mycophenolic-acid and Liver-Diseases

Autoimmune liver disease (ALD) is a chronic liver disease caused by immune dysfunction in the body. However, no causative or curative medical treatment with proven efficacy exists to cure ALDs, and liver transplantation (LT) remains the only effective treatment available. However, the problem of recurrence of ALDs (rALDs) still remains after LT, which seriously affects the survival rate of the patients. Therefore, clinicians need to be aware of the risk factors affecting rALDs after LT. Therefore, this meta-analysis aims to define the risk factors for rALDs, which include the recurrence of primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune hepatitis.. A systematic search in Pubmed, Embase, Cochrane library and Web of Science databases was performed from 1980 to 2019. The inclusion criteria were risk factors for developing rALDs after LT. However, case series, case reports, reviews, meta-analysis and studies only including human immunodeficiency virus cases, children, and pregnant patients were excluded.. The electronic database search yielded 1728 results. Sixty-three retrospective cohort studies met the inclusion criteria and 13 were included in the meta-analysis. The final cohort included 5077 patients, and among them, 21.96% developed rALDs. Colectomy before LT, HR 0.59 (95% confidence interval [CI]: 0.37-0.96), cholangiocarcinoma, HR 3.42 (95% CI: 1.88-6.21), multiple episodes of acute cellular rejection, HR 2.07 (95% CI: 1.27-3.37), model for end-stage liver disease score, HR 1.05 (95% CI: 1.02-1.08), use of mycophenolate mofetil, HR 1.46 (95% CI: 1.00-2.12) and the use of cyclosporin A, HR 0.69 (95% CI: 0.49-0.97) were associated with the risk of rprimary sclerosing cholangitis. In addition, the use of tacrolimus, HR 1.73 (95% CI: 1.00-2.99) and cyclosporin A, HR 0.59 (95% CI: 0.39-0.88) were associated with the risk of rALD.. Multiple risk factors for rALDs were identified, such as colectomy before LT, cholangiocacinoma, multiple episodes of acute cellular rejection, model for end-stage liver disease score, and especially the use of mycophenolate mofetil, cyclosporin A and tacrolimus.

Topics: Adult; Calcineurin Inhibitors; Cholangiocarcinoma; Cholangitis, Sclerosing; Colectomy; Cyclosporine; End Stage Liver Disease; Enzyme Inhibitors; Female; Graft Rejection; Hepatitis, Autoimmune; Humans; Liver Cirrhosis, Biliary; Liver Diseases; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Recurrence; Retrospective Studies; Risk Factors; Survival Rate; Tacrolimus

Despite advances in therapeutic and preventive measures, hematopoietic stem cell transplant recipients remain at risk for a variety of gastrointestinal and liver complications.. To detail the pathologic features of the various gastrointestinal and liver complications occurring after hematopoietic stem cell transplantation in relation to their clinical context. The specific complications covered include graft-versus-host disease, mycophenolate mofetil-induced injury, timeline of infections, neutropenic enterocolitis, gastrointestinal thrombotic microangiopathy, sinusoidal obstruction syndrome, hepatic iron overload, and the controversy around cord colitis syndrome.. The content of this article is based on pertinent peer-reviewed articles in PubMed, relevant textbooks, and on the authors' personal experiences.. The final histopathologic diagnosis requires the integration of clinical and histologic findings and the exclusion of other competing causes of injury. Review of the clinical data, including the original disease pretransplant, the type of transplant, the timing of the gastrointestinal and/or liver manifestations, the timing of the biopsy after transplant, the presence of graft-versus-host disease in other organs and sites, the list of drug regimens, and the clinical and laboratory evidence of infection, is the key to reaching the proper histologic diagnosis.

Topics: Biopsy; Colitis; Enterocolitis, Neutropenic; Gastrointestinal Diseases; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Immunosuppressive Agents; Infections; Liver Diseases; Mucous Membrane; Mycophenolic Acid; Thrombotic Microangiopathies

IgG4-related disease (IgG4-RD) is a newly recognized autoimmune systemic disorder characterized by elevated levels of serum IgG4 and abundant infiltration of IgG4-positive plasmacytes in the affected organs. The liver, biliary system and pancreas are the most commonly affected organs. However, involvement of the digestive tract is very rare. To date, only a few cases of isolated gastric IgG4-RD have been reported.. We present a case of IgG4-RD of the liver, gallbladder, pancreas and duodenum, which was clinically misinterpreted and thereafter over-treated. A 52-year-old male presented with obstructive jaundice for 3 years, melena for 5 months and hematemesis for 10 days. Three years prior, the patient had undergone biopsies of pancreatic lesions, liver lesions, cholecystectomy and choledochojejunostomy. Histopathology showed chronic inflammatory changes. Endoscopy at admission revealed a duodenal ulcer with active bleeding. Despite medical management, the patient presented with repeated gastrointestinal bleeding. Upon evaluation, serum IgG4 levels were found to be elevated. Histopathology of the duodenal ulcer biopsy and repeated examination of the gallbladder and pancreatic and liver biopsies confirmed IgG4 positive plasma cell infiltration. A definitive diagnosis of IgG4-RD was made and steroid administration was initiated. At last follow up, 11 months to-the-day after initiating steroid treatment, the patient was asymptomatic.. Notably, IgG4-RD of multiple digestive organs is still very rare. As a systemic disease, it is characterized by the infiltration of IgG4-bearing plasma cells and raised IgG4 levels. Histopathology findings remain the diagnostic gold standard for this disorder.

