American Journal of Transplantation 2015; 15: 1135–1136 Wiley Periodicals Inc.
C
Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons doi: 10.1111/ajt.13170
Editorial
Can One Pill a Day Keep Rejection Away? S. K. Asrani and J. G. O’Leary* Baylor University Medical Center, Dallas, TX Corresponding author: Jacqueline G. O’Leary, [email protected]
Received 01 December 2014, accepted for publication 14 December 2014 Calcineurin inhibitors, namely tacrolimus, have been the backbone of immunosuppression after liver transplantation (LT) since their inception. In this issue of American Journal of Transplantation, Adam and colleagues examine the selfreported data to the European Liver Transplant Registry (ELTR) on 528 subjects receiving AdvagrafTM (Astellas Pharma, Europe Ltd, UK), an extended release formulation (tacrolimus QD), compared to 3829 subjects receiving immediate release tacrolimus (tacrolimus BID) at 21 European centers that all used both formulations from 2008–2012 (1). They show in multivariable analysis that the use of tacrolimus BID was associated with a higher risk of graft loss (risk ratio ¼ 1.81, p ¼ 0.001) and patient death (risk ratio ¼ 1.72, p ¼ 0.004) than tacrolimus QD. Several observations are worth noting. Data reported to ELTR are collected on a voluntary basis, and despite built-in checks and balances may be fallible to reporting bias. Subjects were not randomized to receive tacrolimus QD versus BID, and therefore may not be comparable. In fact, subjects receiving tacrolimus QD were older, more likely to have hepatocellular carcinoma and less likely to have hepatitis delta, had lower serum creatinine levels, and received younger donors. In addition, subjects receiving tacrolimus QD were more likely to have received mycophenolate mofetil (94% vs. 66%) and less likely to have received steroid induction (58% vs. 95%). In an effort to control for these differences, propensity score matching was undertaken; however, inherent differences, such as socioeconomic differences that were unable to be assessed, may have remained, and 49% of subjects that received tacrolimus QD were ultimately unmatched. It is also possible that certain subsets of patients were never considered for tacrolimus QD (e.g. younger patients with autoimmune disease or those with higher MELD scores). Alternatively, though tacrolimus BID was associated with significantly higher graft failure, it may instead be a surrogate for sicker patients assigned to receive ‘‘traditional’’ tacrolimus dosing. However, bacterial infection resulting in patient mortality
was higher among those receiving tacrolimus QD; a similar theme of numerically higher infection-related mortality was noted in the registration trial, although the distribution of infections was similar (2). Although Adams et al do not explain the mechanism for improved survival, lower tacrolimus levels early after transplant, lower peak concentrations, and reduced interand intra-patient variability have been consistent findings in other studies associated with improved patient outcomes with tacrolimus QD. Notably, despite documented lower tacrolimus concentrations in the first 4 days post-operatively with QD versus BID dosing, rejection rates are similar. Other interesting findings from additional studies with tacrolimus QD include improved long-term renal function, and possibly even lower rejection rates after late conversion (median time 37 months) (3). There is, however, a learning curve in administering tacrolimus QD; one must temper the urge to over immunosuppress. Peak concentrations with tacrolimus QD are achieved after 2 h and oral bioavailability is affected by meals. The long half-life of tacrolimus QD and time to reach steady-state (3–5 days per package insert but may be longer per recent reports) likely is integral to improving renal function when used de novo after LT. In addition, differences in dosing needed in a de novo setting versus late conversion need further investigation (3). Ultimately, Adams et al highlight a universal theme in medicine: simplified dosing regimens improve outcomes. Non-adherence to medications after LT is common (15– 50%) and associated with untoward outcomes such as de novo DSA formation, acute and chronic rejection, and graft dysfunction and loss (4). A higher pill burden in addition to inconvenient dosing are both important contributors to nonadherence. Simplified regimens, such as single tablet formulations (STF), have successfully revolutionized the delivery of HIV medications; patients report improvements in simplicity, convenience, and tolerability. STF regimens in HIV have documented higher rates of compliance, lower rates of resistance, lower rates of discontinuation, and resulted in fewer hospital admissions (5). Similar benefits are anticipated with the approval of the first STF for another viral disease, hepatitis C, which is associated with unprecedented cure rates. Given the positive impact of STF in complementary patient populations, trials to achieve these important advances 1135
Asrani and O’Leary
require strong advocacy to raise money and awareness, the FDAs support for non-inferiority trials and fast-tracking, the acceptance of short-term outcomes as trial endpoints (viremia and viral resistance have been used in viral diseases but renal function, compliance, and alloimmune biomarkers such as de novo DSA formation need to be considered in transplantation), and the incorporation of patient preference in trial design of simplified regimens. Both HIV and HCV treatment began after the advent of LT, yet in LT we still have individually formulated inconveniently dosed medications that have, until recently, not been simplified and never co-formulated. Can one pill a day keep rejection away for all solid organ transplant recipients? Yes, it can and it must! For some transplant patients, tacrolimus QD is that single tablet. But only through collaboration between investigators, pharmaceutical companies, the FDA and patients can we achieve the next level of patient compliance and outcomes for all transplant patients that are already enjoyed in HIV and HCV.
