A clinical research consortium sponsored by NIAID
Shaked A, Feng S, Punch J, Reyes J, Zimmerman M, Kopetskie H, DesMarais M, Sayre P, Levitsky J, Klintmalm G, DePaulis M, Bridges N
University of Pennsylvania, Philadelphia, PA, University of California, San Francisco, San Francisco, CA, University of Michigan, Ann Arbor, MI, University of Washington, Seattle, WA, Northwestern University, Chicago, IL, Baylor, Dallas, TX, University of Colorado, Denver, CO, Rho Federal Systems Division, Chapel Hill, NC, NIAID, Bethesda, MD
ABSTRACT
This prospective study examines ISW feasibility in recipients with hepatitis C (HCV) or nonimmune nonviral (NINV) etiologies. Eligible subjects are randomized (4:1) to undergo ISW 1-2 years after transplantation.
258 (129 HCV) have been enrolled. 65 (9 HCV) have not yet been randomized. 126 (87 HCV) were terminated before randomization. The most common reasons were voluntary withdrawal (39%) in the NINV stratum, or related to HCV activity (37%) in the HCV stratum. (Table 1)
| HCV (n=87) | NINV (n=39) | |
| Voluntary Termination | 10 | 15 |
| Death | 8 | 3 |
| Ineligible for Randomization | 13 | 3 |
| HCV Related | 32 | - |
| Adverse Event | 8 | 5 |
| Other | 16 | 13 |
67 (33 HCV) met randomization criteria including: stable IS monotherapy, acceptable liver function, no evidence of rejection on pre-randomization biopsy and Ishak score ≤2 (HCV). Mean (SD) months from transplant to IS monotherapy were 6.8 (3.9) in the HCV and 7.7 (4.1) in the NINV stratum. 53 were assigned to ISW, 14 to maintenance. At randomization, the mean baseline total daily tacrolimus dose was 4.3 (1.6) mg with a mean trough of 7.1 (3.1) ng/mL. Minimization resulted in successful ISW in 2 and failure in 16. 35 are ongoing. Mild biopsy-proven rejection occurred in 10; moderate in 1; 3 of these required steroid bolus.
Of 36 evaluable subjects who were reduced to 50% of baseline IS (QD dosing), 28 (78%) were successful. In contrast, of 22 who were reduced to 25% (QOD dosing), only 8 (36%) were successful. (Table 2)
| % Baseline IS | HCV | NINV |
| 100 | 22/24 (92%) | 22/23 (96%) |
| 75 | 20/20 (100%) | 20/20 (100%) |
| 50 | 14/18 (78%) | 14/18 (78%) |
| 25 | 5/11 (45%) | 3/11 (27%) |
Monotherapy, once a day dosing and significant minimization without compromise of allograft function are achievable in HCV and NINV recipients early after transplant. However, IS reduction to 25% of baseline was successful only in a small percentage. Disease recurrence limits this approach in HCV patients. In most cases rejection can be reversed by adjustment in IS monotherapy without compromising allograft function.
