Viral load, does it matter? Probably so.

1. Viral load, does it matter? Probably so. Tim Pruett, MD University of Virginia

2. The problem of viral load/activity • An important predictor of transplant outcomes in patients with HBV and HCV • HIV is an unknown, should we be mixing groups? • What is the effect of immunosuppression upon “unchecked” HIV replication and it’s consequences? • What is the effect of transplantation upon HAART and it’s benefits?

3. HIV Viral Load After Liver Transplantation

4. HIV Viral Load After Liver Transplantation

5. Nelfinavir Peak Serum ConcentrationsFollowing Liver Transplant

6. Association of Tacrolimus Dose and Resulting Serum Trough Concentration

7. Conclusion • Don’t mix the protocol questions. If one wants to see if well-controlled HIV infected individuals can be safely transplanted, do that study. • The variables of substantial increases in viral load, unpredictable bioavailability of antiviral agents, possibility of not having a functioning GI tract, makes the use of the “uncontrolled” HIV population a different study from the initial proposal.

8. HBV and the liver transplant recipient

9. Samuel, NEJM. 1993;329:1842

10. Samuel, NEJM. 1993;329:1842

11. Current approach to the HBV infected patient for OLT • Lamivudine therapy to reduce HBV replication and diminish the number of circulating virions • Passive immunization with anti-HBs to remove HBsAg (and virions) from the serum

12. The problem of HBV and HIV • The rate of HBV lamivudine resistance in the HIV+ individual will be high. Benhamou, Hepatology 1999; 30:1302. Many individuals will be HBV-DNA+ in the serum. • The efficacy of HBV immunoglobulin (liver) is unknown. Other antivirals (adefovir) may not be available with significant renal dysfunction.

13. ENVELOPE PROTEIN loss of antibody-antigen interaction first identified in neonatal vaccinees mutation in “a” loci of S protein noted in patients with late allograft infection POLYMERASE changes in polymerase sequences at the catalytic site lead to lack of efficacy (YMDD mutation) typical HBV change associated with lamivudine failure Mutations to HBV therapies in OLT

14. Outcome of OLTx for HBV CirrhosisUniversity of Virginia HBeAg+ (N=23/25) All Patients (N=34/39) HBeAg- (N=11/14) HBeAg+ (N=9/26) All Patients (N=9/40) HBeAg- (N=0/14)

15. ENVELOPE PROTEIN loss of antibody-antigen interaction first identified in neonatal vaccinees mutation in “a” loci of S protein noted in patients with late allograft infection POLYMERASE valine or isoleucine for methionine of the catalytic site (C domain) lead to lack of inhibition (YMDD mutation) typical HBV change associated with lamivudine failure Mutations to HBV therapies in OLT

16. YMDD motif Location of YMDD Motif in HBsAg Reading Frame

17. HBsAg and polymerase gene variants Locarnini Hepatology 27:294, 1998 • Both lamivudine and famciclovir therapy associated with polymerase gene mutations which would alter HBsAg in the major hydrophilic region-suggesting the possible change in “a” antigenicity • use of these agents could result in “the possible generation of the equivalent of vaccine escape mutations, as a consequence of antiviral nucleoside analog therapy,”

18. Will the routine use of antiviral agents pre-liver transplant change the efficacy of HBV control after transplantation?