We found the presence of both risk loci, KIR2DS3 and IL28B-T, significantly increases the odds of failing to achieve SVR when compared to the presence of either marker alone and this improves identification of patients with a high likelihood of SVR prior to commencing antiviral therapy. Combining these no newly identified host genetic factors with other recognised predictors of SVR (age, baseline HCV-RNA levels, HCV genotype, liver fibrosis stage, pre-treatment IP10 levels) will aid patient management by improving prediction potential of SVR prior to embarking on PEG-IFN and ribavirin treatment. Furthermore, we have confirmed a genetic synergy between IL28B and KIR2DS3 in HCV viral clearance, originally observed in spontaneous clearance and now defined in the treatment induced setting.

Although a mechanism for the synergy is not yet known, it is clear that for patients with genotype 1/4 HCV and with both host genetic risk factors, an early and sustained impaired ability to clear virus in response to treatment is evident (see Figure S1). There was no observable impact of host immune genotype on viral kinetics for patients with non-genotype 1/4 HCV that may reflect their well documented rapid response to treatment. These data support the growing body of evidence that the innate immune system plays an important role in HCV clearance. Achievement of RVR is highly predictive of SVR upon completion of a full duration of PEG-IFN and ribavirin. However, failure to achieve RVR in isolation does not sufficiently discriminate responders from non-responders (50% of RVR negative group achieved SVR in this study) and therefore treatment is continued in all individuals.

Identification of factors that predict SVR in these RVR negative patients would significantly improve clinical management of this patient subgroup, and the data presented here provide an important contribution towards this goal. Combining IL28B and KIR2DS3 genotypes increased the likelihood of failing to achieve SVR in the RVR negative cohort of patients. This effect appeared to be independent of HCV genotype although sample numbers were small upon stratification (data not shown). In the RVR negative patients the negative predictive value (indicating correct prediction of treatment failure) of using both risk genetic loci increases to 95.45% (with sensitivity of 90% and specificity of 61,76%) compared to 86.

36% (with sensitivity of 78.57% and specificity Anacetrapib of 64.41%) for the presence of IL28B-T alone. These data suggest that patients that have achieved a RVR, or have one or no genetic risk factors should continue standard treatment. However, co-infected patients with unfavourable pre-treatment characteristics (i.e. HCV genotype 1/4 and/or presence of at least two host genetic risk factors, see Table 6) who fail to achieve RVR are highly unlikely to achieve SVR.