Topics: Anti-Inflammatory Agents; Autoimmune Diseases; Diagnostic Errors; Digestive System Diseases; Duodenal Diseases; Gallbladder Diseases; Gastrointestinal Hemorrhage; Glucocorticoids; Humans; Immunoglobulin G; Liver Diseases; Male; Middle Aged; Mycophenolic Acid; Pancreatic Diseases; Prednisolone; Prednisone; Recurrence

The development of immunosuppression has significantly affected the development of liver transplantation and has helped to switch from the experimental method to a standard treatment of life threatening liver conditions. Tacrolimus is the basic immunosuppressant for patients after a liver transplant and thanks to its prolonged-release dosage form, which due to its simplicity and reliability of use, replaces tacrolimus twice daily early after the transplant and in the longterm administration, will apparently, for a while, defend its position. Other widely used medicines include mycophenolic acid and mTOR inhibitors, sirolimus and everolimus. The induction with antilymphocyte antibodies is used in less than 10% of liver recipients. Only a few new immunosuppresants in this century have passed later stages of clinical studies; the last 2 medicines registered for patients after liver transplantation include Advagraf (Astellas) and Certican (Novartis). Personalised immunosuppression should respect at least the following basic clinical situations: recipients renal function, hepatitis C virus infection, and hepatocellular carcinoma as the liver transplant indication. The results of immunotolerance bio-marker research are necessary for a more successful conduct of protocols minimising immunosuppression and leading to immunotolerance, especially under the efforts of complete withdrawal of immunosupression.

Topics: Antilymphocyte Serum; Carcinoma, Hepatocellular; Everolimus; Graft Rejection; Humans; Immunosuppressive Agents; Liver Diseases; Liver Failure; Liver Neoplasms; Liver Transplantation; Mycophenolic Acid; Reproducibility of Results; Sirolimus; Tacrolimus

The purpose of this review is to evaluate the historical and recent literature as it pertains to current immunosuppression regimens in hepatitis C virus (HCV)-positive (+) liver-transplant recipients.. Recent findings suggest that there are unique differences between HCV transplant recipients and non-HCV transplant recipients, not only in the graft's inflammatory response, but also to the treatments used to prevent and combat rejection.. HCV (+) transplant recipients present unique challenges. Over the years, there has been progress but there is clearly no consensus regarding the optimal immunosuppressive medications or drug regimens; however, there continues to be advancements in the management of patients with HCV. Though current studies do not provide clear evidence as to optimal immunosuppression, they do identify questions ideally addressed by large, randomized controlled trials.

Topics: Adrenal Cortex Hormones; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antilymphocyte Serum; Azathioprine; Basiliximab; Calcineurin Inhibitors; Clinical Trials as Topic; Cyclosporine; Daclizumab; Everolimus; Hepatitis C; Humans; Immunoglobulin G; Immunosuppression Therapy; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Mycophenolic Acid; Receptors, Interleukin-2; Recombinant Fusion Proteins; Sirolimus; Tacrolimus; TOR Serine-Threonine Kinases

Autoimmune Hepatitis (AIH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and overlap syndromes of these three disease entities are regarded as autoimmune liver diseases. These conditions are important differential diagnoses of elevated liver function tests as about 10 % of liver transplantations in Europe and North America are for these indications. The diagnosis is often difficult but can be facilitated by sequential measurement of relevant autoantibodies, exclusion of other liver disease, ultrasound, ERCP and liver histology. In AIH immunosuppressive therapy has been shown to prevent or stop the development of cirrhosis and improve the prognosis of the patients decisively. In other autoimmune liver diseases this evidence is missing making individual therapeutic decisions necessary. Ursodesoxycholic acid (UDCA) seems to slow disease progression in particular in early stages of PBC.

Topics: Adult; Autoantibodies; Autoimmune Diseases; Azathioprine; Biopsy; Child; Cholagogues and Choleretics; Cholangiopancreatography, Endoscopic Retrograde; Cholangitis, Sclerosing; Diagnosis, Differential; Enzyme-Linked Immunosorbent Assay; Female; Hepatitis, Autoimmune; Humans; Immunoassay; Immunosuppression Therapy; Immunosuppressive Agents; Liver; Liver Cirrhosis, Biliary; Liver Diseases; Liver Function Tests; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Prognosis; Ultrasonography; Ursodeoxycholic Acid

The aim of this study was to evaluate the impact of a steroid-free regimen with tacrolimus and mycophenolate mofetil (modified therapy) vs. a standard regimen of tacrolimus and steroids on the cardiovascular risk score of liver transplant recipients. Patients who received a liver transplant were randomized to a modified therapy (n = 58) or a standard regimen (n = 59). Both groups were balanced at baseline, except for a higher prevalence of diabetes mellitus (DM) (p < 0.01) and a higher serum creatinine concentration (p < 0.05) in the modified therapy group. After 12 months, the prevalence of new-onset DM, arterial hypertension, hypercholesterolemia, hypertriglyceridemia, and changes in cardiovascular risk factors was similar in both groups. The increase in serum creatinine (mg/dL) compared to baseline at one yr post-transplantation was numerically lower in the modified therapy group (0.22 ± 0.42) than in the standard regimen group (0.41 ± 0.67) (p = 0.068). Although estimated cardiovascular risk score did not vary significantly compared to baseline in either group, there was a slight reduction in the modified regimen (-0.27 ± 2.87) vs. a mild increase (0.17 ± 2.94) in the standard regimen (p = 0.566). In conclusion, a steroid-free regimen with tacrolimus and mycophenolate mofetil was associated with a trend toward better preservation of kidney function and reduction of cardiovascular risk score.

