Hepatic improvement within 27 days of avenciguat treatment in Child-Pugh A cirrhosis detected by an oral cholate challenge test.

New methods for measuring hepatic improvement in clinical trials and the clinic are needed. One new method, HepQuant SHUNT, detected dose-dependent improvements in hepatic function and portal physiology in the phase 1b study (NCT03842761) of avenciguat, an activator of soluble guanylyl cyclase that is being developed for the treatment of portal hypertension. Herein, we examined whether HepQuant Duo, an easy-to-administer test version, could similarly detect the effects of avenciguat. Twenty-three patients with Child-Pugh A cirrhosis and liver stiffness >15 kPa received either a placebo (n = 5) or a maximum twice-daily avenciguat dose of 1, 2, or 3 mg (n = 6 per group) for 28 days. The DuO test was performed at baseline and on days 11 and 27 in each subject. The test involved administering 40 mg of d4-cholate orally, measuring d4-cholate concentrations in serum at 20 and 60 minutes, and calculating portal hepatic filtration rate, disease severity index, portal-systemic shunting (SHUNT%), and hepatic reserve (HR%). Avenciguat demonstrated dose-dependent improvement in all test parameters. Changes from baseline in SHUNT% after 27 days' treatment were 0.1 ± 9.0% for placebo, 1.7 ± 5.5% for 1 mg twice-daily, -3.2 ± 2.7% for 2 mg twice-daily, and -6.1 ± 5.0% for 3 mg twice-daily (paired t test for change from baseline p = 0.98, 0.48, 0.04, and 0.03, respectively). The changes detected by HepQuant DuO were similar to those previously observed and reported for HepQuant SHUNT. The results support further study of avenciguat in treating portal hypertension and spotlight the utility of HepQuant DuO in the development of drug therapy for liver disease. HepQuant DuO facilitates the use of function testing to measure hepatic improvement in clinical trials and the clinic.

Liver function and portal-systemic shunting quantified by the oral cholate challenge test and risk for large oesophageal varices.

BACKGROUND: The quantitative HepQuant SHUNT test of liver function and physiology generates a disease severity index (DSI) that correlates with risk for clinical complications, such as large oesophageal varices (LEVs). A derivative test, HepQuant DuO, generates an equivalent DSI and simplifies testing by requiring only oral administration of the test solution and two blood samples at 20 and 60 min. AIMS: Since the DSIs measured from DuO and SHUNT are equivalent, we compared the diagnostic performance for large oesophageal varices (LEVs) between the DSIs measured from DuO and SHUNT tests. METHODS: This study combined the data from two prospectively conducted US studies: HALT-C and SHUNT-V. A total of 455 subjects underwent both the SHUNT test and esophagogastroduodenoscopy (EGD). RESULTS: DSI scores correlated with the probability of LEVs (p < 0.001) and demonstrated a stepwise increase from healthy lean controls without liver disease to subjects with chronic liver disease and no, small or large varices. Furthermore, a cutoff of DSI ≤ 18.3 from DuO had a sensitivity of 0.98 (missing only one case) and, if applied to the endoscopy (EGD) decision, would have prevented 188 EGDs (41.3%). The AUROC for DSI from DuO did not differ from that of the reference SHUNT test method (0.82 versus 0.81, p = 0.3500). CONCLUSIONS: DSI from HepQuant DuO links liver function and physiology to the risk of LEVs across a wide spectrum of patient characteristics, disease aetiologies and liver disease severity. DuO is minimally invasive, easy to administer, quantitative and may aid the decision to avoid or perform EGD for LEVs.

Hepatic Dysfunction Quantified by HepQuant DuO Outperforms Child-Pugh Classification in Predicting the Pharmacokinetics of Ampreloxetine.

