tacrolimus and Hepatitis-B--Chronic

The proteinuria remission in hepatitis B virus-associated glomerulonephritis (HBV-GN) patients with massive proteinuria treated with antiviral therapy was low. Tacrolimus (TAC) is effective in primary nephropathy and can inhibit HBV infection by inhibiting HBV binding to sodium taurocholate cotransporting polypeptide on liver cells. This study evaluated the efficacy and safety of TAC combined with ETV compared with entecavir (ETV) monotherapy in HBV-GN.. Patients diagnosed with HBV-GN were recruited for this prospective, randomized, controlled, multicenter, single-blinded study in China. Patients were given TAC and ETV therapy (the TAC+ETV group) or placebo and ETV therapy (the ETV group) for 26 weeks. The efficacy endpoints included proteinuria remission, including complete and partial remission (CR and PR), the change of 24-hour proteinuria (24 h UP) and HBV DNA titer. The safety endpoints were the incidence of HBV virologic breakthrough and adverse events.. There were 14 patients in the TAC+ETV group and 17 patients in the ETV group. In the intention-to-treat analyses, 64.3% (9/14) of patients in the TAC+ETV group and 58.8% (10/17) in the ETV group achieved PR or CR at 26 weeks (P=0.38). At week 14, 42.9% (6/14) and 41.2% (7/17) of patients in the TAC+ETV group and the ETV group, respectively, achieved PR or CR (P=0.23). At week 26, the 24 h UP had decreased by 2.63±6.33 g from baseline in the TAC+ETV group and 1.42±4.34 g in the ETV group (P=0.55). The serum albumin increased by 11.1±7.30 g/L from baseline in the TAC+ETV group and 3.81±5.09 g/L in the ETV group (P<0.001). Log10 HBV DNA decreased by 1.49±2.04 from baseline in the TAC+ETV group and 2.47±2.08 in the ETV group (P=0.37); 28.6% (4/14) patients had HBV DNA virologic breakthrough in the ETV group, while none in the TAC+ETV group (P=0.29).. In adult HBV-GN patients, TAC and ETV combination therapy may significantly improve serum albumin levels without increasing the risk of HBV reactivation compared with entecavir monotherapy.. ClinicalTrials.gov Identifier NCT03062813.

Topics: Adult; Antiviral Agents; DNA, Viral; Glomerulonephritis; Guanine; Hepatitis B virus; Hepatitis B, Chronic; Humans; Prospective Studies; Proteinuria; Serum Albumin; Single-Blind Method; Tacrolimus; Treatment Outcome

To evaluate the safety and efficacy of steroid-minimization therapy in liver transplantation (LT) recipients with hepatitis B virus-related diseases in China.. From March 2000 to June 2007, 502 adult LT recipients, mostly with hepatitis B (HBV)-related diseases, were enrolled in our study. Four study groups were setup according to the steroid-minimization protocols: tacrolimus (TAC) with 6 months steroids withdrawal (6M SW), TAC with 3 months SW (3M SW), TAC with 14 days SW (14d SW), and TAC with basiliximab induction and steroids avoidance (Bas SA). All patients were followed up for at least 36 months after LT.. There were no significant differences in the overall 3-year survival rates of the patients and graft, and chronic rejection among the four groups (P = 0.092, P = 0.113 and P = 0.684, respectively). There was also no difference in acute rejection within 12 months after LT (P = 0.514). The 3-year recurrence rates of HBV infection and hepatocellular carcinoma (HCC) after LT were significantly different among all the groups (lowest in TAC/Bas SA group; P = 0.037 and P = 0.029, respectively). The overall incidence of infection was significantly higher in the 6M SW group (62.2% vs 56.1% in 3M SW, 30.5% in 14d SW, 20.5% in Bas SA; P < 0.01). By the end of the 3-year follow-up, more than 90% of the surviving patients could safely receive TAC monotherapy.. Bas SA immunosuppressive protocol can be achieved safely in LT and reduce HBV infection and HCC recurrence and side effects of steroids after LT.

Topics: Adult; Antibodies, Monoclonal; Bacterial Infections; Basiliximab; Carcinoma, Hepatocellular; Chi-Square Distribution; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Hepatitis B, Chronic; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Male; Methylprednisolone; Middle Aged; Neoplasm Recurrence, Local; Recombinant Fusion Proteins; Recurrence; Statistics, Nonparametric; Survival Rate; Tacrolimus

