HCV 3 Trial: Recurrent Hepatitis Histologic Grade on Day 90 Biopsy Predicts Subsequent HCV Stage at One and Two Years Post Transplantation
GJ Netto, GB Klintmalm, CG Fasola, L Jennings, The HCV 3 Group. Johns Hopkins, Baltimore; Baylor University Med Ctr, Dallas
Background: HCV induced cirrhosis is a main indication for liver transplantation (OLT) in the U.S. Graft survival in HCV patients has not improved in the past decade due to progressive disease recurrence . Better immunosuppressive (IS) regimens could delay progression of recurrent HCV and improve outcome.
Design: The HCV3 randomized prospective multicenter trial compared safety and efficacy of 3 IS regimens in 312 HCV-positive OLT recipients. Arm 1 received tacrolimus (Tac) plus corticosteroids (n=60); arm 2, mycophenolate mofetil (MMF), Tac, and corticosteroids (n=79); and arm 3, MMF, Tac, and daclizumab(n=153). Pts were followed for 2 years. Per protocol, liver biopsies were performed at days 90, 365 and 730. ACR was graded according to Banff schema and HCV recurrence according to Batts and Ludwig classification. All biopsies were reviewed by a central hepatopathologist. Primary endpoints were ACR (grade =>2 + rejection activity index => 4) and, HCV recurrence (stage => 2 at day 365, stage => 3 at day 730 or grade 3 at anytime).
Results: At 2 years F/U, no significant difference in pts survival, graft survival, serum HCV-RNA, incidence of adverse events or ACR was seen among the three arms. The same was true for overall incidence of HCV recurrence as defined by primary end point criteria. Among pts who remained HCV stage =<2 during first year, statistically significant increase in rate of HCV progression to stage 3 or more was seen in arms 1 & 2 (steroid exposure) compared to steroid free arm 3 pts. In patients with HCV stage =<2 during 1st year, freedom from stage 3 or more HCV recurrence at 2 year was: 75%, 85% and 93% respectively (p<0.01). The difference remained significant when grouping Arm 1 + 2 (steroid) vs. 3 (no -steroids): 80% vs. 93% (p=0.01) and Arm 1 (no-MMF) vs. 2 + 3 (MMF): 75% vs. 90% (p<0.01). Furthermore, grade 2-4 histologic grade of HCV recurrence at day-90 biopsy was a strong and significant predictor of stage 3-4 HCV recurrence both at one year (43% vs 11%; p<0.0001) and two year follow up (36% vs 20%; p<0.005) biopsies.
Conclusions: The choice of immunosuppression may affect the development of advanced fibrosis resulting from recurrent HCV. Steroid-free IS (arm 3) is safe and effective and showed a significant advantage in freedom from stage 3 or more post OLT HCV recurrence. Presence of grade 2-4 recurrent HCV in day 90 biopsy predicted subsequent higher stage HCV recurrence at 1 and 2 years post OLT.
Category: Liver & Pancreas
Monday, March 22, 2010 2:00 PM
Platform Session: Section D, Monday Afternoon