Hepatitis C virus: Biological and clinical consequences of genetic heterogeneity

Hepatitis C Virus infection accounts for the majority of post-transfusion and sporadic hepatitis. In Western Europe, anti-HCV is detected in 0.4-1.5% of healthy blood donors. There is a high frequency of progressive chronic hepatitis, ranging from 50 to 80%, which leads to cirrhosis in 20-50% of patients after 10-20 years. Viremic patients with minimal biochemical abnormalities may have chronic liver disease histologically. There is growing evidence that virological features of HCV are associated with different clinical manifestations and response to therapy. The RNA genome consists of a 5' and 3' Untranslated Region, a structural domain encoding the core and envelope proteins, and a non-structural domain. Different HCV isolates show a high sequence heterogeneity, which has led to the classification of currently six genotypes and several subtypes. There is a marked difference in the geographic distribution of HCV genotypes, with types 1, 2 and 3a being most frequently found in western countries. In The Netherlands, subtype 1b accounts for approximately 60% of all cases of chronic HCV. Serologic diagnosis based on recombinant C-100 antigens (first generation immunoassays) only reliably detected type 1, due to the heterogeneity of the NS4 region; inclusion of more conserved proteins c22 and c33 (second generation assays) has largely improved sensitivity of anti-HCV testing. Genotype 1b is associated with more severe liver disease and with lower response rates for antiviral therapy, compared with types 2 and 3. Quasispecies nature and escape mutants may enable viral persistence and the development of chronic liver disease. As cross-reactivity between genotypes is unlikely, prevention of HCV disease may be dependent on the development of multivalent vaccines.