sirolimus and Hepatitis-C--Chronic

The development of calcineurin inhibitors (CNIs) led to marked improvements in patient and graft survival after liver transplantation (LTx). We have been left, however, with a dependence on immunosuppressive agents with nephrotoxicity, neurotoxicity, adverse impacts on cardiac risk profile, and risk for malignancy. These challenges need to be met against a dominance of hepatitis C virus (HCV) and hepatocellular carcinoma (HCC) as indications for liver transplant. Unmet needs for immunosuppression (IS) in LTx include: (1) Effective drugs that avoid CNIs toxicities. (2) Agents without adverse impact on HCV recurrence. (3) Compounds that minimize risk of HCC recurrence. New immunosuppressives will need to address the above needs while supporting patient and graft survival equivalent to those achievable with CNIs, ideally without important new toxicities. Two new classes of agents are currently in advanced clinical development: belatacept, and the mammalian target of rapamycin inhibitors (m-TORi). This manuscript will review evidence for a role for m-TORi in LTx in a range of clinical scenarios including patients with CNI nephrotoxicity or neurotoxicity, patients at risk of (or with) HCV recurrence, and patients at risk of HCC recurrence.

Topics: Adaptive Immunity; Calcineurin Inhibitors; Carcinoma, Hepatocellular; Clinical Trials as Topic; Everolimus; Hepatitis C, Chronic; Humans; Immunity, Innate; Immunosuppressive Agents; Liver Neoplasms; Liver Transplantation; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

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

Direct-acting antivirals (DAAs) have substantially increased sustained virological response rates after liver transplantation, with improved tolerance compared to interferon-based therapy. The influence of immunosuppressive agents on the efficacy of DAAs has not been clarified.. Subgenomic hepatitis C virus (HCV) replicons for genotype (GT) 1b, 2b, 3a, and 4a were treated with the mammalian target of rapamycin (mTOR) inhibitors everolimus and sirolimus or with the calcineurin inhibitors (CNIs) cyclosporine or tacrolimus, either alone or in combination with selected DAAs. Cell proliferation-related effects were excluded with MTT assays. HCV replication activity was quantified by quantitative real-time polymerase chain reaction or luciferase assay.. Addition of either mTOR inhibitor to the DAA daclatasvir (DAC) resulted in a 30% increase in antiviral activity compared to DAC alone for HCV GT2a, GT3a, and GT4a (all P ≤ .01). Similar results were obtained using sofosbuvir and ledipasvir. In contrast, addition of either mTOR inhibitor to DAC induced a 30% reduction in antiviral activity in GT1b cells (P ≤ .01 vs DAC alone). Neither CNI affects the antiviral activity of the DAAs in any HCV GT.. For patients with HCV GT2a, GT3a, or GT4a infection, mTOR-based immunosuppressive therapy may be beneficial. CNI-based therapy may be more efficacious in GT1b patients, as mTOR inhibitors seem to impair antiviral efficacy of DAAs in HCV GT1b infection.

Topics: Antiviral Agents; Benzimidazoles; Calcineurin Inhibitors; Carbamates; Cell Line; Cyclosporine; Everolimus; Fluorenes; Genotype; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Imidazoles; Immunosuppressive Agents; Liver Transplantation; Pyrrolidines; Sirolimus; Sofosbuvir; Valine; Virus Replication

The era of direct acting antivirals has revolutionised the management of chronic hepatitis C infection and improved patient outcomes. The optimal management of patients who require liver transplantation remains a matter of ongoing discussion. Treatment in the post-transplantation setting may be complicated by significant drug-drug interactions between antiviral agents and standard immune suppressive treatment regimens. We describe what we believe to be the first reported case of a patient successfully treated for CHC with ombitasvir/paritaprevir/ritonavir plus dasabuvir, while taking sirolimus following liver transplantation.

Topics: 2-Naphthylamine; Aged; Anilides; Antiviral Agents; Carbamates; Cyclopropanes; Drug Interactions; Drug Therapy, Combination; End Stage Liver Disease; Hepatitis C, Chronic; Humans; Lactams, Macrocyclic; Liver Transplantation; Macrocyclic Compounds; Male; Proline; Ritonavir; Sirolimus; Sulfonamides; Treatment Outcome; Uracil; Valine

