Recurrent HCV Following Liver Transplantation

Transcription

1 Recurrent HCV Following Liver Transplantation Russell H. Wiesner, MD Professor of Medicine Mayo Clinic College of Medicine Rochester, MN, USA ILTS Western/Eastern Perspective Hong Kong, CHINA April 5-6, 2008

2 Conflict of Interest Novartis Roche Wyeth Astellas Advisor Investigator

3 Recurrence of Hepatitis C Virus Infection After Orthotopic Liver Transplantation Paul Martin, Santiago J. Munoz, Adrian M. Di Bisceglie, Raphael Rubin, Jeanne G. Waggoner, Vincent T. Armenti, Michael J. Moritz, Bruce E. Jarrell, and Willis C. Maddrey The results suggest that hepatitis C recurs in a minority of transplant recipients and, only in a few, is this a clinically significant problem. Hepatology 1991;13:719.

4 Recurrent Hepatitis C Universal reinfection RNA levels several logs higher 60-70% histologic recurrence at 1 year Cirrhosis 25% at five years Retransplant - poor results

5 HCV Transplant Prevalence % st OLT Re OLT

6 Future Burden of Hepatitis C % Increase Decomp Liver Disease Demand for OLT HCV deaths

7 Allograft HCV Reinfection: Patterns of Recurrence and Outcome Direct cytopathic effect FCH 2-6% 99% 25-45% 50-98% 8-44% 42% HCV acute chronic graft cirrhosis decompensated RNA+ hepatitis hepatitis in 5-7 years 1 year

8 Fibrosis Progression Adapted from Gane et al, Phoenix ILTS 2002

9 Cumulative Probability of Developing HCV-Graft Cirrhosis Adapted from Gane et al, Phoenix ILTS 2002

10 Patient Survival in HCV (n=4,722) and Non-HCV Infected LT Recipients (n=6,836)

11 Natural History of HCV: Effects of Immunosuppression Immune Competant Post Transplant Fibrosis Progression 0.2 / yr 0.4 / yr Median Time to Cirrhosis years years Decompensation after cirrhosis 20% in 10 yrs 50% in 1 yr Survival after Decompensation 50% in 5 yrs 41% in 1 yr

12 Factors Associated with Severe Recurrence Recipient Factors Donor Factors Age Donor age* Male gender Living donor* Ethnicity Ischemic time?* Virologic Factors Pretransplant viral load* Genotype 1? Post Transplant Factors Rejection Bolus Steroid* Immunosuppression* Antilymphocyte therapy* CMV infection*

13 Recipient and Viral Factors

14 Pre-OLT characteristics associated with increased mortality and graft loss in HCV-infected recipients Characteristic Patient survival Graft survival RR 95% CI p RR 95% CI p HCV RNA 1x10 6 veq/ml Non-Caucasian recipient Recipient age (per year) Recip pre-lt Pugh score >

15 Donor Factors

16 Development of HCV-related graft cirrhosis (fibrosis 4): effect of donor age % with graft cirrhosis % Berenguer et al, Hepatology % < > 60 Years 52%

17 Living Donor Liver Transplant in HCV

18 Graft Survival After DDLT (dotted line) and LDLT Terrault NA, et al. Liver Transplantation 2007;13:

19 Fibrosis in HCV Recipients of LDLT and DDLT DDLT LDLT Portal Fibrosis 60 Bridging Fibrosi MONTHS Shiffman, Liver Transpl 2004

20 Post-Transplant Factors

21 OPTIMAL IMMUNOSUPPRESSION Side Effects, aggressive disease recurrence Over Optimal Under Rejection

22 HCV Recurrence (%) Rejection and Histologic Recurrence of HCV Disease Sheiner et al: Hepatology 1995;21: None 1 >1 SRR

23 Effect of High-Dose Steroids for Rejection on HCV RNA Levels HCV RNA (x10 6 Eq/mL Pre Post Pre Post Gane et al. Gastroenterology 1991; 110:167 Treated Not Treated

24 Impact of IV Corticosteroid Therapy fo Acute Rejection in HCV Recipients 4- to 100-fold increase HCV RNA levels Increased frequency of acute hepatitis C recurrence Decreased time to recurrent hepatitis C Increased histologic severity of recurrent hepatitis C associated with high HCV RNA levels

