Hepatitis C Genotypes and Quasispecies
Hepatitis C Virus Genotypes
An important variable for all patients with chronic hepatitis C virus (HCV) is the "genotype" of HCV with which they are infected. This is the strain of the virus to which they were exposed when they were infected, often many years prior to their evaluation, and it is determined by a simple blood test. Genotypes of HCV are genetically distinct groups of the virus that have arisen during its evolution.(1) Approximately 75% of Americans with HCV have genotype 1 of the virus (subtypes 1a or 1b), and 20-25% have genotypes 2 or 3, with small numbers of patients infected with genotypes 4, 5, or 6.(2) Most patients with HCV are found to have only one principal genotype, rather than multiple genotypes.(3, 4, 5) Genotype 4 is much more common in Africa than in many other parts of the world, genotype 6 is common in Southeast Asia, and each area of the world has its own distribution of genotypes.(6)
Clinical Significance of Hepatitis C Genotypes
Genotype generally has not been found in epidemiological studies to play a large role in liver disease progression due to HCV. Rather, genotype is of clinical importance principally as a factor in response to HCV treatments. With all treatments tested to date, patients with genotypes 2 and 3 are more than twice as likely as patients with genotype 1 to achieve a sustained virological response to therapy.(2, 3, 4 ,5, 7) In addition, when using combination therapy with interferon and ribavirin, patients with genotypes 2 or 3 generally are treated for only 24 weeks, whereas it is recommended that patients infected with genotype 1 receive treatment for 48 weeks.
Within all individuals, slightly different genetic versions of their genotype are present. Viral mutations occur over time spontaneously and in response to pressure from the host immune response, forming genetically distinct viral groups called quasispecies.(1) Genotypes represent major genetic differences, whereas quasispecies represent minor genetic differences within an individual. Quasispecies continue to evolve in an individual over time, whereas genotype does not change. Quasispecies can be measured quantitatively (viral complexity) and qualitatively (viral divergence over time).
Clinical Significance of Quasispecies
HCV quasispecies are of research interest, but their measurement has not yet been directly applicable to HCV management or treatment. An example of the significance of quasispecies is that, in acute HCV infection, isolates develop little genetic diversity in a particular region when they produce self-limited hepatitis, whereas they develop greater genetic diversity in the setting of persistent infection.(8) Thus, the dynamics of quasispecies evolution during acute infection may reflect the future course of infection. Quasispecies diversity also has been found to be stable or to increase in patients being treated with interferon and ribavirin who do not respond to therapy, whereas it decreases in responders.(9) HCV variants also can be used to prove linkage of infections that are associated epidemiologically. For example, molecular analysis has been used to link mother/infant pairs, to define HCV in apparently concordant sexual couples as virologically concordant or discordant, to prove nosocomial transmission of HCV between health care provider and patient, and to link needlestick recipients with the sources of infection.(10)
- Bukh J, Miller R, Purcell R. Genetic heterogeneity of hepatitis C virus: quasispecies and genotypes. Semin Liver Dis 1995;15:41-63
- McHutchison JG, Gordon SC, Schiff ER, et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C . N Engl J Med 1998; 339:1485-1492.
- Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomized trial. Lancet 2001; 358:958-965.
- Fried MW, Shiffman ML, Reddy R, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002; 347:975-982.
- Hadziyannis SJ, Sette H Jr, Morgan TR, et al. Peginterferon alpha-2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 2004; 140:346-355.
- Simmonds P. Genetic diversity and evolution of hepatitis C virus - 15 years on. J Gen Virol. 2004;85:3173-88.
- Zeuzem S. Heterogeneous virologic response rates to interferon-based therapy in patients with chronic hepatitis C: who responds less well?Ann Intern Med 2004; 140:370-381.
- Farci P, Shimoda A, Coiana A, et al. The outcome of acute hepatitis C predicted by the evolution of the viral quasispecies. Science 2000;288:339-344.
- Puig-Basagoiti F, Forns X, Furcic I, et al. Dynamics of hepatitis C virus NS5A quasispecies during interferon and ribavirin therapy in responder and non-responder patients with genotype 1b chronic hepatitis C. J Gen Virol 2005;86:1067-1075.
- Gretch DR. Diagnostic Tests for Hepatitis C. Hepatology (Suppl.)1997;26:43S-47S.