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

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

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

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

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

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

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.

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

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

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

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

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