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15th International HIV Drug Resistance Workshop13-17 June 2006, Sitges, Spain |
HBV DRUG RESISTANCE
Antivir Ther. 2006; 11:P4 (abstract no. P2)
S Locarnini
Victorian Infectious Diseases Reference Laboratory, North Melbourne, Victoria, Australia
The hepatitis B virus (HBV) has evolved a unique life cycle that results in the production of enormous viral loads during active replication without actually killing the infected hepatocyte directly. Most of the disease process of hepatitis B is the result of an inadequate or inappropriate host immune response. Following infection, the relaxed circular (RC) viral DNA genome is converted into covalently closed circular (ccc)DNA. The cccDNA is localised to the nucleus, where it is transcribed to form the viral mRNAs. One of the two largest mRNA molecules, the pregenome (pgRNA), is packaged into viral nucleocapsids in the cell cytosol and there reverse transcribed to produce progeny RC DNA. Some of the newly formed RC DNA in nucleocapsids are transported to the nucleus to amplify the cccDNA copy number (10-50 per cell) whilst the remaining nucleocapsids are enveloped in the ER into complete virions and then secreted from the cell [1]. Since the virus copies its genome by the process of reverse transcription, mutant viral genomes are generated continuously. Particular selection pressures, both endogenous (host immune clearance) and exogenous (vaccines and antivirals), readily select out so called "escape" mutants that have a replicative advantage due to the presence of the selection pressure.
In hepatitis B, antiviral drug resistance depends on at least five factors: (1) viral mutation frequency, (2) magnitude and rate of virus replication, (3) selective pressure exerted by the drug, (4) replication fitness of the mutant, and (5) availability of replication space [2]. The development of drug resistance is not unexpected if viral replication continues in the setting of ongoing treatment, especially monotherapy. Indications of emergence of drug-resistant HBV include: (i) increasing viral load (≥1.0 log IU/ml) and; (ii) identification of known genotypic markers of drug-resistance within the viral polymerase [3].
Two types of mutations in the HBV polymerase can be identified: i). primary resistance associated mutations (Lamivudine: rtM204V/I) and; ii). secondary/compensatory mutations (Lamivudine: rtV173L). Furthermore, three chemical groups within the class of nucleos(t)ide analogue can be recognised: i). L-Nucleoside Group (lamivudine, emtricitabine, telbivudine, clevudine); ii). Acyclic Phosphonate Group (adefovir, tenofovir); iii). Cyclopentene/cyclopentane Group (entecavir/abacavir). This chemical classification has relevance to the drug- resistant patterns observed during treatment failure, both in terms of primary versus secondary mutations. For the L-nucleosides, the major primary mutation directly associated with resistance is the rtM204V/I in the YMDD motif of the C-domain of the HBV polymerase. Once selected, this mutation effectively "burns" all other L-nucleosides. Another primary mutation associated with Lamivudine failure is rtA181T/V[4] which is also cross- resistant with Adefovir. Long term use of Lamivudine monotherapy is associated with the selection of a number of secondary mutations, including rtI169T, rtV173L[5], rtT184S and rtV214A/rtQ215S[6] which directly increase the IC50 for Entecavir, Adefovir and Tenofovir, compromising the use of these agents subsequently as "rescue" therapy for patients with Lamivudine resistant hepatitis B.
Prevention of resistance requires the adoption of strategies that effectively control virus replication. For example, the use of antiviral drugs that require the selection of at least three or four mutations or more in the viral polymerase to occur in order to result in treatment failure (i.e. increasing the genetic barriers for resistance). Also, the use of combinations of drugs that act together at least additively or synergistically against HBV would certainly reduce the rate of emergence of drug resistance and provide an environment of longer term therapeutic control of viral replication (i.e. maximizing antiviral efficacy)[7,8]. However, if the current widespread clinical practice of maintenance Lamivudine monotherapy in the setting of resistance continues then the diversity of HBV quasispecies found in the patient will continue to expand and include dominant isolates cross-resistant to all nucleos(t)ide analogues in the hepatitis B armamentarium. HBV polymerase sequencing is now required in order to determine the various patterns of quasispecies that have been generated in order to guide the choice of rescue therapy.
References
2006-06-13
P2
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