Directly acting antivirals against hepatitis C virus: mechanisms of action and impact of resistant associated variants.

Hepatitis C virus (HCV) drug development has resulted in interferon-free (IFN) regimens of direct-acting antivirals (DAAs). The new therapies are highly effective achieving 90-95% of sustained virologic response (SVR) rates among all genotypes with minimal treatment-related side effects. They opened a new scenario in HCV treatment representing a treatment option for patients who were ineligible to IFN-based regimens as those with decompensated liver disease, autoimmune disorders and psychiatric disturbs. However, numerous research and clinical questions remain. In particular, drug resistance is an upcoming clinical issue in HCV treatment. The aim of this review is to provide an overview of the different DAAs approved or in clinical development and their mechanism of actions. For each class of agents the resistance profile will be examined according to the available in vitro and in vivo data discussing the clinical implications. Resistance-associated variants (RAVs) are driven by the selection of mutations at different virologic targets. The most clinically relevant NS3/4A protease substitutions are detected at positions V36, Q80, T54, R155 and A156. S282T is the most frequent NS5B polymerase aminoacids substitutions. M28, Q30, L31 and Y39 mutations are involved in NS5A proteins associated resistance. The baseline RAVs seems not to affect the SVR rates. Thus, their detection by sequencing analysis should not to be recommended. Conversely, RAVs testing after DAAs failure is of clinical practice concern in order to select the most appropriate retreatment combination.