Paul J. Gaglio

Effectiveness of hepatitis C treatment with pegylated interferon and ribavirin in urban minority patients

Randomized controlled trials of hepatitis C virus (HCV) therapy with pegylated interferon and ribavirin have demonstrated sustained viral response rates (SVRs) of 54%‐63% (efficacy). Treatment results in clinical practice (effectiveness) may not be equivalent. The goal of this study was to assess the effectiveness of HCV treatment with pegylated interferon and ribavirin in a treatment‐naïve, human immunodeficiency virus (HIV)‐negative, United States urban population with many ethnic minority patients. We evaluated 2,370 outpatients for HCV therapy from 2001 to 2006 in the Faculty Practice of the Albert Einstein College of Medicine or the attending‐supervised Montefiore Medical Center Liver Clinic. Care was supervised by one experienced physician under conditions of everyday clinical practice, and appropriate ancillary resources were made available to all patients. Two hundred fifty‐five patients were treated with a mean age of 50 years (60% male, 40% female; 58% Hispanic, 20% African American, 9% Caucasian, 13% other; 68% genotype 1, the remainder genotypes 2 or 3). Patients had at least one liver biopsy. Intention‐to‐treat analysis (ITT) showed SVR in 14% of genotype 1 patients and 37% in genotype 2/3 patients (P < 0.001). SVR was significantly higher in faculty practice (27%) than in clinic patients (15%) by intention‐to‐treat (P = 0.01) but not per‐protocol analysis (46% faculty practice, 34% clinic). 3.3% of 1,656 treatment‐naïve, HIV antibody–negative individuals ultimately achieved SVR. Current hepatitis C therapies may sometimes be unavailable to, inappropriate for, and ineffective in United States urban patients. Treatment with pegylated interferon and ribavirin was less effective in this population than is implied by multinational phase III controlled trials. New strategies are needed to care for such patients. (HEPATOLOGY 2010.)

Hyponatremia in Cirrhosis and End-Stage Liver Disease: Treatment with the Vasopressin V2-Receptor Antagonist Tolvaptan

Hyponatremia is common in patients with cirrhosis and portal hypertension, and is characterized by excessive renal retention of water relative to sodium due to reduced solute-free water clearance. The primary cause is increased release of arginine vasopressin. Hyponatremia is associated with increased mortality in cirrhotic patients, those with end-stage liver disease (ESLD) on transplant waiting lists, and, in some studies, posttransplantation patients. Clinical evidence suggests that adding serum sodium to model for ESLD (MELD) scoring identifies patients in greatest need of liver transplantation by improving waiting list mortality prediction. Hyponatremia is also associated with numerous complications in liver disease patients, including severe ascites, hepatic encephalopathy, infectious complications, renal impairment, increased severity of liver disease in cirrhosis, and increased hospital stay and neurologic/infectious complications posttransplant. Vasopressin receptor antagonists, which act to increase free water excretion (aquaresis) and thereby increase serum sodium concentration, have been evaluated in patients with hypervolemic hyponatremia (including cirrhosis and heart failure) and euvolemic hyponatremia (SIADH). Tolvaptan, a selective vasopressin V2-receptor antagonist, is the only oral agent in this class approved for raising sodium levels in hypervolemic and euvolemic hyponatremia. The SALT trials showed that tolvaptan treatment rapidly and effectively resolved hyponatremia in these settings, including cirrhosis, and it has been shown that this agent can be safely and effectively used in long-term treatment. Fluid restriction should be avoided during the first 24xa0h of treatment to prevent overly rapid correction of hyponatremia, and tolvaptan should not be used in patients who cannot sense/respond to thirst, anuric patients, hypovolemic patients, and/or those requiring urgent intervention to raise serum sodium acutely.

Effect of fibrosis on adverse events in patients with hepatitis C treated with telaprevir

Data about adverse events are needed to optimise telaprevir‐based therapy in a broad spectrum of patients.

