New data presented at the 16th Congress of the European Society for Organ Transplantation (ESOT) demonstrate that in liver transplant patients, initiating ADVAGRAF™ prolonged-release capsules (tacrolimus) therapy immediately post transplant, at a dose 25% lower than the upper recommended limit,(8) in combination with basiliximab, results in significantly better renal function and a lower incidence of acute organ rejection when compared with standard dose ADVAGRAF therapy.(9) Furthermore, delaying the introduction of ADVAGRAF post transplant gives no additional advantage in terms of renal function.(9)
In a separate study and the largest of its kind, MYCAMINE(™) (micafungin) was found to be non-inferior to standard of care in preventing fungal infections in liver transplant patients and showed similar safety outcomes.(10)
Results from the DIAMOND (ADVAGRAF studied In combinAtion with MycOphenolate mofetil aND basiliximab in liver transplantation) study show that an initial dose of prolonged-release tacrolimus (0.15-0.175mg/kg/day) plus MMF and induction therapy (without maintenance steroids) resulted in better renal function and a significantly lower incidence of acute rejection over 24 weeks compared to the other regimens; tacrolimus (initial dose: 0.2mg/kg/day) vs tacrolimus (0.2mg/kg/day delayed to day 5) plus basiliximab.(9)
“These data provide new insights and considerations for immunosuppressive treatment in the immediate post-operative period,” comments Dr. Ayad Abdulahad, Senior Vice President Medical Affairs and Health Economics, Astellas Pharma Europe Ltd. “Renal function is a vital predictor of long-term transplant success; the DIAMOND study suggests potential for balancing the risk of rejection, whilst minimising the risk of renal damage and potentially reducing the risk of long-term complications. This study shows that lower dose tacrolimus, given immediately post-transplantation, offers the potential advantages of an immunosuppressive regimen which minimises risk of graft rejection whilst preserving renal function without the need for maintenance steroids.”
Infections are one of the major complications after transplantation and the incidence of infections in liver transplant patients is higher compared with recipients of other organs.(4) Between 8.4% and 17.7% of liver transplant patients can be affected by fungal infections and these are associated with organ rejection, increased mortality and prolonged stay in the Intensive Care Unit.(4–7)
In the TENPIN (Liver Transplant EuropeaN Study Into the Prevention of Fungal INfection) study, the first randomised controlled trial of an echinocandin in this setting and the largest study of its kind, micafungin proved to be at least as effective as centre-specific standard of care (fluconazole, liposomal amphotericin B or caspofungin) in the prevention of invasive fungal infections in liver transplant patients. Current guidelines recommend either fluconazole or liposomal amphotericin B for prevention of invasive candidiasis in liver transplantation,(11) and either lipid formulations of amphotericin B or an echinocandin for prevention of invasive aspergillosis.(12) In addition, liver and renal safety of micafungin was also similar to study standard of care.(10)
The TENPIN study included more than 340 liver transplant patients at high-risk of fungal infection, who were randomised to micafungin 100mg (2mg/kg in patients ≤40kg) once daily (n=173) or centre-specific standard of care (fluconazole 200-400mg; liposomal amphotericin B 1-3mg/kg/day; or caspofungin 70mg loading, 50mg maintenance) once daily (n=172). At the end of treatment, 98.6% of patients on micafungin in the Per Protocol population (n=140) were free of invasive fungal infections and had no need for further antifungals compared to 99.3% for standard of care (n=137).(10)
“The low incidence of invasive fungal infections seen in this study clearly demonstrates the value of prophylactic antifungal treatment in high risk liver transplant patients,” comments Professor Saliba, Associate Professor in Hepatology and Gastroenterology, Hôpital Paul Brousse Villejuif, France. “With current guideline-recommended treatments having their limitations, with risk of both resistance and drug interactions, micafungin looks to be a welcome and much needed additional treatment option.”
- Cohen AJ, et al. Chronic Renal Dysfunction Late After Liver Transplantation. Liver Transpl. 2002 Vol 8, No 10 (October): pp 916-921.
- Fisher NC, et al. Chronic Renal Failure Following Liver Transplantation. Transplantation. 1998; 66:59-66.
- Ojo AO, et al. Chronic Renal Failure after Transplantation of a Nonrenal Organ. N Engl J Med. 2003; 349:931-40.
- Vera A, et al. Incidence and risk factors for infections after liver transplant: single-center experience at the University Hospital Fundación Santa Fe de Bogotá, Colombia. Transpl Infect Dis. 2011 Dec;13(6):608-15. doi: 10.1111/j.1399-3062.2011.00640.x.
- Zhou T, et al. Invasive fungal infection after liver transplantation: risk factors and significance of immune cell function monitoring. J Dig Dis. 2011 Dec;12(6):467-75. doi: 10.1111/j.1751-2980.2011.00542.x.
- Pacholczyk M, et al. Invasive fungal infections following liver transplantation – risk factors, incidence and outcome. Ann Transplant. 2011 Jul-Sep;16(3):14-6.
- Raghuram A, et al. Invasive fungal infections following liver transplantation: incidence, risk factors, survival, and impact of fluconazole-resistant Candida parapsilosis (2003-2007). Liver Transpl. 2012 Sep;18(9):1100-9. doi: 10.1002/lt.23467.
- European Public Assessment Report (EPAR). Advagraf. Available at http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/000712/WC500022235.pdf. Last accessed August 2013.
- Trunecka P et al. Preserving Renal Function with Prolonged-Release Tacrolimus-Baesd Immunosuppression in De Novo Liver Tranplantation: Initial Results from the DIAMOND Study. 16th Congress of the European Society for Organ Transplantation; Vienna, Austria, 8-11 September 2013. [Abstract No: LB02].
- Saliba F, et al. Micafungin as Antifungal Prophylaxis in High-Risk Liver Transplantation: Randomised Multicentre Trial. 16th Congress of the European Society for Organ Transplantation; Vienna, Austria, 8-11 September 2013. [Abstract No: P217].
- Pappas PG et al. Guidelines for Treatment of Candidiasis. Clin Infect Dis. 2004;38:161-89.