Abstract
While addition of the first-approved protease inhibitors (PIs), telaprevir and boceprevir, to pegylated interferon (PEG-IFN) and ribavirin (RBV) combination therapy significantly increased sustained virologic response (SVR) rates, PI-based triple therapy for the treatment of chronic hepatitis C virus (HCV) infection was prone to the emergence of resistant viral variants. Meanwhile, multiple direct acting antiviral agents (DAAs) targeting either the HCV NS3/4A protease, NS5A or NS5B polymerase have been approved and these have varying potencies and distinct propensities to provoke resistance. The pre-clinical in vivo assessment of drug efficacy and resistant variant emergence underwent a great evolution over the last decade. This field had long been hampered by the lack of suitable small animal models that robustly support the entire HCV life cycle. In particular, chimeric mice with humanized livers (humanized mice) and chimpanzees have been instrumental for studying HCV inhibitors and the evolution of drug resistance. In this review, we present the different in vivo HCV infection models and discuss their applicability to assess HCV therapy response and emergence of resistant variants.
Highlights
The hepatitis C virus (HCV) was identified in 1989 as the etiologic agent for non-A non-B hepatitis [1]
These studies showed a density profile of viral particles isolated from chimpanzees and humanized mice similar to that observed in humans, but different from that of particles produced in cell culture
HCV therapy studies performed in chimpanzees and human-liver chimeric liver chimeric prove of thethese relevance of in these context of antiviral and mice prove themice relevance models the models context in of the antiviral resistance and resistance confirm drug confirm drug class‐specific resistance profiles observed in cell culture systems and clinical trials
Summary
The hepatitis C virus (HCV) was identified in 1989 as the etiologic agent for non-A non-B hepatitis [1]. The structural proteins include the core protein that forms the capsid of the virus, and the envelope glycoproteins E1 and E2 These envelope proteins interact with a variety of specific and non-specific host membrane proteins (attachment factors and (co-)receptors) to initiate viral entry. A variety of non-structural proteins are antiviral agents (DAAs) These include NS3‐4A protease inhibitors, NS5A inhibitors and the target of direct acting antiviral agents (DAAs). These include NS3-4A protease inhibitors, NS5A (non‐)nucleos(t)ide NS5B polymerase inhibitors that possess distinct efficacy and genetic barrier to inhibitors and (non-)nucleos(t)ide NS5B polymerase inhibitors that possess distinct efficacy and genetic resistance. A 48-week combination therapy with pegylated interferon (PEG-IFN) and ribavirin (RBV) has long been the standard treatment protocol for chronic HCV infection.
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