Topics: Adolescent; Adult; Aged; Cardiovascular Diseases; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prognosis; Prospective Studies; Risk Factors; Steroids; Tacrolimus; Young Adult

In the setting of liver transplantation, mycophenolate mofetil (MMF) may be used as an adjuvant therapy for immunosuppression to prevent graft rejection; however, its use may be limited due to severe gastrointestinal (GI) side effects. In contrast, enteric-coated mycophenolate sodium (EC-MPS) may be associated with less severe side effects and hence better tolerability. We compared the side effects of EC-MPS to MMF in liver transplant patients in a de novo study (Study I-randomized, prospective, double-blinded) and a conversion study (Study II). In both studies, the severity of GI symptoms was assessed at various time points using the Gastrointestinal Symptoms Rating Scale (GSRS) survey, a validated survey of GI symptoms (abdominal pain, reflux, indigestion, diarrhea, and constipation). In Study I, the symptoms of 30 recipients receiving EC-MPS (n = 15) were compared to 15 recipients receiving MMF. A multivariate analysis of variance (MANOVA) of the total GSRS scores and symptom syndrome subscores revealed no significant difference (p > 0.05) between the two medications over time. A conversion study (Study II) with 29 participants, however, showed that over time, all GI symptoms improved significantly (p < 0.001) when the patients were treated with EC-MPS instead of MMF.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Double-Blind Method; Female; Follow-Up Studies; Gastrointestinal Diseases; Graft Rejection; Humans; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Prognosis; Prospective Studies; Quality of Life; Risk Factors; Surveys and Questionnaires; Tablets, Enteric-Coated; Transplant Recipients; Young Adult

The pharmacokinetics of the immunosuppressant mycophenolic acid (MPA) demonstrates high inter- and intra-patient variability. Variation in the binding of MPA to albumin has been postulated to be an important factor in this variability, and monitoring of free MPA has been suggested to improve therapeutic drug monitoring (TDM) of MPA. Inosine monophosphate dehydrogenase (IMPDH) is the target enzyme for MPA, therefore the IMPDH activity in lymphocytes can serve as a marker of the MPA-specific response. This study aimed to explore how the albumin concentration influences the free concentration of MPA in liver transplant recipients and to assess whether alteration in the free MPA influences IMPDH activity in CD4 + cells.. Blood samples were taken from 20 liver transplant recipients on two separate occasions (days 3-5 and 16-21). Total and free concentrations of MPA, and IMPDH activity were measured during the first 4 h of each dose interval.. Albumin levels correlated with the free fraction of MPA. However, the total MPA and free MPA were equal predictors of the immunosuppressive response as defined by IMPDH activity.. Total and free MPA are equally good predictors of the immunosuppressive effect exerted by MPA as defined by IMPDH activity. IMPDH activity measurements represent a promising approach to TDM in patients treated with MPA.

Topics: Adult; Aged; CD4-Positive T-Lymphocytes; Female; Graft Rejection; Humans; Immunosuppressive Agents; IMP Dehydrogenase; Liver Diseases; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Young Adult

Calcineurin inhibitor-induced renal dysfunction is a major problem in liver transplantation. Interleukin-2 receptor antagonist induction followed by delayed tacrolimus (Tac) administration may minimize the renal insult without compromising immunoprotection.. This open, randomized, multicenter trial evaluated the benefit of daclizumab induction with delayed Tac on renal function at 6 months; an observational study was continued for 18 months. Liver transplant patients with a 12-hr serum creatinine (SrC) level less than 180 micromol/L received either delayed Tac with daclizumab induction (n=98) or standard Tac (n=101) both combined with mycophenolate mofetil and steroids. The primary endpoint was the incidence of SrC level more than 130 micrommol/L at 6 months.. The incidence was 22.4% with delayed Tac and 29.7% with standard Tac (P=ns), which remained unchanged at 12 months (21.6% and 23.9%) but increasing slightly at 24 months (29.0% and 32.9%), respectively. A post hoc analysis of renal function was done based on patients stratification by SrC at 12 hr (100 micromol/L) showing no difference in SrC values at 6 months regardless of the 12-hr values despite a trend toward better estimated glomerular filtration rate for patients with 12-hr value less than 100 micromol/L in the delayed Tac group. Biopsy-proven acute rejection was similar at 6 months (17.5% and 18.75%), 12 months (23.5% and 23.8%), and 24 months (24.5% and 25.7%), respectively. Patient and graft survival in both groups were comparable and good. Similar types and incidences of adverse events were reported in both groups at all time.. Delay of Tac does not benefit renal function in liver transplant recipients with a good renal function at baseline.

Topics: Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Creatinine; Daclizumab; Female; Humans; Immunoglobulin G; Immunosuppressive Agents; Incidence; Liver; Liver Diseases; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Steroids; Tacrolimus; Time Factors

We report a multicenter, prospective, randomized, open-label trial investigating the effect of lower levels and delayed introduction of tacrolimus on renal function in liver transplant recipients. Adult patients with good renal function undergoing primary liver transplant were randomized to either: group A (standard-dose tacrolimus [target trough levels >10 ng/mL] and corticosteroids; n = 183); group B (mycophenolate mofetil [MMF] 2g/day, reduced-dose tacrolimus [target trough levels

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Daclizumab; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunoglobulin G; Immunosuppressive Agents; Kidney; Kidney Function Tests; Liver Diseases; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Prodrugs; Prospective Studies; Tacrolimus; Treatment Outcome; Young Adult

The exposure of mycophenolic acid in live donor liver transplant patients (those receiving a partial hepatic volume) in comparison to deceased donor liver transplant patients (those receiving the whole hepatic volume) after administration of mycophenolate mofetil has not been reported earlier. The aim of the present study is to compare the pharmacokinetics parameters of mycophenolic acid and mycophenolic acid glucuronide in live donor liver transplant patients versus deceased donor liver transplant patients. Twelve live donor liver transplant and 12 deceased donor liver transplant recipients were studied over a dosing interval after intravenous administration of mycophenolate mofetil. The maximum concentration (Cmax) and the area under the plasma concentration versus time curve (AUC) for mycophenolic acid in live donor liver transplant patients were significantly higher than in deceased donor liver transplant patients (Cmax/AUC: live donor liver transplant patients: 16.1 +/- 6.6 microg/mL/43.9 +/- 12.6 microg/mL.h vs deceased donor liver transplant patients: 10.7 +/- 2.0 microg/mL/28.9 +/- 7.1 microg/mL.h; P = .046/.002). The volume of distribution was higher in the deceased donor liver transplant patients compared with live donor liver transplant patients. However, the mean plasma concentration at 12 hours (Clast), drug disposition rate constant, half-life (t 1/2), and mean residence time were similar in both groups. The mean plasma concentration of mycophenolic acid glucuronide was 1.4 to 2.0 times higher in deceased donor liver transplant patients compared with live donor liver transplant patients. These observations point to the need to use a lower dosage (approximately 30%) of mycophenolate mofetil in live donor liver transplant patients compared with deceased donor liver transplant patients.

