mycophenolic-acid and Hepatitis-C

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

Despite the increase in long-term survival, liver transplant recipients still exhibit higher morbidity and mortality than the general population. This is in part attributed to the lifelong administration of immunosuppression and its associated side effects. Several studies reported in the last decades have evaluated the impact of immunosuppression minimization in liver transplant recipients, but results have been inconsistent due to the heterogeneity of study designs and insufficient sample sizes. On the other hand, complete immunosuppression withdrawal has proven to be feasible in approximately 20% of carefully selected liver transplant recipients, especially in older patients and those with longer duration after transplantation. The long-term risks and clinical benefits of this strategy, however, also need to be clarified. As a consequence, and despite the general perception that a large proportion of liver recipients are over-immunosuppressed, it is currently not possible to derive evidence-based guidelines on how to manage long-term immunosuppression to improve clinical outcomes. Large clinical trials of drug minimization and/or withdrawal focused on clinically-relevant long-term outcomes are required. Development of personalized medicine tools and a deeper understanding of the pathogenesis of idiopathic inflammatory graft lesions will be pre-requisites to achieve these goals.

Topics: Calcineurin Inhibitors; Clinical Trials as Topic; Evidence-Based Medicine; Hepatitis C; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Transplantation; Lymphocyte Depletion; Mycophenolic Acid; Steroids; T-Lymphocytes; 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

Calcineurin inhibitors (CNIs) combined with steroids with or without azathioprine (AZA), have been a standard immunosuppression regimen after liver transplantation (LT). Since 2000 many centers have substituted AZA by mycophenolate mofetil (MMF). However, in LT the superiority of MMF over AZA is not clearly demonstrated. Therefore, we questioned the benefit of MMF versus AZA in LT with regard to rejection, renal dysfunction and hepatitis C virus (HCV) recurrence and survival. Using a literature search, relevant randomized controlled trials (RCT) and cohort studies were identified: two RCTs compared MMF to AZA only for acute rejection. Treated rejection was less with MMF in only one RCT (38.5% vs. 47.7%; p = 0.025), with no difference in patient and graft survival. No RCTs compared MMF and AZA in patients with CNI-related chronic renal dysfunction. Among two studies evaluating MMF, with substitution of AZA, one was stopped due to severe rejection. Recurrent HCV was less severe in 5/9 studies with AZA compared with 2/17 using MMF, six of which documented worse recurrence. Published data in LT show little, if any, clinical benefit of MMF versus AZA. RCTs should reevaluate AZA in LT. Evaluation of HCV replication and recurrence will be particularly important as AZA may have advantages over MMF.

Topics: Azathioprine; Graft Rejection; Hepatitis C; Humans; Immunosuppressive Agents; Kidney; Liver Transplantation; Mycophenolic Acid

Topics: Antiviral Agents; Female; Health Care Rationing; Hepatitis C; Humans; Immunosuppressive Agents; Life Style; Liver Cirrhosis; Liver Transplantation; Male; Mycophenolic Acid; Recurrence; Survival Analysis

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

1. Recurrent hepatitis C is an increasing problem posttransplantation. 2. It is difficult to determine histologically if alloimmunity, i.e., rejection, is also plays a role in posttransplantation hepatitis C. 3. Change in the degree of immunosuppression, rather than the absolute amount of immunosuppression, is bad for HCV-infected recipients. 4. Corticosteroid boluses are bad for HCV-infected recipients.

Topics: Graft Rejection; Hepatitis C; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Transplantation; Mycophenolic Acid; Recurrence; RNA, Viral

