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Fibromax is a diagnostic tool composed of the combination of 4 non-invasive biomarker panels for the diagnosis of steatosis (SteatoTest), necrosis and inflammation (ActiTest and NashTest-2) and fibrosis (FibroTest). The purpose of this study was to assess the performance of these biomarker panels in patients with type 2 diabetes mellitus (T2DM). All patients underwent routine labs, a 75 g oral glucose tolerance test, a liver proton magnetic resonance spectroscopy (1H-MRS) to measure intrahepatic triglyceride content, and a percutaneous liver biopsy to establish the diagnosis of non-alcoholic steatohepatitis (NASH) and to grade and stage the disease in those patients with non-alcoholic fatty liver disease (NAFLD) by 1H-MRS. For determination of the scores, plasma samples were blindly provided to establish the SteatoTest, ActiTest, NashTest-2 and FibroTest scores. A total of 220 patients with T2DM were included in this study. When the ability of the SteatoTest to identify patients with T2DM with NAFLD by 1H-MRS was assessed, the overall performance expressed as the area under the receiver operating characteristic curve was 0.73 (95% CI 0.65 to 0.81). The performance of the ActiTest and NashTest-2 to diagnose definite NASH among patients with T2DM was 0.70 (95% CI 0.63 to 0.77) and 0.69 (95% CI 0.62 to 0.76), respectively. Regarding the FibroTest score, its performance to identify patients with moderate or advanced fibrosis was 0.67 (95% CI 0.58 to 0.76) and 0.72 (95% CI 0.61 to 0.83), respectively. Non-invasive panels for the diagnosis of steatosis, NASH and/or fibrosis, which were developed and validated in non-diabetic cohorts, underperformed when applied to a large cohort of patients with T2DM. Results from non-diabetic populations should not be extrapolated to patients with T2DM.

Patients with nonalcoholic fatty liver disease (NAFLD) are at an increased risk of cardiovascular disease. Hydoxy-3-methyglutaryl-coenzyme reductase inhibitors, statins, reduce the risk of cardiovascular events.1 Studies have shown that statins are safe among patients with liver disease, including those with compensated cirrhosis,2 and their use is associated with lower mortality, hepatic decompensation, and possibly hepatocellular carcinoma.3,4 Despite these data, statins are under prescribed among patients with liver disease due to concerns about hepatotoxicity.5 This study aimed to assess prevalence and patient factors associated with indicated statin use in patients with NAFLD in a real-world cohort.

Nonalcoholic fatty liver disease (NAFLD), including its severe form known as steatohepatitis or NASH, are increasingly common in patients with type 2 diabetes mellitus (T2DM) and can progress to cirrhosis. However, there is limited information on their comorbid medical conditions in “real world” practice. Thus, the disease characteristics of patients with NASH or NASH-cirrhosis (cirrhosis), with or without T2DM, was evaluated in TARGET-NASH, an ongoing longitudinal observational study of patients with NAFLD, who are managed according to local standards at 60 community and academic hepatology and endocrinology practices in the United States. Among 3085 patients enrolled with NASH or cirrhosis, 1645 had NASH (47% T2DM) and 1440 had cirrhosis (72% T2DM). Patients with T2DM were older (median 61 vs. 56 years) and had a higher median BMI (34.0 vs. 32.0 kg/m2, p In conclusion, patients with type 2 diabetes and NASH or cirrhosis had more advanced liver disease compared to those without type 2 diabetes. Patients with type 2 diabetes had more than twice the risk of cirrhosis compared to those without type 2 diabetes. These results support a strong link of type 2 diabetes and metabolic risk factors with advanced NASH. Disclosure K. Cusi: Consultant; Self; Allergan plc., AstraZeneca, Bristol-Myers Squibb, Genentech, Inc., Gilead Sciences, Inc., Merck & Co., Inc. Research Support; Self; Cirius Therapeutics, Echosens, Eli Lilly and Company, Inventiva Pharma, Janssen Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Poxel SA, Zydus Pharmaceuticals, Inc. M. Roden: Advisory Panel; Self; Servier. Board Member; Self; Poxel SA. Consultant; Self; Eli Lilly and Company, Gilead Sciences, Inc., ProSciento, TARGET PharmaSolutions. Research Support; Self; Boehringer Ingelheim International GmbH, Novartis Pharma K.K., Sanofi US. Speaker’s Bureau; Self; Novo Nordisk A/S. A.S. Barritt: Consultant; Self; GENFIT, Intercept Pharmaceuticals, Inc., TARGET PharmaSolutions. R.J. Firpi: None. V. Clark: Research Support; Self; GENFIT, Intercept Pharmaceuticals, Inc., Novo Nordisk Inc. S. Klein: Advisory Panel; Self; Danone Nutricia, Merck & Co., Inc. Research Support; Self; Johnson & Johnson, Pfizer Inc. Stock/Shareholder; Self; Aspire Bariatrics. A. Lok: None. P. Newsome: Research Support; Self; Novo Nordisk A/S. K. Corbin: None. M.B. Vos: Advisory Panel; Self; TARGET PharmaSolutions. Consultant; Self; Boehringer Ingelheim (Canada) Ltd., Immuron, Intercept Pharmaceuticals, Inc., Mallinckrodt Pharmaceuticals, Novo Nordisk A/S. Research Support; Self; Bristol Myers Squibb. R. Reddy: Advisory Panel; Self; Ambys, Epigenomics AG, Mallinckrodt Pharmaceuticals, Merck & Co., Inc. Research Support; Self; Conatus Pharmaceuticals, Exact Sciences, Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc., Mallinckrodt Pharmaceuticals, Merck & Co., Inc. C. Schoen: None. A.R. Mospan: Employee; Self; TARGET PharmaSolutions. J.L. Taunk: None. K. Wyne: Advisory Panel; Self; Novo Nordisk Inc. Research Support; Self; Sanofi. B. Neuschwander-Tetri: Advisory Panel; Self; 89Bio, Allysta, ARTham, Blade, Bristol-Myers Squibb, Gelesis, GENFIT, Histoindex, Madrigal Pharmaceuticals, Inc., Medpace, Merck & Co., Inc., Sagimet, Siemens Corporation. Consultant; Self; Arrowhead Pharmaceuticals, Inc., Axcella, DURECT Corporation, Enanta Pharmaceuticals, Inc., Fortress, Indalo, Innovo, Lipocine, Mundipharma International, pH-Pharma, TARGET PharmaSolutions. A. Sanyal: Consultant; Self; Intercept Pharmaceuticals, Inc., Lilly Diabetes, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Pfizer Inc. Stock/Shareholder; Self; DURECT Corporation, GENFIT, HemoShear, Sanyal Bio, Tiziana Life Sciences plc. Funding TARGET-NASH

