Cytomegalovirus-Responsive CD8+ T Cells Expand After Solid Organ Transplantation in the Absence of CMV Disease.

Cytomegalovirus (CMV) is a major cause of morbidity and mortality in solid organ transplant recipients. Approximately 60% of adults are CMV seropositive, indicating previous exposure. Following resolution of the primary infection, CMV remains in a latent state. Reactivation is controlled by memory T cells in healthy individuals; transplant recipients have reduced memory T cell function due to chronic immunosuppressive therapies. In this study, CD8+ T cell responses to CMV polypeptides immediate-early-1 and pp65 were analyzed in 16 CMV-seropositive kidney and heart transplant recipients longitudinally pretransplantation and posttransplantation. All patients received standard of care maintenance immunosuppression, antiviral prophylaxis, and CMV viral load monitoring, with approximately half receiving T cell-depleting induction therapy. The frequency of CMV-responsive CD8+ T cells, defined by the production of effector molecules in response to CMV peptides, increased during the course of 1 year posttransplantation. The increase commenced after the completion of antiviral prophylaxis, and these T cells tended to be terminally differentiated effector cells. Based on this small cohort, these data suggest that even in the absence of disease, antigenic exposure may continually shape the CMV-responsive T cell population posttransplantation.

Calcineurin Inhibitor Minimization, Conversion, Withdrawal, and Avoidance Strategies in Renal Transplantation: A Systematic Review and Meta-Analysis.

Despite their clinical efficacy, concerns about calcineurin inhibitor (CNI) toxicity make alternative regimens that reduce CNI exposure attractive for renal transplant recipients. In this systematic review and meta-analysis, we assessed four CNI immunosuppression strategies (minimization, conversion, withdrawal, and avoidance) designed to reduce CNI exposure and assessed the impact of each on patient and allograft survival, acute rejection and renal function. We evaluated 92 comparisons from 88 randomized controlled trials and found moderate- to high-strength evidence suggesting that minimization strategies result in better clinical outcomes compared with standard-dose regimens; moderate-strength evidence indicating that conversion to a mammalian target of rapamycin inhibitor or belatacept was associated with improved renal function but increased rejection risk; and moderate- to high-strength evidence suggesting planned CNI withdrawal could result in improved renal function despite an association with increased rejection risk. The evidence base for avoidance studies was insufficient to draw meaningful conclusions. The applicability of the review is limited by the large number of studies examining cyclosporine-based strategies and low-risk populations. Additional research is needed with tacrolimus-based regimens and higher risk populations. Moreover, research is necessary to clarify the effect of induction and adjunctive agents in alternative immunosuppression strategies and should include more comprehensive and consistent reporting of patient-centered outcomes.

Successful Treatment of Hepatitis C in Renal Transplant Recipients With Direct-Acting Antiviral Agents.

The direct-acting antivirals (DAAs) constitute an emerging group of small molecule inhibitors that effectively treat hepatitis C virus (HCV) infection, a common comorbidity in end-stage renal disease patients. To date, there are no data to guide use of these agents in kidney transplant patients. The authors collected data from 20 consecutive kidney recipients treated with interferon-free treatment regimens for HCV at their center: 88% were infected with genotype 1; 50% had biopsy-proved advanced hepatic fibrosis on their most recent liver biopsy preceding treatment (Metavir stage 3 fibrosis [F3] or F4); and 60% had failed treatment pretransplantation with interferon-based therapy. DAA treatment was initiated a median of 888 days after renal transplantation. All patients cleared the virus while on therapy, and 100% have achieved a sustained virologic response at 12 weeks after completion of DAA therapy. The most commonly used regimen was sofosbuvir 400 mg daily in combination with simeprevir 150 mg daily. However, four different treatment approaches were used, with comparable results. The DAAs were well tolerated, and less than half of patients required calcineurin inhibitor dose adjustment during treatment. Eradication of HCV infection with DAAs is feasible after kidney transplantation with few treatment-related side effects.

A National Survey Assessing the Current Workforce of Transplant Pharmacists Across Accredited U.S. Solid Organ Transplant Programs.

Integration of pharmacists into multidisciplinary transplant patient care has advanced in recent years, with limited data available to evaluate the current status of the profession. This was a national survey developed as an AST Pharmacy COP initiative. Responses were solicited from pharmacists practicing at U.S. transplant programs based on UNOS listing; 176 participants from 113 centers (41%) responded, with 79% practicing ≤10 years. There is a median of 1.4 pharmacist full-time equivalents (FTEs) (range 0.1-7.1) for every 100 transplants. The predominant activities performed by pharmacists during the transplant phase include medication review (95%), lab review (92%), allergy review (88%), medication therapy management (92%), bedside rounds (87%), medication education (79%), documentation (71%), and coordinating discharge medications (58%). Similar activities were reported during the other phases, but participation was less common. The involvement of dedicated transplant pharmacists within multidisciplinary care has become standard at a large number of centers, although expansion is still needed to ensure core pharmaceutical care components are provided to all transplant recipients across all centers. These results inform on the typical responsibilities of pharmacists practicing within the field of transplantation and illustrate that the level of pharmacist involvement significantly varies across transplant centers and the phases of transplantation.

