Review: New direct-acting antivirals in the development for hepatitis C virus infection

Abstract

A large number of new therapies are in development for chronic hepatitis C including direct-acting antiviral drugs (DAA), which target specific hepatitis C virus enzymes. Two of these compounds have already advanced into phase 3 development in the USA and EU, and many more are in phase 2 trials and likely to advance. In this review, the results of recent studies on ribavirin analogues, nonstructural (NS) 3/4 serine protease inhibitors, NS5B polymerase inhibitors, cyclophilin inhibitors, silimarin components, and thiazolides have been updated. Each compound includes a brief summary of its proposed mechanism of action, results of early clinical trials, and more advanced trial data where available. These compounds are likely to be the first approved in the USA and EU and will initially be used in combination with the current standard of care. It is possible that future treatment paradigms with these agents will offer the potential of interferon-free regimens. It is most likely that patients for these new therapies will be selected carefully by identifying and treating first those who have excellent sustained virologic response rates with 24 weeks of pegylated interferon and ribavirin, the current standard of care. It is also likely that there will be a need to identify those patients who are not likely to have a sustained virologic response with the addition of a protease inhibitor to the current standard of care and delaying their therapy until combination viral suppression therapy becomes an option. The cost and side effects of the DAA will be important considerations for treating physicians. This review is current through 2009; however, data are rapidly changing.

Chronic hepatitis C: This and the new era of treatment

“…NS3/4A PIs are drugs that inhibit the NS3/4A serine protease, an enzyme involved in post-translational processing and replication of HCV [76] . There are two generation of PIs.…”

Development and Validation of a Simple, Rapid and Inexpensive PCR-RFLP Method for Genotyping of Common IL28B Polymorphisms: A Useful Pharmacogenetic Tool for Prediction of Hepatitis C Treatment Response

“…Also, it has been shown that the rs12979860 CC and rs8099917 TT genotypes are strongly associated with spontaneous resolution of HCV infection (10,11). There are various aspects of the clinical utilization of IL28B testing, but it appears that it can help clinicians in decision-making with regard to treatment (12,13). Recently, the American Association for the Study of Liver Diseases (AASLD) included IL28B testing in its guidelines (14), with a recommendation grade of Class 2a and Level B.…”

Direct-Acting Antivirals (DAAs): Drug-Drug Interactions (DDIs) in the Treatment of Hepatitis C Virus (HCV)

“…Direct-acting antivirals target three of the main proteins involved in viral replication: the NS3/4A protease, the NS5B polymerase, and the NS5A [7].…”

“…In addition to its role in viral processing, the NS3/NS4A protease blocks TRIF-mediated Toll-like receptor signaling and Cardif-mediated retinoic acid-inducible gene 1 (RIG-1) signaling, which result in impaired induction of interferons and blocking viral elimination. Thus, inhibition of the NS3/4A protease could contribute to antiviral activity through two mechanisms [7].…”