tacrolimus and Hepatitis-C--Chronic

Kidney transplantation (KT) is the most effective way to decrease the high morbidity and mortality of patients with end-stage renal disease. However, KT does not completely reverse the damage done by years of decreased kidney function and dialysis. Furthermore, new offending agents (in particular, immunosuppression) added in the post-transplant period increase the risk of complications. Cardiovascular (CV) disease, the leading cause of death in KT recipients, warrants pre-transplant screening based on risk factors. Nevertheless, the screening methods currently used have many shortcomings and a perfect screening modality does not exist. Risk factor modification in the pre- and post-transplant periods is of paramount importance to decrease the rate of CV complications post-transplant, either by lifestyle modification (for example, diet, exercise, and smoking cessation) or by pharmacological means (for example, statins, anti-hyperglycemics, and so on). Post-transplantation diabetes mellitus (PTDM) is a major contributor to mortality in this patient population. Although tacrolimus is a major contributor to PTDM development, changes in immunosuppression are limited by the higher risk of rejection with other agents. Immunosuppression has also been implicated in higher risk of malignancy; therefore, proper cancer screening is needed. Cancer immunotherapy is drastically changing the way certain types of cancer are treated in the general population; however, its use post-transplant is limited by the risk of allograft rejection. As expected, higher risk of infections is also encountered in transplant recipients. When caring for KT recipients, special attention is needed in screening methods, preventive measures, and treatment of infection with BK virus and cytomegalovirus. Hepatitis C virus infection is common in transplant candidates and in the deceased donor pool; however, newly developed direct-acting antivirals have been proven safe and effective in the pre- and post-transplant periods. The most important and recent developments on complications following KT are reviewed in this article.

Topics: Antiviral Agents; Cardiovascular Diseases; Diabetes Mellitus; Hepatitis C, Chronic; Humans; Immunotherapy; Kidney Failure, Chronic; Kidney Transplantation; Mortality; Neoplasms; Postoperative Complications; Risk Factors; Tacrolimus

Studies of boceprevir and telaprevir based antiviral therapy in liver transplant (LT) recipients with hepatitis C genotype 1 infection have demonstrated dramatic increases in tacrolimus, cyclosporine, and mTOR inhibitor exposure. In addition to empiric dose reductions, daily monitoring of immunosuppressant blood levels is required when initiating as well as discontinuing the protease inhibitors to maximize patient safety. Although improved suppression of HCV replication is anticipated, 20 to 40% of treated subjects have required early treatment discontinuation due to various adverse events including anemia (100%), infection (30%), nephrotoxicity (20%) and rejection (5 to 10%). Simeprevir and faldaprevir will likely have improved efficacy and safety profiles but potential drug interactions with other OATP1B1 substrates and unconjugated hyperbilirubinemia are expected. In contrast, sofosbuvir and daclatasvir based antiviral therapy are not expected to lead to clinically significant drug-drug interactions in LT recipients but confirmatory studies are needed. Liver transplant recipients may also be at increased risk of developing drug induced liver injury (DILI). Establishing a diagnosis of DILI in the transplant setting is very difficult with the variable latency, laboratory features and histopathological manifestations of hepatotoxicity associated with a given drug, the need to exclude competing causes of allograft injury, and the lack of an objective and verifiable confirmatory test. Nonetheless, a heightened awareness of the possibility of DILI is warranted in light of the large number of medications used in LT recipients and the potential adverse impact that DILI may have on patient outcomes.

Topics: Administration, Oral; Anti-Bacterial Agents; Antiviral Agents; Calcineurin Inhibitors; Chemical and Drug Induced Liver Injury; Drug Interactions; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Liver Transplantation; Oligopeptides; Proline; Risk Factors; Tacrolimus; TOR Serine-Threonine Kinases

In our series of 1374 renal transplantations performed between February 1970 and December 2002, we observed 6 cases of infection due to Nocardia asteroides. There were 4 males and 2 females, aged 49.8 +/- 12 years (29 to 63 years). One patient received his first transplantation and the 5 others retransplants. Three patients had PRA > 80%, one 28% and one 40%. One patient was diabetic and two had HCV infection. Two of 6 patients experienced acute rejection episodes. Nocardiosis localisation was pulmonary in 5 cases, cerebral in two and mediastinal in one. All patients recovered after reduction of immunosuppression and appropriate antibiotherapy with trimethoprim-sulfamethoxasole (TMP-SMX). When we analyzed the role of immunosuppression, we observed that only two cases were observed in the 933 recipients transplanted between 1985 and 2002 and receiving cyclosporin, contrasting with 4 cases among 174 recipients transplanted between 1996 and 2002 and receiving tacrolimus. Our data suggest that high immunologic risk patients, heavy immunosuppression, and perhaps tacrolimus-based immunosuppression are risk factors of nocardial infection. Early diagnosis of this severe infection, reduction of immunosuppression and appropriate therapy with TMP-SMX resulted in complete recovery in all our patients.

Topics: Adrenal Cortex Hormones; Adult; Aged; Antilymphocyte Serum; Azathioprine; Cyclosporine; Diabetes Complications; Disease Susceptibility; Female; Graft Rejection; Hepatitis C, Chronic; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Nocardia asteroides; Nocardia Infections; Postoperative Complications; Reoperation; Risk Factors; Tacrolimus; Trimethoprim, Sulfamethoxazole Drug Combination

1. Approximately 10% to 25% of hepatitis C virus-infected recipients of liver allografts will develop cirrhosis within 5 years of transplantation; this acceleration of the natural history of hepatitis C is caused in part by immunosuppression. 2. Risk factors for aggressive recurrence, graft loss, and death are treated acute cellular rejection, methylprednisolone pulse therapy, and use of OKT3. There appears to be no consistent difference between cyclosporine and tacrolimus in their effects on hepatitis C. 3. The benefit of steroid withdrawal, although commonly practiced in transplant recipients with hepatitis C, has not been proven. 4. Mycophenolate mofetil may show synergistic antiviral properties when used with interferon; however, posttransplantation use has not been associated with consistent beneficial or deleterious effects. 5. Effects of other agents, such as sirolimus or interleukin-2-receptor antibodies, have not been adequately defined. Early reports suggest that disease activity may be more aggressive when these agents are constituents of the immunosuppressive regimen.

Topics: Cyclosporine; Disease Progression; Glucocorticoids; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Transplantation; Muromonab-CD3; Mycophenolic Acid; Receptors, Interleukin-2; Recurrence; Risk Assessment; Sirolimus; Tacrolimus

NF-kappaB is an inducible nuclear transcription factor regulating the expression of many genes. NF-kappaB activation may function as a master switch in a variety of immune and inflammatory processes, including sepsis and transplant tolerance. In this review, we summarize features of NF-kappaB regulation, as well as describe its role in intracellular signal transduction pathways. Subsequently, we concentrate on the role of NF-kappaB in the field of organ transplantation and the role of NF-kappaB in organ ischemia/reperfusion injury and graft rejection. Finally, potential therapeutic strategies are discussed to modify NF-kappaB activity with certain immunosuppression medications, including cyclosporine, tacrolimus, and glucocorticoids.

Topics: Adenoviridae; Animals; Cyclosporine; Gene Expression Regulation; Genetic Therapy; Graft Rejection; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Mice; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Oligodeoxyribonucleotides; Organ Transplantation; Reperfusion Injury; Signal Transduction; Sulfasalazine; Tacrolimus

Recurrent hepatitis C virus (HCV) infection following liver transplantation is associated with accelerated progression to graft failure and reduced patient survival.. The Phase II, open-label SATURN study (NCT01938625) investigated the combination of simeprevir (SMV), daclatasvir (DCV), and ribavirin (RBV) administered for 24 weeks in 35 patients with recurrent HCV genotype (GT) 1b infection after orthotopic liver transplantation (OLT).. High rates of both on-treatment and sustained virologic response 12 weeks after end of treatment (SVR12) were achieved in patients who were either treatment-naïve or had failed post-OLT treatment with peginterferon and RBV. Overall, 91% of patients (32/35) achieved SVR12. The combination was generally well tolerated, with an adverse event profile consistent with that observed in previous clinical trials of SMV or DCV separately. Co-administration of SMV with cyclosporine resulted in significantly increased SMV plasma exposures, which was not the case with the co-administration of SMV with tacrolimus. Therefore, the concomitant use of SMV with cyclosporine is not recommended.. The interferon-free combination of SMV, DCV, and RBV administered for 24 weeks was shown to be effective and well tolerated in the treatment of post-OLT HCV GT1b-infected patients.

