tacrolimus and Hepatitis-C

To determine the risk factors for new-onset diabetes mellitus (NODM) after liver transplantation by conducting a systematic review and meta-analysis.. We electronically searched the databases of MEDLINE, EMBASE and the Cochrane Library from January 1980 to December 2013 to identify relevant studies reporting risk factors for NODM after liver transplantation. Two authors independently assessed the trials for inclusion and extracted the data. Discrepancies were resolved in consultation with a third reviewer. All statistical analyses were performed with the RevMan5.0 software (The Cochrane Collaboration, Oxford, United Kingdom). Pooled odds ratios (OR) or weighted mean differences (WMD) with 95% confidence intervals (CIs) were calculated using either a fixed effects or a random effects model, based on the presence (I (2) < 50%) or absence (I (2) > 50%) of significant heterogeneity.. Twenty studies with 4580 patients were included in the meta-analysis, all of which were retrospective. The meta-analysis identified the following significant risk factors: hepatitis C virus (HCV) infection (OR = 2.68; 95%CI: 1.92-3.72); a family history of diabetes (OR = 1.69, 95%CI: 1.09-2.63, P < 0.00001); male gender (OR = 1.53; 95%CI: 1.24-1.90; P < 0.0001); impaired fasting glucose (IFG; OR = 3.27; 95%CI: 1.84-5.81; P < 0.0001); a family history of diabetes (OR = 1.69; 95%CI: 1.09-2.63; P = 0.02); use of tacrolimus (OR = 1.34; 95%CI: 1.03-1.76; P = 0.03) and body mass index (BMI)(WMD = 1.19, 95%CI: 0.69-1.68, P < 0.00001). Other factors, such as hepatitis B virus infection and alcoholism, were not found to be associated with the incidence of NODM.. The study showed that HCV infection, IFG, a family history of diabetes, male gender, tacrolimus and BMI are risk factors for NODM after liver transplantation.

Topics: Body Mass Index; Chi-Square Distribution; Diabetes Mellitus; Female; Genetic Predisposition to Disease; Hepatitis C; Heredity; Humans; Immunosuppressive Agents; Incidence; Liver Transplantation; Male; Odds Ratio; Pedigree; Risk Assessment; Risk Factors; Sex Factors; Tacrolimus; Treatment Outcome

Most liver transplant recipients receive calcineurin inhibitors (CNIs), especially tacrolimus and cyclosporine, as immunosuppressant agents to prevent rejection. A controversy exists as to whether the outcomes of hepatitis C virus (HCV)-infected liver transplant patients differ based on the CNIs used. This meta-analysis compares the clinical outcomes of tacrolimus-based and cyclosporine-based immunosuppression, especially cases of HCV recurrence in liver transplant patients with end-stage liver disease caused by HCV infection.. Related articles were identified from the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, Medline, and Embase. Meta-analyses were performed for the results of homogeneous studies.. Nine randomized or quasi-randomized controlled trials were included. The total effect size of mortality (RR = 0.98, 95% CI: 0.77-1.25, P = 0.87) and graft loss (RR = 1.05, 95% CI: 0.83-1.33, P = 0.67) showed no significant difference between the two groups irrespective of duration of immunosuppressant therapy after liver transplantation. In addition, the HCV recurrence-induced mortality (RR = 1.11, 95% CI: 0.66-1.89, P = 0.69), graft loss (RR = 1.62, 95% CI: 0.64-4.07, P = 0.31) and retransplantation (RR = 1.40, 95% CI: 0.48-4.09, P = 0.54), as well as available biopsies, confirmed that histological HCV recurrences (RR =  0.92, 95% CI: 0.71-1.19, P = 0.51) were similar.. These results suggested no difference in posttransplant HCV recurrence-induced mortality, graft loss and retransplantation, as well as histological HCV recurrence in patients treated with tacrolimus-based and cyclosporine-based immunosuppresion.

Topics: Cyclosporine; Graft Rejection; Graft Survival; Hepacivirus; Hepatitis C; Humans; Immunosuppressive Agents; Liver Transplantation; Recurrence; Survival Rate; Tacrolimus

To assess the advantages and disadvantages of immunosuppression monotherapy after transplantation and the impact of monotherapy on hepatitis C virus (HCV) recurrence.. Articles from Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded, including non-English literature identified in these databases, were searched up to January 2013. We included randomized clinical trials comparing various immunosuppression monotherapy and prednisone-based immunosuppression combinations for liver transplantation. The modified Jadad scale score or the Oxford quality scoring system was used. Meta-analyses were performed with weighted random-effects models.. A total of 14 randomized articles including 1814 patients were identified. Eight trials including 1214 patients compared tacrolimus monotherapy (n = 610) vs tacrolimus plus steroids or triple therapy regarding acute rejection and adverse events (n = 604). Five trials, including 285 patients, compared tacrolimus monotherapy (n = 143) vs tacrolimus plus steroids or triple therapy regarding hepatitis C recurrence (n = 142). Four trials including 273 patients compared cyclosporine monotherapy (n = 148) vs cyclosporine and steroids regarding acute rejection and adverse events (n = 125). Two trials including 170 patients compared mycophenolate mofetil monotherapy (n = 86) vs combinations regarding acute rejection (n = 84). There were no significant differences in the acute rejection rates between tacrolimus monotherapy (RR = 1.04, P = 0.620), and cyclosporine monotherapy (RR = 0.89, P = 0.770). Mycophenolate mofetil monotherapy had a significant increase in the acute rejection rate (RR = 4.50, P = 0.027). Tacrolimus monotherapy had no significant effects on the recurrence of hepatitis C (RR = 1.03, P = 0.752). More cytomegalovirus infection (RR = 0.48, P = 0.000) and drug-related diabetes mellitus (RR = 0.54, P = 0.000) were observed in the immunosuppression combination therapy groups.. Tacrolimus and cyclosporine monotherapy may be as effective as immunosuppression combination therapy. Mycophenolate mofetil monotherapy was not considerable. Tacrolimus monotherapy does not increase recurrence of HCV.

Topics: Chi-Square Distribution; Cyclosporine; Drug Therapy, Combination; Graft Rejection; Graft Survival; Hepacivirus; Hepatitis C; Humans; Immunocompromised Host; Immunosuppressive Agents; Liver Transplantation; Mycophenolic Acid; Recurrence; Steroids; Tacrolimus; Time Factors; Treatment Outcome

Cyclosporine A (CSA), but not tacrolimus (TAC), inhibits hepatitis C virus (HCV) replication in vitro. Clinical reports on the efficacy of interferon-α (IFNα)-based antiviral therapy (AVT) for recurrent HCV after liver transplantation (LT) with CSA and TAC are conflicting. Our aim was to assess whether AVT for recurrent HCV after LT is more effective with CSA or TAC. We performed an electronic database search (1995-2012) and a manual abstract search (2005-2012). The a priori defined eligibility criteria included the use of AVT for recurrent HCV with IFN (standard or pegylated) and ribavirin and the reporting of sustained virological response (SVR) rates with CSA and TAC (the primary outcome). Two authors identified and extracted data independently. Dichotomous data were expressed as relative risks (RRs) and 95% confidence intervals (CIs) with a random effects model. In all, 5058 references were retrieved, and 1 randomized controlled trial (RCT) and 17 observational studies (13 full-text articles) met the eligibility criteria; the meta-analysis was based on the latter studies. The pooled SVR rates were 42% (395/945) with CSA and 35% (471/1364) with TAC (RR = 1.18, 95% CI = 1.00-1.39, P = 0.05). Although the pooled data contained significant heterogeneity (I(2) = 45%, P = 0.02), the SVR rates in the RCT were comparable (39% with CSA and 35% with TAC). Limiting the analysis to the 7 studies reporting on 40 or more patients in each group (with 1634 patients in all) favored CSA (RR = 1.23, 95% CI = 1.09-1.38, P < 0.001), and heterogeneity disappeared (I(2) = 0%, P = 0.62). In conclusion, IFN-based AVT for recurrent HCV after LT seems marginally more effective with CSA versus TAC; the study heterogeneity, however, limits firm conclusions.

Topics: Antiviral Agents; Cyclosporine; Female; Hepatitis C; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Tacrolimus

HCV related liver disease is the most common indication for liver transplantation. Recurrence of HCV infection is universal and has a substantial impact on patient and graft survival. Immunosuppression is a major factor responsible for the accelerated recurrence and compressed natural history of recurrent HCV infection. Accumulating experience has provided data to support certain strategies for immunosuppressive regimens. From the available evidence, more severe recurrence results from repeated bolus corticosteroid therapy and anti-lymphocyte antibodies used to treat rejection. Low dose and slow tapering of steroids are better than high dose maintenance and/or rapid tapering. Recent meta-analyses favour steroid-free regimens but these are complicated to interpret as the absence of steroids may simply represent less immunopotency. There is no difference in HCV recurrence between tacrolimus and cyclosporine regimens, but tacrolimus increases graft and patient survival in HCV transplanted patients. There may be a beneficial effect of maintenance azathioprine given for 6 months or longer. There is no conclusive evidence for benefit of mycophenolate and interleukin-2 receptor blockers. Few data are available for mTOR inhibitors. Better evidence is needed to establish the optimal immunosuppressive regimen for HCV recipients and more randomized trials should be performed.

Topics: Azathioprine; Cyclosporine; Graft Survival; Hepatitis C; Humans; Immunosuppressive Agents; Liver Transplantation; Recurrence; Tacrolimus

Calcineurin inhibitors (CNIs), such as cyclosporin A and tacrolimus, are the cornerstone of maintenance immunosuppressive regimens in liver transplantation. CNIs prevent rejection by inhibition of calcineurin, via which lymphocyte proliferation and interleukin (IL)-2 production is prevented. Tacrolimus is now the first-choice immunosuppressant after liver transplantation, since it is associated with fewer episodes of rejection than cyclosporin A. In this review we will discuss interindividual differences, which influence tacrolimus metabolism. Because of these factors and the narrow therapeutic index of tacrolimus, monitoring of drug trough levels is necessary. Furthermore, we will discuss studies concerning conversion from the tacrolimus twice daily to tacrolimus once daily formulation in stable LT patients. Due to adverse effects of CNIs, such as chronic renal failure, hypertension, de novo malignancy and new-onset diabetes mellitus, CNI minimization strategies have been developed, which will be discussed too.

Topics: Calcineurin Inhibitors; Cyclosporine; Diabetes Mellitus; Drug Administration Schedule; Drug Substitution; Graft Rejection; Hepatitis C; Humans; Hypertension; Immunosuppressive Agents; Kidney Failure, Chronic; Liver Transplantation; Tacrolimus; TOR Serine-Threonine Kinases

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

Diabetes mellitus continues to be a common metabolic complication after solid organ transplantation. The etiology is multifactorial and includes both modifiable and nonmodifiable factors. Immunosuppression may play a critical role in its development. Targets of treatment include oral hypoglycemics as well as insulin. More recently, several novel agents have been approved by the Food and Drug Administration for treatment of type 2 diabetes. There is limited experience with these agents in transplant recipients. Use of oral and subcutaneous therapies as well as insulin will be reviewed. As diabetes has a negative impact on patient and graft outcome, the transplant practitioner must be vigilant in screening and managing diabetes after transplantation.

Topics: Age Factors; Black or African American; Diabetes Mellitus; Hepatitis C; Humans; Hypoglycemic Agents; Immunosuppressive Agents; Insulin; Obesity; Organ Transplantation; Risk Factors; Tacrolimus

A controversy exists over whether the outcome of a hepatitis C virus (HCV)-infection-related liver transplant differs based on the calcineurin inhibitor (CNI) used. We have performed a systematic review and a subsequent meta-analysis evaluating tacrolimus (Tac)-based vs. cyclosporine A-based immunosuppression in HCV-infected liver transplant recipients. Searches were conducted to locate randomized controlled trials comparing Tac vs. cyclosporine A. Data on HCV liver transplant recipients were obtained, independently of whether the study was specifically designed for patients with this disease or not. A fixed effects model was used for statistical pooling of the relative risks (RR) for the different outcomes. A total of 5 articles (366 patients) fulfilled the inclusion criteria. Statistically significant differences between Tac-based vs. cyclosporine A-based therapies were not found for mortality (P = 0.11; RR = 0.72; 95% confidence interval [CI], 0.49-1.08), graft survival (P = 0.37; RR = 0.86; 95% CI, 0.61-1.21), biopsy-proven acute rejection (P = 0.65; RR = 0.91; 95% CI, 0.61-1.36), corticoresistant acute rejection (P = 0.26; RR = 2.25; 95% CI, 0.55-9.29), and fibrosing cholestatic hepatitis (P = 0.92; RR = 0.96; 95% CI, 0.41-2.26). In 1 study, no differences were detected regarding severe fibrosis at 1 yr. In conclusion, patient and graft survivals in HCV-positive liver transplant patients are similar independently of the CNI selected as basic immunosuppressant. Unfortunately, data on the severity of recurrence and effect on viremia are scarce. Well-designed randomized prospective studies are needed to determine whether there are differences between the 2 CNIs regarding these specific variables.

Topics: Biopsy; Calcineurin Inhibitors; Clinical Trials as Topic; Cyclosporine; Hepacivirus; Hepatitis C; Humans; Immunosuppressive Agents; Liver Failure; Liver Transplantation; Recurrence; Research Design; Risk; Tacrolimus; Treatment Outcome

Recent advances in immunosuppressive drug regimens have changed the outcome after liver transplantation significantly in the last two decades. However, chronic rejection and long-term graft survival remains a major problem. Side effects like drug-induced nephrotoxicity, hypertension, osteoporosis, hyperlipidaemia and neuropathy of some immunosuppressive agents play an essential role in long-term allograft and patient survival. This review outlines the current treatment of short- and long-term immunosuppression in liver transplanted patients, it summarizes the treatment of acute and chronic rejection, describes the complications and side effects of immunosuppressive therapy and points out the current use of immunosuppressive therapy in living-related liver transplantation.

Topics: Azathioprine; Calcineurin Inhibitors; Glucocorticoids; Graft Rejection; Hepatitis C; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Living Donors; Mycophenolic Acid; Sirolimus; Tacrolimus

Hepatitis C virus (HCV) reinfection is almost universal in patients transplanted for HCV-related cirrhosis. The medium-term survival after orthotopic liver transplantation (OLT) is similar to other transplanted patients, but the long-term survival remains uncertain. The prevention and an effective treatment of progressive liver disease are the primary aims in HCV recurrence. Interferon and ribavirin, as monotherapy or in combination, have been tried to treat or prevent HCV recurrence. Preliminary studies suggest a better chance of initial HCV clearance and better results in preventing HCV recurrence with combination therapy. IFN or ribavirin, as monotherapy, may normalize liver enzymes, but only gives rise to a transient virological response, without histological improvement. Combination IFN and ribavirin may be able to prevent progression of HCV-related graft disease, but indications and duration of treatment need further evaluation. No clear association between type and dose of immunosuppressive and outcome of post-transplant HCV recurrence has been found. Strategies to minimize the effects of immunosuppressive drugs include dose reduction of all agents and the selective discontinuation of individual agents. Initial immunosuppression with a single drug may inhibit or delay the severe fibrosis, and further investigation with a single immunosuppressive regimen to evaluate the outcome of recurrent hepatitis C should be performed. The recent evidence that mycophenolate may have an antiviral effect needs a clinical confirmation. Retransplantation survival is better with early retransplantation, and for indications not directly related to viral recurrence.

Topics: Adrenal Cortex Hormones; Antiviral Agents; Cyclosporine; Hepacivirus; Hepatitis C; Humans; Immunosuppressive Agents; Interferons; Liver Cirrhosis; Liver Transplantation; Ribavirin; Secondary Prevention; Tacrolimus

Clinical liver transplantation became an established therapy of end-stage liver disease since the first at least medium-term successful liver transplantation in 1967. Clinical studies have played a major part in improving peri- and postoperative therapy in liver transplantation. In this article clinical studies of major impact are presented. Main topics are studies dealing with immunosuppressants, improvements in surgical techniques, viral infections and tumor diseases. Controlled randomized multicentric studies are rare; most of the studies are unicentric. Further studies in the fields of reducing side effects of immunosuppression, the introduction of monoclonal antibodies and improvement of the therapy of viral hepatitis would be helpful. These studies should be controlled, randomized and multicentric.

Topics: Carcinoma, Hepatocellular; Cyclosporine; Cytomegalovirus Infections; Double-Blind Method; Hepatitis B; Hepatitis C; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Neoplasms; Liver Transplantation; Multicenter Studies as Topic; Postoperative Complications; Prognosis; Prospective Studies; Randomized Controlled Trials as Topic; Tacrolimus

Topics: Child; Cyclosporine; Graft Survival; Hepatitis B; Hepatitis C; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Transplantation; Recurrence; Survival Rate; Tacrolimus

To study the outcomes of patients who underwent liver transplantation for the primary diagnosis of chronic active hepatitis secondary to hepatitis C virus (HCV).. Retrospective review within a university medical center.. Seventy-four adult recipients who received 78 orthotopic liver allografts for the primary diagnosis of chronic active hepatitis secondary to HCV between January 1990 and December 1994. Sixty-seven patients (91%) survived more than 2 months and were analyzed further for recurrent HCV infection.. Recurrence of HCV infection, hepatitis, or cirrhosis and survival rates for patients who were undergoing orthotopic liver transplantation for chronic active hepatitis secondary to HCV.. Actuarial survival rates for the entire group were 79.3%, 70.9%, and 64.5% at 1,2, and 3 years, respectively. Four patients (5% underwent retransplantation with an actuarial survival rate of 14.3% at 1 year (P<.05). Thirty-eight patients (57%) had evidence of posttransplant HCV infection, 31 patients (46%) showed histologic evidence of viral hepatitis, and 11 patients (16%) experienced portal fibrosis or cirrhosis. Seven (33%) of the deaths and all retransplantations were secondary to recurrent HCV infection. There were no significant differences in age, sex, United Network of Organ Sharing status, associated diagnoses, intraoperative packed red blood cell requirements, OKT3 use, or 1-, 2-, and 3-year survival rates in the recurrent vs nonrecurrent HCV infection groups. A higher incidence of posttransplant cirrhosis was observed in patients who were treated with tacrolimus (FK 506) (31.8% vs 8.9%, P<.05). Twenty-one patients (70%) received interferon alfa antiviral therapy with a significant benefit in the liver function test results during therapy (P<.01).. Despite recurrence of HCV infection in most patients after transplantation, survival following primary orthotopic liver transplantation for chronic active hepatitis secondary to HCV infection remains favorable, and these patients should continue to be candidates for liver transplantation. In contrast, survival following retransplantation for HCV infection is poor and should be reconsidered. There is an apparent association between the intensity of immunosuppression and recurrent HCV infection and cirrhosis that warrants continued evaluation. Interferon therapy appears to afford benefit to patients in whom recurrent HCV hepatitis develops after transplantation.

Topics: Actuarial Analysis; Adult; Aged; Female; Hepatitis C; Hepatitis, Chronic; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Medical Records; Middle Aged; Retrospective Studies; Survival Analysis; Tacrolimus; Treatment Outcome

It has been known for some time that a variety of liver diseases affect kidney function, but renal dysfunction associated with orthotopic liver transplantation has received scant attention. Although the mechanisms mediating these abnormalities are incompletely defined, advances in the understanding of renal pathophysiology after liver transplantation have made it possible to develop new treatment strategies. Aggressive and early intervention to diagnose and treat renal complications associated with liver transplantation should be the goal for transplant centres.

Topics: Chronic Disease; Cyclosporine; Hepatitis C; Hepatorenal Syndrome; Humans; Immunosuppressive Agents; Kidney Transplantation; Liver Failure; Liver Transplantation; Prostaglandins; Renal Dialysis; Renal Insufficiency; Tacrolimus

Topics: Hepatitis B; Hepatitis C; Humans; Immunosuppressive Agents; Liver Diseases, Alcoholic; Liver Transplantation; Tacrolimus; Tissue Donors

Faldaprevir (FDV) is a potent, orally administered inhibitor of hepatitis C virus. In this single-centre, open-label, fixed-sequence, crossover study of 32 healthy adult male and female volunteers, subjects received either a single dose of cyclosporine (CsA) 50 mg (N = 16) or tacrolimus (TAC) 0.5 mg (N = 16), followed by a washout of at least 14 days. Each subject then received a loading dose of FDV 240 mg followed by 120 mg FDV once daily for 6 days. FDV 120 mg was then co-administered with an additional single dose of CsA (50 mg) or TAC (0.5 mg), followed by an additional 6 days of FDV 120 mg once daily. Intensive blood sampling was performed to assess the PK interaction potential. Assessment of relative BA indicated that exposure to CsA co-administered with FDV was similar to CsA alone. However, the AUC

Topics: Adolescent; Adult; Aminoisobutyric Acids; Antiviral Agents; Area Under Curve; Cross-Over Studies; Cyclosporine; Drug Interactions; Female; Graft Rejection; Healthy Volunteers; Hepatitis C; Humans; Immunosuppressive Agents; Leucine; Liver Transplantation; Male; Middle Aged; Oligopeptides; Proline; Prospective Studies; Quinolines; Secondary Prevention; Tacrolimus; Thiazoles; Young Adult

Calcineurin-inhibitors and hepatitis C virus (HCV) infection increase the risk of post-transplant diabetes mellitus. Chronic HCV infection promotes insulin resistance rather than beta-cell dysfunction. The objective was to elucidate whether a conversion from tacrolimus to cyclosporine A affects fasting and/or dynamic insulin sensitivity, insulin secretion or all in HCV-positive renal transplant recipients.. In this prospective, single-center study 10 HCV-positive renal transplant recipients underwent 2h-75g-oral glucose tolerance tests before and three months after the conversion of immunosuppression from tacrolimus to cyclosporine A. Established oral glucose tolerance test-based parameters of fasting and dynamic insulin sensitivity and insulin secretion were calculated. Data are expressed as median (IQR).. After conversion, both fasting and challenged glucose levels decreased significantly. This was mainly attributable to a significant amelioration of post-prandial dynamic glucose sensitivity as measured by the oral glucose sensitivity-index OGIS [422.17 (370.82-441.92) vs. 468.80 (414.27-488.57) mL/min/m2, p = 0.005), which also resulted in significant improvements of the disposition index (p = 0.017) and adaptation index (p = 0.017) as markers of overall glucose tolerance and beta-cell function. Fasting insulin sensitivity (p = 0.721), insulinogenic index as marker of first-phase insulin secretion [0.064 (0.032-0.106) vs. 0.083 (0.054-0.144) nmol/mmol, p = 0.093) and hepatic insulin extraction (p = 0.646) remained unaltered. No changes of plasma HCV-RNA levels (p = 0.285) or liver stiffness (hepatic fibrosis and necroinflammation, p = 0.463) were observed after the conversion of immunosuppression.. HCV-positive renal transplant recipients show significantly improved glucose-stimulated insulin sensitivity and overall glucose tolerance after conversion from tacrolimus to cyclosporine A. Considering the HCV-induced insulin resistance, HCV-positive renal transplant recipients may benefit from a cyclosporine A-based immunosuppressive regimen.. ClinicalTrials.gov NCT02108301.

Topics: Adult; Blood Glucose; Cyclosporine; Diabetes Mellitus, Type 2; Glomerular Filtration Rate; Glucose Tolerance Test; Graft Rejection; Hepatitis C; Humans; Immunosuppressive Agents; Insulin; Insulin Resistance; Kidney Transplantation; Liver; Middle Aged; Prospective Studies; Risk Factors; RNA, Viral; Tacrolimus; Transplant Recipients

Interactions between tacrolimus and cyclosporine (CSA) and the 3 direct-acting antiviral regimen (3D) of ombitasvir, paritaprevir/ritonavir, and dasabuvir necessitate a priori dose adjustments for the immunosuppressants to achieve desired levels. Modeling and simulations based on data in healthy subjects predicted that tacrolimus 0.5 mg every 7 days or 0.2 mg every 3 days, and CSA at one-fifth the total daily dose administered once daily, would achieve desired trough concentrations (Ctrough) during 3D treatment. The success of these dosing recommendations was evaluated by analyzing pharmacokinetic data from liver transplant recipients in the CORAL-I study.. A population pharmacokinetic model was developed using tacrolimus dosing and Ctrough data before and during 3D treatment (n = 29). The model was used to simulate various tacrolimus dosing regimens and predict tacrolimus concentration-time profiles during 3D treatment. CSA Ctrough data before and during 3D treatment (n = 5) were also summarized.. A one-compartment model with first-order absorption adequately described tacrolimus pharmacokinetic profiles during the first 4 weeks of 3D treatment. Estimated tacrolimus Ctrough values (median; interquartile range) before and during 3D treatment were comparable (5.7 ng/mL; 4.9-6.5 ng/mL versus 5.2 ng/mL; 4.2-6.3 ng/mL, respectively). Based on simulations, in a patient with a starting Ctrough of 6 ng/mL, 0.5 mg tacrolimus every 7 or 14 days or 0.2 mg tacrolimus every 3 days will result in Ctrough levels of 6-9 ng/mL, 4-6 ng/mL, and 6-10 ng/mL, respectively, during 3D treatment. For CSA, Ctrough values (median; interquartile range) before and during 3D treatment were comparable (126 ng/mL; 94-140 ng/mL versus 104 ng/mL; 82-140 ng/mL).. Observed data for tacrolimus and CSA in liver transplant recipients confirm that the recommended dosing strategies are valid and therapeutic levels of immunosuppression can be maintained during 3D treatment.

Topics: 2-Naphthylamine; Adolescent; Adult; Aged; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Cyclosporine; Drug Dosage Calculations; Drug Therapy, Combination; Female; Hepatitis C; Humans; Immunosuppressive Agents; Lactams, Macrocyclic; Liver Transplantation; Macrocyclic Compounds; Male; Middle Aged; Models, Biological; Proline; Ritonavir; Sulfonamides; Tacrolimus; Uracil; Valine; Young Adult

ABT-450, ombitasvir, and dasabuvir are direct-acting antiviral agents (DAAs) that have been developed for combination treatment of chronic hepatitis C virus (HCV) infection. Because these DAAs have metabolic and transporter profiles that overlap with cyclosporine and tacrolimus disposition, there is potential for drug interactions. Two Phase 1 studies assessed effects of ABT-450 (150 mg coadministered with ritonavir 100 mg once daily), ombitasvir (25 mg once daily), and dasabuvir (400 mg twice daily) on the pharmacokinetics, safety, and tolerability of a single dose of cyclosporine (30 mg) or tacrolimus (2 mg) in healthy volunteers (N = 12 per study). In the presence of steady-state concentrations of all 3 DAAs, dose-normalized cyclosporine concentration at 24 hours (C₂₄), and area under the concentration-time curve from time 0 to infinity (AUC(∞)) were 15.8-fold and 5.8-fold, respectively, and dose-normalized tacrolimus C₂₄ and AUC(∞) were 17-fold and 57-fold, respectively, of either agent alone. Cyclosporine and tacrolimus half-lives increased from 7 to 25 h and 32 to 232 h, respectively. There were no major safety or tolerability issues in these studies. The results suggest that cyclosporine and tacrolimus doses and dosing frequency should be reduced in HCV-infected posttransplant patients being treated with this 3-DAA regimen.