Topics: Area Under Curve; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Glucuronides; Humans; Immunosuppressive Agents; Injections, Intravenous; Liver Diseases; Liver Transplantation; Living Donors; Male; Metabolic Clearance Rate; Middle Aged; Mycophenolic Acid; Postoperative Period; Prospective Studies; Tissue Donors

Preliminary studies suggest preemptive anti-HCV therapy in liver transplant recipients may enhance the rates of viral clearance, but the applicability and tolerability of preemptive therapy has not been evaluated in a contemporary cohort. In this randomized study, the safety and tolerability of preemptive standard (IFN) or pegylated (peg-IFN) interferon alfa-2b (3 MU thrice weekly or 1.5 microg/kg weekly), or IFN/peg-IFN plus ribavirin (600 mg increased to 1.0-1.2 g daily) was initiated 2-6 weeks post-transplantation and continued for a total of 48 weeks. Only 51 (41%) of 124 transplant recipients were eligible for preemptive treatment; eligible patients had lower model for end-stage liver disease (MELD) and Childs-Pugh scores pre-transplantation and were more frequently live donor transplant recipients than ineligible patients. Dose reductions and discontinuations were required in 85% and 37% of patients, respectively, and 27% experienced serious adverse events. Growth factor (GF) use (erythropoietin and GCSF) in the latter half of the study did not significantly affect the frequency of dose reductions. Only 15% of patients were able to achieve full-dose treatment during treatment. End-of-treatment and sustained virological responses were 13.6% and 9.1%, respectively, with most responders in the combination therapy group. We conclude that preemptive antiviral therapy is applicable to only a portion of transplant recipients, with 'sicker' patients less likely to be managed by this approach. Living donor liver transplant recipients were more frequently eligible for treatment than deceased donor recipients. Virological response rates are low, likely related to the poor tolerability of therapy and the lack of achievement of target drug doses. Future studies should focus on alternative dosing schedules with more aggressive use of adjuvant therapies, including GFs.

Topics: Adult; Aged; Antiviral Agents; Biopsy; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Growth Substances; Hepatitis C; Humans; Immunocompromised Host; Immunosuppressive Agents; Interferon alpha-2; Interferon-alpha; Interferons; Liver; Liver Diseases; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Polyethylene Glycols; Prednisone; Recombinant Proteins; Ribavirin; Tacrolimus; Time Factors

A prospective evaluation was performed to study the potential benefits of the use of interleukin-2 receptor antibody (IL-2Rab) in the induction therapy with early elimination of steroid and reduction of tacrolimus dosage in liver transplant recipients among whom 94% had chronic hepatitis B infection. Thirty-one liver transplant recipients who underwent right-lobe live donor (n = 19) or cadaveric (n = 12) liver transplantation received IL-2Rab, basiliximab 20 mg intravenously within 6 hours of graft reperfusion and on postoperative day 4 (IL-2ab group). Two doses of steroid injection were given intraoperatively and on postoperative day 1. Postoperative immunosuppression was maintained with oral tacrolimus and mycophenolate mofetil without the use of steroids. The operative outcomes were compared with those of 49 patients who received standard immunosuppressive regimen consisting of tacrolimus and corticosteroid (steroid group). The overall postoperative morbidity and hospital stay were comparable between the 2 groups. There were significantly lower incidences of postoperative new-onset diabetes (0% vs 28%, P =.011), acute cellular rejection (6% vs 27%, P =.038), and cytomegalovirus (CMV) antigenemia (0% vs 18%, P =.011) in the IL-2Rab group compared with the steroid group. The blood cholesterol level at 6 months after transplantation was significantly lower in the IL-2Rab group (median, 4.0 vs 4.4 mmol/L, P =.007). On follow-up, none of the patients in the IL-2Rab group had hepatitis B viral breakthrough or hepatocellular carcinoma (HCC) recurrence, whereas 1 and 3 patients in the steroid group developed these complications, respectively. In conclusion, treatment of liver transplant recipients with IL-2Rab with early withdrawal of steroids and reduction of tacrolimus dosage is associated with lower incidences of postoperative new-onset diabetes, acute cellular rejection, and CMV antigenemia, as well as a lower serum cholesterol level. Further studies and long-term follow-up are required to document their potential benefits on hepatitis B and HCC recurrences.

Topics: Adrenal Cortex Hormones; Adult; Antibodies, Monoclonal; Antigens, Viral; Basiliximab; Cytomegalovirus; Diabetes Mellitus; Dose-Response Relationship, Drug; Female; Graft Rejection; Hepatitis B, Chronic; Humans; Immunosuppressive Agents; Incidence; Injections, Intravenous; Liver Diseases; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Receptors, Interleukin-2; Recombinant Fusion Proteins; Tacrolimus

The therapeutic options currently available for treating refractory graft-vs.-host disease (GVHD) are limited. Therefore, the present study evaluated the efficacy of mycophenolate mofetil (MMF) as a salvage treatment for acute and chronic GVHD in allograft patients.. Twenty-six consecutive patients with refractory acute (13 patients) or chronic (13 patients) GVHD were enrolled. The first-line treatment for all patients with acute GVHD consisted of a combination of cyclosporine A (CyA) and steroids, while the first-line treatment for chronic GVHD was steroids with or without CyA according to the risk group. MMF was added at a dose of 1.5 or 2 g daily and the steroids were tapered in the refractory cases.. Four (30.8%) of 13 patients with refractory acute GVHD responded to MMF. When analyzing the overall results according to the type of acute GVHD, improvement was observed in four (30.8%) of 13 skin cases, four (44.4%) of nine liver cases, and two (22.9%) of nine gut cases. Ten (76.9%) of 13 patients with refractory chronic GVHD responded to MMF. The common side effects were gastrointestinal disturbance (26.9%) or infectious complications (23.1%). The estimated 2-yr survival rate for patients with acute GVHD and chronic GVHD was 33.3% and 53.9%, respectively.. MMF would appear to be effective and safe for treating refractory chronic GVHD, yet not as effective for treating refractory acute gut GVHD. Accordingly, a prospective randomized clinical trial is warranted to assess the impact of MMF in the treatment of refractory GVHD.

