viral load, does it matter? probably so

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

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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 Presentation

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Page 1: Viral load, does it matter?  Probably so

Viral load, does it matter? Probably so.

Tim Pruett, MD

University of Virginia

Page 2: Viral load, does it matter?  Probably so

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?

Page 3: Viral load, does it matter?  Probably so

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

Page 4: Viral load, does it matter?  Probably so

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

Page 5: Viral load, does it matter?  Probably so

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

Page 6: Viral load, does it matter?  Probably so

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

Page 7: Viral load, does it matter?  Probably so

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.

Page 8: Viral load, does it matter?  Probably so

HBV and the liver transplant recipient

Page 9: Viral load, does it matter?  Probably so

Samuel, NEJM. 1993;329:1842

Page 10: Viral load, does it matter?  Probably so

Samuel, NEJM. 1993;329:1842

Page 11: Viral load, does it matter?  Probably so

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

Page 12: Viral load, does it matter?  Probably so

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.

Page 13: Viral load, does it matter?  Probably so

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

Page 14: Viral load, does it matter?  Probably so

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)

Page 15: Viral load, does it matter?  Probably so

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

Page 16: Viral load, does it matter?  Probably so

YMDD motif

Location of YMDD Motif in HBsAg Reading Frame

Page 17: Viral load, does it matter?  Probably so

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,”

Page 18: Viral load, does it matter?  Probably so

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

transplantation?