Future treatment of chronic hepatitis C with direct acting antivirals: is resistance important?

Recent advances in molecular biology have led to the development of novel small molecules that target specific viral proteins of the hepatitis C virus (HCV) life cycle. These drugs, collectively termed directly acting antivirals (DAA), include a range of non-structural (NS) 3/NS4A protease, NS5B polymerase and NS5A inhibitors at various stages of clinical development. Some others drugs called 'non DAA'or indirect inhibitors are not focused on one site of the life cycle target and are still in early pre-clinical and clinical phase I, II and III trials. The rapid replication rate of HCV, along with the low fidelity of its polymerase, results in a generation of mutations throughout the viral genome and sequence variation in the HCV population known as a quasispecies. The efficacy of DAA is limited by the presence of these mutations, resulting in amino acid substitutions within the targeted proteins which affect viral sensitivity to these compounds. Thus, attributable to the high genetic variability of HCV, variants with reduced susceptibility to DAA can occur naturally even before treatment begins, but usually at low levels. Thus it is not surprising that these changes are selected in patients that either breakthrough or do not respond to potent DAA treatment. Six major position mutations in the NS3 HCV Protease (36, 54, 155, 156, 168 and 170), fifteen in the NS5B polymerase (96, 282, 316, 365, 414, 419, 423, 448, 482, 494, 495, 496, 499, 554, 559) and five in the NS5 A region (28, 30, 31, 58 and 93) have now been reported in vitro or in vivo associated with different levels of resistance. The amino acid composition at several of the drug resistance sites can vary between the HCV genotypes/subtypes, resulting in different consensus amino acids leading to a reduction in replicative fitness as well as reduced DAA and non- DAA sensitivity. Information on patterns of resistance to and cross resistance between antiviral agents is increasingly available and may be important for decisions on how to combine drugs to achieve an optimum antiviral effect. This review debates the clinical relevance of resistance to direct and indirect inhibitors taking into account the future potential therapeutic strategies to help patients who do develop resistance to HCV inhibitors. Finally, this chapter treats two points of view: 'for' and 'against' the question of the importance of resistance.