No abstract

Cyclosporine is an immunosuppressive agent widely used in the management of liver transplant recipients. Cyclosporine has been shown to have antiviral activities against HIV, herpes simplex, and vaccinia viruses. The aim of this study was to determine the effect of Cyclosporine in viral clearance in the liver transplant recipients during therapy with combination of interferon and ribavirin, and to determine the anti-viral potential of Cyclosporine in vitro. Immunosuppression consisted of either Cyclosporine or Tacrolimus-based therapy. Both groups received therapy with interferon and ribavirin for 48 weeks when evidence of progressive histologic disease was determined. We found that subjects on Cyclosporine-based immunosuppression (n ϭ 56) had a higher sustained virological response of 46% compared to 27% in the patients on Tacrolimus-based therapy (nϭ59, P ϭ 0.03). In vitro studies were performed to evaluate the antiviral effect of Cyclosporine in the replicon system. These studies showed that Cyclosporine inhibits hepatitis C viral replication in a dose-dependent manner. Combination of Cyclosporine with interferon showed additive effect, and its function is independent of interferon signaling pathways. In conclusion, Cyclosporine may offer an advantage to Tacrolimus in those patients undergoing interferon-based therapy and should be studied in a prospective randomized trial. Liver Transpl 12: 51-57, 2006.

Based on animal studies and pilot studies in humans, betaine, a methyl donor for the remethylation of homocysteine, may be a therapeutic agent for nonalcoholic steatohepatitis (NASH). We evaluated the safety and efficacy of betaine for patients with NASH and whether betaine positively modified factors postulated to be "second hits" and underlying mechanisms of NASH. We conducted a randomized placebo-control study of 55 patients with biopsy-proven NASH who received either oral betaine (20 g daily) or placebo for 12 months. Pre-and posttreatment variables were analyzed using the paired t test or Wilcoxon rank test. Treatment groups were comparable at baseline. Of the 35 patients (17 betaine, 18 placebo) who completed the study, 34 patients (16 betaine, 18 placebo) underwent posttreatment liver biopsy. Patients randomized to betaine had a decrease in steatosis grade. No intra-or intergroup differences or changes in nonalcoholic fatty liver disease activity score or fibrosis stage were noted. Elevations of insulin, glucose, and proinflammatory cytokines and the reduced antioxidant status noted in NASH patients did not improve with betaine therapy. The antiinflammatory agent adiponectin was significantly reduced in both groups and did not change with therapy. Lastly, S-adenosylhomocysteine was approximately twice normal and was not reduced by betaine therapy. Conclusion: Compared to placebo, betaine improved hepatic steatosis and may protect against worsening steatosis. High-dose betaine supplementation failed to reduce S-adenosylhomocysteine and did not positively affect any of the second hit mechanisms postulated to contribute to NASH that we studied. Although betaine has been proven effective in treating hepatic steatosis in several animal models, translating novel therapeutic options noted in animal studies to humans with NASH will prove challenging.

SUMMARY BackgroundNewer 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.

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 age > 55 years was associated with rapid fibrosis progression and development of cirrhosis (P < .001). In contrast, donor age < 35 years was associated with slower progression of fibrosis (P ‫؍‬ .003). Risk factors for graft loss due to recurrent HCV included recipient age > 35 years (P ‫؍‬ .01), donor age > 55 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.

An imbalance in Th1 and Th2 cytokine production is implicated in disease progression of HCV. Our aim was to determine the effect of IL-10 administration in patients with HCV-related liver disease. Thirty patients with advanced fibrosis who had failed antiviral therapy were enrolled in a 12-month treatment regimen with SQ IL-10 given daily or thrice weekly. Liver biopsies were performed before and after therapy. Serum and PBMC were collected for HCV RNA, ALT, and functional T-cell analysis. IL-10 led to significant improvement in serum ALT (mean ALT: day 0 = 142 +/- 17 vs. month 12 = 75 +/- 10; P <.05). Hepatic inflammation score decreased by at least 2 in 13 of 28 patients (mean decrease from 4.6 +/- 0.3 to 3.7 +/- 0.3, P <.05) and 11 of 28 showed a reduction in fibrosis score (mean change from 5.0 +/- 0.2 to 4.5 +/- 0.3, P <.05). Serum HCV RNA levels increased by 0.5 log during therapy (mean HCV RNA day 0: 12.3 +/- 3.0 Meq/mL; 12 months: 38 Meq/mL; P <.05) and returned to baseline at the end of follow-up (11.0 +/- 2.4 Meq/mL). Five patients developed viral loads of greater than 120 Meq/mL and two of these developed an acute flare in serum ALT. IL-10 caused a decrease in the number of HCV-specific CD4+ and CD8+ IFN-gamma secreting T cells and alterations in PBMC cytokine production towards a Th2 dominant profile. These changes parallel the improvement in ALT and rise in HCV RNA. In conclusion, long-term rIL-10 therapy appears to decrease disease activity, but also leads to increased HCV viral burden via alterations in immunologic viral surveillance.

No abstract

The primary aim of this study is to determine whether treatment with lamivudine improved pre-liver transplantation (pre-LT) and LT-free survival of patients awaiting LT for hepatitis B virus (HBV)-related cirrhosis. Data from 162 lamivudine-treated and 147 untreated transplant candidates managed at 20 North American transplant centers between 1996 and 1998 were collected and compared. Lamivudine-treated patients were more likely to be men, hepatitis B e antigen positive, HBV DNA positive, and have lower serum albumin levels at listing (P < .05). Actuarial pre-LT and LT-free survival were similar in lamivudine-treated and untreated patients. Using Cox regression analysis, the only significant predictor of pre-LT patient survival was the modified ChildTurcotte-Pugh (mCTP) score, whereas significant predictors of LT-free survival included ethnic background, lamivudine treatment, indication for LT, baseline serum alanine aminotransferase level, and baseline mCTP score. Lamivudine had no apparent effect on liver disease severity in patients undergoing LT, but appeared to improve disease severity in patients still awaiting LT. Breakthrough infection was noted in 11% of lamivudinetreated patients. We conclude that lamivudine therapy is not associated with improved pre-LT or LT-free survival in LT candidates with chronic hepatitis B. However, a subset of patients with less advanced liver failure may derive clinical benefit from lamivudine therapy, thus delaying the need for LT. In the absence of prospective, randomized, controlled trials of lamivudine in patients with decompensated cirrhosis, careful selection of patients and optimal timing of treatment are needed to balance the risk versus benefit of lamivudine therapy in LT candidates. (Liver Transpl 2002;8:433-439.)