The therapeutic potential of new investigational hepatitis C virus translation inhibitors

ABSTRACT

Introduction: Hepatitis C virus (HCV) infection is a leading cause of liver cirrhosis, hepatocellular carcinoma and liver-related death worldwide. Currently, the anti-HCV armamentarium encompasses several direct-acting antivirals (DAA) that achieve very high response rates and have an excellent tolerability profile. However, they do not represent a final solution for HCV global eradication for at least these two reasons: i) some patients harbour resistant strains to DAAs and cannot benefit from currently available treatments; ii) the cost of these drugs remains very high.

Areas covered: This review summarizes pre-clinical and clinical data regarding HCV translation inhibitors, a new class of drugs currently in the pipeline with novel mechanisms of action.

Expert opinion: The availability of DAAs resolved most issues related to HCV treatment compared with the previous interferon-based therapies. However, there are some patients that cannot achieve a viral clearance with currently available treatments. Therefore, there is still room for new drugs in this setting, providing that they demonstrate an advantage in terms of efficacy, safety, cost or or simplicity of use. Based on preliminary results, at least for some promising molecules (e.g. miravirsen and RG-101), studies on safety and efficacy on this intriguing class of drugs are needed.

KEYWORDS:

• Miravirsen
• RG-101
• SPC3649
• ISIS-14803
• TT-034
• AVI-4065
• translation inhibitors
• DAA
• life cycle
• HCV

Article highlights

• Although the high efficacy of direct acting antivirals, the availability of new drugs against HCV is highly desirable for those patients who are not eligible to treatment or are non-responders to currently available drugs

• Targeting the factors involved in HCV translation may be a valid therapeutic approach, with probably no risk of cross-resistance with currently available antivirals

• Pre-clinical data about translation inhibitors showed their virological activity, regardless the presence of resistance to DAAs

• Few clinical trials showed the efficacy of some HCV translation inhibitors in significantly reducing HCV-RNA levels with a good tolerability profile.

• Available data show that translation inhibitors might have a future role in the treatment on HCV infected patients. However, further studies are needed to establish whether their introduction in clinical practice may have a significant impact in reducing treatment costs and in improving treatment efficacy, especially in decompensated patients or in those harboring HCV strains resistant to DAAs

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Declaration of interest

I Gertile has received a grant from Gilead Sciences (In the Framework of a Fellowship Program) for Hepatitis C and acts as a consultant for AbbVie. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.