IL28B testing in a rapidly changing world: Still relevant?

Abstract

In 2009, a now seminal genome wide association study led to the discovery of a nucleotide polymorphism, rs12979860, upstream of the interleukin 28B (IL28B) gene. The CC IL28B genotype was associated with an over twofold improvement in response to treatment with pegylated interferon and ribavirin (PR) in patients with genotype 1 chronic hepatitis C virus (HCV) infection [1]. In an intention-to-treat analysis evaluating on-treatment virologic response and sustained virologic response (SVR) in a large cohort of genotype 1 HCV infected patients, the CC IL28B genotype was associated with an improved SVR in Caucasians of 69% as compared to 33% for the CT and 27% for the TT genotypes. These findings were similar across other ethnic groups. The CC IL28B genotype was the strongest pretreatment predictor of SVR. Rapid virologic response (RVR) was a strong predictor of SVR regardless of IL28B genotype, and in non-RVR patients, the CC IL28B genotype was associated with a higher rate of SVR [2]. Given the lack of alternative therapies, the multiple side effects of dual therapy, and the prolonged course of treatment with overall low rates of cure, IL28B testing held promise as a prime example of applying pharmacogenomics to the planning of antiviral therapy. However, the discovery came at a time when HCV treatment was undergoing significant evolution with the development of direct acting antiviral (DAA) agents. In 2011, the first generation HCV protease inhibitors, telaprevir, and boceprevir, were approved in combination with PR for genotype 1 HCV infection. With a nearly twofold increase in SVR compared to PR alone, the utility of IL28B genotyping could be called into question. Would the improved outcome for all comers accompanying telaprevir and boceprevir effectively nullify the predictive value of IL28B genotype? Or, could IL28B genotyping be used to determine which patients should succeed equally well receiving standard dual therapy versus triple therapy, especially given the cost of the DAAs? Could IL28B genotyping identify those patients who could receive an abbreviated course of therapy or could this question be answered with ontreatment virologic milestones alone? While IL28B genotyping was not available during the prospective randomized trials for