Disclosure The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of
1136
Transplantation. JGO has received honoraria from Novartis, Astellas, and Gilead.
References 1. Adam R, Karam V, Delvart V, et al. Improved survival in liver transplant recipients receiving prolonged-release tacrolimus in the European Liver Transplant Registry. Am J Transplant 2015; doi: 10.1111/ajt.13171. 2. Trune cka P, Boillot O, Seehofer D, et al. Once-daily prolongedrelease tacrolimus (ADVAGRAF) versus twice-daily tacrolimus (PROGRAF) in liver transplantation. Am J Transplant 2010; 10: 2313–2323. 3. Considine A, Tredger JM, Heneghan M, et al. Performance of modified-release tacrolimus after conversion in liver transplant patients indicates potential favourable outcomes in selected cohorts. Liver Transpl 2014; 21: 29–37. 4. Serper M, Patzer RE, Reese PP, et al. Medication misuse, nonadherence, and clinical outcomes among liver transplant recipients. Liver Transpl 2014; 21: 22–28. 5. Thompson MA, Mugavero MJ, Amico KR, et al. Guidelines for improving entry into and retention in care and antiretroviral adherence for persons with HIV: Evidence-based recommendations from an International Association of Physicians in AIDS Care panel. Ann Intern Med 2012; 156: 817–833.
American Journal of Transplantation 2015; 15: 1135–1136
Copyright of American Journal of Transplantation is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
C
Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons doi: 10.1111/ajt.13170
Editorial
Can One Pill a Day Keep Rejection Away? S. K. Asrani and J. G. O’Leary* Baylor University Medical Center, Dallas, TX Corresponding author: Jacqueline G. O’Leary, [email protected]
Received 01 December 2014, accepted for publication 14 December 2014 Calcineurin inhibitors, namely tacrolimus, have been the backbone of immunosuppression after liver transplantation (LT) since their inception. In this issue of American Journal of Transplantation, Adam and colleagues examine the selfreported data to the European Liver Transplant Registry (ELTR) on 528 subjects receiving AdvagrafTM (Astellas Pharma, Europe Ltd, UK), an extended release formulation (tacrolimus QD), compared to 3829 subjects receiving immediate release tacrolimus (tacrolimus BID) at 21 European centers that all used both formulations from 2008–2012 (1). They show in multivariable analysis that the use of tacrolimus BID was associated with a higher risk of graft loss (risk ratio ¼ 1.81, p ¼ 0.001) and patient death (risk ratio ¼ 1.72, p ¼ 0.004) than tacrolimus QD. Several observations are worth noting. Data reported to ELTR are collected on a voluntary basis, and despite built-in checks and balances may be fallible to reporting bias. Subjects were not randomized to receive tacrolimus QD versus BID, and therefore may not be comparable. In fact, subjects receiving tacrolimus QD were older, more likely to have hepatocellular carcinoma and less likely to have hepatitis delta, had lower serum creatinine levels, and received younger donors. In addition, subjects receiving tacrolimus QD were more likely to have received mycophenolate mofetil (94% vs. 66%) and less likely to have received steroid induction (58% vs. 95%). In an effort to control for these differences, propensity score matching was undertaken; however, inherent differences, such as socioeconomic differences that were unable to be assessed, may have remained, and 49% of subjects that received tacrolimus QD were ultimately unmatched. It is also possible that certain subsets of patients were never considered for tacrolimus QD (e.g. younger patients with autoimmune disease or those with higher MELD scores). Alternatively, though tacrolimus BID was associated with significantly higher graft failure, it may instead be a surrogate for sicker patients assigned to receive ‘‘traditional’’ tacrolimus dosing. However, bacterial infection resulting in patient mortality
