Prevalence of Naturally-Occurring NS5A and NS5B Resistance-Associated Substitutions in Iranian Patients With Chronic Hepatitis C Infection

Rahimi, Pooneh; Sharafi, Heidar; Bahramali, Golnaz; SajadianFard, FaridehSadat; Asadi, Nafiseh Sadat; Alavian, Seyed Moayed; Mobarakeh, Vahid Iranpur; Moravej, Seyedeh Zahra

doi:10.3389/fmicb.2020.617375

Cited by 5 publications

(4 citation statements)

References 67 publications

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“…As a result, the detection rate of NS5A RASs in this study is consistent with the following studies ( Wyles, 2017 ; Dietz et al, 2018 ; Hernandez et al, 2013 ; Di Maio et al, 2018 ; Ghany et al, 2019 ; Hezode et al, 2018 ; Sharafi et al, 2019 ). Similarly, the overall proportion of amino acid substitutions at the baseline in the NS5A and NS5B regions of HCV ( Table 4 ) was very high, which is consistent with prior studies ( Lontok et al, 2015 ; Sarrazin, 2016 ; Gane et al, 2017 ; Palanisamy et al, 2018 ; Rahimi, 2021 ).…”

Section: Discussionsupporting

confidence: 88%

Emergence and Persistence of Resistance-Associated Substitutions in HCV GT3 Patients Failing Direct-Acting Antivirals

et al. 2022

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Background: The hepatitis C virus has a high mutation rate, which results in the emergence of resistance-associated substitutions (RASs). Despite direct-acting antivirals (DAAs) efforts to treat chronically infected HCV genotype 3 (GT3) patients, there are concerns about the emergence and persistence of RASs in DAA failures. The objective of this study was to determine the prevalence of clinically relevant RASs in HCV NS5A and NS5B regions before and after treatment to better understand the role of RASs in treatment failures.Methods: Viral RNA was extracted before and after treatment from serum samples. NS5A and NS5B regions of HCV were amplified by nested PCR, followed by Sanger sequencing. The nucleotide sequences were aligned against HCV GT3 reference sequences, and amino acid substitutions were analyzed using the geno2pheno [hcv] webserver.Results: A total of 76 patients failing DAA therapy were stratified from the cohort of 1388. RASs were detected at the baseline in 15/76 patients and at relapse in 20/76 patients with cirrhosis and previously treated with interferons. The most prevalent NS5A RAS was Y93H found in all treatment-failing patients (14/54 in DCV vs. 6/22 in VEL), followed by A62S/T and A30K. No RASs were identified in NS5B. RASs that were present at the baseline persisted through the 24-week follow-up period and were enriched with emerging RASs during the treatment. The presence of RASs may be one of the causes of treatment failures in 26.3% of patients. Amino acid substitutions were present at the baseline in most of the patients with RASs against NS5A inhibitors. Patients with the baseline Y93H and/or A30K relapse more frequently than patients harboring A62S/T.Conclusion: Treatment-failing patients harbored NS5A RASs, and the most frequent were A30K (5/20), A62S/T (20/20), and Y93H (20/20). Direct resistance testing is recommended for optimizing re-treatment strategies in treatment-failing patients.

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Section: Discussionsupporting

confidence: 88%

Emergence and Persistence of Resistance-Associated Substitutions in HCV GT3 Patients Failing Direct-Acting Antivirals

et al. 2022

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“…Baseline RAS were only identified in the NS5A region in Iranian patients with HCV genotypes 1a and 3a with no RAS in the NS5B region[ 54 ]. Among 539 Italian HCV genotype 3 patients (417 DAA-naïve and 135 DAA-failed), Sanger sequencing of NS3/NS5A/NS5B at baseline samples showed a higher prevalence of NS5A RAS in DAA-failed (5/13, 38.5%) vs DAA-naïve (61/393, 15.5%, P = 0.04) patients.…”

Section: Impact Of Direct-acting Antiviral Regimens On Hcv Infectionmentioning

confidence: 99%

Impact of direct-acting antiviral regimens on hepatic and extrahepatic manifestations of hepatitis C virus infection

