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

Takeshi Hirayama, Tadashi Ikegami, Akira Honda, Teruo Miyazaki, Sho Ichiro Yara, Motoyuki Kohjima, Makoto Nakamuta, Yasushi Matsuzaki

研究成果: ジャーナルへの寄稿記事

抄録

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.

元の言語英語
ページ(範囲)1219-1227
ページ数9
ジャーナルInternal Medicine
57
発行部数9
DOI
出版物ステータス出版済み - 1 1 2018

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Chronic Hepatitis C
Virus Diseases
Hepacivirus
Interferons
Cytochrome P-450 CYP3A
Safety
Serum
Ritonavir
Treatment Failure
Therapeutics
cholest-5-ene-3,4-diol
Individuality
Biological Availability
Antiviral Agents
Healthy Volunteers
Biomarkers
Costs and Cost Analysis

All Science Journal Classification (ASJC) codes

  • Internal Medicine

これを引用

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. / Hirayama, Takeshi; Ikegami, Tadashi; Honda, Akira; Miyazaki, Teruo; Yara, Sho Ichiro; Kohjima, Motoyuki; Nakamuta, Makoto; Matsuzaki, Yasushi.

:: Internal Medicine, 巻 57, 番号 9, 01.01.2018, p. 1219-1227.

研究成果: ジャーナルへの寄稿記事

Hirayama, Takeshi ; Ikegami, Tadashi ; Honda, Akira ; Miyazaki, Teruo ; Yara, Sho Ichiro ; Kohjima, Motoyuki ; Nakamuta, Makoto ; Matsuzaki, Yasushi. / 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. :: Internal Medicine. 2018 ; 巻 57, 番号 9. pp. 1219-1227.
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title = "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",
abstract = "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.",
author = "Takeshi Hirayama and Tadashi Ikegami and Akira Honda and Teruo Miyazaki and Yara, {Sho Ichiro} and Motoyuki Kohjima and Makoto Nakamuta and Yasushi Matsuzaki",
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TY - JOUR

T1 - Differences in the serum 4β-hydroxycholesterol levels of patients with chronic hepatitis C virus (HCV) infection

T2 - A possible impact on the efficacy and safety of interferon (IFN)-free treatment

AU - Hirayama, Takeshi

AU - Ikegami, Tadashi

AU - Honda, Akira

AU - Miyazaki, Teruo

AU - Yara, Sho Ichiro

AU - Kohjima, Motoyuki

AU - Nakamuta, Makoto

AU - Matsuzaki, Yasushi

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

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