Race or genetic makeup for hepatitis C virus treatment decisions?
Authors: Thomas R. O'Brien, Shyam Kottilil, Jordan J. Feld, Timothy R. Morgan, Ruth M. Pfeiffer
Journal: Hepatology (2017)

This research was supported by the Intramural Research Program of the National Institutes of Health (National Cancer Institute, Division of Cancer Epidemiology and Genetics). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government.Potential conflict of interest: Dr. Kottilil received grants from Gilead, Arbutus, and Merck. Dr. Morgan received grants from Gilead, AbbVie, Merck, and Roche. Dr. Feld consults and received grants from AbbVie, Gilead, Janssen, and Merck. He received grants from Abbott and Regulus. Author names in bold designate shared co‐first authorship. To the Editor: Examining data from the Veterans Administration health care system, Su et al.1 report high overall response rates with direct‐acting antiviral regimens for hepatitis C but also that 8 weeks of ledipasvir/sofosbuvir was less effective in black patients than whites. They suggest 8‐week treatment is contraindicated in black patients. Rather than race, it is preferable to use an individual's genetic makeup as the basis for clinical decisions. IFNL4 genotypes are strongly associated with spontaneous hepatitis C virus clearance and response to interferon‐α treatment for hepatitis C; higher frequencies of unfavorable IFNL4 alleles in blacks explained racial differences in those outcomes.2IFNL4 genotype may also explain lower response to ledipasvir/sofosbuvir in black patients. Previously, we showed that IFNL4 rs12979860 (IL28B) genotype was associated with relapse after 8‐week therapy with ledipasvir/sofosbuvir in ION‐3.3 Here we expand that analysis to include published data from two other treatment groups with at least 10 patients who suffered relapse after receiving ledipasvir/sofosbuvir in phase 3 trials: ION‐4 (hepatitis C virus/human immunodeficiency virus coinfected, 12‐week treatment)4 and seven pooled clinical trials of patients with compensated cirrhosis (12‐week treatment).5 Full rs12979860 genotype data were published for ION‐3 and ION‐4 (Table 1) with relapse rates of 0%‐2% for rs12979860‐CC genotype compared to 9%‐10% for rs12979860‐TT. Combining those studies reveals a highly significant association across genotype categories (Ptrend=0.0002); patients with rs12979860‐TT genotype were ∼4.5 times more likely to relapse than those with rs12979860‐CC. For patients with cirrhosis, data on all three genotype categories were not published; however, rs12979860‐CC patients had a 1.2% relapse rate (Table 1). Table 1 - Proportions of Patients Who Suffered Virological Relapse in Response to Treatment With Ledipasvir/Sofosbuvir, by IFNL4 rs12979860 Genotype Study/ ION‐3 (20/423) ION‐4 (10/322) ION‐3 and ION‐4 Combinedb Cirrhosis (15/307) (Relapses/Total) Relapse P Relapse P RR 95% CI P Relapse P IFNL4 rs12979860 CC 1.8% 0.0% 1.2% CT 4.9% 1.6% 2.74 0.74‐10.17 5.8%c TT 9.1% 0.03a 10.3% 0.001a 4.58 1.26‐16.56 0.0002a aP value for trend.bCochran‐Mantel‐Haenszel statistics were used to calculate combined relapse rates.cRelapse rate for CT and TT genotypes combined.95% CI, 95% confidence interval; RR, relative risk (of virological relapse). Our analysis is limited because individual patient data were unavailable. Also, although rs12979860 marks the functional IFNL4‐ΔG/TT variant, the latter is a better predictor of treatment response, especially in black patients.2 Therefore, we may have underestimated the association between IFNL4 genotype and relapse. Individual‐level data from populations of diverse racial composition are needed to fully explore relationships between IFNL4 genotype, race, and treatment response. With its large number of hepatitis C virus–infected patients, the Veterans Administration health care system could address this important question.