Management of HCV patients in cases of direct-acting antiviral failure

ABSTRACT

Introduction: Over 70 million people are infected with hepatitis C virus (HCV), increasing the risk of cirrhosis and hepatocellular carcinoma.

Areas covered: Since the approval of the first interferon-free direct-acting antiviral (DAA) therapy in 2011, a number of DAAs have been approved, and HCV is now considered curable. Until recently, however, there were no clear guidelines on how to re-treat patients who fail DAA therapy. Current protease inhibitors (PIs) are generally unaffected by earlier resistance-associated variants (RAVs), but many NS5A inhibitors continue to have overlapping resistance profiles, and NS5A RAVs can persist even in the absence of DAAs.

Expert opinion: Fortunately, RAVs affecting NS5B polymerase inhibitors are rare, making sofosbuvir a safe choice as the backbone of re-treatment therapies. Recent re-treatment guidelines that take into account genotype, fibrosis, treatment history, and RAV suggest that >90% of patients with prior treatment failures can be successfully re-treated with sofosbuvir/velpatasvir, sofosbuvir/velpatasvir/voxilaprevir or glecaprevir/pibrentasvir.

KEYWORDS:

• Direct-acting antiviral agents
• interferon-free therapy
• NS5A inhibitor
• polymerase inhibitor
• protease inhibitor
• resistance-associated variants
• sustained virological response
• sofosbuvir/velpatasvir/voxilaprevir
• glecaprevir/pibrentasvir

Article highlights

• Over 70 million people throughout the world have chronic HCV infection, placing them at a much greater risk of liver cirrhosis or cancer.

• Until recently, HCV therapies were based on interferon, which not only resulted in few cures but also frequently caused side effects, making many patients ineligible.

• In 2011, the first interferon-free direct-acting antiviral (DAA) therapy for HCV was approved in Japan, where it became widely used.

• Since then, a large number of new DAAs representing several classes have been introduced, leading to sustained virological response (SVR) rates above 95%, to the extent that HCV is now considered curable.

• However, the remaining 5% of patients fail to clear the virus, and unsuccessful treatment with DAA therapy can make the patient ineligible for re-treatment with certain regimens.

• Resistance-associated variants (RAVs) have been reported for all DAA classes and most if not all currently approved drugs, although their likely effect on re-treatment depends on multiple factors.

• Recent treatment guidelines recommend that nearly all patients with chronic HCV should be promptly treated.

• Even patients who have experienced prior DAA treatment failure are expected to respond well to either sofosbuvir/velpatasvir (with or without voxilaprevir) or glecaprevir/pibrentasvir.

Declaration of interest

Kazuaki Chayama received honoraria from MSD K.K., Bristol-Meyers Squibb, Gilead Sciences and AbbVie and research funding from Dainippon Sumitomo Pharma, TORAY, Eisai, Otsuka Pharma, Mitsubishi Tanabe Pharma, Daiichi Sankyo and Bristol-Meyers Squibb. Michio Imamura received honoraria and research funding from Bristol-Meyers Squibb.

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 apart from those disclosed.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they have served as a speaker or advisor for: Abbvie, Gilead, Merck and Biotest. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This research is partially supported by research funding from the Research Program on Hepatitis from the Japan Agency for Medical Research and Development [AMED] [grant number: 15fk0210001h0002].