HepQuant tests quantify liver function from clearance of deuterium- and 13C-labeled cholates administered either intravenously and orally (SHUNT) or orally (DuO). Hepatic impairment studies have relied on clinical or laboratory criteria like Child-Pugh classification to categorize the degree of hepatic dysfunction. We compared HepQuant tests with Child-Pugh classification in predicting the pharmacokinetics of ampreloxetine. Twenty-one subjects with hepatic impairment (8 Child-Pugh A, 7 Child-Pugh B, and 6 Child-Pugh C), and 10 age- and sex-matched controls were studied. The pharmacokinetics of ampreloxetine were measured after oral administration of a single dose of 10 mg. Disease severity index (DSI), portal-systemic shunting (SHUNT%), hepatic reserve, and hepatic filtration rates (HFRs) were measured from serum samples obtained after intravenous administration of [24-13C]-cholate and oral administration of [2,2,4,4-2H]cholate. Ampreloxetine plasma exposure (AUC0-inf) was similar to controls in Child-Pugh A, increased 1.7-fold in subjects with Child-Pugh B, and 2.5-fold in subjects with Child-Pugh C and correlated with both Child-Pugh score and HepQuant parameters. The variability observed in ampreloxetine exposure (AUC0-inf) in subjects with moderate (Child-Pugh B) and severe hepatic impairment (Child-Pugh C) was explained by HepQuant parameters. Multivariable regression models demonstrated that DSI, SHUNT%, and Hepatic Reserve from SHUNT and DuO were superior predictors of ampreloxetine exposure (AUC0-inf) compared to Child-Pugh score. HepQuant DSI, SHUNT%, and hepatic reserve were more useful predictors of drug exposure than Child-Pugh class for ampreloxetine and thus may better optimize dose recommendations in patients with liver disease. The simple-to-administer, oral-only DuO version of the HepQuant test could enhance clinical utility.

Within-individual reproducibility of a dual sample oral cholate challenge test (DuO) and simplified versions of the HepQuant SHUNT test.

Current noninvasive liver tests measure fibrosis, inflammation, or steatosis and do not measure function. The HepQuant platform of noninvasive tests uniquely assesses both liver function and physiology through the hepatic uptake of stable isotopes of cholate. However, the prototypical HepQuant SHUNT test (SHUNT V1.0) is cumbersome to administer, requiring intravenous and oral administration of cholate and six peripheral venous blood samples over 90 min. To alleviate the burden of test administration, we explored whether an oral only (DuO) version, and other simplified versions, of the test could provide reproducible measurements of liver function. DuO requires only oral dosing and two blood samples over 60 min. The simplified SHUNT test versions were SHUNT V1.1 (oral and IV dosing but four blood samples) and SHUNT V2.0 (oral and IV dosing but only two blood samples over 60 min). In this paper, we describe the reproducibility of DuO and the simplified SHUNT tests relative to that of SHUNT V1.0; equivalency is described in a separate paper. Data from two studies comprising 236 SHUNT tests in 94 subjects were analyzed retrospectively by each method. All simplified methods were highly reproducible across test parameters with intraclass correlation coefficients >0.93 for test parameters Disease Severity Index (DSI) and Hepatic Reserve. DuO and SHUNT V2.0 improved reproducibility in measuring portal-systemic shunting (SHUNT%). These simplified tests, particularly DuO and SHUNT V2.0, are easier to administer and less invasive, thus, having the potential to be more widely accepted by care providers administering the test and by patients receiving the test.

Advances in noninvasive measurement of liver function and physiology: The HepQuant DuO test.

Current noninvasive liver tests are surrogates for fibrosis and lack ability to directly measure liver function. HepQuant tests measure liver function and physiology through hepatic uptake of stable cholate isotopes. HepQuant SHUNT (V1.0) involves oral and intravenous dosing and six blood samples over 90 min. We developed simplified test versions: SHUNT V2.0 (oral and intravenous dosing, two blood samples over 60 min) and DuO (oral dosing only, two blood samples over 60 min). The aim of this study was to evaluate equivalency of the simplified tests to the original SHUNT test. Data from three studies comprising 930 SHUNT tests were retrospectively analysed by each method. Equivalence was evaluated in terms of proportion of tests in which the difference between methods was less than any clinically meaningful difference and additionally by two one-sided t-test and bioequivalence methods. DuO and SHUNT V2.0 were equivalent to the original SHUNT test for Disease Severity Index, with >99% and >96% of tests falling within equivalence bounds. DuO and SHUNT V2.0 met equivalency criteria by two one-sided t-tests and bioequivalence. DuO and SHUNT V2.0 are easier to administer, are less invasive than the original SHUNT test and have potential to be more accepted by patients and providers.