Topics: Adult; Aged; Antiviral Agents; Carbamates; Cyclosporine; Drug Therapy, Combination; Female; Genotype; Graft Rejection; Hepacivirus; Hepatitis C, Chronic; Humans; Imidazoles; Immunosuppressive Agents; Interferon-alpha; Liver Transplantation; Male; Middle Aged; Pyrrolidines; Recurrence; Ribavirin; RNA, Viral; Simeprevir; Tacrolimus; Treatment Outcome; Valine; Viral Load

The new directly acting antivirals (DAAs) enable all-oral interferon-free treatment of chronic hepatitis C virus (HCV) infection. We here investigated the effect of DAAs on the enzymatic liver function of liver transplant recipients with recurrent hepatitis C.. Twenty-one patients with elevated liver enzymes or advanced fibrosis/compensated cirrhosis caused by recurrent HCV were treated with sofosbuvir either in combination with simeprevir, or in combination with ribavirin or daclatasvir with or without ribavirin for 12 weeks. Biochemical parameters, tacrolimus trough levels, and the maximal liver function capacity (LiMAx) were measured monthly during the treatment and 12 weeks after the end of treatment.. All patients achieved sustained virological response 12 weeks after the end of the treatment. The transaminases and cholestasis parameters normalized until week 8 of treatment. The mean LiMAx (normal ranges >315 μg/kg/h) increased from 344±142 μg/kg/h before treatment to 458±170 μg/kg/h (P<.0001) at the 12-week follow-up. In parallel, the tacrolimus trough level to dose ratio decreased from 4.68 down to 2.72 (P=.0004).. Antiviral treatment with DAAs enabled sustained elimination of recurrent HCV in liver transplant recipients and was associated with a significant improvement of the enzymatic liver function.

Topics: Administration, Oral; Aged; Antiviral Agents; Biopsy; Carbamates; Cohort Studies; Drug Therapy, Combination; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Imidazoles; Immunosuppressive Agents; Liver; Liver Cirrhosis; Liver Function Tests; Liver Transplantation; Male; Middle Aged; Pyrrolidines; Recurrence; Ribavirin; Simeprevir; Sofosbuvir; Tacrolimus; Transaminases; Valine

Choice of calcineurin inhibitor may influence response to antiviral therapy in liver transplant patients with hepatitis C virus (HCV) infection.. In a randomized, multicenter, 80-week trial, liver transplant recipients (>6 months and £10 years post-transplant) with recurrent HCV infection received cyclosporine (n=50) or tacrolimus (n=42) with a 48-week course of pegylated interferon (peg-IFNα2a) and ribavirin. Twenty-three patients in each group completed the trial on study medication. The primary endpoint was sustained virological response (SVR) 24 weeks after the end of antiviral therapy, for which 43 patients were eligible for analysis.. The rate of SVR was 60.0% (12/20) with cyclosporine and 43.5% (10/23) with tacrolimus (adjusted odds ratio 1.85; 95% CI 0.53-6.43; p=0.331). There were no significant intergroup differences for rapid or early virological response, relapse, HCV RNA viral load, or fibrosis progression. One cyclosporine-treated patient experienced acute rejection. One patient died in each group. Adverse events, treatment-related adverse events, and serious adverse events were similar between groups.. Since fewer patients were recruited than planned (92 versus 355), the study was underpowered and robust conclusions cannot be drawn regarding the effect of cyclosporine and tacrolimus on virological responses to antiviral treatment for recurrent HCV after liver transplantation. However, as reported in other trials, SVR was higher in cyclosporine-treated patients.

Topics: Adolescent; Adult; Aged; Antiviral Agents; Calcineurin Inhibitors; Cyclosporine; Drug Therapy, Combination; Female; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Interferon-alpha; Liver Transplantation; Male; Middle Aged; Polyethylene Glycols; Recombinant Proteins; Ribavirin; Tacrolimus; Treatment Outcome; Young Adult

Early results of a randomised trial showed reduced fibrosis due to recurrent HCV hepatitis with tacrolimus triple therapy (TT) versus monotherapy (MT) following transplantation for HCV cirrhosis. We evaluated the clinical outcomes after a median 8 years of follow-up, including differences in fibrosis assessed by collagen proportionate area (CPA).. 103 consecutive liver transplant recipients with HCV cirrhosis receiving cadaveric grafts were randomised to tacrolimus MT (n=54) or TT (n=49) with daily tacrolimus (0.1 mg/kg divided dose), azathioprine (1 mg/kg) and prednisolone (20 mg), the last tailing off to zero by 6 months. Both groups had serial transjugular biopsies with hepatic venous pressure gradient (HVPG) measurement. Time to reach Ishak stage 4 was the predetermined endpoint. CPA was measured in all biopsies. Factors associated with HCV recurrence were evaluated. Clinical decompensation was the first occurrence of ascites/hydrothorax, variceal bleeding or encephalopathy.. No significant preoperative, peri-operative or postoperative differences between groups were found. During 96 months median follow-up, stage 4 fibrosis was reached in 19 MT/11 TT with slower fibrosis progression in TT (p=0.009). CPA at last biopsy was 12% in MT and 8% in TT patients (p=0.004). 14 MT/ three TT patients reached HVPG≥10 mm Hg (p=0.002); 10 MT/three TT patients, decompensated. Multivariately, allocated MT (p=0.047, OR 3.23, 95% CI 1.01 to 10.3) was independently associated with decompensation: 14 MT/ seven TT died, and five MT/ four TT were retransplanted.. Long term immunosuppression with tacrolimus, azathioprine and short term prednisolone in HCV cirrhosis recipients resulted in slower progression to severe fibrosis assessed by Ishak stage and CPA, less portal hypertension and decompensation, compared with tacrolimus alone. ISRCTN94834276--Randomised study for immunosuppression regimen in liver transplantation.

Topics: Anti-Inflammatory Agents; Azathioprine; Drug Therapy, Combination; Female; Hepatitis C, Chronic; Humans; Hypertension, Portal; Immunosuppressive Agents; Liver Cirrhosis; Liver Failure; Liver Transplantation; Male; Middle Aged; Prednisolone; Recurrence; Tacrolimus; Time Factors

This randomized, prospective, multicenter trial compared the safety and efficacy of steroid-free immunosuppression (IS) to the safety and efficacy of 2 standard IS regimens in patients undergoing transplantation for hepatitis C virus (HCV) infection. The outcome measures were acute cellular rejection (ACR), severe HCV recurrence, and survival. The patients were randomized (1:1:2) to tacrolimus (TAC) and corticosteroids (arm 1; n = 77), mycophenolate mofetil (MMF), TAC, and corticosteroids (arm 2; n = 72), or MMF, TAC, and daclizumab induction with no corticosteroids (arm 3; n = 146). In all, 295 HCV RNA-positive subjects were enrolled. At 2 years, there were no differences in ACR, HCV recurrence (biochemical evidence), patient survival, or graft survival rates. The side effects of IS did not differ, although there was a trend toward less diabetes in the steroid-free group. Liver biopsy samples revealed no significant differences in the proportions of patients in arms 1, 2, and 3 with advanced HCV recurrence (ie, an inflammation grade ≥ 3 and/or a fibrosis stage ≥ 2) in years 1 (48.2%, 50.4%, and 43.0%, respectively) and 2 (69.5%, 75.9%, and 68.1%, respectively). Although we have found that steroid-free IS is safe and effective for liver transplant recipients with chronic HCV, steroid sparing has no clear advantage in comparison with traditional IS.