25 Factors Associated with the Development o Graft Cirrhosis in HCV Recipients Without Cirrhosis cirrhosis Acute rejection (%) <0.02 OKT3 (%) 17 4 <0.05 Severe rejection (%) 25 1 <0.009 Rejections (no.) <0.001 Steroid boluses (no.) <0.03 P Prieto et al: Hepatology 29:250, 1999

26 Graft Survival in HCV(+) Recipients No Acute Rejection Percentage of Patients Acute Rejection p = % 75.8% N No AR AR Years Post-Transplantation

27 Impact of CMV Infection in HCV Liver Transplant Recipients CMV+ CMVn=26 n=68 Graft failure (%) Fibrosis stage (1 year) % AR (%) OKT3 (%) 4 3 Burak et al: Hepatology 34:408A, 2000

28 Timing for Potential Interventions for Prevention and Treatment of Recurrent Hepatitis C Before OLT Immunologic Prophylactic Preemptive Recurrent ReTrx Transplant Management Disease

29 Pretransplant Treatment for HCV Patients with mild- moderate decompensated cirrhosis Mean MELD 18, CPT class A 45% STD interferon / RBV (accelerating dose) EOT 39% SVR 24%; G 2,3 60%; G1 7% AEs leading to discontinuation - 20% Overall interferon tolerated poorly With SVR No recurrence after transplantation Everson, et al

30 Pretransplant Treatment of HCV Patients with Childs B and C cirrhosis 20 SAEs in 15 patients 2/15 died of serious infection Study stopped Crippin, et al

31 Conclusion In select patients with pretransplant HCV 1) Only patients with mild decompensation should be treated, particularly those with Genotype 2, 3, Child s A 2) Goals should be HCV/RNA negativity at transplant to prevent recurrence of disease.

32 Immunosuppression and HCV Recurrence 1) Calcineurin inhibitors no difference 2) Triple drug with Tacro/MMF rejection 3) Antilymphocyte induction / rejection. Campath bad 4) Steroid-free - no effect. Taper steroids slowly 5) Cyclosporin? Better response to interferon therapy 6) Avoid treating Grade 1 rejection with bolus steroids 7) Early recurrence of HCV in Twins without immunosuppression 8) CMV prophylaxis

33 True Prophylaxis - Passive Immunit Goal Prevent Reinfection

34 Representative Posttransplant HCV 10 9 anhepatic Kinetics HCV RNA (IU/ml) reperfusion hours month

35 Early Posttransplant Immunoprophylaxis with Hepatitis C Immunoglobulin HCV - RNA (U / ml) Placebo Low-dose HCIG High-dose HCIG Weeks after transplantation Jessner et,al., Journal of Hepatology, 2002; 36:32A

36 XLT - Monoclonal anti-hcv Phase 1A: 15 patients, single IV infusion doses: 0.25, 1, 2.5, 10, and 40 mg Significant HCV viral load reductions in 8 our of 15 patients following a single dose of HCV-AB 68. Reductions, though transient, ranged between 2 to 100 fold. 3/8 reduction in HCV 1 log

37 Pre-emptive Antiviral Therapy Institute therapy 1-6 months after transplant before clinical or histologic evidence of recurrent disease

38 Results of Preemptive Therapy Not applicable to all patients SVR 9-18% Dose reductions 75-85% Discontinued therapy 30-40% SAE 30% (growth factors) Acute rejection 33-40% Not prevent recurrent disease or fibrosis progression

39 Treatment of Established Recurrent HCV Disease

40 Challenges with Treatment of Recurrent HCV in LT Recipients High prevalence of HCV genotype 1 HCV RNA levels tend to high Most are previous nonresponders to IFN Insulin resistance more frequent Associated with lower rates of response to peg-ifn + ribavirin in non-lt patients IMS limits antiviral efficacy Limit tolerability of peg-ifn and Ribavirin (due to reduced CrCl and BM suppressive effects Risk of precipitating acute or chronic rejection Additional limitations in LT patients

41 Antiviral Therapy in Liver Transplant Setting High prevalence of HCV genotype 1 Inability to tolerate full dose IFN/ribavirin Previous non-response to IFN Reduced sensitivity to IFN?