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

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

The aim of this study was to analyze the influence of cyclosporine A (CsA) taper in conjunction with mycophenolate mofetil (MMF) therapy on recurrent hepatitis C virus (HCV) in liver transplant patients.. Nineteen liver recipients with serologically and morphologically confirmed recurrent HCV were included in this study. After MMF introduction up to a maximum dose of 2000 mg/day, CsA dose was significantly tapered. In the control group immunosuppression remained unchanged. Allograft function and morphology, viral loads, and renal function were analyzed continuously.. MMF treatment was well tolerated without risk of rejection. Allograft fibrosis progressed in 6 patients of the MMF group (66.6%) and none (0%) of the controls at 12-month biopsy (P=0.005). Moreover, aminotransferases and viral loads increased slightly in the MMF-treated patients. Renal function improved significantly (serum creatinine: 239.3+/-90.2 micromol/L vs. 175.8+/-46.0 micromol/L; P=0.008) in the treatment group, while deteriorating (serum creatinine: 156.8+/-44.6 micromol/L vs. 214.8+/-120.1 micromol/L; P=0.06) in the controls.. MMF introduction allows a safe CsA taper in HCV-positive liver transplant patients and results in significant improvement of renal function. However, there seems to be a risk of marked progression of HCV-induced allograft injury.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Cyclosporine; Dose-Response Relationship, Drug; Drug Administration Schedule; Hepacivirus; Hepatitis C; Humans; Immunosuppressive Agents; Kidney Function Tests; Liver Transplantation; Middle Aged; Mycophenolic Acid; Recurrence; Treatment Outcome

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 aim of this study was to evaluate the impact of mycophenolate mofetil (MMF) on incidence, delay, severity and clinical course of early recurrent hepatitis C after liver transplantation (LT). A total of 21 hepatitis C virus (HCV)-positive patients after LT were prospectively enrolled in this study. All of them received a quadruple induction cyclosporine A (CsA)-based immunosuppression, augmented by MMF (n=12) or by azathioprine (n=9, AZA). MMF tended to delay recurrent disease (50+/-35 versus 35+/-35 weeks, P=0.5) with significantly lower levels of aminotransferases (P<0.05). Furthermore, patients under MMF revealed less severe allograft fibrosis at disease recurrence (stage of fibrosis: 1.5+/-0.5 versus 2.2+/-1.2; P=0.07). But stage of fibrosis significantly increased in the MMF-group (P<0.05) during 6 months of antiviral treatment. Three patients in the MMF-group and none of the controls suffered from severe fibrosing cholestatic recurrent hepatitis C. Initial post-LT administration of MMF tended to delay recurrent hepatitis C and to limit initial HCV-related biochemical and morphological graft dysfunction. But during clinical follow-up, its immunosuppressive capabilities exceeded possible antiviral properties, finally leading to significant progression of graft fibrosis. Thus, concomitant dose reduction of other basic immunosuppressants might be useful in this clinical setting.

Topics: Adult; Azathioprine; Cyclosporine; Female; Fibrosis; Graft Rejection; Hepatitis C; Humans; Immunosuppressive Agents; Incidence; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Recurrence; Severity of Illness Index

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

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

Topics: Azathioprine; Brazil; Hepatitis C; Humans; Immunosuppressive Agents; Kidney Transplantation; Liver Function Tests; Mycophenolic Acid

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

Topics: Antilymphocyte Serum; Azathioprine; Cyclosporine; Cytomegalovirus Infections; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Hepatitis C; Humans; Immunosuppressive Agents; Incidence; Liver Transplantation; Male; Methylprednisolone; Mycophenolic Acid; Patient Selection; Postoperative Complications; Prospective Studies; Reoperation; Safety; Survival Rate; Time Factors

No drug-drug interaction study has been conducted to date for the combination of ombitasvir, paritaprevir/ritonavir, dasabuvir (3D), and mycophenolic acid (MPA). We here report the case of a hepatitis C virus-infected patient treated with 3D and MPA for vasculitis. In light of the threat of drug-drug interaction, the concentration of MPA was measured before, during, and 15 days after the end of the 3D treatment. Similar values were found at all 3 time points, thus indicating that there is probably no need to adapt MPA dosage to 3D.

Topics: 2-Naphthylamine; Aged; Anilides; Antibiotics, Antineoplastic; Antiviral Agents; Carbamates; Cyclopropanes; Cytochrome P-450 CYP3A Inhibitors; Disease Management; Drug Interactions; Drug Monitoring; Drug Therapy, Combination; Hepatitis C; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Male; Mycophenolic Acid; Proline; Ritonavir; Sulfonamides; Uracil; Valine

Topics: Adult; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antiviral Agents; Biopsy; Combined Modality Therapy; Disease Progression; Hepatitis C; Humans; Immunocompromised Host; Immunosuppressive Agents; Lip Neoplasms; Liver Function Tests; Liver Transplantation; Lung Neoplasms; Male; Melanoma; Mycophenolic Acid; Neoplasm Staging; Steroids