Topics: Adrenal Cortex Hormones; Antibodies, Monoclonal, Humanized; Antiviral Agents; Biopsy; Chi-Square Distribution; Daclizumab; Drug Therapy, Combination; Female; Graft Rejection; Hepacivirus; Hepatitis C, Chronic; Humans; Immunoglobulin G; Immunosuppressive Agents; Kaplan-Meier Estimate; Liver Failure; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Proportional Hazards Models; Prospective Studies; Recurrence; Risk Assessment; Risk Factors; RNA, Viral; Survival Rate; Tacrolimus; Time Factors; Treatment Outcome; United States

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

Topics: Adult; Aminoisobutyric Acids; Antiviral Agents; Benzimidazoles; Cyclopropanes; Drug Combinations; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Leucine; Liver Transplantation; Living Donors; Proline; Pyrrolidines; Quinoxalines; Sulfonamides; Tacrolimus; Uremia

The pharmacokinetic implications of direct-acting antiviral (DAA) use on tacrolimus posttransplant are unknown. This study sought to investigate the effects of glecaprevir/pibrentasvir (G/P), a CYP3A4 substrate and inhibitor, on weight-adjusted tacrolimus (FK) trough/dose ratio (T/D) following heart or kidney transplantation.. This was a single-center, retrospective analysis of hepatitis C virus (HCV) viremic donors to HCV negative heart or kidney transplant recipients who received 12 weeks of G/P therapy. Weight-adjusted T/D was assessed while patients were at steady-state before, during, and after G/P treatment. Forty-one HCV negative recipients (three heart, 38 kidney) were evaluated.. The weight-adjusted T/D significantly increased during G/P treatment (119.31, IQR 88-173.8) compared to before G/P treatment (67.4, IQR 53.4-115.9) (p < 0.01), but decreased after completion of treatment (90.1, IQR 52.9-122.7) (p < 0.01). There was no difference in weight-adjusted T/D before and after G/P treatment (p = 0.42). Four patients experienced acute rejection.. Initiation of G/P in heart or kidney transplant recipients induces a reversible change in tacrolimus metabolism. A 33%-50% tacrolimus dose reduction may be considered at the time of G/P initiation. Regardless of tacrolimus dose adjustment, tacrolimus trough levels should be monitored 3 days after initiation of G/P. No clear relationship between HCV viremic organ transplantation and rejection risk was found. Larger studies are warranted to validate these findings.

Topics: Aminoisobutyric Acids; Antiviral Agents; Benzimidazoles; Cyclopropanes; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Kidney Transplantation; Lactams, Macrocyclic; Leucine; Proline; Pyrrolidines; Quinoxalines; Retrospective Studies; Sulfonamides; Tacrolimus; Transplant Recipients

Treatment of chronic hepatitis C infection after renal transplantation has been controversial due to the high rate of graft rejections with interferon (IFN)-based therapies. The aim of this study is to review our experience of direct acting antiviral therapy for the recipients of renal transplantation. Eleven recipients who were hepatitis C virus-polymerase chain reaction (PCR) positive were eligible for the treatment with direct acting antivirals. Six recipients were treated with sofosbuvir and ledipasvir, three were treated with elbasvir and grazoprevir, and one was treated with sofosbuvir and ribavirin for 12 weeks. One recipient was treated with glecaprevir and pibrentasvir for 8 weeks. All of the 11 recipients exhibited sustained virologic response at week 12 after the end of treatment. Adverse events were scarce including the two recipients who switched to tacrolimus from cyclosporine at the beginning of the treatment. The direct acting antiviral therapy including new agents appears to be safe and highly efficacious for the recipients after renal transplantation.

Topics: Adult; Aged; Antiviral Agents; Cyclosporine; Female; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Sustained Virologic Response; Tacrolimus; Treatment Outcome

The influence of immunosuppression on the response to antiviral therapy (AVT) for recurrent hepatitis C virus (HCV) infection in liver transplant (LT) recipients remains controversial, especially for the rarely investigated genotype 4. This study aims to compare the effects of the two widely used calcineurin inhibitors (CNIs) (cyclosporine A (CsA) and tacrolimus (Tac)) on the therapeutic response to different AVT regimens.. A prospective, dual-centre, cohort study of 126 Egyptian living donor liver transplant (LDLT) recipients with recurrent HCV genotype 4 infection, who were categorized into three groups according to the AVT used. Group I received pegylated interferon (Peg-IFN-α 2a) plus ribavirin (RBV) (n = 44), group II received the direct antiviral agent (DAA) sofosbuvir plus RBV (n = 52) and group III received daclatasvir and sofosbuvir (also DAAs) plus RBV (n = 30). Each group was further subdivided according to the primary immunosuppression (CsA or Tac). The sustained virological response (SVR) and relapse rates were considered the primary therapeutic outcomes of AVT.. No significant intergroup differences were observed in the achievement of primary and secondary outcomes. SVR rates in the IFN-based regimen were 75% and 66.7% in CsA and Tac users and 81.2% and 83% in DAAs, respectively. Relapse rates in the IFN-based regimen were 10% and 16.7% in CsA and Tac users and 12.5% and 14.9% in DAAs, respectively.. Within the limitations of a relatively small study, CsA did not offer an advantage over Tac regarding the response to AVT after HCV genotype 4 recurrence in LDLT recipients.

Topics: Adult; Aged; Antiviral Agents; Calcineurin Inhibitors; Cyclosporine; Drug Interactions; Drug Therapy, Combination; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Interferon-alpha; Liver Transplantation; Male; Middle Aged; Polyethylene Glycols; Prospective Studies; Recombinant Proteins; Recurrence; Ribavirin; Sofosbuvir; Tacrolimus; Young Adult

A 37-year-old man with hepatitis C virus (HCV) genotype 3A developed renal failure. In 2007, the patient received a renal transplant and started receiving tacrolimus (Tac); the transplant subsequently failed. In April 2015, the patient restarted haemodialysis and in May initiated sofosbuvir 400 mg and ribavirin 400 mg daily. Baseline Tac level was 6.6 ng/mL and haemoglobin (Hb) was 10.3 g/dL. The patient then left the country for vacation and Hb was found to be dramatically low at 3.7 g/dL on return on 5 August. Ribavirin was put on hold, while darbepoetin dose was increased. On 23 August, Tac level was found undetectable; hence, dosage was increased. Hb eventually bounced back to >10 g/dL in October and Tac to 7.2 ng/mL; ribavirin was restarted at 200 mg three times weekly. HCV RNA level was undetectable at 3 months and remained undetectable 12 weeks after therapy finished.

Topics: Adult; Anemia; Darbepoetin alfa; Hematinics; Hemoglobins; Hepatitis C, Chronic; Humans; Male; Renal Dialysis; Ribavirin; Tacrolimus; Treatment Outcome

Topics: Aged; Antiviral Agents; Drug Therapy, Combination; Female; Glucocorticoids; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Lupus Nephritis; Nephrotic Syndrome; Prednisolone; Remission Induction; Ribavirin; Sofosbuvir; Tacrolimus

Topics: DNA, Viral; Graft Survival; Hepatitis B; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; RNA, Viral; Tacrolimus; Treatment Outcome

Atopic dermatitis (AD) is the most frequent chronic inflammatory skin disorder in children and is usually accompanied by genetic and environmental factors. Effective management and treatment of AD is challenging and often requires systemic immunosuppressive therapy when refractory to topical treatments. We report a rare association between chronic hepatitis C virus (HCV) and severe AD, management of which required systemic cyclosporine because of its favorable effects on inflammatory and viral-related clinical outcomes.

