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Baseline resistance associated substitutions in HCV genotype 1 infected cohort treated with Simeprevir, Daclatasvir and Sofosbuvir in Brazil - 20/06/20

Doi : 10.1016/j.clinre.2019.07.015 
Bruna Forte Aguiar a, 1 , Guilherme Rodrigues Fernandes Campos b, 1, , João Paulo Vilela Rodrigues a , Nayara Nathie Marques b , Bárbara Floriano Molina b , Cintia Bittar b , Fernanda Fernandes Souza c , Ana de Lourdes Candolo Martinelli c , Paula Rahal b , Leonardo Régis Leira Pereira a
a FCFRP-USP - University of São Paulo, Ribeirão Preto Faculty of Pharmaceutical Sciences–Café avenue, 14040-903 Ribeirão Preto, SP, Brazil 
b UNESP - São Paulo State University, Institute of Bioscience, Language and Exact Science–IBILCE, Department of Biology, Cristóvão Colombo Street, 2265, 15054-000 São José do Rio Preto, SP, Brazil 
c FMRP-USP–University of São Paulo, Ribeirão Preto School of Medicine, Bandeirantes Avenue, 3900, 14049-900 Ribeirão Preto, SP, Brazil 

Corresponding author.

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Highlights

The sustained virological response at 12 weeks post-treatment rate was 92.7% (93.9% for SOF plus DCV and 91.7% for SOF plus SMV).
No clinical or laboratorial factor was statistically associated with SVR.
Out of 144 blood samples, 70 (48.6%) had detected resistance associated substitutions (34.8% treated with SOF+DCV±ribavirin and 61.3% SOF+SMV±ribavirin).
Important mutations associated with resistance against DAAs were detected in NS3 (G122S, I170V, Y56F and V132I), NS5A (R30Q, P58H and Q62E) and NS5B (A421V, L159F and C316N).
Three out of 4 relapsing patients presented virus carrying baseline resistance substitutions.
Substitutions with direct effect on virus resistance were observed occurring simultaneously with compensatory mutations that can improve virus replication.

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Summary

Background

The World Health Organization estimates that 1% of the world population (71 million) is infected with hepatitis C virus (HCV). In 2015, three direct-acting antivirals (DAAs), simeprevir (SMV), sofosbuvir (SOF) and daclatasvir (DCV) were included in the Brazilian protocol for the treatment of chronic hepatitis C. Despite the fact that the use of these drugs is associated with higher treatment response rates and with lower incidence of side effects, studies have shown the association between the presence of viral resistance mutations and the failure of pharmacological treatment.

Aim

This way, this study aimed to evaluate the safety and effectiveness of treatment for HCV genotypes 1a and 1b infected patients with these DAAs, also analyzing the occurrence and prevalence of baseline resistance associated substitutions (RAS), observing the impact of these mutations into the treatment success.

Methods

Clinical data were collected from all the 262 HCV infected patients included for comparative analysis, while serum samples collected from 144 of these individuals, before treatment, were submitted to molecular biology approaches for mutation analysis into NS3, NS5A and NS5B regions.

Results

Regarding the treatment regimens, 49.6% of the patients received SOF+DCV±ribavirin and 50.4% used SOF+SMV±ribavirin. The sustained virological response at 12 weeks post-treatment (SVR12) rate was 92.7% (93.9% for SOF plus DCV and 91.7% for SOF plus SMV). No clinical or laboratorial factor was statistically associated with SVR. The most common adverse reactions were haematological events, nausea/vomiting, headache and asthenia. Out of 144 blood samples, 70 (48.6%) had detected RAS, 34.8% treated with SOF+DCV±ribavirin and 61.3% SOF+SMV±ribavirin. The resistance mutations against SMV were detected into NS3: substitutions G122S (28%), I170V (22.7%), Y56F (17.3%) and V132I (14.7%). The mutations against DCV R30Q (9.1%), P58H (6.1%) and Q62E (6.1%) were observed into NS5A, and for SOF the mutations A421V (10.6%), L159F (6.4%) and C316N (6.4%) were present inside NS5B viral protein. Four patients did not reach SVR, three of them presented viruses carrying RAS (1 treated with SOF+DCV and 2 with SOF+SMV). Some of these mutations, like R30Q (present in relapsing samples) and L159F, are well known by their influence on antiviral resistance, while others, like C316N, have a compensatory effect on viral fitness, maintaining these baseline RAS.

Conclusion

The use of treatment regimens composed of SOF and DCV or SOF and SMV showed a high SVR rate, despite of a high rate of RAS, and a good tolerability profile in patients with HCV genotype 1. However, the high occurrence of baseline RAS observed in this casuistic is still a concern and studies like this show the necessity to understand how they are maintained in the population and to direct more efficiently the use of DAAs.

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Keywords : HCV, Genotype 1, Baseline mutations, DAA treatment, Antiviral resistance


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