Dynamic Elevation of Aromatic Amino Acids in Hepatitis C Virus-Induced Cirrhosis After a Standard Meal.

INTRODUCTION: Perturbations in aromatic (AAAs) and branched-chain amino acids (BCAAs) are seen in decompensated liver disease. The aim of this study was to evaluate the dynamic, postprandial relationship between hepatitis C virus-induced liver disease and amino acid concentrations in patients with compensated liver disease. METHODS: Patients infected with hepatitis C virus underwent a baseline liver biopsy to determine Ishak Fibrosis Score and evaluate the liver transcriptome. Patients ate a standard meal and underwent peripheral vein sampling at defined intervals. Quantitative analysis of amino acids was performed using liquid chromatography-tandem mass spectrometry. RESULTS: At baseline, there was no difference in AAA and BCAA concentrations between patients with cirrhosis and non-cirrhotic patients. After a standard meal, AAAs, but not BCAAs, were elevated in patients with cirrhosis compared with non-cirrhotic patients at every time point. The HepQuant SHUNT fraction was significantly higher in patients with cirrhosis and positively correlated with AAA concentration at all time points, but not BCAA. Analysis of the hepatic transcriptome demonstrated greater downregulation of the AAA degradation pathways than the BCAA degradation pathways. DISCUSSION: At baseline, cirrhotic patients with compensated liver disease have adequate reserve liver function to metabolize AAAs and BCAAs. When faced with a metabolic stressor, such as a standard meal, patients with cirrhosis are less able to metabolize the increased load of AAAs. This impairment correlates with portosystemic shunting. Further evaluation of AAA levels in compensated liver disease might further the understanding of the liver-muscle axis and the role it may play in the development of sarcopenia in liver disease.

Compartmental model describing the physiological basis for the HepQuant SHUNT test.

The HepQuant SHUNT test quantifies hepatic functional impairment from the simultaneous clearance of cholate from the systemic and portal circulations for the purpose of monitoring treatment effects or for predicting risk for clinical outcome. Compartmental models are defined by distribution volumes and transfer rates between volumes to estimate parameters not defined by noncompartmental analyses. Previously, a noncompartmental analysis method, called the minimal model (MM), demonstrated reproducible and reliable measures of liver function (Translational Research 2021). The aim of this study was to compare the reproducibility and reliability of a new physiologically based compartmental model (CM) vs the MM. Data were analyzed from 16 control, 16 nonalcoholic steatohepatitis (NASH), and 16 hepatitis C virus (HCV) subjects, each with 3 replicate tests conducted on 3 separate days. The CM describes transfer of cholates between systemic, portal, and liver compartments with assumptions from measured or literature-derived values and unknown parameters estimated by nonlinear least-squares regression. The CM was compared to the MM for 6 key indices of hepatic disease in terms of intraclass correlation coefficient (ICC) with a lower acceptable limit of 0.7. The CM correlated well with the MM for disease severity index (DSI) with R2 (95% confidence interval) of 0.96 (0.94-0.98, P < 0.001). Acceptable reproducibility (ICC > 0.7) was observed for 6/6 and 5/6 hepatic disease indices for CM and MM, respectively. SHUNT, a measure of the absolute bioavailability, had ICC of 0.73 (0.60-0.83, P = 0.3095) for MM and 0.84 (0.76-0.90, P = 0.0012) for CM. The CM, but not the MM, allowed determination of anatomic shunt and hepatic extraction and improved the within individual reproducibility.

HepQuant SHUNT Detects Portal Hypertension in Early Stages of Clinically Compensated Chronic Liver Disease.

Physicians use portal pressure measurements in clinical practice and research but the methods are invasive, can cause complications, and are resource intensive.1-3 Herein we describe preliminary findings of the minimally invasive HepQuant-SHUNT test in the diagnosis of portal hypertension in precirrhotic and compensated cirrhotic patients.

Predicting clinical decompensation in patients with cirrhosis using the Hepquant-SHUNT test.

