Prevalence of naturally occurring NS5A resistance-associated substitutions in patients infected with hepatitis C virus subtype 1a, 1b, and 3a, co-infected or not with HIV in Brazil

Abstract

BackgroundNon-structural 5A protein (NS5A) resistance-associated substitutions (RASs) have been identified in patients infected with hepatitis C virus (HCV), even prior to exposure to direct-acting antiviral agents (DAAs). Selection for these variants occurs rapidly during treatment and, in some cases, leads to antiviral treatment failure. DAAs are currently the standard of care for hepatitis C treatment in many parts of the world. Nevertheless, in Brazil, the prevalence of pre-existing NS5A RASs is largely unknown. In this study, we evaluated the frequency of naturally occurring NS5A RASs in Brazilian patients infected with HCV as either a monoinfection or coinfection with human immunodeficiency virus (HIV).MethodsDirect Sanger sequencing of the NS5A region was performed in 257 DAA-naïve patients chronically infected with HCV (156 monoinfected with HCV and 101 coinfected with HIV/HCV).ResultsThe frequencies of specific RASs in monoinfected patients were 14.6% for HCV GT-1a (M28 V and Q30H/R), 6.0% for GT-1b (L31F/V and Y93H), and 22.6% for GT-3a (A30K and Y93H). For HIV/HCV-coinfected patients, the frequencies of RAS were 3.9% for GT-1a (M28 T and Q30H/R), and 11.1% for GT-1b (Y93H); no RASs were found in GT-3a sequences.ConclusionsSubstitutions that may confer resistance to NS5A inhibitors exist at baseline in Brazilian DAA-naïve patients infected with HCV GT-1a, −1b, and -3a. Standardization of RAS definitions is needed to improve resistance analyses and to facilitate comparisons of substitutions reported across studies worldwide. Therapeutic strategies should be optimized to efficiently prevent DAA treatment failure due to selection for RASs, especially in difficult-to-cure patients.

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 .…”

“…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.…”

Pretreatment Hepatitis C Virus NS5A/NS5B Resistance-Associated Substitutions in Genotype 1 Uruguayan Infected Patients

“…The presence of substitutions conferring resistance to NS5A inhibitors has been widely reported both in therapy-naïve and in relapser patients from Europe [ 10 , 33 , 35 – 38 ], USA [ 37 , 39 , 40 ], and Asia [ 41 – 43 ]. However, NS5A sequences from South America are poorly analyzed yet [ 9 , 44 ]. Recent studies have revealed that the mean prevalence of NS5A genotype 1 baseline RASs to different inhibitors ranges from 6% to 16% using population sequencing or deep sequencing [ 27 , 37 , 45 , 46 ].…”

Avaliação da efetividade e segurança dos novos fármacos de ação direta indicados no tratamento da hepatite C

“…Em estudo de vida real francês, que avaliou a efetividade do uso de SOF e DCV em 768 pacientes com genótipo 1, 95% dos pacientes alcançaram RVS12. Este estudo também demonstrou que a duração ideal do tratamento para pacientes não cirróticos é de 12 semanas e para pacientes cirróticos é de 24 semanas (POL et al, 2017 apresentavam tais mutações, sendo as mais frequentemente descritas M28V e Q30H/R; enquanto 6,0% dos pacientes genótipo 1b as apresentava, com predominância de L31F/V e Y93H (MALTA et al, 2017). Em nosso estudo observamos somente a mutação Y93H em dois dos pacientes testados.…”