viral load, does it matter? probably so
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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? - PowerPoint PPT PresentationTRANSCRIPT
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
0
100000
200000
300000
400000
500000
600000
700000
800000
0 50 100 150 200 250 300
Post Operative Day
HIV
Vir
al L
oad
HAART Restarted
Viral Load Undetectable
HIV Viral Load After Liver Transplantation
0
25000
50000
75000
100000
-10 10 30 50 70 90 110 130 150
Post Operative Day
HIV
Vir
al L
oad HAART Restarted
Viral Load Undetectable
Nelfinavir Peak Serum ConcentrationsFollowing Liver Transplant
0
1
2
3
4
5
0 20 40 60 80 100 120
Days Post Liver Transplant
Nel
fina
vir
Con
cent
rati
on
(mcg
/ml)
Suggested Peak Concentration
HAART Restarted
Association of Tacrolimus Dose and Resulting Serum Trough Concentration
0
5
10
15
20
25
30
0 20 40 60 80 100 120Post Operative Day
Dai
ly T
acro
limus
Dos
e (m
g)
Total Daily FK Dose Trough Concentration
Tro
ugh
Con
cent
rati
on (
mcg
/ml)
HAART Restarted
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
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 CirrhosisUniversity of Virginia
0
20
40
60
80
100
0 10 20 30 40 50 60 70Months Post Transplant
Pat
ien
t O
utc
ome
(%)
Allograft Infection
Survival
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?