UBC Theses and Dissertations
The pharmacogenomics of hepatitis C : optimizing effectiveness and safety on treatment Lin, Jennifer Jae
Hepatitis C infection affects an estimated 71 million people globally and is responsible for 399,000 fatalities annually. Research advancing hepatitis C treatment practices are rapidly advancing, with abundant focus given to increasing optimizing efficacy of treatment and safety of the patients taking them. Considered a key drug in treating hepatitis C, sofosbuvir is widely used though expensive. Failed treatments are costly to the healthcare system and expose patients unnecessarily to risks of severe adverse reactions. Treatment failures are presumed to be due to viral or clinical risk factors, while patient-specific genetic factors are largely unexplored. This study recruited 359 real-world patients to assess the influence of genetic variation on the risks sofosbuvir-based treatment failure. The study replicated associations with IFNL4 (rs12979860; OR:2.25, 95%CI:1.15-4.06; P:0.0071), and found variants novel predictors in CES1 (rs115629050 or rs4513095; odds ratio (OR):5.43, 95%CI:1.64-18.01; P:0.0057) which activates sofosbuvir and IL10RB (rs2834167; OR:1.81, 95%CI:1.01-3.24; P:0.047) the receptor for IFNL4. Combining genetic risk factors with treatment regimen choice significantly improved the ability to predict treatment failure (P:0.0080). Once a staple of interferon-based regimens, ribavirin is currently used to increase treatment effectiveness in difficult-to-treat chronic hepatitis C patients. Its usefulness is constrained by the development of ribavirin-induced anemia requiring dosage modification or discontinuation in 30% of treated patients. Genetic variants in ITPA have been identified to predict this adverse effect, however known clinical and genetic factors do not entirely explain the risk. In 188 patients, this study replicated the associations of ITPA and VDR genetic variants with the development of ribavirin-induced anemia (rs1127354; OR:0.13, 95%CI:0.04-0.41, P:8.66x10⁻⁵; and rs1544410; OR:1.65, 95%CI:1.01-2.70, P:0.0437). Genome-wide analyses identified a novel association in GYPC (rs6741425; OR:0.12, 95%CI:0.04-0.34, P: 2.94 x10⁻⁶) that protects against ribavirin-induced anemia by increasing erythrocyte structural strength. Addition of GYPC significantly improved the model for predicting ribavirin-induced anemia (P:0.00216) in comparison to ITPA and VDR alone. Overall, patient-specific genetic factors were found to identify patients with double the risk of sofosbuvir treatment failure and five-fold reduced likelihood of serious ribavirin-induced anemia. The implementation of these findings can allow for patients to receive safer, more effective therapy sooner.
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