A prospective evaluation was performed to study the potential benefits of the use of interleukin-2 receptor antibody (IL-2Rab) in the induction therapy with early elimination of steroid and reduction of tacrolimus dosage in liver transplant recipients among whom 94% had chronic hepatitis B infection. Thirty-one liver transplant recipients who underwent right-lobe live donor (n = 19) or cadaveric (n = 12) liver transplantation received IL-2Rab, basiliximab 20 mg intravenously within 6 hours of graft reperfusion and on postoperative day 4 (IL-2ab group). Two doses of steroid injection were given intraoperatively and on postoperative day 1. Postoperative immunosuppression was maintained with oral tacrolimus and mycophenolate mofetil without the use of steroids. The operative outcomes were compared with those of 49 patients who received standard immunosuppressive regimen consisting of tacrolimus and corticosteroid (steroid group). The overall postoperative morbidity and hospital stay were comparable between the 2 groups. There were significantly lower incidences of postoperative new-onset diabetes (0% vs 28%, P =.011), acute cellular rejection (6% vs 27%, P =.038), and cytomegalovirus (CMV) antigenemia (0% vs 18%, P =.011) in the IL-2Rab group compared with the steroid group. The blood cholesterol level at 6 months after transplantation was significantly lower in the IL-2Rab group (median, 4.0 vs 4.4 mmol/L, P =.007). On follow-up, none of the patients in the IL-2Rab group had hepatitis B viral breakthrough or hepatocellular carcinoma (HCC) recurrence, whereas 1 and 3 patients in the steroid group developed these complications, respectively. In conclusion, treatment of liver transplant recipients with IL-2Rab with early withdrawal of steroids and reduction of tacrolimus dosage is associated with lower incidences of postoperative new-onset diabetes, acute cellular rejection, and CMV antigenemia, as well as a lower serum cholesterol level. Further studies and long-term follow-up are required to document their potential benefits on hepatitis B and HCC recurrences.

Topics: Adrenal Cortex Hormones; Adult; Antibodies, Monoclonal; Antigens, Viral; Basiliximab; Cytomegalovirus; Diabetes Mellitus; Dose-Response Relationship, Drug; Female; Graft Rejection; Hepatitis B, Chronic; Humans; Immunosuppressive Agents; Incidence; Injections, Intravenous; Liver Diseases; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Receptors, Interleukin-2; Recombinant Fusion Proteins; Tacrolimus

While several alternatives to cyclophosphamide have been proposed for refractory eosinophilic granulomatosis with polyangiitis (EGPA), therapeutic options are limited in patients with chronic infections. We report a case of refractory EGPA complicated by invasive aspergillosis and chronic hepatitis B. Although multiple immunosuppressants, including cyclophosphamide, were not effective, tacrolimus was used successfully to control disease without exacerbating concomitant infections in the long term. Tacrolimus could be an alternative choice in the treatment of EGPA, especially when aggressive immunosuppression is unfeasible.

Topics: Antifungal Agents; Antiviral Agents; Churg-Strauss Syndrome; Drug Substitution; Hepatitis B, Chronic; Humans; Immunocompromised Host; Immunosuppressive Agents; Invasive Pulmonary Aspergillosis; Male; Middle Aged; Opportunistic Infections; Tacrolimus; Treatment Outcome

Hepatitis E virus infection usually causes an acute and self-resolving hepatitis. In areas where chronic hepatitis B virus infection is prevalent, acute hepatitis E virus superinfection on chronic hepatitis B virus infection occurs sporadically. In recent years, however, chronic hepatitis E virus infection has been recognized in patients under immunosuppressant therapy. To the best of our knowledge, cases involving patients with chronic hepatitis E virus and hepatitis B virus dual infection have never been reported.. A 47-year-old Taiwanese woman who was a renal transplant recipient with chronic hepatitis B virus infection was under immunosuppressant and antiviral treatment. An episode of hepatitis B exacerbation developed due to withdrawal of antiviral treatment against advice, but the flare subsided following antiviral re-treatments. However, an episode of hepatitis exacerbation developed following removal of the renal graft because of graft failure. During the hepatitis flare, she was still under successful antiviral suppression against hepatitis B virus, while her serum samples were positive for hepatitis E virus RNA. Following the hepatitis flare, seroclearance of hepatitis B virus surface antigen developed. From then on, she was under regular hemodialysis. Five years later, another episode of mild hepatitis exacerbation occurred again with positive serum hepatitis E virus RNA. Tracing back the longitudinal serum samples, serum hepatitis E virus RNA was persistently positive throughout the course. This patient was thus recognized to have chronic hepatitis E virus and hepatitis B virus dual infection with intermittent hepatitis E exacerbations.. In areas where chronic hepatitis B virus infection is prevalent, chronic hepatitis E virus coinfection can occur in organ transplant recipients receiving immunosuppressant. Intermittent hepatitis E exacerbations may develop, interfering with the status of hepatitis B virus infection.

Topics: Adenine; Coinfection; Disease Progression; DNA, Viral; Female; Graft Rejection; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Hepatitis E; Hepatitis E virus; Humans; Immunosuppressive Agents; Kidney Transplantation; Lamivudine; Medication Adherence; Middle Aged; Organophosphonates; Reverse Transcriptase Inhibitors; Reverse Transcriptase Polymerase Chain Reaction; Tacrolimus

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

Topics: Blindness, Cortical; Blood Group Incompatibility; Calcineurin Inhibitors; Carcinoma, Hepatocellular; Confusion; Drug Substitution; Drug Therapy, Combination; Emergencies; Everolimus; Graft Rejection; Hepatitis B, Chronic; Humans; Immunosuppressive Agents; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Photopheresis; Plasmapheresis; Sirolimus; Syndrome; 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

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

Posterior reversible encephalopathy syndrome, a serious neurotoxicity, may develop rarely in patients receiving tacrolimus. Because the underlying etiology of posterior reversible encephalopathy syndrome is vasogenic edema, it is generally accepted to be a reversible neurologic condition. Cranial magnetic resonance imaging techniques enable detection of the type of edema, and they are widely used in the differential diagnosis and prognostic prediction of posterior reversible encephalopathy syndrome. Presented here is a case of posterior reversible encephalopathy syndrome in which the patient recovered completely, despite radiologic findings indicating the coexistence of vasogenic and cytotoxic edema secondary to tacrolimus therapy after liver transplantation.

