To the Editor:

We read with interest the article from Noureddin et al.[1] 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[2] and chronic[3] infection. In the InC3 Study, a collaborative of nine prospective international cohorts of acute HCV infection,[4] 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,[5] 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.


The InC3 Study is supported by the National Institute on Drug Abuse Award Number R01DA031056. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Drug Abuse or the National Institutes of Health. The Kirby Institute is funded by the Australian Government Department of Health and Ageing. The views expressed in this publication do not necessarily represent the position of the Australian Government. JGr is supported by a National Health and Medical Research Council (NHMRC) Career Development Fellowship. GD is supported by an NHMRC Practitioner Research Fellowship.

  • Jason Grebely, Ph.D.1

  • Bart Grady, M.D.2

  • Behzad Hajarizadeh, M.D.1

  • Kimberly Page, Ph.D.3

  • Gregory J. Dore, B.Sc., MBBS, MPH, Ph.D.1On Behalf of the InC3 Study Group

  • 1The Kirby Institute The University of New South Wales Sydney, Australia

  • 2GGD Public Health Service of Amsterdam Amsterdam, The Netherlands

  • 3Department of Epidemiology and Biostatistics University of California, San Francisco San Francisco, CA, USA


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