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Reverse inflammaging: Long-term
effects of HCV cure on biological age
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• Individuals with chronic hepatitis C have accelerated epigenetic age compared to healthy controls.
DAA treatment and HCV elimination partially reverse the accelerated epigenetic ageduring 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.
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.
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.
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.

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