Background: Opioid use is a topic of growing concern among patients with nonalcoholic fatty liver disease (NAFLD). Given safety concerns of opioids, proactively identifying subgroups of patients with an increased probability of opioid use may encourage practitioners to recommend alternative therapies for pain, thus reducing the likelihood of opioid misuse. This work assessed the prevalence and patient characteristics associated with opioid use in a real-world cohort of patients with NAFLD. Methods: TARGET-NASH, an observational study of participants at 55 academic and community sites in the United States, includes patients with NAFLD defined by pragmatic case definitions. Opioid use was defined as any documented opioid prescriptions in the year prior to enrollment. The association between patient characteristics and the odds of opioid use were modeled with stepwise multivariable logistic regression and tree ensemble methods (Classification and regression tree/Boosted Tree). Results: The cohort included 3,474 adult patients with NAFLD including 18.0% with documented opioid use. Variables associated with opioid use included presence of cirrhosis (OR 1.51, 95% CI 1.16–1.98), BMI ≥32 kg/m2 (OR 1.29, 95% CI 1.05–1.59), depression (OR 1.87, 95% CI 1.50–2.33), and anxiety (OR 1.59, 95% CI 1.27–1.98). In the boosted tree analysis, history of back pain, depression, and fibromyalgia had the greatest relative importance in predicting opioid use. Conclusion: Prescription opioids were used in nearly 1 of 5 patients with NAFLD. Given the safety concerns of opioids in patients with NAFLD, alternative therapies including low-dose acetaminophen and nonpharmacologic treatments should be considered for these patients.

Nonalcoholic fatty liver disease (NAFLD) is typically associated with obesity. Little is known about the prevalence of cirrhosis in patients with NAFLD and a normal body mass index (BMI).We determined prevalence of cirrhosis, cardiovascular disease (CVD), and metabolic abnormalities among participants in all BMI categories in the TARGET-NASH study. A total of 3386 patients with NAFLD were enrolled from August 2016 through March 2019. The odds ratios of cirrhosis, CVD, and metabolic abnormalities were estimated by age and race, adjusting for sex and center type.Based on standard BMI cutoff values, 12.8% of study subjects were lean, 27.1% were overweight, 26.5% had class 1 obesity, and 33.7% had class 2 or 3 obesity. Asians accounted for 48.7% of lean participants, and proportions decreased as BMI categories increased (P .0001). Lower proportions of lean participants had cirrhosis (22.6% vs 40.2% of non-lean participants), CVD history (9.0% vs 14.8% of nonlean participants), diabetes (32.6% vs 53.5% of non-lean participants), hypertension (47.8% vs 67.4% of non-lean participants), or dyslipidemia (54.0% vs 64.1% of non-lean participants). Asian participants had a lower prevalence of cirrhosis, history of CVD, cardiovascular events, and diabetes compared with non-Asians, independent of BMI category. After we adjusted for age, sex, and center type and site, the odds of NAFLD-associated cirrhosis in Asians who were lean was almost half the odds of NAFLD-associated cirrhosis in non-Asians who were lean (odds ratio, 0.47; 95% CI, 0.29-0.77).More than 10% participants in a cohort of persons with NAFLD in the United States are lean; Asians account for almost half of the lean persons with NAFLD. Lean participants had a lower prevalence of cirrhosis, CVD, and metabolic abnormalities than non-lean persons with NAFLD. Asian participants had a significantly lower prevalence of cirrhosis, CVD, and metabolic abnormalities than non-Asians in all BMI categories. ClinicalTrials.gov, Number: NCT02815891.

Objective The objective of this study was to compare posttransplant outcomes in patients undergoing bridging locoregional therapy (LRT) with Y-90 transarterial radioembolization (TARE) based protocol compared with transarterial chemoembolization based protocol for hepatocellular carcinoma (HCC) prior liver transplantation (LT). Materials and methods Patients listed for LT with HCC within the Milan criteria at our center who had bridging LRT were treated according to transarterial chemoembolization (TACE) based protocol from May 2012 to April 2014 and a TARE based protocol from October 2014 to December 2017. Early posttransplant survival and tumor recurrence were compared between the groups. Tumor response to LRT, microvascular invasion (mVI), and the rate of delisting was also evaluated. Results One hundred three patients who were listed for LT with HCC within the Milan criteria received LRT. LT was performed in 65 patients, 28 treated with TARE protocol and 37 on TACE protocol. There were no statistical differences in baseline pretransplant characteristics and tumor recurrence. There was a trend toward improved 3-year survival in the TARE group (92.9% vs. 75.7%; P=0.052). The mVI was seen in 1/28 (3.6%) explants in the TARE group compared with 10/37 (27%) in the TACE group (P=0.013). The TARE group also required fewer LRT treatments (1.46 vs. 2.43; P=0.001) despite no difference in time on the transplant list. Conclusions Despite requiring fewer LRT treatments, there was significantly less mVI in the explants of patients treated with TARE protocol LRT as a bridge to LT as well as a trend toward improved 3-year survival. Therefore, TARE may be associated with improved tumor control and reduced post-LT recurrence.

The programmed death 1 (PD-1), programmed death ligand 1 (PD-L1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) immune checkpoints are negative regulators of T-cell immune function. Inhibition of these targets by antibodies (PD-1 blocking therapy) has been explored to treat solid malignancies such as melanoma, non-small cell lung cancer and other cancers. PD-1 blocking therapy is known to cause gastrointestinal tract adverse events in some patients and some of the adverse events are thought to be immune-mediated. Cancer patients receiving PD-1 blocking therapy have often failed several lines of chemotherapy and thus potentially are susceptible to a variety of infections including cytomegaloviral infection. However, there has not been any report of concurrent immune-mediated gastroenterocolitis and cytomegaloviral infection in cancer patients receiving PD-1 blocking therapy. Herein, we report one unusual case of histologically confirmed gastritis with features of immune-mediated pangastritis and cytomegaloviral infection in one patient who had metastatic urothelial carcinoma and received PD-1 blocking therapy, initially with atezolizumab (anti-PD-L1 antibody) followed by a switch to pembrolizumab (anti-PD-1 antibody) because of tumor progression. Pembrolizumab was held and intravenous ganciclovir treatment was started, the patient’s symptoms (abdominal pain and vomiting) were significantly improved and she was discharged from the hospital in stable conditions on hospital day 5. Pathologists should be aware of PD-1 blocking therapy-associated immune-mediated gastrointestinal tract adverse effect and concurrent cytomegaloviral infection.

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.

