Hepatitis C virus resistance to the new direct-acting antivirals

ABSTRACT

Introduction: The treatment of hepatitis C virus (HCV) infection has dramatically improved in recent years with the widespread use of interferon-free combination regimens. Despite the high sustained virological response (SVR) rates (over 90%) obtained with direct-acting antivirals (DAAs), drug resistance has emerged as a potential challenge. The high replication rate of HCV and the low fidelity of its RNA polymerase result in a high degree of genetic variability in the HCV population, which ultimately explains the rapid selection of drug resistance associated variants (RAVs).

Areas covered: Results from clinical trials and real-world experience have both provided important information on the rate and clinical significance of RAVs. They can be present in treatment-naive patients as natural polymorphisms although more frequently they are selected upon treatment failure. In patients engaged in high-risk behaviors, RAVs can be transmitted.

Expert opinion: Although DAA failures generally occur in less than 10% of treated chronic hepatitis C patients, selection of drug resistance is the rule in most cases. HCV re-treatment options are available, but first-line therapeutic strategies should be optimized to efficiently prevent DAA failure due to baseline HCV resistance. Considerable progress is being made and next-generation DAAs are coming with pangenotypic activity and higher resistance barrier.

KEYWORDS:

• Drug resistance
• HCV
• resistance testing
• simeprevir
• sofosbuvir
• NS5A inhibitors

Article highlights

• The rapid development of DAAs has replaced interferon-based regimens as HCV therapy. However, the effectiveness of DAAs may be compromised by drug resistance.

• NS3/4A inhibitors and NS5A inhibitors display low barrier to resistance and broad cross-resistance to compounds within the same drug family. However, combination DAA therapy generally allows to overcome antiviral resistance.

• Sofosbuvir exhibits a high barrier to resistance, being mutation S282T rarely been recognized in vivo.

• RAVs causing resistance to NS5A inhibitors tend to compromise SVR in patients with advanced cirrhosis, infection with genotype 1a and 3 and/or prior interferon failure.

• The elevated costs of all-oral DAA therapies may push tailoring therapy; DAA resistance testing may be useful to help to identify the most convenient (cost-effective) treatment and retreatment option for each patient.

• Viral gene sequencing may recognize RAVs, with rates depending on HCV geno/subtype and sensitivity of methods used.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no 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 work was supported in part by grants from Instituto de Salud Carlos III (project nos. ICI14-00372, CES12/003, PI13/01574) and Fundación Investigación y Educación en Sida (IES).