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    • adenosine triphosphate br Discussion As expected RAS prevale

    2022-01-29


    Discussion As expected, RAS prevalence for treatment-experienced patients who failed therapy with first-wave, first-generation drugs telaprevir/boceprevir was higher compared to non-experienced patients likely due to drug-selective pressure. For non-responders to previous therapy, resistance substitutions represent a negative prognosis factor for new treatments with DAAs [26], [27], [28]. For 4 patients analyzed in the present study who failed previous therapy, the presence of RAS might have been the cause of non-response while for other telaprevir/boceprevir non-responder patients in whom no RASs were detected, other host or virological factors could have contributed to unsuccessful treatment. Medical records did not describe how long, after the treatment with first-wave drugs, serum samples from non-responder patients were collected. Thus, since it would be expected that wild-type strains could re-emerge as the major viral population some time after the absence of selective pressure imposed by drugs, a therapeutic failure due to the presence of RAS could not be excluded. However, previous DAAs non-response could also be associated with other factors, such as infection with HCV subtype 1a, cirrhosis and high infective viral load [29]. NS3 RAS prevalence in group 2 was lower in subtype 1a (5.6%) compared to subtype 1b (18.1%). The presence of resistance in patients of subtype 1b not exposed to drug-selective pressure suggests a prime infection with RASs strains. Considering both groups, this study identified higher proportion of RASs in HCV subtype 1b sequences when compared to subtype 1a (17.4% vs. 12%), a distinct pattern from that observed in a previous Brazilian study enrolling blood donors, where the presence of RAS in subtype 1a was significantly higher than in subtype 1b (20% vs. 8%) [30]. This might be related to differences in the study population (more than 20% of our samples were from individuals previously experimented with DAAs) and/or which amino adenosine triphosphate positions were evaluated and taken in consideration when calculation RAS proportion between subtypes. According to literature, RASs V36M, T54S, Q80K and R155K are considered primary resistance mutations to different PIs. RASs V36M and R155K can reduce susceptibility to recently approved PIs simeprevir, paritaprevir and grazoprevir [18], [31], [32]. T54S is associated to resistance for first-wave telaprevir [33]. Q80K is highly associated with resistance to simeprevir [34]. The presence of RAS V36M in HCV strains could be related with therapeutic failure experimented by four patients in a previous treatment with telaprevir. The identification of this substitution in one patient from group 2 suggested a primary infection with a drug-resistant viral variant, an observation that warns for the circulation of resistant strains that could impact the effectiveness of DAAs in the near future. For all five patients with RAS V36M, combined therapy with new generation PIs should not be considered since V36M is associated with resistance to the majority of approved NS3 DAAs. Indeed, since it was already available in Brazil, treatment with sofosbuvir combined with daclatasvir was chosen and all five patients had similar treatment outcome which was undetectable HCV RNA after 12 weeks post-treatment. A study conducted a retrospective analysis to determine the prevalence of resistance mutations among telaprevir-treated patients [33] and V36M mutation was identified in 28/232 (12%) patients which failed telaprevir therapy, thus demonstrating its importance as a mutation indicative of resistance whose poor prognosis does not reveal reliability in the use of first-generation PI. Barnard et al. [35] identified resistance mutations in non-responders to triple therapy with boceprevir/peg-IFN/RBV infected with subtype 1a and concluded that V36M can be a major cause of therapeutic failure with the use of first-wave PIs. Results from the present study demonstrated that mutations at position 36 were found in both DAA-experienced and non-experienced patients included in the study, which indicated that treatment with DAAs other than PI should be considered in order to minimize risk of resistance and achieve SVR in these patients.