Adefovir dipivoxil for the treatment of lamivudine-resistant hepatitis B mutants

Abstract

Lamivudine has been shown to be an effective therapy for chronic hepatitis B, but resistance to this nucleoside agent is common after prolonged use. Five patients with chronic hepatitis B virus (HBV) infection developed resistance to lamivudine after 9 to 19 months of treatment. In 4 patients this occurred after liver transplantation and the remaining individual had stable cirrhosis. In each case, resistance was confirmed to be caused by one or more mutations in the HBV-DNA polymerase gene and was associated with active underlying liver disease. The patients were treated with adefovir dipivoxil in a dose of 5 to 30 mg daily. Two to 4 log 10 reductions in HBV-DNA levels were observed in 4 cases, and the fifth patient became negative by quantitative polymerase chain reaction (PCR) after retransplantation in conjunction with hepatitis B immunoglobulin (HBIg). Virologic improvement was associated with stable or declining serum alanine transaminase levels in 4 patients. HBV-DNA suppression has been sustained during a mean treatment period of 13 months (range 11 to 15 months), including 1 patient in whom lamivudine has been discontinued. Mild changes in renal function were observed during treatment in most cases but did not require early discontinuation of the drug. This study provides evidence that adefovir dipivoxil can be an effective treatment for lamivudine-resistant HBV mutants as well as wild-type HBV. (HEPATOLOGY 2000;32:129-134.)recently has been licensed in the United States, Canada, Europe, and Asia for the treatment of chronic hepatitis B. This drug has been shown to be highly effective in inhibiting hepatitis B virus (HBV) replication. [1][2][3][4] Clinical trials have provided evidence for histologic improvement as well as rates of hepatitis B e antigen (HBeAg) disappearance and seroconversion to anti-HBe that are similar to those observed with interferon alfa therapy. [1][2][3][4] One of the observations common to all of these studies, however, is the emergence of lamivudineresistant HBV mutants that undergo mutation in the HBV DNA polymerase gene. Two types of mutation have been identified to account for lamivudine resistance. 5 Mutation at codon M552 of the YMDD motif results in substitution of isoleucine for methionine (M552I). An alternate mutation at this site results in substitution of methionine by valine (M552V). The M552V mutation is accompanied by a second mutation at codon 528 that results in the substitution of leucine by methionine (L528M). In a recent analysis of data from the phase III trials of lamivudine, Atkins et al. 6 reported that resistance to lamivudine developed in 16% to 32% of patients after 1 year of treatment. 6 More recently, resistance has been shown to occur in 38% and 49% of patients after 2 and 3 years of treatment, respectively. 7,8 The natural history of hepatitis B in this situation is not yet well defined, but there have been well documented cases in which clinical and histologic progression has occurred after liver transplantation, including rapid progression to cir...

Pretreatment and on-treatment predictors of viral breakthrough in lamivudine therapy for chronic hepatitis B

“…One of the nucleoside analogue lamivudine (LAM) has been shown to be highly effective in inhibiting hepatitis B virus (HBV) replication [1][2][3]. LAM therapy for CHB patients with advanced fibrosis significantly reduced the incidence of hepatic decompensation and hepatocellular carcinoma [4].…”

Increased risk of adefovir resistance in patients with lamivudine-resistant chronic hepatitis B after 48 weeks of adefovir dipivoxil monotherapy

“…9 Adefovir dipivoxil (ADV), an oral pro-drug of adefovir, has an antiviral activity against not only wild-type HBV but also LAM-resistant HBV mutants in vitro and in vivo. [10][11][12][13] Therefore, a switch to ADV is usually recommended for patients with LAM-resistant CHB. 14 In contrast to LAM, ADV therapy in treatment-naïve patients is associated with delayed and infrequent emergence of drug-resistant mutations.…”

Comparison of ligase detection reaction and real-time PCR for detection of low abundant YMDD mutants in patients with chronic hepatitis B

“…Several antiviral agents, such as adefovir and entecavir, can provide effective therapies in patients with lamivudineresistant HBV [25][26][27] . Pegylated interferon also induces sustained responses in a portion of lamivudine-resistant patients [28][29][30] .…”