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

Development of liver disease after hematopoietic cell transplantation is common and the causes diverse. Infection by hepatitis C virus (HCV) can be seen in patients who are chronically infected before transplant or from passage of virus from an infected donor; the normal 10-year course of hepatitis C after transplant is one of waxing and waning of serum aminotransferase enzymes, with little morbidity. In the series of 3 patients reported here, the course of hepatitis C was rapidly fatal, with the onset of jaundice at day 60 to 80 after transplant and liver histology typical of fibrosing cholestatic hepatitis (marked bile ductular proliferation, ballooned hepatocytes, and associated collagenous fibrosis centered around ductules). The bile ductular reaction pattern varied from elongated structures without a recognizable lumen to a pattern of cuboidal cells with a clear lumen. There was significant cholestasis with bile within hepatocytes and canalicular bile plugs. In situ HCV RNA hybridization studies from 1 patient showed a robust infection with high levels of HCV-infected hepatocytes and active viral replication. All 3 patients were on immunosuppressive drugs after transplant, including mycophenolate mofetil (MMF), which irreversibly inhibits inosine monophosphate dehydrogenase, on which T and B lymphocytes are dependent. We speculate that fatal fibrosing cholestatic hepatitis C in these cases was related to the immunosuppressive effects of MMF, as we had not recognized this presentation of HCV infection before the introduction of MMF.

Topics: Adult; Cholestasis; Fatal Outcome; Fibrosis; Hematopoietic Stem Cell Transplantation; Hepatitis C; Humans; Immunocompromised Host; Immunosuppressive Agents; Leukemia; Male; Middle Aged; Mycophenolic Acid

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

It is well known that cyclosporine A (CsA), a widely used immunosuppressant for clinical organ transplantation, has the ability to inhibit HCV replication. In this study, the effects of several other immunosuppressants, including mycophenolic acid (MPA), rapamycin and FK-506, on HCV replication were examined in human hepatocytes.. HCV JFH-l-infected hepatocytes were treated with immunosuppressants or with control vehicles. The levels of viral RNA and the expression of HCV core protein were determined by quantitative real-time RT-PCR and Western Blot assay, respectively.. MPA-treated cells showed significant decreases in both viral RNA and HCV Core protein expression compared with the control cells. Moreover, MPA treatments of hepatocytes before, during or after HCV infection could significantly inhibit viral replication. In contrast, rapamycin and FK-506 had little effect on HCV replication. Mechanism research disclosed that the inhibition of HCV replication by MPA was mainly due to its depletion of guanosine, a purine nucleoside crucial for synthesis of guanosine triphosphate (GTP), which is required for initiation of HCV RNA replication. The supplement of exogenous guanosine could reverse most of anti-HCV effect of MPA.. These results indicate that MPA, through the depletion of guanosine, inhibits HCV JFH-1 replication in hepatocytes, suggesting that MPA may be beneficial for HCV-infected transplant recipients.

Topics: Cell Line, Tumor; Hepacivirus; Hepatitis C; Hepatocytes; Humans; Immunosuppressive Agents; Mycophenolic Acid; RNA, Viral; Virus Replication

Topics: Calcineurin Inhibitors; Graft Rejection; Graft Survival; Hepacivirus; Hepatitis C; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Transplantation; Mycophenolic Acid; Steroids; 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

Mycophenolic acid (MPA) is a highly effective immunosuppressant that has broad antiviral activity against different viruses and can act in synergy with interferon-α (IFN-α) on hepatitis C virus (HCV) replication. MPA is a potent inosine monophosphate dehydrogenase (IMPDH) inhibitor but the antiviral mechanisms are less understood. The aim of this study was to investigate the inhibition of HCV infection by MPA and the molecular basis for its synergy with IFN-α. The role of IMPDH and interferon-stimulated genes (ISGs) was investigated in two HCV models using gain- or loss-of-function approaches. The in vivo effect of MPA treatment was studied in NOD/SCID mice engrafted with HCV replicon cells. Potent antiviral effects of MPA at clinically relevant concentrations were observed with both the subgenomic and JFH1-derived infectious HCV models. MPA treatment in mice resulted in a specific and robust inhibition of HCV replication. Ectopic expression of an MPA-resistant IMPDH2 mutant in HCV host cells completely reversed the antiproliferative effect of MPA but only partially affected the antiviral potency. However, similar to ribavirin, MPA induced expression of multiple antiviral ISGs, including interferon regulatory factor 1 (IRF1). Cotreatment of MPA with IFN-α resulted in additive effects on ISG expression and enhanced IFN-induced luciferase reporter activity. Knockdown of IRF1, but not IFITM3, significantly attenuated the inhibition of HCV replication by MPA.. MPA exerts a potent anti-HCV effect in vitro and in mice and acts in synergy with IFN-α. MPA's antiviral activity partially depends on IMPDH but also involves stimulation of ISGs, providing a molecular basis for its synergy with IFN-α.

