Treatment of recurrence of hepatitis B in transplant patients

With significant improvements in immunosuppressive therapy and surgical techniques over the past two decades, liver transplantation has become the definitive and effective therapy for patients with end-stage liver disease with survival rates approaching 90–95% and 65–80% after 1 and 5 years of follow-up, respectively [1]. Among several circumstances that may pose a threat to long-term survival, the greatest is likely the recurrence of the original liver disease [2]. Although hepatitis B recurrence has been effectively contained by the use of combination therapy with hepatitis B immunoglobulin (HBIG) and lamivudine, there remains the possibility of post-transplantation HBV disease of the allograft. Fortunately in the past decade several effective drugs have been developed for the management of patients with HBV disease undergoing liver transplantation, so that outcomes with the patient group are now excellent and allograft infection poses a relatively minor threat to long-term survival. In the United States and Europe, HBV disease accounts for fewer liver transplantations than HCV disease, yet the outcomes in 2002 are better for HBV than for HCV [3]. Treatment of hepatitis B after liver transplantation is less of a clinical problem today than it was a decade ago, largely due to effective interventions to prevent post-transplantation recurrence—namely high doses of HBIG in combination with antivirals such as lamivudine. Historically, rates of recurrence of HBV were high (90%) and the consequences of reinfection were devastating, such that HBV was considered a relative contraindication to liver transplantation. There has been a step-wise reduction in likelihood of recurrence with each intervention—down to 25% with high dose HBIG alone, and even further reductions with HBIG plus lamivudine. With pre-transplantation lamivudine plus HBIG at low doses, rates of reinfection are as low as 10%. In addition, post-transplantation HBV disease may occur in patients who were HBsAg negative prior to transplantation [4]. Thus, treatment of HBV after liver transplantation remains an important, albeit relatively uncommon clinical dilemma. A recent summary of a single clinical center’s experience supports the excellent outcomes of patients undergoing liver transplantation for HBV-related liver disease [5]. A 20-year experience in 206 patients spanning the period of evolution of HBV therapies has demonstrated an improvement in patient survival and a reduction in incidence of rates of recurrence. All patients received long-term immunoprophylaxis, maintaining trough anti-HBs at greater than 100 U/l. Since 1993, antivirals have been used prior to transplantation and for management of HBV reinfection. The 1, 5, and 10-year patient survival rates were 91%, 81%, and 73%. Survival was even good in patients with preoperative positive HBV DNA, detectable by hybridization-assays (78% 5-year survival), although preoperative positive hepatitis B e antigen (HBeAg) was associated with a worse survival than patients negative for HBeAg (P , 0:05) [5]. Two-year patient survival increased from 85% in 1988– 1993, prior to availability of antivirals, to 94% since 1997, in which period patients received combination of hepatitis B immune globulin and lamivudine (P , 0:05). The 2-year recurrence rates in these two periods were 42% and 8% (P , 0:05). In summary, with currently available combination therapy, survival is excellent in patients undergoing liver transplantation for HBV disease, even in those with active pre-transplantation viral replication, and risk of recurrent disease of the allograft is low (less than 10%). Thus in 2002, there are three categories of patients who are potential candidates for HBV therapy after liver transplantation: (i) those who have undergone liver transplantation in the pre-HBIG and/or lamivudine era; (ii) those who have undergone liver transplantation in the postHBIG/lamivudine era and who have broken through treatment; (iii) those with apparent ‘de novo’ acquisition of HBV [4]. Selection of therapy for post-transplantation recurrence likely depends on the category to which the patient belongs. For example, patients in the first category who have received either no therapy or HBIG alone, may have indolent infection or, if these patients have active liver disease, treatment options include lamivudine, entecavir or Journal of Hepatology 39 (2003) S190–S193 www.elsevier.com/locate/jhep