Topics: Acute Disease; Adolescent; Adult; Bone Marrow Transplantation; Chronic Disease; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Liver Diseases; Lung Diseases; Male; Middle Aged; Mycophenolic Acid; Peripheral Blood Stem Cell Transplantation; Salvage Therapy; Skin Diseases; Stem Cell Transplantation; Time Factors; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome

The pharmacokinetics of mycophenolic acid (MPA) was studied after oral administration of mycophenolate mofetil (MMF) in 8 liver transplant patients. The mean (+/- SD) maximum MPA plasma concentration of 10.6 (+/- 7.5) mg/ml was achieved within 0.5 to 5 hours. The mean (+/- SD) steady-state area under the plasma concentration versus time curve (AUC(0-12)) was 40 (+/- 30.9) mg/ml/h. The mean (+/- SD) half-life was 5.8 (+/- 3.8) hours. There was poor correlation between trough blood concentrations of tacrolimus (r = -0.004) or serum creatinine (r = 0.689) with MPA AUC, while the serum bilirubin concentrations correlated (r = 0.743) well with MPA AUC, suggesting impairment in MPA conjugation in patients with liver dysfunction. The mean (+/- SD) ratio of the AUC of mycophenolic acid glucuronide (MPAG) to MPA was 64 (+/- 84), which correlated significantly with serum creatinine (r = 0.72) but not with serum bilirubin concentrations (r = 0.309), indicating accumulation of MPAG in patients with renal dysfunction. In 7 primary liver transplant patients on the same dose of MMF, the trough plasma concentrations of MPA during the first week of therapy ranged from < 0.3 to 1.5 microg/ml. The MPA concentrations increased by several folds during the next few weeks, which correlates well with increases in serum albumin concentrations. Changes in albumin appear to partially contribute to the variations in the pharmacokinetics of MPA in liver transplant patients.

Topics: Adult; Aged; Area Under Curve; Bile; Bilirubin; Chromatography, High Pressure Liquid; Creatinine; Drug Therapy, Combination; Enzyme Inhibitors; Female; Glucuronates; Glucuronides; Half-Life; Humans; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Prodrugs; Serum Albumin; Tacrolimus; Time Factors

Renal dysfunction is related to short- and long-term survival after liver transplantation. We present herein a retrospective analysis of our experience with liver transplantation in recipients with pretransplant renal dysfunction treated with induction therapy followed by delayed/reduced de novo once-daily tacrolimus.. Liver transplantations performed between April 2008 and August 2011 were included in this study. Pretransplant renal dysfunction was defined as estimated glomerular filtration rate <60 mL/min. Interleukin-2 receptor antagonists were used for induction therapy. Initial once-daily tacrolimus dose was 0.10 mg/kg/day or 0.07 mg/kg/day if combined with mycophenolate mofetil (MMF). Tacrolimus target trough levels were 4 to 6 ng/mL during the first post-transplant year and <4 ng/mL the rest of the follow-up.. Nineteen patients comprised the study cohort with a median follow-up of 56.4 months (range, 11-78). Median day of tacrolimus introduction was 7 (range, 3-12). Once-daily tacrolimus was withdrawn in 6 patients (31.6%) due to evolution of renal dysfunction in all cases. At 5 years, 30% of the patients were under MMF monotherapy. Mean tacrolimus trough levels were maintained under 5 ng/mL. Mean estimated glomerular filtration rate at 5 years was 55.3 ± 12.7 mL/min. No patient needed hemodialysis or renal transplantation over the follow-up. Patient survival at 5 years was 78.9%.. Induction therapy followed by delayed/reduced de novo once-daily tacrolimus and maintenance of low tacrolimus exposition during the follow-up is effective to maintain long-term renal function and to achieve favorable patient survival in liver transplant recipients with pretransplant renal dysfunction.

Topics: Aged; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Induction Chemotherapy; Kidney; Kidney Diseases; Liver Diseases; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Preoperative Period; Retrospective Studies; Tacrolimus; Treatment Outcome

Topics: Adult; Atrioventricular Block; Bone Marrow Transplantation; Bradycardia; Electrocardiography; Female; Graft vs Host Disease; Heart Block; Hemorrhage; Humans; Immunosuppressive Agents; Leukemia, Lymphocytic, Chronic, B-Cell; Liver Diseases; Lung Diseases; Methicillin-Resistant Staphylococcus aureus; Methylprednisolone; Mycophenolic Acid; Pneumonia, Staphylococcal; Skin Diseases; Tacrolimus; Transplantation, Homologous

Liver disease (LD), defined as ≥ 2-fold elevation of aspartate aminotransferase (AST) or alanine aminotransferase (ALT), was examined in a longitudinal study of systemic lupus erythematosus (SLE) patients. Among 435 patients, 90 (20.7%) had LD with a greater prevalence in males (15/39; 38.5%) than females (75/396; 18.9%; p = 0.01). SLE disease activity index (SLEDAI) was greater in LD patients (7.8 ± 0.7) relative to those without (5.8 ± 0.3; p = 0.0025). Anti-smooth muscle antibodies, anti-DNA antibodies, hypocomplementemia, proteinuria, leucopenia, thrombocytopenia, and anti-phospholipid syndrome were increased in LD. An absence of LD was noted in patients receiving rapamycin relative to azathioprine, cyclosporine A, or cyclophosphamide. An absence of LD was also noted in patients treated with N-acetylcysteine. LFTs were normalized and SLEDAI was diminished with increased prednisone use in 76/90 LD patients over 12.1 ± 2.6 months. Thus, LD is attributed to autoimmunity and disease activity, it responds to prednisone, and it is potentially preventable by rapamycin or N-acetylcysteine treatment.

