What are the comorbidities in£uencing the management of patients and the response to therapy in chronic hepatitis C? Alfredo Alberti Department of Histology, Microbiology and Medical Biotechnologies, University of Padova, Padova, Italy Keywords comorbidities – depression – hepatitis C – HCV – insulin resistance Correspondence Alfredo Alberti, Venetian Institute of Molecular Medicine, Via Orus, 2, 35128 Padova, Italy Tel: 100 39 497 923 224 Fax: 100 39 497 923 250 e-mail: alfredo.alberti@unipd.it Received 1 November 2008 Accepted 10 November 2008 DOI:10.1111/j.1478-3231.2008.01945.x Abstract The natural history of chronic hepatitis C has been defined in several retrospective and prospective studies conducted in the last 20 years. These studies have clearly demonstrated that the outcome of chronic hepatitis C virus infection is profoundly influenced by a variety of cofactors and comorbidities. Many of the cofactors that affect the course of liver disease in hepatitis C also have a significant influence on the result of antiviral therapy. Unfortunately, comorbidities that have been shown to negatively influence the course and outcome of liver disease often reduce the chance of achieving a sustained virological response with pegylated interferon (PEG-IFN) and ribavirin treatment. The most important and frequent comorbid- ity influencing the course of chronic hepatitis C and the response to antiviral therapy is represented by the metabolic syndrome, and by the associated state of insulin resistance. Other comorbidities that have a negative influence on the progression of hepatitis C and on the response to antiviral therapy include excess alcohol intake, human immunodeficiency virus and hepatitis B virus co-infection and a number of conditions that reduce the benefit of therapy by affecting negatively compliance and/or adherence to adequate PEG-IFN or ribavirin doses. The management and treatment of chronic hepatitis C depend on a number of virus and host parameters and should be individualized. Virus-related factors that influence the management of patients with hepatitis C virus (HCV) and particularly the decision to observe or to treat and the schedule of pegylated interferon (PEG-IFN) plus ribavirin combination to be used are the serum viral load and the HCV genotype. The host factors that need to be taken into con- sideration primarily include age, stage of liver disease and all the many comorbidities that may influence the course of disease and the response to antiviral treat- ments. The decision to monitor the patients without therapy or to start antiviral treatment should be based on the integrated evaluation of prognostic factors in terms of the progression of disease and the probability of achieving a sustained virological response (SVR) and of contraindications to IFN and ribavirin. Young individuals infected with ‘easy-to-treat’ virus geno- types such as HCV-2 and HCV-3 are usually treated even with no or mild liver disease while, on the other side of the spectrum, elderly patients with high viraemia and HCV-1 are proposed for treatment only in the presence of progressive and/or advanced liver damage. A number of comorbidities have been shown to influence the course of chronic hepatitis C in a significant manner, and many of them also affect the probability of achieving a SVR with PEG-IFN plus ribavirin combination therapy. Unfortunately, most of the cofactors that negatively influence the natural course of liver disease, being associated with more rapid progression to cirrhosis and to end-stage com- plications, also influence negatively the response to antiviral therapy by reducing the probability of achiev- ing SVR. The comorbidities that have been shown to affect the course of hepatitis C (some of which can be modified or attenuated by intervention) consist ‘in primis’ of co-infection with hepatitis B virus (HBV) and/or human immunodeficiency virus (HIV) and of the metabolic syndrome inclusive of obesity, of insulin resistance and of overt type 2 diabetes. Other cofactors affecting both the course of the disease and the response to therapy are excess alcohol abuse and conditions favouring an iron overload. Finally, a group of comorbidities specifically affect the response to antiviral therapy by reducing adherence to adequate dosing and compliance. The most frequent in clinical practice are depression and a number of c  2009 John Wiley & Sons A/S 15 Liver International 2009; 29(s1): 15–18