Topics: 2-Naphthylamine; Adolescent; Adult; Anilides; Antiviral Agents; Area Under Curve; Carbamates; Cyclopropanes; Cyclosporine; Drug Administration Schedule; Female; Healthy Volunteers; Hepacivirus; Hepatitis C; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Proline; Sulfonamides; Tacrolimus; Uracil; Valine; Young Adult

REFINE was a 12-month, prospective, open-label study in 356 patients receiving de novo liver transplantation for hepatitis C virus (HCV) cirrhosis, randomized to cyclosporine A (CsA) or tacrolimus with (i) no steroids, IL-2 receptor antibody induction and mycophenolic acid, or (ii) slow steroid tapering. The primary analysis population based on availability of liver biopsies comprised 165 patients (88 CsA, 77 tacrolimus). There was no difference in the primary endpoint, fibrosis stage ≥2 at 12 months, which occurred in 63/88 CsA-treated patients (71.6%) and 52/77 tacrolimus-treated patients (67.5%) (odds ratio [OR] 1.11; 95% CI 0.56, 2.21; p = 0.759). Similarly, no significant between-group difference occurred at month 24 (OR 1.15; 95% CI 0.47, 2.80; p = 0.767). Among steroid-free patients, fibrosis score ≥2 was significantly less frequent with CsA versus tacrolimus at month 12 (7/37 [18.9%] vs. 16/38 [42.1%]; p = 0.029). HCV viral load was similar in both the tacrolimus- and CsA-treated cohorts. Mean blood glucose was significantly higher with tacrolimus from day 15 onward. Biopsy-proven acute rejection, graft loss and death were similar. These results showed no differences in posttransplant HCV-induced liver fibrosis between patients treated with CsA or tacrolimus in steroid-containing regimens, whereas CsA in steroid-free protocols was associated with reduced severity of fibrosis progression at 1 year posttransplant.

Topics: Cyclosporine; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Hepacivirus; Hepatitis C; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Prognosis; Prospective Studies; Survival Rate; Tacrolimus

This exploratory phase II study evaluated the safety and efficacy of belatacept in de novo adult liver transplant recipients. Patients were randomized (N = 260) to one of the following immunosuppressive regimens: (i) basiliximab + belatacept high dose [HD] + mycophenolate mofetil (MMF), (ii) belatacept HD + MMF, (iii) belatacept low dose [LD] + MMF, (iv) tacrolimus + MMF, or (v) tacrolimus alone. All received corticosteroids. Demographic characteristics were similar among groups. The proportion of patients who met the primary end point (composite of acute rejection, graft loss, death by month 6) was higher in the belatacept groups (42–48%) versus tacrolimus groups (15–38%), with the highest number of deaths and grafts losses in the belatacept LD group. By month 12, the proportion surviving with a functioning graft was higher with tacrolimus + MMF (93%) and lower with belatacept LD (67%) versus other groups (90%: basiliximab + belatacept HD; 83%: belatacept HD; 88%: tacrolimus). Mean calculated GFR was 15–34 mL/min higher in belatacept-treated patients at 1 year. Two cases of posttransplant lymphoproliferative disease and one case of progressive multifocal leukoencephalopathy occurred in belatacept-treated patients. Follow-up beyond month 12 revealed an increase in death and graft loss in another belatacept group (belatacept HD), after which the study was terminated.

Topics: Abatacept; Adult; Aged; Drug Administration Schedule; Female; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Hepatitis C; Humans; Immunoconjugates; Immunosuppression Therapy; Immunosuppressive Agents; Leukoencephalopathies; Liver Failure; Liver Transplantation; Lymphoproliferative Disorders; Male; Middle Aged; Mycophenolic Acid; Recurrence; Tacrolimus; Treatment Outcome

The purpose of this prospective, randomized, multicenter trial was to evaluate the effects of a steroid-avoiding immunosuppression protocol on hepatitis C virus (HCV)-positive recipients of living donor liver transplantation (LDLT). Seventy-five HCV-positive LDLT recipients were included in this study, and they were randomized to receive tacrolimus (TAC) plus a corticosteroid (ST; n = 35) or TAC plus mycophenolate mofetil (MMF; n = 40). Biopsy-proven acute rejection (BPAR) was treated with steroid pulse therapy in both groups. Protocol biopsy was performed 3, 6, and 12 months after LDLT and annually thereafter. Histological recurrence of HCV (fibrosis stage ≥ F1 according to the METAVIR score), BPAR resistant to 2 sets of steroid pulse therapy, hepatocellular carcinoma (HCC) recurrence, retransplantation, and patient death were defined as events, and the primary endpoint was event-free survival. The median follow-up was 55 months. The event-free survival rates at 1, 3, and 5 years were 38.2%, 11.8%, and 5.9%, respectively, for the ST group and 25.0%, 17.5%, and 14.6%, respectively, for the MMF group (P = 0.45). The overall 5-year patient survival rates were similar for the ST group (82.7%) and the MMF group (81.0%, P = 0.28). Steroid-resistant BPAR occurred in only 1 patient from the MMF group. HCC recurrence occurred for 1 patient from the ST group and 2 patients from the MMF group. HCV recurrence rates with a fibrosis stage ≥ F1 1 and 3 years after LDLT were 59.4% and 85.9%, respectively, for the ST group and 74.2% and 81.9%, respectively, for the MMF group (P = 0.57). In conclusion, our steroid-avoidance regimen had no apparent impact on LDLT outcomes for HCV-positive recipients.

Topics: Adult; Aged; Biopsy; Disease-Free Survival; Female; Follow-Up Studies; Hepacivirus; Hepatitis C; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Failure; Liver Transplantation; Living Donors; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Recurrence; Steroids; Tacrolimus; Treatment Outcome; Young Adult

study impact of steroid avoidance on HCV recurrence after transplantation.. 35 HCV pats, being part of prospective, randomized, double-blind, placebo-controlled study comparing Tacrolimus (TAC)-Placebo (PLAC) (n = 14) to TAC-short-term (2 mo) low-dose steroid (STER) (n = 21), had 5 years follow-up. Primary endpoint was 1 and 5 years survival; secondary (composite) endpoint comprised HCV related cirrhosis, re-transplantation (re-LT) and death.. 1 and 5-years survival were 93% and 75% in TAC-PLAC group; 91% and 66% in TAC-STER group (p 0.38). Two (14.3%) TAC-PLAC pats died due to HCV cirrhosis at 54 and 72 mo; 7 (33%) TAC-STER pats died due to cholestatic hepatitis at 5.8 and 9 mo, to cirrhosis at 18, 22, 34, 73 and 79 mo (p 0.20). Composite endpoint at 5 years didn't show advantage in favor of TAC-PLAC patients (5/14 [35.7%] vs. 9/21 [42.8%] pts, p.0.69). Early biopsies seemed more favorable in TAC-PLAC pats; at 5 years results were identical for both groups. Only 1 (7.1%) TAC-PLAC and 2 (9.5%) TAC-STER pats needed rejection treatment.. immunosuppression using steroid avoidance or short-term use had similar outcomes. Well documented long-term follow-up, including biopsies, is necessary in order to make conclusions in relation to impact of steroid use on outcome of HCV liver recipients.

Topics: Adrenal Cortex Hormones; Adult; Aged; Antiviral Agents; Biopsy; Double-Blind Method; Female; Graft Rejection; Graft Survival; Hepatitis C; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Monitoring, Immunologic; Secondary Prevention; Survival Analysis; Tacrolimus; Time; Treatment Outcome

We aimed at determining the effect of maintenance therapy with ribavirin alone, after a year of combined peginterferon-alfa 2a (PegIFNα-2a) and ribavirin therapy, on viral response and liver histology after liver transplantation (LT).. Hundred and one patients with recurrent HCV and a minimum of stage 1 fibrosis (METAVIR scoring), 1-5years after LT, were enrolled. PegIFNα-2a and ribavirin were initiated at 90 μg/wk and 600 mg/d, respectively, then increased or adjusted as a function of tolerance. At 12 months, combination therapy was discontinued and patients were randomized to ribavirin or placebo for a further 12 months. Growth factor use was permitted.. At 18 months, a sustained virological response (SVR) was obtained in 47.9% of patients in Per Protocol (PP) analysis, and was higher in patients with genotype 2 or 3 than in patients with genotype 1 or 4, in patients with genotypes 1+4 receiving ciclosporine than in those receiving tacrolimus, in patients with worse renal function, in those having received EPO, in patients with lower weight, and in those with lower viral load at 3 months. Using logistic regression, only the early viral response, recipient weight and renal function were independently associated with better SVR. SVR, viral load, activity, and fibrosis scores were similar, at M18 and M30, in patients randomized to ribavirin, or to placebo.. A PP SVR was achieved in 47.9% of patients with established recurrent hepatitis C after LT. Maintenance therapy with ribavirin alone does not improve the virological response or the histological parameters.

Topics: Antiviral Agents; Cyclosporine; Double-Blind Method; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C; Humans; Immunosuppressive Agents; Induction Chemotherapy; Interferon-alpha; Kidney; Liver Cirrhosis; Liver Transplantation; Logistic Models; Maintenance Chemotherapy; Male; Middle Aged; Placebos; Polyethylene Glycols; Recombinant Proteins; Recurrence; Ribavirin; Tacrolimus; Treatment Outcome; Viral Load

The hepatitis C virus protease inhibitor telaprevir is an inhibitor of the enzyme cytochrome P450 3A, responsible for the metabolism of both cyclosporine and tacrolimus. This Phase I, open-label, nonrandomized, single-sequence study assessed the effect of telaprevir coadministration on the pharmacokinetics of a single dose of either cyclosporine or tacrolimus in two separate panels of 10 healthy volunteers each. In Part A, cyclosporine was administered alone as a single 100-mg oral dose, followed by a minimum 8-day washout period, and subsequent coadministration of a single 10-mg oral dose of cyclosporine with either a single dose of telaprevir (750 mg) or with steady-state telaprevir (750 mg every 8 hours [q8h]). In Part B, tacrolimus was administered alone as a single 2-mg oral dose, followed by a minimum 14-day washout period, and subsequent coadministration of a single 0.5-mg dose of tacrolimus with steady-state telaprevir (750 mg q8h). Coadministration with steady-state telaprevir increased cyclosporine dose-normalized (DN) exposure (DN_AUC(0-∞)) by approximately 4.6-fold and increased tacrolimus DN_AUC(0-∞) by approximately 70-fold. Coadministration with telaprevir increased the terminal elimination half-life (t(½)) of cyclosporine from a mean (standard deviation [SD]) of 12 (1.67) hours to 42.1 (11.3) hours and t(½) of tacrolimus from a mean (SD) of 40.7 (5.85) hours to 196 (159) hours.. In this study, telaprevir increased the blood concentrations of both cyclosporine and tacrolimus significantly, which could lead to serious or life-threatening adverse events. Telaprevir has not been studied in organ transplant patients; its use in these patients is not recommended because the required studies have not been completed to understand appropriate dose adjustments needed for safe coadministration of telaprevir with cyclosporine or tacrolimus, and regulatory approval has not been obtained.

Topics: Adolescent; Adult; Antiviral Agents; Area Under Curve; Cyclosporine; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Drug Interactions; Female; Follow-Up Studies; Hepatitis C; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Oligopeptides; Tacrolimus; Young Adult

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 > or = 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, HCVRNA 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.

Topics: Antiviral Agents; Cyclosporine; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C; Humans; Immunosuppressive Agents; Interferon alpha-2; Interferon-alpha; Liver; Liver Transplantation; Male; Middle Aged; Polyethylene Glycols; Recombinant Proteins; Recurrence; Ribavirin; RNA, Viral; Tacrolimus

The aim of this prospective, randomized, double-blinded, placebo-controlled single center study was to evaluate an early steroid-free immunosuppression in liver transplant patients.. From March 2000 to October 2004, 110 patients were included. All patients received tacrolimus and steroids during the first 2 weeks after orthotopic liver transplantation (OLT). Thereafter, patients in the steroid group (n=54) received steroids and the remaining 56 a placebo. After 6 months, the immunosuppression for all was steroid free. Thirty patients were hepatitis C positive. Five years after inclusion, patient survival, organ survival, steroid side effects, and recirrhosis in hepatitis C virus (HCV) patients were reevaluated.. After 5 years, the following parameters were comparable in both groups: patient survival (P=0.236), organ survival (P=0.509), and acute rejections (P=0.409). Steroid-free immunosuppression lead to a higher rate of chronic rejections (P=0.023). Six months after OLT, there was a difference in rates of posttransplant diabetes mellitus (PTDM) (P=0.024) and hypercholesterolemia (P=0.002). However, 5 years after OLT, there was no difference in hypertension (P=0.647), PTDM (P=0.453), hypercholesterolemia (P=0.412), and osteoporosis (P=0.624). In HCV patients, we could not find any differences in patient survival (P=0.096), organ survival (P=0.424), time free from recirrhosis (P=0.647). The rate of recirrhosis was influenced by steroid bolus therapy (P=0.01) but not by avoiding continuous steroid therapy.. Early tapering down of steroids to a tacrolimus monotherapy is possible with comparable acute rejection rates. During steroid therapy, PTDM and hypercholesterolemia are cumulative. These side effects are reversible. The recirrhosis in HCV patients is not influenced by continuous steroid therapy but more frequent in HCV patients receiving a steroid bolus therapy.

Topics: Adrenal Cortex Hormones; Diabetes Mellitus; Dose-Response Relationship, Drug; Double-Blind Method; Graft Survival; Hepatitis C; Humans; Hypercholesterolemia; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Postoperative Complications; Recurrence; Survival Rate; Tacrolimus; Time Factors; Treatment Outcome

There is a paucity of good studies evaluating the impact of calcineurin inhibitors on posttransplantation outcome in hepatitis C virus (HCV)-infected liver transplant (LT) recipients.. We sought to determine whether there are differences on posttransplantation survival and histologic recurrence in HCV-LT recipients based on initial immunosuppression (IS) by conducting a prospective study comparing tacrolimus (Tac) versus cyclosporine-based IS in patients undergoing LT between 2001 and 2007. Protocol liver biopsies were performed.. Baseline characteristics (demographics, liver function at LT, genotype distribution, donor, surgery, and IS except for the type of calcineurin inhibitor) did not differ between groups. Severe disease (defined as bridging fibrosis, cirrhosis, cholestatic hepatitis, or allograft loss or death because of recurrent disease in the first year) was present in 67 of 253 (26.5%) and was equally distributed in the CsA and Tac groups (27% vs. 26%; P=0.68). Two thirds of protocol biopsies performed at 1 year showed some fibrosis without differences between CsA and Tac groups (75% vs. 70%). Advanced fibrosis (bridging fibrosis and cirrhosis) was diagnosed in 30% CsA and 24.5% Tac patients (P=NS). No differences in survival at 1 and 7 years were observed (83% and 67% vs. 78% and 64%, respectively, P=0.4). In summary, in patients undergoing LT for HCV-related liver disease, posttransplantation outcome is not related to the calcineurin inhibitor used.

Topics: Adult; Aged; Antiviral Agents; Biopsy; Calcineurin Inhibitors; Chi-Square Distribution; Cyclosporine; Disease Progression; Drug Therapy, Combination; Female; Graft Survival; Hepatitis C; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Prednisone; Prospective Studies; Recurrence; Risk Assessment; Risk Factors; Spain; Tacrolimus; Time Factors; Treatment Outcome

Less potent immunosuppression is considered to reduce the severity of hepatitis C virus (HCV) recurrence after liver transplantation. An optimal regimen is unknown. We evaluated tacrolimus monotherapy versus triple therapy in a randomized trial of 103 first transplants for HCV cirrhosis. One hundred three patients who underwent transplantation for HCV were randomized to tacrolimus monotherapy (n = 54) or triple therapy with tacrolimus, azathioprine, and steroids (n = 49), which were tapered to zero by 3 to 6 months. Both groups had serial transjugular biopsies with hepatic venous pressure gradient (HVPG) measurement. The time to reach Ishak stage 4 was the predetermined endpoint. All factors documented in the literature as being associated with HCV recurrence and the allocated treatment were evaluated for reaching stage 4 and HVPG >or= 10 mm Hg. No significant preoperative, perioperative, or postoperative differences, including the frequency of biopsies between groups, were found. During a mean follow-up of 53.5 months, 9 monotherapy patients and 6 triple therapy patients died, and 5 monotherapy patients and 4 triple therapy patients underwent retransplantation. Stage 4 fibrosis was reached in 17 monotherapy patients and 10 triple therapy patients (P = 0.04), with slower fibrosis progression in the triple therapy patients (P = 0.048). Allocated therapy and histological acute hepatitis were independently associated with stage 4 fibrosis. HVPG increased to >or=10 mm Hg more rapidly in monotherapy patients versus triple therapy patients (P = 0.038). In conclusion, long-term maintenance immunosuppression with azathioprine and shorter term prednisolone with tacrolimus in HCV cirrhosis recipients resulted in a slower onset of histologically proven severe fibrosis and portal hypertension in comparison with tacrolimus alone, and this was independent of known factors affecting fibrosis.

Topics: Adolescent; Adult; Aged; Azathioprine; Biopsy; Child; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Hepatitis C; Humans; Hypertension, Portal; Immunosuppressive Agents; Kaplan-Meier Estimate; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Prednisolone; Proportional Hazards Models; Recurrence; Risk Assessment; Risk Factors; Severity of Illness Index; Tacrolimus; Time Factors; Treatment Outcome; Young Adult

To characterise the interactions between tacrolimus and antiretroviral drug combinations in hepatitis C virus-HIV co-infected patients who had received a liver transplant.. An observational, open-label, multiple-dose, two-period, one-sequence design clinical trial in which patients received tacrolimus as an immunosuppressive therapy during the postoperative period and then had an antiretroviral drug regimen added. Tacrolimus pharmacokinetics were evaluated at steady state during these two periods.. Fourteen patients participated in the study and seven participated in the intensified pharmacokinetic protocol. Patients were included if they had undergone liver transplantation for end-stage chronic hepatitis C, absence of opportunistic infection, a CD4 cell count of >150 cells/microL and an undetectable HIV plasma viral load (<50 copies/mL) under highly active antiretroviral therapy. During the posttransplantation period, the tacrolimus dose was adjusted according to blood concentrations. When liver function and the tacrolimus dose were stable, antiretroviral therapy was reintroduced.. When lopinavir/ritonavir were added to the tacrolimus regimen (seven patients), the tacrolimus dose was reduced by 99% to maintain the tacrolimus concentration within the therapeutic range. Only two patients were treated with nelfinavir, which led to a wide variation in inhibition of tacrolimus metabolism. When efavirenz (four patients) or a nucleoside analogue combination (one patient) was added, very little change in tacrolimus dosing was required.. The lopinavir/ritonavir combination markedly inhibited tacrolimus metabolism, whereas the effect of efavirenz was small. Tacrolimus dosing must be optimised according to therapeutic drug monitoring and the antiretroviral drug combination.

Topics: Adult; Aged; Alkynes; Antiretroviral Therapy, Highly Active; Area Under Curve; Benzoxazines; CD4 Lymphocyte Count; Cyclopropanes; Dose-Response Relationship, Drug; Female; Graft Rejection; Half-Life; Hepatitis C; HIV; HIV Infections; Humans; Liver Transplantation; Lopinavir; Male; Middle Aged; Nelfinavir; Pyrimidinones; Ritonavir; Tacrolimus; Viral Load

This work is a 1-yr interim analysis of a prospective, randomized, multicenter trial evaluating the effect of corticosteroid-free immunosuppression on hepatitis C virus-positive (HCV(+)) liver transplant recipients following liver transplantation (LT). Patients received tacrolimus and corticosteroids (Arm 1; n = 80); tacrolimus, corticosteroids, and mycophenolate mofetil (MMF) (Arm 2; n = 79); or daclizumab induction, tacrolimus, and MMF (Arm 3; n = 153). At 1 yr, 64.1%, 63.4%, and 69.4% of patients achieved the composite primary endpoint of freedom from rejection, freedom from HCV recurrence, and freedom from treatment failure, respectively. Excellent patient and graft survival did not differ significantly among treatment arms. Freedom from HCV recurrence at 1 yr was 61.8 +/- 6.2%, 60.1 +/- 6.1%, and 67.0 +/- 4.3% in Arms 1, 2, and 3, respectively (P = not significant). Freedom from rejection was significantly higher in Arm 3 compared to Arm 1 (93.0 +/- 2.2% vs. 81.9 +/- 4.4%; P = 0.011). Multivariate analysis identified acute rejection (hazard ratio = 2.692; P = 0.001) and donor age (hazard ratio = 1.015; P = 0.001) as significant risk factors for HCV recurrence. HCV recurrence was not influenced by recipient demographics, HCV genotype, or immunosuppression. In conclusion, these results suggest that a corticosteroid-free regimen of tacrolimus and MMF following daclizumab induction is safe and effective in HCV(+) liver transplant recipients.

Topics: Adrenal Cortex Hormones; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Daclizumab; Drug Therapy, Combination; Female; Graft Rejection; Hepacivirus; Hepatitis C; Humans; Immunoglobulin G; Immunosuppression Therapy; Immunosuppressive Agents; Liver; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Secondary Prevention; Tacrolimus; Treatment Outcome

Due to the known high recurrence rate of hepatitis C virus (HCV) among orthotopic liver transplant (OLT) recipients who receive tacrolimus+corticosteroid maintenance, use of steroid-free induction was considered.. OLT recipients with HCV were randomized to receive tacrolimus+daclizumab (steroid-free) vs. tacrolimus+corticosteroids during 1999-2001 and then tacrolimus+mycophenolate mofetil (MMF)+daclizumab (steroid-free) vs. tacrolimus+MMF+corticosteroids during 2002-2005. Patients in the steroid-free arm of both periods received no steroids except for treating biopsy-proven rejection. Primary objective was to compare mean fibrosis stage at the 1-year protocol biopsy, between the steroid-free and corticosteroid arms, stratifying by period.. No noticeable differences in mean fibrosis stage between the two treatment arms, either averaging across periods (P=0.99) or during either period (P>0.35) were found. Occurrence of acute rejection during the first year was the only factor associated with a significantly increased fibrosis stage at 1 year (P=0.0003); stage > or =2 was seen in 63% (17 of 27) vs. 19% (8 of 43) of those with vs. without rejection. In addition, MMF use was associated with significantly fewer patients experiencing acute rejection during the first 6 and 12 months posttransplant (P=0.006 and 0.046). Regarding steroid-related side effects, posttransplant diabetes mellitus occurred in 10% vs. 45%, and wound infection in 6% vs. 31% of steroid-free vs. corticosteroid patients (P=0.003 and 0.01).. OLT recipients with HCV tolerated the steroid-free protocol with fewer side effects; however, its use had no apparent impact on hepatic fibrosis progression. Occurrence of acute rejection was strongly associated with increased hepatic fibrosis at 1 year, and MMF use appears to have significantly reduced the rejection rate.

Topics: Adrenal Cortex Hormones; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Biopsy; Daclizumab; Disease Progression; Female; Fibrosis; Hepacivirus; Hepatitis C; Humans; Immunoglobulin G; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Recurrence; Steroids; Tacrolimus; Treatment Outcome

The severity of recurrent hepatitis C virus (HCV) is likely related to several factors. Controversial results have been reported regarding the effect of specific calcineurin-inhibitors. The aim of this research was to determine whether there are differences on posttransplantation outcome in HCV-infected patients based on initial immunosuppression. Prospective randomized trial comparing tacrolimus vs. cyclosporine-based immunosuppression in a cohort of patients undergoing primary orthotopic liver transplantation between 2001 and 2003 was used. Yearly biopsies were performed. Patients with at least 1 protocol biopsy and those with very severe recurrence despite a follow-up of less than 1 yr (cholestatic hepatitis, progression to bridging fibrosis/cirrhosis) were included. Baseline characteristics (demographics, liver function at transplantation, genotype distribution, donor, surgery, immunosuppression except for the type of calcineurin inhibitor) did not differ between the 2 groups. Severe disease (defined as bridging fibrosis, cirrhosis, cholestatic hepatitis, and/or death due to recurrent disease in the first year) was present in 27 in 90 (30%), and was equally distributed in the cyclosporine and tacrolimus groups (15/46 vs. 12/44, respectively). A total of 33 in 90 (37%) patients had no fibrosis in the first year biopsy with no difference between the cyclosporine and tacrolimus groups (36.5 vs. 37%). The percentage of patients developing recurrent acute hepatitis was also similar (32% vs 35%); time to acute hepatitis though was shorter in the tacrolimus group (59 days [35-185] vs. 92 days [39-343] in the cyclosporin group; P = 0.02). Cholestatic hepatitis was observed in 4 of 44 and 5 of 46 patients under cyclosporine and tacrolimus, respectively (P = not significant). In conclusions, the short-term posttransplantation course of hepatitis C is not related to the calcineurin inhibitor used.

Topics: Adult; Aged; Calcineurin Inhibitors; Cyclosporine; Female; Hepatitis C; Humans; Immunosuppressive Agents; Liver; Liver Transplantation; Male; Middle Aged; Prospective Studies; Recurrence; Tacrolimus

Reducing immunosuppression not only reduces complications but also may lessen recurrent hepatitis C virus (HCV) infection after liver transplantation.. HCV-infected cirrhotic patients randomised to tacrolimus monotherapy (MT) or triple therapy (TT) using tacrolimus 0.1 mg/kg/day, azathioprine 1 mg/kg/day, and prednisolone 20 mg/day, tapering over 3 months.. Twenty-seven patients (MT) and 29 (TT)--median follow up 661 days (range, 1-1603). Rejection episodes (protocol/further biopsies) within first 3 months and use of empirical treatment were evaluated. New rejection was diagnosed if repeat biopsy (5-day interval) did not show improvement. Treated rejection episodes: 20 MT (15 biopsy-proven) vs. 24 TT (21 biopsy-proven), with 19 (MT) vs. 24 (TT) methylprednisolone boluses. Overall: 35 episodes (MT) and 46 (TT). Fewer MT patients had histological rejection (70%) than TT patients (86%), with fewer episodes of rejection (18.5% vs. 10%), and more moderate rejection (22% vs. 41%). The MT group had higher early tacrolimus levels. Rates of renal dysfunction, retransplantation, and death were not significantly different.. Tacrolimus monotherapy is a viable immunosuppressive strategy in HCV-infected liver transplant recipients.

Topics: Adult; Aged; Azathioprine; Drug Therapy, Combination; Female; Graft Rejection; Hepatitis C; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Prednisolone; Secondary Prevention; Survival Analysis; Tacrolimus; Time Factors; Transplantation, Homologous; Treatment Outcome

Choice of calcineurin inhibitor may be a contributing factor to deteriorating patient and graft survival following liver transplantation for hepatitis C virus (HCV). In our multicenter, open-label LIS2T study, de novo liver transplant patients stratified by HCV status were randomized to cyclosporine or tacrolimus. Follow-up data were obtained in an observational study of 95 patients. Mean follow-up was 34 and 37 months, respectively, for cyclosporine-treated (n = 47) and tacrolimus-treated (n = 48) patients. In patients not receiving antiviral therapy, 22 of 31 given cyclosporine (72%) and 24 of 29 given tacrolimus (83%) had biochemical recurrence of HCV. In 68 patients with at least one biopsy, histological evidence of HCV-related hepatitis was present in 27 of 31 (87%) cyclosporine-treated patients and 37 of 37 (100%) tacrolimus-treated patients (P = .02, chi-square test). Three-year actuarial risk of fibrosis stage 2 was 66% with cyclosporine and 90% with tacrolimus; for fibrosis stage 3 or 4 it was 46% and 80%, respectively. Three graft losses were attributed to HCV recurrence in cyclosporine-treated patients and six in tacrolimus-treated patients. Tacrolimus may be associated with increased risk of histological HCV disease recurrence compared to cyclosporine.