Nonalcoholic Fatty Liver Disease (NAFLD), ranging from simple steatosis to its more severe form, steatohepatitis (NASH), is an increasingly common problem in patients with T2DM and is associated with progression to cirrhosis and extrahepatic complications (i.e., cardiovascular disease [CVD]). There is limited information on the clinical profile of T2DM patients with NASH in “real world” practice. Accordingly, we studied the clinical profile of participants (pts) with NASH, with or without T2DM (nonDM), enrolled in TARGET-NASH, a large longitudinal observational study of patients with NAFLD followed at 54 sites (39 academic/15 community) across the U.S. Data collected from medical records (including lab data, imaging, pathology, procedures, and outcomes) is sent to a central database utilizing novel data abstraction technology. Among 1743 pts studied to date in TARGET-NASH, 1261 had NASH diagnosed by biopsy or clinical criteria (699 T2DM and 562 nonDM). Pts with T2DM and NASH were older (median 61 vs. 56 years) and had a higher BMI than nonDM (34.0 vs. 32.0 kg/m2, both p Disclosure K. Cusi: Consultant; Self; Janssen Global Services, LLC., Eli Lilly and Company. Research Support; Self; Cirius Therapeutics. Other Relationship; Self; Nordic Bioscience. Research Support; Self; Novartis Pharmaceuticals Corporation, Novo Nordisk Inc.. Other Relationship; Self; Quest Diagnostics. Research Support; Self; Zydus Pharmaceuticals (USA) Inc.. Other Relationship; Self; OWL metabolomics, Echosens. Research Support; Self; Janssen Global Services, LLC.. Consultant; Self; Tobira Therapeutics, Pfizer Inc. A.S. Barritt: Consultant; Self; Targetpharma solutions. Consultant; Spouse/Partner; Targetpharma solutions, Takeda Pharmaceuticals U.S.A., Inc., AbbVie Inc.. V. Clark: None. R.J. Firpi: None. S. Klein: Stock/Shareholder; Self; Aspire Bariatrics. Consultant; Self; Pfizer Inc.. Research Support; Self; Merck & Co., Inc., Johnson & Johnson Services, Inc., REMD Biotherapeutics. A. Lok: None. R. Loomba: Research Support; Self; Adheron, Arora, BMS, Daiichi-Sankyo Inc., Galectin, Galmed, GE, Genfit, Gilead, Immuron, Intercept, Kinemed, Madrigal, Merck, NGM, Promedior, Prometheus, Siemens, Sirius, Tobira. Advisory Panel; Self; Arrowhead Research, Conatus, Galmed, Gilead, Intercept, NGM, Nimbus, Octeta, Tobira. Consultant; Self; Alnylam, Bird Rock Bio, BMS, Boehringer Ingleheim, Celgene, Conatus, DeuteRx, Eli Lily, Enanta, Fibrogen, Genkyotex, Gilead, GRI Bio, ISIS, Janssen Inc.Kirin, Madrigal, Metacrine, NGM, Nitto Denko, Pf, Sanofi,Scholar Rock, Shire, Tasly, Viking, Yuhan Pharmaceuticals, Zafgen. L. Malahias: None. B. Neuschwander-Tetri: None. C. Schoen: None. K. Reddy: Advisory Panel; Self; Gilead Sciences, Inc., Merck & Co., Inc., AbbVie Inc.. Other Relationship; Self; Novartis AG, Gilead Sciences, Inc., Merck & Co., Inc., AbbVie Inc., Mallinckrodt Pharmaceuticals, Conatus Pharmaceuticals Inc., Intercept Pharmaceuticals, Inc.. J.L. Taunk: None. K. Wyne: Research Support; Self; Sanofi. Advisory Panel; Self; Novo Nordisk Inc.. Research Support; Self; Eli Lilly and Company. A.J. Sanyal: Stock/Shareholder; Self; Sanyal Bio, Genfit, Durect, Indalo, Exhalenz. Consultant; Self; Gilead, Boehringer Ingelheim, Intercept. Advisory Panel; Self; Galectin, NGM. Consultant; Self; Pfizer.

We present a rare case of a 46-year-old man presenting with mucinous ascites secondary to malignant peritoneal mesothelioma (MPM) that was diagnosed via colonoscopy with biopsies. Both our findings and the clinical presentation were unique. While it is widely known that asbestos exposure is commonly associated with pleural mesothelioma, 6-10% of malignant mesotheliomas arise from the peritoneum. To date, only 4 cases of MPM with the primary tumor site in the colon have been described in the literature.

Liver transplantation (LT) is the main intervention to improve survival of end-stage liver disease (ESLD) patients. There are conflicting reports on the association of pre LT diastolic dysfunction (DD) with post LT risk of clinical heart failure (HF) and mortality. We aimed to retrospectively study

The aim of the present study was to determine the treatment outcome and prognostic factors for survival in patients with peripheral intrahepatic cholangiocarcinoma (ICC). A retrospective chart review was performed for patients diagnosed with ICC between 2000 and 2009 at a single institution. We identified a total of 105 patients with ICC. Among them, 63.8% were older than 60 years of age, 50.5% were male and 88.6% were Caucasian. By preoperative imaging approximately half of the patients (50.5%) were surgical candidates and underwent resection. The other half of the patients (49.5%) were unresectable. The unresectable group received chemoradiotherapy (53%) and transarterial chemoembolization (7.7%) as palliative treatments while 23.0% of the patients (12/52) received best supportive care alone. The median survival rates were 16.1 months (13.1‑19.2) for the entire cohort, 27.6 months (17.7-37.6) for curative resection, 12.9 months (6.5-19.2) for palliative chemoradiotherapy and 4.9 months (0.4-9.6) for best supportive care (p0.001). Independent predictors on multivariate analysis were advanced stage at diagnosis and treatment received. In those patients who underwent resection, advanced AJCC stage and presence of microvascular invasion were also independent predictors of poor survival. We concluded that surgery offers the most beneficial curative option and outcome, emphasizing the importance of resectability as a major prognostic factor. The present study also revealed that use of chemoradiotherapy in the adjuvant setting failed to improve survival but its palliative use in those patients with unresectable ICC offered a modest survival advantage over best supportive care. The overriding factors influencing outcome were stage and the presence of microvascular invasion on pathology.

Preservation injury in the HCV liver transplant population has been reported to correlate with poorer survival outcomes compared to preservation injury in the non-HCV liver transplant population. However, determinants of progression to cirrhosis in HCV infection remain poorly defined in this population.This study aimed to determine if the presence and severity of preservation injury impact the acceleration of HCV recurrence and survival after liver transplant.We retrospectively reviewed liver transplant HCV patients over a 10-year period. Biopsies from postoperative day 7 were assessed for preservation injury and 4- and 12-month biopsies were assessed for fibrosis. Patients with Ishak fibrosis0.8 Units/year were considered rapid fibrosers.Our study group consisted of 255 patients. The mean age was 49.3 years old, 180 (70.6 %) were male, and 221 (86.7 %) were Caucasian. The incidence of preservation injury on the 7-day biopsy was 69.0 %. A strong correlation between postoperative peak AST within the first week and preservation injury was found. The overall prevalence of rapid fibrosers at 4 months, 1 and 2 years was 47.4, 75.2, and 58.9 %, respectively. The prevalence of rapid fibrosers at 4 months, 1 and 2 years between patients with or without preservation injury was not statistically significant (p = 0.39, p = 0.46, and p = 0.53, respectively). No differences were seen between patients with and without PI in terms of patient and graft survival.In this study, the presence and severity of preservation injury were not associated with development of rapid HCV recurrence or worsening in survival.

