Treatment of chronic hepatitis C: Anticipated impact of resistance in patients treated with protease inhibitors

Abstract

A main target of specifically targeted antiviral therapy for hepatitis C (STAT-C) is the NS3-protease, which has key functions in the hepatitis C virus (HCV) replication cycle. HCV/NS3-protease inhibitors have shown high antiviral activity in vitro and in patients with chronic hepatitis C. Protease-resistant HCV variants occurred rapidly in patients receiving protease-inhibitor monotherapy. The development of resistance can be best explained by selection of preexisting resistant variants, which grow out under selective pressure. Numerous mutations associated with resistance were identified. Clinical trials showed that protease-resistant strains are sensitive to interferon and that a triple combination of protease inhibitors, peginterferon, and ribavirin may improve the sustained virologic response rate compared with standard peginterferon/ribavirin combination therapy. Overall, it can be anticipated that successful treatment with protease inhibitors will require either combination therapy with peginterferon/ribavirin or a combination of STAT-C compounds with distinct modes of action and resistance patterns.

Specific Detection of Naturally Occurring Hepatitis C Virus Mutants with Resistance to Telaprevir and Boceprevir (Protease Inhibitors) among Treatment-Naïve Infected Individuals

“…Boceprevir-resistant mutations included changes at positions V55A and V170A in addition to the previously known telaprevir mutations at positions V36A/M, T54A/S, R155K/T, and A156S (25). Development of drug-resistant HCV mutants generally occurs shortly after starting therapy, suggesting that generation of such viral variants is the result of purifying selection of preexisting resistant viruses, consequently leading to treatment failure (16). Thus, monitoring of resistant HCV mutants among individuals undergoing anti-HCV therapy is of importance to define the course of treatment.…”

Effect on Hepatitis C Virus Replication of Combinations of Direct-Acting Antivirals, Including NS5A Inhibitor Daclatasvir

“…In practice, resistance has emerged to all small-molecule inhibitors of HCV tested as monotherapy except some nucleoside-nucleotide NS5B inhibitors. Resistance mutations have been identified both in vitro and in vivo upon treatment with nearly all inhibitors of HCV serine protease, NS5A, or allo-steric RNA polymerase inhibitors advanced to date (3,19,22,23,24,30,36,38,51,52,57,60,62), with good correlation observed between resistance emergence in the replicon system and in vivo. Recent literature indicates that treatment with combinations of non-cross-resistant inhibitors not only improves antiviral activity during treatment but also suppresses the posttreatment viral rebound often associated with monotherapy (19,21,26).…”

Pharmacokinetics and Antiviral Activity of Phx1766, a Novel HCV Protease Inhibitor, Using An Accelerated Phase I Study Design

“…These compounds have been shown to induce impressive HCV RNA declines, and are at present investigated in Phase III studies [16,17]. However, it should be anticipated that DAAs still require combination therapy with PEG-IFN, and ribavirin as monotherapy is associated with frequent selection of resistant HCV variants [18][19][20].Triple therapy has been shown to improve sustained virological response rates but also induced additional side effects to the standard of care; rash is seen more often with the addition of telaprevir and anaemia is more severe when PEG-IFN and ribavirin are combined with boceprevir [21][22][23][24].…”