Antiviral Treatment and Response are Associated With Lower Risk of Dementia Among Hepatitis C Virus-Infected Patients.

OBJECTIVE: Eradication of hepatitis C virus (HCV) infection has been linked with improvement in neurocognitive function, but few studies have evaluated the effect of antiviral treatment/ response on risk of dementia. Using data from the Chronic Hepatitis Cohort Study (CHeCS), we investigated how antiviral therapy impacts the risk of developing dementia among patients with HCV. METHODS: A total of 17,485 HCV patients were followed until incidence of dementia, death, or last follow-up. We used an extended landmark modeling approach, which included time-varying covariates and propensity score justification for treatment selection bias, as well as generalized estimating equations (GEE) with a link function as multinominal distribution for a discrete time-to-event data. Death was considered a competing risk. RESULTS: After 15 years of follow-up, 342 patients were diagnosed with incident dementia. Patients who achieved sustained virological response (SVR) had significantly decreased risk of dementia compared to untreated patients, with hazard ratios (HRs) of 0.32 (95% CI 0.22-0.46) among patients who received direct-acting antiviral (DAA) treatment and 0.41 (95% CI 0.26-0.60) for interferon-based (IFN) treatment. Risk reduction remained even when patients failed antiviral treatment (HR 0.38, 95% CI 0.38-0.51). Patients with cirrhosis, Black/African American patients, and those without private insurance were at significantly higher risk of dementia. CONCLUSION: Antiviral treatment independently reduced the risk of dementia among HCV patients, regardless of cirrhosis. Our findings support the importance of initiation antiviral therapy in chronic HCV-infected patients.

Impact of hepatitis C treatment status on risk of Parkinson's disease and secondary parkinsonism in the era of direct-acting antivirals.

Research suggests a possible link between chronic infection with hepatitis C virus (HCV) and the development of Parkinson's Disease (PD) and secondary Parkinsonism (PKM). We investigated the impact of antiviral treatment status (untreated, interferon [IFN] treated, direct-acting antiviral [DAA] treated) and outcome (treatment failure [TF] or sustained virological response [SVR]) on risk of PD/PKM among patients with HCV. Using data from the Chronic Hepatitis Cohort Study (CHeCS), we applied a discrete time-to-event approach with PD/PKM as the outcome. We performed univariate followed by a multivariable modelling that used time-varying covariates, propensity scores to adjust for potential treatment selection bias and death as a competing risk. Among 17,199 confirmed HCV patients, we observed 54 incident cases of PD/PKM during a mean follow-up period of 17 years; 3753 patients died during follow-up. There was no significant association between treatment status/outcome and risk of PD/PKM. Type 2 diabetes tripled risk (hazard ratio [HR] 3.05; 95% CI 1.75-5.32; p < .0001) and presence of cirrhosis doubled risk of PD/PKM (HR 2.13, 95% CI 1.31-3.47). BMI >30 was associated with roughly 50% lower risk of PD/PKM than BMI <25 (HR 0.43; 0.22-0.84; p = .0138). After adjustment for treatment selection bias, we did not observe a significant association between HCV patients' antiviral treatment status/outcome on risk of PD/PKM. Several clinical risk factors-diabetes, cirrhosis and BMI-were associated with PD/PKM.

Factors associated with a positive phosphatidylethanol test during liver transplantation evaluation.

BACKGROUND: Early identification of alcohol use is crucial for informing recommendations of appropriate follow-up treatment pre-liver transplant and optimizing post-liver transplant outcomes. The purpose of the study was to investigate whether there are psychosocial factors associated with a positive PEth test. METHODS: All patients who underwent a routine pre-surgical psychological evaluation for liver transplant listing (all etiologies, including acute liver failure, dual organ, and re-transplantation) at a single health care system in 2020 were included in a retrospective chart review. Data extraction included results from PEth testing and information from the psychological evaluation (i.e., demographic, psychiatric symptoms, and cognitive functioning). RESULTS: There were 158 patients (73.8%) who had a PEth test, of whom 21.5% had a positive result (n = 34). Younger age was associated with a positive PEth (p < .001). ALD status and type of ALD (hepatitis vs. cirrhosis) were also associated with a positive PEth test. Other demographic characteristics and psychiatric symptoms were not associated with a positive PEth result (p > .05). CONCLUSION: Younger age was the only significant demographic variable associated with a positive PEth test. Given the difficulty of predicting who may be using alcohol, it may be useful to use PEth testing for all patients during the pre-liver transplant evaluation and while patients are listed for liver transplant. Early identification of alcohol use through routine PEth testing will help identify patients who are using alcohol and need further treatment for alcohol use to optimize health and post-transplant outcomes.