Topics: Adult; Carcinoma, Hepatocellular; Cyclosporine; Female; Follow-Up Studies; Hepatitis C; Humans; Immunosuppressive Agents; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Recurrence; Risk Factors; Tacrolimus; Time Factors; Treatment Outcome

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

Recurrence of hepatitis C (HepC) has been a most difficult dilemma in liver transplantation (OLT) because the effects of immunosuppression with steroid, mycophenolate mofetil (MMF) calcineurin antagonists, and anti-interleukin-2 antibody as well as the role of preemptive antiviral therapy are uncertain. In this study, we randomized OLT recipients with HepC into two treatment arms: tacrolimus+daclizumab+MMF (study arm) versus tacrolimus+steroids+MMF (control arm). The study arm only received steroids for the treatment of biopsy-proven rejection episodes. Both arms received preemptive anti-viral therapy with Pegasys and ribavirin. The 39 enrolled patients (among 50 to be enrolled) have median follow-up of 458 days with 23 patients (8 in study arm, 15 in control arm) having reached 1 year. The incidences of rejection episodes within 0 to 3 months, 3 to 6 months, and 6 to 12 months were (study vs control): 0% vs 28%; 0% vs 6%; and 13% vs 20%; respectively (P = NS). The 1-year protocol biopsies showed advanced fibrosis (stage 3 or greater) in 20% (3 of 15) of the control arm, but none (0 of 7) of the study arm (P = NS). We compared anticipated side effects of steroids in the first 3 months (study vs control): hypertension (36% vs 58%, P = NS), PTDM (7% vs 43%, P = .02), and wound infections (14% vs 37%, P = NS). In conclusion, liver transplant recipients with HepC tolerate a steroid-free protocol. There was a trend toward reduced steroid side effects and a lower incidence of advanced fibrosis in 1-year biopsy samples among patients receiving the steroid-free protocol.

Topics: Adrenal Cortex Hormones; Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antiviral Agents; Daclizumab; Drug Therapy, Combination; Female; Graft Rejection; Hepatitis C; Humans; Immunoglobulin G; Immunosuppressive Agents; Interferon alpha-2; Interferon-alpha; Liver Transplantation; Male; Middle Aged; Polyethylene Glycols; Recombinant Proteins; Recurrence; Ribavirin; Tacrolimus; Viral Load

The aim of this prospective randomized trial was to study the efficacy and safety of tacrolimus monotherapy (TACRO) and compare it with our standard treatment of tacrolimus plus steroids (TACRO + ST) after liver transplant (LT). Furthermore, the impact of steroid-free immunosuppression on outcome of hepatitis C virus (HCV) was analysed. Between 1998 and 2000, 60 patients (mean age: 57 years) were included in the study and randomized to receive TACRO (n = 28) or TACRO + ST (n = 32). Indication for LT was postnecrotic cirrhosis in all cases (58.3% were HCV-positive). Mean follow-up was 44 months. Survival, incidence of rejection, infection and side-effects were compared between the two groups. In patients with HCV infection, incidence and severity of acute hepatitis C, long-term outcome of recurrent hepatitis C and survival were studied in an intention-to-treat analysis or in the real group analysis (real-TACRO versus real-TACRO + ST). Patient survival at 1, 3 and 5 years, tacrolimus pharmacokinetics, incidence of rejection infections and side-effects were similar. In patients with HCV, the incidence and severity of graft hepatitis C tended to be lower in TACRO (47%) compared with TACRO + ST (67%) (P = NS), and also in real-TACRO (42%) compared with real-TACRO + ST (61%) (P = NS). A poor outcome considered as evolution to cirrhosis at 3 years was observed in one (9%) living patient in real-TACRO and nine (45%) in real-TACRO + ST (P = 0.04). Patient survival at 1, 3 and 5 years was 92%, 92% and 73% for real-TACRO and 78%, 61% and 51% for real TACRO + ST (P = 0.07). Steroid-free immunosuppression appears to be safe and efficacious. The main advantage of this regimen could be in HCV patients, as recurrence of hepatitis in the graft was less severe in the group of patients in whom steroids could be avoided completely.

Topics: Adult; Aged; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Hepatitis C; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Recurrence; Steroids; Tacrolimus; Time Factors; Tissue Donors; Treatment Outcome

Hepatitis C virus (HCV)-induced cirrhosis is the commonest indication for orthotopic liver transplantation, but HCV recurrence is nearly universal and may worsen patient / graft outcomes. The frequency and severity of HCV recurrence has apparently increased in recent years, raising concern about a possible role for newer immunosuppression regimens in this increase, including potentially tacrolimus. We randomized 79 patients to receive tacrolimus or cyclosporine as primary immunosuppressant posttransplantation. A pathologist blinded to treatment reviewed serial liver biopsies. Month 12 cumulative probabilities of histological hepatitis C recurrence for tacrolimus- and cyclosporine-treated patients were .38 and .54 (P = .19) and failure / death were .25 and .28, respectively (P = .789). Although cyclosporine-treated patients had significantly larger increases in median serum HCV RNA levels (months 1, 6, and 12), no significant differences were observed between the two treatment arms in histologically-diagnosed HCV recurrence / survival rates. In conclusion, choice of calcineurin inhibitors does not impact severity of recurrent HCV.

Topics: Adult; Biopsy, Needle; Cyclosporine; Female; Hepacivirus; Hepatitis C; Humans; Immunosuppressive Agents; Liver; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Prospective Studies; Recurrence; RNA, Viral; Tacrolimus; Treatment Outcome

In 2001, we published early results of a prospective randomized trial of 71 patients who received either steroids or rabbit antithymocyte globulin (RATG) for orthotopic liver transplantation (OLT). We now report follow-up on these patients and additional patients undergoing steroid-free OLT.. A total of 119 adult OLT recipients were prospectively randomized to receive either methylprednisolone 1,000 mg followed by a 3-month steroid taper or a steroid-free regimen of RATG 1.5 mg/kg during the anhepatic phase followed by a 1.5 mg/kg dose on posttransplant day 1. Maintenance immunosuppression consisted of tacrolimus and mycophenolate mofetil in both groups. Mycophenolate mofetil was weaned over 3 months in the first 71 patients and over 2 weeks in the last 48 patients, achieving tacrolimus monotherapy by 2 weeks posttransplant. Subsequently, a group of 24 sequential OLT recipients received the steroid-free (RATG) protocol. Endpoints of the study were survival, rejection, infectious complications, posttransplant diabetes, and recurrent hepatitis C virus.. One-year patient survival was 85% in each group of the prospective randomized trial with a mean follow-up of 18.5 months. One-year graft survival was 82% in the RATG group and 80% in the steroid group (P=not significant). Patient and graft survival of the 24 nonrandomized RATG patients was 96% with a mean follow-up of 3 months. The incidence of rejection was not significantly different; however, 50% of the patients in the steroid group required pulse steroids to reverse the rejection compared with only one patient (1.6%) in the RATG group (P=.03). The incidence of cytomegalovirus infection (P<.05) and posttransplant diabetes was higher in the steroid group (P=.03). There was a trend toward decreased severity of hepatitis C virus in the RATG group.. Steroid-free liver transplantation using RATG and early tacrolimus monotherapy effectively reduces immunosuppression-related complications with excellent survival.

Topics: Adult; Animals; Antilymphocyte Serum; Drug Therapy, Combination; Follow-Up Studies; Glucocorticoids; Graft Rejection; Graft Survival; Hepatitis C; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Methylprednisolone; Mycophenolic Acid; Rabbits; Survival Analysis; Tacrolimus

Topics: Adrenal Cortex Hormones; Adult; Aged; Drug Therapy, Combination; Female; Follow-Up Studies; Hepatitis C; Humans; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prednisolone; Prospective Studies; Tacrolimus; Time Factors

Hepatitis C is the most common indication for liver transplantation (LT) in the United States. Recurrence of hepatitis C virus (HCV) infection post-LT remains a problem for which there is no completely satisfactory treatment. The aim of the present study is to evaluate mycophenolate mofetil (MMF), which has both immunosuppressive and antiviral properties, to determine whether it is associated with a difference in the rate of HCV recurrence and also examine its impact on patient and graft survival. Between August 1995 and May 1998, a total of 106 patients who were HCV positive before LT were randomized to tacrolimus (TAC) and prednisone versus TAC, prednisone, and MMF therapy. The rate of recurrence of HCV, patient and graft survival, incidences of rejection, and histological findings were examined. Fifty six patients were randomized to TAC and steroid therapy (double [D] drug; group D), and 50 patients were randomized to TAC, steroid, and MMF therapy (triple [T] drug; group T). Liver biopsies were performed when liver function was abnormal; protocol liver biopsies were not performed. Mean follow-up was 4.3 +/- 0.8 years. Actuarial patient survivals at 4 years were 72.6% in group D and 73.8% in group T (P = not significant). Actuarial graft survivals at 4 years were 65.6% in group D and 65.4% in group T. One patient in group D and 2 patients in group T underwent a second LT for recurrent HCV. One patient in each group died of recurrent HCV without re-LT. Twenty-six patients in group D (46.4%) and 23 patients in group T (46.0%) showed signs of recurrent HCV. Mean hepatitis activity index (HAI) scores were 7.4 +/- 2.7 in group D and 7.0 +/- 3.4 in group T, and mean fibrosis scores were 2.9 +/- 1.7 in group D and 2.6 +/- 1.1 in group T. The rate of rejection was 0.57/patient in each group for the entire follow-up period. None of these values reached statistical significance. Rates of HCV recurrence, graft loss or death from recurrent HCV, and 4-year actuarial patient and graft survival were not different between the groups. In liver transplant recipients with HCV, MMF has no impact on patient survival, graft survival, rejection, or rate of HCV recurrence based on biochemical changes and histological findings. In addition, there was no difference in HAI or fibrosis score between the two groups. Either MMF has no anti-HCV effect or its immunosuppressive properties overwhelm its antiviral effect in the clinical setting.

Topics: Adult; Aged; Cause of Death; Female; Graft Rejection; Hepatitis C; Humans; Immunosuppressive Agents; Liver; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prospective Studies; Secondary Prevention; Tacrolimus

Corticosteroids have long been a cornerstone of orthotopic liver transplant (OLTx) immunosuppression. Newer, more potent, agents have successfully allowed for more rapid tapering and discontinuation of corticosteroids in OLTx recipients. We hypothesize that corticosteroids can be safely avoided after the first postoperative day (POD) using these newer agents.. Thirty adult OLTx recipients were prospectively enrolled in a randomized open-label, institutional review board-approved protocol. Fifteen patients (group A) received our standard regimen of tacrolimus, mycophenolate mofetil, and corticosteroids, and 15 patients (group B) received daclizumab, 2 mg/kg on POD 0 and 14, with tacrolimus, mycophenolate mofetil, and corticosteroids on POD 0 and 1 and then discontinuation. In both groups, mycophenolate mofetil was tapered off between 3 and 4 months after OLTx. Bone mineral densitometry was performed at 1, 3, and 6 months after OLTx. Quantitative hepatitis C virus (HCV) polymerase chain reaction was obtained at days 0, 7, 14, 21, and 28. Retransplant recipients, patients with autoimmune hepatitis, or status 1 or 2A patients were excluded.. Patient and graft survival rates were 93% (group A) and 100% (group B) with mean follow-up of 18 months. Patients in group B had more rejection diagnosed (25%) compared with group A (6.7%). Yet, the incidence of biopsy-proven acute rejection requiring steroid therapy was 6.7% in both groups. Hispanic race was common in groups A and B (87% and 74%). A total of six biopsies were performed in group B, with three patients having mild rejection responding to an increase in tacrolimus without the need for corticosteroids. One patient in group B was switched to cyclosporine for severe neurotoxicity and remains on monotherapy with normal graft function. No patient in either group developed a requirement for additional antihypertensive medication. Likewise, there were no patients with new-onset diabetes. The bone mineral densitometry was higher in group B at every time point but did not reach statistical significance. Serum cholesterol level was significantly (P=0.03) lower in group B at 6 months after OLTx. Serum triglycerides were also lower, but the difference was not significant. Quantitative polymerase chain reaction for HCV-positive patients (group A, n=7; group B, n=8) frequently increased after OLTx. There was no correlative decrease associated with daclizumab. At present, two patients in group A have documented HCV recurrence.. Corticosteroids can be safely avoided after POD 1 with the current regimen. With early follow-up, there is no difference in hypertension or diabetes or bone density. Lipid panels tended to be lower in patients who were not on corticosteroids. Longer term follow-up will be needed to demonstrate the potential advantage of corticosteroid avoidance in regard to hypertension, diabetes, and possibly HCV recurrence.

Topics: Adrenal Cortex Hormones; Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Bone Density; Cholesterol; Daclizumab; Female; Hepatitis C; Humans; Immunoglobulin G; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Recurrence; Tacrolimus; Time Factors

Immunosuppression in patients with hepatitis C virus (HCV) following orthotopic liver transplantation can lead to significant increases in serum viral loads. Our aim was to analyze the effect of a randomized study of two immunosuppressive agents (tacrolimus vs. microemulsion cyclosporine) on the outcome of HCV patients following orthotopic liver transplantation.. From December 1995 to September 1996, 50 adult patients transplanted for HCV cirrhosis were randomly assigned to receive tacrolimus (Prograf) (group 1, 25 patients) or microemulsion cyclosporine (Neoral) (group 2, 24 patients). All patients received alpha-interferon after transplantation, and the overall steroid doses were no different between the groups. Serum RNA levels were measured by signal amplification of Chiron. Biopsies were taken when transaminases were greater than 2x base line or when there was an inappropriate response to alterations in immunosuppression regimens.. There were more episodes of rejection in the Neoral group, but there were no differences in bacterial and viral infections, nor in the rate of HCV recurrence between the two groups. There were seven deaths in group 1 and eight in group 2. Overall patient and graft survival rates in the Prograf and Neoral groups at 18 months were 72 and 68% and 67 and 64%, respectively.. (a) Both immunosuppression regimens had similar HCV recurrence rates; (b) there were no differences in bacterial or opportunistic infections; and (c) patient and graft survival was similar between the two groups.

Topics: Adult; Aged; Cyclosporine; Emulsions; Female; Graft Rejection; Graft Survival; Hepacivirus; Hepatitis C; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Recurrence; Reoperation; RNA, Viral; Survival Rate; Tacrolimus

Topics: Adult; Aged; Cyclosporine; Female; Follow-Up Studies; Hepatitis C; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Retrospective Studies; Tacrolimus; Time Factors

Topics: Adult; Aged; Cyclosporine; Female; Graft Rejection; Hepacivirus; Hepatitis C; Humans; Immunosuppressive Agents; Incidence; Liver Neoplasms; Male; Methylprednisolone; Middle Aged; Recurrence; RNA, Viral; Tacrolimus

The introduction of tacrolimus as rescue therapy represents a significant advance in the prevention of late graft failure and second liver transplantation. The authors report the blood level monitoring of tacrolimus as a rescue therapy in 21 children who underwent liver transplantation, and they report the dose-concentration relationship in the presence or absence of hepatitis C virus (HCV) in these patients. This was a retrospective study conducted from May 1993 to January 1997. Indication for the conversion from cyclosporine (CsA) to tacrolimus were acute rejection (62%), chronic rejection (33%), and CsA toxicity (5%). Mean daily dose in the first month was 0.32 mg/kg, whereas at the end of the follow-up period it was 0.14 mg/kg. Tacrolimus mean whole blood concentration levels were between 7.1 ng/ml and 9.4 ng/ml, without significant differences over time. Mean daily doses in HCV+ and HCV- patients were 0.08 and 0.24 mg/kg, respectively (p < 0.01), and mean concentrations were 8.3 and 8.4 ng/ml (NS). HCV+ children required a mean dose three times lower than the dose used in HCV- children to obtain the same tacrolimus trough blood level. Therefore, doses in HCV+ children must be decreased to achieve levels within the therapeutic range.

Topics: Adolescent; Child; Child, Preschool; Cyclosporine; Dose-Response Relationship, Drug; Drug Monitoring; Female; Follow-Up Studies; Graft Rejection; Hepacivirus; Hepatitis C; Humans; Immunosuppressive Agents; Infant; Liver Transplantation; Male; Retrospective Studies; Tacrolimus

Topics: Adult; Anti-Infective Agents; Azathioprine; Contraindications; Creatinine; Dose-Response Relationship, Drug; Drug Resistance; Female; Follow-Up Studies; Ganciclovir; Graft Rejection; Graft Survival; Hepatitis B; Hepatitis C; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Muromonab-CD3; Steroids; Tacrolimus; Time Factors; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Alanine Transaminase; Cyclosporine; Female; Follow-Up Studies; Hepacivirus; Hepatitis C; Humans; Interferon alpha-2; Interferon-alpha; Liver Transplantation; Male; Middle Aged; Polymerase Chain Reaction; Recombinant Proteins; RNA, Viral; Tacrolimus; Time Factors

Topics: Brain; Cyclosporine; Drug Therapy, Combination; Electroencephalography; Hepatitis B; Hepatitis C; Humans; Immunosuppression Therapy; Incidence; Liver Transplantation; Magnetic Resonance Imaging; Neurotoxins; Survival Rate; Tacrolimus; Tomography, X-Ray Computed

Liver transplant recipients have an increased risk of osteoporosis and fractures. The aim of this study was to identify risk factors for fractures after liver transplant in a Taiwanese population.. We identified newly diagnosed liver transplant recipients from the National Health Insurance Research Database in Taiwan between 2003 and 2015. Risk factors of post-transplant fractures were analyzed using a Cox proportional hazards model.. A total of 4821 patients underwent liver transplantation, of whom 419 (8.7%) had post-transplant fractures. Independent predictors of post-transplant fractures were age ≥65 years at transplantation (hazard ratio (HR): 1.566; 95% confidence interval (CI) 1.122-2.186), female sex (HR: 1.648; 95% CI 1.319-2.057), fractures within 1 year prior to transplant (HR: 3.664; 95% CI 2.503-5.364), hepatitis C carriers (HR: 1.594; 95% CI 1.289-1.970), alcoholism (HR: 1.557; 95% CI 1.087-2.230) and daily prednisolone dose >1.61-3.78 mg/day (HR: 1.354; 95% CI 1.005-1.824), >3.78-9.18 mg (HR: 4.182; 95% CI 3.155-5.544) and >9.18 mg (HR: 13.334; 95% CI 9.506-18.703). Post-transplant fractures were inversely correlated with tacrolimus (HR: 0.617; 95% CI 0.417-0.913) and sirolimus/everolimus (HR: 0.504; 95% CI 0.391-0.650) treatment.. The liver transplant recipients, and especially those who were aged ≥65 years, female, hepatitis C carriers, had a history of fractures within 1 year prior to transplant, alcoholism, and higher daily prednisolone dose were associated with an increased risk of post-transplant fractures. Conversely, the use of tacrolimus and sirolimus/everolimus was associated with a decreased risk of fractures.. This study identified risk factors for fractures after liver transplant in a population-based study in an area with high prevalence of hepatitis B and hepatitis C.Recipients who were aged ≥65 years, female, hepatitis C carriers, had a history of fractures within 1 year prior to transplant, alcoholism, and higher daily prednisolone dose were independent risk factors for post-transplant fractures.Our findings highlight the importance of identifying individuals at high risk of fractures and concomitant tacrolimus and sirolimus/everolimus treatment to avoid the use of high-dose steroids and prevent post-transplant fractures.

Topics: Alcoholism; Cohort Studies; Everolimus; Female; Fractures, Bone; Hepatitis C; Humans; Immunosuppressive Agents; Liver Transplantation; Prednisolone; Proportional Hazards Models; Risk Factors; Sirolimus; Tacrolimus

Topics: Everolimus; Graft Rejection; Hepacivirus; Hepatitis C; Humans; Immunosuppressive Agents; Liver Transplantation; Tacrolimus; Treatment Outcome

Background and objective The main objective was to evaluate the impact of Hepatitis C Virus treatment with direct-acting antiviral agents on tacrolimus blood levels in recipients of kidney and heart allografts. Method We analysed Hepatitis C Virus infected adult patients who received tacrolimus as immunosuppressive maintenance therapy and received direct-acting antiviral agents treatment in a tertiary hospital with solid transplant multidisciplinary program in Madrid, Spain. Liver and renal function, tacrolimus dose and blood levels were analysed before and 12 weeks after the end of treatment. Results We identified 7 kidney and 2 heart transplant recipients. All patients achieved sustained virologic response at 24 weeks. At week 12 after treatment, all liver functionality tests improved significantly with no significant changes in renal function. A decrease in the tacrolimus blood level/dose ratio for every patient was observed (370.04 ± 253.93 vs. 186.44 ± 123.74 ng/mL per mg/kg; p < 0.05). The requirements of tacrolimus dose increased after Hepatitis C Virus treatment (0.03 ± 0.04 vs. 0.04 ± 0.03 mg/kg/day, p < 0.05) to reach lower blood levels than before treatment (6 ± 2.25 vs. 4.67 ± 1.51 ng/mL, p < 0.05). Conclusion Caution is advised to clinicians; close monitoring of tacrolimus levels after direct-acting antiviral agents is recommended in order to avoid infradosification that could pose a risk of graft rejection.

Topics: Adult; Antiviral Agents; Hepatitis C; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Kidney Transplantation; Tacrolimus; Treatment Outcome

The Social Security System of our country reimburses only paritaprevir, ritonavir, ombitasvir, and dasabuvir (PrOD) regime in treatment-naive patients with hepatitis C regardless of kidney disease. Most of our renal transplant (RT) recipients were treated with PrOD. The aim of the present study was to investigate the efficacy and safety of PrOD in RT patients with hepatitis C virus (HCV) infection in a single center real-life experience.. RT recipients with a post-transplant follow-up of at least 1 year were included in the study. The patients were treated and monitored according to the guidelines. Blood levels of immunosuppressive patients were closely followed up and adjusted.. A total of 21 (12 male and nine female) patients were assessed. The age of the patients was 50.8±8.5 years. Ten patients were infected with G1a, 10 patients with G1b, and one patient with G4 HCV. Two patients had compensated cirrhosis. Eighteen patients were treatment-naive, and three were peginterferon+ribavirin-experienced. Sustained virologic response (SVR12) was achieved in all patients. None of the patients discontinued the treatment. Cyclosporine (Csa) and tacrolimus (Tac) doses were reduced to once a day to once a week to maintain the blood level within normal range. The most common adverse effect was anemia in patients receiving ribavirin. Renal functions did not change during the treatment period.. In this real-life experience, all of the 21 PrOD-treated RT recipients reached SVR12. Tac or Csa serum levels were maintained within the normal range with close monitoring. PrOD regime can be successfully and safely used in RT recipients with HCV infection with close follow-up.

Topics: 2-Naphthylamine; Adult; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Cyclosporine; Female; Hepacivirus; Hepatitis C; Humans; Kidney Transplantation; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Middle Aged; Postoperative Complications; Proline; Ritonavir; Sulfonamides; Sustained Virologic Response; Tacrolimus; Uracil; Valine

Direct-acting antivirals (DAAs) have transformed hepatitis C virus (HCV) management post-liver transplant. As HCV clears during DAA treatment, hepatic metabolism improves, resulting in decreased tacrolimus concentrations that may require dose adjustment. The purpose of this study was to determine appropriate management of immunosuppression in liver transplant recipients during and following treatment of HCV.. This study was a single-center retrospective analysis of 71 liver transplant recipients who were treated for HCV with DAAs. The primary outcome was change in dose-normalized tacrolimus concentrations from the start of DAA treatment to 12 weeks following therapy.. The mean change in log-transformed dose-normalized tacrolimus concentrations was a reduction of 0.43 ng/mL/mg (95% CI; 0.26-0.60, P < 0.0001). The greatest decrease occurred in the first 4 weeks of treatment, after which levels stabilized. The overall mean tacrolimus concentration was 4.8 ng/mL (±2.5). Two patients (3%) developed acute cellular rejection and two patients (3%) had graft loss and died.. From the start of treatment to 12 weeks post-DAA therapy, liver transplant recipients experienced a significant decrease in dose-normalized tacrolimus concentrations. In conclusion, close monitoring of tacrolimus concentrations is warranted during and following treatment with DAAs, as dose increases may be indicated in order to maintain therapeutic concentrations to prevent graft rejection.

Topics: Aged; Antiviral Agents; Disease Management; Drug Interactions; Drug Therapy, Combination; Female; Hepatitis C; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Retrospective Studies; Sofosbuvir; Tacrolimus

Direct-acting antiviral agents have demonstrated their efficacy in treating HCV recurrence after liver transplantation and particularly the sofosbuvir/daclatasvir combination. Pharmacokinetic data on both calcineurin inhibitors and direct-acting antiviral exposure in liver transplant recipients remain sparse.. Patients were enrolled from the ANRS CO23 CUPILT cohort. All patients treated with sofosbuvir/daclatasvir with or without ribavirin were included in this study when blood samples were available to estimate the clearance of immunosuppressive therapy before direct-acting antiviral initiation and during follow-up. Apparent tacrolimus and cyclosporine clearances were estimated from trough concentrations measured using validated quality control assays.. Sixty-seven mainly male patients (79%) were included, with a mean age of 57 years and mean MELD score of 8.2; 50 were on tacrolimus, 17 on cyclosporine. Ribavirin was combined with sofosbuvir/daclatasvir in 52% of patients. Cyclosporine clearance remained unchanged as well as tacrolimus clearance under the ribavirin-free regimen. Tacrolimus clearance increased 4 weeks after direct-acting antivirals and ribavirin initiation versus baseline (geometric mean ratio 1.81; 90% CI 1.30-2.52). Patients under ribavirin had a significantly higher fibrosis stage (> 2) (p = 0.02) and lower haemoglobin during direct-acting antiviral treatment (p = 0.02) which impacted tacrolimus measurements. Direct-acting antiviral exposure was within the expected range.. Our study demonstrated that liver transplant patients with a recurrence of hepatitis C who are initiating ribavirin combined with a sofosbuvir-daclatasvir direct-acting antiviral regimen may be at risk of lower tacrolimus concentrations because of probable ribavirin-induced anaemia and higher fibrosis score, although there are no effects on cyclosporine levels.. NCT01944527.

