1. Hepatitis B virus infection in renal transplant recipients
Mini-topic
Hepatitis B virus infection in renal transplant recipients
박원영

2. Introduction
HBV infection is a major risk factor for hepatic dysfunction after renal transplantation
because of the requirement for immunosuppressive therapies
the incidence of HBV infection among dialysis patients
but, the prevalence is still high in endemic areas

3. Epidemiology & Risk factors
Incidence and prevalence 
In endemic areas, HBsAg positive patients undergoing kidney transplantation : 15%
much lower in areas in which HBV is less common.
the prevalence in most countries
< HBV vaccination programs in the general and dialysis patient population
< strict precautions to prevent transmission of HBV infection in dialysis units

4. Epidemiology & Risk factors
Risk factors for reactivation of HBV replication
Reactivation of HBV replication among HBsAg positive patients
: 1) the appearance of HBV DNA in a patient who has had undetectable HBV DNA
previously
2) >1 to 2 log increase in HBV DNA.
Reactivation among HBsAg negative, anti-HBc positive patients
: 1) the reappearance of HBsAg or HBV DNA
2) an increase in HBV DNA in those with detectable HBV DNA prior to start of
immunosuppressive therapy
The risk of reactivation of HBV replication following transplantation
: the status of serologic & virologic markers at the time of kidney transplantation : HBsAg positive > HBsAg negative, anti-HBc positive
: among HBsAg positive, HBeAg positive or high levels of HBV DNA : higher
: HBeAg negative, undetectable serum HBV DNA prior to transplant
HBsAg negative but anti-HBc positive

5. Epidemiology & Risk factors
Risk factors for liver failure among infected patients
1) Immunosuppression can accelerate progression of HBV-related liver disease.
2) Hepatitis associated with HBV reactivation can lead to liver failure
3) the risk is higher in patients with cirrhosis.
Among HBsAg positive patients, a liver biopsy, performed prior to and, if indicated, after renal transplant, can help determine the stage of liver disease and assess the risk of liver failure.
administration of prophylactic or pre-emptive antiviral therapy
> incidence of liver failure
Risk factors for de novo HBV infection following transplantation
may occur through receipt of a kidney from an infected donor
Matching the serologic and virologic status of the donor and the potential kidney recipient
The kidney from an HBsAg-positive donor must not be transplanted into an HBsAg-negative and anti-HBs-negative recipient.
low risk of transmission from HBsAg-negative, anti-HBc positive donors to HBsAg-negative recipients; lower if the recipient is anti-HBs positive

6. Evaluation prior to transplantation
All patients for renal transplantation should be tested for HBV infection.
Standard tests (donor & recipients) : HBsAg, anti-HBs, anti-HBc
Chronic HBV infection
not a contraindication to kidney transplantation
all HBV-infected patients should be tested for HBeAg and serum HBV DNA in order to determine the risk for reactivation of HBV infection
HBsAg-positive patients
liver biopsy to determine whether cirrhosis is present
Patients with cirrhosis are at higher risk for hepatic failure following transplantation
> may be considered for kidney transplantation
1) compensated cirrhosis & 2) no evidence of portal hypertension
> antiviral agents
Non-invasive assessments of liver fibrosis and cirrhosis
: special biomarkers such as FibroTest, measurement of liver stiffness using
ultrasound or magnetic resonance

7. Prevention of reactivation of HBV replication after transplantation
HBsAg positive patients
Antiviral therapy
for all HBsAg-positive patients who are undergoing kidney transplantation.
Antiviral therapy has been shown to be effective in preventing reactivation in non-transplant HBV-infected patients who are receiving immunosuppressive therapy
Systematic review: the effect of preventive lamivudine on hepatitis B reactivation during chemotherapy. - Ann Intern Med. 2008;148(7):519
Preemptive lamivudine therapy based on HBV DNA level in HBsAg-positive kidney allograft recipients. -Hepatology. 2002;36(5):1246
Antiviral therapy is more effective in preventing hepatic decompensation if it is administered before there is evidence of hepatic dysfunction or an increase in transaminase levels rather than as salvage therapy
Results on preemptive or prophylactic treatment of lamivudine in HBsAg (+) renal allograft recipients: comparison with salvage treatment after hepatic dysfunction with HBV recurrence.- Transplantation. 2001;71(3):387.
prophylactic approach vs preemptive approach
HBeAg or HBV DNA status prior to transplantation has only limited ability to predict subsequent HBV reactivation.
a preemptive strategy requires close monitoring of serum HBV DNA, which may not always be feasible in clinical practice.

8. Prevention of reactivation of HBV replication after transplantation
HBsAg positive patients
Antiviral therapy
Lamivudine, adefovir, entecavir, telbivudine, tenofovir
Entecavir , Tenofovir (lamivudine resistance)
the duration of antiviral treatment
: no consensus
: for at least one to two years after transplantation
or potent immunosuppression
: HBeAg negative & undetectable HBV DNA prior to transplant
> may be possible to attempt discontinuation of treatment
should be closely monitored
renally excreted > dose adjustments with impaired renal allograft function

9. Prevention of reactivation of HBV replication after transplantation
HBsAg positive patients
Reduction of immunosuppression
For patients at risk for reactivation of HBV replication,
> the lowest level of immunosuppression
For patients who are at low risk for rejection, w
> reduce the dose of prednisone to 5 mg daily or below
may attempt to discontinue glucocorticoids completely
not utilized in all centers

10. Prevention of reactivation of HBV replication after transplantation
HBsAg negative, anti-HBc positive patients
at lower risk of reactivation post-transplantation
insufficient evidence to recommend routine antiviral prophylaxis
Should monitor ALT levels and check HBV DNA levels

11. Monitoring after transplantation
all HBsAg patients should be closely monitored for HBV reactivation, hepatitis flares, hepatic dysfunction, and the development of hepatocellular carcinoma
patients with prophylactic antiviral therapy
: check HBV DNA levels every 3 to 6 months
: high HBV DNA prior to start of antiviral therapy>check HBV DNA every 1 to 3
months until HBV DNA is undetectable.
no prophylactic antiviral therapy
> check serum HBV DNA at least every 2 months for the first year
and every 6 months thereafter
check transaminase levels weekly for the first 16 weeks, followed by every 2 weeks for the remainder of the first year and then every 3 months thereafter

12. Reactivation of HBV replication after transplantation
All HBV-infected transplant recipients with increased HBV DNA concentration either with or without abnormal ALT > should be treated with an antiviral agent
The optimal antiviral agent depends upon the preventive therapy used
lamivudine-naïve patient
: entacavir : the potent agents, low rate of resistance with long-term treatment
(1% after 5 years of therapy), not nephrotoxic (< adefovir or tenofovir)
: tenofovir : in patients with lamivudine resistance, nephrotoxicity (+)
patients with prophylactic lamivudine or lamivudine –esistance
: adefovir or tenofovir + lamivudine (rather than stopping lamivudine)
< combination therapy may reduce the development of resistance to the second drug
entecavir, telbivudine, tenofovir : the most potent
entecavir & tenofovir : the lowest risk of drug resistance
lamivudine : most extensively used, high rate of drug resistance
adefovir : less frequently used, potential nephrotoxicity
tenofovir : small risk of nephrotoxicity
interferon alfa should NOT be used in kidney transplant recipients
d/t acute allograft rejection