Topics: Adolescent; Cyclosporine; Dermatitis, Atopic; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Male; Tacrolimus

Topics: Arthroplasty, Replacement, Hip; Cecal Diseases; Female; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Intestinal Perforation; Liver Cirrhosis; Liver Transplantation; Middle Aged; Periprosthetic Fractures; Peritonitis; Tacrolimus; Therapeutic Irrigation

Chronic hepatitis C virus (HCV) infection can cause severe liver cirrhosis, for which liver transplantation is the only therapy. To prevent organ rejection, transplanted patients are treated with immunosuppressive agents. We describe two transplanted patients treated with tacrolimus who were simultaneously treated with direct-acting antivirals (DAAs) for their chronic HCV infection. No pharmacokinetic drug-drug interactions (DDIs) were expected between tacrolimus and the selected DAAs. However, in both patients, tacrolimus plasma concentrations decreased during HCV treatment. We hypothesise that decreased plasma concentrations were not caused by a DDI but were an indirect result of the clearance of the HCV infection. During chronic HCV infection, pro-inflammatory cytokines may inhibit cytochrome P450 (CYP) enzymes, which are primarily responsible for tacrolimus metabolism. If this is true, then with clearance of the virus the activity of these enzymes will normalise and tacrolimus metabolism will increase. These changes were clinically relevant because the tacrolimus dosage needed to be adjusted. Therefore, physicians should be aware that CYP substrates with narrow therapeutic ranges might require dose adaption during HCV therapy with DAAs.

Topics: Aged; Antiviral Agents; Cytochrome P-450 Enzyme System; Drug Interactions; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Plasma; Tacrolimus; Transplant Recipients

Topics: Adult; Aged; Carbamates; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Hepatitis C, Chronic; Humans; Imidazoles; Interferons; Isoquinolines; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Pyrrolidines; Recurrence; Sampling Studies; Sulfonamides; Tacrolimus; Valine

Drug adherence is one of the most important factors determining graft and patient survivals after liver transplantation. A systematic pharmaceutical educational approach has been implemented to improve adherence in immunosuppressive drugs therapy at Siriraj Hospital.. This study was a single-center cross-sectional study of liver transplant patients who received pharmaceutical care from transplant pharmacists. The clinical pharmacy services, including medication review to emphasize patients' knowledge and awareness of immunosuppressive and general drug therapies with the use of various tools, were used to educate the patients. Drug-related problems (DRPs) and pre- and post-transplantation educational tests (divided into 3 parts: immunosuppressants [12 points], drug monitoring [6 points], and general drugs [2 points]) were analyzed.. From October 2012 to September 2014, a total of 50 liver transplant recipients (86 visits) were enrolled. After the systematic pharmaceutical educational program, the average total score of post-transplantation educational test improved from 3.48 to 13.30 (P < .001). Likewise, the mean scores of all 3 parts significantly increased (part I: 2.28 vs 8.18 [P < .001]; part II: 0.75 vs 3.63 (P < .001); and part III: 0.46 vs 1.50 [P < .001]). The incidences of major DRPs, nonadherence, and adverse drug reactions were 8%, 4%, and 2%, respectively.. A systematic pharmaceutical educational approach can significantly improve patients' knowledge and awareness concerning immunosuppressive drug usage.

Topics: Adult; Carcinoma, Hepatocellular; Cross-Sectional Studies; Drug Monitoring; Drug-Related Side Effects and Adverse Reactions; End Stage Liver Disease; Female; Graft Rejection; Hepatitis B, Chronic; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Incidence; Liver Neoplasms; Liver Transplantation; Male; Medication Adherence; Middle Aged; Mycophenolic Acid; Patient Education as Topic; Pharmaceutical Services; Risk Factors; Tacrolimus

Severe hepatitis C virus (HCV) recurrence affects post-transplant survival in HIV/HCV co-infected patients. This article describes the results of triple anti-HCV therapy with boceprevir or telaprevir in seven HIV/HCV co-infected patients following liver transplantation.. All patients had severe HCV recurrence [fibrosis stage ≥F2 or acute hepatitis ≥A2 (n = 5) or fibrosing cholestatic hepatitis (n = 2)] associated with genotype 1a (n = 4) or 1b (n = 3). Patients were treated with Peg-interferon/ribavirin and boceprevir (n = 2) or telaprevir (n = 5) immediately (n = 3) or after a 4-week lead-in phase (n = 4). Immunosuppression included either cyclosporine (n = 5) or tacrolimus (n = 2). Prior to introducing telaprevir, combined antiretroviral therapy was switched in one patient to prevent drug-drug interactions.. At 24 weeks after the end of treatment, sustained virological response was observed in 60% (3/5) of the patients treated with telaprevir; no responders were observed in the boceprevir group. Triple anti-HCV therapy was prematurely discontinued in six patients [treatment failure (n = 2), infection (n = 2), acute rejection (n = 1) and myocardial infarction (n = 1)]. Anaemia occurred in all patients, requiring erythropoietin, ribavirin dose reduction and red blood cell transfusions in five patients.Average cyclosporine doses were reduced by 50-84% after telaprevir initiation and by 33% after boceprevir initiation. Tacrolimus doses were reduced by 95% with telaprevir.. Our data suggest that in HIV/HCV co-infected patients, triple anti-HCV therapy with telaprevir greatly improved efficacy despite poor tolerability. Significant decreases in cyclosporine or tacrolimus doses are necessary prior to introduction of boceprevir or telaprevir. Close monitoring is essential to prevent drug-drug interactions among antiretroviral therapy, immunosuppressive agents and anti-HCV therapy.

Topics: Adult; Antiviral Agents; Coinfection; Cyclosporine; Drug Therapy, Combination; Female; Hepatitis C, Chronic; HIV Infections; Humans; Immunosuppression Therapy; Interferon alpha-2; Interferon-alpha; Liver Transplantation; Male; Middle Aged; Oligopeptides; Polyethylene Glycols; Proline; Recombinant Proteins; Recurrence; Ribavirin; Tacrolimus; Viral Load

Aim: Pegylated-interferon/ribavirin/simeprevir (PEG-IFN/RBV/SMV) combination therapy is widely used for hepatitis C virus (HCV) treatment after liver transplantation (LT). Here, we observed two cases of extended severe anemia during PEG-IFN/RBV/SMV therapy for HCV serological type 1 re-infected after LT. Immunosuppressants consisted of tacrolimus and mycophenolate mofetil (MMF). Case 1 was a 65-year-old-woman treated with PEG-IFN/RBV/SMV therapy and 500 mg MMF/day 9 months after LT. Her serum hemoglobin (Hb) level decreased from 10 to 8.4 mg/dL on day 25. Despite discontinuing the PEG-IFN/RBV/SMV treatment on day 32, her Hb level decreased to 5.1 mg/dL on day 40. Case 2 was a 61-year-old-woman started on PEG-IFN/RBV/SMV therapy 20 months after LT. Her serum Hb level decreased from 12.2 to 7.1 mg/dL on day 39. The MMF dose was reduced from 1,500 to 1,000 mg/day, and her Hb level was maintained. Red blood cell transfusions were required in both cases, and anemia persisted for 2 months. These patients had the C/C major type inosine triphosphatase (ITPA) polymorphism. In conclusion, MMF induced severe persistent anemia by co-treatment with IFN/RBV in patients who underwent LT. Thus, the immunosuppressant dose should be chosen carefully for patients with the high-risk ITPA allele.

