Reverse Inflammaging: Long-term effects of HCV cure on biological age
Authors: Oltmanns Carlos , Liu Zhaoli , Mischke Jasmin , Tauwaldt Jan , Mekonnen Yonatan Ayalew , Urbanek-Quaing Melanie , Debarry Jennifer , Maasoumy Benjamin , Wedemeyer Heiner , Kraft Anke R.M. , Xu Cheng-Jian , Cornberg Markus 
Published: March 2022

AbstractBackground and AimsChronic hepatitis C virus (HCV) infection can be cured with direct-acting antiviral agents (DAA). 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.MethodsWe included 54 well-characterized patients with chronic hepatitis C 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 from peripheral blood mononuclear cells (PBMC) was generated and used to calculate epigenetic age acceleration (EAA) using Horvath’s clock.ResultsHCV patients had an overall significant EAA of 3.12 years at baseline compared with -2.61 years in the age-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 patients who developed hepatocellular carcinoma after SVR had the highest EAA and showed no evidence of reversal after SVR.ConclusionsOur data contribute to the understanding of the biological impact of HCV elimination after DAA and demonstrate that HCV elimination can lead to “reverse inflammaging”. In addition, we provide new conceptual ideas for the use of biological age as a potential biomarker for HCV sequelae after SVR.Lay SummaryChronic hepatitis C virus infection is now curable with direct acting antiviral agents (DAA), but are concomitant and sequelae also fully reversible after cure? Recent data demonstrate that chronic viral infections lead to an increase in biological age as measured by epigenetic DNA methylation status. Using a unique cohort of hepatitis C patients with and without cirrhosis as well as progression to HCC, we demonstrated that these epigenetic changes and concomitant increase in biological age are also observed in chronic HCV infection. Our data further suggest that this effect seems to be partially reversible in the long-term course after sustained virological response (SVR) by DAA therapy and that biological regeneration occurs. In this regard, the recovery effect appears to be dependent on disease course and was significantly lower in patients with progression to HCC. This suggests the use of biological age based on epigenetic state as a potential biomarker for HCV sequelae.Graphical abstractHighlights-Patients with chronic hepatitis C have accelerated epigenetic age compared with healthy controls.-DAA treatment and HCV elimination partially reverse the accelerated epigenetic age in the long-term follow-up.-Patients who developed hepatocellular carcinoma after HCV elimination did not show reversal of accelerated epigenetic aging during the follow-up.