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  • The occurrence of naturally HCV NS resistance

    2021-11-29

    The occurrence of naturally HCV NS3 resistance-associated substitutions (RAS) affects virological outcome of DAA-based combination therapies [14], [15], [16], [17], [18], [19]. For the majority of NS3 protease inhibitors the frequency of natural occurrence of single RASs in HCV genotype 1-infected patients is between 0.1% and 3.1% [20] and patients who failed to respond to simeprevir treatment had mutations at NS3 positions 80, 122, 155, and/or 168 [21]. Naturally occurring resistance have been reported in 4.1% to 18.9% of HCV infected patients with baseline NS3 mutations [22], [23]. Detecting resistant variants at baseline in treatment-naïve patients infected with genotype 1 strains could represent an important background information to a more specific and efficient clinical conduct. The aim of this study was to determine the prevalence of naturally occurring RASs in the serine protease domain of HCV NS3 region in patients chronically infected with subtypes 1a and 1b.
    Patients and methods
    Results Overall RAS prevalence in this study was 13.7% (10/73). Among 73 patients enrolled in this study, 15 were treatment-experienced with first-wave PIs telaprevir/boceprevir (group 1) and 58 have not been treated with DAAs (group 2). The observation of amino SR 1555 hydrochloride residues of HCV NS3 in group 2 identified RASs at positions 36, 43, 54 and 80 in 6/58 (10.3%) patients. Regarding group 1 patients, RASs were identified in 4/15 (26.7%) at positions 36 (n = 3) and 155 (n = 1) in HCV 1a sequences. Regarding HCV subtypes, the frequency of RAS in subtype 1b was 17.4% (4/23) while in subtype 1a was 12% (6/50). Primary mutations V36M and R155K were observed only in HCV subtype 1a, whereas T54S and Q80K were identified only in HCV subtype 1b. The positions 156 and 168, which are highly related to resistance to PIs, remained conserved in all 73 sequences. The association between amino acid mutations identified in NS3 region and resistance to protease inhibitors for HCV subtypes 1a and 1b is exposed in Table 3. Regarding patients infected with HCV subtype 1a, 28.6% (4/14) from group 1 presented RASs while resistance strains were identified in 5.6% (2/36) of the individuals from group 2 (P = 0.044). For both groups, substitutions were observed at NS3 residue 36: 3 patients from group 1 presented RAS V36M and a combination of V36M+R155K was identified in another individual. For group 2, resistance strains V36L and V36M were found in two non-experienced patients.
    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 acid positions were evaluated and taken in consideration when calculation RAS proportion between subtypes.