BACKGROUND: Early identification of risk for decompensation in clinically stable cirrhotic patients helps specialists target early interventions and supports effective referrals from primary care providers to specialty centres. AIMS: To examine whether the HepQuant-SHUNT test (HepQuant LLC, Greenwood Village, Colorado, USA) predicts decompensation and the need for liver transplantation, hospitalisation or liver-related death. METHODS: Thirty-five compensated and 35 subjects with a previous episode of decompensation underwent the SHUNT Test and were followed for a median of 4.2 years. The disease severity index (DSI) (range 0-50) was examined for association with decompensation in compensated patients; and liver transplantation, liver-related death, and the number and days of liver related hospitalisations in all. DSI prediction of decompensation was also evaluated in 84 subjects with compensated cirrhosis from the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis Trial (HALT-C) followed for a median of 5.8 years. RESULTS: At baseline, subjects with prior decompensation had significantly higher DSI than compensated subjects (32.6 vs 20.9, P < 0.001). DSI ≥24 distinguished the decompensated from the compensated patients and independently predicted adverse clinical outcomes (hazard ratio: 4.92, 95% confidence interval: 1.42-17.06). In the HALT-C cohort, 65% with baseline DSI ≥24 vs 19% with DSI <24 experienced adverse clinical outcomes (relative risk 3.45, P < 0.0001). CONCLUSIONS: The SHUNT test is a novel, noninvasive test that predicts risk of decompensation in previously compensated patients. DSI ≥24 is independently associated with risk for clinical decompensation, liver transplantation, death and hospitalisation.

The within-individual reproducibility of the disease severity index from the HepQuant SHUNT test of liver function and physiology.

The HepQuant SHUNT test quantifies liver function and blood flow using systemic and portal clearances of cholate. The test can identify the risk of well-compensated patients to develop complications of cirrhosis. To confirm the reliability of a single HepQuant SHUNT test we defined its within-individual reproducibility. Healthy subjects (n = 16), 16 with nonalcoholic steatohepatitis (NASH), and 16 with chronic hepatitis C virus (HCV) underwent 3 HepQuant SHUNT tests on 3 separate days within 30 days. The test involves simultaneous administration of 20 mg 13C-cholate IV and 40 mg d4-cholate PO, and subsequent collection of 3 mL blood samples at 5, 20, 45, 60, and 90 minutes. Clearances are expressed as systemic and portal hepatic filtration rate. Portal-systemic shunting (SHUNT), a disease severity index (DSI), and an estimate of DSI (STAT) are calculated from the clearances. Reproducibility was determined by the intraclass correlation coefficient (ICC > 0.70) and Bland-Altman analysis. Equal numbers of NASH and HCV patients had either early (F0-F2) or advanced (F3/F4) stages of fibrosis. All F3/F4 subjects were clinically compensated. The intraclass correlation coefficient (ICC) for DSI was 0.94 (0.90-0.96 95% confidence interval) indicating excellent reproducibility. The other test parameters had ICCs ranging from 0.74 (SHUNT) to 0.90 (STAT). In Bland-Altman analysis, the mean of differences between measurements of DSI was 0.13 with standard deviation 2.12. The excellent reproducibility of the HepQuant SHUNT test, particularly DSI, supports the use this minimally invasive, blood-based test as a reliable test of liver function and physiology.

Clinical Research in Hepatology in the COVID-19 Pandemic and Post-Pandemic Era: Challenges and the Need for Innovation.

The severe acute respiratory syndrome coronavirus 2 pandemic has drastically altered all facets of clinical care and research. Clinical research in hepatology has had a rich tradition in several domains, including the discovery and therapeutic development for diseases such as hepatitis B and C and studying the natural history of many forms of chronic liver disease. National Institutes of Health, foundation, and industry funding have provided important opportunities to advance the academic careers of young investigators while they strived to make contributions to the field. Instantaneously, however, all nonessential research activities were halted when the pandemic started, forcing those involved in clinical research to rethink their research strategy, including a shift to coronavirus disease 2019 research while endeavoring to maintain their preexisting agenda. Strategies to maintain the integrity of ongoing studies, including patient follow-up, safety assessments, and continuation of investigational products, have included a shift to telemedicine, remote safety laboratory monitoring, and shipping of investigational products to study subjects. As a revamp of research is being planned, unique issues that face the research community include maintenance of infrastructure, funding, completion of studies in the predetermined time frame, and the need to reprogram career path timelines. Real-world databases, biomarker and long-term follow up studies, and research involving special groups (children, the homeless, and other marginalized populations) are likely to face unique challenges. The implementation of telemedicine has been dramatically accelerated and will serve as a backbone for the future of clinical research. As we move forward, innovation in clinical trial design will be essential for conducting optimized clinical research.

