Pathogenesis, diagnosis and management of hepatitis C

The hepatitis C virus (HCV) is the leading cause of chronic liver disease w orldwide. It is estimated that about 170 million people are chronically inf ected with HCV. Chronic hepatitis C is a major cause of cirrhosis and hepat ocellular carcinoma and HCV-related endstage liver disease is, in many coun tries, the first cause of liver transplantation. HCV infection is characterized by its propensity to chronicity. Because of its high genetic variability, HCV has the capability to escape the immune r esponse of the host. HCV is not directly cytopathic and liver lesions are m ainly related to immune-mediated mechanisms, which are characterized by a p redominant type 1 helper cell response. Co-factors influencing the outcome of the disease including age, gender and alcohol consumption are poorly und erstood and other factors such as immunologic and genetic factors may play an important role. Recent studies have shown that the combination therapy with alpha interfero n and ribavirin induces a sustained virological response in about 40% of pa tients with chronic hepatitis C. The sustained response rates are mainly de pendent on the viral genotype (roughly 60% in genotype non-1 and 30% in gen otype 1). Reliable diagnostic tools are now available and useful for detecting HCV in fection, to quantify viral load and to determine the viral type. The assess ment of the viral quasispecies and the characterization of viral sequences might be clinically relevant but standardized and simple techniques are nee ded. The lack of animal models and of in vitro culture systems hampers the under standing of the pathogenesis of chronic hepatitis C and the development of new antivirals. New therapeutic schedules with higher and/or daily doses of alpha interferon do not seem to improve the efficacy greatly. The conjugat ion with polyethylene glycol (PEG) improved the pharmacodynamics and the ef ficacy of alpha interferon. Emerging new therapies include inhibitors of viral enzymes (protease, helic ase and polymerase), cytokines (IL-12 and IL-10), antisense oligonucleotide s rand ribozymes. The first candidate compounds should be available in the next few years. The development of an effective vaccine remains the most difficult and pres sing challenge. Because of the high protein variability of HCV, protective vaccines could be extremely difficult to produce and therapeutic vaccines s eem more realistic. Considerable progress has been made in the held of HCV since its discovery 10 years ago but a major effort needs to be made in the next decade to cont rol HCV-related liver disease.