Patient-specific genetic factors predict treatment failure in sofosbuvir-treated patients with chronic hepatitis C.

Abstract

BACKGROUND & AIMS:

According to pivotal clinical trials, cure rates for sofosbuvir-based antiviral therapy exceed 96%. Treatment failure is usually assumed to be because of virological resistance-associated substitutions or clinical risk factors, yet the role of patient-specific genetic factors has not been well explored. We determined if patient-specific genetic factors help predict patients likely to fail sofosbuvir treatment in real-world treatment situations.

METHODS:

We recruited sofosbuvir-treated patients with chronic hepatitis C from five Canadian treatment sites, and performed a case-control pharmacogenomics study assessing both previously published and novel genetic polymorphisms. Specifically studied were variants predicted to impair CES1-dependent production of sofosbuvir's active metabolite, interferon-λ signalling variants expected to impact a patient's immune response to the virus and an HLA variant associated with increased spontaneous and treatment-induced viral clearance.

RESULTS:

Three hundred and fifty-nine sofosbuvir-treated patients were available for analyses after exclusions, with 34 (9.5%) failing treatment. We identified CES1 variants as novel predictors for treatment failure in European patients (rs115629050 or rs4513095; odds ratio (OR): 5.43; 95% confidence interval (CI): 1.64-18.01; P = .0057), replicated associations with IFNL4 variants predicted to increase interferon-λ signalling (eg rs12979860; OR: 2.25; 95% CI: 1.25-4.06; P = .0071) and discovered a novel association with a coding variant predicted to enhance the activity of IFNL4's receptor (rs2834167 in IL10RB; OR: 1.81; 95% CI: 1.01-3.24; P = .047).

CONCLUSIONS:

Ultimately, this work demonstrates that patient-specific genetic factors could be used as a tool to identify patients at higher risk of treatment failure and allow for these patients to receive effective therapy sooner.

• Authors: Catrina M Loucks, Jennifer J Lin, Jessica N Trueman, Britt I Drögemöller, Galen E B Wright, Wan-Chun Chang, Kathy H Li, Eric M Yoshida, Jo-Ann Ford, Samuel S Lee, Pam Crotty, Richard B Kim, Bandar Al-Judaibi, Ute I Schwarz, Alnoor Ramji, Jeanette F Farivar, Edward Tam, Lori Lee Walston, Colin J D Ross, Bruce C Carleton
• Journal: Liver international : official journal of the International Association for the Study of the Liver (Liver Int) Vol. 42 Issue 4 Pg. 796-808 (04 2022) ISSN: 1478-3231 [Electronic] United States
• PMID: 35107877 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd.

Chemical References

• Antiviral Agents
• IFNL4 protein, human
• Interleukins
• Ribavirin
• Sofosbuvir

Topics

• Antiviral Agents (adverse effects)
• Canada
• Drug Therapy, Combination
• Genotype
• Hepacivirus (genetics)
• Hepatitis C, Chronic (drug therapy, genetics)
• Humans
• Interleukins (genetics)
• Ribavirin (pharmacology, therapeutic use)
• Sofosbuvir
• Treatment Failure
• Treatment Outcome