Topics: Aged; Anemia; Antiviral Agents; Carbamates; Cyclosporine; Drug Interactions; Drug Therapy, Combination; Female; Hepatitis C; HIV Infections; Humans; Imidazoles; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Pyrrolidines; Ribavirin; Sofosbuvir; Tacrolimus; Valine

Graft-versus-host disease (GvHD) is a rare but fatal complication after solid organ transplantation arising in 1% to 2% of cases. We report 2 cases of GvHD after orthotopic liver transplantation. Both patients had a history of hepatitis C virus (HCV) infection prior to transplantation. Both cases presented between 1 and 4 months after transplantation with rash, pancytopenia, and/or diarrhea. Our second case also developed oral and ocular manifestations after liver transplantation, which are more commonly described after stem cell transplantation. Diagnosis in both cases was made by clinical presentation in conjunction with histopathology and flow cytometry. Both patients were treated by increasing immunosuppression with tacrolimus and high-dose steroids. Response to treatment differed based on the degree of pancytopenia. Our case report is distinguished by several factors such as the context of GvHD presentation and the role of HCV treatment. Diagnosis of GvHD is difficult and often delayed due to nonspecific presentation that overlaps with other conditions. Furthermore, the relation between HCV treatment and potential initiation of GvHD in solid organ transplant patients is unclear.

Topics: Graft vs Host Disease; Hepatitis C; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Tacrolimus; Treatment Outcome

This study's aim was to investigate the safety and effectiveness of asunaprevir and daclatasvir treatment for recurrent hepatitis C virus (HCV) infection in transplant recipients. The study cohort comprised 14 transplant recipients with recurrent hepatitis C who were receiving asunaprevir and daclatasvir.. Serum concentrations of asunaprevir and daclatasvir, their therapeutic effects, trough concentrations/dose ratios of tacrolimus, and adverse effects were evaluated.. Hepatitis C virus was still undetectable in 12 (85.7%) out of 14 patients 12 weeks after completing treatment. One week after starting treatment, asunaprevir concentrations were significantly higher in patients with baseline albumin concentrations ≤3.6 g/dl than in those with baseline albumin concentrations >3.6 g/dl. No marked fluctuations were identified in tacrolimus trough concentrations/dose ratios during the 24 weeks of therapy.. Full doses of asunaprevir and daclatasvir-based treatment can be safely and effectively administered to liver transplant recipients for recurrent HCV genotype 1b after living donor liver transplantation (LDLT) with little effect on blood concentrations of tacrolimus.

Topics: Aged; Antiviral Agents; Carbamates; Drug Interactions; Drug Monitoring; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C; Humans; Imidazoles; Immunosuppressive Agents; Isoquinolines; Liver Transplantation; Living Donors; Male; Middle Aged; Prospective Studies; Pyrrolidines; Recurrence; Sulfonamides; Tacrolimus; Time Factors; Treatment Outcome; Valine; Viral Load

A 53-year-old woman who had undergone deceased donor kidney transplantation twice, at 35 and 43 years of age, presented with renal impairment. She was infected with hepatitis C virus (HCV). The histology of the graft kidney revealed post-transplant membranous nephropathy (MN) with podocytic infolding and antibody-mediated rejection (AMR). IgG subclass staining showed fine granular deposits of IgG1 and IgG3, but not IgG4, in the glomerular capillary walls. Panel reactive antibody scores for human leukocyte antigen class I and class II were 92.67% and 66.68%, respectively. Thus, this case of post-transplanted MN was considered to be associated with AMR and HCV infection.

Topics: Female; Glomerulonephritis, Membranous; Graft Rejection; Hepatitis C; Histocompatibility Antigens Class I; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Methylprednisolone; Middle Aged; Prednisolone; Reoperation; Tacrolimus; Time Factors; Treatment Outcome

We assessed the effect of hepatitis C seropositivity on the percentage of various T-cells in living donor renal transplant recipients (LDRTRs) and their association with intercurrent infections post renal transplantation (post-Tx).. One hundred and thirty-three matching LDRTRs [A (seronegative) (68 patients) and B (seropositive) (65 patients) by ELISA] were studied prospectively 10 days, 6 months and 12 months post-Tx for intercurrent infections, acute rejection and T-cell% by flow cytometry.. CD4(+), CD8(+), CD4/CD8 were significantly higher 10 days post-Tx in Group B compared to Group A, p < 0.001. A significant increase in CD8% was seen 6-month post-Tx among Group B compared to Group A. No difference was detected between groups in (CD4(+), CD8(+), CD4/CD8, CD3-CD16/65(+)%), rate and severity of intercurrent infection, rate of acute rejection, 12 months post-Tx. A significantly higher rate of severe infections particularly urinary tract infections (UTI) was noted in Group B compared to Group A the first 3 months post-Tx particularly in those who received the combination of antithymocyte globulin (ATG) or basiliximab, tacrolimus, steroids, mycophenolate mofetil (MMF). CD4(+)% correlated negatively with intercurrent infections in Group B 6 months post-Tx.. HCV(+) patients are more prone to intercurrent infections the first 3 months post-Tx. Infection rate correlates positively with pre-transplant HCV seropositivity and immunosuppressive regimen.

Topics: Adolescent; Adult; Aged; Antibodies, Monoclonal; Basiliximab; CD4-CD8 Ratio; Child; Egypt; Female; Graft Rejection; Graft Survival; Hepatitis C; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Recombinant Fusion Proteins; Regression Analysis; T-Lymphocytes; Tacrolimus; Urinary Tract Infections; Young Adult

The relationship between patient survival and biopsy-proven acute rejection (BPAR) in liver transplant recipients with hepatitis C remains unclear. The aims of this study were to compare the characteristics of patients with and without BPAR and to identify risk factors for BPAR.. We retrospectively reviewed the records of 169 HCV-RNA-positive patients who underwent LT at three centers.. BPAR occurred in 39 (23.1%) of the HCV-RNA-positive recipients after LT. The 1-, 3-, and 5-year survival rates were 92.1%, 90.3%, and 88.5%, respectively, in patients without BPAR, and 75.7%, 63.4%, and 58.9% in patients with BPAR (. The results of the present study suggest that the immunosuppression status of HCV-RNA-positive LT recipients should be carefully determined in order to prevent BPAR and to improve patient survival.

Topics: Antibodies, Monoclonal; Basiliximab; Biopsy; Cyclosporine; Drug Therapy, Combination; Genotype; Graft Rejection; Hepacivirus; Hepatitis C; Humans; Immunosuppressive Agents; Liver Transplantation; Polymerase Chain Reaction; Recombinant Fusion Proteins; Recurrence; Retrospective Studies; RNA, Viral; Survival Rate; Tacrolimus

Hepatitis C virus (HCV) still has significant prevalence in kidney transplant (KT) recipients and is related to poor recipient and graft survival. New direct-acting antivirals (DAA) are leading to a radical change in the problem.. We studied HCV prevalence at the time of transplantation and in follow-up patients, the way cases are handled, and the results of DAA.. A total of 2,001 KT had been performed in our center since 1978. Pre- or post-transplantation HCV serology was present in 1,880 cases and was positive in 13.4%. A total of 1,195 transplant recipients were still being monitored by us, with only 60 (5%) HCV+ and 45 (3.6%) RNA+ cases. Of these 45 HCV+/RNA+, 25 had been or were being treated, 7 were about to begin treatment, 1 was awaiting new DAA treatment owing to low glomerular filtration rate (GFR), 3 were being evaluated, 2 had been excluded owing to high comorbidity, 2 refused to be treated, 2 needed to return to hemodialysis, and 1 was lost to follow-up. Except 1 case where Viekira Pak was used because of low GFR, all cases included sofosbuvir as the main drug associated with either ledipasvir (70%) or daclatasvir (25%). Ribavirin was added as coadjuvant in 35% of cases. Twenty-one patients had completed treatment (84%). Two patients had to interrupt DAA therapy (8%), one because of hepatotoxicity and the other as a result of a liver transplantation. In every case, the graft maintained function and negativization of viral replication occurred.. Side effects have been low, anemia related to ribavirin being the main one. Just one case needed to be interrupted at the 7th week of DAA therapy due to hepatotoxicity. It has frequently been necessary to adjust immunosuppression treatment with the use of higher doses of tacrolimus.

Topics: Adult; Antiviral Agents; Female; Graft Survival; Hepacivirus; Hepatitis C; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Kidney; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Ribavirin; Sofosbuvir; Tacrolimus

Recurrence of hepatitis C virus (HCV) infection after orthotopical liver transplantation (OLT) is common and associated with reduced graft and patient survival. The protease inhibitor telaprevir may enhance virological response rates in patients after OLT in combination with pegylated interferon-alfa and ribavirin. Pharmacokinetic studies have shown significant drug-drug interactions between telaprevir and immunosuppression (IS), but telaprevir pharmacokinetics in OLT patients with IS are unknown. Aim of the present study was to analyse telaprevir plasma concentrations in patients with HCV genotype 1 infection after OLT in comparison to patients without OLT and IS.. Five patients with HCV genotype 1 infection after OLT and 37 HCV genotype 1-infected patients patients without prior OLT were treated with telaprevir 2250 mg daily, ribavirin 1000/1200 mg daily and pegylated interferon-alfa-2a 180 μg once weekly (triple therapy). Telaprevir plasma concentrations were analysed by liquid chromatography-electrospray-ionization-tandem mass spectrometry. HCV RNA was assessed by automatized reverse-transcription polymerase chain-reaction.. Median (range) telaprevir plasma concentrations of TW 4, 8 and 12 were 3970 (1980-4430) ng/ml and 2520 (1870-8730) ng/ml in patients after OLT and ciclosporin- or tacrolimus-based IS, respectively, as compared to 2790 (1870-3140) in non-OLT patients (P = 0.3). In one patient with tacrolimus-based IS, telaprevir dose had to be adjusted to achieve virological response. Telaprevir plasma concentrations were steady at treatment weeks 4, 8 and 12 in patients with and without IS.. Telaprevir drug monitoring may be necessary in patients with tacrolimus-based IS in patients with HCV graft infection after OLT.

Topics: Antiviral Agents; Chromatography, Liquid; Drug Monitoring; Drug Therapy, Combination; Hepatitis C; Humans; Immunosuppression Therapy; Interferon-alpha; Liver Transplantation; Oligopeptides; Polyethylene Glycols; Prospective Studies; Recombinant Proteins; Recurrence; Ribavirin; Statistics, Nonparametric; Tacrolimus; Tandem Mass Spectrometry

Graft loss because of hepatitis C virus recurrence is a serious problem after liver transplantation (LT), and the response to pegylated interferon (PEG-IFN) and ribavirin (RBV) is poor. The significantly better response rates achieved with telaprevir (TVR)-based triple therapy have led to better graft and patient survival rates, but severe drug interactions may limit the usefulness of this therapy for LT patients. We report our single-center experience with a specially developed protocol that involved administering a low daily dose of tacrolimus (TAC) to a cohort of 17 patients with a recurrence of hepatitis C virus genotype 1 after LT.. Patients were treated with TVR, PEG-IFN, and RBV for 12 weeks, followed by 12 or 36 weeks of dual therapy with PEG-IFN and RBV. After TVR administration was initiated, the TAC dosage was skipped until trough levels began to decline; it was then administered at a dose of 0.1 mg once or twice daily. Tacrolimus trough levels and laboratory values were closely monitored during the TVR phase.. Deviations in trough levels were avoided, thus preventing any clinically evident renal toxicity related to TAC. In addition, histologic studies performed at the end of therapy showed that no rejection episodes had occurred. All patients tolerated the medication. Sustained virologic response was documented for 10 of 17 patients (58%) 24 weeks after end of treatment.. In conclusion, substantial dose reduction and daily administration of low doses of TAC compose a safe and efficient immunosuppressive regimen during TVR-based triple therapy.

Topics: Adult; Aged; Antiviral Agents; Drug Monitoring; Drug Therapy, Combination; Feasibility Studies; Female; Genotype; Germany; Hepacivirus; Hepatitis C; Humans; Immunosuppressive Agents; Interferons; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Oligopeptides; Recurrence; Retrospective Studies; Ribavirin; Tacrolimus; Time Factors; Treatment Outcome; Virus Activation

We previously reported our data on telaprevir (TVR) used in combination with pegylated-interferon and ribavirin (PEG-IFN/RBV) for the treatment of recurrent hepatitis C virus (HCV) genotype 1 infection after liver transplantation (LT). TVR substantially increases the blood levels of immunosuppressive agents such as cyclosporine and tacrolimus for drug-drug interactions. On the other hand, the effect of simeprevir (SMV) on the blood levels of these immunosuppressive agents is unclear. We report 2 patients who achieved viral responses with little effect on the blood levels of cyclosporine and tacrolimus using SMV plus PEG-IFN/RBV treatment. The first was a 71-year-old woman with HCV-related liver cirrhosis and hepatocellular carcinoma who failed to respond to PEG-IFN/RBV after living donor LT. She was treated with 40 mg/d of cyclosporine, and received SMV plus PEG-IFN/RBV treatment. The second was a 65-year-old man with HCV-related liver cirrhosis who failed to respond to PEG-IFN/RBV after living donor LT. He was treated with 3 mg/d of tacrolimus, and received SMV plus PEG-IFN/RBV treatment. Serum HCV RNA became undetectable using TaqMan polymerase chain reaction (PCR) test after 4 weeks of treatment in both patients, and no remarkable fluctuation in blood concentration was observed either in cyclosporine or tacrolimus during the 12 weeks of SMV treatment. Completion of 12-week SMV triple therapy was followed by PEG-IFNα2b plus RBV, and both patients achieved sustained virological response 12 weeks after the end of treatment. SMV plus PEG-IFNRBV treatment showed a remarkable viral response with little effect on blood levels of immunosuppressive agents for recurrent HCV genotype 1 infection after LT.

Topics: Aged; Antiviral Agents; Cyclosporine; Drug Therapy, Combination; Female; Hepatitis C; Humans; Immunosuppressive Agents; Interferon alpha-2; Interferon-alpha; Liver Cirrhosis; Liver Transplantation; Living Donors; Male; Polyethylene Glycols; Protease Inhibitors; Recombinant Proteins; Ribavirin; Simeprevir; Tacrolimus; Treatment Outcome

Topics: Antiviral Agents; Female; Hepacivirus; Hepatitis C; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Male; Oligopeptides; Tacrolimus

Recurrent hepatitis C infection leads to accelerated graft loss in liver transplant recipients. Telaprevir offers a higher chance of cure in these patients. We sought to assess the effectiveness of telaprevir in treatment of hepatitis C in liver transplant recipients.. We report a series of 17 patients who received telaprevir for recurrent hepatitis C virus infection. These patients were previous treatment failures including 10 null responders. All patients received pegylated interferon alpha 2a (180 μg/wk) and ribavirin (800 mg/d) for 1 year and telaprevir 750 mg every 8 hours for 12 weeks. The immunosuppressive regimen was not changed during therapy, but the dosages were modified based on serum levels of the drugs.. In an intention-to-treat analysis, the overall sustained virologic response 12 was 58%, with a relapse rate of 24%. Nine patients (52%) achieved extended rapid virologic response. Seven patients (77%) with extended rapid virologic response achieved sustained virologic response 12. Four patients (40%), who were previous null responders to interferon and ribavirin also achieved sustained virologic response 12. Anemia and ribavirin dosage reduction were common. Severe thrombocytopenia was seen in 2 patients resulting in discontinuation of therapy. A tacrolimus-based immunosuppressive regimen could be continued with close monitoring. During the initial 4 weeks of therapy, there were wide fluctuations in tacrolimus levels. However, after 4 weeks, tacrolimus could be dosed weekly maintaining a trough level of 3 to 10 ng/mL.. Telaprevir can be used effectively in liver transplant recipients receiving tacrolimus-based immunosuppression. Sustained virologic response 12 can be achieved in a significant number of these "difficult-to-treat" patients.

Topics: Aged; Antiviral Agents; Drug Administration Schedule; Drug Therapy, Combination; Female; Hepatitis C; Humans; Immunosuppressive Agents; Interferon-alpha; Liver Transplantation; Male; Middle Aged; Oligopeptides; Polyethylene Glycols; Recombinant Proteins; Recurrence; Ribavirin; Tacrolimus; Time Factors; Treatment Outcome; Viral Load

Topics: Aged; Alcoholism; Biopsy; Carcinoma, Hepatocellular; Drug Administration Schedule; Female; Hepatitis C; Humans; Immunosuppressive Agents; Infusions, Intravenous; Kidney; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; Tacrolimus; Time Factors

We report our experience with a 61-year-old patient with alcoholic and hepatitis C cirrhosis who underwent liver transplantation. On the 3rd postoperative day he presented a mediastinitis secondary to esophageal perforation produced by a Linton tube. An esophagectomy with jejunostomy was performed. Tacrolimus granules for oral suspension (Modigraf) were administered through the jejunostomy. This case report highlights the use of Modigraf and the absence of secondary effects. We observed biochemical parameters during the jejunostomy period. We discuss the administration strategy applied and whether tacrolimus granules for oral suspension by jejunostomy affect the bioavailability and its side effects.

Topics: Administration, Oral; Biological Availability; Carcinoma, Hepatocellular; Chemistry, Pharmaceutical; Esophageal Perforation; Esophagectomy; Hepatitis C; Humans; Immunosuppressive Agents; Jejunostomy; Liver Cirrhosis; Liver Cirrhosis, Alcoholic; Liver Neoplasms; Liver Transplantation; Male; Mediastinitis; Middle Aged; Tacrolimus; Tomography, X-Ray Computed; Treatment Outcome

The development of end-stage graft disease is suspected to be partially determined by an individual genetic background. The aim of our study was to determine the prevalence of YKL-40-gene polymorphism in hepatitis C virus (HCV)-positive patients and its impact on the incidence of acute cellular rejection (ACR), graft fibrosis and antiviral treatment response.. A total of 149 patients, who underwent liver transplantation for HCV-induced liver disease, were genotyped for YKL-40 (rs4950928; G/C) by TaqMan Genotyping Assay. The results were correlated with 616 post-transplant graft biopsies regarding inflammation, fibrosis and evidence for ACR.. No association of YKL-40-genotypes was observed regarding mean inflammation grade (P = 0.216) and antiviral treatment outcome (P = 0.733). However, the development of advanced fibrosis (F3-4) was significantly faster in patients with YKL-40-G-allele: t(CC) = 4.6 versus t(CG/GG) = 2.4 years; P = 0.006. Patients with lower fibrosis (F0-2) compared to advanced fibrosis (F3-4) received significantly more frequent dual immunosuppression (calcineurin inhibitors [CNIs]/mofetile mycophenolate [MMF] vs CNIs; P = 0.003). ACR-occurrence was associated with YKL-40-genotypes (ACR: CC = 60.4%, CG = 25.0% and GG = 14.6% vs non-ACR: CC = 74.2%, CG = 23.8% and GG = 2.0%; P = 0.009) and with gender compatibility between donor and recipient (P = 0.012).. Fibrosis progression and ACR-incidence after transplantation for HCV-induced liver disease seem to be under genetic control. The negative impact of G-allele on post-transplant events observed in our study, deserves attention and should be verified in larger liver transplantation-cohorts.

Topics: Adipokines; Adult; Antiviral Agents; Chitinase-3-Like Protein 1; Cyclosporine; Disease Progression; Drug Therapy, Combination; End Stage Liver Disease; Female; Genotype; Graft Rejection; Hepacivirus; Hepatitis C; Humans; Immunosuppressive Agents; Interferon alpha-2; Interferon-alpha; Lectins; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Polyethylene Glycols; Polymorphism, Single Nucleotide; Recombinant Proteins; Ribavirin; Sex Factors; Statistics, Nonparametric; Tacrolimus; Time Factors; Young Adult

Liver transplant (LT) patients might be overimmunosuppressed as recommendations for tacrolimus trough concentrations (TC) within 4-6 weeks after liver transplantation are set too high (10-15 ng/ml). Early tacrolimus exposure was evaluated in relation to acute rejection and long-term outcomes.. Four hundred and ninety-three consecutive LT patients receiving tacrolimus as primary immunosuppression (1995-2008) were analyzed. Acute rejection was diagnosed using protocol biopsies at day 6.1 ± 2.5. Median follow-up was 7.3 years (IQR 3.9-10.5). Early tacrolimus exposure (<15 days) was evaluated against moderate/severe acute rejection, chronic rejection, graft loss, chronic renal impairment and mortality using multiple logistic and Cox regression.. Maintenance immunosuppression was tacrolimus monotherapy (48.1%), double therapy combination with antimetabolites or steroids (18%), or triple therapy combination with antimetabolites and steroids (33.9%). Histological grade of acute rejection was moderate in 157 cases (31.8%) and severe in 19 cases (3.9%). Tacrolimus TC>7 ng/ml on the day of protocol biopsy was associated with less moderate/severe rejection (23.8%) compared with<7 ng/ml (41.2%) (p = 0.004). Mean tacrolimus TC 7-10 ng/ml within 15 days after LT were associated with reduced risk of graft loss (RR = 0.46; p = 0.014) compared to TC 10-15 ng/ml. A peak TC>20 ng/ml within this period was independently related to higher mortality (RR = 1.67; p = 0.005), particularly due to cardiovascular events, infections and malignancy (RR = 2.15; p = 0.001). Early tacrolimus exposure did not influence chronic rejection (p = 0.58), or chronic renal impairment (p = 0.25).. During the first 2 weeks after LT, tacrolimus TC between 7 and 10 ng/ml are safe in terms of acute rejection and are associated with longer graft survival.

Topics: Adult; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Graft Rejection; Hepatitis C; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Liver Failure, Acute; Liver Neoplasms; Liver Transplantation; Logistic Models; Longitudinal Studies; Male; Middle Aged; Prospective Studies; Severity of Illness Index; Survival Rate; Tacrolimus; Time Factors; Treatment Outcome

Topics: Female; Graft Rejection; Graft Survival; Hepatitis C; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Sirolimus; Tacrolimus

Cyclosporine A (CSA) has potent effects against hepatitis C virus (HCV) in vitro, but its clinical efficacy after liver transplantation (LT) is uncertain. We evaluated the impact of CSA and tacrolimus (TAC) with or without concomitant interferon (IFN) therapy on serum HCV titers in a chimeric mouse model of HCV infection. Six groups of HCV-infected mice received only the vehicle, IFN, CSA, CSA and IFN, TAC, or TAC and IFN for 4 weeks. The quantitative HCV polymerase chain reaction levels were determined after 1, 2, and 4 weeks of drug administration. There were no significant differences in the HCV titers after 4 weeks of treatment between the non-IFN-treated groups (log HCV titers: 3.5 ± 0.3 for the vehicle group, 4.4 ± 0.6 for the CSA group, and 4.3 ± 0.4 for the TAC group, P = 0.3). Although IFN had a consistent effect of reducing HCV titers across the groups, there was no significant impact of CSA on HCV levels when it was used alone or in combination with IFN at any time point. The 4-week HCV titers were as follows: 3.2 ± 0.3 for the IFN group, 4.7 ± 0.4 for the CSA/IFN group, and 4.0 ± 0.5 for the TAC/IFN group (P = 0.07). The CSA/IFN and TAC/IFN groups did not differ significantly (P = 0.6). Six of the 7 animals in the IFN group (85.7%) had an HCV titer decline ≥ 1 log, whereas in the test groups (CSA/IFN and TAC/IFN), 6 of 9 animals (66.7%) achieved a 1-log decline in the HCV titer (P = 1). Using this animal model, we could find no evidence supporting the routine use of CSA after LT in HCV-infected patients.

Topics: Animals; Antiviral Agents; Calcineurin Inhibitors; Chimera; Cyclosporine; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Hepacivirus; Hepatitis C; Interferon alpha-2; Interferon-alpha; Mice; Mice, SCID; Recombinant Proteins; Tacrolimus; Treatment Outcome; Viral Load; Virus Replication

The aim of this retrospective study is to assess the impact of calcineurin inhibitors on hepatitis C virus recurrence following liver transplantation.. A total of 396 patients underwent liver transplantation for hepatitis C virus-induced liver disease between 1991 and 2005 at a single center. We examined the pre- and post-operative characteristics of patients who received either cyclosporine (n = 126) or tacrolimus (n = 270) as maintenance immunosuppression. In addition, we compared the postoperative course, including patient, graft and hepatitis C virus recurrence-free survival between the two groups.. There were no significant differences between the two groups in either post-operative hepatitis C virus-ribonucleic acid or histological fibrosis score (performed within 6 months after transplant per protocol). The graft and patient survivals did not differ between the two groups (logrank p = 0.34 and 0.15, respectively). Histologic hepatitis C virus recurrence-free survival, however, was significantly higher in the cyclosporine group than in the tacrolimus group (55.4 vs. 30.8% at 1 year, 18.6 vs. 10.3% at 3 years, 16.7 vs. 8.1% at 5 years, p < 0.001).. Patients transplanted for hepatitis C virus and treated with cyclosporine versus tacrolimus may have a higher recurrence-free survival.

Topics: Calcineurin Inhibitors; Cyclosporine; Female; Graft Survival; Hepatitis C; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Multivariate Analysis; Retrospective Studies; Risk Factors; Secondary Prevention; Tacrolimus; Transplantation, Homologous

Topics: Animals; Calcineurin Inhibitors; Cyclosporine; Hepacivirus; Hepatitis C; Interferon alpha-2; Interferon-alpha; Recombinant Proteins; Tacrolimus; Virus Replication

The hepatitis C virus protease inhibitor boceprevir is a strong inhibitor of cytochrome P450 3A4 and 3A5 (CYP3A4/5). Cyclosporine and tacrolimus are calcineurin inhibitor immunosuppressants used to prevent organ rejection after liver transplantation; both are substrates of CYP3A4. This two-part pharmacokinetic interaction study evaluated boceprevir with cyclosporine (part 1) and tacrolimus (part 2). In part 1, 10 subjects received single-dose cyclosporine (100 mg) on day 1, single-dose boceprevir (800 mg) on day 3, and concomitant cyclosporine/boceprevir on day 4. After washout, subjects received boceprevir (800 mg three times a day) for 7 days plus single-dose cyclosporine (100 mg) on day 6. In part 2A, 12 subjects received single-dose tacrolimus (0.5 mg). After washout, they received boceprevir (800 mg three times a day) for 11 days plus single-dose tacrolimus (0.5 mg) on day 6. In part 2B, 10 subjects received single-dose boceprevir (800 mg) and 24 hours later received boceprevir (800 mg) plus tacrolimus (0.5 mg). Coadministration of boceprevir with cyclosporine/tacrolimus was well tolerated. Concomitant boceprevir increased the area under the concentration-time curve from time 0 to infinity after single dosing (AUC(inf) ) and maximum observed plasma (or blood) concentration (C(max) ) of cyclosporine with geometric mean ratios (GMRs) (90% confidence interval [CI]) of 2.7 (2.4-3.1) and 2.0 (1.7-2.4), respectively. Concomitant boceprevir increased the AUC(inf) and C(max) of tacrolimus with GMRs (90% CI) of 17 (14-21) and 9.9 (8.0-12), respectively. Neither cyclosporine nor tacrolimus coadministration had a meaningful effect on boceprevir pharmacokinetics.. Dose adjustments of cyclosporine should be anticipated when administered with boceprevir, guided by close monitoring of cyclosporine blood concentrations and frequent assessments of renal function and cyclosporine-related side effects. Administration of boceprevir plus tacrolimus requires significant dose reduction and prolongation of the dosing interval for tacrolimus, with close monitoring of tacrolimus blood concentrations and frequent assessments of renal function and tacrolimus-related side effects.

