Antiviral therapy for pre- and post-liver transplantation patients with hepatitis B

Abstract

The goals of antiviral therapy for hepatitis B patients on the liver transplantation (LT) waiting list are 2-fold: 1) to achieve clinical stabilization, thereby delaying/preventing the need for LT; and 2) to attain low hepatitis B virus (HBV) deoxyribonucleic acid (DNA) levels prior to transplant, thereby reducing the risk of recurrent HBV postLT. Lamivudine was the first nucleoside analog to be approved for use in HBV treatment, and has been shown to be safe for long-term use. The combination of hepatitis B immune globulin and lamivudine has been the most common prophylactic therapy to prevent recurrent HBV infection post-LT since the late 1990s, and lamivudine monotherapy was the mainstay of treatment of recurrent HBV in the late 1990s and early 2000. The initial enthusiasm of lamivudine was tempered by the realization that lamivudine does not eradicate HBV, thus most preand post-LT patients require lifelong treatment to maintain viral suppression. Unfortunately, long-term use of lamivudine is associated with increasing rates of drug resistance, from 15 to 30% of patients after 1 yr of treatment to 70% of patients after 4 to 5 yr. Virologic breakthrough due to antiviral resistance has been reported to cause hepatitis flares and in rare instances hepatic decompensation. In the transplant setting, where patients already have decompensated cirrhosis or are receiving immunosuppressive therapy, the risk of severe hepatitis flare and worsening liver failure is higher, and for patients whomanage to receive a timely transplant, the risk of HBV recurrence post-LT is increased. With the approval of 2 nucleoside/tide analogs: adefovir and entecavir, and others in development, the management of preand post-LT hepatitis B patients is continuously evolving. There is an urgent need for safe and effective rescue therapy for patients with lamivudine-resistant HBV, and alternative first-line antiviral therapy with a lower rate of resistance for treatmentnaive patients. These therapies must have rapid and potent antiviral activity, long-term safety, and very low rates of resistance. In this issue of the Journal, Schiff et al. report the final results of a large open-label, multicenter study with 226 waitlisted and 241 post-LT patients with lamivudine-resistant HBV treated with adefovir dipivoxil 10 mg once daily for a median duration of 39 and 99 weeks, respectively. Almost all patients continued lamivudine at some time, but the exact duration of overlapping treatment is not certain. Adefovir resulted in a mean decrease in serum HBV DNA level of 3.5 to 4.0 log10 copies/mL after 48 weeks of treatment, and an increasing proportion of patients had undetectable serum HBV DNA over time. The high proportion of patients with substantial viral suppression may be related to the concomitant use of lamivudine in all patients. In 1 small study of patients with compensated liver disease and lamivudine-resistant HBV, serum HBV DNA decreased at a similar rate in patients randomized to adefovir monotherapy or a combination of lamivudine and adefovir. However, several recent studies have showed that combination of lamivudine and adefovir results in more marked viral suppression and lower risk of adefovir resistance than adefovir monotherapy. Despite the use of combination therapy, 35% of waitlisted patients and 22% of post-LT patients in the current study still had detectable serum