Topics: Aged; Anemia; Antiviral Agents; Erythrocyte Transfusion; Female; Hepatitis C, Chronic; Humans; Immunocompromised Host; Immunosuppressive Agents; Interferon-alpha; Liver Transplantation; Middle Aged; Mycophenolic Acid; Recurrence; Ribavirin; Simeprevir; Tacrolimus

The role of Interleukin 28B (IL-28B) genetic polymorphisms in influencing the occurrence of biliary complications after liver transplantation has never been evaluated. This study aimed to investigate whether IL-28B rs12979860C/T polymorphisms associate with the occurrence of biliary complications after liver transplantation and if these complications may influence survival.. One hundred seventy one recipients (133 males) who underwent liver transplantation were recruited. To confirm the mechanical etiology of cholestasis, endoscopic cholangio pancreatography, percutaneous and/or trans-Kehr cholangiography or cholangio magnetic resonance were performed. Two main clinical pictures were identified: biliary strictures and biliary leakage. Immunosuppressive therapy was based on cyclosporine (N = 54) or tacrolimus (N = 117), in association with steroids during the first month after operation. IL-28B rs12979860C/T genotypes were detected by means of polymerase chain reaction.. Forty patients (23.4%) presented anastomotic strictures, 7 (4.1%) non-anastomotic strictures, 10 (5.8%) leakage, 8 (4.7%) leakage plus anastomotic strictures. IL-28B rs12979860C/C genotype in association with cyclosporin was found to be an independent predictor of anastomotic strictures occurrence (p = 0.008). A significant difference in 5 years survival was observed between patients with viral etiology of liver disease experiencing either anastomotic or non-anastomotic strictures (16/23) and the remaining patients (104/112, p = 0.001).. In recipients carrying rs12979860 IL-28B C/C genotype the use of cyclosporine seems to contribute to enhance the probability of developing biliary complications which in hepatitis B and C positives appear to reduce patient survival. If confirmed in larger studies the use of cyclosporine in these patients could be revised.

Topics: Adult; Aged; Anastomotic Leak; Cholestasis; Cyclosporine; Female; Genetic Variation; Genotype; Hepatitis B, Chronic; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Interferons; Interleukins; Liver Transplantation; Male; Middle Aged; Retrospective Studies; Risk Factors; Tacrolimus

Topics: Antiviral Agents; Drug Interactions; Hepatitis C, Chronic; Humans; Interferon-alpha; Liver Transplantation; Male; Middle Aged; Polyethylene Glycols; Postoperative Complications; Proline; Protease Inhibitors; Recombinant Proteins; Recurrence; Ribavirin; Tacrolimus; Treatment Outcome

The management of hepatitis C virus (HCV) recurrence after liver transplantation (LTx) is a major challenge in patient care. For patients with HCV GT1, treatment standard with pegylated interferon (PEG-IFN) and ribavirin (RBV) has been augmented in 2011 by first generation protease inhibitors (PI), telaprevir (TVR) and boceprevir (BOC). We report our first experiences with TVR-based triple therapy in patients with GT1-reinfection of the graft.. 13 patients with histologically proven HCV GT1-reinfection of the graft received 12 weeks of PEG-IFN/RBV/TVR followed by 12 weeks of PEG-IFN/ RBV only. During the triple therapy phase immune suppression was tightly monitored, and the patients were also closely monitored for side effects.. The dosage of immunosuppressants had to be reduced significantly (TAC: 30-fold; CSA 3,5-fold). Stable levels were achieved by daily or over-daily dosing of a special size application of 0,1 mg tacrolimus (Tac) bid or a minimal dose of 10 mg cyclosporine (CSA) bid or qd, respectively. In all patients hematological side effects were observed, 65 % of which required RBV dose reduction, administration of erythropoietin or blood transfusions. Increase of kidney retention values requiring infusions occurred in 50 %. All side effects were reversible. There were no early discontinuations of therapy. An early viral response (EVR) with viral decline below limit of detection was noted at week 12 in 9/13 patients and at week 12 in further 3 patients.. Our preliminary results show high EVR response rates of TVR-based triple therapy in LTx patients with HCV-GT1 re-infection.

Topics: Adult; Antiviral Agents; Cyclosporine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Interferon-alpha; Liver Transplantation; Male; Middle Aged; Oligopeptides; Polyethylene Glycols; Postoperative Complications; Recombinant Proteins; Recurrence; Ribavirin; Tacrolimus; Viral Load

Genetic polymorphisms adjacent to IL28B have been previously associated with spontaneous clearance of hepatitis C virus (HCV) and a higher rate of sustained virological response to interferon-based treatment in HCV genotype 1-infected patients. A recent study has shown that patients with the CC genotype of the rs12979860 single nucleotide polymorphism upstream from the IL28B gene are more likely to clear HCV spontaneously relative to the CT or TT genotype. In the liver transplant cohort, HCV recurs almost universally in patients with detectable HCV RNA at the time of transplantation. The spontaneous clearance of HCV infection after transplant is very rare. We report two cases of spontaneous clearance of HCV genotype 1 infection after liver transplantation from homozygous IL28B CC donors. This finding may be explained by alterations in the host immune responses to HCV after transplantation with a CC donor liver, which has potential implications for donor selection in HCV-positive recipients.

Topics: Adult; Alcoholism; Drug Therapy, Combination; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Interferons; Interleukins; Liver Transplantation; Living Donors; Male; Methylprednisolone; Mycophenolic Acid; Polymorphism, Genetic; Remission, Spontaneous; Tacrolimus; Treatment Outcome

Hepatitis C virus (HCV) recurrence is the most important complication in HCV liver transplant patients. Boceprevir with pegylated interferon and ribavirin (PegIFN/RBV) enabled improvement in sustained virological response rates of patients with genotype 1 HCV. Boceprevir interacts with immunosuppressive therapy (IT) by inhibiting the cytochrome P450 3A enzyme. Our aim was to study interactions and assess the safety of boceprevir in the context of HCV recurrence. Boceprevir (800 mg three times a day) initiated after a 4-week lead-in phase was associated with cyclosporine (three patients), tacrolimus (two patients), and everolimus (one patient) in five liver transplant patients with genotype 1 HCV infection who experienced HCV recurrence. The mean follow-up period after HCV therapy was 14.8 ± 3.1 weeks. Estimated oral clearances of IT decreased on average by 50%, requiring reduced dosing regimens. Anemia occurred in all patients, with a mean fall in hemoglobin levels between baseline and week 12 of 3.12 ± 2.27 g/dl. All patients required administration of β-erythropoietin (n = 5), three needed ribavirin dose reduction, and one needed a blood transfusion. A virological response was observed in all patients (mean HCV viral load [HVL] decrease at week 12, 6.64 ± 0.35 log(10) IU/ml). These preliminary results in liver transplant patients with HCV recurrence demonstrate the feasibility and safety of coadministration of boceprevir and IT.

Topics: Aged; Antiviral Agents; Cyclosporine; Disease Management; Drug Therapy, Combination; Everolimus; Hepacivirus; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Interferon-alpha; Liver Transplantation; Male; Middle Aged; Polyethylene Glycols; Proline; Recombinant Proteins; Recurrence; Ribavirin; Sirolimus; Tacrolimus; Viral Load

Among patients after renal transplantation (NTx), hepatitis C virus (HCV) infection is a risk factor for graft loss and patient death caused by hepatic decompensation. Also, HCV has been implicated in the pathogenesis of glomerular diseases in native and transplanted kidneys. Therefore, the aim of this retrospective cohort study was to determine the effects of the widely used calcineurin inhibitors (CNI) cyclosporine A (CsA) and tacrolimus (Tac) on hepatitis C virus replication, inflammatory activity, development of liver fibrosis, and long-term renal graft function.. A cohort of 71 patients with HCV infection after kidney transplantation under immunosuppression with either CsA or Tac were analyzed for viral kinetics and serum transaminases. In addition, presence of liver fibrosis was detected by non-invasive measurements using the FibroScan. Graft function was determined biochemically. Patients with interferon therapy prior to transplantation were excluded from the study in order to avoid any impact of the antiviral therapy on outcomes.. In the early period after transplantation, hepatitis C viral load was lower in patients treated with Tac as compared to CsA. This effect became negligible 3 months after transplantation. However, hepatic inflammatory activity was reduced in the CsA-treated group. Extent of liver fibrosis was similar in both groups of HCV-infected patients as well as in a control group of non-HCV-infected patients after renal transplantation (NTx), respectively. Renal function and glomerular filtration rate, as calculated by the modification of diet in renal disease (MDRD) formula, were significantly better in patients treated with Tac.. During long-term immunosuppression, the CNIs cyclosporine A versus tacrolimus showed no significant differences in HCV-infected patients after renal transplantation with respect to viral replication and development of liver fibrosis. However, function of the renal graft is significantly better preserved in patients receiving tacrolimus.

