Resistance to nucleotide analogue inhibitors of hepatitis C virus NS5B: mechanisms and clinical relevance.

The high barrier to the development of resistance to nucleotide analogue inhibitors of the hepatitis C virus (HCV) RNA-dependent RNA polymerase is an intriguing property of this class of drugs. The S282T substitution in the viral polymerase confers resistance to 2'-C-methylated nucleotide analogues. Although this mutation can be selected in HCV replicons, it has only been identified in very few cases in the clinic. Alternative resistance pathways are likewise rarely seen in vivo. Possible underlying mechanisms that are associated with the selection and establishment of a resistant genotype are discussed in this review.