Incidentally discovered hepatocellular carcinomas (iHCC) are tumors which are discovered on the explanted liver which were not present on imaging prior to transplant. The natural history, histopathologic characteristics and prognosis of iHCC are not clearly defined. Methods: A retrospective analysis was performed to compare the characteristics of iHCC and established HCC within Milan criteria (eHCC) in patients who underwent liver transplantation at our center between 2000 and 2010. Results: During the study period a total of 975 adult patients were transplanted in our center; 124 (12.7%) patients had eHCC and 26 (2.6%) patients had iHCC. A larger number of patients with iHCC (73.1%) had ascites when compared to eHCC (41.3%) (p = 0.035). Patients with iHCC had a higher mean bilirubin (p 0.001) and mean INR (p = 0.05) than patients with eHCC. Around 70% of patients with iHCC had a Model for End Stage Liver Disease (MELD) score greater than 15 at the time of listing while only 25% of patients with eHCC had a MELD greater than 15 at listing (p 0.001).The mean alphafetoprotein (AFP) in patients with iHCC was significantly lower (11.6 ± 16.5) than the patients with eHCC (564.9 ± 2180; p = 0.024). In patients with iHCC, 30.8% had a multiple tumors and 23% had bilobar involvement. The average number of tumors was 1.6 and the cumulative tumor size was 2.1 cm (SD 1.4). The cumulative tumor size in iHCC was significantly smaller than in eHCC (mean 3.9 cm) (p = 0.035). American Joint Committee on Cancer (AJCC) T1 tumor stage was found in 58% of patients with iHCC and 48.4% of patients with eHCC (p = 0.829).The median survival was 9.47 years for iHCC (95% CI 7.0 - 11.9) and 8.7 years (95% CI 6.1 - 11.4) for eHCC (p = 0.328). While none of the patients with iHCC had recurrence of HCC, the incidence of recurrence in patients with eHCC was 6.4%. Conclusion: iHCC occurred in patients with more advanced liver disease than eHCC. AFP was usually not elevated in patients with iHCC. The cumulative tumor size of iHCC was smaller than eHCC but around a third of iHCC were multifocal, supporting the theory of multicentric hepatic carcinogenesis. Survival of patients with iHCC was similar to patients with eHCC and recurrence was not noted in patients with iHCC.

This prospective, randomized, phase 2 study in subjects with recurrent hepatitis C virus (HCV) genotype 1 postorthotopic liver transplant evaluated once-daily simeprevir 150 mg + sofosbuvir 400 mg, with and without ribavirin 1000 mg. Primary endpoint was proportion of subjects with week 12 sustained virologic response (SVR12). Thirty-three subjects without cirrhosis were randomized 1:1:1 into three arms (stratified by genotype/subtype and Q80K): Arm 1, simeprevir + sofosbuvir + ribavirin, 12 weeks; Arm 2, simeprevir + sofosbuvir, 12 weeks; Arm 3, simeprevir + sofosbuvir, 24 weeks; 13 additional subjects (two with cirrhosis, 11 without cirrhosis) entered Arm 3. All 46 subjects received at least one dose of study drug; median age, 60 years; 73.9% male; 80.4% White; 71.7% genotype/subtype 1a [12 (36.4%) of these had Q80K]; median 4.5 years post-transplant. Among randomized subjects, SVR12 was achieved by 81.8% in Arm 1, 100% in Arm 2, and 93.9% in Arm 3; two subjects did not achieve SVR12: one viral relapse (follow-up week 4; Arm 1) and one missing follow-up week 12 data. In total, five subjects had a serious adverse event, considered unrelated to treatment per investigator. Simeprevir exposure was increased relative to the nontransplant setting, but not considered clinically relevant. Simeprevir + sofosbuvir treatment, with or without ribavirin, was efficacious and well tolerated (ClinicalTrials.gov Identifier: NCT02165189).

Aim The goal of this study is to evaluate whether an elevated neutrophil–lymphocyte ratio (NLR) at the time of diagnosis predicts survival of patients with hepatocellular carcinoma (HCC) after liver transplantation (LT). We hypothesize that the NLR is predictive of overall survival (OS) and recurrence-free survival (RFS) in patients with HCC who undergo LT. Methods This is a retrospective analysis of adult patients undergoing LT for HCC between 2000 and 2008 at our institution. We define an elevated NLR as a ratio of 5 or greater. Results We included 160 patients who underwent LT for HCC in the time period, of whom 28 had an elevated NLR. Seventeen subjects experienced recurrent HCC during the study period. The cumulative survival among subjects with an elevated NLR was significantly lower than among subjects with a normal NLR. On univariate analysis, several factors (including an elevated NLR) predicted decreased OS and RFS. However, after multivariate analysis, only three factors (including elevated NLR) remained significant as predictors of OS. Additionally, multivariate analysis revealed that an elevated NLR was the only significant independent predictor of RFS. Conclusion Preoperative NLR is a powerful independent predictor of OS and RFS in patients undergoing LT for HCC. Measurement of NLR could serve as a useful and easily obtained adjunct to the Model for End-Stage Liver Disease score and Milan criteria when evaluating this patient population and determining which patients will gain the most survival benefit from transplantation.

Hepatitis C (HCV) is the most common indication for liver transplant (LT) in the United States. HCV recurrence is universal following transplantation and leads to allograft failure in about ten percent of recipients by the fifth postoperative year.(1) In the LT setting, the factors associated with the more aggressive disease progression are complex and multi-factorial, including recipient, donor and viral components. It is likely that host immune responses, both innate and adaptive, play a pivotal role in the clearance of viral infections, ongoing liver damage, and response to antiviral therapy. Therefore, defining the mechanisms of host immune system interaction with HCV after LT is critical for understanding HCV-related allograft injury and response to antiviral treatment. This knowledge is also vital to guide immunosuppression strategies that minimize HCV disease progression and increase the overall survival of the graft. Although multiple host factors have been implicated in HCV disease progression, interleukin-28B (IL-28B) single nucleotide polymorphism (SNP) on the chromosome 19, rs12979860, seems to be strongly associated with HCV clearance and treatment response.(2) So far, this SNP is the strongest predictor for sustained viral response (SVR) to interferon (IFN)-based therapy in the HCV population. The C allele is the most frequent allele in the white population associated with SVR. Patients with CC genotype have a two-fold chance of SVR compared to patients with T alleles.(3) In a recent study of IL-28B SNP in HCV LT recipients and donors, IL-28B genotypes predicted an SVR with 83% sensitivity and 82% specificity.(4) In addition, IL-28B recipient genotype was predictive of fibrosis, with the TT allele associated with more rapid fibrosis. Similar to interferon-based therapy in non-transplant patients, the CC genotype in either recipient or donor has been associated with increased rate of SVR.(5–7) Emerging evidence suggests that both donor and recipient IL-28B SNP background may play an important role in post-transplant HCV recurrence and its response to current therapy (8), but the available data is limited. Recently, others have reported that follow up liver biopsies may not be suitable for IL-28B determination.(9) Therefore, the objective of our study was to examine the role of IL-28B polymorphism of both donor and recipient livers in HCV disease progression after LT and its response to interferon-based therapy in a well characterized group of transplant patients.