Liver and Kidney Recipient Selection of Hepatitis C Virus Viremic Donors: Meeting Consensus Report From the 2019 Controversies in Transplantation.

The development of multiple highly effective and safe direct-acting antivirals to treat hepatitis C virus (HCV) has resulted in greater ease and confidence in managing HCV infection in transplant recipients that in turn has impacted the solid organ transplant community as well. In the United States, the opioid epidemic has increased the number of overdose deaths with a concomitant increase in younger HCV viremic donors after brain death being identified. At the same time, a decrease in HCV viremic transplant candidates has led to a growing interest in exploring the use of HCV viremic liver and kidney donor allografts in HCV-negative recipients. To date, experience with the use of HCV viremic liver and kidney allografts in HCV-negative recipients is limited to a few small prospective research trials, case series, and case reports. There are also limited data on recipient and donor selection for HCV viremic liver and kidney allografts. In response to this rapidly changing landscape in the United States, experts in the field of viral hepatitis and liver and kidney transplantation convened a meeting to review current data on liver and kidney recipient selection and developed consensus opinions related specifically to recipient and donor selection of HCV viremic liver and kidney allografts.

Assessing hepatic impairment in Fontan-associated liver disease using the HepQuant SHUNT test.

BACKGROUND & AIMS: Fontan surgery for single ventricle congenital heart disease leads to Fontan-associated liver disease (FALD). Typical laboratory tests, imaging, and histopathology cannot predict clinical severity in FALD. HepQuant SHUNT is a proprietary serum test of hepatic function and physiology that has not yet been evaluated in FALD. METHODS: Fourteen adult FALD patients at a single urban tertiary care center who underwent a Fontan procedure in childhood received HepQuant SHUNT testing between September 2015 and April 2018. The HepQuant SHUNT disease severity index (DSI) assesses global liver function and physiology from systemic and portal hepatic filtration rates (HFRs, clearances adjusted for body mass) of orally and intravenously administered cholates labeled with deuterium or 13C. The SHUNT parameter of the test measures portal systemic shunting from the ratio of Systemic HFR to Portal HFR. Chart review included laboratory tests, imaging, and clinical findings. Data from FALD patients were compared with data from healthy controls. RESULTS: The average DSI and SHUNT values for the FALD patients were 17.5% and 36.1%, respectively, compared to 9.2% and 24.1%, respectively, for controls. Twelve (85.7%) FALD patients had a DSI >15 (upper limit of normal). Seven (50.0%) FALD patients had SHUNT values >30% (upper limit of normal), while three FALD patients (21.4%) had SHUNT values >49%. One FALD patient with preoperative SHUNT of 69%, who underwent a combined heart-liver transplant, had confirmed cirrhotic morphology within the liver explant. CONCLUSIONS: This pilot study demonstrated that most FALD patients had hepatic impairment detected by abnormal DSI, with a smaller number having markedly elevated SHUNT values >49% suggesting intrinsic liver disease. The HepQuant SHUNT test may be useful in detecting and quantifying liver disease severity in FALD patients.

Elbasvir/Grazoprevir in People With Hepatitis C Genotype 1 Infection and Child-Pugh Class B Cirrhosis: The C-SALT Study.

