March 6, 2014

Antiviral Research
Available online 25 February 2014
In Press, Uncorrected ProofNote to users

Commentary

Maximilian David Schneider, Christoph Sarrazin

Highlights

  • Hepatitis C virus resistance-associated variants (RAVs) pre-exist in quasispecies and can be selected under drug exposure.
  • NS3/4A protease inhibitors and NS5a inhibitors have a low genetic barrier to resistance and a high level of cross-resistance.
  • No significant resistance concerns have been observed for nucleoside polymerase inhibitors.
  • Resistance testing can be useful in special cases, such as DAA-experienced patients, HCV-subtype 1a.
  • Combination therapy with different classes of DAA can overcome antiviral resistance in the future.

Abstract

The treatment of chronic hepatitis C has fundamentally changed since the approval of the first direct-acting antivirals (DAA) in 2011. In addition to telaprevir and boceprevir, in 2014 two new NS3 protease inhibitors (simeprevir and faldaprevir), one non-nucleoside polymerase inhibitor (sofosbuvir) and one NS5a replication complex inhibitor (daclatasvir) have expanded the treatment options for chronic hepatitis C. Resistance-associated variants (RAV) are naturally produced during the HCV life cycle. The frequency of RAVs within HCV quasispecies mainly depends on their replicational fitness. Variants conferring resistance to nucleos(t)ide analogues have not been detected, and the majority of NS3 protease-resistant variants are present at low frequencies (0.1–3%) before initiation of DAA-based therapies. However, the Q80K variant conferring resistance to simeprevir has been observed in 9–48% of untreated HCV genotype 1a-infected patients, leading to reduced SVR rates. Resistant variants are detectable in the majority of patients with treatment failure to NS3 protease inhibitor- or NS5a inhibitor-based antiviral therapy. Long-term follow-up studies by population-based sequence analysis have shown the disappearance of resistant variants in the majority of patients, with median times to loss of mutations of 4–64 weeks. For the nucleotide analogue sofosbuvir, the emergence of the S282T resistant variant has been observed only in single patients, with reversion to wild-type within several weeks. Data are sparse on retreatment of patients with the same DAA or the same class of DAAs. However, retreatment with a different class of DAAs after failure of NS3 protease inhibitor-based therapy has been successful in small studies. This article forms part of a symposium in Antiviral Research on “Hepatitis C: next steps toward global eradication.”

Keywords: Hepatitis C virus; Direct-acting antivirals; Drug resistance; Sequencing

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