Topics: Adult; Aged; Calcineurin Inhibitors; Cyclosporine; Female; Germany; Graft Survival; Hepacivirus; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Liver Cirrhosis; Liver Function Tests; Male; Middle Aged; Retrospective Studies; RNA, Viral; Tacrolimus; Time Factors; Transaminases; Treatment Outcome; Viral Load; Virus Replication

Topics: Antirheumatic Agents; Antiviral Agents; Drug Therapy, Combination; Hepatitis C, Chronic; Humans; Hydroxychloroquine; Immunosuppressive Agents; Interferon alpha-2; Interferon-alpha; Lupus Erythematosus, Systemic; Male; Middle Aged; Polyethylene Glycols; Recombinant Proteins; Tacrolimus; Treatment Outcome

Recurrent hepatitis C virus (HCV) remains a problematic cause of morbidity and mortality for liver transplant patients. Immunosuppression including calcineurin-inhibitors has been implicated in the acceleration of recurrent HCV. Recent studies suggest that outcomes may be better with cyclosporine (CSA-ME) compared to tacrolimus (TAC), but the data are inconclusive. We retrospectively analyzed data received from the United Network for Organ Sharing on 8809 chronic HCV liver transplant recipients receiving either cyclosporine microemulsion (CSA-ME) or tacrolimus (TAC) as maintenance immunosuppression prior to discharge. We analyzed patient death, graft failure, failure due recurrent disease and acute cellular rejection (ACR) for CSA-ME versus TAC treated patients. Three-year unadjusted patient and graft survival rates were 76.8% and 71.5%, respectively, in the CSA-ME group versus 79.9% and 75.0% in the TAC group. Propensity score-adjusted results suggest CSA-ME treated patients are at increased risk of patient death and graft failure [Hazards ratio (HR) = 1.17; 95% CI = 1.01-1.36 and HR = 1.19; 95% CI = 1.04-1.35, respectively] and biopsy-confirmed AR (HR = 2.03; 95% CI = 1.54-2.67) compared to TAC treated patients. These results provide evidence to reconsider the targeted administration of CSA-ME to HCV-infected liver transplant recipients.

Topics: Adult; Cohort Studies; Cyclosporine; Database Management Systems; Female; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Proportional Hazards Models; Tacrolimus; Treatment Outcome

Highly effective antiretroviral therapy in the last decade has increased the survival rates of HIV-positive patients, yielding a greater number of HIV patients suffering from liver-related disease. Liver transplantation (LT) is the only curative treatment for end-stage liver disease (ESLD) associated or not with hepatocellular carcinoma (HCC).. From June 2003 to September 2010, 23 patients underwent cadaveric donor LT for ESLD at our institution. Inclusion criteria followed the Italian Protocol for LT in HIV-positive patients. Immunosuppressive regimens were based on cyclosporine or tacrolimus, eventually switched to Rapamycin.. The median CD4 T-cell count was 275/mmc (range=119-924). All patients were affected by ESLD, which was associated with HCC in 14 cases. Ten patients were within the Milan criteria and four patients exceeded them but were within the San Francisco criteria. Conversion from calcineurin inhibitors (CNI) to rapamycin occurred in ten cases. Hepatitis C virus (HCV) recurrence occurred in 13/21 HCV-positive patients. Acute cellular rejection occurred in eight patients with one developing chronic cellular rejection. Overall patient and graft survivals at 80 months were 50% and 45% respectively.. LT in HIV-positive patients is a feasible procedure, even if in our experience was burdened by a greater incidence of complications including HCV recurrence and infection compared with HIV-negative patients.

Topics: Adult; Antiretroviral Therapy, Highly Active; Carcinoma, Hepatocellular; CD4 Lymphocyte Count; Cyclosporine; Drug Substitution; End Stage Liver Disease; Female; Graft Rejection; Graft Survival; Hepatitis C, Chronic; HIV; HIV Infections; Hospitals, University; Humans; Immunosuppressive Agents; Italy; Kaplan-Meier Estimate; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Recurrence; RNA, Viral; Severity of Illness Index; Sirolimus; Tacrolimus; Time Factors; Treatment Outcome; Viral Load

1. The natural history of recurrent hepatitis C virus (HCV) is highly variable. Old donor age is a factor that has consistently been shown to affect disease progression. 2. Overall, immunosuppression determines the progression of HCV-related disease; however, the type of immunosuppressive agent used for induction or maintenance is not a key factor. 3. Steroid boluses should be avoided; they are associated with increased viremia, fibrosis progression, and reduced survival. 4. Antiviral therapy, particularly if it is successful, is associated with improved outcomes for liver transplant recipients with HCV. 5. There are no convincing data for modifying the type of immunosuppression before antiviral therapy is started.

Topics: Antiviral Agents; Calcineurin Inhibitors; Cyclosporine; Graft Rejection; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Liver Transplantation; Mycophenolic Acid; Receptors, Interleukin-2; Recurrence; Risk Factors; Tacrolimus; TOR Serine-Threonine Kinases

Central nervous system (CNS) complications are common after liver transplantation (LT). According to the literature, the most common causes are infections and the neurotoxicity of immunosuppressive drugs (cyclosporine and tacrolimus). The aim of this study was to evaluate the incidence, clinical presentations, etiologies, and outcomes of CNS complications in a series of 395 consecutive LT recipients whose immunosuppression regimen was designed for low tacrolimus blood levels. An analysis of the 12-hour trough concentrations of tacrolimus in the study population showed that the target drug levels, which were designed to maintain minimal immunosuppression, were usually achieved. In all, 64 patients (16.2%) developed major neurological symptoms (37 within 30 days of LT). None of the observed CNS complications were caused by infections (viral, bacterial, or fungal), and only 3 of the 395 patients (0.8%) received a diagnosis of tacrolimus-related leukoencephalopathy. Cerebrovascular disease was identified in 15 patients (3.8%; 8 had cerebral hemorrhages, 5 had ischemic strokes, and 2 had subdural hemorrhages). Pontine myelinolysis was found in 2 patients (0.5%). Notably, no clear cause was identified for the remaining 44 cases (11.1%): brain imaging was negative for 22 cases, and diffuse hypoxic changes were present for the other 22. CNS complications were significantly associated with a reduction in 3-month patient survival (88.8% versus 95.4%) and 5-year patient survival (57.3% versus 84.1%). Among the pretransplant variables that were analyzed, the incidence of portosystemic encephalopathy, the peak serum bilirubin levels, and the lowest serum total cholesterol levels were significantly different between the 64-patient group with CNS complications and the asymptomatic group of 331 patients.

Topics: Adult; Carcinoid Tumor; Carcinoma, Hepatocellular; Central Nervous System Diseases; Female; Graft Rejection; Hepatitis B, Chronic; Hepatitis C, Chronic; Hepatitis, Autoimmune; Hepatolenticular Degeneration; Humans; Immunosuppressive Agents; Incidence; Liver Cirrhosis; Liver Cirrhosis, Biliary; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Risk Factors; Tacrolimus

Topics: Cyclosporine; Database Management Systems; Female; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Tacrolimus; Treatment Outcome

Patients who undergo organ transplantation are now known to be at increased risk of the development of de novo malignant tumors. This is primarily a consequence of immunosuppression, which may promote tumor development and progression by a variety of mechanisms. It was also reported recently that the relative ratio of lung tumors developing in orthotopic liver transplantation patients was 3.7 times greater than in the general population. We report a case of de novo lung cancer diagnosed in a 65-year-old man 32 months after he underwent liver transplantation for hepatocellular carcinoma secondary to hepatitis C virus cirrhosis. He had received tacrolimus as immunosuppressive therapy after the liver transplantation. The tumor was resected, and he remains well almost 3 years later. Previous reports provide evidence that immunosuppressive therapy is a risk factor for de novo lung cancer; thus, it is important to reduce immunosuppression for orthotropic liver transplantation patients, and to screen them carefully to detect the tumor at an early stage.