Topics: Adult; Antiviral Agents; Area Under Curve; Cyclosporine; Dose-Response Relationship, Drug; Drug Interactions; Female; Hepatitis C; Humans; Immunosuppressive Agents; Male; Proline; Protease Inhibitors; Tacrolimus; Young Adult

Topics: Female; Graft Rejection; Graft Survival; Hepatitis C; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Sirolimus; Tacrolimus

By analyzing 26,414 patients [12,589 with hepatitis C virus (HCV)] in the Scientific Registry of Transplant Recipients Database, we sought to determine comparative risk factors (including primary immunosuppression) predictive of death and graft loss among patients with HCV and patients without HCV. Immunosuppression was examined at the baseline and as a time-dependent variable, and the results were stratified by the transplant center and were adjusted for variables well known to affect patient and graft survival. A multivariate analysis of patient mortality demonstrated that recipient age, donor age, hepatocellular carcinoma, diabetes, and creatinine were significantly associated with increased 3-year mortality for both groups. Tacrolimus-based immunosuppression was associated with superior survival in both groups. In contrast, the use of sirolimus was strongly associated with increased mortality in the HCV group, and cyclosporine was associated with increased mortality in the non-HCV group. Adjusting for known and unknown factors predictive of posttransplant outcomes, a propensity analysis confirmed the association of sirolimus use with an increased risk of death in HCV patients as well as the association of tacrolimus use with a decreased risk of death in all patients. In conclusion, this study suggests a novel association between sirolimus use and an increased risk of death and graft loss after liver transplantation in HCV patients that is not seen in patients without HCV. This study confirms the association of tacrolimus with superior outcomes. Sirolimus should be used sparingly in recipients with HCV infections.

Topics: Adult; Female; Graft Rejection; Graft Survival; Hepatitis C; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Liver Transplantation; Logistic Models; Male; Middle Aged; Multivariate Analysis; Patient Selection; Propensity Score; Proportional Hazards Models; Registries; Risk Assessment; Risk Factors; Sirolimus; Tacrolimus; Time Factors

Establishing a small animal model that accurately recapitulates hepatotropic pathogens, including hepatitis C virus (HCV) infection and immunopathogenesis, is essential for the study of hepatitis virus-induced liver disease and for therapeutics development. This protocol describes our recently developed humanized mouse model for studying HCV and other hepatotropic infections, human immune response and hepatitis and liver fibrosis. The first 5-h stage is the isolation of human liver progenitor and hematopoietic stem cells from fetal liver. Next, AFC8 immunodeficient mice are transplanted with the isolated progenitor/stem cells. This generally takes 2 h. The transplanted mice are then treated for a month with the mouse liver apoptosis-inducing AFC8 dimerizer and left for an additional 2-month period to permit human liver and immune cell growth as well as system reconstitution and development before inoculation with HCV clinical isolates. HCV infection, human immune response and liver disease are observed with high incidence from approximately 2 months after inoculation.

Topics: Animals; Chimera; Dimerization; DNA-Binding Proteins; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Hepatitis C; Humans; Liver; Mice; Mice, Inbred BALB C; Mice, Knockout; Models, Animal; Tacrolimus

Topics: Adult; Bilirubin; Cystic Fibrosis; Hepatitis C; Hepatocytes; Humans; Immunosuppressive Agents; Liver; Liver Diseases; Lung Transplantation; Male; Respiratory Insufficiency; Tacrolimus

We sought to study the prevalence, risk factors, and long-term prognosis of posttransplant diabetes mellitus.. We studied all patients with end-stage renal disease without diabetic nephropathy who received a kidney transplant and were followed-up at our center since 1983 (n=218; age, 44.3 ± 13.1 y). Patients with new-onset diabetes after transplant were compared to kidney transplant recipients without risk factors for diabetes mellitus. Patients with new-onset diabetes after transplant were divided into subgroups according to time of onset (early; < 90 d vs late, ≥ 90 d).. In total, 73/218 patients (33%) developed new-onset diabetes after transplant. Patients with new-onset diabetes after transplant were significantly older (51.2 ± 11.4 vs 40.7 ± 12.5 y; P < .001) and had a tendency to have a higher body mass index (29.6 ± 8.7 vs 21.6 ± 7.8 kg/m2; P =.05) than those that did not have new-onset diabetes after transplant. In multivariate analysis, age (P < .001), hepatitis C virus infection (P < .05), family history of diabetes mellitus (P < .03), and tacrolimus use (P < .001) were independent risk factors. Five- and 10-year death censored patient survival rates were worse in those that had new-onset diabetes after transplant compared with controls (log rank, 0.04), whereas there was no difference in outcomes between the early and late subgroups.. The prevalence of new-onset diabetes after transplant was 33%. Age, body weight at time of transplant, tacrolimus use, family history of diabetes mellitus, and hepatitis C virus infection are independent risk factors for new-onset diabetes after transplant. New-onset diabetes after transplant has a negative effect on patient survival, irrespective of the time of onset and duration of diabetes.

Topics: Adult; Age Distribution; Body Mass Index; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Hepatitis C; Humans; Immunosuppressive Agents; Incidence; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Multivariate Analysis; Postoperative Complications; Prevalence; Prognosis; Retrospective Studies; Risk Factors; Tacrolimus; Treatment Outcome

A minority of liver transplant (OLT) recipients with hepatitis C virus (HCV) develop fibrosing cholestatic hepatitis (FCH), a severe form of HCV recurrence associated with early graft failure and death. There are few reports of successful salvage strategies. In this retrospective study, we sought to determine the characteristics and outcomes for patients with FCH at our transplant center.. All cases of HCV-positive OLT recipients from July 2007 through July 2010 were reviewed. Patient demographics, donor characteristics, and the post-OLT clinical course were analyzed. Tacrolimus-based immunosuppression was used. FCH was treated by conversion to cyclosporine A (CsA) and aggressive treatment with pegylated interferon (IFN) alpha2A and ribavirin (RBV). Liver biopsies and HCV RNA were obtained frequently per protocol or for cause.. The rate of FCH during the study period was 13.5% (5/37). Of the 5 patients with FCH (4 males, 4 Caucasian), mean age was 51 (± 4.8) years and the Model for End-Stage Liver Disease (MELD) score at listing was 26.6 (± 10). Three of the 5 received liver and kidney (L/K) transplants (60%); the rate of L/K transplant in non-FCH patients was 12.5%. HCV RNA levels ranged from 5 to 6.69 log IU/mL pre-OLT; none were on anti-HCV therapy at the time of OLT. Mean ischemic time was 385 (± 152) minutes; donor age was 34.4 (± 13.7) years. No CMV infections developed postoperatively. Time to histologic HCV recurrence was 2 (± 2.23) months (range, 1-6); FCH occurred at 2.2 (± 2.2) months. Patients were converted from tacrolimus to CsA and treated with IFN and RBV; 2 were changed to consensus IFN. HCV RNA increased post-OLT in all, but responded to therapy in 4 of 5. None of the L/K recipients experienced renal graft rejection during treatment. Four of 5 had clinical and histologic improvement; 1 progressed to cirrhosis with minimal inflammation. One-year patient survival after OLT in this group was 80%. Liver allograft rejection occurred in 60% at 4.7 (± 5.5) months and was treated by CsA and prednisone dosage adjustments. In this cohort of patients undergoing OLT for HCV, FCH occurred early after OLT but responded to aggressive management with conversion from tacrolimus to CsA and treatment with pegylated IFN or consensus IFN/RBV. There was a higher rate of combined L/K transplants in the FCH group compared with the non-FCH group. Liver allograft rejection occurred in 60% of cases, but responded to treatment in all; no renal graft rejection occurred in the 3 with L/K transplants while on IFN. One-year graft and patient survival was 80%.. Better survival with FCH is possible with early initiation of IFN/RBV therapy with close monitoring of biopsies and viral load, and conversion from tacrolimus to CsA. Treatment can be performed even in L/K transplantation recipients, although it is associated with a higher incidence of treatable liver allograft rejection.

Topics: Antiviral Agents; Cholestasis, Intrahepatic; Cohort Studies; Cyclosporine; Female; Hepacivirus; Hepatitis C; Humans; Immunosuppressive Agents; Interferon alpha-2; Interferon-alpha; Liver Transplantation; Male; Middle Aged; Polyethylene Glycols; Recombinant Proteins; Ribavirin; RNA, Viral; Tacrolimus; Treatment Outcome

The aim of this study is to clarify the association between hepatitis C virus (HCV) infection and post-transplant lymphoproliferative disease (PTLD) in the liver allograft.. Of the 933 adults who underwent liver transplantation (LT) between 1990 and 2005, 10 patients developed PTLD. Seven of the 10 patients that were HCV(+) (group 1) were compared with three HCV-negative recipients (group 2).. The mean time between LT and PTLD was 24.5 months. There were no differences between in Epstein-Barr virus antibody status or tumor lymphocyte subsets. In five of the seven HCV-positive recipients who developed PTLD, PTLD recurred preferentially in the liver allograft, whereas none of the three HCV-negative patients who developed PTLD did so in the liver (71.4 vs. 0%, respectively, P=0.038). In all five patients with graft PTLD, HCV recurred within 12 months followed by PTLD. There were significant differences between groups 1 and 2 in mean lymphocyte infiltrate scores (6.0±2.1 vs. 2.0±0.7, P=0.037), fibrosis stage (2.4±0.5 vs. 0.7±0.5, P=0.029), and frequency of lymphoid follicles in portal areas (33.6±14.8% vs. 1.1±2.3%, P=0.0002).. When PTLD occurs in patients with HCV recurrence after LT, it does so preferentially in the liver allograft.

Topics: Adolescent; Aged; Antibodies, Viral; Azathioprine; Cohort Studies; Cyclosporine; Drug Therapy, Combination; Female; Graft Rejection; Hepatitis C; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Liver Transplantation; Lymphoproliferative Disorders; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Steroids; Tacrolimus

Topics: Antiviral Agents; Cyclosporine; Cytochrome P-450 Enzyme Inhibitors; Dose-Response Relationship, Drug; Drug Interactions; Hepatitis C; Humans; Immunosuppressive Agents; Liver Transplantation; Oligopeptides; Proline; Tacrolimus

Topics: Antiviral Agents; Cyclosporine; Hepatitis C; Humans; Immunosuppressive Agents; Liver Transplantation; Retrospective Studies; Secondary Prevention; Tacrolimus

Liver transplantation is the only curative treatment in patients with end-stage liver disease. Neurological complications (NC) are increasingly reported to occur in patients after cadaveric liver transplantation. This retrospective cohort study aims to evaluate the incidence and causes of NC in living donor liver transplant (LDLT) patients in our transplant center. Between August 1998 and December 2005, 121 adult LDLT patients were recruited into our study. 17% of patients experienced NC, and it occurred significantly more frequently in patients with alcoholic cirrhosis (42%) and autoimmune hepatitis (43%) as compared with patients with hepatitis B or C (9/10%, P = 0.013). The most common NC was encephalopathy (47.6%) followed by seizures (9.5%). The choice of immunosuppression by calcineurin inhibitor (Tacrolimus or Cyclosporin A) showed no significant difference in the incidence of NC (19 vs. 17%). The occurrence of NC did not influence the clinical outcome, since mortality rate, median ICU stay and length of hospital stay were similar between the two groups. Most patients who survived showed a nearly complete recovery of their NC. NCs occur in approximately 1 in 6 patients after LDLT and seem to be predominantly transient in nature, without major impact on clinical outcome.

Topics: Brain Diseases; Cohort Studies; Cyclosporine; Female; Hepatitis B; Hepatitis C; Hepatitis, Autoimmune; Humans; Immunosuppressive Agents; Incidence; Liver Cirrhosis, Alcoholic; Liver Diseases; Liver Transplantation; Male; Middle Aged; Nervous System Diseases; Retrospective Studies; Seizures; Tacrolimus; Treatment Outcome

Tumor recurrence represents the main limitation of liver transplantation in patients with hepatocellular carcinoma (HCC) and can be favored by exposure to calcineurin inhibitors.. We investigated the effect of an immunosuppressant schedule that minimizes the exposure to calcineurin inhibitors on patients transplanted for HCC to ascertain whether this can reduce the tumor recurrence rate. For this purpose, we conducted a matched-cohort study: 31 patients with HCC transplanted between 2004 and 2007 who received sirolimus as part of their immunosuppression (group A) were compared with a control group of 31 patients (group B) transplanted in the same period who had the same prognostic factors but were given standard immunosuppression based on tacrolimus.. Three-year recurrence-free survival was 86% in group A and 56% in group B (P=0.04). Although the prevalence of microvascular invasion G3-G4 grading and alpha-fetoprotein more than 200 ng/mL was identical in the two groups, exposure to tacrolimus was significantly higher in patients of group B (median, 8.54; range, 5.5-13.5) in comparison with those of group A (median, 4.6; range, 1.8-9.1) (P=0.0001).. By using sirolimus, exposure to calcineurin inhibitors can be minimized, reducing the risk of HCC recurrence.

Topics: Adrenal Cortex Hormones; Adult; Aged; Carcinoma, Hepatocellular; Cohort Studies; Disease-Free Survival; Drug Administration Schedule; Female; Hepatitis B; Hepatitis C; Humans; Immunosuppressive Agents; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Neoplasm Recurrence, Local; Risk Factors; Sirolimus; Survivors; Tacrolimus; Young Adult

Immunosuppression considerably affects hepatitis C virus (HCV) recurrence and the outcome of antiviral treatment after liver transplantation. Recent findings have suggested that the calcineurin inhibitor tacrolimus (Tac), unlike cyclosporine A (CsA), interferes with the antiviral activity of interferon-alpha (IFN-alpha) in vitro. The aim of this study was to more extensively investigate the effects of calcineurin inhibitors on IFN-alpha signaling and antiviral activity in subgenomic and infectious HCV models. Treatment with Tac and CsA did not affect Huh7 cell proliferation at doses of 10 to 500 ng/mL; however, it completely inhibited T cell proliferation. In contrast to previous reports, Tac had no effect on IFN-alpha-stimulated reporter gene expression, even at the dose of 5 microg/mL. Furthermore, in Huh7 subgenomic HCV replicon cells, treatment with Tac had no significant effect on the suppression of viral replication by IFN-alpha. In the infectious HCV model, treatment with IFN-alpha effectively inhibited both viral RNA replication and de novo production of virus particles, and neither was attenuated at any concentration of Tac. CsA had no significant effect on IFN-alpha-stimulated reporter gene expression; however, as shown previously, a combination of CsA (at 500 ng/mL and higher) and IFN-alpha resulted in enhanced inhibition of viral replication in both the subgenomic and infectious HCV models. In conclusion, our study shows no evidence that Tac or CsA interferes with IFN-alpha-mediated inhibition of HCV replication and virion production in vitro. Therefore, no further mechanistic arguments have been found to break the clinical controversy about the choice of calcineurin inhibitors during posttransplantation antiviral therapy.

Topics: Antiviral Agents; Calcineurin Inhibitors; Cell Proliferation; Cell Survival; Gene Expression Regulation; Hepacivirus; Hepatitis C; Humans; Immunosuppressive Agents; Interferon-alpha; T-Lymphocytes; Tacrolimus; Tetrazolium Salts; Thiazoles

Cytomegalovirus (CMV) infection is not only a common complication after liver transplantation but also a significant contributing factor to morbidity and mortality. We investigated whether preemptive therapy can prevent CMV syndrome or tissue-invasive CMV disease in an endemic area. Preemptive therapy was initiated when more than 10 positive CMV pp65 antigen-positive cells per 400,000 white blood cells were detected, regardless of clinical manifestations. Intravenous ganciclovir as preemptive therapy was administered daily for 10 to 14 days until negative results were achieved. The incidence of initial CMV antigenemia and CMV syndrome during the posttransplantation period was 49.7% (353/710) and 5.2% (37/710), respectively. One hundred eight-two patients (51.6%) received ganciclovir as preemptive therapy. Patients with CMV antigenemia who received preemptive therapy had high Model for End-Stage Liver Disease score, repeat operation, renal dysfunction, infection, low hemoglobin concentration, low platelet count, low albumin concentration, high international normalized ratio, high total bilirubin value, high aspartate transaminase concentration, and high CMV peak titer. Cytomegalovirus syndrome and tissue-invasive CMV disease were more common in these patients. The survival curve in patients without CMV syndrome was better than that in those with CMV syndrome (P=.000). Patients with more than 10 pp65 antigen-positive cells per 400,000 white blood cells should be treated aggressively with an antiviral agent as preemptive therapy because CMV infection is common in CMV-endemic areas and patients with CMV syndrome demonstrate poor survival rates.

Topics: Adult; Cadaver; Cyclosporine; Cytomegalovirus; Cytomegalovirus Infections; Endemic Diseases; Female; Graft Rejection; Hepatitis B; Hepatitis C; Humans; Immunosuppressive Agents; Korea; Liver Transplantation; Living Donors; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; Tacrolimus; Tissue Donors

Topics: Adrenal Cortex Hormones; Adult; Antibodies, Monoclonal; Antilymphocyte Serum; Black People; Drug Administration Schedule; Female; Follow-Up Studies; Hepatitis C; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Methylprednisolone; Middle Aged; Mycophenolic Acid; Renal Dialysis; Reoperation; Risk Assessment; Sirolimus; Tacrolimus; Transplantation, Homologous

Topics: Graft Rejection; Hepatitis C; Humans; Immunosuppressive Agents; Liver Transplantation; Postoperative Complications; Randomized Controlled Trials as Topic; Secondary Prevention; Tacrolimus

Hepatitis C virus (HCV) recurrence after orthotopic liver transplantation (OLT) is almost universal; cirrhosis develops in up to 30% of cases. Currently there is interest in the midterm outcomes of HCV patients with concomitant hepatitis B virus (HBV) infection among OLT recipients. We therefore retrospectively analyzed our database of patients who underwent OLT for HCV-HBV-related cirrhosis. Between April 1992 and December 2008, 350 patients underwent OLT, including 20 (5.7%) transplanted for HBV-HCV cirrhosis. We assessed patient and graft survivals at 1 and 5 years, as well as the progression of fibrosis. Protocol liver biopsies were available yearly after OLT. The survival curves were analyzed by the Kaplan-Meier approach and chronic hepatitis evaluated according to the Ishak scoring system. At a median follow-up of 68.4 +/- 53 months, the 1- and 5-year patient and graft survival rates were 80% and 70%, respectively. The 5-year fibrosis progression rate was 0.17 +/- 0.08 units of fibrosis. The only patient who developed histologic cirrhosis within 10 years of follow-up showed a lamivudine-resistant HBV recurrence. Patients transplanted for HBV-HCV coinfection showed a lower fibrosis progression rate compared with HCV monoinfected subjects.

Topics: Azathioprine; Cyclosporine; Graft Survival; Hepatitis B; Hepatitis C; Humans; Immunoglobulins; Immunosuppressive Agents; Liver Transplantation; Prednisone; Retrospective Studies; Survival Rate; Tacrolimus; Treatment Outcome

Cytomegalovirus (CMV) infection represents one of the most frequent opportunistic infections following solid-organ transplantation. The incidence and severity of CMV infection depend on the immunosuppressive regimen, the CMV serostatus of donor and recipient, and the type of transplant.. We evaluated CMV infection rates during the last 2 years in our center: March 2007 to March 2009. We enrolled 55 patients-13 females and 42 males-who underwent liver transplantation (OLT) due to hepatitis C virus (HCV) cirrhosis (n = 9), hepatitis B virus (HBV) cirrhosis (n = 5) HCC both on HCV and HBV cirrhosis (n = 37), or autoimmune disease (n = 4). Fifty percent of the patients received tacrolimus (TRL) and the others cyclosporine (CsA), both dosed according to weight. All patients received oral acyclovir (400 mg/td or less, adapted to renal function) as herpes simplex prophylaxis for 6 months. CMV prophylaxis prescribed CMV- hyperimmunoglobulin on postoperative days 1 and 7. CMV infection was monitored using polymerase chain reaction (PCR <1000 IU/mL) according to the following schedule: every week for the first month, every 2 weeks from month 2 to 3 and monthly from month 4 to 6. Patients were treated when three positive PCR results not affected by immunosuppressive dose reduction or when the PCR showed DNA greater than three times the limit of detection. CMV treatment stipulated valgancyclovir (900 mg twice daily) until three consecutive PCRs were negative or for 3 months dosed according to renal function. PCR was measured every 2 weeks during treatment.. Among the patients who were all D(+)/R(+) (CMV-Immunoglobulin G [IgG](+)/IgG(+)). 10 required treatment (18%) within 3 months from OLT. There subjects were prescribed TRL (n = 4) or CsA (n = 6). No renal impairment was observed among treated patients. Of those having the infection, one died due to other causes-sepsis from candida at 5 months after OLT.. CMV-hyperimmunoglobulin on postoperative days 1 and 7 did not confer protection for CMV among OLT patients. Preemptive treatment with intravenous gancyclovir plus valgancyclovir per os seemed to be useful and safe in infected patients requiring treatment.

Topics: Acyclovir; Antiviral Agents; Corticosterone; Cyclosporine; Cytomegalovirus Infections; Female; Graft Rejection; Hepatitis B; Hepatitis C; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Male; Methylprednisolone; Middle Aged; Retrospective Studies; Tacrolimus

A 2-center retrospective analysis was performed in 60 patients undergoing liver transplantation for hepatitis C virus (HCV)-related disease (cyclosporine in 20, tacrolimus in 40). Mean (±SEM) follow-up was 23.6 ± 22.5 and 22.3 ± 13.7 months in patients receiving cyclosporine or tacrolimus, respectively. Clinically indicated biopsies were performed in 15/20 cyclosporine patients (75%) and 22/40 tacrolimus patients (55%; P = .17). The Ishak fibrosis score was significantly lower in cyclosporine-treated patients versus tacrolimus-treated patients (mean 1.7 ± 0.4 vs 3.1 ± 0.4; P = .023), as was percentage of fibrosis grade Ishak ≥4 (7% vs 41%; P = .028). The mean time to moderate fibrosis (Ishak score ≥3) was 38.2 ± 15.1 months in cyclosporine patients (4/15) and 23.5 ± 12.6 months in tacrolimus patients (14/22); the difference was not statistically significant (P = .09). This retrospective study suggests that cyclosporine-based immunosuppression is associated with less severe hepatic fibrosis in HCV-positive liver transplant recipients compared with tacrolimus-based regimens, but a larger prospective comparative trial is necessary to confirm these findings.

Topics: Cyclosporine; Disease Progression; Female; Hepatitis C; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Retrospective Studies; Tacrolimus

Topics: Antiviral Agents; Fatal Outcome; Hepatitis C; Humans; Immunosuppressive Agents; Interferon alpha-2; Interferon-alpha; Jaundice; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Polyethylene Glycols; Postoperative Complications; Recombinant Proteins; Ribavirin; Tacrolimus

The whole blood concentration of tacrolimus is required for therapeutic drug monitoring of this immunosuppressive drug. Abnormal tacrolimus levels affect its efficacy or toxicity, leading to changes in its dosage. Here, we report analytical interference in the affinity column-mediated immunoassay tacrolimus method on the Xpand autoanalyzer in a kidney transplant human immunodeficiency virus-infected patient. Tacrolimus concentrations obtained by affinity column-mediated immunoassay are 3- to 7-fold higher than measurements with the enzyme multiplied immunoassay technique assay. The cause of this interference remains unknown. However, it would be necessary to identify this type of interference to measure tacrolimus concentration with another method to avoid analytical error, which may lead to a poor clinical outcome.

Topics: Adult; Drug Monitoring; False Positive Reactions; Hepatitis C; HIV Infections; Humans; Immunoassay; Immunosuppressive Agents; Kidney Transplantation; Male; Tacrolimus

To report a severe interaction between simvastatin and rapamycin resulting in rhabdomyolysis and acute renal failure in a liver transplant patient.. A 56-year-old man with hepatitis C virus cirrhosis (Child B) was diagnosed with hepatocellular carcinoma and underwent liver transplantation in April 2007. He was immunosuppressed with tacrolimus (FK) and mycophenolate mofetil (MMF). Postoperative complications were arterial hypertension and renal insufficiency. In June 2007, liver dysfunction was detected and acute rejection was diagnosed by biopsy. He received three 500-mg boluses of methylprednisolone and FK levels were maintained between 10 and 12 ng/mL. Laboratory values revealed persistent rejection and MMF was stopped with initiation of rapamicin. One month later, hyperlipidemia appeared as a consequence of rapamicin therapy; simvastatin was administered. In August 2007, the patient was readmitted due to severe muscule pain and the inability to ambulate. Laboratory values were: total bilirubin 16 mg/dL, serum creatinine 4.3 mg/dL, and total creatine kinase (CK) 42,124 U/L. With the suspicion of rhabdomyolysis, leading to worsening of his basal renal insufficiency, rapamycin and tacrolimus were stopped. Hemodialysis was initiated owing to renal failure and hyperkalemia. Some hours later, the patient developed ventricular fibrillation and respiratory failure and succumbed.. Calcineurin inhibitors (CNI), corticosteroids, and mammalian target of rapamycin (m-TOR) inhibitors are associated with adverse dyslipidemic effects. To reduce the overall cardiovascular risk in these patients, lipid-lowering drugs, especially 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, have been widely used. CNI and m-TOR inhibitors, as well as most statins, are metabolized by cytochrome P450 (CYP)3A4; thus, pharmacokinetic interactions between these drugs are possible. Previous reports have indicated an increased risk of rhabdomyolysis in the presence of concomitant drugs that inhibit simvastatin metabolism.. Concomitant administration of statin therapy and drugs that inhibit cytochrome P450 (CYP)3A4 increased the risk of rhabdomyolysis in a patient suffering liver and renal dysfunction.

Topics: Acute Kidney Injury; Anticholesteremic Agents; Drug Therapy, Combination; Fatal Outcome; Hepatitis C; Humans; Hypertension; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Rhabdomyolysis; Simvastatin; Tacrolimus

Posttransplant hepatitis C virus (HCV) recurrence has been shown to negatively impact graft and patient survivals. It has been suggested that HCV recurrence among HIV- and HCV-coinfected transplant recipients is even more aggressive.. To compare the histological severity and survival of posttransplant HCV recurrence between HIV- and HCV-coinfected and HCV-monoinfected patients.. Among 72 adult patients who underwent primary liver transplantation at our institution for HCV-related cirrhosis between October 2001 and April 2007. We excluded one coinfected patient who died on postoperative day 5 leaving 12 HIV- and HCV-coinfected patients for comparison with 59 monoinfected patients. When listed, all coinfected patients fulfilled the criteria of the Spanish Consensus Document for transplantation in HIV patients. Immunosuppression did not differ between the two groups: all were treated with tacrolimus + steroids (slow tapering). Aggressive HCV recurrence was defined as cholestatic hepatitis and/or a fibrosis grade > or =2 during the first posttransplant year.. Coinfected patients were younger than monoinfected patients: 45 +/- 6 years vs 55 +/- 9 years (P = .0008). There were no differences in Child score, Model for End-stage Liver Disease score, donor age, graft steatosis, ischemia time, HCV pretransplant viral load or genotype between the groups. Significant rejection episodes were also equally distributed (25% vs 14%; P = .38). Seven coinfected patients and 29 monoinfected patients developed aggressive HCV recurrences (58% vs 49%; P = .75). Median follow-up was 924 days. Global survival at 3 years was 80%. Survivals at 1, 2, and 3 years were 83%, 75%, 62% in the coinfected vs 98%, 89%, 84% in the monoinfected patients, respectively (log-rank test = 0.09).. The severity of histological recurrence was similar among HIV- and HCV-coinfected and monoinfected HCV liver recipients in the first posttransplant year. Mortality attributed to recurrent HCV was similar in the groups. There were no short-term (3-year) differences in survival between the two groups of patients.

