Drug Resistance in Antiviral Therapy
Section snippets
Antiviral drug resistance: background
The management of CHB has advanced significantly during the past 10 years because of the development of safe and efficacious oral antiviral nucleos(t)ide analogs (NAs). Approved medications include lamivudine (LMV), a synthetic deoxycytidine analog with an unnatural l-conformation, and the related l-nucleoside, telbivudine (LdT; β-l-thymidine). A second group, the acyclic phosphonates, includes adefovir dipivoxil (ADV), a prodrug for the acyclic 2′-deoxyadenosine monophosphate analog adefovir,
Causes of antiviral drug resistance
The development of antiviral drug resistance depends on at least six factors: (1) magnitude and rate of virus replication, (2) the fidelity of the viral polymerase, (3) selective pressure or potency of the drug, (4) amount of replication space in the liver, (5) replication fitness of the drug-resistant virus, and (6) genetic barrier of the drug.
LMV resistance mutations
Antiviral resistance to LMV has been mapped to the tyrosine-methionine-aspartate-aspartate (YMDD) locus in the catalytic or C domain of HBV rt/polymerase (Table 1).34 The primary resistance mutations result in the replacement of the methionine by valine, leucine, or occasionally serine and are designated rtM204I/V/S. Although rtM204I can be found in isolation, M204V/S are only found with other changes, in particular rtL180M (in domain B).35, 36 Other primary mutations that also confer LMV
Impact on Disease Severity
Following the development of drug resistance, there is an increase in viral load and consequent increase in serum ALT levels several weeks to months later, which in time may manifest as progressive liver disease.10, 11, 15 In patients refractory to l-nucleoside therapy, the risk of increased serum ALT levels is usually temporally correlated with the establishment of resistant virus.64 Such patients may also be at risk of an ALT flare, which may be accompanied by hepatic decompensation if there
Prevention of drug resistance
The spread of drug-resistant HBV can be reduced by avoiding unnecessary drug use, choosing drugs and combinations more carefully, and continually monitoring or performing targeted surveillance for drug resistance.21 Because of the unusual replication strategy of HBV, viral populations are genetically heterogeneous, so that even treatment-naive patients have pre-existing minor populations encoding resistance in the absence of selection pressure from antiviral drugs. Most patients may not require
Management of drug resistance
The management of NA drug resistance has been recently updated in the European Association for the Study of the Liver Clinical Practice Guidelines58 and reviewed by Zoulim and Locarnini.73 Virologic breakthrough in compliant patients is typically associated with the emergence of viral resistance. Resistance is associated with prior treatment with NAs or, in treatment-naive patients, with high baseline levels of HBV DNA, a slow decline in HBV DNA levels, and partial virologic response to
Summary
The current emerging patterns of antiviral drug resistance mapped to the HBV rt/polymerase are complex. The eight substitutions associated with primary drug resistance fall into four major pathways, however, which seem reasonably predictable based on analysis. Nevertheless, broad clusters of compensatory mutations, especially during LMV therapy, are compromising future salvage therapy options. Algorithms for the use of viral load and HBV genotyping and P gene sequencing clearly need to be
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