Abstract
The selection of viral strains with resistance-associated substitutions at hepatitis C virus (HCV) NS5A and NS5B genes is considered one of the limiting factors for achieving sustained virologic response (SVR) to combination of direct-acting antivirals daclatasvir (DCV) and sofosbuvir (SOF). Since 2015, this interferon-free regimen has been available in Brazilian clinical routine for treating mono- and HCV/HIV-coinfected patients chronically infected with genotypes 1 and 3. Our aim was to assess SVR rate for Brazilian patients chronically infected with genotypes 1 and 3 after DCV/SOF therapy and the frequency of baseline RASs in HCV NS5A and NS5B genes. Serum samples were collected from 107 monoinfected patients and 25 HCV/HIV co-infected patients before antiviral therapy with DCV/SOF. Genetic diversity of NS5A and NS5B genes was assessed by direct nucleotide sequencing. Overall, SVR rate was 95.4% (126/132), and treatment failure occurred in five monoinfected and one HCV/HIV co-infected patient. NS5A RASs frequency was higher for HCV/HIV patients (28%) than monoinfected patients (16.8%). No difference was evidenced between mono- and HCV/HIV-coinfected groups (15% vs. 16%) regarding NS5B gene. Genotype (GT) 1b strains had significantly more baseline substitutions in NS5A (31.6%) than GT 1a and 3a. At least one primary NS5A RAS described in literature at loci 28, 30, 31 or 93 was identified in HCV GTs 1 strains for both groups. As for NS5B, RASs at positions 159 and 316 was observed only in GT 1b strains. This study highlighted that SVR rate in clinical routine in Brazil was similar to randomized clinical trials (89–98%). Our research provided genetic data about the circulation of resistant variants in Brazil. Despite its presence, most of identified baseline mutations did not negatively impact treatment outcome. Genetic diversity of circulating strains suggested that most of the Brazilian HCV chronic carriers are susceptible to new therapeutic regimens including recently approved DAAs.
Highlights
It is estimated that 71 million people worldwide are chronically infected with hepatitis C virus (HCV) and approximately 2.3 million individuals have HCV/HIV-coinfection [1]
An update in treatment guidelines has determined the incorporation of new direct-acting antivirals (DAAs) options for patients infected with GT 1a, such as: (1) NS3/4A protease inhibitor (PI) paritaprevir boosted with ritonavir (PTV/r) plus NS5A inhibitor ombitasvir (OBV) in combination with a non-nucleoside polymerase inhibitor dasabuvir (DSV); (2) SOF plus ledipasvir (LDV) and (3) elbasvir (EBV) and grazoprevir (GZV) [5]
Based on inclusion criteria indicated in 2015 clinical guidelines for using therapeutic regimen with DCV and SOF, this study enrolled 132 NS5A and NS5B inhibitors-naïve individuals chronically infected with HCV GTs 1 or 3a with advanced fibrosis (METAVIR score F3) or cirrhosis (F4), which attended the National Institute of Infectology Evandro Chagas (INI) and Gaffree & Guinle University Hospital (UNIRIO)
Summary
It is estimated that 71 million people worldwide are chronically infected with hepatitis C virus (HCV) and approximately 2.3 million individuals have HCV/HIV-coinfection [1]. The availability of all-oral direct-acting antivirals (DAAs) has further increased sustained virological response (SVR) rates, the primary objective for a successful therapy, usually evaluated 12 weeks after treatment conclusion [3]. These drugs target viral non-structural proteins NS3/4A, NS5A and NS5B. An update in treatment guidelines has determined the incorporation of new DAAs options for patients infected with GT 1a, such as: (1) NS3/4A protease inhibitor (PI) paritaprevir boosted with ritonavir (PTV/r) plus NS5A inhibitor ombitasvir (OBV) in combination with a non-nucleoside polymerase inhibitor dasabuvir (DSV); (2) SOF plus ledipasvir (LDV) and (3) elbasvir (EBV) and grazoprevir (GZV) [5]
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