Alcohol-related hepatitis admissions increased 50% in the first months of the COVID-19 pandemic in the USA.

Early reports suggest that alcohol misuse increased in 2020 as a result of the COVID-19 pandemic. Using retrospective data from Henry Ford Health System in Detroit MI-an area that experienced an early and severe COVID-19 outbreak-we investigated the impact of the pandemic on alcohol-related liver disease (ARLD) in the summer of 2020 compared with the same period in 2016-2019. Both the number of ARLD admissions and the proportion of total admissions represented by ARLD patients increased significantly in 2020 compared with previous years. The number of ARLD admissions as a proportion of all hospitalizations was 50% higher in 2020 than in 2016-2019 (0.31% vs 0.21%; P = .0013); by September 2020, the number of admissions was 66% higher than previous years. Despite racial and geographical disparities in direct and indirect COVID-related stressors across the Detroit metropolitan area, the demographic profile of ARLD patients did not change compared with previous years.

Availability of PEth testing is associated with reduced eligibility for liver transplant among patients with alcohol-related liver disease.

BACKGROUND: Serum phosphatidylethanol (PEth) is a highly sensitive test to detect alcohol use. We evaluated whether the availability of PEth testing impacted rates of liver transplant evaluation terminations and delistings. METHODS: Medical record data were collected for patients who initiated transplant evaluation due to alcohol-related liver disease in the pre-PEth (2017) or PEth (2019) eras. Inverse probability weighting (IPW) was used to balance baseline patient characteristics. Outcomes included termination of evaluation or delisting due to alcohol use; patients were censored at receipt of transplant; death was considered a competing risk. The Fine-Gray method was performed to determine whether PEth testing affected risk of evaluation termination/ delisting due to alcohol use. RESULTS: Three hundred and seventy-five patients with alcohol-related indications for transplant (157 in 2017; 210 in 2019) were included. The final IPW-adjusted model for the composite outcome of terminations/delisting due to alcohol use retained two significant variables (P < .05): PEth era and BMI category. Patients evaluated during the PEth era were almost three times more likely to experience an alcohol-related termination/delisting than those in the pre-PEth era (sHR = 2.86; 95%CI 1.67-4.97) CONCLUSION: We found that availability of PEth testing at our institution was associated with a higher rate of exclusion of patients from eligibility for liver transplant. Use of PEth testing has significant potential to inform decisions regarding transplant candidacy for patients with alcohol-related liver disease.

Post-liver transplant outcomes in patients with major psychiatric diagnosis in the United States.

INTRODUCTION AND OBJECTIVES: Higher rates of psychiatric disorders are reported among cirrhotic patients. This study examines the demographic and clinical outcomes post-liver transplant (LT) among cirrhotic patients with a major psychiatric diagnosis (cases) compared to those without psychiatric diagnosis (controls). MATERIALS AND METHODS: Retrospective case control design was used among 189 cirrhotic patients who had undergone LT at Methodist University Hospital Transplant Institute, Memphis, TN between January 2006 and December 2014. Multivariable regression and Cox proportional hazard regression were conducted to compare allograft loss and all-cause mortality. RESULTS: The study sample consisted of a matched cohort of 95 cases and 94 controls with LT. Females and those with Hepatic Encephalopathy (HE) were more likely to have psychiatric diagnosis. Patients with hepatocellular carcinoma (HCC) were twice as likely to have allograft loss. Psychiatric patients with HCC had two and a half times (HR 2.54; 95% CI: 1.20-5.37; p = 0.015) likelihood of all-cause mortality. Data censored at 1-year post-LT revealed that patients with psychiatric diagnosis have a three to four times higher hazard for allograft loss and all-cause mortality compared to controls after adjusting for covariates, whereas when the data is censored at 5 year, allograft loss and all-cause mortality have two times higher hazard ratio. CONCLUSIONS: The Cox proportional hazard regression analysis of censored data at 1 and 5 year indicate higher allograft loss and all-cause mortality among LT patients with psychiatric diagnosis. Patients with well-controlled psychiatric disorders who undergo LT need close monitoring and medication adherence.

Effect of opioid treatment on clinical outcomes among cirrhotic patients in the United States.