Sorafenib is currently the only approved systemic therapy shown to have efficacy in the treatment of advanced hepatocellular carcinoma (HCC). Recent studies suggest that hepatitis C (HCV)-related HCC patients derive more clinical benefit from sorafenib than other subgroups, but the mechanism for this effect is unknown. In vitro data suggest that sorafenib may exert anti-viral properties, and thus our aim in this study was to evaluate potential anti-viral activity of sorafenib in patients with HCV-related HCC.To evaluate potential anti-viral activity of sorafenib in patients with HCV-related HCC.We prospectively enrolled patients with HCV-related HCC treated with sorafenib for up to 6 months. Baseline clinical, viral and oncologic data were collected. Patients' HCV viral loads were obtained at various time points, and compared with their baseline viral levels. No patients received any known anti-viral therapy during this time.Thirty-three patients were identified with baseline and subsequent HCV levels available for analysis. Six patients completed 6 months of full dose sorafenib, and comparisons of their HCV viral loads showed no significant change at week 24 (difference of means = 0.3500, CI: -0.1799-0.8799, P = 0.150), or the interim time points. Similarly, the HCV viral loads of all patients who received sorafenib and the viral loads of those patients who had tumour response to sorafenib showed no significant changes at any time point.Despite preclinical data and previous subgroup analyses suggesting that sorafenib has an anti-viral effect against HCV, this study suggests that sorafenib lacks significant anti-viral activity in HCV patients with HCC.

To evaluate the impact of long-term outcomes of transarterial embolization (TAE) therapy in patients with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) on the waiting list for liver transplantation (LT).We retrospectively evaluated the post-LT patients with HCV-related HCC who received TAE intervention (n=33) and those who had no treatment (n=47) while on the waiting list to determine long-term outcomes.Over a 10-year period, of the 424 patients transplanted with HCV, 80 patients had HCC with a tumor burden within Milan criteria. For the entire study cohort, the mean duration of post-LT follow-up was 3.5 years; mean time of transplant waiting list was 120 days; and median post-LT survival was 8.9 years. The survival rates at 1, 3, 5, and 10 years were 82%, 70%, 55%, and 35%, respectively. From the study cohort, 33 patients received TAE and 47 patients did not while on the waiting list. The 2 groups were well matched, except, that the intervention patients received post-LT interferon more often and had a shorter time on the waiting list (56.2 d) when compared with the no treatment group (164.6 d, P0.001). Median survival in the TAE group was 4.8 years and 8.9 years in the no treatment group. The recurrence rate was 15.6% in the treatment group and 6.9% in the no therapy group (P=0.275).Pre-LT transarterial therapy has no benefit on post-LT survival and tumor recurrence in patients with HCV-related HCC who underwent a mean waiting period of3 months to transplant.

Chronic hepatitis C virus (HCV) infection affects approximately 3% of the world’s population, with cirrhosis caused by chronic HCV the most frequent indication for liver transplantation (LT) in the United States and Europe. 1 Between 1999 and 2007, 37% to 41% of all recipients of LT in the United States had chronic HCV. 2 However, survival of LT recipients with chronic HCV remains lower than that of recipients without HCV. This decreased survival is related to the near-universal recurrence of HCV after transplantation as well as the accelerated course of recurrent HCV after LT. 3 Between 25% and 30% of LT recipients with HCV develop graft cirrhosis, with a median time to recurrent cirrhosis of 8 to 10 years. 4,5 The clinical outcomes of these patients, and the likelihood of graft cirrhosis, are affected by multiple factors, including donor demographics, recipient virological status, posttransplant immunosuppression, and antiviral therapy. This article reviews the natural history and management of HCV following LT.

Aliment Pharmacol Ther 2011; 34: 205–213 Summary Background Standard of practice involves using transarterial therapy for multifocal hepatocellular carcinoma (HCC) alone and sorafenib only for more advanced HCC, but the sorafenib and transarterial therapy combination may provide greater efficacy. Aim To evaluate the safety and efficacy of concurrent sorafenib and transarterial therapy in HCC. Methods Consecutive cases of HCC were treated with sorafenib and transarterial therapy, receiving sorafenib 2 to 4 weeks before transarterial therapy. Baseline clinical parameters, adverse events (AEs) and survival were collected. Results A total of 47 patients received sorafenib and transarterial therapy. The majority of the patients were male (70%) with HCV (60%), median age of 60 years, good performance status (0–1), stable cirrhosis (Child: A 72%; B 28%), unresectable tumour (stage: B 81%; C 19%) and median AFP of 24 ng/mL. Median follow-up was 12 months and median time on sorafenib was 6 months. LC Bead TACE was used with a median frequency of 3. The majority of the patients (89%) experienced AEs. The most common AEs were fatigue (51%), hand-foot skin reaction (51%) and diarrhoea (43%). Grade 3 and 4 AEs included fatigue (13%) and hand-foot skin reaction (26%). Most patients required a dose reduction (66%). The main AE related to transarterial therapy was post-TACE syndrome (23%). The disease control rate was 68% at 6 months. Overall median survival rate was 18.5 months (95% CI 16.1–20.9 months). Conclusion Concurrent sorafenib and transarterial therapy is overall safe with no unexpected side effects and encouraging efficacy that warrants further study.

Aliment Pharmacol Ther 2011; 33: 235–242 Summary Background Newer therapies are needed for patients with primary biliary cirrhosis and incomplete response to ursodeoxycholic acid (UDCA). Fenofibrate is a fibric acid postulated to regulate immune response and cell proliferation. Aim To evaluate the efficacy and safety of fenofibrate in patients with primary biliary cirrhosis and incomplete response to UDCA. Methods We undertook a pilot study involving 20 patients with primary biliary cirrhosis and serum alkaline phosphatase (ALP) ≥ 2× ULN. Nonparametric statistical tests and Spearman correlation test were used as appropriate. Results Twenty patients received fenofibrate (160 mg/day) in addition to UDCA for 48 weeks. Median serum ALP decreased significantly at 48 weeks compared with baseline values [351 (214–779) U/L at baseline vs. 177 (60–384) U/L at 48 weeks, P

Background: The literature suggests that blood product transfusions have a negative impact on the survival of liver transplant patients. We investigated the impact of intraoperative blood product usage on the survival of liver transplantation patients being transplanted for hepatitis C-related end-stage liver disease. In addition, we analyzed a potentially more sensitive metric, namely disease recurrence and fibrosis progression, obtained from follow-up liver biopsies. Methods: We retrospectively studied 194 consecutive patients with hepatitis C virus (HCV) undergoing liver transplantation. To investigate the effect of red blood cell (RBC) or platelet transfusions on post-transplant HCV recurrence, hepatic biopsy data from 4 months and 1 year after transplantation were studied. In addition, survival data were analyzed. Results: There was no effect of intraoperative RBC or platelet transfusion on either 1- or 5-year patient survival following liver transplantation. There was no difference in HCV disease recurrence or progression of hepatic fibrosis at 4 months or 1 year attributable either to RBC or to platelet transfusion. Conclusion: This study was not able to confirm an effect on the survival of HCV-infected liver transplant patients related to intraoperative transfusion of RBCs or platelets. In addition, these transfusions had no effect on HCV recurrence or fibrosis progression. This is not to condone a liberal transfusion practice, but rather to reassure that when clinically indicated, transfusion does not have a significant impact on patient survival or disease recurrence in HCV-infected liver transplant patients.