Topics: Animals; Antiviral Agents; Cells, Cultured; Drug Synergism; Female; Gene Expression; Hepacivirus; Hepatitis C; Humans; Immunosuppressive Agents; IMP Dehydrogenase; Interferon Regulatory Factor-1; Interferon-alpha; Membrane Proteins; Mice; Mice, SCID; Mycophenolic Acid; RNA-Binding Proteins; Virus Replication

Hepatitis C virus (HCV) infection is the most common indication for liver transplantation and the major cause of graft failure. A widely used immunosuppressant, cyclosporine A (CsA), for people who receive organ transplantation, has been recognized to have the ability to inhibit HCV replication both in vivo and in vitro. In this study, we investigated the effects of several other immunosuppressants, including mycophenolate mofetil (MMF), rapamycin and FK506, on HCV replication in human hepatic cells. MMF treatment of hepatic cells before or during HCV infection significantly suppressed full cycle viral replication, as evidenced by decreased expression of HCV RNA, protein and production of infectious virus. In contrast, rapamycin and FK506 had little effect on HCV replication. Investigation of the mechanism(s) disclosed that the inhibition of HCV replication by MMF was mainly due to its depletion of guanosine, a purine nucleoside crucial for synthesis of guanosine triphosphate, which is required for HCV RNA replication. The supplement of exogenous guanosine could reverse most of anti-HCV effect of mycophenolate mofetil. These data indicate that MMF, through the depletion of guanosine, inhibits full cycle HCV JFH-1 replication in human hepatic cells. It is of interest to further determine whether MMF is indeed beneficial for HCV-infected transplant recipients in future clinical studies.

Topics: Antiviral Agents; Cell Line; Down-Regulation; Hepacivirus; Hepatitis C; Hepatocytes; Humans; Mycophenolic Acid; Virus Replication

Hepatitis C virus (HCV) recurrence after orthotopic liver transplantation (LT) is universal. We designed a retrospective case-control study to evaluate the effect of mycophenolate mofetil (MMF) monotherapy in patients with recurrent hepatitis C. Fifteen patients with histologically proven hepatitis C recurrence after LT were switched from calcineurin inhibitors (CNIs) to MMF monotherapy because of impairment of kidney function and/or metabolic side effects, and treated for 48 months (MMF group). Fifteen well-matched LT recipients who continued to receive CNIs therapy over the same period served as control group. Demographics, clinical data, time after LT, and baseline liver biopsies were similar in the two groups. There was no worsening of hepatic fibrosis during the study in the MMF group [2.6 ± 1.5 (baseline) Ishak Units vs. 2.7 ± 1.8 (after 48 months of MMF treatment), P = 0.6]. In contrast, a significant increase in the fibrosis score [2 ± 1.1 (baseline) vs. 3.2 ± 1.7 (after 48 months of CNI treatment), P = 0.0002] was observed in the control group. The yearly fibrosis progression rate was of 0.05 ± 0.44 in the MMF group and 0.33 ± 0.24 in the CNI group (P = 0.04). MMF monotherapy is associated with a favourable effect on hepatic fibrosis progression in HCV liver transplant recipients.