Topics: Acetylcysteine; Adult; Alanine Transaminase; Antibodies, Antinuclear; Aspartate Aminotransferases; Azathioprine; Biomarkers; Cohort Studies; Complement System Proteins; Cyclosporine; Diabetes Mellitus; Female; Free Radical Scavengers; Humans; Immunosuppressive Agents; Liver Diseases; Longitudinal Studies; Lupus Erythematosus, Systemic; Male; Middle Aged; Mycophenolic Acid; Prednisone; Prevalence; Retrospective Studies; Severity of Illness Index; Sex Distribution; Sirolimus

Cost of post liver transplant immunosuppression is a major financial burden to patients in developing countries. In India, generic varieties of various immunosuppressants are often used without any definite evidence to their efficacy. This study was aimed at studying the dosage, side effect profile and cost of post-liver transplant immunosuppression using generic products in Indian population following living donor liver transplantation (LDLT).. Data on dose, cost, and toxicity of immunosuppression were retrieved retrospectively from case records of 59 patients who had undergone LDLT at our center.. Adequate immunosuppression was obtained by tacrolimus (Pangraf(®)-Panacea) of 0.04 to 0.05 mg/Kg, and mycophenolate (Mycept(®)-Panacea) of 500 to 1,000 mg; the acute rejection rate was 15% during the first month. Serum tacrolimus levels were 5.4 to 7.3 ng/mL. The cost of immunosuppression varied from Rs. 28,705 in the first month to Rs. 8,820 per month at the end of first year, amounting to an average monthly cost of Rs. 17,250. Approximately 23% and 51% of cost was for mycophenolate and for drug level measurement of tacrolimus, respectively.. Average cost of immunosuppression after LDLT in India is much lower than that reported elsewhere in the world, since lower drug doses are needed and cheaper generic drugs are available. This can be reduced further by decreasing the frequency of tacrolimus drug level measurement.

Topics: Health Care Costs; Humans; Immunosuppression Therapy; Immunosuppressive Agents; India; Liver Diseases; Liver Transplantation; Living Donors; Mycophenolic Acid; Retrospective Studies; Tacrolimus; Treatment Outcome

CD4+FOXP3+ regulatory T cells (Treg) depend on interleukin (IL)-2 for their function and survival. By interfering with the IL-2 production, calcineurin inhibitors (CNI) may negatively affect Treg. Here, we describe the effects of conversion from CNI to mycophenolate mofetil (MMF) monotherapy on renal function, and on Treg frequency and phenotype in liver transplant recipients.. Patients (n=16) with renal impairment on CNI were converted to MMF and received a single dose of IL-2-receptor blocking antibody (Daclizumab). Control patients (n=8) continued CNI treatment.. Renal function rapidly and significantly improved after conversion. Daclizumab treatment resulted in a 75% blocking of CD25 at 1 month causing a significant reduction in the percentage of CD4+CD25+ cells but not affecting the percentage of CD4+CD25+Foxp3+ cells. Six months after conversion to MMF, the percentage of CD4+CD25+Foxp3+ cells increased significantly by 125%. FOXP3 mRNA analysis of mononuclear cells confirmed the enrichment of Foxp3 in peripheral blood. Interestingly, the CD25 expression level on CD4+Foxp3+, but not CD4+Foxp3-, cells significantly increased compared with preconversion.. Conversion to MMF increases the percentage and CD25 expression of CD4+FOXP3+ cells indicating that MMF therapy can overturn the repressive effect of CNI on circulating Treg levels and therefore may promote Treg-mediated suppression of alloreactivity.

Topics: Aged; Antigens, CD; Blood Urea Nitrogen; Calcineurin; CD4 Antigens; Creatinine; Female; Follow-Up Studies; Forkhead Transcription Factors; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Interleukin-2 Receptor alpha Subunit; Kidney Function Tests; Liver Diseases; Liver Function Tests; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; T-Lymphocytes, Regulatory

Nephrotoxicity of calcineurin inhibitors (CNI) may exert detrimental effects, particularly in orthotopic liver transplantation (OLT) patients with impaired kidney function. Immunosuppression with daclizumab permits delayed introduction of CNI, and may be preferred for patients with kidney dysfunction. This retrospective analysis of our experience using daclizumab was performed among patients who underwent transplantation with impaired kidney function.. We analyzed 168 patients. A serum creatinine (Cr) level >1.5 mg/dL was the indication for a protocol with low-dose daclizumab (50 mg intravenous [IV], day 0 and day 4), mycophenolate mofetil (MMF; 500 mg twice daily IV/orally), and tapering doses of prednisolone from day 0 after OLT. CNI were introduced at day 4-15 after OLT. Patients with a Cr level <1.5 mg/dL received immunosuppression with CNI+MMF+steroids or CNI+steroids.. Fourteen patients fulfilled the criterion for daclizumab immunosupression. Their Cr and creatinine clearance (CrCl) values at OLT were 2.85 +/- 1.22 mg/dL and 19 +/- 11 mL/min, respectively. In the remaining 154 patients, Cr and CrCl results were 0.88 +/- 0.3 mg/dL and 107 +/- 82 mL/min, respectively. At discharge, the daclizumab group showed Cr and CrCl estimates of 0.97 +/- 0.45 mg/dL and 86 +/- 34 mL/min (P < .0001 for both, when compared with prior to OLT). Both Cr and CrCl levels at discharge were not different from those values of patients who underwent transplantation with normal kidney function. The incidence of acuterejection was 14% in the daclizumab group and 18% in the other recipients (P = not significant [NS]).. Immunosuppression with low-dose daclizumab and delayed introduction of CNI was safe and did not increase the risk of an acute rejection episode, thus offerring an excellent therapeutic option for patients who undergo transplantation with impaired kidney function.