Cyclosporine has antiviral activity in vitro against hepatitis C (HCV). We performed a pilot study to prospectively determine the antiviral effect of cyclosporine during therapy with PEGalfa-2a and ribavirin in liver transplant recipients with recurrent HCV infection. Patients with HCV recurrence (Ishak Fibrosis Stage ≥ 2) were enrolled for 2 years at the University of Florida. Thirty-eight patients were randomized to continued tacrolimus or switched to cyclosporine. Both groups received PEGalfa-2a and ribavirin. Twenty patients received tacrolimus and 18 cyclosporine, with a mean age of 53. Eighty-two percent were men, 84% Caucasian, and 90% genotype 1. In patients switched from tacrolimus to cyclosporine, HCV-RNA levels decreased by a mean of 0.39 million IU/ml during the 1 month prior to initiating PEG/RBV. Sustained viral response for cyclosporine was higher than in patients on tacrolimus receiving PEG/RBV therapy. This randomized controlled pilot study is the first in vivo study evaluating cyclosporine versus tacrolimus in liver transplant recipients undergoing antiviral therapy. Change from tacrolimus to cyclosporine led to a modest HCV RNA drop and appeared to enhance the antiviral response of PEG/RBV. A larger randomized study is necessary to see if cyclosporine offers any advantage over tacrolimus.

Non–organ-specific autoantibodies, including antinuclear antibodies, anti–smooth muscle antibodies, and anti–liver/kidney microsomal type 1 antibodies, are present in about one third of patients with chronic hepatitis C. Two theories of autoantibody generation in patients with hepatitis C are proposed. The first proposes that the binding of hepatitis C virus to CD81 on B-lymphocytes lowers the activation threshold of these cells, thus facilitating the production of autoantibodies. The second proposes that the autoantibodies are produced through molecular mimicry. Unfortunately, the pathogenic role of these autoantibodies remains controversial. In addition, whether the autoantibodies can adversely affect treatment outcomes when patients receive interferon-α is unclear. Although the presence of autoantibodies in patients with hepatitis C is not considered a contraindication to interferon therapy, patients should be monitored carefully while on therapy.

In transplant recipients transplanted for hepatitis C, presentation of abnormal transaminases can herald the presentation of recurrent hepatitis C, cellular rejection, or both. Given the sometimes ambiguous histology with these 2 entities, the ability to distinguish them is of great importance because misinterpretation can potentially affect graft survival. We used an immune functional assay to help assess the etiology of abnormal liver function test results in liver transplant recipients. Blood samples for the immune functional assay were taken from 42 recipients prospectively at various times post-transplant and compared with clinical and histologic findings. In patients whose liver biopsy showed evidence of cellular rejection, the immune response was noted to be very high, whereas in those with active recurrence of hepatitis C, the immune response was found to be very low. This finding was found to be statistically significant (P < 0.0001). In those patients in whom there was no predominant histologic features suggesting 1 entity over the other, the immune response was higher than in those with aggressive hepatitis C but lower than in those with cellular rejection. In conclusion, these data show the potential utility of the ImmuKnow assay as a means of distinguishing hepatitis C from cellular rejection and its potential usefulness as a marker for outlining the progression of hepatitis C.

This retrospective analysis was conducted to identify factors predictive of survival after transjugular intrahepatic portosystemic shunt (TIPS) creation.Patients who underwent TIPS creation between January 1991 and December 2005 at a tertiary-care center were identified. Log-rank tests were used to compare the cumulative survival functions among groups of patients who underwent TIPS creation for various indications. Thirty-day mortality after TIPS creation was examined by logistic regression. Cox proportional-hazards analyses were performed to analyze the cumulative 90-day and 1-year survival. Selected variables such as creatinine, bilirubin, and International Normalized Ratio (INR) were assessed with respect to survival.The study included 352 patients, of whom 229 (65.1%) were male. The mean age at the time of TIPS creation was 53.6 years (range, 21-82 y). A Model for End-stage Liver Disease (MELD) score greater than 15 was significantly associated with poor survival (P.05) at 30 days, 90 days, and 1 year after TIPS creation. Independently, a serum total bilirubin level greater than 2.5 mg/dL, an INR greater than 1.4 (P.05), and a serum creatinine level greater than 1.2 mg/dL were predictive of poor survival. Finally, age greater than 70 years was associated with poor survival at 90 days and 1 year after TIPS creation (P.05).The choice to create a TIPS in individuals whose MELD score is greater than 15 and/or whose age is greater than 70 years should involve a careful consideration of risk/benefit ratio, taking into account the finding that such patients have significantly poorer survival after TIPS creation.

Treatment of chronic hepatitis C patients has evolved significantly in the past 15 years. With a better knowledge of viral kinetics and molecular virology of the hepatitis C virus, we have gone from a low chance of viral eradication to a chance as high as 50%. Despite this, current therapies are not ideal and are associated with side effects, complications, and poor patient tolerability. Therefore, an urgent need to look for better strategies to treat this disease is imperative. Thanks to the current knowledge and ongoing research, we know the way we treat hepatitis C today will change dramatically in the next 5-10 years. This review will focus on current therapies for hepatitis C and the most recent advances in the search for new therapies.

Background & Aims: Esophageal varices and bleeding are among the most feared complications of primary biliary cirrhosis (PBC). We aimed to determine the prevalence of esophageal varices in patients with PBC, to evaluate noninvasive markers of esophageal varices in this population, and to validate the results in an independent set of patients. Methods: Data were collected on all patients with PBC seen for the first time at the University of Florida (study group) and at Case Western Reserve University hospitals (cross-validation group) during 7 consecutive years. Logistic regression analysis was used to identify independent predictors of esophageal varices. The best cut-off values were calculated based on receiver operating characteristic curves. The diagnostic accuracy of the independent predictors of esophageal varices identified in the study group were retested in the cross-validation group. Results: Of 210 patients with PBC seen at the University of Florida, 113 had an endoscopy and 49.6% (56 of 113) were found to have esophageal varices. After excluding 22 patients with a history of variceal bleeding, data on 91 patients were analyzed. Thirty-four patients had esophageal varices (37%). Multivariate analysis revealed that a platelet count of less than 140,000 (odds ratio, 7.6; 95% confidence interval, 1.6–37) and a Mayo risk score of 4.5 or greater (odds ratio, 10.6; 95% confidence interval, 1.8–62) were independent predictors of esophageal varices. The diagnostic accuracy of these predictors was confirmed in an independent set of patients. Conclusions: Among patients with PBC, a platelet count of less than 140,000 and/or a Mayo risk score of 4.5 or greater appears to identify those patients more likely to benefit from a screening endoscopy.