Topics: Aged; Antiviral Agents; Biopsy; Case-Control Studies; Cohort Studies; Disease Progression; Female; Fibrosis; Hepatitis C; Humans; Immunosuppressive Agents; Liver Failure; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Recurrence; Retrospective Studies; 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: Female; Fibrosis; Hepatitis C; Humans; Immunosuppressive Agents; Liver Failure; Liver Transplantation; Male; Mycophenolic Acid

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

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

Ribavirin is ineffective against hepatitis C virus as mono-therapy but is critical in attaining both early virologic response and sustained virologic response when combined with pegylated interferon. Ribavirin has significant dose-limiting toxicities, the most important of which is hemolytic anemia. Taribavirin is a ribavirin pro-drug, which targets the liver and has less incidence of anemia, and it may be a promising alternative to ribavirin in the future.

Topics: Anemia, Hemolytic; Antiviral Agents; Carbamates; Hepacivirus; Hepatitis C; Humans; IMP Dehydrogenase; Mycophenolic Acid; Phenylurea Compounds; Ribavirin

Hepatitis C virus (HCV) infection is common among end-stage renal disease patients receiving hemodialysis and a kidney transplant. HCV-positive kidney transplant recipients have worse clinical outcomes than those who are HCV negative. The optimal immunosuppressive regimen in this group of patients remains uncertain.. Using data obtained from the Organ Procurement and Transplantation Network/Scientific Registry of Transplant Recipients, we studied the impact of induction and maintenance immunosuppression on risk of patient death, with death-censored graft failure and death with a functioning graft as secondary endpoints. Cox regression analysis was used to estimate hazard ratios (HR) adjusted for donor, recipient, and transplant variables. A total of 3708 HCV-positive and 75,629 HCV-negative kidney transplant recipients were analyzed.. Patient survival was negatively affected by HCV-positive serology. Among HCV-positive kidney transplant recipients, a reduced HR for patient death was observed with the use of induction therapy (HR=0.75, 95% CI 0.61-0.90, P=0.003) and with the use of mycophenolate mofetil (HR=0.77, 95% CI 0.64-0.92, P=0.005).. In kidney transplant recipients with HCV-positive serology, the use of antibody induction did not negatively affect patient survival and the use of mycophenolate mofetil as part of maintenance immunosuppression was associated with better patient survival.

Topics: Adult; Cause of Death; Female; Follow-Up Studies; Graft Rejection; Hepacivirus; Hepatitis C; Hepatitis C Antibodies; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prodrugs; Proportional Hazards Models; Retrospective Studies; Risk Factors; Survival Rate; Treatment Outcome; United States

Mycophenolate mofetil (MMF) monotherapy has recently been proposed for liver transplant recipients with adverse events (nephrotoxicity, hypertension) related to calcineurin inhibitors. We analyzed the influence of MMF on the clinical course of recurrent hepatitis C.. Among 1038 patients who underwent liver transplantation (OLT) from April 1986 to October 2006, we analyzed 48 adult recipients (4.6%) whose diagnosis was hepatitis C virus (HCV) cirrhosis and who were converted from calcineurin inhibitors to MMF monotherapy.. The 36 men and 12 women, had a mean age at OLT of 52.9 +/- 7.2 years; the time elapsed from OLT to the onset of MMF monotherapy was 72.5 +/- 47.6 months (range = 11-210). The mean follow-up after monotherapy was 19 +/- 16.1 months (range = 2-67). Indications for conversion were: chronic renal dysfunction with HCV in 45 patients; HCV recurrence in two; and hypertension plus HCV recurrence in one subject. When the indication was renal dysfunction (excluding three patients who underwent hemodialysis), the mean creatinine values decreased significantly from baseline to 6 months of monotherapy from 1.63 +/- 0.61 mg/dL to 1.51 +/- 0.78 mg/dL (P < .03). The creatinine clearance only improved significantly from the baseline value of 56.6 +/- 16.8 mL/min to the value at 3 months of monotherapy-63.6 +/- 18.4 mL/min (P < .001). At the last outpatient visit, creatinine and creatinine clearances had not changed significantly. The mean diastolic blood pressure did improve significantly at the end of the study. The mean glucose levels decreased but not significantly at the last outpatient visit. Liver function tests did not change significantly after conversion to MMF monotherapy. The acute rejection rate was 8.3%, and adverse events related to MMF monotherapy were present in 9 patients (18.7%).. Conversion from calcineurin inhibitors to MMF monotherapy in patients who underwent OLT for HCV transiently improved renal function and hypertension. The acute rejection rate was low, and adverse events were usually well tolerated.

