Monitoring Drug Resistance in Chronic Hepatitis B Virus (HBV)-Infected Patients during Lamivudine Therapy: Evaluation of Performance of INNO-LiPA HBV DR Assay

Abstract

Although safe and effective vaccines for the prevention of hepatitis B virus (HBV) infection have been available for almost 20 years, the disease remains a major cause of morbidity and mortality worldwide. It is currently estimated that 350 million people are chronic carriers of the virus, often as a result of infection during childhood. Approximately one third to one quarter of these individuals will develop progressive liver disease, including cirrhosis and primary hepatocellular carcinoma (13, 15). Some 1.2 million people die prematurely each year from conditions directly related to HBV infection.Current treatment of chronic hepatitis B aims at interrupting the progression and clinical outcomes of the disease by suppressing viral replication, as evidenced by hepatitis B virus E antigen seroconversion to hepatitis B virus E antibodies (14) or by a decrease in viral load. The first approved therapeutic agent was alpha interferon. Unfortunately, alpha interferon is expensive, is effective in no more than 30% of patients, has to be administered by injection, and is associated with numerous side effects which may necessitate dosage reduction or even treatment discontinuation (13,15).In 1998, the nucleoside analogue lamivudine was approved for use in patients with chronic hepatitis B (7). The convenience of a one-pill-per-day regimen and the low incidence of side effects make it a preferred treatment for many physicians and patients. However, viral breakthrough is detected in approximately 16% to 32% of patients after 1 year of treatment (12). Newer oral nucleoside/nucleotide analogues in clinical trials, such as adefovir dipivoxil (4), entecavir (6), and emtricitabine (19, 18), appear to be at least as potent as lamivudine. In vitro and in vivo studies showed that adefovir and entecavir are also effective in suppressing lamivudine-resistant HBV (8).Mutations in codon 552 [204] (proposed revised nomenclature according to Stuyver et al. [22] is shown in brackets) within the YMDD (tyrosine-methionine-aspartic acid-aspartic acid) motif of the HBV reverse transcriptase/polymerase with substitution of the methionine for valine or isoleucine (M552V/I [M204V/I]) are implicated in the decrease of viral susceptibility to lamivudine (1,5,10,11). In addition, mutations in codons 528 [180] (2, 3, 11) and 555 [207] (9, 17) have also been linked to lamivudine and famciclovir resistance. Sensitive and early detection of emerging resistance may not only help monitor

Dynamics of Hepatitis B Virus Resistance to Lamivudine

“…However, this approach is too cumbersome to be used in clinical practice. Reverse hybridization with the line probe assay, which can detect variant populations representing approximately 10% of the HBV quasispecies, is usable in practice and was recently reported to reveal the emergence of resistance variants an average of 2 weeks before the HBV DNA load started to increase (26,30). The time of virological breakthrough is too late for diagnosis of HBV resistance, because most of the quasispecies variants are already both resistant and highly fit.…”

Antiviral drug-resistant HBV

“…LiPA assays can detect emerging viral resistance when HBV encoding the resistance mutations constitute 5% or more of the total viral population. 21,[23][24][25] Their major limitation is that new sets of specific probes are required for every mutant and due to genotype variability a number of probes may be required to detect a single nucleotide change.…”

British HIV Association guidelines for the management of coinfection with HIV‐1 and hepatitis B or C virus 2010

“…A line probe assay for the detection of hepatitis B wild-type virus and a drug-induced mutation using direct sequencing can identify specific resistance mutations [107,108]. Direct sequencing of the HBV polymerase gene can detect variants that are present in 10-20% of the virus population [109].…”