Hepatitis C is a devastating illness which has the potential in the majority of cases to lead to significant morbidity and mortality. Worldwide, the number living with chronic hepatitis C approaches 185 million. Up until recently, the regimen of peg-IFN and ribavirin stood as the standard of care and is still commonly used as first line therapy. This is rapidly changing. Direct acting antivirals have altered the landscape drastically. By understanding the genome of the hepatitis C virus, scientists and researchers have been able to exploit its mechanism of transmission by creating inhibitors against several of the nonstructural proteins that are integral to HCV replication and function [NS3/4 protease, NS5A polymerase, and NS5B polymerases (nucleoside and non-nucleoside)]. The previously reported 50%-70% SVR rates achieved with peg-IFN and RBV are no longer the standard of care. Thanks to direct acting antivirals, IFN free as well as “all oral” regimens are being used to treat HCV. In addition to this, ribavirin-free regimens are also available. These highly effective therapies also provide far less side effects and accomplish better results in less time, thus shortening treatment duration significantly. Additionally, even in the notori‐ ously difficult -to-treat populations, results have been promising.

Over the past several years, more so recently, treatment options for hepatitis C virus (HCV) have seemed to exponentially grow. Up until recently, the regimen of pegylated interferon (peg-IFN) and ribavirin (RBV) stood as the standard of care. Direct acting antivirals, which target nonstructural proteins involved in replication and infection of HCV were first approved in 2011 as an addition to the peg-IFN and RBV regimen and with them have come increased sustained virological response rates (SVR). The previously reported 50%-70% SVR rates using the combination of peg-IFN and RBV are no longer the standard of care with direct acting antiviral (DAA) based regimens now achieving SVR of 70%-90%. Peg-IFN free as well as “all oral” regimens are also available. The current randomized controlled trials available show favorable SVRs in patients who are naive to treatment, non-cirrhotic, and not human immunodeficiency virus (HIV)-co-infected. What about patients who do not fit into these categories? In this review, we aim to discuss the currently approved and soon to be approved DAAs while focusing on their roles in patients that are treatment experienced, cirrhotic, or co-infected with HIV. In this discussion, review of the clinical trials leading to recent consensus guidelines as well as discussion of barriers to treatment will occur. A case will attempt will be made that social services, including financial support and drug/alcohol treatment, should be provided to all HCV infected patients to improve chances of cure and thus prevention of late stage sequela.

End-stage liver disease associated with hepatitis C virus (HCV) infection is the most common indication for liver transplantation in the United States. Recurrent HCV infection is nearly universal and disease progression is accelerated in the immunocompromised host. In the post-transplant setting, the HCV-specific immune response plays a critical role in viral surveillance and disease progression. A failure to mount an efficient response to HCV antigens, either because of selective defects in the host immune system or because of viral interference with the normal function of the immune cells, could account for the inability of most transplant recipients to eradicate HCV.

Background & Aims: Percutaneous liver biopsy is the gold standard in the diagnosis and staging of a wide variety of hepatic disorders. Complications, post-procedure monitoring, and recovery time have limited the ability for liver biopsies to be performed in a busy gastroenterology community practice. The aim of this study was to determine whether ambulatory patients requiring percutaneous liver biopsy can be safely discharged after a short recovery time period. Methods: All ambulatory patients undergoing a percutaneous liver biopsy at the University of Florida between February 1995 and June 2004 were evaluated in this study. A 15-gauge Jamshidi needle was used after percussion (before February 2002) or ultrasound guidance (starting February 2002). Major complications were defined as those events that required either immediate or delayed hospitalization or resulted in death within 2 weeks after the liver biopsy. Results: Three thousand two hundred fourteen outpatient liver biopsies were performed at our institution from March 1995 to June 2004. During this time, our recovery time was gradually decreased from 6 hours before 1997 to 1 hour in 2002. The majority of the complications occurred within 1 hour of the observation period or within 24 hours after discharge. The major complication rate was ≤1.7%, regardless of the observation period. Conclusions: A shorter observation time after ambulatory percutaneous liver biopsy is safe and might facilitate the physician's ability to optimally utilize procedural space and ancillary staff in a busy ambulatory care unit.

Recurrent hepatitis C after liver transplantation is a serious problem faced by liver transplant recipients. Activation of hepatic stellate cells is an early step in hepatic fibrogenesis. The aim of this study was to evaluate hepatic stellate cell activation, early after liver transplantation, as a predictor for the subsequent development of advanced fibrosis. Forty-six patients who underwent liver transplantation for hepatitis C and protocol liver biopsies were divided into rapid fibrosers (n = 21), defined as recipients who developed bridging fibrosis or cirrhosis within 2 years of liver transplantation, and slow fibrosers (n = 25). The protocol liver biopsy obtained 4 months after transplantation was stained and quantitated for hepatic stellate cell activation with antibody to alpha smooth muscle actin. Hepatic stellate cell activity was independently associated with rapid fibrosis (odds ratio: 1.6 [95% CI: 1.1,2.2], P = 0.013). The c-statistics for the receiver operating characteristic curve for stellate cell activity and fibrosis were 0.78 and 0.67, respectively, P = 0.36. The receiver operating characteristic curve for a model including stellate cell activity, histology activity index, and alanine aminotransferase. obtained at month 4 had the best c-statistic (0.88). In recipients with stage 0 or 1 fibrosis on the month 4 liver biopsy who subsequently developed advanced fibrosis, the c-statistic for the receiver operating characteristic curves was significantly better for stellate cell activity than for stage of fibrosis (0.77 and 0.51, respectively; P = 0.004). In conclusion, hepatic stellate cell activation early after liver transplantation complements traditional testing for identifying liver transplant recipients with hepatitis C at greatest risk for developing advanced fibrosis. (Liver Transpl 2005;11:1235–1241.)

