We read with interest the article from Noureddin et al. demonstrating that interleukin-28B (IL28B) CC genotype was associated with greater hepatic inflammation, higher alanine aminotransferase (ALT), and worse clinical outcomes in patients with chronic hepatitis C virus (HCV) infection. However, we wonder whether the authors considered adjusting for HCV RNA levels? The hypothesis would be that the relationship between IL28B CC genotype and increased disease progression may be confounded by HCV RNA levels in those with the IL28B CC genotype.
Individuals with the IL28B CC genotype have higher HCV RNA levels during acute and chronic infection. In the InC3 Study, a collaborative of nine prospective international cohorts of acute HCV infection, among those with untreated persistent HCV infection and HCV RNA levels 12 months following infection (n = 224), male gender (versus female, adjusted odds ratio [AOR] = 2.38; 95% confidence interval [CI] = 1.19-4.76; P = 0.02), IL28B CC genotype (versus TT/CT, AOR = 2.26; 95% CI = 1.21-4.20; P = 0.03), and HCV genotype 1 (versus genotype 3, AOR = 2.13; 95% CI = 1.03-4.55; P = 0.04) were independently associated with high HCV RNA levels at 12 months following infection.
Although studies have suggested that HCV RNA levels are not associated with disease progression, HCV RNA may mediate liver disease progression by cumulative HCV RNA exposure (over the duration of infection) or by absolute HCV RNA levels (by way of immune responses and/or hepatic inflammation). It is possible that HCV RNA levels have greater clinical effect in later stages of liver disease.
To better understand the independent effect of IL28B genotype on HCV natural history, the impact of HCV RNA levels should be considered as a potential confounder which may partially explain or contribute to the observed associations or lack thereof. This important work could shed light on whether increased HCV RNA levels or cumulative HCV RNA exposure among those with IL28B CC genotype has any impact on HCV natural history during advanced disease. We urge the authors to assess whether HCV RNA levels and duration of infection were associated with outcomes measured in their study and whether this varied by IL28B genotype.