INTRODUCTION: Treatment options are limited for people infected with hepatitis C virus (HCV) with decompensated liver disease. The C-SALT study assessed elbasvir (EBR) plus grazoprevir (GZR) in individuals with HCV genotype 1 infection and Child-Pugh class B (CP-B) cirrhosis. METHODS: In this 12-week, phase 2, nonrandomized, open-label study (NCT02115321; Protocol MK-5172-059), participants with CP-B cirrhosis received EBR 50 mg plus GZR 50 mg once daily, and a control group of noncirrhotic participants received EBR 50 mg plus GZR 100 mg once daily. The primary endpoint was sustained virologic response 12 weeks after the end of therapy. RESULTS: Sustained virologic response at 12 weeks after the end of therapy was achieved by 27/30 (90.0%) CP-B participants and 10/10 (100.0%) noncirrhotic participants. Two participants relapsed, and one died during follow-up after having undetectable HCV RNA at the end of treatment. Most CP-B participants had stable or improved model for end-stage liver disease and Child-Pugh scores at follow-up week 12 compared with baseline. There was no significant difference in drug exposure between groups, despite the differing GZR dose. Adverse events occurring in >10% of participants were fatigue (CP-B: 30.0%; noncirrhotic: 30.0%), arthralgia (16.7%; 20.0%), nausea (10.0%; 20.0%), and headache (10.0%; 50.0%). No serious treatment-related adverse events or hepatic events of clinical interest occurred. CONCLUSIONS: EBR 50 mg plus GZR 50 mg once daily for 12 weeks was highly effective and well tolerated in a traditionally hard-to-treat population. TRANSLATIONAL IMPACT: Although EBR plus reduced-dose GZR is not available for people with CP-B cirrhosis, these results complement phase 2/3 trial data and real-world experience with EBR/GZR.

Ombitasvir/paritaprevir/ritonavir and dasabuvir with or without sofosbuvir for patients with hepatitis C virus genotype 1 infection who failed a prior course of direct-acting antiviral therapy.

INTRODUCTION: Despite high efficacy of current direct-acting antiviral agents (DAAs) in treating chronic hepatitis C virus (HCV) infection, a small portion of patients fail treatment. QUARTZ-I was a phase 2, open-label, multicenter, two-part study that assessed the safety and efficacy of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) with dasabuvir (DSV) with or without the addition of sofosbuvir (SOF) and/or ribavirin (RBV) in DAA treatment-experienced adults with chronic HCV GT1 infection. MATERIALS AND METHODS: Genotype 1 HCV-infected patients with or without compensated cirrhosis had prior treatment failure to any DAA (part 1) or ledipasvir/SOF (part 2). Patients received OBV/PTV/r + DSV ± SOF with or without RBV for 12 or 24 weeks. The primary endpoint of this study is the percentage of patients achieving sustained virologic response at post-treatment week 12 (SVR12). RESULTS: In part 1 of the study, 95.5% (21/22) of patients achieved SVR12, and in part 2, the SVR12 rate was 85.7% (6/7). Most adverse events (AEs) were mild and moderate in severity. Two serious AEs occurred and were assessed as not being related to study drug, of which one resulted in study drug discontinuation. Two patients experienced grade 3 elevations of serum alanine aminotransferase, and no other grade ≥3 laboratory abnormalities were observed. CONCLUSION: The multi-targeted regimen of OBV/PTV/r + DSV ± SOF with or without RBV was effective in the treatment of patients who failed previous DAA regimens including NS3/4A protease and NS5A and NS5B polymerase inhibitors. These results provide a promising outcome for patients that traditionally had limited treatment options.

Characteristics and Outcomes Reported by Patients With Primary Sclerosing Cholangitis Through an Online Registry.

BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is a fibrostenosing disease of the bile ducts associated with inflammatory bowel disease (IBD), for which the only treatment is liver transplantation. PSC progression has been defined in cohorts from referral centers or single-nation population databases. However, observations made from these cohorts have limited applicability owing to referral bias and demographic confounders. We analyzed data from the worldwide PSC Partners Patient Registry, an international online database established in 2014 to obtain information from individuals with PSC or their caretakers and compare symptoms, disease progression, and treatments of PSC in the United States and other countries. METHODS: We analyzed demographic and clinical characteristics, symptoms, and clinical outcomes of patients with PSC using the PSC Partners Patient Registry. Participants completed an online standardized questionnaire and electronic case report, providing information on age, age at symptom onset, age at PSC diagnosis, methods of diagnosis, concurrent diagnoses, family history, and medication use. RESULTS: Of 873 registrants, 811 (92.9%) had completed questionnaires and 528 (65.1%) had their PSC diagnosis confirmed; we found no significant demographic or clinical differences between patients with vs without a confirmed diagnosis. In contrast to other studies, we found a higher proportion of individuals with PSC to be female (52.5%). However, the mean age at PSC diagnosis (32.4 ± 14.7 y) and the proportion of individuals with PSC and IBD (67.1%) were similar to those from prior reports. Most cases in the database were from the United States (74.9%). More than half of the participants reported having pruritus, abdominal pain, fatigue, or sleep disturbances; rates were not significantly different among participants within vs outside the United States. There was no significant difference in treatment with ursodeoxycholic acid between participants within vs outside the United States (50.0% and 57.8%; P = .07). The median time of transplant-free survival was 21 years; transplant-free survival was associated with female sex and Crohn's disease. CONCLUSIONS: Our findings from an analysis of data from the PSC Partners Patient Registry confirm those from previous studies, although we found a higher proportion of individuals with PSC to be female. In addition to allowing efficient collection of patient-reported outcomes, the patient-driven registry allows for inclusion of previously under-represented cases of PSC.

