Allan Peres-da-Silva1, Adilson José de Almeida2, Elisabeth Lampe3. 1. Laboratório de Hepatites Virais, Instituto Oswaldo Cruz/FIOCRUZ, Rio de Janeiro, RJ, Brazil. 2. Laboratório de Hepatites Virais, Instituto Oswaldo Cruz/FIOCRUZ, Rio de Janeiro, RJ, Brazil Hospital Universitário Gaffrée e Guinle/UNIRIO, Rio de Janeiro, RJ, Brazil. 3. Laboratório de Hepatites Virais, Instituto Oswaldo Cruz/FIOCRUZ, Rio de Janeiro, RJ, Brazil elampe@ioc.fiocruz.br.
Abstract
OBJECTIVES: Several promising NS5A protein inhibitors for hepatitis C virus (HCV) treatment, showing good antiviral activity, are currently being evaluated in clinical trials. However, viral breakthroughs associated with resistant variants have been observed, especially in patients infected with HCV-1a. We aimed to evaluate the occurrence of potential resistance mutations in the NS5A gene of HCV among Brazilian treatment-naive patients. METHODS: Direct sequencing of the HCV NS5A gene was performed in serum samples of 106 treatment-naive patients infected with subtypes 1a (n = 52) and 1b (n = 54). The sequence variability, signature patterns in amino acid sequences and variants associated with NS5A inhibitors were evaluated. RESULTS: The M28T and Y93H mutations were found in the subtype 1a sequences of two (3.85%) patients, and seven (13.46%) other patients presented the secondary mutation(s) H58P, E62D or H58P-E62D. For subtype 1b, the Y93H mutation was found in two (3.70%) patients and the substitutions R30Q, L31M, P58S and I280V were found in eight (14.81%) patients. Two distinct HCV-1a clades were distinguished by a phylogenetic analysis performed along with representative HCV-1a sequences and sequences containing HCV NS5A inhibitor resistance mutations retrieved from the Los Alamos database. All Brazilian sequences formed a large group of related sequences inside clade 1. It is noteworthy that 65.85% of sequences with substitution at sites 28, 30, 31 and 93 were found in clade 1. CONCLUSION: Brazilian HCV-1a sequences presented a peculiar pattern of amino acid composition, mutations and frequencies, which is distinct from other previously characterized sequences from other locations. The association of these findings with the outcome of treatment with NS5A inhibitors awaits further analysis.
OBJECTIVES: Several promising NS5A protein inhibitors for hepatitis C virus (HCV) treatment, showing good antiviral activity, are currently being evaluated in clinical trials. However, viral breakthroughs associated with resistant variants have been observed, especially in patients infected with HCV-1a. We aimed to evaluate the occurrence of potential resistance mutations in the NS5A gene of HCV among Brazilian treatment-naive patients. METHODS: Direct sequencing of the HCV NS5A gene was performed in serum samples of 106 treatment-naive patients infected with subtypes 1a (n = 52) and 1b (n = 54). The sequence variability, signature patterns in amino acid sequences and variants associated with NS5A inhibitors were evaluated. RESULTS: The M28T and Y93H mutations were found in the subtype 1a sequences of two (3.85%) patients, and seven (13.46%) other patients presented the secondary mutation(s) H58P, E62D or H58P-E62D. For subtype 1b, the Y93H mutation was found in two (3.70%) patients and the substitutions R30Q, L31M, P58S and I280V were found in eight (14.81%) patients. Two distinct HCV-1a clades were distinguished by a phylogenetic analysis performed along with representative HCV-1a sequences and sequences containing HCV NS5A inhibitor resistance mutations retrieved from the Los Alamos database. All Brazilian sequences formed a large group of related sequences inside clade 1. It is noteworthy that 65.85% of sequences with substitution at sites 28, 30, 31 and 93 were found in clade 1. CONCLUSION: Brazilian HCV-1a sequences presented a peculiar pattern of amino acid composition, mutations and frequencies, which is distinct from other previously characterized sequences from other locations. The association of these findings with the outcome of treatment with NS5A inhibitors awaits further analysis.
Authors: Ana Paula de Torres Santos; Vanessa Cristina Martins Silva; Maria Cássia Mendes-Corrêa; Marcilio Figueiredo Lemos; Fernanda de Mello Malta; Rúbia Anita Ferraz Santana; Gregório Tadeu Fernando Dastoli; Vanessa Fusco Duarte de Castro; João Renato Rebello Pinho; Regina Célia Moreira Journal: Rev Inst Med Trop Sao Paulo Date: 2022-09-30 Impact factor: 2.169
Authors: André F Santos; Gonzalo Bello; Luãnna L Vidal; Suiane L Souza; Daiana Mir; Marcelo A Soares Journal: Sci Rep Date: 2016-08-17 Impact factor: 4.379
Authors: Vanessa D Costa; Carlos E Brandão-Mello; Estevão P Nunes; Pedro Guilherme Corôa Dos Santos Silva; Lia Laura Lewis Ximenez de Souza Rodrigues; Elisabeth Lampe; Francisco Campello do Amaral Mello Journal: PLoS One Date: 2019-05-07 Impact factor: 3.240