BACKGROUND: Opioid medications are frequently used to address pain among patients with cirrhosis, including those on the liver transplant (LT) waitlist and after transplantation. However, opioid use has been associated with poor allograft outcomes and reduced transplant survival. We examined the impact of opioid use across the spectrum of advanced liver disease, from the initial hepatology consultation for cirrhosis through transplant referral, listing, and the post-LT process. METHODS: The study includes all patients referred for cirrhosis management in a single healthcare system in the United States. Data were extracted retrospectively through medical chart review. RESULTS: Of 414 patients included in the study, 104 (25%) were treated with opioid. Patients on opioids were more likely to be White, have body mass indices (BMI) >30, have HCV, suffer from hepatic encephalopathy, cigarette smokers, and use benzodiazepines concurrently. Higher doses of opioids were associated with multiple emergency department (ED). Eighty-nine underwent LT, including 20 opioid-treated patients. There was no difference found between the opioid and non-opioid groups with regard to allograft loss, ED visits, and hospital readmissions at 2 years post-LT follow-up. CONCLUSIONS: Opioid treatment was common among patients with cirrhosis. We did not find increased negative outcomes among opioid users across the spectrum of cirrhosis. However, the sample for LT patients was small.

Association of Pretransplant Renal Function With Liver Graft and Patient Survival After Liver Transplantation in Patients With Nonalcoholic Steatohepatitis.

Nonalcoholic steatohepatitis (NASH) is one of the top 3 indications for liver transplantation (LT) in Western countries. It is unknown whether renal dysfunction at the time of LT has any effect on post-LT outcomes in recipients with NASH. From the United Network for Organ Sharing-Standard Transplant Analysis and Research data set, we identified 4088 NASH recipients who received deceased donor LT. We divided our recipients a priori into 3 categories: group 1 with estimated glomerular filtration rate (eGFR) <30 mL/minute/1.73 m2 at the time of LT and/or received dialysis within 2 weeks preceding LT (n = 937); group 2 with recipients who had eGFR ≥30 mL/minute/1.73 m2 and who did not receive renal replacement therapy prior to LT (n = 2812); and group 3 with recipients who underwent simultaneous liver-kidney transplantation (n = 339). We examined the association of pretransplant renal dysfunction with death with a functioning graft, all-cause mortality, and graft loss using competing risk regression and Cox proportional hazards models. The mean ± standard deviation age of the cohort at baseline was 58 ± 8 years, 55% were male, 80% were Caucasian, and average exception Model for End-Stage Liver Disease score was 24 ± 9. The median follow-up period was 5 years (median, 1816 days; interquartile range, 1090-2723 days). Compared with group 1 recipients, group 2 recipients had 19% reduced trend for risk for death with a functioning graft (subhazard ratio [SHR], 0.81; 95% confidence interval [CI], 0.64-1.02) and similar risk for graft loss (SHR, 1.25; 95% CI, 0.59-2.62), whereas group 3 recipients had similar risk for death with a functioning graft (SHR, 1.23; 95% CI, 0.96-1.57) and graft loss (SHR, 0.18; 95% CI, 0.02-1.37) using an adjusted competing risk regression model. In conclusion, recipients with preserved renal function before LT showed a trend toward lower risk of death with a functioning graft compared with SLKT recipients and those with pretransplant severe renal dysfunction in patients with NASH.

Increased Waitlist Mortality and Lower Rate for Liver Transplantation in Hispanic Patients With Primary Biliary Cholangitis.

BACKGROUND & AIMS: Data on the differences in ethnicity and race among patients with primary biliary cholangitis (PBC) awaiting liver transplantation (LT) are limited. We evaluated liver transplant waitlist trends and outcomes based on ethnicity and race in patients with PBC in the United States. METHODS: Using the United Network for Organ Sharing (UNOS) registry, we collected data on patients with PBC on the liver transplant waitlist, and performed analysis with a focus on ethnicity and race-based variations clinical manifestations, waitlist mortality and LT rates from 2000 to 2014. Outcomes were adjusted for demographics, complications of portal hypertension, and Model for End-stage Liver Disease score at time of waitlist registration. RESULTS: Although the number of white PBC waitlist registrants and additions decreased from 2000 to 2014, there were no significant changes in the number of Hispanic PBC waitlist registrants and additions each year. The proportion of Hispanic patients with PBC on the liver transplant waitlist increased from 10.7% in 2000 to 19.3% in 2014. Hispanics had the highest percentage of waitlist deaths (20.8%) of any ethnicity or race evaluated. After adjusting for demographic and clinical characteristics, Hispanic patients with PBC had the lowest overall rate for undergoing LT (adjusted hazard ratio, 0.71; 95% CI, 0. 60-0.83; P < .001) and a significantly higher risk of death while on the waitlist, compared to whites (adjusted hazard ratio, 1.41; 95% CI, 1.15-1.74; P < .001). Furthermore, Hispanic patients with PBC had the highest proportion of waitlist removals due to clinical deterioration. CONCLUSIONS: In an analysis of data from UNOS registry focusing on outcomes, we observed differences in rates of LT and liver transplant waitlist mortality of Hispanic patients compared with white patients with PBC. Further studies are needed to improve our understanding of ethnicity and race-based differences in progression of PBC.