Topics: Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Creatinine; Daclizumab; Female; Humans; Immunoglobulin G; Immunosuppressive Agents; Kidney Diseases; Length of Stay; Liver Diseases; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Prednisolone; Retrospective Studies

The enteric-coated mycophenolate sodium (EC-MPS) is a new formulation of mycophenolic acid with a gastro-resistant enteric coating, which releases the drug in the intestine, reducing the incidence of the gastrointestinal (GI) adverse effects. The present work provided a summary of 20 patients with liver transplantation and more than a 1 year of treatment with mycophenolate mofetil (MMF) who, after presentation of GI complications, were converted to EC-MPS. The patients were followed over a 3-month period after beginning EC-MPS treatment. The mean age of the cohort was 53 +/- 10 years and included 75% men. The reasons for transplantation were ethanol cirrhosis (70%), hepatitis C cirrhosis (30%), hepatocarcinoma (5%), and Wilson's disease (5%). At baseline, all patients were being treated with cyclosporine (CsA). CsA doses and levels were reduced during follow-up: baseline dose 179 mg/day versus 143 mg/day at 3 months; levels: 90.4 ng/mL versus 85.8 ng/mL, respectively (P = .017). The administered dose of EC-MPS was 720 mg/day in all cases. The GI complications at baseline were: diarrhea 60% (92% moderate-severe), abdominal discomfort 60% (58% moderate), abdominal pain 45% (44% moderate-severe), gas 40% (38% moderate-severe), nausea 20% (25% moderate), and dyspepsia 20% (mild). After 3 months of EC-MPS treatment, only two patients (10%) displayed moderate diarrhea. The renal evolution was favorable, serum creatinine was reduced, and 24-hour creatinine clearance significantly increased (creatinine: 1.78 +/- 1.6 mg/dL at baseline versus 1.30 +/- 0.3 mg/dL at 3 months, P = .002; creatinine clearance: 72.8 +/- 18 mL/min versus 79.6 +/- 13 mL/min, P = .001). Conversion of MMF to EC-MPS in liver transplant recipients solved the GI tolerability problems and improved renal function during the first 3 months, probably due to the concomitant reduction of anticalcineurinic dose.

Topics: Adult; Aged; Cyclosporine; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Gastrointestinal Diseases; Graft Survival; Humans; Immunosuppressive Agents; Kidney; Liver Diseases; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Retrospective Studies

Rapamycin (Rapa), one of the newer immunosuppressants has been found to control and prevent autoimmune features in animal models. This is the first report describing the successful control of post-transplant autoimmune hepatitis (AIH) with Rapa. Post-transplant AIH is diagnosed in the presence of raised transaminases, elevated immunoglobulin G, presence of autoantibodies and histologic changes consistent with AIH on liver biopsy. It may represent a recurrence of the original AIH that led to transplantation or present as a de novo AIH after liver transplant. Post-transplant AIH has conventionally been treated with Prednisolone (Pred) and Azathioprine (AZA). In this report, tailoring of immunosuppression after diagnosis of post-transplant AIH is described with special emphasis on those treated successfully with Rapa. Fifteen of 21 patients responded to treatment with an increase in dose of Pred and addition of AZA or Mycophenolate Mofetil (MMF) to calcineurin inhibitor. Five non-responders and one other patient with post-transplant AIH were treated with addition of Rapa. All six responded to treatment but drug was withdrawn in one patient. Adverse events were minimal. Rapa may prove to be an important addition in the control of autoimmune liver disease.

Topics: Autoantibodies; Azathioprine; Biopsy; Calcineurin Inhibitors; Child; Child, Preschool; Hepatitis, Autoimmune; Humans; Immunoglobulin G; Immunosuppressive Agents; Infant; Infant, Newborn; Liver; Liver Diseases; Male; Mycophenolic Acid; Postoperative Complications; Prednisolone; Sirolimus; Time Factors; Transaminases; Treatment Outcome

Cyclosporine A (CsA) and tacrolimus (Tac) provide effective immunosuppression after orthotopic liver transplantation (OLT) but can cause renal dysfunction that may progress to end-stage renal failure (ESRF). Mycophenolate mofetil (MMF) is a newer immunosuppressant that does not affect renal function. Its long-term use in children with renal dysfunction after OLT has not yet been fully evaluated.. A retrospective analysis was performed of all children begun on MMF for renal dysfunction and followed up for at least 1 year. Renal dysfunction was defined as calculated glomerular filtration rate (cGFR) of less than 65 mL/min/1.73 m2. cGFR and liver function were measured before and after transfer. Data were analyzed using the Wilcoxon signed rank test.. Forty-eight children (23 males) began MMF at a median age of 11.1 (0.9-18.1) years and at a median of 4.0 (0.3-12.4) years postOLT. Median baseline cGFR was 54 (range 29-65) mL/min/1.73 m2. Immunosuppression after transfer was MMF monotherapy in 36, MMF with steroids, in 4 and MMF with low-dose CsA or Tac in 8. In 44 (92%) patients, there was a statistically significant increase to a median cGFR of 69 (28-114) mL/min/1.73 m2 by 1 month and a further increase to a median cGFR of 77 (24-105) mL/min/1.73 m2 by 2 months of MMF treatment, after which time cGFR was maintained. Children aged less than 3 years at OLT or who were less than 5 years postOLT when MMF was begun demonstrated greater increases in cGFR. Four children with a median baseline cGFR of 34 (range 31-49) mL/min/1.73 m2 did not respond and progressed to ESRF. Mild side effects occurred in seven (15%) and gastrointestinal bleeding requiring discontinuation of MMF in one (2%). Liver function abnormalities occurred in seven (15%): transient transaminitis in three, acute rejection in two, and chronic rejection in two, of whom one required retransplantation.. In 92% children with renal dysfunction after OLT, MMF treatment provided safe and effective immunosuppression and allowed CsA or Tac to be discontinued or reduced, leading to improvement of renal function. The improvement was greatest in younger children and those who began MMF early postOLT. Side effects were uncommon. Additional steroid cover during the transfer to MMF should be considered to prevent liver-allograft rejection.