Topics: Adenocarcinoma; Aged; Carcinoma, Hepatocellular; Hepatitis C, Chronic; Humans; Immunocompromised Host; Immunosuppression Therapy; Immunosuppressive Agents; Liver Neoplasms; Liver Transplantation; Lung Neoplasms; Male; Neoplasms, Second Primary; Tacrolimus

Tacrolimus-related posterior reversible leukoencephalopathy (PRLE) is a rare complication which should be recognized by clinicians who regularly use immunosuppressive therapy. We report the case of an HIV-positive, hepatitis C-positive liver transplant patient who presented with this complication. Immunosuppression with tacrolimus was started after postsurgery. On the 20th day, the patient suffered two tonic-clonic convulsive attacks against a background of hypertension. Cerebral magnetic resonance imaging and lumbar puncture led to diagnosis of tacrolimus-related PRLE after eliminating other possible diagnoses. Therapeutic management consisted of withdrawing tacrolimus and initiating treatment with antiepileptogenic and antihypertensive drugs, supplemented with magnesium sulphate. The symptoms regressed in the days following withdrawal of tacrolimus and the majority of lesions on magnetic resonance imaging disappeared within two weeks. The aim of which should be to identify patients at risk of developing this complication. This would enable targeted prevention involving magnesium supplementation, strict control of blood pressure and serial monitoring of tacrolimus blood concentrations.

Topics: Hepatitis C, Chronic; HIV Infections; Humans; Immunosuppressive Agents; Leukoencephalopathies; Liver Transplantation; Magnetic Resonance Imaging; Tacrolimus

Topics: Adult; Antiviral Agents; Critical Care; Diagnosis, Differential; Disease Outbreaks; Drug Resistance, Viral; Drug Therapy, Combination; Female; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Influenza A Virus, H1N1 Subtype; Influenza, Human; Intensive Care Units; Kidney Failure, Chronic; Liver Cirrhosis; Liver Transplantation; Opportunistic Infections; Oseltamivir; Postoperative Complications; Prednisone; Respiratory Insufficiency; Tacrolimus

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

Necrolytic acral erythema is a relatively recently described psoriasis-like skin eruption seen in people infected with hepatitis C virus. Hepatitis C virus infection is endemic in many parts of the world with a steady increase of incidence in Pakistan. Recognition of this disorder is crucial to an early treatment of the underlying liver disease. Herein, we report the first case of necrolytic acral erythema from Asia and also describe good therapeutic response to topical tacrolimus ointment.

Topics: Adolescent; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Male; Necrosis; Ointments; Skin Diseases, Papulosquamous; Tacrolimus

Hepatitis C virus (HCV)-induced cirrhosis is the most common indication for liver transplantation (LT). However, graft reinfection is nearly universal. The choice of immunosuppression, including the calcineurin inhibitor (CNI), may have some effect on severity of recurrence and graft survival. In addition, HCV recurrence may have some impact on metabolism of immunosuppressive drugs. In this retrospective study, we examined the dose and blood levels of tacrolimus (TAC) and cyclosporin A (CYA) in HCV patients consecutively undergoing transplantation (TAC, n = 44; CYA, n = 60) and surviving 12 months post-LT. In addition, we examined the CNI dose and blood levels in an age- and gender-matched comparison group of patients who were transplanted for alcoholic liver disease (ALD) (TAC, n = 44; CYA, n = 47). During the 12-month period of observation, TAC levels were significantly higher for HCV than for ALD patients (P = 0.002). The dose of TAC decreased over time for both HCV and ALD patients (P < 0.001), but the reduction was greater for HCV patients (P = 0.03). CYA dose decreased over time for both groups (P < 0.001) but a greater reduction was observed for the HCV group (P = 0.007). For both HCV and ALD patients, CYA levels decreased over time (P < 0.001) but there was no significant difference between HCV and ALD patients. Thus, to maintain comparable blood levels, a greater reduction of dose was required for HCV than for ALD patients. In conclusion, our observations demonstrate a likely effect of HCV infection on CNI metabolism, an effect that is not clearly due to graft damage. Physicians need to be alert to this interaction and to the need to respond quickly to changes in CNI levels that may be associated with HCV infection and with HCV clearance during antiviral therapy.

Topics: Adult; Aged; Biopsy; Cyclosporine; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Graft Rejection; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Diseases, Alcoholic; Liver Transplantation; Male; Middle Aged; Recurrence; Retrospective Studies; Tacrolimus; Treatment Outcome

Interferon (IFN)-based antiviral therapy is increasingly used in immunocompromised patients with chronic hepatitis C after orthotopic liver transplantation (OLT) and HIV-HCV co-infection. Differences in early viral kinetics have not been compared in these patients.. We retrospectively analysed 76 patients (31 OLT, 20 HIV-HCV and 25 HCV control patients) undergoing IFN sensitivity testing before starting antiviral therapy with pegylated IFN-alpha 2a (180 microg week(-1)) plus ribavirin (0.8-1.2 g day(-1)) for 48 weeks. We compared baseline parameters, response to IFN and treatment outcome between the groups and assessed the influence of specific calcineurin inhibitors in OLT patients and immune status in HIV-HCV patients on treatment response.. Viral loads pretherapy were higher in OLT compared to nontransplanted HCV controls (P = 0.003). The same trend was present in HIV-HCV (P = 0.09). The log-drop after test dose was less in OLT compared to HCV (P = 0.02), while no significant difference was found between HIV-HCV and HCV. In HIV-HCV patients viral load log-drop correlated significantly with CD4(+) cell counts (P = 0.001). No difference in viral load pretherapy, log-drop and treatment outcome was noted between different calcineurin inhibitors in OLT patients. Sustained virological response rates were 28% in OLT, 50% in HIV-HCV and 56% in HCV patients.. Immunosuppression results in high HCV viral loads. Initial efficacy of IFN is significantly impaired in OLT patients, but not in HIV-HCV with largely preserved CD4(+) cell counts. Sustained virological response rates of 28% in OLT patients are suboptimal, but encouraging results are shown for HIV-HCV patients with relatively high CD4(+) cell counts.

Topics: Adult; Aged; Antiviral Agents; Calcineurin Inhibitors; CD4 Lymphocyte Count; Cyclosporine; Drug Therapy, Combination; Female; Hepacivirus; Hepatitis C, Chronic; HIV Infections; Humans; Immunocompromised Host; Interferon alpha-2; Interferon-alpha; Liver Transplantation; Male; Middle Aged; Polyethylene Glycols; Prognosis; Recombinant Proteins; Retrospective Studies; Ribavirin; Statistics, Nonparametric; Tacrolimus; Treatment Outcome; Viral Load

Liver transplantation (LT) for hepatitis C virus (HCV)-associated cirrhosis in human immunodeficiency virus (HIV)-infected patients was compared with non-HIV patients. Nine patients with HIV-HCV coinfection were compared with patients transplanted before and after each HIV patient (control group). Immunosuppression consisted in tacrolimus with steroids or mycophenolate mofetil. Acute cellular rejection and three-year actuarial patient survival were respectively 44% and 87.5% in HIV group and 22% and 93.7% in the control group (P=NS). Acute hepatitis C virus occurred earlier (2.3 vs. 4.3 months) and was more cholestatic (mean bilirubin: 10.8 vs. 1.6 mg/dL) in the HIV group. Eight (100%) HIV and nine (64.3%) control patients received antiviral treatment with pegylated interferon and ribavirin. One patient (11.1%) of the control group and one patient (20%) of the HIV group presented a sustained virologic response (P=NS). Short- to midterm results of LT in HIV-HCV co-infected patients were excellent and similar to non-HIV patients.

