Patient-specific genetic factors predict treatment failure in sofosbuvir-treated patients with chronic hepatitis C.
Liver Int
; 42(4): 796-808, 2022 04.
Article
em En
| MEDLINE
| ID: mdl-35107877
ABSTRACT
BACKGROUND & AIMS:
According to pivotal clinical trials, cure rates for sofosbuvir-based antiviral therapy exceed 96%. Treatment failure is usually assumed to be because of virological resistance-associated substitutions or clinical risk factors, yet the role of patient-specific genetic factors has not been well explored. We determined if patient-specific genetic factors help predict patients likely to fail sofosbuvir treatment in real-world treatment situations.METHODS:
We recruited sofosbuvir-treated patients with chronic hepatitis C from five Canadian treatment sites, and performed a case-control pharmacogenomics study assessing both previously published and novel genetic polymorphisms. Specifically studied were variants predicted to impair CES1-dependent production of sofosbuvir's active metabolite, interferon-λ signalling variants expected to impact a patient's immune response to the virus and an HLA variant associated with increased spontaneous and treatment-induced viral clearance.RESULTS:
Three hundred and fifty-nine sofosbuvir-treated patients were available for analyses after exclusions, with 34 (9.5%) failing treatment. We identified CES1 variants as novel predictors for treatment failure in European patients (rs115629050 or rs4513095; odds ratio (OR) 5.43; 95% confidence interval (CI) 1.64-18.01; P = .0057), replicated associations with IFNL4 variants predicted to increase interferon-λ signalling (eg rs12979860; OR 2.25; 95% CI 1.25-4.06; P = .0071) and discovered a novel association with a coding variant predicted to enhance the activity of IFNL4's receptor (rs2834167 in IL10RB; OR 1.81; 95% CI 1.01-3.24; P = .047).CONCLUSIONS:
Ultimately, this work demonstrates that patient-specific genetic factors could be used as a tool to identify patients at higher risk of treatment failure and allow for these patients to receive effective therapy sooner.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Hepatite C Crônica
/
Sofosbuvir
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Humans
País/Região como assunto:
America do norte
Idioma:
En
Revista:
Liver Int
Assunto da revista:
GASTROENTEROLOGIA
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Canadá