Natural course of treated and untreated chronic HCV infection: results of the nationwide Hepnet.Greece cohort study E. K. MANESIS*, G. V. PAPATHEODORIDIS  , G. TOULOUMI à , A. KARAFOULIDOU§, J. KETIKOGLOU – , G. E. KITIS**, A. ANTONIOU à , S. KANATAKIS   , S. J. KOUTSOUNAS àà & I. VAFIADIS§§, FOR THE HEPNET.GREECE COHORT STUDY *Liver Unit, Euroclinic, Athens, Greece;  Academic Department of Medicine, Hippokration General Hospital, Athens, Greece; àDepartment of Hygiene, Epidemiology & Medical Statistics, Athens University Medical School, Athens, Greece; §2nd Regional Blood Transfusion & Hemophilia Center, ‘‘Laikon’’ Hospital, Athens, Greece; –State Department of Medicine, Hippokration General Hospital, Athens, Greece; **Department of Gastroenterology, ‘‘Papanikolaou’’ Hospital, Thessaloniki, Greece;   Department of Medicine, Red Cross Hospital, Athens, Greece; ààHepatology Service, Foundation of Social Insurance (IKA), Athens, Greece; §§Department of Propedeutic Medicine, Athens University Medical School, ‘‘Laikon’’ Hospital, Athens, Greece Correspondence to: Dr E. K. Manesis, Liver Unit, Euroclinic, Athens 115 21, Greece. E-mail: emanesis@med.uoa.gr Publication data Submitted 29 November 2008 First decision 13 January 2009 Resubmitted 26 January 2009 Accepted 11 February 2009 Epub Accepted Article 15 February 2009 SUMMARY Background Interferon (IFN-a)-based regimens have been used with varying success in the treatment of chronic hepatitis C (CHC) for over two decades. The effect of such treatments on the natural course of CHC has been evalu- ated in small clinical trials with conflicting results. Aim To investigate the natural course of IFNa-based -treated and untreated patients with CHC by analysing data from the HEPNET.GREECE study. Methods We retrospectively analysed 1738 patients from 25 Greek Centres (med- ian age 40.1; males 57.6%; cirrhosis 9.2%), 734 untreated and 993 trea- ted with IFNa-based regimens [44.7% sustained viral response (SVR)], followed-up for median 25.2 and 46.8 months, respectively. Results During follow-up, 48 patients developed liver decompensation and 24 HCC. Older age was significantly related to disease progression (HR = 2.6 per 10 years of increasing age). Stratified by baseline cirrho- sis, Cox analysis showed that patients with SVR, but not without SVR, had significantly lower hazard for events compared with nontreated patients (HR = 0.16; P < 0.001), whereas the detrimental effect of older age remained highly significant. Separate group analysis demonstrated that in cirrhosis, the beneficial effect of treatment was evident even without SVR. Treatment effect interacted significantly with age, indicat- ing that older patients, mainly noncirrhotic, gained the most benefit. Conclusions IFNa-based treatment does alter the natural course of CHC. A protective effect is mostly present in patients with SVR, but older patients, at higher risk of events, gain the greatest benefit. In established cirrhosis, treatment carries a protective effect even among those without SVR. Aliment Pharmacol Ther 29, 1121–1130 Alimentary Pharmacology & Therapeutics ª 2009 Blackwell Publishing Ltd 1121 doi:10.1111/j.1365-2036.2009.03974.x