Profound suppression of hepatitis B virus replication with lamivudine

Abstract

The therapeutic goals in chronic hepatitis B are to prevent or decrease cirrhosis and hepatocellular carcinoma in patients with pre-cirrhotic or early cirrhotic disease and to stabilise patients with end-stage cirrhosis. Lamivudine is an oral nucleoside analogue that suppresses hepatitis B virus (HBV) replication, and so may achieve both these treatment objectives. The active 5'-triphosphate metabolite of lamivudine has two modes of viral suppression. First, it mimics deoxycytidine triphosphate and is incorporated into newly synthesised HBV DNA to cause chain termination. Second, it demonstrates competitive inhibition of viral DNA-dependent and RNA-dependent DNA polymerase activity (i.e., reverse transcriptase activity). Lamivudine may, therefore, act at four possible stages during HBV replication: reverse transcription of pre-genomic mRNA into nascent minus-strand DNA; formation of plus strand DNA from nascent minus-strand DNA; completion of double-stranded DNA; and formation of covalently closed circular DNA. In clinical studies, lamivudine therapy reduced serum HBV DNA and this was associated with significant improvements in liver histology and significant and sustained enhancement of the proliferative CD4-mediated response to HBeAg and hepatitis B core antigen (HBcAg), and an increased frequency of HBeAg-specific T cells. HBV DNA concentrations often returned to pre-treatment values when therapy ended prior to the loss of hepatitis B e antigen (HBeAg). Although the emergence of HBV variants with a mutation in the YMDD (tyrosine-methionine-aspartate-aspartate) motif has been observed, such variants show reduced susceptibility to lamivudine due to limited replication competence, and their emergence is not a signal to cease lamivudine therapy. In conclusion, viral suppression with lamivudine offers a means of disease improvement and immunological control in chronic hepatitis B.

Sustained response to peginterferon alfa-2a (40 kD) with or without lamivudine in Asian patients with HBeAg-positive and HBeAg-negative chronic hepatitis B

“…Previous studies of interferon or lamivudine treatment of CHB had suggested that patients who had achieved HBeAg seroconversion had lower baseline serum HBV DNA levels and higher baseline serum ALT levels compared with those patients who did not seroconvert [15,39]. The results for peginterferon alfa2a in these 2 clinical trials support the findings of an earlier study which reported that low viral load (odds ratio 1.6 [1.3-1.8], P = 0.009) and high baseline ALT levels (odds ratio 1.1 [1.0-1.2], P = 0.02) were also predictive of seronconversion in HBeAg-positive patients treated with peginterferon alfa-2b alone or in combination with lamivudine [26].…”

Factors associated with hepatitis B virus DNA breakthrough in patients receiving prolonged lamivudine therapy

“…1 Because of its profound suppression of HBV replication resulting in significant histologic improvement, lamivudine is commonly used as a treatment of chronic HBV infection. [2][3][4] However, in 14% to 32% of patients, a 1-year treatment regimen of lamivudine 100 mg daily is associated with mutation of the tyrosine, methionine, aspartate, aspartate (YMDD) motif in the C domain of the HBV DNA polymerase gene, corresponding to the amino acid codon 552 of the HBV. 2,3 The number of patients with YMDD mutation is higher with prolonged use of lamivudine.…”

Patterns of hepatitis B virus infection in Brazilian human immunodeficiency virus infected patients: high prevalence of occult infection and low frequency of lamivudine resistant mutations

“…This drug is widely used as part of the treatment of HIV infection and has also been used in the treatment of HBV infection (Dienstag et al 1995, Lai & Yuen 2000, Leung 2004). The serum HBV DNA decrease due to lamivudine treatment is frequently accompanied by significant histological and biochemical improvement (Loriot et al 1992).…”

“…The resistance in the YMDD motif occurs by replacement of the methionine residue at position 550 by either valine (M550V) or isoleucine (M550I). The M550V variant may be accompanied by a mutation that changes leucine into methionine at residue 526 (L526M) (Lai & Yuen 2000, Leung 2004). Such mutations have notably been reported in studies performed with HIV-HBV co-infected patients (Dore et al 1999, Thibault et al 1999, Hoff et al 2001).…”