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  • Among RASs observed in patients from

    2022-07-04

    Among RASs observed in patients from group 2, RAS T54S was identified in one patient infected with subtype 1b. This mutation had been shown to cause resistance to boceprevir and telaprevir, but not to simeprevir [36]. This was confirmed here since this patient achieved SVR after 12 weeks of treatment with simeprevir. The low prevalence of RAS T54S (4.6%) in patients not treated with DAAs was also reported in previous Brazilian studies [30], [37]. In the present study, RAS Q80K was not observed in isolates of subtype 1a and was only detected in one subtype 1b sample from a group 2 patient with compensated hepatic cirrhosis, type 2 diabetes mellitus and systemic arterial hypertension. In 2016, this patient was asymptomatic and decided not to continue with other available DAA therapeutic options. Q80K is most frequently observed in subtype 1a isolates and is rarely detected in HCV subtype 1b [20]. Studies had reported the high prevalence of Q80K mutation in USA (37–47%) [38], [39]. Sarrazin et al. [40] evaluated NS3 baseline RASs from 467 patients and results for Q80 polymorphisms demonstrated high prevalence for PI treatment-experienced patients (110/265; 41.5%) and PI treatment-naive patients (93/202; 46%). In 3-isomangostin receptor to data from other countries, Q80K prevalence in Brazil is low [30], [37], [41]. Therefore, due to low prevalence of this mutation in Brazilian strains reported in previous studies and corroborated here, there is no need to incorporate pretreatment resistance tests for infected patients with subtypes 1a and 1b of HCV in Brazil. Even with the identification of this variant, the use of other PIs is not limited since there is no evidence with resistance. RAS R155K is related to resistance to first and second-wave PIs. A study reported a higher frequency of treatment failure for subtype 1a due to low genetic barrier to viral resistance when compared to subtype 1b [13]. Sarrazin et al. [36] described that combination of substitutions V36M + R155K induces high resistance to telaprevir and may inhibit drug action. In the present study, combination of mutations at loci 36 (V36M) and 155 (R155K) was identified in one telaprevir-experienced patient infected with HCV subtype 1a. After 12 weeks of therapy with telaprevir, viral load was 4.74 log10 IU/mL and it was decided to suspend the treatment. RAS R155K confers resistance to all available PIs for subtype 1a strains and new therapeutic options for this patient should target other non-structural HCV proteins. Indeed, in this case, a rescue therapy with NS5B and NS5A inhibitors was selected and HCV RNA was undetectable after 4 weeks. Substitutions V36L, F43V and Q80H were identified in the present study. RAS V36L is associated with resistance to boceprevir [18]. In 2015, Brazilian clinical practice guidelines on the management of hepatitis C no longer included combined therapies with boceprevir or telaprevir as a treatment option. RAS V36L was identified in one subtype 1a patient from group 2. A 12-week therapy with simeprevir was initiated. V36L was not related with less susceptibility to this drug and SVR was 3-isomangostin receptor achieved post-treatment. Analysis of mutations associated with resistance among patients infected with HCV subtype 1b indicated the presence of RAS F43V in a DAA treatment-naïve patient. To our knowledge, this is the first report of this mutation in vivo. Resistance profile for PIs was described in vitro and pointed out F43 locus as associated with resistance to simeprevir [18]. RAS Q80H, which can reduce susceptibility to simeprevir, was identified in one patient from group 2 infected with subtype 1b. Treatment with boceprevir was selected for this patient and Q80H did not influenced treatment response since SVR was achieved after treatment. No Brazilian data have described this mutation among treatment-naive patients.
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