Differences in the Serum 4β-hydroxycholesterol Levels of Patients with Chronic Hepatitis C Virus (HCV) Infection: A Possible Impact on the Efficacy and Safety of Interferon (IFN)-free Treatment

Autor: Tadashi Ikegami, Motoyuki Kohjima, Sho Ichiro Yara, Makoto Nakamuta, Yasushi Matsuzaki, Teruo Miyazaki, Akira Honda, Takeshi Hirayama
Rok vydání: 2018
Předmět:
Cyclopropanes
Male
0301 basic medicine
Pyrrolidines
medicine.disease_cause
Gastroenterology
cytochrome P450 (CYP) 3A4
chemistry.chemical_compound
0302 clinical medicine
4β-hydroxycholesterol
direct acting antivirals
Cytochrome P-450 CYP3A
Anilides
Treatment Failure
Sulfonamides
Imidazoles
Valine
General Medicine
Hepatitis C
Middle Aged
HCV
Original Article
Drug Therapy
Combination
Female
030211 gastroenterology & hepatology
oxysterol
medicine.drug
medicine.medical_specialty
Macrocyclic Compounds
Daclatasvir
Genotype
Proline
Lactams
Macrocyclic
Hepatitis C virus
Antiviral Agents
03 medical and health sciences
Sex Factors
Internal medicine
Internal Medicine
medicine
Humans
Aged
Ritonavir
business.industry
Case-control study
Hepatitis C
Chronic
Isoquinolines
medicine.disease
Hydroxycholesterols
Ombitasvir
030104 developmental biology
chemistry
Paritaprevir
Case-Control Studies
Asunaprevir
Carbamates
Interferons
business
Zdroj: Internal Medicine
ISSN: 1349-7235
0918-2918
DOI: 10.2169/internalmedicine.9479-17
Popis: Objective Since the majority of direct-acting antivirals (DAAs) that are used in the treatment of hepatitis C virus (HCV) infection are mainly metabolized by CYP3A4, it is hypothesized that inter-individual differences in CYP3A4 activity may be associated with the bioavailability of these agents. Methods The level of serum 4β-hydroxycholesterol (4βHC), a surrogate marker of CYP3A4 activity, was determined by LC-MS/MS in samples obtained from patients with HCV infection (CHCs) as well as healthy control subjects (CTLs). Serum samples obtained from patients treated with either asunaprevir/daclatasvir (ASV/DCV) or ombitasvir/paritaprevir/ritonavir (OTV/PTV/r) were used for additional assays. Results The serum 4βHC level in CHCs was significantly higher than that in CTLs, and a gender difference was seen among CHCs. In patients treated with OTV/PTV/r, the serum 4βHC level was observed to gradually decrease during the treatment period. In the cohort treated with ASV/DCV, 4 of 83 patients showed virological treatment failure. In pretreatment testing, an Invader assay detected a low prevalence of resistance-associated variants in these four patients. The average serum concentration of DCV/ASV in the treatment-failed group tended to be lower than that in the sustained virological response (SVR) group. The pretreatment serum 4βHC level in patients with treatment failure was significantly higher than that in patients with an SVR but in whom the prevalence of resistance-associated variants was low in the pretreatment setting. Conclusion The evaluation of CYP3A4 activity by measuring 4βHC before treatment may provide additional information that can potentially be used to select cost- and efficacy-optimized treatment of HCV.
Databáze: OpenAIRE
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