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You have full access to this article via your institution. Download PDF The current standard of care (SOC) for hepatitis C virus (HCV) infection involves treatment with ribavirin and
pegylated interferon (PEG-IFN). This stimulates the immune system rather than targeting the virus directly, and is associated with severe side effects. Earlier this year, the first two
direct-acting antiviral agents (DAAs), the protease inhibitors telaprevir (Incivek; Vertex/Johnson & Johnson) and boceprevir (Victrelis; Merck), were approved by the US Food and Drug
Administration; however, these still have to be administered in combination with ribavirin and PEG-IFN. Now, data presented at the American Association for the Study of Liver Diseases
(AASLD) 2011 Annual Meeting show that the goal of achieving an all-oral and IFN-free treatment regimen is achievable and might be close. In particular, clinical trial results with HCV
polymerase inhibitors have generated excitement. Michael Manns, Medical School of Hannover, Germany, explains: “The advantage of nucleoside polymerase inhibitors is that they are
pan-genotypic, which means that they show activity against various — maybe all — HCV subtypes, which is in contrast to most HCV protease inhibitors. Moreover, they have a high genetic
barrier to resistance, strong antiviral potency and a favourable safety profile.” He is particularly excited about the uracil nucleotide analog polymerase inhibitor PSI-7977 (Pharmasset). “A
two-drug combination, PSI-7977 plus ribavirin, was shown to be successful for HCV genotype 2 and 3 patients and another study with PSI-7977 in combination with PEG-IFN and ribavirin showed
promising results for HCV genotype 1, which is currently more difficult to treat.” Pharmasset announced the initiation of a Phase III programme that will evaluate PSI-7977 in a 12-week,
all-oral, IFN-free regimen in combination with ribavirin. Another nucleoside polymerase inhibitor, INX-189 (Inhibitex), was shown to achieve robust and dose-dependent decreases in HCV RNA
levels after 7 days of monotherapy or in combination with ribavirin in treatment-naive patients with chronic HCV genotype 1. The company announced that it will now expand its clinical
development programme to include IFN-free combinations of INX-189 with other DAAs in patients with HCV genotype 1, 2 and 3. Pharmasset will test PSI-7977 in combination with the
small-molecule NS5A replication complex inhibitor BMS-790052 (Bristol-Myers Squibb). BMS-790052 showed promising results in combination with the protease inhibitor BMS-650032 in an
early-stage, all-oral, IFN-free combination study, achieving a 100% cure rate in all nine Japanese patients with HCV genotype 1b who completed treatment. Manns points out that this provides
proof of concept for all-oral IFN and ribavirin-free anti-HCV therapies. Finally, Roche and Anadys Pharmaceuticals have announced a merger agreement, in which Roche acquires Anadys for
US$230 million in an all-cash deal. This follows promising data for Anadys's setrobuvir (ANA598), a non-nucleoside oral small-molecule HCV polymerase inhibitor that is currently in a
Phase II study in combination with PEG-IFN and ribavirin. Again, the aim for this drug is to ultimately form part of an IFN-free oral DAA treatment regimen. “IFN has numerous side effects
and many patients cannot be included in SOC treatments because of exclusion criteria,” notes Ralf Bartenschlager, University of Heidelberg, Germany. “These problems are circumvented with
combinations of DAAs and, therefore, more patients can be treated and side effects are lower.” He sees the future of IFN-free anti-HCV treatments in DAA combinations such as an NS5A
inhibitor (as these have shown high potency), a nucleoside polymerase inhibitor and eventually a second-generation protease inhibitor, which has higher potency, fewer side effects and less
genotype dependency compared with the first-generation protease inhibitors. “An IFN-free (and also ribavirin-free) therapy is the main goal, and given the very promising data from clinical
trials, this seems to be realistic. The prospects for curing a patient with HCV by an IFN-free treatment regimen will become very high,” he concludes. RIGHTS AND PERMISSIONS Reprints and
permissions ABOUT THIS ARTICLE CITE THIS ARTICLE An all-oral and interferon-free future for HCV therapy?. _Nat Rev Drug Discov_ 10, 891 (2011). https://doi.org/10.1038/nrd3623 Download
citation * Published: 01 December 2011 * Issue Date: December 2011 * DOI: https://doi.org/10.1038/nrd3623 SHARE THIS ARTICLE Anyone you share the following link with will be able to read
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