was higher among those receiving tacrolimus QD; a similar theme of numerically higher infection-related mortality was noted in the registration trial, although the distribution of infections was similar (2). Although Adams et al do not explain the mechanism for improved survival, lower tacrolimus levels early after transplant, lower peak concentrations, and reduced interand intra-patient variability have been consistent findings in other studies associated with improved patient outcomes with tacrolimus QD. Notably, despite documented lower tacrolimus concentrations in the first 4 days post-operatively with QD versus BID dosing, rejection rates are similar. Other interesting findings from additional studies with tacrolimus QD include improved long-term renal function, and possibly even lower rejection rates after late conversion (median time 37 months) (3). There is, however, a learning curve in administering tacrolimus QD; one must temper the urge to over immunosuppress. Peak concentrations with tacrolimus QD are achieved after 2 h and oral bioavailability is affected by meals. The long half-life of tacrolimus QD and time to reach steady-state (3–5 days per package insert but may be longer per recent reports) likely is integral to improving renal function when used de novo after LT. In addition, differences in dosing needed in a de novo setting versus late conversion need further investigation (3). Ultimately, Adams et al highlight a universal theme in medicine: simplified dosing regimens improve outcomes. Non-adherence to medications after LT is common (15– 50%) and associated with untoward outcomes such as de novo DSA formation, acute and chronic rejection, and graft dysfunction and loss (4). A higher pill burden in addition to inconvenient dosing are both important contributors to nonadherence. Simplified regimens, such as single tablet formulations (STF), have successfully revolutionized the delivery of HIV medications; patients report improvements in simplicity, convenience, and tolerability. STF regimens in HIV have documented higher rates of compliance, lower rates of resistance, lower rates of discontinuation, and resulted in fewer hospital admissions (5). Similar benefits are anticipated with the approval of the first STF for another viral disease, hepatitis C, which is associated with unprecedented cure rates. Given the positive impact of STF in complementary patient populations, trials to achieve these important advances 1135
Asrani and O’Leary
require strong advocacy to raise money and awareness, the FDAs support for non-inferiority trials and fast-tracking, the acceptance of short-term outcomes as trial endpoints (viremia and viral resistance have been used in viral diseases but renal function, compliance, and alloimmune biomarkers such as de novo DSA formation need to be considered in transplantation), and the incorporation of patient preference in trial design of simplified regimens. Both HIV and HCV treatment began after the advent of LT, yet in LT we still have individually formulated inconveniently dosed medications that have, until recently, not been simplified and never co-formulated. Can one pill a day keep rejection away for all solid organ transplant recipients? Yes, it can and it must! For some transplant patients, tacrolimus QD is that single tablet. But only through collaboration between investigators, pharmaceutical companies, the FDA and patients can we achieve the next level of patient compliance and outcomes for all transplant patients that are already enjoyed in HIV and HCV.
Disclosure The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of
1136
Transplantation. JGO has received honoraria from Novartis, Astellas, and Gilead.
References 1. Adam R, Karam V, Delvart V, et al. Improved survival in liver transplant recipients receiving prolonged-release tacrolimus in the European Liver Transplant Registry. Am J Transplant 2015; doi: 10.1111/ajt.13171. 2. Trune cka P, Boillot O, Seehofer D, et al. Once-daily prolongedrelease tacrolimus (ADVAGRAF) versus twice-daily tacrolimus (PROGRAF) in liver transplantation. Am J Transplant 2010; 10: 2313–2323. 3. Considine A, Tredger JM, Heneghan M, et al. Performance of modified-release tacrolimus after conversion in liver transplant patients indicates potential favourable outcomes in selected cohorts. Liver Transpl 2014; 21: 29–37. 4. Serper M, Patzer RE, Reese PP, et al. Medication misuse, nonadherence, and clinical outcomes among liver transplant recipients. Liver Transpl 2014; 21: 22–28. 5. Thompson MA, Mugavero MJ, Amico KR, et al. Guidelines for improving entry into and retention in care and antiretroviral adherence for persons with HIV: Evidence-based recommendations from an International Association of Physicians in AIDS Care panel. Ann Intern Med 2012; 156: 817–833.
American Journal of Transplantation 2015; 15: 1135–1136
Copyright of American Journal of Transplantation is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
