Resistance to HCV Treatment Can Still Be a Challenge

More than 3% of the global population is chronically infected with the hepatitis C virus (HCV). In the United States, chronic HCV infection is the most common cause of liver-related death and liver transplantation, and recently surpassed HIV infection as a cause of mortality.

The treatment of chronic HCV has been revolutionized by the development of direct-acting antivirals (DAAs). According to a recent editorial in a special issue of Viruses that is devoted to HCV drug resistance, French researchers Che C. Colpitts, PhD, and Thomas F. Baumert, MD, wrote that the development of DAAs provides the first real opportunity for global cure of a chronic viral infection and have markedly improved the outlook for HCV patients. However, as the editorial notes, a small fraction of patients taking DAAs do experience resistance and treatment failure.

Although antiviral resistance has been a significant challenge for interferon-based HCV therapies, drug resistance in patients taking DAAs seems to be limited to a small fraction of patients, the editorial states. Distinct genotypes, patients with advanced liver disease, liver transplantation, or patients with HIV/HCV co-infection may pose special challenges.

Resistant variants are seen in most patients who do not achieve a sustained virological response (SVR) to DAAs, underscoring the fact that resistance is a critical determinant of treatment outcome, Colpitts and Baumert noted. The mechanisms of resistance may vary depending upon the class of DAA, the genotype of HCV, and the patient group. The editorial notes that the research into these aspects of resistance is important because understanding these mutations has substantial clinical implications. Clinically relevant resistance data can help guide the choice and combination of DAAs used in therapy.

About 10% to 20% of patients with decompensated cirrhosis do not respond to current DAAs. And viral resistance and treatment failure has been observed among patients taking state-of-the-art DAAs pre- or post-liver transplantation, making management of patients difficult.

The editorial describes research now under way in a number of areas related to resistance to DAAs:

• DAAs that target the HCV RNA-dependent RNA polymerase (RdRp)
• Mode of action of different classes of RdRp and mechanisms of antiviral resistance.
• The selection of DAA-resistant viruses through the lens of quasispecies dynamics, highlighting genetic and phenotypic barriers to resistance that could be used to diminish the probability of viral breakthrough during therapy.
• Diagnostic tools that can monitor HCV resistance to new drugs in development and in patients receiving DAA therapy.
• The ability of DAAs to prevent liver graft reinfection.
• Host-targeting agents that target cellular factors involved in the HCV life cycle as a potential option to prevent and treat viral resistance, particularly in the context of liver transplantation.
• Chronic viral infections and an ongoing state of chronic inflammation that may contribute to the development of HCV-induced liver disease.
• The creation of in-vivo HCV infection models that will be critical for the assessment of HCV therapy response and the emergence of resistant variants.

There are new strategies under way to prevent and address the challenges of DAA resistance that will help to bring the goal of global HCV eradication closer to reality.