Topics: Adult; Calcineurin Inhibitors; Creatinine; Female; Hepatitis C; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Recurrence; Retrospective Studies; 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

Hepatitis C virus (HCV) recurrence after liver transplantation (LT) is almost universal, but the natural history of recurrent HCV in the allograft is highly variable. Our study had two aims: 1) to assess the impact of different pre- and postLT factors on graft and patient survival in HCV transplant recipients and 2) to create a model which may predict the patients at risk for HCV-related graft cirrhosis at 5 years postLT.. A total of 168 LTs were considered for this study. Univariate and multivariate Cox proportional hazards regression model was used, as well as logistic regression analysis to create a model of prediction of HCV cirrhosis within 5 years after LT.. Predictive factors for both decreased graft and patient survival included patients recently transplanted (2000-2004), induction without azathioprine, short-term therapy with mycophenolate mofetil and prednisone (< or =6 months), presence of early cholestasis, histologically proven early recurrence of hepatitis C. Recipient human leukocyte antigen DR3 positivity, presence of early cholestasis, and donor age >50 years were identified as independent predictors of graft cirrhosis within 5 years. A predictive model was established in order to calculate at 6 months a risk score for graft HCV cirrhosis within 5 years postLT using a formula that included the identified independent predictors. The area under receiver operating characteristic curve was 0.83, indicating a good ability to predict medium-term HCV allograft cirrhosis.. This model may be a useful tool for better identifying high-risk HCV patients who should be selected for early initiation of antiviral therapy.

Topics: Cohort Studies; Drug Administration Schedule; Female; Graft Rejection; Graft Survival; Hepatitis C; HLA-DR3 Antigen; Humans; Immunosuppressive Agents; Incidence; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Models, Theoretical; Mycophenolic Acid; Postoperative Complications; Postoperative Period; Predictive Value of Tests; Prednisone; Recurrence; Retrospective Studies; Risk Assessment; Survival Analysis; Time Factors

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

Topics: Antiviral Agents; Hepatitis C; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Recurrence; Red-Cell Aplasia, Pure; Ribavirin

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

Mycophenolate mofetil (MMF) used in a triple-drug regimen has been shown to decrease acute rejection rates, compared to a double-drug regimen. The impact of MMF on late acute rejection (LAR) episodes has not been well described. To investigate the risk of LAR (rejection > or = 6 months post-transplantation) data from the Scientific Registry of Transplant Recipients (SRTR) were used. We studied adult primary liver transplant recipients transplanted between June 1, 1995, and April 30, 2004, with hepatitis C virus (HCV) (n = 3356), hepatitis B virus (HBV) (n = 550) or a nonviral (n = 5740) primary cause of liver disease who were recorded as receiving continuous 3-(MMF + Tacro + steroids) versus 2-drug (Tacro + steroids) therapy for at least 6 months immediately post transplantation. Kaplan-Meier analysis showed significantly lower LAR rates 4 years post-transplant in 3- versus 2-drug HCV, HBV and nonviral disease patients. Multivariate regression confirmed 3- versus 2-drug therapy to be associated with a decreased risk of LAR. Late graft survival was significantly lower at 4 years post-transplant for patients with LAR 6-12 months post-transplantation versus patients with early rejection (78.0% vs. 87.0%, p < 0.001) and no rejection (88.1%, p < 0.001). Three-drug versus 2-drug therapy for a minimum of 6 months may offer a better treatment strategy to avoid the consequences and expense of LAR episodes.

Topics: Acute Disease; Adolescent; Adult; Aged; Female; Follow-Up Studies; Graft Rejection; Hepacivirus; Hepatitis B; Hepatitis B virus; Hepatitis C; Humans; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Risk Factors; Time Factors

To discuss adequate application of mycophenolate mofetil (MMF) in hepatitis C patients after kidney transplantation.. A one-year follow-up study was conducted in 49 patients with hepatitis C but normal liver function before kidney transplantation, who were given postoperatively immunosuppressants of predisone, MMF and CsA/FK506. Patients with abnormal liver function after kidney transplantation who continued MMF therapy at routine dose and those with reduced or suspended MMF therapy all received intravenous therapy for liver protection, and the duration of therapies was recorded.. Nineteen patients presented with abnormal liver function after operation, and the duration of abnormal liver function till recovery was 32.82-/+4.13 days in the patients with unsuspended MMF therapy and 13.31-/+2.98 days in those with reduced or suspended MMF (P<0.05); the former patients required subsequently 62.7-/+3.23 days to recover normal liver function and the latter need only 23.4-/+2.29 days (P<0.05).. MMF should be reduced or suspended when liver function abnormality occurred in patients with hepatitis C after kidney transplantation, and immediate intravenous therapy for liver protection may prove beneficial.

