Treatment decisions in patients with chronic hepatitis C infection are currently based on clinical, demographic and virologic characteristics of infected patients. While these may be helpful from a population point of view, for any individual patient and provider, these baseline pretreatment characteristics are inaccurate in predicting treatment response in hepatitis C patients infected with genotype 1, the most common genotype found in the United States. We have confirmed in this study that the recently identified common genetic variant in the interferon lambda gene region is strongly associated with response to standard of care PEG-IFN/RBV in a tertiary care setting. The association among Caucasians was thus validated outside of the clinical trial setting. Because of the limited sample size of African Americans and other racial groups in this current study, we had inadequate power to detect statistical association in these groups, as was observed by Ge et al
. Nonetheless, inclusion of rs12979860 genotype and race in a multivariable model caused an attenuation of the effect of race on treatment response, indicating that the effect of race may be mediated in part through this polymorphism.
Our results extend the observations of Ge et al. and indicate that, among Caucasians, rs12979860 has a high specificity, similar to HCV genotype, the current best baseline indicator used for identifying patients who will achieve a SVR to anti-viral therapy. Used in conjunction with HCV genotype, rs12979860 may provide additional discriminatory power to identify likely responders to treatment.
Another interesting and previously unreported observation was the significantly different frequency of the rs12979860 genotype according to HCV genotype in Caucasian patients. HCV genotype 1 infected patients were less likely to have the rs12979860 ‘response’ genotype than were patients infected with HCV genotypes 2 or 3. While interesting, this relationship does not fully explain why patients infected with HCV genotypes 2 or 3 have significantly higher sustained response rates compared to those infected with HCV genotype 1; both the gene variant and HCV genotype remain independently associated with treatment response in the multivariable models we ran. Nonetheless, this observation could theoretically have some biological bearing on development of persistent or chronic (versus spontaneously cleared) HCV infection. The data could be interpreted in the context of a case-only study design, where an association between two factors (rs12979860 and HCV genotype) among cases of chronic HCV may reflect interaction between rs12979860 and HCV genotype in the development of chronic HCV 18, 19
. Based on these results, we would hypothesize that subjects with both HCV genotype 2/3 and rs12979860 CC would be more likely to develop chronic HCV and hence, less likely to spontaneously clear the virus than those with HCV genotype 1 and rs12979860 CT/TT. While this relationship may seem counterintuitive on account of HCV genotype 2/3 subjects having a significantly higher rate of treatment-induced viral clearance, it warrants further exploration in appropriate prospective studies of spontaneous clearance. We also considered that the association could have been due to referral bias, whereby chronic HCV patients who are difficult to treat may be over-represented among the Duke cohort, and these patients would be more likely to be HCV genotype 1 and rs12979860 CT/TT genotype. This bias could lead to an overestimate of the association between rs12979860 genotype and HCV genotype. However, when we analyzed a subset of treatment eligible patients with no prior treatment history we found a similar trend of association.
Although the rs12979860 SNP showed a remarkably strong association with treatment response in both the study by Ge et al
and our replication study, the exact causal variant underlying the observed genetic association has not been identified. This SNP lies closest to two genes encoding for interferon lambda proteins, λ2 and λ3. Interferon lambdas have previously been studied in the context of HCV infection and shown to suppress HCV replication in vitro20-22
. It is possible that the causal variant affects expression or function of one of these anti-viral genes, which may in turn affect viral control.
Interestingly, Ge et al.7
reported a paradoxical relationship to viral load in that the ‘responder’ allele of rs12979860 was statistically associated with a higher baseline viral load, inconsistent with the clinical observation that higher baseline viral load is typically associated with a poorer treatment response4-6
. We also confirmed this paradoxical association with off-treatment viral load in our expanded cohort of Caucasian patients from a tertiary care setting. The exact mechanism underlying this genetic association with high viral load and yet increased likelihood of treatment response remains to be determined.
There are several important clinical implications of this genetic association, originally reported by Ge et al 7
in a clinical trial population and confirmed in the present study in a tertiary care population. First, the rs12979860 SNP may be useful in determining which chronic HCV genotype 1 patients would be most likely to respond to treatment with PEG-IFN/RBV. Given the high prevalence of the rs12979860 ‘responder genotype’ in Caucasians (~40%), this could have a substantial impact on treatment decision-making. Our data support the potential utility of rs12979860 in predicting SVR in Caucasians, regardless of treatment history. However, additional prospective studies are needed to determine the true predictive value of this marker among all treatment-eligible patients including those from other racial/ethnic and HCV genotype groups, and taking into account non-compliant and relapsing patients as well. Ultimately, chronic HCV patients with the rs12979860 responder genotype may be more motivated to comply with treatment, or to undergo treatment in the presence of mild underlying liver disease, knowing that they have a higher likelihood of SVR.
These important genetic findings related to treatment response in patients with chronic hepatitis C infection suggest the possibility of personalized medicine for the treatment of this disease. Clinical trials are now necessary to determine whether HCV genotype 1 infected patients with the favorable rs12979860 responder genotype would benefit equally from shorter treatment duration with our current therapies or future therapies, thus reducing the cost and side effects associated with longer term treatment. How the rs12979860 responder genotype influences the outcomes to future anti-viral strategies, including those based upon protease and polymerase inhibition requires immediate attention and investigation. Understanding the clinical implications of this genetic, biologically plausible finding will be a major research agenda and priority.