The CD4(+)CD25(+) regulatory T lymphocytes have been implicated in suppressing T cell immune responses. Our aim was to characterize the frequency, phenotype, function, and specificity of CD4(+)CD25(+) T cells in hepatitis C virus (HCV) infection. Peripheral CD4(+)CD25(+) cells from recovered (n = 15), chronic infected (n = 30), and normal control (n = 15) subjects were analyzed ex vivo for quantitation, phenotype, and effect on HCV-specific interferon gamma production and proliferation. CD4(+)CD25(+) specificity was determined by intracellular cytokine staining for interleukin 10 (IL-10). A higher proportion of CD4(+)CD25(+) were found in chronic infection (mean, 3.02%) when compared with recovered (1.64%, P = .001) and normal controls (2.27%, P = .02). CD4(+)CD25(+) cells display CD45RO(high), CD45RA(low), CD28(high), CD62L(high), and CD95(high) phenotype. HCV-specific interferon gamma activity was enhanced in peripheral blood mononuclear cells depleted of CD4(+)CD25(+) and suppressed in peripheral blood mononuclear cells enriched with CD4(+)CD25(+). Depletion of CD4(+)CD25(+) cells also enhanced HCV-specific CD4(+) and CD8(+) T cell proliferation. Cytokine analysis suggested CD4(+)CD25(+) cells secrete transforming growth factor beta (TGF-beta(1)) and IL-10. The inhibitory role for TGF-beta(1) was confirmed by anti-TGF-beta(1). Transwell studies showed CD4(+)CD25(+) mediated suppression to be dose dependent and requiring cell contact. CD4(+)CD25(+) cells showed HCV-specificity through IL-10 production, with a frequency ranging from 1.9% to 5.3%. A positive correlation was detected between CD4(+)CD25(+) T cell frequency and HCV RNA titer, whereas an inverse relation was found with liver inflammatory activity. In conclusion, CD4(+)CD25(+) T lymphocytes constitute a highly differentiated population and appear to play a role in viral persistence by suppressing HCV-specific T cell responses in a cell-cell contact manner.

Summary Background : Sirolimus is a potent immunosuppressive medication that acts by inhibiting T-cell proliferation. It has been used in kidney transplantation because of its lack of nephrotoxicity. It is now being investigated in liver transplantation, but there are concerns about safety and long-term side effects such as dyslipidaemia. Hypertriglyceridaemia is a common adverse event seen with sirolimus use, and often does not respond to dose reduction or anti-lipemic drugs. Method : We report six patients who have developed significant hyperlipidaemia while receiving sirolimus, in spite of therapeutic trough levels. Conclusion : All six patients showed either resolution or improvement in lipid levels with discontinuation of sirolimus.

Recurrent hepatitis C infection is an important cause of progressive fibrosis, cirrhosis, and graft loss following orthotopic liver transplantation. Treatment for posttransplant recurrence of hepatitis C with interferon-based therapy is difficult but results in loss of detectable virus in up to 30% of patients. However, the durability of viral clearance and the associated histologic response in this setting is unknown. The aim of this study was to determine whether viral loss in response to antiviral therapy is durable and associated with improvement in liver histology. All liver transplant recipients who received interferon-based treatment for recurrent hepatitis C virus (HCV) at the University of Florida from 1991 to 2002 were included in this study. Patients who lost detectable HCV after treatment with interferon alone or in combination with ribavirin were followed to assess the durability of viral response and its impact on liver histology. One hundred nineteen transplant recipients were treated with interferon or combination therapy. Twenty-nine (20 men, 9 women; mean age, 54 yrs [range, 42-74 yrs]) lost detectable HCV RNA and remained virus negative for at least 6 months after discontinuing therapy (sustained viral response[SVR]). The mean follow-up after discontinuing therapy was 24.7 months (range, 6-70 mos). Our study cohort included one patient with SVR following interferon monotherapy and 28 patients with SVR following combination therapy with interferon plus ribavirin. All patients remained HCV RNA negative (assessed by polymerase chain reaction or branched-DNA assay) during follow-up of up to 5 years. Liver histology assessed 2 years after treatment showed less inflammation compared with before treatment in 50% and showed no change in 38%. By 3 to 5 years post-treatment (n = 15 recipients), inflammation was reduced in 60% and remained unchanged in 33%. Fibrosis stage at 2 years improved by > or = 1 stage in 27 %, remained unchanged in 38 %, and worsened in 35% despite viral clearance. At 3 to 5 years, the fibrosis stage had improved in 67%, remained unchanged in 13%, and worsened in 20%. Both grade of inflammation and fibrosis stage improved by 3 to 5 years posttreatment compared with baseline histology (p < 0.05). In conclusion, loss of HCV after treatment of recurrent chronic hepatitis C with interferon and ribavirin is durable, and the durability of the SVR is associated with improvement in hepatic inflammation and regression of fibrosis.

Determinants of progression to cirrhosis in hepatitis C virus (HCV) infection have been well described in the immunocompetent population but remain poorly defined in liver transplant (LT) recipients. This cohort study determines the factors contributing to the development of fibrosis and its rate of progression in the allograft. Predictive factors analyzed include: demographics, host and donor factors, surgery-related variables (cold and warm ischemia time), rejection episodes, cytomegalovirus infection (CMV), and immunosuppression. Over 12 years, 842 adult LTs were performed at our institution; 358 for the indication of HCV. A total of 264 patients underwent protocol liver biopsies at month 4 and yearly after LT. Using the modified Knodell system of Ishak for staging fibrosis, the median fibrosis progression rate was .8 units/year (P.001). Rapid fibrosis progression (.8 units/year) was best identified by liver histology performed at 1 year. Donor age55 years was associated with rapid fibrosis progression and development of cirrhosis (P.001). In contrast, donor age35 years was associated with slower progression of fibrosis (P = .003). Risk factors for graft loss due to recurrent HCV included recipient age35 years (P = .01), donor age55 years (P = .005), and use of female donor allografts (P = .03). In conclusion, fibrosis progression in HCV-infected LT recipients occurs at a rate of .8 units/year. Increased donor age has a major impact on disease progression, graft failure, and patient survival. A liver biopsy performed at 1 year posttransplant can help identify those patients more likely to develop progressive disease and may allow better targeting of antiviral therapy.

Recurrent hepatitis C virus (HCV) infection is an important cause of fibrosis and cirrhosis after liver transplantation (LT), with histological recurrence developing in at least 50% of patients within the first year. The aim of this study is to assess the safety and efficacy of interferon alfa-2b plus ribavirin in treating histological recurrent HCV after LT. Since 1998, patients with HCV with significant histological recurrence (fibrosis ≥ 3 and/or histological activity index ≥ 5) or progressive cholestatic disease after LT were treated with interferon alfa-2b (3 million units subcutaneously three times weekly) plus ribavirin (800 to 1,000 mg/d) for 12 months. Immunosuppression was tapered to cyclosporine/FK506 monotherapy. HCV RNA was assessed at entry, week 24, end of treatment, and 6 months after therapy. The primary end point was loss of HCV RNA 6 months after therapy, whereas the secondary end point was histological response. Fifty-four patients met criteria for treatment and have completed follow-up. Patients were mainly men (71% men; mean age, 51 ± 5 years) with genotype 1 infection (88%) and high viral load (mean HCV RNA, 38 ± 9 mEq/mL). Dose modification was required in 72% of patients because of cytopenia or side effects. Intent-to-treat analysis showed that serum HCV RNA was undetectable in 19 patients (35%) week 24, 21 patients (38%) week 48, and 16 patients (30%) at the 6-month follow-up. Paired liver biopsy results (before and within 6 months after treatment) were available for 35 patients. Patients who achieved viral eradication had no significant progression of fibrosis after 1 year of therapy. In summary, combination therapy is a reasonable antiviral option for recurrent HCV infection for established post-LT hepatitis and appears to prevent histological progression of disease if viral eradication is successful. (Liver Transpl 2002;8:1000-1006.)