Topics: Adult; Female; Follow-Up Studies; Hepatitis C; Humans; Immunosuppressive Agents; Kidney Transplantation; Liver Function Tests; Male; Middle Aged; Mycophenolic Acid; Postoperative Period; Uremia

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

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

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

It has been suggested that Mycophenolate Mofetil (MMF) may have an antiviral effect in patients with recurrent HCV infection post-liver transplantation. We conducted a prospective cross-over study in liver transplant recipients with recurrent chronic HCV infection to examine whether substitution of azathioprine (AZA) with MMF would reduce HCV load and improve allograft function. Thirteen long standing HCV liver transplant recipients receiving AZA were enrolled in a 9-month prospective cross-over study. In the initial 3 months lead-in period, baseline viral loads and biochemistry were recorded. Following this, MMF was substituted for AZA at a dose of 1 gm twice/day for a period of 3 months after which patients were switched back to AZA and observed for a further 3 months. Viral loads, biochemical allograft function, and adverse effects were closely monitored during the study period. Thirteen patients (12 males and 1 female) were enrolled. The mean age was 54 (+/-8) years and the mean time from transplantation was 68 (+/-35) months. Baseline mean viral load was 0.74 x 10(6)(+/-0.47 x 10(6)) messenger RNA (mRNA) copies/ml. By the end of the MMF treatment period, the mean viral load increased to a level of 1.64 x 10(6) (+/-1.3 x 10(6)) mRNA copies/ml (P = 0.026) compared to baseline. The increase in viral load however was not associated with an increase in ALT level. In a cohort of 13 HCV liver transplant recipients with recurrent chronic HCV infection, substitution of azathioprine with MMF did not lead to a decrease in viral load.

Topics: Azathioprine; Creatinine; Cross-Over Studies; Cyclosporine; Female; Hepatitis C; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Recurrence; Viral Load

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

Topics: Antiviral Agents; Drug Therapy, Combination; Female; Hepatitis C; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Mycophenolic Acid; Recurrence; Retrospective Studies; Survival Rate

Topics: Disease Progression; Follow-Up Studies; Hepatitis C; Humans; Immunosuppressive Agents; Liver Transplantation; Mycophenolic Acid; Postoperative Complications; Recurrence; Time Factors

Topics: Disease Progression; Follow-Up Studies; Graft Rejection; Hepatitis C; Humans; Immunosuppressive Agents; Liver Transplantation; Mycophenolic Acid; Prognosis; Recurrence; Retrospective Studies; RNA, Viral; Time Factors; Viral Load

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

Topics: Adult; Follow-Up Studies; Graft Survival; Hepatitis B; Hepatitis B Surface Antigens; Hepatitis C; Hepatitis C Antibodies; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Survival Analysis; Time Factors

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Daclizumab; Hepatitis C; Humans; Immunoglobulin G; Immunosuppressive Agents; Liver; Liver Transplantation; Mycophenolic Acid; Secondary Prevention

Topics: Hepacivirus; Hepatitis C; Humans; Immunosuppressive Agents; Liver Transplantation; Mycophenolic Acid; Postoperative Complications; Recurrence; RNA, Viral

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antiviral Agents; Glomerulonephritis; Hepacivirus; Hepatitis C; Humans; Interferon-alpha; Male; Middle Aged; Mycophenolic Acid

Topics: Adult; Female; Hepatitis C; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Myasthenia Gravis; Mycophenolic Acid; Syndrome

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

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

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: Antibodies, Monoclonal; Antilymphocyte Serum; Cyclosporine; Graft Rejection; Hepacivirus; Hepatitis C; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Function Tests; Liver Transplantation; Mycophenolic Acid; Recurrence; Retrospective Studies; RNA, Viral; Time Factors; Virus Replication

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: 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