Topics: Adult; Aged; Antiviral Agents; Case-Control Studies; Female; Hepatitis C, Chronic; HIV Infections; Humans; Immunosuppression Therapy; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Steroids; Tacrolimus; Treatment Outcome

Chronic hepatitis C virus (HCV) is usually associated with high levels of hepatic interleukin (IL)-2 and low levels of IL-4 transcripts. HCV frequently recurs after liver transplantation, and its course is accelerated in this setting. We compared in situ expression of IL-2 and IL-4 in transplanted and nontransplanted patients with HCV.. A total of 74 liver biopsy specimens were studied; 52 came from transplanted patients, 38 of whom were HCV-positive (17 mild and 21 severe cases of recurrent HCV) and 22 came from nontransplanted patients, 17 of whom were HCV-positive (7 mild and 10 severe cases of HCV). The expression of IL-2 and IL-4 mRNA and IL-4 protein was studied using the reverse transcriptase polymerase chain reaction and immunohistochemical methods, respectively.. IL-2 transcript levels were significantly higher in severe than in mild HCV in both liver graft recipients and nontransplanted patients. However, IL-2 levels were higher in nontransplanted than in transplanted patients. IL-4 transcripts and protein were preferentially detected in graft recipients with severe recurrent HCV.. IL-4 expression is elevated in severe recurrent HCV and may play a role in the progression of hepatic lesions after liver transplantation.

Topics: Adrenal Cortex Hormones; Adult; Biopsy; Cyclosporine; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Interleukin-2; Interleukin-4; Liver Transplantation; Male; Middle Aged; Recurrence; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tacrolimus; Transcription, Genetic

Cyclosporine is an immunosuppressive agent widely used in the management of liver transplant recipients. Cyclosporine has been shown to have antiviral activities against HIV, herpes simplex, and vaccinia viruses. The aim of this study was to determine the effect of Cyclosporine in viral clearance in the liver transplant recipients during therapy with combination of interferon and ribavirin, and to determine the anti-viral potential of Cyclosporine in vitro. Immunosuppression consisted of either Cyclosporine or Tacrolimus-based therapy. Both groups received therapy with interferon and ribavirin for 48 weeks when evidence of progressive histologic disease was determined. We found that subjects on Cyclosporine-based immunosuppression (n = 56) had a higher sustained virological response of 46% compared to 27% in the patients on Tacrolimus-based therapy (n = 59, P = 0.03). In vitro studies were performed to evaluate the antiviral effect of Cyclosporine in the replicon system. These studies showed that Cyclosporine inhibits hepatitis C viral replication in a dose-dependent manner. Combination of Cyclosporine with interferon showed additive effect, and its function is independent of interferon signaling pathways. In conclusion, Cyclosporine may offer an advantage to Tacrolimus in those patients undergoing interferon-based therapy and should be studied in a prospective randomized trial.

Topics: Adult; Cyclosporine; Follow-Up Studies; Graft Rejection; Graft Survival; Hepacivirus; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; In Vitro Techniques; Liver Failure; Liver Transplantation; Middle Aged; Postoperative Complications; Retrospective Studies; Secondary Prevention; Tacrolimus; Treatment Outcome

To determine the effects of the calcineurin inhibitors, cyclosporine and tacrolimus, on hepatitis C virus (HCV) replication and activity of recurrent hepatitis C in patients post liver transplantation.. The data of a cohort of 107 patients who received liver transplantation for HCV-associated liver cirrhosis between 1999 and 2003 in our center were retrospectively analyzed. The level of serum HCV-RNA and the activity of recurrent hepatitis were compared between 47 patients who received either cyclosporine or tacrolimus as the primary immunosuppressive agent and an otherwise similar immunosuppressive regimen which did not lead to biliary complications within the first 12 mo after transplantation.. HCV-RNA increased within 3 mo after transplantation but the differences between the cyclosporine group and the tacrolimus group were insignificant (P=0.49 at 12 mo). In addition, recurrent hepatitis as determined by serum transaminases and histological grading of portal inflammation and fibrosis showed no significant difference after 12 mo (P=0.34).. Cyclosporine or tacrolimus as a primary immunosuppressive agent does not influence the induction or severity of recurrent hepatitis in HCV-infected patients after liver transplantation.

Topics: Adult; Cohort Studies; Cyclosporine; Female; Hepacivirus; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Recurrence; Retrospective Studies; RNA, Viral; Tacrolimus; Virus Replication

Neuropsychiatric complications are an important source of morbidity following orthotopic liver transplantation. Etiology of liver disease and type of immunosuppression are possible related factors. The aim of this study was to describe the prevalence of neuropsychiatric complications after liver transplantation, the role of immunosuppression, and the association between these and specific liver diseases such as hepatitis C. One hundred twenty-eight patients with liver transplants were studied. Tacrolimus was the primary immunosuppressant in 101 patients and cyclosporine in 27 patients. Seventy-five complications in 49 patients (38.2%) were reported. In 43 patients, the etiology was associated with immunosuppression: 36 on tacrolimus and 7 on cyclosporine (P = 0.34). Seventeen and four-tenths percent of patients with hepatitis C and 4.6% of patients without hepatitis C developed depression (P = 0.02). There is no difference between types of primary immunosuppression and neuropsychiatric complications. There is a significantly greater incidence of depression in patients transplanted for hepatitis C.

Topics: Adult; Aged; Cyclosporine; Depressive Disorder; Female; Hepatitis C, Chronic; Humans; Immunocompromised Host; Immunosuppressive Agents; Incidence; Liver Diseases; Liver Transplantation; Male; Medical Records; Middle Aged; Postoperative Complications; Retrospective Studies; Tacrolimus; Tennessee

We retrospectively analyzed 42 hepatitis C virus (HCV)-infected patients who underwent cadaveric liver transplantation under two strategies of immunosuppression: (1) daily tacrolimus (TAC) throughout and an initial cycle of high-dose prednisone (PRED) with subsequent gradual steroid weaning, or (2) intraoperative antithymocyte globulin (ATG) and daily TAC that was later space weaned. After 36 +/- 4 months, patient and graft survival in the first group was 18/19 (94.7%) with no examples of clinically serious HCV recurrence. In the second group, the three-year patient survival was 12/23 (52%), and graft survival was 9/23 (39%); accelerated recurrent hepatitis was the principal cause of the poor results. The data were interpreted in the context of a recently proposed immunologic paradigm that is equally applicable to transplantation and viral immunity. In the framework of this paradigm, the disparate hepatitis outcomes reflected different equilibria reached under the two immunosuppression regimens between the relative kinetics of viral distribution (systemically and in the liver) and the slowly recovering HCV-specific T-cell response. As a corollary, the aims of treatment of the HCV-infected liver recipients should be to predict, monitor, and equilibrate beneficial balances between virus distribution and the absence of an immunopathologic antiviral T-cell response. In this view, favorable equilibria were accomplished in the nonweaned group of patients but not in the weaned group. In conclusion, since the anti-HCV response is unleashed when immunosuppression is weaned, treatment protocols that minimize disease recurrence in HCV-infected allograft recipients must balance the desire to reduce immunosuppression or induce allotolerance with the need to prevent antiviral immunopathology.

Topics: Analysis of Variance; Antilymphocyte Serum; Cadaver; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Hepatitis C, Chronic; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Function Tests; Liver Transplantation; Male; Middle Aged; Prednisone; Probability; Proportional Hazards Models; Retrospective Studies; Severity of Illness Index; Survival Rate; Tacrolimus; Transplantation Immunology

Erosive lichen planus is a painful and disabling disease that is frequently resistant to topical and systemic therapies. Current therapies are considered palliative rather than curative as many patients relapse after discontinuing treatment. An association has been reported between some cases of oral lichen planus (OLP) and chronic hepatitis C infection.. We report on a 51-year-old hepatitis C-positive man with corticosteroid refractory erosive lichen planus of the lip who had a rapid resolution of his lesions following a two-week course of topical 0.1% tacrolimus ointment. The patient remains symptom-free at one year post-treatment.. This case supports the safety and efficacy of topical tacrolimus in patients with steroid-refractory OLP associated with chronic hepatitis C.

Topics: Administration, Topical; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Lichen Planus, Oral; Male; Middle Aged; Mouth Mucosa; Ointments; Tacrolimus; Treatment Outcome