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

Abstract

Factors associated with hepatitis B virus (HBV) DNA breakthrough and the significance of YMDD variants without the presence of wild-type YMDD during prolonged lamivudine treatment are unknown. We studied the amino acid sequence of codon 552 (YMDD motif) and codon 528 by means of a line probe assay in 159 chronic HBV patients (median follow-up 29.6 months). Pretreatment HBV DNA levels and alanine transaminase (ALT) levels correlated inversely with the time to HBV DNA breakthrough with YMDD variants (r ‫؍‬ ؊0.46, P ‫؍‬ .001; r ‫؍‬ ؊0.45, P ‫؍‬ .001 respectively). Patients harboring YMDD variants 3 months before HBV DNA breakthroughs had higher HBV DNA breakthrough levels compared with those without YMDD variants 3 months before HBV DNA breakthroughs (18.9 ؋ 10 6 vs. 5.4 ؋ 10 6 copies/mL, P ‫؍‬ .007). Patients with HBV DNA breakthroughs had higher percentages of YMDD variants without the presence of wild-type YMDD compared with patients without HBV DNA breakthrough (25.6% vs. 9%, P ‫؍‬ .007 for single M552I variant; 20.9% vs. 8.1%, P ‫؍‬ .026 for single M552V variant; 30.2% vs. 9.9%, P ‫؍‬ .004 for M552I/M552V variants). Patients with HBV DNA levels of more than 10 3 copies/mL after 6 months of lamivudine therapy had a 63.2% chance of subsequently developing YMDD variants. HBeAg seroconversion occurred in 2 patients after the emergence of YMDD variants. Only one patient developed YMDD variant after HBeAg seroconversion. There was no increase in the rate of development of YMDD variants or L528M mutation in patients receiving lamivudine 25 mg daily or famciclovir 500 mg 3 times a day before being given lamivudine 100 mg daily. (HEPATOLOGY 2001;34:785-791.)Hepatitis B virus (HBV) infection is a major international health problem leading to around 1.2 million deaths per year world-wide. 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. 5 For the YMDD variants, the methionine is substituted with either isoleucine (I), designated M552I or valine (V), giving rise to M552V. There may be another concomitant mutation occurring at the B domain of the HBV polymerase gene with the leucine (L) at amino acid codon 528 substituted by methionine (L528M). This mutation has been described for patients on famciclovir. 6,7 With lamivudine treatment, L528M is usually associated with M552V though M552I/L528M has also been reported. 8 Both in vitro and in vivo studies show that YMDD variants are less replication-competent compared with the wild-type, are associated with lower HBV DNA levels compared with pretreatment HBV DNA levels, and can...

Efficacy of Entecavir in Patients with Chronic Hepatitis B Resistant to Both Lamivudine and Adefovir or to Lamivudine Alone†

“…14,15 Previous studies with LAM and telbivudine demonstrated a positive correlation between early profound HBV suppression and long-term clinical outcome. 25,31,32 Our study also showed that virological responses to ETV at week 12 of treatment determined the degree of HBV DNA reduction over 48 weeks, regardless of previous antiviral drug resistance.…”

“…23 Studies with LAM or ADV suggested that the presence of high pretreatment HBV DNA levels was a risk factor for increased antiviral drug resistance and attenuation of virological response in treatment-naïve or LAM-resistant patients. 24,25 In the current study, pretreatment serum HBV DNA levels were lower in LAMr/ADVr patients. Given that pretreatment low viral load is predictive of HBe seroconversion, 26 it was interesting to note that the rate of HBeAg loss (including seroconversion) after ETV monotherapy was no higher in LAMr/ADVr patients (with lower pretreatment viral loads) than in LAMr patients.…”

Serological and molecular epidemiological outcomes after two decades of universal infant hepatitis B virus (HBV) vaccination in Nunavut, Canada

“…Both interferon and reverse transcriptase inhibitors are used to treat chronic HBV infection [31][32][33]. Although there is no cure for HBV infection, these treatments manage infection, preventing viral replication, leading to a lowered viral load and amount of virus in the blood.…”

Antiviral drug-resistant HBV

“…5 Monitoring for primary nonresponse is important because a high residual viral level after the first 6-12 months of therapy has been demonstrated to be associated with increased risk of antiviral resistance. [6][7][8] (ii) Secondary Antiviral Treatment Failure (or Virologic Breakthrough). Virologic breakthrough, which is usually associated with drug resistance, is defined as a Ն1 log 10 IU/ml increase in serum HBV DNA level from nadir in two consecutive samples 1 month apart in patients who have responded and have been compliant with antiviral medication(s).…”