Topics: Adrenal Cortex Hormones; Adult; Biopsy; Drug Therapy, Combination; Female; Graft Rejection; Hepatitis C; HIV Infections; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Recurrence; Retrospective Studies; RNA, Viral; Survival Rate; Survivors; Tacrolimus; Tissue Donors; Viral Load

Most reported data on posttransplantation diabetes mellitus (PTDM) are from Western countries with patients who underwent deceased donor liver transplantation. A retrospective study was performed to assess the prevalence and predictive factors of PTDM in the context of living donor liver transplantation (LDLT) in the Chinese population using the definition of PTDM proposed in 2003 by the World Health Organization and the American Diabetes Association. The prevalence of DM after LDLT in our study was 25% (21/84), and the incidence of PTDM was 14.9% (11/74) with 64% of cases diagnosed within 3 months after LDLT; 9.5% were observed to show impaired fasting glucose postoperatively. Multivariate analysis identified body mass index >or= 25 kg/m(2) before LDLT as the only independent risk factor for developing PTDM. Only one patient was operated for hepatitis C virus (HCV) infection. Hepatitis B virus (HBV)-related diseases were common in our study population, accounting for 78.6% of all patients. Both HCV and HBV infection status were not independent risk factors for developing PTDM. In addition, a greater tacrolimus trough blood level in the PTDM group versus no-DM group was observed at 3 months post-LDLT (11.03 ng/mL vs 4.87 ng/mL). The mean tacrolimus dose was not significantly different between the two groups. In conclusion, PTDM was prevalent among Chinese LDLT recipients.

Topics: Adult; Blood Glucose; China; Diabetes Mellitus; Female; Glucose Intolerance; Hepatitis B; Hepatitis C; Humans; Immunosuppressive Agents; Incidence; Liver Transplantation; Living Donors; Male; Middle Aged; Multivariate Analysis; Odds Ratio; Postoperative Complications; Prevalence; Retrospective Studies; Risk Factors; Tacrolimus

We hypothesized that antiviral efficacy [sustained virologic response (SVR)] has improved in recent years in the transplant setting. Our aim was to assess whether the efficacy of pegylated interferon (PegIFN)-ribavirin (Rbv) has improved over time. One hundred seven liver transplant patients [74% men, 55.5 years old (range: 37.5-69.5), 86% genotype 1a or 1b] were treated with PegIFN-Rbv for 355 (16-623) days at 20.1 (1.7-132.6) months after transplantation. Tacrolimus was used in 61%. Sixty-seven percent had baseline F3-F4 (cirrhosis: 20.5%). Donor age was 49 (12-78) years. SVR was achieved in 39 (36.5%) patients, with worse results achieved in recent years (2001-2003: n = 27, 46.5%; 2004: n = 23, 43.5%; 2005: n = 21, 35%; 2006 to January 2007: n = 36, 24%; P = 0.043). Variables associated with SVR in the univariate analysis included donor age, baseline viremia and cirrhosis, bilirubin levels, rapid virologic response and early virologic response (EVR), premature discontinuation of PegIFN or Rbv, and accumulated Rbv dose. In the multivariate analysis, the variables in the model were EVR [odds ratio (OR): 0.08, 95% confidence interval (CI): 0.016-0.414, P = 0.002] and donor age (OR: 1.039, 95% CI: 1.008-1.071, P = 0.01). Variables that had changed over time included donor age, baseline viremia, disease severity (cirrhosis, baseline bilirubin, and leukocyte and platelet counts), interval between transplantation and therapy, and use of growth factors. In the multivariate analysis, variables independently changing were donor age (OR: 1.041, 95% CI: 1.013-1.071, P = 0.004), duration from transplantation to antiviral therapy (OR: 1.001, 95% CI: 1.000-1.001, P = 0.013), and baseline leukocyte count (OR: 1.000, 95% CI: 1.000-1.000, P = 0.034). In conclusion, the efficacy of antiviral therapy with PegIFN-Rbv has worsened over time, at least in our center. The increase in donor age and greater proportion of patients treated at advanced stages of disease are potential causes.

Topics: Adolescent; Adult; Age Factors; Aged; Antiviral Agents; Child; Female; Fibrosis; Hepatitis C; Humans; Immunosuppressive Agents; Liver Transplantation; Living Donors; Male; Middle Aged; Recurrence; Retrospective Studies; Tacrolimus

Factors associated with sustained virological response (SVR) in patients treated for hepatitis C virus (HCV) recurrence after liver transplantation (LT) are unclear. Ninety-nine HCV-positive/hepatitis B surface antigen-negative patients received antiviral treatment (AVT) with interferon/peginterferon plus ribavirin for HCV recurrence after LT. Cyclosporine (CyA) or tacrolimus (TAC) was used as the main immunosuppressor in 37 (37%) and 62 (63%) patients, respectively. Twenty-five patients (25%) achieved an SVR. Twenty-seven donor-related, recipient-related, HCV-related, and immunosuppression-related variables were investigated for their association with SVR. In logistic regression analysis, donor age < 60 years (odds ratio = 4.45, 95% confidence interval = 1.39-14.19, P = 0.01), viral genotype other than 1 (odds ratio = 4.97, 95% confidence interval = 1.59-15.48, P = 0.006), and the use of CyA during treatment (odds ratio = 6.85, 95% confidence interval = 2.15-21.73, P = 0.001) were predictors of SVR. Patients treated with CyA (SVR rate: 43%) and those treated with TAC (SVR rate: 14%) were comparable for all variables, except for a shorter ischemia time and shorter timing of AVT initiation in the TAC group (P = 0.02 and P = 0.005, respectively) and a greater use of anti-CD25 antibodies, azathioprine, and mycophenolate mofetil in the CyA group (P = 0.03, P < 0.001, and P = 0.001, respectively). The rate of AVT discontinuation due to side effects was similar between groups (16% versus 8%, P = 0.3). In conclusion, the type of immunosuppression during AVT may predict SVR in patients treated for HCV recurrence after LT.

Topics: Adult; Aged; Antiviral Agents; Cyclosporine; Female; Hepatitis C; Humans; Immunosuppressive Agents; Liver Failure; Liver Transplantation; Male; Middle Aged; Odds Ratio; Recurrence; Regression Analysis; Tacrolimus; Treatment Outcome

Efficacy and long-term outcome of antiviral therapy for recurrent hepatitis C after liver transplantation is poorly defined.. This study aimed at assessing the efficacy of antiviral therapy regarding sustained hepatitis C virus (HCV) clearance, liver histology, and patient survival.. We retrospectively reviewed all 446 patients who received a liver allograft at our institution for HCV-related cirrhosis between January 1992 and December 2006. Two hundred thirty-two patients (52%) were eligible for antiviral therapy based on predefined criteria (Metavir stage > or =1 and/or grade > or =2; protocol biopsies). One hundred seventy-two patients (39%) had no contraindication for treatment, received more than or equal to 1 dose of interferon-alpha-based combination therapy, and form the basis of this analysis. Therapy was aimed for 48 weeks; median posttreatment follow-up was 68 months.. The overall sustained virological response (SVR) rate was 50% (genotype 1/4: 40%; genotype 2/3: 76%). SVR was higher on cyclosporine A (CsA) (56%) than on tacrolimus (44%, P=0.05), largely because of a lower relapse rate (6% vs. 19%, P=0.01). In multivariate analysis, genotype 2/3, CsA use, donor age, and pretreatment necroinflammatory activity were independently associated with SVR. SVR significantly improved histology and long-term survival (actuarial 5-year survival 96% vs. 69% in nonresponders, P<0.0001).. Antiviral therapy of recurrent hepatitis C after liver transplantation is able to clear HCV in half the patients, more likely on CsA than on tacrolimus, and markedly improves outcome.

Topics: Adrenal Cortex Hormones; Adult; Aged; Antiviral Agents; Drug Tolerance; Female; Follow-Up Studies; Genotype; Hepatitis C; Humans; Immunosuppressive Agents; Interferon alpha-2; Interferon-alpha; Liver Failure; Liver Transplantation; Male; Middle Aged; Polyethylene Glycols; Recombinant Proteins; Recurrence; Retrospective Studies; Ribavirin; Survival Rate; Tacrolimus; Time Factors; Tissue Donors; Treatment Outcome

A perfect or nearly perfect human leukocyte antigen (HLA) match has been associated with better immediate and long-term survival of diseased donor kidney transplants. However, the effect of HLA matching for hepatic allografts remains poorly defined. Using data from the National Institutes of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database, we investigated the association between HLA mismatches and hepatic allograft survival, disease recurrence, and immunosuppression interactions. A, B, and DR loci were used to calculate total mismatch scores of 0 (no mismatches in any loci) to 6 (mismatches in all loci). Seven hundred ninety-nine adults (male, 55%; female, 45%) underwent 883 liver transplants. The 10-year graft survival according to total mismatch score was as follows: 0-2, 60%; 3-4, 54%; and 5-6, 57%. There was a negative effect of mismatching at the A locus on patient survival, with shorter survival for patients with 1 or 2 mismatches compared with 0 mismatches [P = 0.05, hazard ratio (HR) = 1.6]. Patients on tacrolimus with 1 or 2 mismatches at B or DR loci appeared to have increased rates of patient and graft survival compared to patients with 0 mismatches, with the appearance of a protective effect of tacrolimus (HR = 0.67). The effect of HLA mismatching was more pronounced on certain disease recurrences. DR-locus mismatch increased recurrence of autoimmune hepatitis (P = 0.01, HR = 4.2) and primary biliary cirrhosis (P = 0.04, HR = 2). Mismatch in the A locus was associated with more recurrence of hepatitis C virus (P = 0.01, HR = 1.6) and primary sclerosing cholangitis (P = 0.03, HR = 2.9).. Mismatching at the A locus decreases patient survival in liver transplant recipients, and mismatching at the DR and A loci affects recurrence of autoimmune liver diseases and hepatitis C, respectively.

Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Cyclosporine; Databases as Topic; Female; Follow-Up Studies; Graft Survival; Hepatitis C; Hepatitis, Autoimmune; HLA Antigens; HLA-A Antigens; HLA-DR Antigens; Humans; Immunosuppressive Agents; Liver Cirrhosis, Biliary; Liver Transplantation; Longitudinal Studies; Male; Middle Aged; National Institute of Diabetes and Digestive and Kidney Diseases (U.S.); Tacrolimus; Treatment Outcome; United States

The purpose of this study was to analyze the effects of immunosuppressants on hepatitis C virus (HCV) replication to establish optimal immunosuppressive therapy in HCV-positive renal transplantation.. Cyclosporine (CsA), tacrolimus (Tac), mycophenolate acid (MPA), the active metabolite of mycophenolate mofetil (MMF), and methylprednisolone (MP) were administered to HCV replicon cells alone or in combination with interferon (IFN). HCV RNA was quantitatively determined. Of our 2064 recipients of renal transplantations between 1980 and 2005, 153 were HCV-positive. We analyzed changes in hepatic function and the efficacy of IFN therapy in these patients.. Only CsA strongly inhibited the growth of HCV RNA (13.1% at 1.0 microg/mL). MPA enhanced the inhibition of the growth of HCV RNA in the presence of IFN. Tac and MP reduced, rather than enhanced, the efficacy of IFN. Progression to chronic hepatitis occurred in a significantly smaller number of patients in the CsA than the Tac group (6 vs 19; P = .04). Serum alanine aminotransferase (ALT) levels were comparable pretransplantation and posttransplantation in the CsA group (24.8 +/- 20.5 vs 28.9 +/- 28.3 IU/L, respectively, while a significant elevation was noted in the Tac group (22.2 +/- 21.5 vs 32.6 +/- 30.8 IU/L, respectively; P = .024). Two of 4 patients who underwent combination therapy with IFN and ribavirin during treatment with CsA and MMF obtained an HCV-negative status for over 24 weeks.. CsA effectively prevents the progression of chronic hepatitis in HCV-positive renal transplant patients. A greater response rate can be expected by concurrent administration of CsA and MMF under IFN therapy.

Topics: Alanine Transaminase; Cyclosporine; Disease Progression; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Immunosuppressive Agents; Japan; Kidney Transplantation; Postoperative Complications; Retrospective Studies; RNA, Viral; Tacrolimus; Virus Replication

The prevalence of glucose metabolic abnormalities (GMA) and overt diabetes in the Indian population is higher than the Western population. Tacrolimus (generic form), which is known to cause GMA, was recently introduced in India and data on its use in India are scarce. Herein we have presented our experience of the use of tacrolimus in renal transplantation.. We performed a retrospective analysis of 122 consecutive patients receiving tacrolimus-based triple drug immunosuppression at a single center. Target levels were 10 to 15 ng/mL in the first month, 8 to 10 ng/mL in the second to third months, and 5 to 8 ng/mL thereafter. GMA was defined as fasting blood sugar >110 mg% or postprandial blood sugar >140 on more than one occasion. All episodes of graft dysfunction were evaluated by graft biopsy. In addition, all consenting patients underwent protocol biopsy at 1, 3, and 6 months. Overall mean age of recipients was 34.5 +/- 10.1 years; male to female ratio 108:14; mean donor age 40.1 +/- 10.1 years; and mean follow-up 16.8 +/- 5.9 months.. The patient and graft survivals at 18 months were 96.7% and 94.8%, respectively. Incidence of clinical biopsy-proven acute rejection was 5.7%. In addition, 8.13% patients had subclinical rejection. The mean serum creatinine at last follow-up was 1.3 +/- 0.6 mg%. Of the nondiabetic recipients, 54.5% developed GMA and 32.7% required drug therapy for glycemic control, of which only 5.5% were insulin dependent. The prevalence of hepatitis C virus (HCV) infection was 20.0% in the cohort.. Use of tacrolimus results in a low incidence of clinical acute rejection but a high incidence of GMA in Indian transplant recipients.

Topics: Diabetes Mellitus; Glucose; Glucose Metabolism Disorders; Graft Rejection; Graft Survival; Hepatitis C; Humans; Immunosuppressive Agents; India; Kidney Transplantation; Survival Analysis; Tacrolimus

Topics: Adult; Antiviral Agents; Brain; Cerebrovascular Circulation; Cerebrovascular Disorders; Female; Hepatitis C; Humans; Immunosuppressive Agents; Liver Transplantation; Magnetic Resonance Imaging; Purpura, Thrombotic Thrombocytopenic; Tacrolimus

New-onset posttransplantation diabetes mellitus (PTDM), with an incidence of 10% to 30%, increased graft and patient morbidity and mortality. Such causal factors as age, obesity, therapy, immunosuppression, and hepatitis C virus (HCV) contribute to this disease.. We sought to determine the incidence of PTDM and impaired fasting glucose (IFG) concentration in transplant recipients to define the causal variables.. The study included 127 patients. Patients with pretransplantation diabetes and those with less than 6 months of follow-up were excluded. A descriptive observational study to assess the association between PTDM and IFG and the immunosuppression therapy used was performed by monitoring the potential confounding variables of age, obesity, and HCV.. During mean follow-up of 73.7 months (range, 7-120 mo), 93 patients received cyclosporine A (CyA) and 34 received tacrolimus (Tac) therapy. Thirty patients (23.6%) developed PTDM or IFG including 15 (16%; PTDM, six IFG, nine) in the CyA group and 15 (PTDM, seven; IFG, eight) in the Tacrolimus group (P = .001; odds ratio [OR], 4.1). They were homogeneous with respect to confounding variables except for HCV (P = .01). Of the 55 patients with HCV infection, 12 developed PTDM or IFG, including three in the CyA group and nine in the tacrolimus group (P = .03; OR, 7.7), whereas in the 72 patients without HCV infection, the CyA or tacrolimus association with PTDM or IFG was significant (P = .05), Mantel-Haenszel test; OR, 4.9). The interaction between HCV and immunosuppression therapy was primarily produced in the IFG group (HCV-positive; P = .008; OR, 8).. We observed an association between the use of tacrolimus and the development of PTDM or IFG. There is greater risk in HCV-positive patients, in particular in relation to IFG. The choice of immunosuppressive treatment might be decided on the basis of the patient's pretransplantation status.

Topics: Adult; Aged; Blood Glucose; Diabetes Mellitus; Female; Follow-Up Studies; Hepatitis C; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Patient Selection; Retrospective Studies; Tacrolimus; Time Factors; Young Adult

Topics: Antiviral Agents; Calcineurin Inhibitors; Cyclosporine; Hepacivirus; Hepatitis C; Humans; Interferon-alpha; Interferons; Recurrence; Signal Transduction; Tacrolimus; Virus Replication

This report describes a patient who developed human T-cell leukemia virus type I-associated myelopathy (HAM) following a living-donor liver transplantation (LDLT) for liver cirrhosis due to hepatitis C virus (HCV) infection. Both the recipient and the living donor (his sister) were human T-cell leukemia virus type I (HTLV-I) carriers. Since the LDLT, he had been treated with immunosuppressive drugs such as tacrolimus and steroids as well as interferon-alpha to prevent rejection and a recurrence of the HCV infection, respectively. Even though the HTLV-I proviral load had decreased upon interferon treatment, he developed a slowly progressive gait disturbance with urinary disturbance 2 years after the LDLT and was diagnosed with HAM. This appears to be the first report of HAM development in an HLTV-I-infected LDLT recipient.

Topics: Antiviral Agents; Drug Therapy, Combination; Gait Disorders, Neurologic; Graft Rejection; Hepatitis C; Humans; Immunosuppressive Agents; Interferon alpha-2; Interferon-alpha; Liver Cirrhosis; Liver Transplantation; Living Donors; Male; Middle Aged; Paraparesis, Tropical Spastic; Recombinant Proteins; Steroids; Tacrolimus; Treatment Outcome; Urination Disorders

New-onset diabetes mellitus (NODM) remains a common complication of liver transplantation (LT). We studied incidence and risk factors in 211 French patients who had undergone a primary LT between 6 and 24 months previously. This is a cross-sectional and retrospective multicenter study. Data were collected on consecutive patients at a single routine post-LT consultation. Demographic details, immunosuppressive regimens, familial and personal histories, hepatitis status, and cardiovascular risk were analyzed to compare those who developed NODM (American Diabetes Association/World Health Organization criteria) with the others. The overall incidence of NODM was 22.7%: 24% in tacrolimus (Tac)-treated patients (n = 175; 82.9%) and 16.7% in cyclosporine-treated patients (n = 36; 17.1%). A total of 81% of the cases were diagnosed within 3 months of LT (M3). Among hepatitis C virus (HCV)-infected (HCV(+)) patients, NODM incidence was 41.7% whereas among those patients negative for this virus (HCV(-)), the incidence was only 18.9% (P = 0.008). In Tac-treated patients, the incidence of NODM in the HCV(+) patients was significantly higher than in the HCV(-) patients (46.7% and 19.3%, respectively, P = 0.0014). Only 1 of 6 (16.7%) of the HCV(+) patients developed NODM on cyclosporine. Other independent pretransplantation risk factors for NODM included impaired fasting glucose (IFG) and a maximum lifetime body-mass index (BMI) over 25 kg/m2. In conclusion, emergence of NODM after LT is related to risk factors that can be detected prior to the graft, like maximum lifetime BMI, IFG, and HCV status. Tac induced a significantly higher incidence of NODM in the HCV(+) compared to the HCV(-) patients. The treatment should therefore be tailored to the patient's risk especially in case of HCV infection.

Topics: Adult; Aged; Calcineurin Inhibitors; Diabetes Mellitus; Female; Glucose; Hepatitis C; Humans; Immunosuppressive Agents; Liver Diseases; Liver Transplantation; Male; Middle Aged; Multicenter Studies as Topic; Risk Factors; Tacrolimus

The ulcerative variant of lichen planus (LP) commonly involves the oral mucosa but is uncommon and difficult to treat when located on other areas. We describe an unusual case of ulcerative LP involving several surfaces, including the palms and scrotum, in a 50-year-old man with hepatitis C. The patient was recalcitrant to treatment with conventional therapy but obtained clearance with a sustained response using low molecular weight heparin (LMWH). This treatment is an option for patients with LP who are not ideal candidates for standard therapy.

Topics: Anti-Inflammatory Agents; Anticoagulants; Clobetasol; Genital Diseases, Male; Hand Dermatoses; Heparin, Low-Molecular-Weight; Hepatitis C; Humans; Immunosuppressive Agents; Lichen Planus; Male; Middle Aged; Scrotum; Skin Ulcer; Tacrolimus

New-onset diabetes mellitus (NODM)-a common complication of kidney transplantation-is associated with increases in graft loss, morbidity and mortality.. This is a purely observational study of 527 patients taking a calcineurin inhibitor (CNI), based on data collected at a single routine visit 6-24 months after kidney transplantation. Diabetes was defined according to ADA/WHO guidelines.. The mean age of the patients was 47.2 years and 61.1% were men; 49.5% were receiving cyclosporine microemulsion (CsA-ME) and 50.5% tacrolimus (Tac). NODM developed in 7.0% after a median interval of 1.6 months. In CsA-ME-treated patients, the unadjusted cumulative risks of NODM were 5.5% and 8.4% at 1- and 2-year post-transplantation, while in Tac-treated patients, the risks were respectively 17.4% and 21%. Four independent risk factors (RFs) were identified by multivariate analysis: maximum lifetime body mass index>25 [odds ratio (OR)=5.1], pre-transplantation impaired fasting glucose (OR=4.7), hepatitis C status (OR=4.7) and Tac vs CsA-ME treatment (OR=3.0).. NODM is associated with certain RFs present prior to kidney transplantation, and with treatment with Tac as opposed to CsA-ME.

Topics: Adult; Blood Glucose; Body Mass Index; Calcineurin Inhibitors; Cyclosporine; Diabetes Mellitus; Emulsions; Fasting; Female; France; Hepatitis C; Humans; Immunosuppressive Agents; Incidence; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Retrospective Studies; Risk Factors; Tacrolimus; Time Factors

We retrospectively analyzed the impact of sirolimus addition (SRL) with a 25% dosing reduction in calcineurin inhibitors on liver function among patients with or without hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.. Forty-eight renal transplant recipients (HBsAg-positive, n = 5; anti-HCV-positive, n = 7) with allograft dysfunction (serum creatinine: mean 2.7, median 2.0 mg/dL) and normal liver function were enrolled. The duration of the SRL add-on therapy was 8.0 +/- 3.6 months. SRL trough levels were maintained within 6.5 +/- 3.7 ng/mL. The trough levels of tacrolimus and the 2-hour cyclosporine postdose levels were tapered to 4.6 +/- 1.9 ng/mL (24.6% reduction) and 650 +/- 170 ng/mL (24.3% reduction), respectively. SRL-related hepatitis was defined as a rise in liver transferase or alkaline phosphatase or bilirubin over twice the upper limit of normal. Thirty-six HBsAg-negative and anti-HCV-negative patients served as the controls.. Hepatotoxicity developed in 6 (12.5%) of the 48 patients and in 3 (8.3%) of 36 control subjects. One (20.0%) of five HBsAg-positive patients (P = .959) and two (28.6%) of seven anti-HCV-positive patients (P = .496) developed hepatotoxicity, respectively. Three (25.0%) of the 12 HBsAg-positive or anti-HCV-positive patients developed hepatotoxicity (P = .420).. Patients with seropositivity of HBsAg or anti-HCV had an insignificantly higher percentage of hepatitis. Use of SRL in the HBV/HCV patients is not contraindicated, but needs monitoring for HBV/HCV activation.

Topics: Adult; Drug Therapy, Combination; Female; Hepacivirus; Hepatitis B; Hepatitis B Surface Antigens; Hepatitis C; Histocompatibility Testing; Humans; Immunosuppressive Agents; Kidney Transplantation; Lamivudine; Liver; Male; Middle Aged; Monitoring, Immunologic; Mycophenolic Acid; Retrospective Studies; Sirolimus; Tacrolimus

We assessed whether conversion from tacrolimus (TAC) to cyclosporine (CsA) was associated with a reduction in hepatitis C virus (HCV) viral load among HCV-positive liver transplant (OLT) patients.. Nine OLT patients with recurrent HCV have TAC and prednisone immunosuppression. None received any HCV antiviral therapy. After the last intake of TAC, the patients underwent a 12-hour area under the curve (AUC(12)) measurement of both TAC and HCV viral loads. The next morning (D(0)) patients were given CsA (4 mg/kg bid). At the first intake of CsA and at 1 month (M(1)) later, the patients underwent AUC(12) for CsA and HCV viral loads. Biological data, including aspartate (AST) and alanine (ALT) aminotransferase, gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (AP), and bilirubin levels, were collected during AUC(12), and at M(1) and M(3).. With respect to liver enzymes (AST, ALT, GGT), there was no significant difference between D(0), M(1), and M(3). Conversely, there was a significant decrease in AP between D(0) and M(3) (P = .02), and a significant increase in total bilirubin between D(0) and M(1) (P = .04), and between D(0) and M(3) (P = .01). HCV viral load significantly increased by M(3) (P = .01). At no time (D(0), M(1)) was there any correlation between the AUC(12) of TAC or CsA, and between AUC(12) HCV viral load.. This pilot study found no acute or chronic anti-HCV effects from CsA that were evident within 12 hours after CsA administrations or beyond 1 month of CsA therapy, respectively.

Topics: Aged; Alkaline Phosphatase; Cyclosporine; Hepacivirus; Hepatitis C; Humans; Immunosuppressive Agents; Liver Function Tests; Liver Transplantation; Middle Aged; Pilot Projects; Prednisone; RNA, Viral; Tacrolimus; Viral Load

After liver transplantation, reinfection of the newly engrafted liver with hepatitis C virus is essentially universal in patients who are viremic at the time of transplantation. Treatment with interferon preparations with or without ribavirin is recommended in patients with marked histologic injury; however, hematologic toxicity associated with therapy has been reported, which is usually treated with growth factor support, including erythropoietin analogues. We present the first reported case of anti-erythropoietin antibody-mediated pure red cell aplasia arising in the setting of hepatitis C virus therapy in a patient who underwent living donor liver transplantation.

