We studied with interest the correspondence letter by Galmozzi et al.1 externally validating the findings about the impact of the combined genotyping of interleukin-28B (IL28B) polymorphisms rs12979860 and rs8099917 on the treatment outcome after interferon-based dual combination therapy.2 The authors genotyped 187 hepatitis C virus (HCV)-1 infected patients from an Italian cohort who received pegylated interferon and ribavirin. The overall genotype distribution of rs12979860 and rs8099917 and of the most prevalent combined genotypes rs12979860CC/rs8099917TT, rs12979860CT/rs8099917TT, and rs12979860CT/rs8099917TG were comparable to our cohort, as were the sustained virologic response (SVR) rates for the individual single nucleotide polymorphisms (SNPs). In contrast to our results, the authors were not able to confirm that carriers of the heterozygous genotype rs12979860CT benefit from the additional determination of rs8099917 for SVR prediction (rs12979860CT/rs8099917TT versus rs12979860CT/rs8099917TG: 43% vs 39%).
As the authors suggest, these discrepancies may be caused by divergences in sample size and differences in patient cohorts. To show this, we randomized our HCV samples into nine groups with different sample sizes, starting with 10% of the initial cohort. Significant differences between SVR rates of patients carrying the genotypes rs12979860CT/rs8099917TT and rs12979860CT/rs8099917TG were primarily observed in cohorts with ∼400 patients (Table 1), pointing out the importance of sample sizes. We further analyzed the effects of baseline parameters such as age, HCV RNA level, HCV subtype, gender, and fibrosis stage on the SVR rates of genotype rs12979860CT/rs8099917TT and rs12979860CT/rs8099917TG (Supporting Table 1). Again, it becomes obvious that the impact of additional genotyping of rs8099917 on the prediction of SVR is improved in patients with heterozygous genotype of rs12979860 who have high baseline HCV RNA levels (P = 3.7 × 10−5), HCV subtype 1a (P = 3.3 × 10−5), or severe fibrosis stages (P = 0.001), being female (P = 0.023), or of younger age (P = 0.029). Thus, the different patient characteristics most likely explain the differences in the SVR rates.
|Random Sample Size||Sample Number||Mean Age ±SD||Male||HCV RNA ≥400.000 IU/mL||Severe Fibrosis||SVR||P-value|
|rs12979680CT/ rs8099917TT||rs12979680CT/ rs8099917TG|
From that, one possibly may conclude that two SNPs are good in large cohorts but not relevant for clinical practice. However, the idea of large studies is to inform individual clinical practice. Our results derived from a large cohort suggest that algorithms and models that include both rs12979860 and rs809917 as well as baseline parameters and viral factors are informative to guide therapeutic decision making.3