Prevalence and Factors Related to Natural Resistance-Associated Substitutions to Direct-Acting Antivirals in Patients with Genotype 1 Hepatitis C Virus Infection

Abstract

This study aimed to assess the prevalence of natural resistance-associated substitutions (RASs) to NS3, NS5A and NS5B inhibitors in 86 genotype 1 Hepatitis C Virus (HCV)-infected patients from Buenos Aires, Argentina, and to determine their effect on therapy outcome. Additionally, virological, clinical and host genetic factors were explored as predictors of the presence of baseline RASs. NS3 RASs (39.2%) were more prevalent than NS5A RASs (25%) and NS5B RASs (8.9%). In the three regions, the frequencies of RASs were significantly higher in HCV-1b than in HCV-1a. The prevalence of Y93H, L159F and Q80K were 1.3%, 6.3% and 2.5%, respectively. IFNL3 CC genotype was identified as an independent predictor of the presence of baseline RASs in NS5A and NS3 genes (p = 0.0005 and p = 0.01, respectively). Sustained virologic response was achieved by 93.3% of the patients after receiving direct-acting antivirals (DAAs), although 48.7% of them showed baseline RASs related to the DAA-regimen. Notably, the prevalence of clinically relevant RASs in the three genes was lower than that observed around the world. The baseline presence of RASs in both subtypes did not appear to affect therapy outcome. These results support the need to evaluate resistance patterns in each particular country since RASs´ prevalence significantly vary worldwide.

Hepatitis C virus genotype 1 infection: Prevalence of NS5A and NS5B resistance‐associated substitutions in naïve patients from Argentina

“…Among the positions analyzed for NS5A, the L31M and Y93H ones have been evaluated as relevant resistance mutations since their baseline presence significantly affects DAA treatment outcomes . In the present study, the prevalence of L31M (6.7%) seemed to be higher than the one observed by most researchers, who found a prevalence around 0%‐5% . On the contrary, the frequency of Y93H (2.3%) did not reach the prevalence reported in Asiatic countries (10%‐19%) but was similar to that observed in studies carried out in Brazil .…”

“…In the present study, RASs were present in 25.8% of the NS5A sequences analyzed from Buenos Aires, Argentina. Even when RASs frequencies informed in the literature comprise wide values ranging between less than 10% to more than 40%, the prevalence observed in this study is higher when compared to most regional and worldwide studies . Differences in sample characteristics such as cohort size, positions analyzed, applied detection methods, uncertainty about prior exposure to DAA, and acting viral genotypes/subtypes can affect the rate of RASs, hindering comparison among different studies.…”

“…Contrary to expectations, findings from this study show a similar prevalence of NS5A RASs in patients infected with HCV‐1a and HCV‐1b. Most previous studies report a higher NS5A RASs prevalence in HCV‐1b infected patients; other studies from Brazil had shown similar prevalence in both subtypes or even higher in HCV‐1a …”

“…While several works had determined the worldwide prevalence of NS5A/B RASs, the information coming from South América is very scarce . It is known that RASs prevalence in both proteins varies by geographic region.…”

Direct-acting Antiviral in the Treatment of Chronic Hepatitis C: Bonuses and Challenges

“…Thence, amplification in HCV-specific CD8+ T cell responses is a direct result of decreased expression of T cell depletion markers [71]. In addition, 4 years after HCV clearance by DAA, a steady growth in the number of regulatory T cells was observed in patients, indicating that DAA has a sustained effect on immune function in the liver for a long period of time after the clearance of HCV [72]. Interestingly, however, the memory phenotype of CD4 T cells and CD8 T cells did not make changes during the course of treatment.…”