Social barriers to listing for adult liver transplantation: Their prevalence and association with program characteristics

Social barriers to effective medical care are mandated to be routinely assessed as part of an evaluation for liver transplantation. This study explores how frequently liver transplant programs encounter these barriers in patients undergoing an evaluation and whether programs with higher proportions of Medicaid patients, historically disadvantaged minority patients, and rural patients encounter social barriers more frequently. A survey for assessing patient demographics and social barriers was electronically completed by representatives of 61 of 104 eligible US adult liver transplant programs (59%). Fifty‐eight of the 61 programs identified themselves, and their characteristics were similar to those of all 104 US programs according to publicly available data from the Organ Procurement and Transplantation Network. Social barriers were reported to be encountered sometimes (10%‐30%) or frequently (>30%) by the 61 programs as follows: inadequate or unstable health insurance (68.9% of the programs), a chaotic social environment (63.9%), a lack of a care partner (60.7%), an inability to obtain transportation (49.2%), a low educational level (36.1%), inadequate housing (23.0%), a language barrier (19.7%), no reliable way of contacting the patient (16.4%), difficulty in obtaining child care (11.5%), and food insecurity (8.2%). The frequencies of perceived social barriers did not differ significantly between programs reporting higher or lower proportions of Medicaid, minority, or rural patients. Our analysis suggests that program‐level operational planning for addressing social barriers to transplant listing should be considered regardless of the proportions of Medicaid‐insured, racial or ethnic minority, and rural patients in the population. Liver Transpl 17:1167–1175, 2011.

Direct-Acting Antiviral Therapy for Hepatitis C: Attitudes Regarding Future Use

IntroductionResponse to current therapy of hepatitis C virus (HCV) is suboptimal. Direct-acting antiviral therapies (DAA) are expected to improve treatment outcomes. Additional treatments for HCV will invariably make therapeutic choices and patient management more complex. We hypothesize that current perceptions regarding the complexity of DAA therapy will influence attitudes towards future use by practitioners who are currently treating HCV.MethodsAn Internet-based survey was sent to 10,082 AASLD and AGA members to determine if they treat HCV infection, their knowledge of DAA therapies, attitudes towards current and future HCV treatments, and if they participated in clinical trials using DAA agents.ResultsOut of a total of 1,757 individuals responding to the survey, 75% treat HCV; 79% were MDs, 67% were Gastroenterologists, and 24% were Hepatologists. Of the respondents, 77% indicated they were “very aware” or “aware” of DAA therapies, 20% participated in clinical trials, and 3% had minimal knowledge of DAA agents. Comparing treatment “today” versus in the future when DAAs were available, 85 vs. 81% would treat (pxa0=xa00.0054), 6 vs. 10% would refer to an “HCV expert” (pxa0=xa00.016), and 1% would refer to an ID specialist. Of respondents with “minimal knowledge” of DAA, 52% stated that they would use them in the future.ConclusionsAlthough the majority of respondents appear ready to utilize DAA agents in the future, referrals to “hepatitis C experts” will increase. More than half of respondents with “minimal knowledge” of DAA therapies also appear to be willing to utilize these compounds, raising concerns regarding their inappropriate use. Broad education of healthcare providers to prevent inappropriate use of these agents will be critical.

Meet the Classes of Directly Acting Antiviral Agents: Strengths and Weaknesses

This article discusses direct-acting antiviral agents that target hepatitis C virus replication, their mechanism of action, strengths, and weaknesses. In addition, varying strategies using combinations of these agents are discussed.