Salama¹,

Raslan²,

Abdel‐Latif³

et al. 2022

WJH

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Hepatitis C virus (HCV) is a common cause of liver disease and is associated with various extrahepatic manifestations (EHMs). This mini-review outlines the currently available treatments for HCV infection and their prognostic effect on hepatic manifestations and EHMs. Direct-acting antiviral (DAA) regimens are considered pan-genotypic as they achieve a sustained virological response (SVR) > 85% after 12 wk through all the major HCV genotypes, with high percentages of SVR even in advanced fibrosis and cirrhosis. The risk factors for DAA failure include old males, cirrhosis, and the presence of resistance-associated substitutions (RAS) in the region targeted by the received DAAs. The effectiveness of DAA regimens is reduced in HCV genotype 3 with baseline RAS like A30K, Y93H, and P53del. Moreover, the European Association for the Study of the Liver recommended the identification of baseline RAS for HCV genotype 1a. The higher rate of hepatocellular carcinoma (HCC) after DAA therapy may be related to the fact that DAA regimens are offered to patients with advanced liver fibrosis and cirrhosis, where interferon was contraindicated to those patients. The change in the growth of pre-existing subclinical, undetectable HCC upon DAA treatment might be also a cause. Furthermore, after DAA therapy, the T cell-dependent immune response is much weaker upon HCV clearance, and the down-regulation of TNF-α or the elevated neutrophil to lymphocyte ratio might increase the risk of HCC. DAAs can result in reactivation of hepatitis B virus (HBV) in HCV co-infected patients. DAAs are effective in treating HCV-associated mixed cryoglobulinemia, with clinical and immunological responses, and have rapid and high effectiveness in thrombocytopenia. DAAs improve insulin resistance in 90% of patients, increase glomerular filtration rate, and decrease proteinuria, hematuria and articular manifestations. HCV clearance by DAAs allows a significant improvement in atherosclerosis and metabolic and immunological conditions, with a reduction of major cardiovascular events. They also improve physical function, fatigue, cognitive impairment, and quality of life. Early therapeutic approach with DAAs is recommended as it cure many of the EHMs that are still in a reversible stage and can prevent others that can develop due to delayed treatment.

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“…Portanto, o uso do método Sanger para a análise genotípica foi adequado, considerando o objetivo do estudo de analisar substituições de aminoácidos clinicamente relevantes. A respeito da amplificação dos genes, a eficiência acima de 90% para a NS5A foi similar àquela encontrada por Walker et al (2017) ZHOU, 2017;WELZEL et al, 2017;BERTOLI et al, 2018;KYUREGYAN et al, 2020;RAHIMI et al 2021). No estudo brasileiro supracitado, a Y93H foi identificada em apenas dois pacientes (1,2% do total de amostras amplificadas para a NS5A).…”

Section: O Estudo Foi Aprovado Pelounclassified

“…A S282T é a principal mutação potencialmente causadora de resistência ao SOF in vitro para todos os genótipos virais (SARRAZIN, 2016;SORBO et al, 2018;YOUNAS et al, 2022). Não foi encontrada nenhuma SAR na posição 282 à partir das análises pré-tratamento, o que corrobora os achados de outros trabalhos (BERTOLI et al, 2018;RAHIMI et al 2021;SANTOS et al, 2021) Nesse período, recomendava-se o uso de SOF + PEG + RBV com base em ensaios clínicos que mostraram taxas de RVS próximas a 90% (FOSTER et al, 2015;LAWITZ et al, 2015).…”

Section: O Estudo Foi Aprovado Pelounclassified

Efetividade, segurança e dinâmica de seleção de mutações de resistência envolvendo o uso de fármacos de ação direta na infecção crônica pelo genótipo 3 do HCV

Rodrigues

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Dedico este trabalho aos meus pais, José Lucas e Josefina, pelo exemplo que sempre foram por meio de valores e de suas condutas e por ensinarem, desde muito cedo, que a educação é o agente transformador que pode fazer a diferença na vida das pessoas e tornar a sociedade mais justa! Aos meus irmãos Carolline e Rodrigo, pela amizade e por também serem um exemplo de dedicação àquilo que fazem! À Marina, pela parceria e paciência, especialmente na parte final desta jornada! Ao amor da minha vida, Júlia, minha luz e o maior motivo para que eu siga em frente buscando ser um profissional e, principalmente, uma pessoa melhor! AGRADECIMENTOS Agradeço, em primeiro lugar, a Deus por me proporcionar saúde para conduzir esse trabalho!

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Prevalence of Naturally-Occurring NS5A and NS5B Resistance-Associated Substitutions in Iranian Patients With Chronic Hepatitis C Infection

Cited by 5 publications

References 67 publications

Emergence and Persistence of Resistance-Associated Substitutions in HCV GT3 Patients Failing Direct-Acting Antivirals

Emergence and Persistence of Resistance-Associated Substitutions in HCV GT3 Patients Failing Direct-Acting Antivirals

Impact of direct-acting antiviral regimens on hepatic and extrahepatic manifestations of hepatitis C virus infection

Efetividade, segurança e dinâmica de seleção de mutações de resistência envolvendo o uso de fármacos de ação direta na infecção crônica pelo genótipo 3 do HCV

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