The influence of immunosuppressants on hepatitis C virus (HCV) re-infection after liver transplantation, particularly mammalian target of rapamycin inhibitors, remains unclear. The aim of our study was to analyze the influence of everolimus (EVR) on HCV replication activity in the context of underlying molecular mechanisms, with focus on the pro-myelocytic leukemia protein (PML).. HCV viral load was recorded in 40 patients with post-transplant HCV re-infection before and 8 weeks after introduction of EVR. An HCV cell culture replicon system for genotype (GT) 1b, GT2b, and GT3a was used to compare the influence of EVR on HCV replication for the respective genotypes in vitro. Fluorescence-activated cell-sorting analysis was used to test for effects on cell proliferation. PML expression was silenced with the use of small hairpin RNA constructs, and PML expression was quantified by means of quantitative real-time polymerase chain reaction.. In patients with HCV, the viral load of GT1a and GT1b was hardly affected by EVR, whereas the viral load was reduced in patients with GT2a (P ≤ .0001) or GT3 infection (P ≤ .05). In vitro EVR impairs HCV replication activity of GT2a and GT3a up to 60% (P ≤ .0005), whereas in GT1b cells, HCV replication activity is increased by 50% (P ≤ .005). Replicon cell viability was not impaired. HCV replication activity is impaired in the absence of PML, which can be reversed by overexpression of PML isoforms. Furthermore, in the absence of PML, the effect of EVR on HCV replication activity is nearly abrogated.. The mammalian target of rapamycin inhibitor EVR influences HCV replication via PML. The herein presented results suggest a genotype-dependent benefit for an EVR-based immunosuppressive regimen in patients with GT2a or GT3 re-infection after liver transplantation.

Topics: Everolimus; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; In Vitro Techniques; Liver Transplantation; Real-Time Polymerase Chain Reaction; RNA, Viral; Sirolimus; TOR Serine-Threonine Kinases; Viral Load; Virus Replication

Late decapsulation with fluid collection is a rare complication of renal transplantation with deleterious effects on kidney function. Its physiopathology is unclear but there might be an association with mammalian target of rapamycin (m-TOR) inhibitors, especially in patients with chronic hepatitis C. We report a case of late spontaneous decapsulation 12 years after kidney transplant in a patient infected with hepatitis C under treatment with sirolimus. He underwent marsupialisation of the collection, sirolimus was converted to cyclosporine and hepatitis C treatment was performed with success. This is the first successful case report of late spontaneous decapsulation of the kidney graft in a patient with hepatitis C.

Topics: Antiviral Agents; Cyclosporine; Drug Substitution; Graft Rejection; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Prednisolone; Risk Factors; Sirolimus; Tomography, X-Ray Computed

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

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 treatment of rejection is an important factor associated with the severe recurrence of hepatitis C virus (HCV) after liver transplantation. 2. The effects of calcineurin inhibitors, corticosteroids, and mycophenolate mofetil on HCV recurrence are equivocal. 3. Cyclosporine is associated with a higher sustained virological response in patients treated for HCV. 4. Because insulin resistance and diabetes are associated with fibrosis in HCV-infected liver transplant recipients, the use of immunosuppressive agents without this side effect may slow the posttransplant disease progression.

Topics: Adrenal Cortex Hormones; Calcineurin Inhibitors; Cyclosporine; Graft Rejection; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Liver Transplantation; Mycophenolic Acid; Recurrence; Risk Factors; Sirolimus

Late spontaneous kidney graft decapsulation with fluid collection is a rare condition with only a few cases reported in the literature. Common causes of renal allograft rupture include acute rejection, acute tubular necrosis, renal vein thrombosis, and trauma. Sirolimus related late spontaneous decapsulation has not been reported in the past. Interestingly, sirolimus may promote lymphocele formation in renal transplant recipients, including those presenting with chronic hepatitis B or C. Herein, we report a case of late spontaneous decapsulation with subcapsular hematoma formation developing 12 years after receipt of a cadaveric allograft. The patient was infected with both hepatitis B and C viruses. Cyclosporine was replaced by sirolimus for maintenance therapy because of chronic rejection and acute deterioration of renal function. He presented to the hospital at 9 months after sirolimus inception because of a sudden onset of pain and swelling over the kidney graft. Magnetic resonance imaging found the capsule to be stripped from the kidney by a collection of liquefied hematomas. A laparoscopic fenestration was performed by creation of a peritoneal window adjacent to the renal allograft. When patients have chronic hepatitis, tacrolimus might be a better choice than sirolimus.

Topics: Bowman Capsule; Cadaver; Creatinine; Glomerulonephritis; Hepatitis B, Chronic; Hepatitis C, Chronic; Humans; Immunosuppressive Agents; Kidney Transplantation; Kidney Tubular Necrosis, Acute; Magnetic Resonance Imaging; Male; Renal Artery; Sirolimus; Tissue Donors; Ultrasonography

Topics: Acidosis, Renal Tubular; Acute Kidney Injury; Drug Therapy, Combination; Glomerular Filtration Rate; Hepatitis C, Chronic; HIV Infections; HIV Integrase Inhibitors; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Pyrrolidinones; Raltegravir Potassium; Sirolimus