42 Post-Transplant Antiviral Therapy for Recurrent HCV Disease Meta Analysis ETR SVR Hx Improvement Therapy Reduction Therapy D/C 0 IFN + R Peg-IFN Peg-IFN + R

43 SVR Rates with Peg-IFN + Ribavirin Liver Transplant Recipients in Recent Cohorts SVR SVR G1 % SVR * * * % 0 Berenguer n=36 Oton n=53 Sharma n=35 Honouneh n=53 Castells n=24 Carrion n-54 Angelico n=21 * Includes only reports with 20 patients, treatment duration 48 wks with Peg-IFN and ribaviri

44 Impact of SVR on Patient Survival Picciotto FP, et al. J Hepatology 2007;46:

45 Delayed Histologic Effects Associated with SVR Pre 1-Yr 3-Yr 5-Yr N=28 0 Fibrosis Necroinflammation Bahra, Transplantation 2007

46 Does Interferon / Ribavirin Therapy have Histologic Impact on Non Responders?

47 Decrease in Fibrosis Progression Rate Units/Year 2 5-year follow-up 1.5 p = Treated Patients Untreated Patients Veldt BJ, et al. Hepatology 2008

48 Impact of Treatment on Survival in Treated vs Non treated HCV Recurrent Disease Treated Graft survival (%) year survival: Treated: 92.5% (CI ) Untreated 66.1% (CI ) Log rank p = Untreated Time (years after HCV recurrence) At risk: Treated: Events: Veldt et al, Hepatology, in press Untreated: Events:

49 Antiviral Therapy for Recurrent HCV SVR rates low Summary 23-33% for genotype 1; >50% for genotype 2/3 Dose reductions reduce SVR rates significantly Histologic benefits apparent in those with SVR Stabilization or improved fibrosis scores in majority, but effects can be delayed Prolongs survival Histologic benefits in virologic non-responders with biochemical response? If treatment in absence of SVR confers survival and histologic benefit

50 Tolerability and Safety of Peginterferon + Ribavirin Dose Reductions Peg-INF: 40-60% Ribavirin: 50-90% Drug discontinuation Peg-IFN: 10-15% Ribavirin: 20-25% (more in early post-lt period) Risk of Rejection No difference in controlled trials, but uncontrolled studies range 0-33%

51 Questions Remaining Optimal time to start therapy? Optimal dose? Optimal duration of therapy? How to best monitor therapy? 20% of those with SVR fibrosis progression to cirrhosis Why?

52 Retransplantation for Recurrent HCV Disease Outcome in patients with recurrent HCV with comparable severity of disease is not worse than non-hcv patient Timing and severity of recurrence HCV after transplant is not predictive of timing and severity of recurrence after retransplant Because of rapid decompensation of patients with recurrent HCV, the window of opportunity for retransplant is narrow. High MELD score is predictive for poor survival in patients retransplanted for recurrent HCV disease

53 Summary 1) The natural history of hepatitis C is more aggressive in transplant recipients 2) Pre-transplantation and preemptive post-transplant therapies are limited by low applicability and tolerability. 3) Posttransplant treatment is recommended for those with acute early recurrence and those with chronic progressive histologic disease. 4) Combination therapy with PEG-Inf/RBV is superior to monotherapy. 5) Improved therapy is needed and the impact of protease and polymerase inhibitors is eagerly awaited.

54 Management to Minimize Recurrence of HCV 1) Try to make RNA negative at time of transplant 2) Try to avoid donor greater than 50 years old 3) Avoid T-cell depleting regimens 4) Minimize calcineurin inhibitor dosing

55 Immunosuppressive Approach Triple drug with MMF to reduce incidence of rejection Avoid treating Grade 1 rejection with bolus steroid Avoid antilymphocyte therapy for rejection if possible CMV prophylaxis Taper steroid slowly

56 Maximize Treatment of Recurrent HCV 1) Avoid prophylaxis and preemptive interferon therapy side effects 2) Time of treatment = F(o) F(2) {less response with advanced disease} 3) Better response on cyclosporine therapy 4) Modify based on treatment factors PEG-INF and Ribavirin dose Utilize on treatment response to adjust duration of treatment Try to avoid dose reductions Dose Ribavirin based on renal function