Topics: Adolescent; Child; Child, Preschool; Chromium; Creatinine; Cyclosporine; Female; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Infant; Liver Diseases; Liver Transplantation; Male; Metabolic Clearance Rate; Mycophenolic Acid; Postoperative Complications; Retrospective Studies; Treatment Outcome

To evaluate the impact of mycophenolate mofetil (MMF) on long-term outcomes of tacrolimus and corticosteroids, we analyzed data reported to the Scientific Registry of Transplant Recipients for 11,670 adult patients (3463 with hepatitis C [HCV]) who underwent primary, single-organ, liver transplantation between 1995 and 2001. Patients who were discharged from the hospital on tacrolimus-based immunosuppression with (n = 4466; n = 1323 HCV) or without MMF (n = 7204; n = 2140 HCV) were included in the analysis. Recipients treated at discharge with MMF, tacrolimus, and corticosteroids had significantly increased patient survival (81.0% vs. 77.0% at 4 years, P < 0.0001) and graft survival (76.4% vs. 72.9%, P < 0.0001), and lower rates of acute rejection (29.0% vs. 33.4%, P < 0.001) as compared to recipients treated at discharge with tacrolimus and corticosteroids alone. A trend toward lower rates of death from infection was observed (6.1% at 4 years for MMF vs. 7.1% at 4 years for tacrolimus and corticosteroids, P = 0.0508), but this result did not reach statistical significance. In multiple regression analyses, MMF triple therapy at discharge was associated with a reduced risk of death (hazard ratio [HR] = 0.77, P < 0.001), graft loss (HR = 0.81, P < 0.001), acute rejection (HR = 0.89, P = 0.002), and death from infectious complications (HR = 0.80, P = 0.007). Outcomes were similar for the cohort with HCV.In conclusion, the addition of MMF at discharge to tacrolimus-based immunosuppression is associated with improved long-term outcomes after liver transplantation in patients with and without HCV.

Topics: Adrenal Cortex Hormones; Adult; Aged; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Hepatitis C; Humans; Immunosuppressive Agents; Infections; Liver Diseases; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Care; Postoperative Complications; Recurrence; Registries; Survival Analysis; Tacrolimus; Treatment Outcome

Topics: Adult; Cord Blood Stem Cell Transplantation; Female; Humans; Immunosuppressive Agents; Kidney Diseases; Liver Diseases; Mycophenolic Acid; Sepsis; Transplantation, Homologous

To report our experience with mycophenolate mofetil (MMF) for induction and maintenance therapy to prevent acute liver transplant rejection.. A retrospective analysis of 66 elective, noncombined liver transplant patients treated beginning de novo MMF and follow for a minimum of 2 years. Thirty-nine of the 66 cases received MMF, calcineurin inhibitors, and steroids. In 11 cases daclizumab was added; in 16 daclizumab was added without steroids.. The global survival rate was 91% at 6 months, 89.4% at 1 year, and 87.9% after 2 years. Acute rejection episodes were observed in six patients (9.1%). All episodes responded to corticoids. Toxicity possibly, probably, or partially related to MMF was observed in 35 patients (53%) with definitive suspension required in 13 cases (20%), with dose reduction or temporary suspension in 22 (33%). Hematological toxicity associated with MMF was observed in 12 patients (18%), leading to definitive suspension in two patients (3.03%), temporary suspension in two cases (3.03%), and dose reduction in eight cases (12%). Opportunistic infection was observed in seven cases (10%). Gastrointestinal toxicity was mild and infrequent (five cases, 7.5%).. Regimens containing MMF reduce rejection episodes with high survival rates and low toxicity.

Topics: Adult; Aged; Follow-Up Studies; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Middle Aged; Mycophenolic Acid; Retrospective Studies; Safety; Survival Analysis; Time Factors

Topics: Adult; Bilirubin; Cholesterol; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Liver Diseases; Liver Function Tests; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Retrospective Studies; Tacrolimus; Treatment Outcome

Topics: Adult; Aged; Calcineurin Inhibitors; Cyclosporine; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney Diseases; Liver Diseases; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Portugal; Postoperative Complications; Retrospective Studies; Time Factors

The pathogenesis of hepatitis C virus (HCV) recurrence after liver transplantation (LT) is poorly understood, but the cellular immune response is likely to have a major role. Daclizumab, an interleukin-2 receptor (IL-2R) antibody that blunts T-cell activation, leading to a decreased risk for cellular rejection, is used frequently in transplant recipients. The aim of this study is to evaluate the effect of daclizumab therapy on the incidence and severity of recurrent HCV. Forty-one liver transplant recipients (21 patients, HCV positive; 20 patients, HCV negative) at high risk for neurological or renal complications of calcineurin inhibitors were administered daclizumab, mycophenolate mofetil (MMF), and steroids in the early post-LT period, followed by tacrolimus and a steroid taper. All patients were followed up prospectively for graft function and disease recurrence with protocol liver biopsies day 7, month 4, and yearly. Compared with patients without HCV, patients with HCV administered daclizumab had greater 4-month serum alkaline phosphatase, total bilirubin, and alanine aminotransferase (ALT) levels. These biochemical differences resolved by 12 months, except for persistent elevation of ALT levels. Compared with a well-matched HCV control population, patients with HCV administered daclizumab were more likely to have an earlier onset of hepatitis, jaundice, and greater histological activity. Recurrent hepatitis progressed more rapidly in the daclizumab group; 45% developed advanced disease within 1 year. HCV viral load in the daclizumab group was significantly greater at both 4 months and 1 year. Results of this study suggest that the use of adjuvant IL-2R antibodies in combination with MMF in the early peritransplantation period may be associated with early recurrence of hepatitis C and more rapid histological progression of disease.

Topics: Adult; Alanine Transaminase; Alkaline Phosphatase; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Bilirubin; Daclizumab; Drug Therapy, Combination; Female; Hepatitis C; Humans; Immunoglobulin G; Immunosuppressive Agents; Incidence; Liver Diseases; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Receptors, Interleukin-2; Recurrence; Severity of Illness Index; Viral Load