Liver transplantation for patients with lamivudine-resistant HBV: What is the optimal prophylactic strategy?

Abstract

The use of hepatitis B immune globulins (HBIG) revolutionized liver transplantation for hepatitis B. In the landmark paper by Samuel et al. in 1993, recurrence of hepatitis B virus (HBV) infection 3 years after liver transplantation was reduced from 75% in patients who received no HBIG to 36% in those who received HBIG for at least 6 months.1 However, the benefit of HBIG was mainly seen in patients with fulminant hepatitis or coexistent hepatitis D virus infection, clinical conditions associated with low HBV replication. Among patients with HBV cirrhosis, the HBV recurrence rate was 83% in those with detectable serum HBV DNA at the time of transplantation and 58% in those with undetectable HBV DNA or hepatitis B e antigen. These results stimulated efforts to reduceHBV replication in patients with HBV cirrhosis while waiting for liver transplantation. Early studies using interferon2 failed to reduce HBV recurrence because of poor tolerability and low efficacy. The availability of lamivudine, a nucleoside analog that is safe and effective in suppressing HBV replication, in the 1990s rekindled efforts to treat patients with HBV cirrhosis. Several studies have shown that lamivudine is safe in patients with decompensated cirrhosis and effective not only in suppressing HBV replication, but also in stabilizing or in improving liver disease.3-7 However, long-term use of lamivudine was limited by the high rate of drug resistance; resistant mutations involving the YMDD motif in HBV polymerase can be detected in 15% to 30% of patients after 1 year of treatment and in 50% after 3 years of treatment.7-9 Although in vitro studies showed that lamivudine-resistant mutants have decreased replication compared to wild-type HBV,10 clinical studies found that over timemost patients with lamivudine resistance have increasing serum HBV DNA and alanine aminotransferase (ALT) levels, some patients develop hepatitis flares, and occasional patients experience hepatic decompensation.9,11,12 In the late 1990s, the concern about fatal hepatitis flares associated with lamivudine resistance led many transplant centers to reserve lamivudine until transplantation was imminent. Around the same time, it was also recognized that while reduction in serum HBV DNA levels can be observed within 4 weeks of treatment, improvement in liver function and clinical status takes 3 to 6 months.3,6,7 Thus, delaying treatment until transplantation is imminent may not benefit patients who have advanced liver failure. The dilemma regarding when to initiate lamivudine treatment in the late 1990s and early 2000 was related to the unavailability of a salvage treatment that can suppress lamivudineresistant HBV. Patients with lamivudine-resistant HBV may experience rapid worsening of liver failure leading to death or removal from the transplant waiting list. Additionally, the risk of HBV recurrence after transplantationmay be increased because of high serum HBV DNA levels at the time of transplantation. Since 2002, adefovir dipivoxil, a nucleotide analog that is effective in suppressing wild-type and lamivudine-resistant HBV, has been approved in the United States and subsequently in Europe and many other countries. However, its use as a first-line antiviral agent, particularly in patients with decompensated cirrhosis, has evolved slowly. Thus, lamivudine continues to be a first-line antiviral agent in patients with decompensated HBV cirrhosis in many transplant centers. With the move to initiate treatment earlier and the increase in waiting time on the transplant list, many transplant centers now face a rising number of patients who have lamivudine-resistant HBV prior to transplantation. Abbreviations: HBIG, hepatitis B immune globulins; HBV, hepatitis B virus; ALT, alanine aminotransferase; PCR, polymerase chain reaction. From the Division of Gastroenterology, University of Michigan, Ann Arbor, MI. Address reprint requests to Anna S.F. Lok, MD, Division of Gastroenterology, University of Michigan Medical Center, 3912 Taubman Center, Ann Arbor, MI 48109-0362. Telephone: 734-615-4628; FAX: 734-936-7392; E-mail: aslok@umich.edu Copyright © 2005 by the American Association for the Study of Liver Diseases Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/lt.20409