)-compliant Institutional Review Board (IRB)-approved retrospective study of 68 patients with diffuse liver disease was performed at a tertiary liver center. All patients underwent double contrast-enhanced MRI, with histopathology-based staging of fibrosis obtained within 12 months of imaging. The MaZda software program was used to compute 279 texture parameters for each image. A statistical regularization technique, generalized linear model (GLM)-path, was used to develop a model based on texture features for dichotomous classification of fibrosis category (F ≤2 vs. F ≥3) of the 68 patients, with histology as the reference standard. The model's performance was assessed and cross-validated. There was no additional validation performed on an independent cohort. RESULTS: Cross-validated sensitivity, specificity, and total accuracy of the texture feature model in classifying fibrosis were 91.9%, 83.9%, and 88.2%, respectively. CONCLUSION: This study shows proof of concept that accurate, noninvasive classification of liver fibrosis is possible by applying quantitative texture analysis to double contrast-enhanced MRI. Further studies are needed in independent cohorts of subjects.

Neuropsychological test performance in patients co-infected with hepatitis C virus and HIV.

OBJECTIVE: To determine the effect of co-infection on neuropsychological performance in relatively healthy hepatitis C virus (HCV)-alone patients when compared with HCV/HIV-co-infected patients. DESIGN: To test whether the burden of co-infection with HCV and HIV on the central nervous system results in increased cognitive deficits, we tested 47 HCV-alone and 29 HCV/HIV-co-infected patients on a neuropsychological screening battery of tests of attention, concentration and psychomotor speed. METHODS: The neuropsychological test performance of HCV-alone and HCV/HIV-co-infected patients was compared with normative samples. The test performance between HCV-alone and HCV/HIV-co-infected patients was also assessed. Patients with chronic liver disease were divided on the basis of disease severity as determined by fibrosis stage, according to the METAVIR system. Neuropsychological test performance was correlated with fibrosis stage. RESULTS: As previously reported, HCV patients independent of co-infection status demonstrated deficits on neuropsychological measures of attention, concentration and psychomotor speed. No significant differences were found between patients with HCV-alone and HCV/HIV-co-infected patients on the neuropsychological measures. There was a relationship between neuropsychological test performance and fibrosis stage. CONCLUSION: Relatively healthy patients with HCV (either alone or when co-infected with HIV) may have deficits in the domains of attention, concentration and psychomotor speed. In this study no significant differences were found between patients with HCV alone and HCV/HIV-co-infected patients on neuropsychological measures, but as previously demonstrated, greater fibrosis was associated with poorer performance.

Assessment and usefulness of clinical scales for semiquantification of overt hepatic encephalopathy.

Hepatic encephalopathy (HE) represents the effects of liver dysfunction on the brain. When HE is clinically obvious (eg, confusion, poor judgment, personality change), it is termed overt HE. The severity of HE is measured by different methods. Assessing the severity of HE is important for determining patient prognosis and effectiveness of therapy. This article discusses the different methods for grading HE, including clinical rating scales, neuropsychological tests, and neurophysiologic measures.

Role of Sleep Disturbance in Chronic Hepatitis C Infection.

Chronic infection with the hepatitis C virus (CHC) is associated with physical and mental symptoms including fatigue and depression that adversely affect quality of life. A related complaint, sleep disturbance, has received little attention in the literature, with the exception of sleep changes noted in cirrhosis and end-stage liver disease. We present an overview of studies indicating sleep problems in patients with CHC, with about 60% to 65% of individuals reporting such complaints. Evidence suggests that impairments in sleep quality exist independent of antiviral therapy with interferon-alpha and prior to advanced stages of liver disease. Further investigation of sleep disturbance in CHC patients with a mild stage of liver disease may provide important information on disease course as well as allow additional opportunities for patient support.