Naturally occurring NS3-protease-inhibitor resistant mutant A156T in the liver of an untreated chronic hepatitis C patient

Abstract

An increasing number of new hepatitis C virus NS3-protease inhibitors are being evaluated for the treatment of chronic hepatitis C. Treatment-induced selection of mutants conferring resistance to protease inhibitors has been shown both in vivo and in vitro. A specific mutation, A156T has been shown to confer high-level resistance to several such agents (BILN2061, VX-950, SCH446211 (SCH6) and SCH503034). Here we report the presence of the A156T mutation in close to 1% of NS3 sequences within the liver quasispecies of a chronic hepatitis C patient never treated with anti-NS3-protease inhibitors.

Development of an Intergenotypic Hepatitis C Virus (HCV) Cell Culture Method To Assess Antiviral Susceptibilities and Resistance Development of HCV NS3 Protease Genes from HCV Genotypes 1 to 6

“…Several resistant phenotypes have been observed in patients experiencing viral rebound during therapy and in replicon experiments (8,23,25,28). Resistant mutations arising under BILN 2061 pressure have been described at the three main positions, Arg155, Ala156, and Asp168 (8,25,28).…”

Variability and resistance mutations in the hepatitis C virus NS3 protease in patients not treated with protease inhibitors

“…Although some studies have reported a frequency of resistance mutations of less than 1% (Lu et al 2007, Bartels et al 2008, Cubero et al 2008, others have demonstrated a frequency that oscillates between 0.3-2.8% (Kuntzen et al 2008). Few studies have been conducted in Brazil and currently, there is only one study, which was conducted in Rio de Janeiro (RJ), that has reported the presence of a subtype 1a virus with a T54S mutation at a frequency of 4.1%.…”

“…Notably, resistant mutants may already be present in minor populations at a frequency of less than 1%, forming "quasispecies" in infected patients (Lu et al 2007, Cubero et al 2008). These mutants can then rapidly emerge after only a few days of treatment ).…”

Tracking the Evolution of MultipleIn VitroHepatitis C Virus Replicon Variants under Protease Inhibitor Selection Pressure by 454 Deep Sequencing

“…A viral quasispecies is characterized by a dominant nucleotide sequence, called a master sequence, and a surrounding mutant spectrum, which can harbor minority subpopulations (42). Although in theory all single and double mutants are produced daily in an infected person (6,40), it is important to note that mutation rates are not equally distributed over the entire genome and that additional factors, such as viral fitness and the replication environment, determine whether a mutation becomes fixed in a viral quasispecies population (12). The diversity of the viral variants present in an infected individual facilitates the adaptation of the quasispecies to external pressure, such as antiviral treatment, improving the survival chances of the population (53).…”

“…Recent reports have demonstrated that mutations known to affect the activities of DAA compounds in vitro are present in some treatment-naive patients as either dominant or minority species (6,13,19,21,27). With the eradication of variants susceptible to the antiviral drugs, resistant viruses initially present as minority species may expand to occupy the freed replicative space, thus becoming the dominant master sequence (1); this may lead to failure of the antiviral regimen.…”