Topics: Anemia; Antibodies; Antiviral Agents; Epoetin Alfa; Erythropoietin; Graft Rejection; Hematinics; Hepatitis C; Humans; Immunocompromised Host; Immunosuppressive Agents; Interferon alpha-2; Interferon-alpha; Liver Transplantation; Living Donors; Male; Middle Aged; Mycophenolic Acid; Polyethylene Glycols; Prednisone; Recombinant Proteins; Red-Cell Aplasia, Pure; Ribavirin; Secondary Prevention; Tacrolimus

Recently we reported that signal transmission of interferon is more suppressed by tacrolimus (Tac) than cycrosporine (CyA). Therefore, although CyA might be beneficial immunosuppressive drug after liver transplantation (LT) on interferon therapy against hepatitis C virus, it is hesitated because of the risk for provocation of rejection. Herein initial outcome of our strategy, i.e. intentional conversion from Tac to CyA during preemptive interferon therapy after living donor LT (LDLT) was reported.. Of 62 patients who had undergone LDLT in Nagasaki University Hospital between 1997 and November 2006, 16 patients showed indications for hepatitis C-related liver cirrhosis. The median follow-up period was 15 months. Tac was used for all patients as induction therapy combined with steroids tapering.. In 11 out of 16 cases (68.8%), preemptive Pegylated (Peg)-IFN-alpha 2b+Ribavirin therapy was initiated. When Peg-IFN-alpha 2b+Ribavirin therapy was commenced, Tac-to- CyA conversion was done. The median period of conversion from Tac to CyA was 1.5 month after LDLT. After the conversion, ACR occurred in one case. Out of 11 patients, 3 patients (21.4%) showed early viral response (VR) at 3 months, 2 showed end-treatment response at 48 weeks (14.3%) and 3 showed sustained VR (21.4%).. Intentional conversion from Tac to CyA can be safely performed without increasing the risk of ACR.

Topics: Antiviral Agents; Cohort Studies; Cyclosporine; Female; Hepatitis C; Humans; Immunosuppressive Agents; Interferon alpha-2; Interferon-alpha; Liver Transplantation; Living Donors; Male; Middle Aged; Polyethylene Glycols; Recombinant Proteins; Retrospective Studies; Ribavirin; Tacrolimus

Recurrent HCV-cirrhosis occurs in a substantial proportion of transplant recipients, with higher rates reported in patients who had recently received a transplant. Over-immunosuppression has been implicated in this more unfavorable outcome. To determine whether the implementation of specific measures aimed at reducing or avoiding negative predictive variables is associated with an improvement in the outcome of recurrent hepatitis C.. Comparative study between a cohort of patients who had recently received a transplant (2001-2004) and a historical group of HCV-infected patients transplanted before the implementation of two simple measures (1999-2000): (i) use of dual initial immunosuppression (steroids + cyclosporine neoral or tacrolimus); (ii) slow steroid tapering (>6 months). Yearly biopsies were performed in these recipients, and only those with at least one protocol biopsy and those with cholestatic hepatitis (regardless of follow-up) were included in the study. End-point: rate of HCV-related severe disease (defined as bridging fibrosis, cirrhosis or fibrosing cholestatic hepatitis) within the first year post-transplantation.. Severe disease was significantly lower in this cohort compared to the historical group (26/90, 29% vs 25/52, 48%; p=0.02). While other factors remained unchanged between the two cohorts, the proportion of patients on triple-quadruple regimes and the number of boluses of methyl-prednisolone were lower and the duration of prednisone therapy longer in more patients who had recently received a transplant.. Improving the outcome of recurrent hepatitis C may be achieved by reducing overall immunosuppression and avoiding abrupt variations in immunosuppression.

Topics: Adult; Aged; Biopsy; Cohort Studies; Cyclosporine; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Hepacivirus; Hepatitis C; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver; Liver Transplantation; Male; Middle Aged; Prednisone; Recurrence; Severity of Illness Index; Steroids; Tacrolimus; Time Factors; Treatment Outcome

Topics: Adrenal Cortex Hormones; Cyclosporine; Hepacivirus; Hepatitis C; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver; Liver Transplantation; Muromonab-CD3; Mycophenolic Acid; Recurrence; RNA, Messenger; RNA, Viral; Tacrolimus; Treatment Outcome

A 23-year-old man with hepatitis C was observed with brownish dome-shaped papules in a linear pattern on the chest. The papules were determined clinically and pathologically to be linear lichen planus. These lesions appeared during an interferon-alpha therapy for his hepatitis and resolved after topical treatment with tacrolimus ointment. Linear lichen planus and hepatitis C have been reported only twice previously. The association between these disorders and the potential role of interferon therapy are discussed.

Topics: Adult; Antiviral Agents; Hepatitis C; Humans; Immunosuppressive Agents; Interferon-alpha; Lichen Planus; Male; Tacrolimus

Rapid recurrence of severe hepatitis C (HCV) after liver transplantation is a major barrier to survival of the transplanted liver. While cyclosporine (CsA) in vitro has been shown to suppress HCV replication, an effect is not seen with tacrolimus (Tac). Evidence is inconsistent whether or how this translates to clinical practice. To expand the evidence on this issue, we analyzed graft survival and histological outcomes after liver transplantation for HCV hepatitis.. Using our longitudinal database (1991 onward) graft outcomes for all liver transplant recipients with HCV were evaluated (105 grafts in 97 patients). Severe activity, severe fibrosis, and graft survival were analyzed. All liver biopsies were scored (blinded) according to the Ludwig scale. Immunosuppression was based on prednisone and a calcineurin inhibitor (Tac n = 89, 85%; CsA n = 15, 14%). Comparisons of outcomes using CsA versus Tac therapy were done using survival analysis via the log-rank test.. Graft survival was significantly better in the CsA group. Although there was no apparent difference in severe activity (grade 2), there was a statistically significant difference in graft survival without fibrosing cholestatic hepatitis (P = .01) and a trend toward a difference in fibrosis-free survival (P = 0.1). The rate of sustained response to antiviral therapy was twice as high in the CsA group, 50% versus 22% (P = 0.16; NS).. Graft survival in liver transplant recipients with HCV may be greater with CsA-based immunosuppression. There may also be a lower rate of fibrosing cholestatic hepatitis in this group.

Topics: Biopsy; Cyclosporine; Databases, Factual; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Hepatitis C; Humans; Immunosuppressive Agents; Liver Transplantation; Longitudinal Studies; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; Tacrolimus; Transplantation, Homologous; Treatment Outcome

Hepatitis C virus (HCV) recurrence after orthotopic liver transplantation (OLT) is almost universal. The optimal immunosuppression for these patients is still under discussion. We designed a retrospective case-control study to evaluate the effect of mycophenolate mofetil (MMF) treatment in patients with recurrent hepatitis C. Forty patients with histologically proven hepatitis C recurrence after OLT were treated with MMF and calcineurin inhibitor (CNI) taper for 24 months and matched with 40 non-MMF-treated positive liver transplant recipients. Liver biopsies were obtained prior to MMF treatment and after a mean follow-up of 24 months. Histological changes were evaluated utilizing the Metavir score. Comparison of fibrosis/inflammation showed no impairment of histological findings during MMF treatment. In contrast, histological findings of the 40 non-MMF patients showed a significant increase of severity for inflammation/fibrosis. Viral load was similar in both groups. The course of alanin amino transferase (ALT) levels measured during MMF treatment showed a significant decrease. MMF in combination with CNI taper showed a positive effect on fibrosis progression, graft inflammation and ALT levels and may improve the clinical course of HCV after OLT, however, the antiviral properties of MMF are still unconfirmed.

Topics: Calcineurin Inhibitors; Case-Control Studies; Female; Graft Rejection; Hepacivirus; Hepatitis C; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Mycophenolic Acid; Retrospective Studies; RNA, Viral; Tacrolimus; Time Factors

Induction with thymoglobuline, a potent anti-thymocyte polyclonal antibody, has been recently reported to allow minimization of postoperative immunosuppression in organ transplantation. The relationship with recurrence of hepatitis C virus (HCV) after liver transplantation (LTx) has never been investigated. We report here on the outcome in 22 HCV+ patients receiving thymoglobuline pre-treatment and minimal immunosuppression after LTx. Patient survival and acute rejection rates were good, and remarkably low dosages and levels of immunosuppression were achieved with thymoglobuline, without exposing patients to an elevated risk of rejection. A progressive weaning of the primary immunosuppressor was also possible in the majority of patients without complications. The HCV recurrence rate was similar to what is reported in the literature, although lower HCV-RNA viral loads were obtained with thymoglobuline, with a mild histologic course. Although our results need to be validated in large cohort studies, our experience shows that minimization of immunosuppression with thymoglobuline is effective in protecting against rejection and demonstrated a positive impact on HCV recurrence that deserves further investigation.

Topics: Adult; Aged; Antilymphocyte Serum; DNA, Viral; Follow-Up Studies; Graft Rejection; Graft Survival; Hepacivirus; Hepatitis C; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Transplantation; Methylprednisolone; Middle Aged; Recurrence; Survival Rate; T-Lymphocytes; Tacrolimus; Transplantation Conditioning; Treatment Outcome; Viral Load

In HCV cirrhotic patients after liver transplantation, survival and recurrence of HCV appears to be worsening in recent years. Donor age has been suggested as a cause. However, it is not clear if early and/or late mortality is affected and whether donor age is a key factor, as opposed to changes in immunosuppression. The aim of this study was to assess impact of donor age and other factors with respect to the severity of HCV recurrence posttransplant. A consecutive series of 193 HCV cirrhotic patients were transplanted with cadaveric donors, median age 41.5 years (13-73) and median follow-up of 38 months (1-155). Donor age and other factors were examined in a univariate/multivariate model for early/late survival, as well as fibrosis (grade 4 or more, Ishak score) with regular biopsies, 370 in total, from 1 year onwards. Results of the study indicated that donor age influenced only short-term (3 months) survival, with no significant effect on survival after 3 months. Known HCC independently adversely affected survival, as did the absence of maintenance azathioprine. Severe fibrosis (stage > or = 4) in 51 patients was related to neither donor age nor year of transplantation, but it was independently associated with combined biochemical/histological hepatitis flare (OR 2.9, 95% CI 1.76-4.9) whereas maintenance steroids were protective (OR 0.4, 95% CI 0.23-0.83). In conclusion, in this cohort donor age did not influence late mortality in HCV transplanted cirrhotic patients or development of severe fibrosis, which was related to absence of maintenance steroids and a hepatitis flare. Maintenance azathioprine gave survival advantage.

Topics: Adult; Age Factors; Aged; Azathioprine; Cyclosporine; Drug Therapy, Combination; Female; Glucocorticoids; Graft Survival; Hepatitis C; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Prednisolone; Recurrence; Tacrolimus

The optimal immunosuppressive regimen for HCV-positive liver transplant recipients has not been established. Treatment for acute cellular rejection (ACR) with steroids is associated with increased viral replication and graft hepatitis. We retrospectively analyzed 232 patients after orthotopic liver transplantation (OLT) for HCV cirrhosis to determine the influence of methylprednisolone pulse therapy on long-term outcome after OLT.. Two hundred thirty-two liver transplants were performed in HCV-positive recipients between 1989 and 2001. Median follow-up was 4.4 years and median age of patients was 53 years (range 15 to 72 years). Immunosuppression consisted of tacrolimus (Tac) or cyclosporine (CyA) in different protocols. All rejection episodes were histologically proven.. Twenty-eight of 232 (12.06%) graft losses were due to severe hepatitis C reinfection. Of 232 patients, 105 showed a minimum of one episode of ACR (45.25%). Of 232 patients, 71 (30.6%) received methylprednisolone pulse therapy once and 15 of 232 required OKT3 treatment for steroid-resistant rejection (6.4%). Of 232 patients, 19 (8.1%) required repeated steroid pulse therapy due to more than one episode of ACR. In patients with more than one episode of ACR, the risk of HCV-related graft loss was significantly enhanced (6/19, P < .05). The primary immunosuppression had no influence on the outcome in our data.. Our data show that outcome of HCV-positive patients who require repeated steroid pulse therapy (RSPT) for ACR is significant worse than that in patients with a single pulse therapy. Therefore RSPT should be avoided in HCV-positive transplant recipients. New strategies to manage acute rejection are required for these patients.

Topics: Adolescent; Adult; Aged; Cyclosporine; Drug Administration Schedule; Follow-Up Studies; Glucocorticoids; Hepatitis C; Humans; Immunosuppressive Agents; Liver Transplantation; Methylprednisolone; Middle Aged; Muromonab-CD3; Retrospective Studies; Survival Analysis; Tacrolimus; Treatment Outcome

In our cohort of patients with hepatitis-C virus, which is the most common indication for liver transplantation, we have noted higher relative blood levels of tacrolimus compared to patients without hepatitis-C virus.. To verify this observation and determine its clinical significance, we performed a comparison of doses and blood levels of tacrolimus in hepatitis-C virus and non- hepatitis-C virus liver transplantation recipients.. Tacrolimus dose and trough level, as well as mean alanine aminotransferase, for all patients transplanted at our center with a deceased donor between 1/1995 and 12/1999 with hepatitis-C virus were recorded at monthly intervals during the first 24 months following transplantation and compared to patients without hepatitis-C virus.. The tacrolimus levels for hepatitis-C virus and non-hepatitis-C virus patients were not significantly different at any of the monthly intervals, except month 9. In addition, the overall mean tacrolimus levels for hepatitis-C virus and non-hepatitis-C virus patients were not significantly different (P = ns). However, the mean tacrolimus dose (mg/kg) was significantly higher for hepatitis-C virus patients at 12, 15, 18, 21 and 24 months, P < 0.01. The total mean tacrolimus dose in hepatitis-C virus patients was lower during year one by 39% (P = 0.018) and by 73% (P = 0.001) during year two. The total difference in cost of tacrolimus (for year one and two) administered to hepatitis-C virus patients was $4920, P = 0.03. The serum alanine aminotransferase was significantly higher in hepatitis-C virus patients at each monthly interval except month 1, P < or = 0.01.. Liver transplant recipients with hepatitis-C virus require significantly lower oral doses of tacrolimus to achieve the same blood levels compared to non-hepatitis-C virus patients. This difference may result in a significant reduction in the cost of tacrolimus in hepatitis-C virus patients. The most likely explanation for these findings is decreased hepatic clearance of tacrolimus caused by mild hepatic injury from recurrent hepatitis-C virus.

Topics: Dose-Response Relationship, Drug; Female; Hepatitis C; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Retrospective Studies; Tacrolimus

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

Recent reports demonstrate the efficacy of induction immunosuppression with Thymoglobulin, a potent antithymocyte polyclonal antibody, in allowing acquired tolerance by means of a tolerogenic regimen of recipient pretreatment and low-dose postoperative immunosuppression. The effect of this novel approach on recurrence of hepatitis C viral disease after liver transplantation has never been investigated. We report the preliminary results of a retrospective analysis aimed at discovering any relationship between Thymoglobulin immunosuppression and the pattern of recurrence of hepatitis C.. Thymoglobulin induction plus tacrolimus monotherapy was used in a group of 22 hepatitis C virus (HCV)+ patients receiving liver transplantation; 30 HCV+ patients receiving transplants within the same year received conventional tacrolimus plus steroid immunosuppression and represented the comparison group.. Patient survival and acute rejection rate did not differ between the two groups. Significantly lower dosages and levels of tacrolimus were possible with Thymoglobulin, and a progressive weaning of tacrolimus monotherapy was accomplished in most patients, without major rejection complications. The HCV recurrence rate was similar in both groups, although significantly lower HCV RNA loads were obtained with Thymoglobulin pretreatment. The mean time to histologic recurrence was shorter in Thymoglobulin-treated patients; however, no significant difference was observed in mean Ishak's histologic grading and staging of HCV recurrence.. In our preliminary experience, a "prope" tolerogenic regimen with Thymoglobulin pretreatment and low-dose immunosuppression in liver-transplant recipients gave good protection against rejection and permitted lower HCV viral loads, whose significance in the long-term outcome of HCV patients deserves further investigation.

Topics: Adult; Aged; Antilymphocyte Serum; Female; Graft Rejection; Hepatitis C; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Recurrence; Retrospective Studies; Survival Analysis; Tacrolimus; Transplantation Tolerance

Previous studies suggest the association of recipient hepatitis C seropositivity (HCV+) and use of tacrolimus (TAC) with post-transplant diabetes mellitus (PTDM) may differ by manifestations of type I or type II diabetes, but this has not been assessed in the era of current immunosuppression.. We performed a retrospective cohort study of 10,342 Medicare primary renal transplantation recipients without evidence of diabetes at the time of listing in the United States Renal Data System between January 1, 1998 and July 31, 2000, followed until December 31, 2000. Outcomes were hospitalizations for a primary diagnosis of diabetic ketoacidosis (DKA) or hyperglycemic hyperosmolar syndrome (HHS). Cox regression analysis was used to calculate adjusted hazard ratios (AHR) for time to DKA or HHS, stratified by diabetes status at the time of transplant.. In Cox regression analysis, use of TAC at discharge was independently associated with shorter time to DKA (AHR, 1.88; 95% CI, 1.05-3.37, p=0.034) but not HHS. In contrast, recipient HCV+ was independently associated with shorter time to HHS (AHR, 3.90; 1.59-9.60, p=.003), but not DKA. There was no interaction between TAC and HCV+ for either outcome.. These results confirm earlier findings that TAC and HCV+ may mediate the risk of PTDM through different mechanisms, even in the modern era.

Topics: Diabetes Mellitus; Female; Graft Rejection; Hepatitis C; Hospitalization; Humans; Immunosuppressive Agents; Insulin; Insulin Secretion; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Tacrolimus; United States

Induction therapy with T-cell depleting drugs in liver transplantation is controversial. This study examined the use of rabbit antithymocyte globulin (RATG) with delayed introduction of tacrolimus in liver transplant recipients. Additional subgroup analysis compared patients with or without hepatitis C (HCV) cirrhosis. Over 17 months, 116 adults received 120 liver allografts. Four patients who died before receiving RATG were excluded. Immunosuppression included steroids, 3 doses of RATG (2 mg/kg), and tacrolimus started on postoperative day 3 to 4. Ninety-six percent of patients were alive with a mean follow-up of 12.9+/-4.5 months. No graft was lost to rejection. Two patients developed hepatic artery thrombosis. Six percent of patients had acute rejection. No patient had steroid resistant or recurrent rejection. RATG related drug events were limited to fever, chills, tachycardia, and oxygen desaturation. There were no cases of lymphoproliferative disease. Forty-two percent of patients were transplanted for HCV. Thirty-two percent of HCV-patients had biopsy proven hepatitis C recurrence occurring at 4 weeks to 10 months posttransplant. RATG induction therapy is associated with good patient and graft survival, a low incidence of rejection, and minimal side effects. In addition, RATG induction is safe in patients transplanted for HCV.

Topics: Adult; Antilymphocyte Serum; Graft Rejection; Graft Survival; Hepatitis C; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Diseases; Liver Transplantation; Methylprednisolone; Survival Analysis; Tacrolimus; Time Factors; Treatment Outcome

There has been concern that adult living-donor liver transplantation (LLTx) for hepatitis C virus (HCV) infection may lead to recurrent disease that is more severe compared with the results of cadaveric LTx (CLTx), because the smaller sized graft in LLTx regenerates and may increase viral replication. This study examines the survival outcome and HCV recurrence in CLTx versus LLTx performed at a single institution.. A total of 100 consecutive adult recipients (75 men and 25 women; mean age 49.9+/-8.4 years) of LTx (65 CLTxs and 35 LLTxs performed July 2000-July 2002) who tested positive for HCV by polymerase chain reaction were examined retrospectively until October 2003. All patients received tacrolimus-based immunosuppression with mycophenolate mofetil and steroids.. The overall actual patient survival was 85% (83.1% for CLTx vs. 88.6% for LLTx). The 39-month Kaplan-Meier actuarial patient survivals were 75.1% for CLTx and 88.6% for LLTx. Of 15 deaths, 6 were the result of recurrent HCV (five CLTxs and one LLTx), and of 10 retransplants, 2 were related to recurrent HCV (one CLTx and one LLTx). The rates of recurrence were 72.3% and 77.1%, the hepatitis activity indices were 5.4 + 2.4 and 6.2 + 2.8, the fibrosis scores were 1.4+/-1.4 and 1.5+/-1.3, and the times to recurrence were 318+/-269 days and 394+/-250 days for CLTx and LLTx, respectively. None of the differences between the two groups were significant.. No detrimental effect of HCV infection was found in LLTx recipients when compared with contemporaneous CLTx recipients. Patient survival, graft survival, rate of HCV recurrence, severity of HCV recurrence, graft loss from HCV, and interval for recurrence in CLTx and LLTx were similar.

Topics: Adult; Aged; Cadaver; Cause of Death; Graft Survival; Hepatitis C; Humans; Immunosuppressive Agents; Liver Transplantation; Living Donors; Middle Aged; Recurrence; Retrospective Studies; Tacrolimus; Transplantation, Homologous

The objective of this study was to evaluate the association between previous hepatitis C virus (HCV) infection and the occurrence of posttransplant diabetes mellitus (PTDM) among patients undergoing kidney transplants using tacrolimus (FK). From August 1999 to January 2003, 66 patients (36.4 +/- 15.5 years) underwent kidney transplantation using an immunosuppressive regimen of tacrolimus, mycophenolate mofetil, or azathioprine and steroids. Thirty-four patients (52%) received kidneys from living donors and 32 (48%) from cadaveric donors. The diagnosis of diabetes mellitus was established after two consecutive ambulatory measurements of fasting glycemia > or = 126 mg/dL. Thirty-five percent of the patients (23/66) were HCV+ and 65% (43/66) HCV-. Of the 66 patients, 33% (22) developed PTDM, 19 (82%) from the HCV+ group and only 3 (7%) from the HCV- group. Among those who developed PDTM, the diagnosis was established in the first 2 posttransplant months in most cases (68.2%). The results showed a significant association between HCV and PTDM (P < or = .0001). In this group of patients HCV infection was strongly associated with the development of PTDM. Therefore, additional care is required regarding the immunosuppressive regimen among patients with chronic HCV infection.

Topics: Diabetes Complications; Hepatitis C; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Retrospective Studies; Risk Factors; Tacrolimus

The aim of this study was to assess the possible association between posttransplant diabetes mellitus (DM) and hepatitis C virus (HCV) infection in renal transplant recipients. This study included 124 patients who underwent renal transplantation between 1997 and 2002. Inclusion criteria were patients who were not diabetic prior to transplantation and posttransplant follow-up longer than 6 months. DM was defined as fasting blood glucose levels higher than 126 mg/dL on at least two occasions. HCV infection was detected using second- or third-generation ELISA methods and/or polymerase chain reactions for HCV-RNA. Twenty-five HCV positive (HCV+) patients were compared with 25 consecutive HCV negative (HCV-) transplant patients. Demographic and clinical data of the groups were compared. Posttransplantation DM was observed in 24% of the HCV+ patients. There were no statistical differences in age, gender, race, family history of DM, follow-up, or body mass index between the two groups. There was a higher prevalence of posttransplantation DM in HCV+ patients, but the difference did not reach statistical significance (24% vs 12%, P = NS). Alternatively, comparing patients of the two groups (n = 50) who did versus not develop DM, the incidence of posttransplantation DM was higher among HCV+ patients, but the difference did not reach statistical significance (66.6% vs 46.3%, P = NS). In conclusion, there was no association between HCV infection and the development of posttransplantation DM in this cohort of renal transplant recipients. However, there was a trend that suggested an association.

Topics: Adult; Brazil; Creatinine; Cyclosporine; Diabetes Mellitus; Female; Hepatitis C; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Prednisone; Racial Groups; Retrospective Studies; Tacrolimus

The effects of rapid steroid withdrawal (SW) on kidney transplantation (KT) outcome were investigated in 12 HCV+ patients in a prospective cohort study. These results were compared with 17 HCV+ patients who received KT in the prior 2 yr and treated with a standard prednisone taper protocol. SW patients received only 6 d of steroid treatment after transplantation. Eleven received Thymoglobulin and one Basiliximab induction treatment along with a calcineurin inhibitor and mycophenolate mofetil. Patient and graft survival was 92% in SW group (median follow-up 12 months, range 6-17), and 92 and 82% in the historic control group respectively (median follow-up 21 months, range 11-27). In the SW and control group, acute rejection rates were 9 and 18%, and mean creatinine levels at last follow-up 1.30 +/- 0.36 and 1.68 +/- 0.58 mg/dL respectively. Only two SW patients had an increase in liver function tests during follow-up (18%), compared with six patients in the control group (43%). This study demonstrates that rapid SW is safe for HCV+ KT recipients, without an increase in acute rejection episodes or liver function abnormalities in the short term.

Topics: Adult; Aged; Antibodies, Monoclonal; Basiliximab; Cyclosporine; Disease Progression; Drug Therapy, Combination; Emulsions; Female; Glucocorticoids; Hepatitis C; Humans; Immunosuppressive Agents; Kidney Transplantation; Liver Function Tests; Male; Middle Aged; Mycophenolic Acid; Prednisolone; Prospective Studies; Recombinant Fusion Proteins; Tacrolimus; Treatment Outcome

Steroids can increase hepatitis C virus (HCV) replication. After liver transplantation (LTx), steroids are commonly used for immunosuppression and acute rejection is usually treated by high steroid dosages. Steroids can worsen the outcome of recurrent HCV infection. Therefore, we evaluated the outcome of HCV infected liver recipients receiving initial steroid-free immunosuppression.. Thirty patients undergoing LTx received initial steroid-free immunosuppression. Indication for LTx included 7 patients with HCV related cirrhosis. Initial immunosuppression consisted of tacrolimus 2X0.05 mg/kg.d po and mycophenolate mofetil (MMF) 2X15 mg/kg.d po. The tacrolimus dosage was adjusted to trough levels in the target range of 10-15 microg/L during the first 3 mo and 5-10 microg/L thereafter. Manifestations of acute rejection were verified histologically.. Patient and graft survival of 30 patients receiving initial steroid-free immunosuppression was 86% and 83% at 1 and 2 years. Acute rejection occurred in 8/30 patients, including 1 HCV infected recipient. All HCV-infected patients had HCV genotype II (1b). HCV seropositivity occurred within the first 4 mo after LTx. The virus load was not remarkably increased during the first year after LTx. Histologically, grafts had no severe recurrent hepatitis.. From our experience, initial steroid-free immunosuppression does not increase the risk of acute rejection in HCV infected liver recipients. Furthermore, none of the HCV infected patients developed serious chronic liver diseases. It suggests that it may be beneficial to avoid steroids in this particular group of patients after LTx.

Topics: Adult; Drug Therapy, Combination; Female; Hepatitis C; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Care; Tacrolimus

We report a case of a 32-year-old female with histologically and clinically inactive chronic hepatic C infection, who received a cadaveric renal transplant from a hepatitis C-positive donor with a different genotype. The genotype mismatch (genotype 1 to genotype 2) and change to tacrolimus-based immunosuppression resulted in severe hepatitis C infection characterized by a 10-fold increase in transaminase levels and grade 3 inflammation histologically. Our report highlights the risk of genotype-mismatch transplants in solid organ transplantation.

