sirolimus and End-Stage-Liver-Disease

De novo PTAID may develop in pediatric solid organ transplant recipients, have a diverse spectrum, and are occasionally treatment resistant. Previous reports showed resolution of immune cytopenias in solid organ transplant recipients following replacement of the calcineurin inhibitor tacrolimus with the mTOR inhibitor sirolimus. Herein we describe a retrospective review (2000-2017) of subjects who developed PTAID in whom immunosuppression was changed to sirolimus. Eight recipients (6 males) of either liver (n = 7) or multivisceral transplant (n = 1) suffered from severe, treatment-resistant PTAID and were switched from tacrolimus to sirolimus. The median age at transplant was 1 year (range 0.5-2.4 years). Six (75%) recipients developed de novo allergy and 2 immune-mediated diseases. The median age at presentation of PTAID was 2.7 (1.4-9) years at a median of 1.3 (0.25-8) years after transplantation. The median time from PTAID presentation to conversion to sirolimus was 1.8 (0.45-10) years. Complete resolution of symptoms was seen in 4 (50%) patients after a median of 12 (range 4-24) months including 2 patients with immune-mediated disease, 1 eczema, and 1 with eosinophilic colitis. One patient with multiple food allergies had a partial response and 3 (38%) had no response. None of the 8 recipients developed sirolimus-attributed adverse events or acute rejection during a median follow-up of 5 (0.6-8) years after the conversion. Immunosuppression conversion from tacrolimus to sirolimus can be an effective therapy in patients suffering severe or treatment-resistant PTAID, suggesting a potential role for tacrolimus in the pathogenesis of PTAID.

Topics: Calcineurin Inhibitors; Child; Child, Preschool; End Stage Liver Disease; Female; Follow-Up Studies; Graft Rejection; Humans; Immune System; Immunosuppression Therapy; Immunosuppressive Agents; Infant; Liver Transplantation; Male; Retrospective Studies; Sirolimus; Tacrolimus; TOR Serine-Threonine Kinases; Treatment Outcome

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

For recipients of liver transplantations (LTs) for hepatocellular carcinoma (HCC), HCC recurrence after transplantation remains a major concern. Sirolimus (SRL), an immunosuppressant with anticarcinogenic properties, may reduce HCC recurrence and improve survival. In our study, the US Scientific Registry of Transplant Recipients was linked to pharmacy claims. For liver recipients transplanted for HCC, Cox regression was used to estimate associations of early SRL use with recurrence, cancer-specific mortality, and all-cause mortality, adjusting for recipient ethnicity, calendar year of transplant, total tumor volume, alpha-fetoprotein, transplant center size, use of interleukin 2 induction therapy, and allocated and calculated Model for End-Stage Liver Disease score. We performed stratified analyses among recipients who met Milan criteria, among those without renal failure, among those with deceased liver donors, by age at transplantation, and by tumor size. Among the 3936 included HCC LTs, 234 (6%) were SRL users. In total, there were 242 recurrences and 879 deaths, including 261 cancer-related deaths. All-cause mortality was similar in SRL users and nonusers (adjusted hazard ratio [aHR], 1.01; 95% CI, 0.73-1.39). HCC recurrence and cancer-specific mortality rates appeared lower in SRL users, but associations were not statistically significant (recurrence aHR, 0.86; 95% CI, 0.45-1.65; cancer-specific mortality aHR, 0.80; 95% CI, 0.43-1.50). Among recipients >55 years old, associations were suggestive of better outcomes for SRL users (all-cause mortality aHR, 0.62; 95% CI, 0.38-1.01; recurrence aHR, 0.52; 95% CI, 0.19-1.44; cancer-specific mortality aHR, 0.34; 95% CI, 0.11-1.09), whereas among recipients ≤55 years old, SRL users had worse outcomes (all-cause mortality aHR, 1.76; 95% CI, 1.12-2.75; recurrence aHR, 1.49; 95% CI, 0.62-3.61; cancer-specific mortality aHR, 1.54; 95% CI, 0.71-3.32). In conclusion, among HCC liver recipients overall, SRL did not appear beneficial in reducing all-cause mortality. However, there were suggestions of reductions in recurrence and cancer-specific mortality, and effects appeared to be modified by age at transplantation. Liver Transplantation 22 627-634 2016 AASLD.

Topics: Carcinoma, Hepatocellular; Drug Administration Schedule; End Stage Liver Disease; Female; Humans; Immunosuppressive Agents; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Proportional Hazards Models; Severity of Illness Index; Sirolimus; Transplant Recipients; 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