Achieving Sustained Virological Response in Liver Transplant Recipients With Hepatitis C Decreases Risk of Decline in Renal Function.

The effect of antiviral therapy (AVT) on kidney function in liver transplantation (LT) recipients has not been well described despite known association of hepatitis C virus (HCV) infection with chronic kidney disease (CKD). We compared the incidence of CKD and end-stage renal disease (ESRD) in 204 LT recipients with HCV based on treatment response to AVT. The mean estimated glomerular filtration rate (eGFR) at baseline (3 months after LT) was similar in the sustained virological response (SVR; n = 145) and non-SVR group (n = 59; 69 ± 21 versus 65 ± 33 mL/minute/1.73 m2 ; P = 0.27). In the unadjusted Cox proportional regression analysis, the presence of SVR was associated with an 88% lower risk of CKD (hazard ratio, 0.12; 95% confidence interval [CI], 0.05-0.31) and 86% lower risk of ESRD (odds ratio, 0.14; 95% CI, 0.05-0.35). Similar results were found after adjusting for propensity score and time-dependent Cox regression analyses. The estimated slopes of eGFR based on a 2-stage mixed model of eGFR were calculated. Patients with SVR had a less steep slope in eGFR (-0.60 mL/minute/1.73 m2 /year; 95% CI, -1.50 to 0.30; P = 0.190) than recipients without SVR (-2.53 mL/minute/1.73 m2 /year; 95% CI, -3.99 to -1.07; P = 0.001), and the differences in the slopes were statistically significant (P = 0.026). In conclusion, in LT recipients with chronic HCV infection, achieving SVR significantly lowers the risk of decline in renal function and progression to ESRD independent of the AVT therapy used.

Virologic Cure of Hepatitis C: Impact on Hepatic Fibrosis and Patient Outcomes.

Treatment with direct-acting antiviral agents has revolutionized the approach to hepatitis C. We are now able to obtain high sustained virological response (SVR) rates, even in the historically difficult-to-treat patient populations. SVR translates into improved clinical outcomes, particularly overall and liver-related mortality, and benefits are more striking in patients with cirrhosis. A 2.5- to 5-fold risk reduction in the incidence of hepatocellular carcinoma and improvement in complications derived from portal hypertension have been reported as well. It is hypothesized that the benefits from SVR occur largely due to regression of fibrosis, which arises from the halt on the fibrogenic stimuli and activation of extracellular matrix reabsorption signals. Non-invasive markers of fibrosis are being utilized to assess regression, but it is still unclear how accurate they are in this clinical scenario. Interventions aiming to improve liver wellness and screening for cirrhosis-related complications should continue to be the norm after SVR.

Lack of health insurance limits the benefits of hepatitis C virus screening: insights from the National Health and Nutrition Examination Hepatitis C follow-up study.

OBJECTIVES: Identifying barriers to access to hepatitis C virus (HCV) treatment among screen detected subjects is critical for any public health strategy aimed at controlling HCV infection in the general population. METHODS: Data from the National Health and Nutrition Examination Survey HCV Follow-up study from 2001 to 2010 were used. Participants who tested positive for HCV were sent a letter informing them of their test results and advised to pursue further evaluation. Information on HCV transmission and its potential complications was also provided to all positive participants. These subjects were recontacted 6 months after notification to determine what action they had taken regarding the positive result. RESULTS: Of 38,025 participants, 502 tested positive for HCV infection, giving a prevalence of 1.3% (95% confidence interval (CI) 0.8%, 1.8%). A total of 205 subjects participated in the 6-month follow-up interview. Those who could not be reached were more likely to be less educated, injecting drugs, and not to have health insurance. Half (50.2%) of the positive individuals were not aware of their status before notification. A total of 166 (81%) had pursued further evaluation. Only 18 (26.9%) received therapy. The main reason for not receiving treatment was high cost (19.4%). In adjusted analysis, the only barrier to pursuing downstream HCV care was the lack of health insurance (2.76, 95% CI 1.54, 7.69; P=0.007). CONCLUSIONS: This study suggests that the lack of health insurance may attenuate the theoretical benefits of a screening program that identifies asymptomatic HCV-infected individuals who are less likely to pursue downstream care.