Topics: Adult; Biopsy; Female; Genotype; Graft Rejection; Hepacivirus; Hepatitis C; Histocompatibility Testing; Humans; Immunosuppressive Agents; Kidney Transplantation; Liver; Liver Transplantation; Polymerase Chain Reaction; Tacrolimus; Time Factors; Transaminases; Transplantation, Homologous; Treatment Outcome

Hepatitis C virus (HCV)-related end-stage liver disease (ESLD) is the leading cause for orthotopic liver transplantation (OLT). However, in recent years, the long-term results of OLT in this setting are worsening, possibly due to the powerful immunosuppressants in use. The aim of our study was to assess the safety and efficacy of induction therapy using rabbit antithymocyte globulin antibodies (RATG).. Over an 18-month period from January 2000 to June 2001, 16 patients underwent OLT for HCV-related ESLD and survived more than 1 month posttransplantation. They received induction therapy based on RATG (Thymoglobulins, Sangstat, France) at 1 mg/kg per day for 3 consecutive days, and it was then adjusted to maintain a CD2 count below 50/mm(3). Overall, RATG was given for a median of 5 days for a total dose of 406 +/- 45 mg. Steroids were started pretransplant and tacrolimus on day 1. The primary end-points were patient and graft survivals at 6 months posttransplantation, incidence of rejection, infectious complications (bacterial, viral, and fungal) and recurrence of HCV infection based on biochemical, virological, and histologic criteria.. The survival rates were 100% for patients and 93.7% for grafts. The acute rejection rate was 37.5%. The median time to acute rejection was 15.5 days. There was only one serum sickness case. Cytomegalovirus infections occurred in 25% of patients. The rate of de novo diabetes that required insulin therapy was at 50%. The rate of HCV recurrence was 56.25%. In addition, HCV RNA serum concentrations increased significantly posttransplantation (>1 log). In conclusion, RATG induction therapy is safe and efficient in HCV-positive liver recipients.

Topics: Adult; Alanine Transaminase; Animals; Antilymphocyte Serum; Aspartate Aminotransferases; Female; Hepatitis C; Humans; Immunosuppressive Agents; Leukocyte Count; Liver Failure; Liver Transplantation; Male; Middle Aged; Rabbits; Retrospective Studies; Safety; Tacrolimus; Tissue Donors

Topics: Hepatitis C; Humans; Immunosuppressive Agents; Liver Transplantation; Tacrolimus

Topics: Cyclosporine; Female; Hepatitis C; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Recurrence; Retrospective Studies; Tacrolimus

We recently reported on a series of patients who experienced acute cellular rejection (ACR) during the treatment of hepatitis C virus (HCV) infection in our posttransplantation cohort. Our hypothesis is that HCV clearance improves hepatic microsomal function, which in turn results in lower trough cyclosporine (CyA) and tacrolimus (TAC) levels, predisposing the patient to ACR. Records of all patients receiving transplants for HCV infection at our center from 1993 to June 2002 were reviewed. Two hundred three patients were identified. Thirty-seven patients (18%) were treated with interferon-based therapies in combination with ribavirin. Twelve patients were selected for analysis because they became HCV RNA negative during therapy, and 18 patients with no antiviral response were selected as controls (7 other patients had incomplete data or had switched from one immunosuppression [IS] therapy to the other). Baseline IS levels were compared with the first available level after documented negative HCV RNA results in the study group and the last on-treatment IS level in the control group. We also compared frequency and percentage of change in IS levels during therapy. Mean decline in CyA trough levels in the study group was from 187.28 ng/mL at baseline to 118.14 ng/mL immediately after becoming HCV RNA negative (-36.92%; P =.018). Mean decline in TAC levels was from 7.34 ng/mL at baseline to 5.02 ng/mL immediately after becoming HCV RNA negative (-29.17%; P =.044). Overall, 6 of 12 patients who cleared HCV RNA during therapy experienced ACR; 1 patient died as a result of ACR. Using percentage of decrease from baseline IS level, we combined results for patients administered CyA and TAC and found a significant decrease from baseline IS levels in responders (-31.8% after HCV RNA clearance on treatment; P =.0001). Nonresponders experienced a 0.98% decline in IS levels while on treatment, and the difference was significant compared with the change in the responder group (P =.006). A greater proportion of antiviral therapy responders also experienced trough IS levels 20% less than baseline than nonresponder controls during therapy (P =.0006). In conclusion, IS levels decreased significantly in patients responding favorably to anti-HCV therapy. This decrease in IS levels may have a key role in predisposing these patients to ACR.

Topics: Alkaline Phosphatase; Cyclosporine; Graft Rejection; Hepatitis C; Hepatocytes; Humans; Immunosuppressive Agents; Liver Transplantation; Microsomes, Liver; Retrospective Studies; Tacrolimus

Topics: Adult; Boston; Diabetes Mellitus; Female; Hepatitis C; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Racial Groups; Retrospective Studies; Tacrolimus

Topics: Alanine Transaminase; Antidepressive Agents, Second-Generation; Aspartate Aminotransferases; Cyclosporine; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Drug Interactions; Hepatitis C; Humans; Liver Transplantation; Male; Mixed Function Oxygenases; Piperazines; Substance-Related Disorders; Tacrolimus; Triazoles

Topics: Alanine Transaminase; Aspartate Aminotransferases; Cyclosporine; Drug Therapy, Combination; Graft Rejection; Hepatitis C; Humans; Immunosuppressive Agents; Liver Transplantation; Mycophenolic Acid; Recurrence; Retrospective Studies; Tacrolimus; Viral Load

Tacrolimus (FK-506) is a calcium-calcineurin inhibitor, successfully used in transplant recipients. We report the successful use of tacrolimus as a single immunosuppressant in a patient who had developed myasthenia gravis (MG) during interferon alpha treatment. In this case, the coexistence of hepatitis C and type 2 diabetes mellitus contraindicated the use of both steroids and azathioprine, and cyclosporine A, although effective, had induced renal failure. Tacrolimus proved to be effective in the treatment of MG, was not significantly hepatotoxic, and was less nephrotoxic than cyclosporine.

Topics: Antiviral Agents; Hepatitis C; Humans; Immunosuppressive Agents; Interferon-alpha; Male; Middle Aged; Myasthenia Gravis; Tacrolimus

Topics: Adult; Alanine Transaminase; Aspartate Aminotransferases; Cyclosporine; Hepatitis C; Humans; Immunosuppressive Agents; Kidney Transplantation; Liver Function Tests; Middle Aged; Postoperative Complications; Retrospective Studies; Tacrolimus

Posttransplant diabetes mellitus (PTDM) remains a common complication of immunosuppression. Although multiple risk factors have been implicated, none have been clearly identified as predisposing to the increased PTDM frequency observed in patients on tacrolimus. Hepatitis C virus (HCV) has been associated with diabetes and is a significant renal transplant comorbidity. In this study, records of 427 kidney recipients who had no known diabetes before transplantation were retrospectively examined. A multivariate logistic regression model was fit with covariates that had unadjusted relationships with PTDM to examine the independent relationship of HCV and the odds of development of PTDM by 12 mo posttransplant. A potential interaction between HCV and the use of tacrolimus as maintenance therapy on the odds of the development of PTDM was examined. Overall, PTDM occurred more frequently in HCV(+) than HCV(-) patients (39.4% versus 9.8%; P = 0.0005). By multivariate logistic regression, HCV (adjusted odds ratio [OR], 5.58; 95% confidence interval [CI], 2.63 to 11.83; P = 0.0001), weight at transplantation (adjusted OR 1.028; 95% CI, 1.00 to 1.05; P = 0.001), and tacrolimus (adjusted OR, 2.85; 95% CI, 1.01 to 5.28; P = 0.047) were associated with PTDM. A significant interaction (P = 0.0001) was detected between HCV status and tacrolimus use for the odds of PTDM. Among the HCV(+) cohort, PTDM occurred more often in tacrolimus-treated than cyclosporine A-treated patients (57.8% versus 7.7%; P < 0.0001). PTDM rates in HCV(-) patients were similar between the two calcineurin inhibitors (10.0% versus 9.4%; P = 0.521, tacrolimus versus cyclosporine A). In conclusion, HCV is strongly associated with PTDM in renal transplant recipients and appears to account for the increased diabetogenicity observed with tacrolimus.

Topics: Adult; Diabetes Complications; Diabetes Mellitus; Female; Hepatitis C; Humans; Immunosuppressive Agents; Kidney Transplantation; Logistic Models; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Risk Factors; Tacrolimus

An association between hepatitis C virus and (post-transplant) diabetes mellitus has been reported.. We report a patient on tacrolimus-based immunosuppression who developed an episode of post-transplant diabetes mellitus (PTDM) 2 years after renal transplantation, after contracting a hepatitis C infection. Her glucose metabolism was evaluated regularly by intravenous glucose tolerance tests before and after the PTDM episode.. Before contracting hepatitis C, the patient's insulin resistance and insulin secretion were normal. After contracting hepatitis C, tacrolimus exposure increased, insulin resistance increased, and insulin secretion decreased markedly. Despite low tacrolimus exposure in the last 4 years, glucose metabolism did not recover completely. Although PTDM resolved and insulin resistance normalized, pancreatic beta cell secretion remained impaired by approximately 50% compared with the period before hepatitis C infection.. After an initial increase in insulin resistance, insulin secretion decreased markedly in a patient who contracted hepatitis C 12 to 22 months after renal transplantation. This change resulted in an episode of PTDM. Increased tacrolimus exposure secondary to reduced cytochrome P-450 metabolism as a result of impaired hepatocellular function at the time of the development of PTDM seems a likely explanation for the marked decrease in insulin secretion. Viral toxicity to the beta cell might be an additional explanation. The latter might be suspected from several reports about an association between diabetes mellitus and hepatitis C in patients who do not use drugs that interfere with glucose metabolism.

Topics: Adult; Diabetes Mellitus; Drug Administration Schedule; Female; Hepacivirus; Hepatitis C; Hepatitis C Antibodies; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Retrospective Studies; RNA, Viral; Tacrolimus; Transplantation, Homologous

End-stage renal failure after successful liver transplantation (LTx) has been described in up to 5% of patients. Kidney transplantation (KTx) has been the treatment of choice in these cases. However, in recipients infected with hepatitis C virus (HCV), the augmentation of immunosuppression after KTx may result in an increased viral load. This, in turn, may adversely affect the liver allograft.. The present study retrospectively examined the outcome in 17 patients (3 females and 14 males, mean age 51.1+/-11.3 years) who received KTx after LTx. The mean interval from LTx to KTx was 57.6+/-32.1 months. The mean follow-up was 41.7+/-20.5 months after KTx, and 99.6+/-37.7 months after LTx. Sixteen of the 17 patients received tacrolimus-based immunosuppression at the time of KTx.. During the follow-up period, one patient underwent combined liver and kidney retransplantation 3.7 years after KTx and 12.7 years after LTx. She subsequently died secondary to primary nonfunction. Four other patients died, two of lung cancer, one of pancreatitis/sepsis, and one of severe depression leading to noncompliance. A total of 29 episodes of biopsy-proven acute renal allograft rejection (1.7 episodes/ patient) were encountered and treated with steroids. Seven patients experienced a rise in liver function tests during the period of increased steroid dosage. Four patients received no treatment, and their liver function returned to baseline. The remaining three were treated with interferon. Overall 1- and 3-year actuarial patient and liver allograft survival was 88% and 71% (after renal transplantation); corresponding 1- and 3-year actuarial graft survival was 88% and 61%. Twelve patients are alive with normal liver function. One patient is on dialysis, because of renal allograft loss to noncompliance.. In this series, LTx recipients with HCV infection were able to undergo KTx with a reasonable degree of success. KTx should be offered for end-stage renal failure after LTx, even in the presence of HCV infection, to individuals with stable liver function and no signs of liver failure.

Topics: Adult; Biopsy; Female; Graft Survival; Hepacivirus; Hepatitis C; Humans; Immune Tolerance; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Liver; Liver Transplantation; Male; Middle Aged; Quality of Life; Survival Rate; Tacrolimus; Virus Replication

Topics: Administration, Oral; Cyclosporine; Cytomegalovirus Infections; Drug Therapy, Combination; Graft Rejection; Hepatitis C; Humans; Immunosuppressive Agents; Liver Transplantation; Middle Aged; Postoperative Complications; Recurrence; Reoperation; Retrospective Studies; Survival Rate; Tacrolimus; Time Factors

Nuclear factor kappaB (NF-kappaB) is activated during viral infection and is central to the regulation of host immune responses. The NF-kappaB activation status and its morphological sources were assessed by immunohistochemistry in allograft biopsy specimens of orthotopic liver transplantation patients with recurrent hepatitis C virus (HCV). Hepatocellular NF-kappaB immunostaining was detected in HCV cases compared with controls (nontransplant: P <.001; transplant: P =.006), which correlated with the number of NF-kappaB positive hepatocytes (P =.007) and contrasted to the absent to weak staining of controls (nontransplant: P =.001; transplant: P =.009). Enhanced NF-kappaB staining of cytokeratin 19-positive bile ducts and proliferating ductules in the HCV group was in contrast to controls. Intense NF-kappaB immunoreactivity was detected in CD68-positive Kupffer cells and macrophages of all HCV specimens compared with a few controls (nontransplant: P <.001; transplant: P =.001) and contrasted to the weak staining of controls (nontransplant: P <.001; transplant: P =.001). NF-kappaB-positive immunoreactivity correlated with the number of T cell receptor (TCR) alpha/beta-positive lymphocytes (P <.001), which was not observed in controls. In those HCV cases showing evidence of necroinflammatory activity (grade) and individual features of portal inflammation, periportal inflammation/piecemeal necrosis, lobular inflammation, and fibrosis (stage), higher NF-kappaB staining intensity scores within bile ducts, proliferating ductules, hepatocytes (piecemeal necrosis: P =.016; stage: P =.030), and lymphocytes (stage: P =.044) and increased number of NF-kappaB-positive cells within bile ducts, proliferating ductules (grade, lobular inflammation, piecemeal necrosis, stage: P =.022), hepatocytes, and lymphocytes were observed. Increased staining intensity and frequency of NF-kappaB-positive cells were similarly observed in HCV-positive allografts obtained from patients under tacrolimus- compared with cyclosporine-based immunosuppression. These data implicate an immunoregulatory role of intragraft NF-kappaB activation in the pathogenesis and progression of posttransplantation HCV disease recurrence.

Topics: Adult; Aged; Cyclosporine; Dimerization; Female; Hepatitis C; Humans; Immunohistochemistry; Liver Transplantation; Male; Middle Aged; NF-kappa B; Recurrence; RNA, Viral; Tacrolimus

A 49-year old male patient with severe hemophilia A, coinfected with HIV and HCV, who underwent orthoptic liver transplantation because of hepatitis C cirrhosis is presented. We describe a strong interaction between nelfinavir and tacrolimus postoperatively, that caused a reduction of the dose of tacrolimus by a factor 70 compared with normal, to achieve therapeutic blood concentrations and to avoid toxic side effects. We suggest that nelfinavir inhibits the metabolism of tacrolimus because both compounds are well-known substrates for the cytochrome P450 isoenzyme CYP 3A4. The nelfinavir serum concentrations were not affected by the institution of tacrolimus. Although the interaction dramatically changed the tacrolimus dose-concentration relationship, the situation was manageable by frequent monitoring of blood concentrations of tacrolimus.

Topics: Drug Interactions; Drug Monitoring; Hemophilia A; Hepatitis C; HIV Infections; HIV Protease Inhibitors; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Nelfinavir; Tacrolimus

Hepatitis C is the most common cause of end-stage liver disease leading to liver transplant. The disease can recur after transplant, resulting in clinical hepatitis in up to 75% of patients and severe disease in approximately 7%. Treatment of rejection with steroid boluses and treatment of steroid-resistant rejection with OKT3 have both been shown to increase the incidence of recurrent hepatitis C. The use of OKT3 for steroid-resistant rejection is reportedly associated with more severe recurrence. The calcineurin inhibitors tacrolimus and cyclosporine have not been conclusively associated with different rates or severity of recurrence. Viral levels rise 10- to 15-fold after transplant and appear to be associated with the use of immunosuppression. Studies suggest that high viral levels, either pretransplant or early after transplant, may be associated with severe recurrent disease. Although the role of genotype is still unclear, genotype 1b is known to be associated with a poorer prognosis in nontransplanted patients and a lesser response to treatment than other genotypes. Furthermore, some reports suggest that after transplant, recurrent disease may progress more rapidly in patients with genotype 1. Treatment options after recurrence remain poor. Neither interferon nor ribavirin alone provides any true benefit. Combination therapy appears to have a better short-term outcome but may be poorly tolerated, and long-term benefits are unknown. Prophylaxis with combination therapy may be a better option but requires further study. Finally, retransplantation for recurrent hepatitis C is complicated not by rapid recurrence of disease in the new allograft but by high perioperative mortality that may be predicted by the presence of renal failure or sepsis preretransplant.

Topics: Cyclosporine; Disease Progression; Drug Therapy, Combination; Hepatitis C; Humans; Immunosuppressive Agents; Liver Failure; Liver Transplantation; Prognosis; Recurrence; Renal Insufficiency; Risk Factors; Sepsis; Tacrolimus; Treatment Outcome

Topics: Antibodies, Monoclonal; Cyclosporine; Graft Rejection; Hepatitis C; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Methylprednisolone; Muromonab-CD3; Mycophenolic Acid; Receptors, Interleukin-2; Recurrence; Reoperation; Retrospective Studies; Survival Rate; Tacrolimus; Time Factors

Topics: Azathioprine; Cyclosporine; Drug Therapy, Combination; Follow-Up Studies; Hepatitis C; Humans; Immunosuppressive Agents; Liver Transplantation; Prednisone; Recurrence; Reoperation; Retrospective Studies; Tacrolimus; Time Factors

The outcome of hepatitis C virus (HCV) infection on patient and graft survival after orthotopic liver transplantation (OLT) has been controversial. An earlier experience with a higher dose of tacrolimus (>/=0.1 mg/kg/d intravenously and >/=0.2 mg/kg/d orally) was associated with a worse clinical outcome in patients infected with HCV. The clinical outcome of 183 liver transplant recipients with end-stage liver disease (ESLD) secondary to HCV infection (HCV group) was compared with a contemporary cohort of 556 patients with HCV infection who underwent transplantation for nonviral, nonmalignant ESLD (control group). All patients were prospectively screened for anti-HCV antibodies and HCV RNA by reverse-transcriptase polymerase chain reaction. All OLT patients were receiving low-dose tacrolimus immunosuppression. Cumulative patient survival rates for the HCV group were 80% after 1 year and 75% after 3 years compared with rates of 84% and 78%, respectively, in the control group (P = .452). Primary graft survival rates at the same time intervals for the HCV group and the control group were 72% and 77.5% at 1 year and 67% and 72% at 3 years, respectively (P = .144). The incidence of re-transplantation (re-OLT) in the HCV group and the control group was 12.6% and 10.4%, respectively (P = .42). Chronic HCV infection as an indication for OLT with a lower dose of tacrolimus immunosuppression (

Topics: Adult; Chi-Square Distribution; Cohort Studies; Female; Graft Rejection; Graft Survival; Hepacivirus; Hepatitis C; Hepatitis C Antibodies; Humans; Immunoenzyme Techniques; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Proportional Hazards Models; Reoperation; Retrospective Studies; Reverse Transcriptase Polymerase Chain Reaction; RNA, Viral; Survival Rate; Tacrolimus; Treatment Outcome

Topics: Acute Disease; Adolescent; Adrenal Cortex Hormones; Adult; Azathioprine; Cyclosporine; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Hepatitis B; Hepatitis C; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Muromonab-CD3; Postoperative Complications; Retrospective Studies; Tacrolimus; Time Factors

Topics: Actuarial Analysis; Cyclosporine; Cytokines; Drug Therapy, Combination; Extracellular Matrix Proteins; Fibronectins; Gene Expression Regulation; Glutathione Transferase; Graft Rejection; Hepatitis C; Humans; Hyaluronic Acid; Immunosuppressive Agents; Interferon-gamma; Interleukin-6; Interleukin-8; Laminin; Liver Transplantation; Prednisolone; Recurrence; Retrospective Studies; Survival Rate; Tacrolimus; Time Factors

Hepatitis C virus (HCV) is the predominant cause of posttransplant non-A, non-B hepatitis among renal allograft recipients. Prior studies evaluating the impact of HCV in kidney transplantation have been retrospective in design and based largely on changes in serum transaminases. We studied a group of HCV-infected end-stage renal disease patients prospectively with pretransplant liver biopsies and close virologic and biochemical follow-up posttransplant. Fourteen patients have been followed a mean of 11.6 +/- 5.6 months posttransplant (range, 5-21 months). Six had changes of chronic hepatitis on pretransplant liver biopsy while 8 showed only mild histologic abnormalities. Circulating viral titers increased several-fold over baseline levels during posttransplant follow-up. Viral replication was particularly enhanced immediately following a course of antilymphocyte therapy. Although all patients showed a 2-3 fold increase in alanine aminotransferase (ALT) following transplantation, there were no association noted between pretransplant liver histology, the use of FK506 and/or cyclosporine-based immunosuppression, and the magnitude of ALT change posttransplant. The only clinical outcome found to differ significantly was a higher incidence of cytomegalovirus infection among patients with chronic hepatitis. All patients are alive with functioning grafts. There have been no episodes of fulmiinant or subfulminant liver failure. We conclude that HCV-infected patients can be safely transplanted with excellent short-term follow-up. Continued monitoring with sequential liver biopsies will be needed to define the long-term course of HCV infection in an immuno-suppressed population.

Topics: Adult; Biopsy; Follow-Up Studies; Genotype; Hepacivirus; Hepatitis C; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Liver; Middle Aged; Prospective Studies; Tacrolimus; Treatment Outcome

Recurrent hepatitis C virus is associated with significant morbidity and mortality after liver transplantation. However, the risk factors for clinical recurrence including the role of rejection and immunosuppression have not been defined in patients receiving tacrolimus (FK506) as primary immunosuppression.. Sixty-six consecutive adult liver transplant recipients receiving tacrolimus as primary immunosuppression were monitored; 31 of 66 underwent transplantation for end-stage liver disease caused by hepatitis C virus. Median follow-up for the patients in the study was 3 1/2 years. Recurrent hepatitis C virus hepatitis determined on histopathologic evaluation developed in 58% (18 of 31). A number of clinical variables including rejection and intensity of immunosuppression were assessed for patients with and without recurrence.. Rejection episodes preceding recurrence were documented in 72% (13 of 18) of patients with recurrence compared with 23% (3 of 13) in those without recurrence (p=0.007). A total of 33% (5 of 15) of patients with no rejection experienced recurrence versus 83% (5 of 6) with one episode of rejection (p=0.06) and 80% (8 of 10) with more than one episode of rejection (p=0.04). The mean number of steroid boluses for the treatment of rejection was higher for patients with recurrence (2.3 versus 0.77, p=0.01). Overall immunosuppression (as measured by steroids boluses, recycles, OKT3, and azathioprine) was significantly more intense for patients with recurrence (p=0.013).. Greater rejection concurrent with increased immunosuppression was associated with a higher recurrence of hepatitis C in liver transplant recipients.

Topics: Adult; Graft Rejection; Hepatitis C; Humans; Immune Tolerance; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Recurrence; Tacrolimus

Topics: Carcinoma, Hepatocellular; Cyclosporine; Graft Rejection; Hepatitis C; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Liver Neoplasms; Liver Transplantation; Postoperative Complications; Recurrence; Retrospective Studies; Survival Rate; Tacrolimus

Topics: Carcinoma, Hepatocellular; Cyclosporine; Follow-Up Studies; Hepatitis B; Hepatitis C; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Lymphoma; Neoplasms; Postoperative Complications; Retrospective Studies; Tacrolimus; Time Factors

The liver transplant program at the University of Miami, established in 1987, was rejuvenated in June 1994 with the addition of new staff and expanded to include all organs of the gastrointestinal tract. Since its inception, 630 patients have been transplanted in the program. During the past 2 years we performed 349 transplants in 318 patients (livers n = 323 in 298 patients, liver + kidneys n = 13, liver + islet n = 10, liver + kidney + islets n = 1, liver + heart n = 10, liver + lung n = 1). These included 4 split-liver, 3 living-related, multiple reduced-sized and one "Domino" liver transplant. We have an active pediatric program and 10% of our transplanted patients are pediatric. Our overall patient and graft survival rates were 81% and 78%, respectively. The intestinal transplant program was launched in August 1994. To date we have performed 22 intestinal transplants, in 9 adults and 13 children. These transplants included 4 isolated intestinal, 11 combined liver-intestinal and 7 multivisceral transplants. Overall patient and graft survival rates were 55% and 50%, respectively. During the past 2 years several studies involving immunosuppressive agents were carried out: 1)Mycophenolate Mofetil (MMF) was used as induction therapy and as rescue therapy in patients with steroid-resistant rejection. Tacrolimus toxicity, and chronic rejection; 2) Neoral was compared with Tacrolimus in patients with Hepatitis C; and 3) MMF was added as triple therapy for the intestinal transplants. We used alpha interferon-2b (alpha-IFN) in hepatitis C positive patients in the early posttransplant period and found that it appears to be a safe drug. There was no increase in rejection in patients receiving alpha-IFN, and patient and graft survival were the same as in our overall patient population. A combination a-IFN with Ribavirin will be undertaken in the near future. The use of Lamivudine in hepatitis B patients was shown to be effective in preventing and treating recurrence of hepatitis B posttransplant. Unmodified donor bone marrow cells (DBMC) were isolated from the vertebral bodies of the same cadaveric liver donors. Donor bone marrow dose, number of cells and/or number (or timing) of infusions were investigated to determine which variables affected the ability of DBMC to engraft in the liver recipient. The long-term benefit of DBMC needs further follow-up. Although, our patient and graft survival for liver transplant recipients is comparable to other large centers na

Topics: Adult; Bone Marrow Transplantation; Child; Florida; Graft Rejection; Hepatitis C; Hospitals, University; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Intestines; Liver Transplantation; Mycophenolic Acid; Recurrence; Retrospective Studies; Survival Rate; Tacrolimus; Transplantation, Homologous

Topics: Azathioprine; Cyclosporine; Follow-Up Studies; Graft Survival; Hepatitis B; Hepatitis C; Humans; Interferon-alpha; Kidney Transplantation; Pilot Projects; Retrospective Studies; Tacrolimus; Time Factors

Topics: Adult; Cyclosporine; Diagnostic Errors; Follow-Up Studies; Graft Rejection; Hepatitis C; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Transplantation; Retrospective Studies; Tacrolimus; Time Factors

Topics: Adult; Bilirubin; Child; Child, Preschool; Cyclosporine; Drug Monitoring; Follow-Up Studies; Graft Rejection; Hepatitis C; Humans; Liver Transplantation; Middle Aged; Recurrence; Reoperation; Tacrolimus; Treatment Failure; Treatment Outcome

Topics: Cyclosporine; Drug Monitoring; Graft Rejection; Hepatitis B; Hepatitis C; Humans; Immunosuppression Therapy; Incidence; Liver Cirrhosis; Liver Cirrhosis, Alcoholic; Liver Cirrhosis, Biliary; Liver Transplantation; Muromonab-CD3; Retrospective Studies; Survival Rate; Tacrolimus; Time Factors

Topics: Adult; Carcinoma, Hepatocellular; Cyclosporine; Female; Graft Rejection; Hepatitis C; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Function Tests; Liver Neoplasms; Liver Transplantation; Muromonab-CD3; Mycophenolic Acid; Tacrolimus