Highlights
- •Individuals with chronic hepatitis C have accelerated epigenetic age compared to healthy controls.
- •DAA treatment and HCV elimination partially reverse the accelerated epigenetic age during long-term follow-up.
- •Accelerated epigenetic aging was not reversed during follow-up in those who developed HCC after HCV elimination.
Background & Aims
Chronic hepatitis C virus (HCV) infection can be cured with direct-acting antivirals
(DAAs). However, not all sequelae of chronic hepatitis C appear to be completely reversible
after sustained virologic response (SVR). Recently, chronic viral infections have
been shown to be associated with biological age acceleration defined by the epigenetic
clock. The aim of this study was to investigate whether chronic HCV infection is associated
with epigenetic changes and biological age acceleration and whether this is reversible
after SVR.
Methods
We included 54 well-characterized individuals with chronic hepatitis C who achieved
SVR after DAA therapy at three time points: DAA treatment initiation, end of treatment,
and long-term follow-up (median 96 weeks after end of treatment). Genome-wide DNA
methylation status was determined in peripheral blood mononuclear cells (PBMCs) and
used to calculate epigenetic age acceleration (EAA) using Horvath’s clock.
Results
Individuals with HCV had an overall significant EAA of 3.12 years at baseline compared
with -2.61 years in the age- and sex-matched reference group (p <0.00003). HCV elimination resulted in a significant long-term increase in DNA methylation
dominated by hypermethylated CpGs in all patient groups. Accordingly, EAA decreased
to 1.37 years at long-term follow-up. The decrease in EAA was significant only between
the end of treatment and follow-up (p = 0.01). Interestingly, eight individuals who developed hepatocellular carcinoma
after SVR had the highest EAA and showed no evidence of reversal after SVR.
Conclusions
Our data contribute to the understanding of the biological impact of HCV elimination
after DAA therapy and demonstrate that HCV elimination can lead to “reverse inflammaging”.
In addition, our data support the potential use of biological age as a biomarker for
HCV sequelae after SVR.
Impact and implications
Chronic hepatitis C virus infection is now curable with direct-acting antivirals,
but it remains unclear whether hepatitis C sequelae are fully reversible after viral
elimination. Our results suggest that epigenetic changes or acceleration of biological
age are reversible in principle, but this requires time, while a lack of reversibility
appears to be associated with the development of hepatocellular carcinoma. While most
clinical risk scores now take chronological age into account, it may be worthwhile
to explore how biological age might improve these scores in the future. Biological
age may be a cornerstone for the individualized clinical assessment of patients in
the future, as it better reflects patients' lifestyle and environmental exposures
over decades.
Graphical abstract
Graphical Abstract
Keywords
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Article info
Publication history
Published online: September 21, 2022
Accepted:
August 30,
2022
Received in revised form:
July 14,
2022
Received:
March 14,
2022
Footnotes
Author names in bold designate shared co-first authorship
Identification
Copyright
© 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
