Prevention and management of treatment failure to new oral hepatitis C drugs

ABSTRACT

Introduction: Chronic hepatitis C virus (HCV) infection has become a curable disease. Sustained virologic response rates above 90% have been achieved with recommended direct-acting antiviral (DAA) combinations in most registration trials. However, outcomes in real-world patients are lower. In patients experiencing DAA failure, resistance-associated variants (RAVs) are almost universally selected. At this time it is unclear when and how to re-treat hepatitis C in patients with prior DAA failure.

Areas covered: The rate of DAA failure and predictors of lack of treatment response using distinct DAA combinations are analyzed. We discuss the management of HCV treatment failure and the impact of RAVs on re-treatment strategies.

Expert opinion: Failure to DAA combinations occurs more often in chronic hepatitis C patients with baseline predictors of poor response, such as those with RAVs, genotypes 3 or 1a, advanced liver cirrhosis, elevated serum HCV-RNA and perhaps HIV coinfection. Impaired antiviral efficacy is more frequent when multiple factors are present. On-treatment predictors of DAA failure are poor drug adherence and development of side effects. Extending the length of therapy, adding ribavirin and/or using DAA from other drug families may allow successful re-treatment of most prior DAA failures.

KEYWORDS:

• Hepatitis C
• treatment failure
• drug resistance
• sofosbuvir
• daclatasvir
• simeprevir
• paritaprevir

Article highlights

• Failure to current DAA combinations occurs in roughly 10% of chronic hepatitis C patients treated outside clinical trials.

• Most failures to oral DAA combinations are relapses instead of viral breakthroughs on therapy.

• DAA failures occur more frequently in treatment-experienced patients, those with advanced cirrhosis and HCV genotypes 3 or 1a infections.

• In non-cirrhotics patients, DAA failure is rare and generally seen only when therapy is given for less than 12 weeks.

• Virologic breakthrough during DAA therapy generally reflects poor drug adherence.

• DAA failure is frequently associated with emergence of RAVs but to sofosbuvir.

• HCV drug resistance testing will help choosing the most convenient salvage DAA regimen as re-treatment of prior DAA failures.

This box summarizes key points contained in the article.

Declaration of interests

This work was supported in part by grants from ISCIII-Fondos Feder (PI13/01574; ICI14/00372; CD14/0243; FI14/0264; CM13/0309; CES12/003; AC15/00038; and AC1500041) and Fundación Investigación y Educación en SIDA (F-IES). 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