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

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?

HIV Viral Load After Liver Transplantation

Nelfinavir Peak Serum Concentrations Following Liver Transplant

Association of Tacrolimus Dose and Resulting Serum Trough Concentration

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.

HBV and the liver transplant recipient

Samuel, NEJM. 1993;329:1842

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

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.

Mutations to HBV therapies in OLT 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

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

Mutations to HBV therapies in OLT 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

YMDD motif Location of YMDD Motif in HBsAg Reading Frame

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,”

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