Expedited liver allocation in the United States: A critical analysis

The fate of donor livers allocated via an out‐of‐sequence expedited placement (EP) pathway has not been previously examined. We determined the originating and receiving United Network for Organ Sharing (UNOS) regions of all donor livers procured between January 1, 2010 and October 31, 2012 and placed out of sequence with UNOS bypass code 863 (EP attempt) or 898 (miscellaneous). We reviewed the early function of these liver grafts and assessed the effect of EP allocation on wait‐listed patients at our center. Registrants at our center were eligible to receive 1298 liver offers during the interval studied: 218 (16.8%) of these liver offers bypassed our center and were allocated to other centers and used in patients lower on the match‐run list. During the study interval, 560 livers were allocated in the United States by EP. Regions 1, 5, 7, 9, and 10 used the greatest number of EP‐placed grafts. Region 1 (New England) used the greatest proportion of all EP livers (33% of all imported EP livers in the United States, Pu2009<u20090.001 versus all other regions). Graft function data were available for 560 livers placed by EP: 491 (88%) of these grafts were functioning at a mean of 399.5 days after transplantation. In conclusion, the transplantation of livers allocated by means of an expedited refusal code is asymmetric across regions and, in some instances, results in the bypassing of patients with higher wait‐list priority but without notification of the bypassed center. Short‐term graft function after EP allocation is excellent. Policies governing EP allocation should be created in order to improve access to available organs. Liver Transpl 19:1159‐1165, 2013.

Limited Fibrosis Progression but Significant Mortality in Patients Ineligible for Interferon-Based Hepatitis C Therapy

BACKGROUNDnIndividuals ineligible for interferon-based hepatitis C therapy may have a worse prognosis than patients who have failed or not received treatment.nnnAIMSnTo provide information about the limitations of medical treatment of hepatitis C in real-world patients.nnnMETHODSnWe studied 969 treatment-ineligible patients and 403 treated patients enrolled between 1/1/01 and 6/30/06; data were collected until 3/31/13. Treatment barriers were grouped into five categories and classified as health-related or health-unrelated. Fibrosis stage was assessed initially and at the end of follow-up. Mortality was determined by search of the Social Security database. Death certificates of treatment-ineligible patients were reviewed.nnnRESULTSnInitially, 288 individuals had advanced fibrosis and compensated disease; 87 untreated patients developed advanced fibrosis during follow-up. Health-related treatment barriers were more commonly associated with fibrosis progression and worse survival. During follow-up, 247 untreated patients died: 47% of liver-related and 53% of liver-unrelated causes. Patients with significant comorbid illness had the worst five- (70%) and ten-year (50.5%) survival. Despite high mortality (47%) in persons with decompensated liver disease, no treatment barrier was associated with a greater incidence of liver-related death. Only significant comorbid medical illness was an independent predictor of disease progression; however, it was not associated with a greater incidence of liver-related death. Furthermore, treated patients had better 10-year survival than untreated patients on Kaplan-Meier analysis (80.3% vs. 74.5%, Pxa0=xa00.005).nnnCONCLUSIONnMany patients with hepatitis C will die of non-liver-related causes and may not be helped by anti-viral treatment.

A Rare Finding on Liver Explant

A55-year-old man with nonalcoholic fatty liver disease, refractory ascites, and hepatic encephalopathy after placement of a transjugular intrahepatic portosystemic shunt was referred for liver transplantation. He was placed on the transplantation waiting list in October 2009. Magnetic resonance imaging performed in March 2010 identified a 2.0-cm lesion concerning for hepatocellular carcinoma (HCC) in segment VII. Transarterial chemoembolization (TACE) was performed. Recurrence at the periphery of the post-TACE cavity occurred 1 year after the initial TACE, which was treated with stereotactic body radiation therapy. Two years later, a new 3.0-cm lesion in the caudate lobe was identified. Because the patient was near the top of the transplant waiting list, treatment was differed. On October 4, 2013, the patient underwent orthotopic liver transplantation. The surface of the explanted liver was firm and micronodular. A 3.0-cm, well-circumscribed HCC was present in the caudate lobe. Inspection of the previously treated HCC in segment VII showed dense fibrosis and a 1.2-cm, firm, irregular, white nodule (Figure A). Microscopy showed spindle cells and multinucleated tumor adjacent to TACE microspheres, (Figure B) with frequent mitoses (Figure C). This lesion was consistent with sarcomatoid HCC. Conventional HCC with clear cell morphology was noted next to the sarcomatoid HCC at the region of previous TACE and stereotactic body radiation therapy (Figure D). Sarcomatoid HCC is a rare entity, found in approximately 2% of surgical cases and up to 9.4% of autopsy cases. The incidence of sarcomatoid HCC has increased over the past 3 decades coincident with increasing use of nonsurgical anticancer therapies such as TACE,