Idenix Pharmaceuticals (IDIX)

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Viral Resistance to Emerging HCV Therapies

In general, as indicated throughout this review, direct targeting of the HCV replicative cycle can increase the risk of resistance to varying degrees. Data suggest that the inclusion of an immune-based therapy, such as peginterferon with or without ribavirin, can dramatically reduce the selection for HCV variants resistant to these small molecule agents. Thus, the development of combination therapeutic approaches, may be essential for producing durable responses. However, further studies will be necessary to determine the usefulness and effectiveness of this approach, and it should be noted that phenotypic resistance to HCV therapy has been attributed to amino acid variations within distinct regions of the HCV polyprotein, and sensitivity to interferon alfa–based antiviral therapy in vivo has been correlated with the number of mutations within the HCV NS5A, core, and envelope proteins. Although this has not been observed in all study cohorts and is highly controversial, the underlying functional mechanisms for this potential association are unknown, it should be considered when designing combination trials.

In addition, several in vitro mechanisms to circumvent the host immune defense or to block treatment-induced antiviral activities have been described. As is the case with hepatitis B and HIV, the introduction of direct antiviral drugs represents a promising new era of treatment, but the development of resistance may become the primary clinical concern. As resistance data are gathered, it appears likely that, for the near future, most of the small molecule inhibitors, such as telaprevir (VX-950), valopicitabine, R1626, and HCV-796, will be used in combination with peginterferon alfa with or without ribavirin. Eventually, combinations of small molecules from different classes will likely be studied without peginterferon or ribavirin, although it is not known if this will be sufficient to induce sustained virologic response.


...Future Directions

Given the scope of recent advances that have furthered general understanding of HCV, and the therapeutic possibilities already demonstrated in this context, the coming years are expected to yield substantial progress in the utility and effectiveness of small targeted agents for the treatment and prevention of chronic hepatitis C.