Chronic hepatitis C infection as a risk factor for renal cell carcinoma.

BACKGROUND: Chronic hepatitis C virus (HCV) infection causes cirrhosis and hepatocellular carcinoma but is also etiologically linked to several extrahepatic medical conditions including renal disorders. HCV is also associated with extrahepatic malignancies and may be oncogenic. Whether HCV confers an increased risk of renal cell carcinoma (RCC) remains controversial. AIMS: Prospectively determine whether chronic HCV is associated with an increased risk of RCC. METHODS: At an integrated medical center in Detroit, Michigan, adult patients with suspected RCC or newly diagnosed colon cancer (controls) were screened for hepatitis C antibody (HCAB) and HCV RNA. Renal or colon cancers were confirmed histologically. The proportion of patients with HCAB and HCV RNA in each group was compared, and risk factors for renal cell carcinoma were determined by multivariable logistic regression analysis. RESULTS: RCC patients had a higher rate of HCAB positivity (11/140, 8 %) than colon cancer patients (1/100, 1 %) (p < 0.01). Of the HCAB-positive patients, 9/11 RCC and 0/1 controls had detectable HCV RNA. HCV RNA positivity was a significant risk factor for RCC (OR 24.20; 95 % CL 2.4, >999.9; p = 0.043). Additionally, viremic RCC patients were significantly younger than RCC patients who were HCV RNA negative (p = 0.013). CONCLUSIONS: Patients with chronic HCV are at heightened risk of RCC.

The Health Care Burden of Hepatic Encephalopathy.

Hepatic encephalopathy-a common and debilitating complication of cirrhosis-results in major health care burden on both patients and caregivers through direct and indirect costs. In addition to risk of falls, inability to work and drive, patients with hepatic encephalopathy often require hospital admission (and often readmission), and many require subacute care following hospitalization. The costs and psychological impact of liver transplantation often ensue. As the prevalence of chronic liver disease increases throughout the United States, the health care burden of hepatic encephalopathy will continue to grow.

Improved Waitlist Outcomes in Liver Transplant Patients With Mid-MELD-Na Scores Listed in Centers Receptive to Use of Organs Donated After Circulatory Death.

BACKGROUND: Liver transplant (LT) using organs donated after circulatory death (DCD) has been increasing in the United States. We investigated whether transplant centers' receptiveness to use of DCD organs impacted patient outcomes. METHODS: Transplant centers were classified as very receptive (group 1), receptive (2), or less receptive (3) based on the DCD acceptance rate and DCD transplant percentage. Using organ procurement and transplantation network/UNOS registry data for 20 435 patients listed for LT from January 2020 to June 2022, we compared rates of 1-y transplant probability and waitlist mortality between groups, broken down by model for end-stage liver disease-sodium (MELD-Na) categories. RESULTS: In adjusted analyses, patients in group 1 centers with MELD-Na scores 6 to 29 were significantly more likely to undergo transplant than those in group 3 (aHR range 1.51-2.11, P < 0.001). Results were similar in comparisons between groups 1 and 2 (aHR range 1.41-1.81, P < 0.001) and between groups 2 and 3 with MELD-Na 15-24 (aHR 1.19-1.20, P < 0.007). Likewise, patients with MELD-Na score 20 to 29 in group 1 centers had lower waitlist mortality than those in group 3 (scores, 20-24: aHR, 0.71, P = 0.03; score, 25-29: aHR, 0.51, P < 0.001); those in group 1 also had lower waitlist mortality compared with group 2 (scores 20-24: aHR0.69, P = 0.02; scores 25-29: aHR 0.63, P = 0.03). One-year posttransplant survival of DCD LT patients did not vary significantly compared with donation after brain dead. CONCLUSIONS: We conclude that transplant centers' use of DCD livers can improve waitlist outcomes, particularly among mid-MELD-Na patients.

Role of liver biopsy in the era of direct-acting antivirals.

An accurate assessment of the degree of fibrosis or presence of cirrhosis is critical both for the appropriate management of, and to provide prognosis for, patients with chronic hepatitis C infection. In the new era of direct acting antivirals, large numbers of patients may enter therapy, and although liver biopsy remains the gold standard, it is not practical in all settings. In recent years, a variety of noninvasive methods have been developed that may obviate the need for liver biopsy in most settings. Indirect laboratory formulas, tests, panels of biomarkers and imaging modalities may accurately stage the degree of fibrosis in hepatitis C monoinfection, hepatitis C/HIV coinfection, and post-transplant recurrent hepatitis C.