RESUMO
Spontaneously occurring resistance may impair the success of protease inhibitors based regimens in HCV treatment. This study aimed to evaluate associations between amino acid substitutions in NS3/NS4A domain and clinical features of 247 HCV mono or HCV/HIV co-infected patients. Fourteen samples (5.7%) harbored at least one resistance-associated substitution (RAS). The following RASs were detected in NS3 region: T54S (6-2.4%), V55A (7-2.8%), and Q80R (2-0.8%). S122G occurred in 86.9% of HCV genotype 1b samples with either natural polymorphisms or RASs. Advanced liver fibrosis and HIV co-infection were not related to NS3/NS4A amino acid substitutions.
Assuntos
Coinfecção , Infecções por HIV/complicações , Hepacivirus/genética , Hepatite C Crônica/virologia , Polimorfismo Genético , Proteínas não Estruturais Virais/genética , Adulto , Antivirais/uso terapêutico , Brasil/epidemiologia , Farmacorresistência Viral/genética , Feminino , Genótipo , Infecções por HIV/epidemiologia , Infecções por HIV/virologia , Hepacivirus/enzimologia , Hepacivirus/isolamento & purificação , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/epidemiologia , Humanos , Cirrose Hepática/epidemiologia , Cirrose Hepática/etiologia , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Inibidores de Proteases/uso terapêutico , Análise de Sequência de DNARESUMO
BACKGROUND: Nucleoside/nucleotide analogue (NA) treatment causes selection pressure for HBV strains carrying mutations conferring NA resistance. Drug-resistance mutations occur in the reverse transcriptase (RT) region of the HBV polymerase gene and spontaneously arise during viral replication. These mutations can also alter the hepatitis B surface (HBs) protein and in some cases reduce binding to HBs antibodies. The spread of NA-resistant HBV may impact the efficacy of antiviral treatment and hepatitis B immunization programmes. In this study, we used direct sequencing to assess the occurrence of HBV carrying known mutations that confer NA resistance in the largest cohort of treatment-naive patients with chronic hepatitis B (CHB) to date. METHODS: HBV DNA samples isolated from 702 patients were sequenced and the RT region subjected to mutational analysis. RESULTS: There was high genetic variability among the HBV samples analysed: A1 (63.7%), D3 (14.5%), A2 (3.3%), A3 (0.1%), B1 (0.1%), B2 (0.1%), C2 (0.9%), D1 (0.9%), D2 (4.6%), D4 (5.1%), D unclassified subgenotype (0.7%), E (0.6%), F2a (4.6%), F4 (0.4%) and G (0.4%). HBV strains harbouring mutations conferring NA resistance alone or combined with compensatory mutations were identified in 1.6% (11/702) of the patients. CONCLUSIONS: HBV strains harbouring resistance mutations can comprise the major population of HBV quasispecies in treatment-naive patients. In Brazil, there is a very low frequency of untreated patients who are infected with these strains. These findings suggest that the spread and natural selection of drug-resistant HBV is an uncommon event and/or most of these strains remain unstable in the absence of NA selective pressure.
Assuntos
Antivirais/farmacologia , Farmacorresistência Viral/genética , Produtos do Gene pol/genética , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/virologia , Mutação , Adenina/análogos & derivados , Adenina/farmacologia , Anticorpos Antivirais/genética , Anticorpos Antivirais/imunologia , Brasil , DNA Viral/genética , DNA Viral/imunologia , Produtos do Gene pol/antagonistas & inibidores , Produtos do Gene pol/metabolismo , Genótipo , Guanina/análogos & derivados , Guanina/farmacologia , Antígenos de Superfície da Hepatite B/genética , Antígenos de Superfície da Hepatite B/imunologia , Vírus da Hepatite B/genética , Vírus da Hepatite B/imunologia , Hepatite B Crônica/diagnóstico , Hepatite B Crônica/imunologia , Humanos , Lamivudina/farmacologia , Testes de Sensibilidade Microbiana , Organofosfonatos/farmacologia , Estudos Retrospectivos , Análise de Sequência de DNA , Tenofovir/farmacologia , Replicação Viral/efeitos dos fármacosRESUMO
BACKGROUND: HCV has a high replication rate and a lack of proofreading activity, leading to a greatly diverse viral population. This diversity may lead to emergence of resistant strains in direct-acting antiviral therapy. The frequency of naturally occurring HCV protease inhibitor (PI) mutations has been addressed in many countries, but there are few data on the prevalence of these mutations in Brazilian patients. METHODS: We evaluated the sequence of HCV NS3 protease gene in 247 patients (135 HCV-monoinfected and 112 HIV-HCV-coinfected patients). HCV RNA was extracted from plasma and a fragment of 765 base pairs from the NS3 region was amplified and sequenced with Sanger-based technology. RESULTS: HIV-HCV-coinfected patients were more likely to be older than 40 years and have an HCV subtype-1a infection. Overall, 21.9% of patients had at least one amino acid substitution in the NS3 region; 14 patients (5.7%) harboured at least one resistance mutation (T54S, V55A, Q80R) and the Q80K mutation was not found in our case series. There was no difference between monoinfected and coinfected patients regarding the frequency of natural polymorphisms and resistance mutations. CONCLUSIONS: Baseline HCV NS3 amino acid substitutions identified herein are considered mostly natural polymorphisms with no clinical impact on PI-based therapy. The identified resistance mutations may be associated with low-level resistance to PIs in vitro. Q80K substitution seems to be a rare event in Brazil. HIV coinfection was not associated with a greater frequency of such substitutions in the studied sample.