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Predicting responsiveness of genotype 1 hepatitis C viral infections to combined pegylated-interferon and ribavirin-based therapies
Individuals with hepatitis C virus (HCV) genotype 1 infections have variable responses to treatment with pegylated-interferon and ribavirin combination therapy. Some individuals will respond to treatment with sustained viral response, while other patients have poor response and fail to achieve sustained viral clearance.
Response to pegylated-interferon and ribavirin combination therapy in HCV genotype 1-infected individuals has been found to be closely associated with a single-nucleotide polymorphism (SNP), designated rs12979860, located 3 kilobases upstream from the interleukin 28B gene locus (IL28B) present on human chromosome 19.
HCV genotype 1-infected individuals with the CC genotype, as compared to either the CT or TT genotypes, of this SNP in IL28B have approximately 2- to 3-fold greater rates of sustained viral response to combined pegylated-interferon and ribavirin therapy.(1) Similar increases in sustained viral response rates were observed across various racial groups, including European Americans (95% CI, 1.8- to 2.3-fold), African Americans (95% CI, 1.9- to 4.7-fold), and Hispanics (95% CI, 1.4- to 3.2-fold).(1) The CC genotype has also been associated with a 3-fold increase in rate of spontaneous clearance of HCV.(2) The SNP in IL28B is only 1 of many factors that can influence response rates to pegylated-interferon and ribavirin combination therapy in HCV genotype 1 infection, and the SNP genotype result should be interpreted in the context of other clinical factors present in a given patient.
Frequency of the rs12979860 C allele varies across different racial and ethnic groups. The rs12979860 C variant is most frequently present in individuals from East Asia (allele frequency >0.9) and least common in individuals of African origin (allele frequency 0.2-0.5).(2) In a recent US-based study, the favorable CC genotype was observed in 37% of Caucasians, 29% Hispanics, and 14% of African Americans tested.
The mechanism by which the IL28B genotype mediates response to pegylated-interferon and ribavirin combination therapy among HCV genotype 1-infected individuals is not yet understood and is the subject of intense ongoing research. The impact of the IL28B-related polymorphism on response rates in patients infected with HCV genotypes other than genotype 1 is still being investigated.
An individual with IL28B-related rs12979860 CC genotype (ie, 2 copies of the C allele for the rs12979860 single-nucleotide polymorphism) responds more to pegylated-interferon and ribavirin combination therapy. Patients with CC genotype also show more spontaneous clearance of hepatitis C virus infection.
An individual carrying the IL28B-related rs12979860 CT genotype is less likely to respond to pegylated-interferon and ribavirin combination therapy.
An individual carrying the IL28B-related rs12979860 TT genotype is less likely to respond to pegylated-interferon and ribavirin combination therapy.
Patients who have received a heterologous blood transfusion within the preceding 6 weeks, or who have received an allogeneic blood or marrow transplant, can have inaccurate genetic test results due to presence of donor DNA. For liver transplant patients, the IL28B genotype of the recipient and the donor are independent predictors of sustained virologic response with combined pegylated-interferon and ribavirin therapy.(4)
This test does not detect polymorphism or mutations other than the single-nucleotide polymorphism of rs12979860 CT.
Drug-drug interactions and drug-metabolite inhibition must be considered.
Rare polymorphisms exist and could lead to false-negative or false-positive results.
1. Ge D, Fellay J, Thompson AJ, et al: Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 2009;461:399-401
2. Thomas DL, Thio CL, Martin MP, et al: Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature 2009;461:798-801
3. Thompson AJ, Muir AJ, Sulkowski MS, et al: Interleukin-28B polymorphism improves viral kinetics and is the strongest pre-treatment predictor of sustained virologic response in hepatitis C virus-1 patients. Gastroenterology 2010;139:120-129
4. Chalton MR, Thompson A, Veldt BJ, et al: Interleukin-28B polymorphisms are associated with histological recurrence and treatment response following liver transplantation in patients with hepatitis C virus infection. Hepatology 2011;53:317-324