Topics: Brain Edema; Child; Diffusion Magnetic Resonance Imaging; Hepatitis B, Chronic; Humans; Immunosuppressive Agents; Leukoencephalopathies; Liver Failure, Acute; Liver Transplantation; Male; Tacrolimus

Topics: Calcineurin Inhibitors; Cyclosporine; Dermatitis, Atopic; Drug Therapy, Combination; Female; Hepatitis B, Chronic; Humans; Immunosuppressive Agents; Middle Aged; Skin; Tacrolimus

Hepatitis B virus (HBV) recurrence after orthotopic liver transplantation (OLT) is associated with poor graft- and patient-survival. Treatment with HBV-specific immunoglobulins (HBIG) in combination with nucleos(t)ide analogs is effective in preventing HBV reinfection of the graft and improving OLT outcome. However, the role of HBV-specific cellular immunity in viral containment in immune suppressed patients in general and in OLT recipients in particular is unclear. To test whether or not OLT recipients maintain robust HBV-specific cellular immunity, the cellular immune response against HBV was assessed in 15 OLT recipients and 27 individuals with chronic and 24 subjects with self-limited HBV infection, respectively; using an overlapping peptide set spanning the viral nucleocapsid- and envelope-protein sequences. The data demonstrate that OLT recipients mounted fewer but stronger clusters of differentiation (CD)8 T cell responses than subjects with self-limited HBV infection and showed a preferential targeting of the nucleocapsid antigen. This focused response pattern was similar to responses seen in chronically infected subjects with undetectable viremia, but significantly different from patients who presented with elevated HBV viremia and who mounted mainly immune responses against the envelope protein. In conclusion, virus-specific CD4 T cell-mediated responses were only detected in subjects with self-limited HBV infection. Thus, the profile of the cellular immunity against HBV was in immune suppressed patients similar to subjects with chronic HBV infection with suppressed HBV-DNA.

Topics: Antibody Specificity; Cyclosporine; DNA, Viral; Hepatitis B; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Immunosuppressive Agents; Liver Transplantation; Lymphocytes; Nucleocapsid; Recurrence; T-Lymphocytes; Tacrolimus; Viral Load

Recurrence of hepatitis B virus (HBV) in the graft is the major problem for patients with chronic HBV infection undergoing liver transplantation, which could be potentiated by the immunosuppression. In the present study, we used lymphocytes and hepatocytes isolated from patients with chronic HBV infection to investigate in vitro the effects of FK506 with and without methylprednisolone (25 ng/mL) on mitogen-induced lymphocyte proliferation, T-cell activation marker expression, and HBV replication in human hepatocytes. Increasing concentrations of FK506 (0.1, 0.5, and 5 ng/mL) resulted in a dose-dependent inhibition of lymphocyte proliferation with a reduction of the stimulation index by 9.2%, 39.0%, and 55.1%, respectively, with no difference between 25 chronic HBV carriers and normal controls. Methylprednisolone alone had no effect but potentiated the inhibitory effect of all three FK506 concentrations, such that the stimulation index was decreased by 20%, 56.2%, and 65.7%, respectively. FK506 (0.5 ng/ mL) reduced both the percentage of interleukin-2 receptor expressing T cells and the cell surface density of this receptor by 7.1% and 8.7% (P < .01), whereas it only reduced the proportion of HLA-DR expressing T cells by 6.8%. FK506 did not change significantly the intracellular HBV DNA or the hepatic expression of hepatitis B surface antigen (HBsAg) in short-term culture of human hepatocytes, whereas methylprednisolone increased the percentage of HBsAg-positive hepatocytes in all 5 patients with active viral replication. These results indicate that the effects of FK506 on T-cell activation in chronic HBV carriers are identical to normal subjects, resulting in marked suppression of T-lymphocyte function but only modest reduction in the expression of cell surface activation markers. The drug showed no direct stimulatory effect on viral replication, suggesting that FK506 can be a useful, steroid-sparing immunosuppressive agent for liver graft recipients with chronic HBV infection.

Topics: Adult; Cell Culture Techniques; Cell Division; DNA, Viral; Drug Synergism; Female; Glucocorticoids; Hepatitis B Antibodies; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; HLA-DR Antigens; Humans; Immunosuppressive Agents; Liver Transplantation; Lymphocyte Activation; Male; Methylprednisolone; Middle Aged; T-Lymphocytes; Tacrolimus; Virus Replication