Co-existing Hepatitis C and Alcoholic Liver Disease: A Diminishing Indication for Liver Transplantation?

AIMS: To provide an overview of published literature on the interaction of alcohol and hepatitis C virus (HCV) in the accelerated progression of liver disease to cirrhosis as relates to decision-making for the management of the liver transplant candidate and recipient. METHODS: General PubMed search was employed along with expert input to identify the relevant articles on the topic. The authors also utilized both backward and forward citation review of the relevant articles and reviews to identify articles on identified topic. RESULTS: In HCV cases, heavy alcohol use has been associated with more severe fibrosis, but even low rates of use may have deleterious effects. Patients with chronic hepatitis C and alcoholic liver disease can be cured of the HCV-theoretically positively impacting outcome and reducing the need for liver transplantation. Current antiviral therapy achieves virologic cure or sustained viral response (SVR) in over 90% of cases. Antiviral therapy is so effective that most liver transplant candidates or recipients can be cured of HCV either prior to or after transplantation. However, despite successful antiviral therapy, liver disease may progress after SVR due to the effects of ongoing alcohol use. CONCLUSION: Antiviral therapy in patients with HCV plus alcohol should improve pre- and post-transplant outcomes, but providers must remain firm in limiting use of alcohol to avoid progression of liver disease post HCV cure. SHORT SUMMARY: Abusive alcohol use and chronic hepatitis C virus (HCV) commonly co-exist and both need to be addressed in liver disease. With high rates of HCV cure with new therapies, attention needs to turn toward ongoing abusive alcohol patterns that may determinately impact liver health both before and after liver transplant.

Curing Chronic Hepatitis C: A Cost Comparison of the Combination Simeprevir Plus Sofosbuvir vs. Protease-Inhibitor-Based Triple Therapy

ABSTRACT Introduction. Interferon-free, multi-direct acting antiviral (DAA) therapy for chronic hepatitis C virus (HCV) infection is highly effective and well tolerated, but costly. To gain perspective on the evolving economics of HCV therapy, we compared the cost per cure of a multi-DAA regimen with the prior standard of triple therapy. Material and methods. Patients infected with HCV genotype 1 who were treated through the University of Colorado Hepatology Clinic between May 2011 and December 2014 comprised the study population. The multi-DAA regimen of simeprevir plus sofosbuvir (SMV/SOF) was compared to the triple therapy regimen consisting of peginterferon and ribavirin, with either boceprevir or telaprevir (TT). Sustained-virologic response (SVR) rates, total costs per treatment and adverse events were recorded. Total cost per SVR were compared for the two treatments, controlling for patient demographics and clinical characteristics. Results. One hundred eighty-three patients received SMV/SOF (n = 70) or TT (n = 113). Patients receiving SMV/SOF were older, more treatment experienced, and had a higher stage of fibrosis. SVRs were 86% and 59%, average total costs per patient were $152,775 and $95,943, and average total costs per SVR were $178,237 vs. $161,813.49 for SMV/SOF and TT groups, respectively. Medication costs accounted for 98% of SMV/SOF and 85% of TT treatment costs. Conclusion. The high cure rate of multi-DAA treatment of HCV is offset by the high costs of the DAAs, such that the cost per cure from TT to multi-DAA therapy has been relatively constant. In order to cure more patients, either additional financial resources will need to be allocated to the treatment of HCV or drug costs will need to be reduced.