Increased risk of breakthrough infection among cytomegalovirus donor-positive/recipient-negative kidney transplant recipients receiving lower-dose valganciclovir prophylaxis.

OBJECTIVE: We compared the effectiveness of lower-dose (LD) (450 mg/day for 6 months) to standard-dose (SD) (900 mg/day for 6 months) valganciclovir (VGCV) prophylaxis for prevention of cytomegalovirus (CMV) infection and disease in high-risk CMV donor-positive/recipient-negative (D+/R-) kidney recipients. METHODS: We performed a single-center, retrospective cohort study, in a 750-bed academic medical center, involving a total of 90 evaluable CMV high-risk kidney recipients. All patients were retrospectively followed from day of transplantation to November 1, 2012, or to the development of CMV infection or disease, death, or loss to follow-up. CMV screening was only done if suggestive symptoms or abnormal laboratory values were present. Our immunosuppressive protocol otherwise did not differ between periods. RESULTS: In total, 45 consecutive eligible patients initiated SD prophylaxis in the 22 months before the institutional protocol change regarding CMV prophylaxis. One patient developed CMV infection in the setting of non-adherence. In the 16 months after the protocol update, 45 consecutive eligible patients receiving LD prophylaxis were evaluated: 6 developed CMV infection while receiving prophylaxis (P = 0.11). Ganciclovir (GCV)-resistant infection was confirmed in 1 patient in the LD prophylaxis group. Late-onset CMV infection or disease occurred in 11 patients (24%) in the SD group and in 12 patients (27%) in the LD group (P = 0.86). More patients in the SD group developed leukopenia (75% vs. 44%, P < 0.01). During the study period, no significant differences were seen between the groups in mean mg/kg exposure to rabbit anti-thymocyte globulin induction courses, mean tacrolimus troughs, number of rejection episodes, mean estimated renal function, graft survival, or patient survival. Overall mean follow-up (± standard deviation) was 357 days (± 53) in the SD group and 320 days (± 103) in the LD group (P = 0.03). CONCLUSION: Breakthrough CMV infection while receiving VGCV prophylaxis occurred more often after the institutional protocol revision to LD VGCV prophylaxis. Given our concern for increased risk of breakthrough infection and GCV resistance when prophylaxis is under-dosed, our institutional protocols were revised back to SD prophylaxis for all CMV D+/R- kidney transplant recipients.

A randomized, crossover pharmacokinetic study comparing generic tacrolimus vs. the reference formulation in subpopulations of kidney transplant patients.

An exploratory, post hoc analysis was performed using data from a prospective, multicenter, open-label, randomized, two-period (14 d per period), two-sequence, crossover, steady-state pharmacokinetic study comparing generic tacrolimus (Sandoz) vs. reference tacrolimus in stable renal transplant patients receiving their pre-study twice-daily dose. Pharmacokinetic parameters were compared in 68 patients according to gender, African American ethnicity, the presence or absence of diabetes, and use of steroids. The ratios of tacrolimus AUC0-12 h , Cmax , and C12 with generic vs. reference tacrolimus were calculated using the geometric mean (GM) of dose-normalized values at days 14 and 28. Mean (SD) tacrolimus dose at baseline was 5.7 (4.2) mg/d. There were no consistent differences in dose-normalized AUC0-12 h , C12 , Cmax, or tmax between the generic and reference preparations within subpopulations. The 90% confidence intervals (CI) for the ratios of dose-normalized AUC0-12 h and C12 with generic vs. reference tacrolimus were within 80-125% for all subpopulations, as were 90% CIs for Cmax other than for females, African Americans, and non-diabetics, which is not unexpected given the wide variability of tacrolimus Cmax and the small subpopulation sizes. These exploratory results suggest that this generic tacrolimus preparation would be expected to offer comparable bioavailability to the reference drug in these patient subpopulations.

A randomized pharmacokinetic study of generic tacrolimus versus reference tacrolimus in kidney transplant recipients.

Pharmacokinetic analyses comparing generic tacrolimus preparations versus the reference drug in kidney transplant patients are lacking. A prospective, multicenter, open-label, randomized, two-period (14 days per period), two-sequence, crossover and steady-state pharmacokinetic study was undertaken to compare twice-daily generic tacrolimus (Sandoz) versus reference tacrolimus (Prograf®) in stable renal transplant patients. AUC(0-12h) and peak concentration (C(max) ) were calculated from 12 h pharmacokinetic profiles at the end of each period (days 14 and 28). Of 71 patients enrolled, 68 provided evaluable pharmacokinetic data. The ratios of geometric means were 1.02 (90% CI 97-108%, p = 0.486) for AUC(0-12h) and 1.09 (90% CI 101-118%, p = 0.057) for C(max) . Mean (SD) C(0) was 7.3(1.8) ng/mL for generic tacrolimus versus 7.0(2.1) ng/mL for reference tacrolimus based on data from days 14 and 28. Correlations between 12 h trough levels and AUC were r = 0.917 for generic tacrolimus and r = 0.887 for reference drug at day 28. These data indicate that generic tacrolimus (Sandoz) has a similar pharmacokinetic profile to the reference drug and is bioequivalent in kidney transplant recipients according to US Food and Drug Administration and European Medicines Agency guidelines.