DSEN Abstract
Hepatitis C Virus Treatment: Contribution of Patient Genetics in Ribavirin-induced Anemia
Summary and implications
In the treatment of chronic hepatitis C, ribavirin is often incorporated to improve treatment effectiveness. However, 1 in 3 treated patients develop severe anemia. This study found that a genetic variant in ITPA, which relieves oxidative stress, leads to a decreased risk of ribavirin-induced anemia. In contrast, a variant in the VDR gene increases oxidative stress and doubles the risk of anemia. Promising protective roles were identified for variants in GYPC, which is involved in red blood cell stability, and variants in IRF7 and RASGRP3, which play roles in red blood cell production.
Based on genetics, patients who are at a high risk of ribavirin-induced anemia can be identified before treatment begins.
Predicting which patients are at a high risk of serious ribavirin-induced anemia before treatment enables the use of risk-based ribavirin dosing. This would improve both health and safety for the patient and the likelihood of completing successful treatments in difficult-to-treat populations.
Authors: SEARCH & PREVENT Team of the CIHR Drug Safety and Effectiveness Network (DSEN)
For more information, please contact Dr. Bruce Carleton: bcarleton@popi.ubc.ca.
What is the current situation?
- In Canada, 12,447 cases of hepatitis C virus (HCV) were reported in 2018, representing a rate of 33.6 per 100,000 people and an increase of 13% since 2014.
- If untreated, hepatitis C infection can lead to liver-related complications (e.g., liver cancer) where complications resulted in approximately 400,000 deaths worldwide in 2015.
- Ribavirin, a broad-spectrum antiviral, is added in regimens for difficult-to-treat cases to prevent resistance and lower relapse rates of HCV to improve treatment effectiveness.
- Ribavirin is also used to treat hepatitis E, paramyxovirus infections, and it is the only known or licenced treatment for Lassa fever and pediatric repiratory syncytial virus.
- Despite its clinical utility, ribavirin use is accompanied by the development of serious hemolytic anemia in 1 of 3 treated patients, which can lead to treatment discontinuation.
- Clinical risk factors are not sufficient to predict who will develop serious ribavirin-induced anemia.
What was the aim of the study?
- To examine the extent to which patient-specific genetic factors help predict ribavirin-induced anemia in Canadian patients with chronic HCV.
How was the study conducted?
- Patients who received ribavirin-containing antiviral therapy to treat hepatitis C were recruited from adverse drug reaction surveillance sites across Canada that are part of the SEARCH & PREVENT Team of the CIHR Drug Safety and Effectiveness Network (DSEN)
- 235 patients were recruited from multiple HCV clinic sites in three provinces: British Columbia, Alberta and Ontario.
- Patient DNA samples, along with clinical data, were collected and tested for approximately 700,000 genetic variants across the genome for use in both candidate gene and genome-wide analyses.
What did the study find?
- This study showed that the presence of a variant in the VDR gene, doubles the risk of ribavirin-induced anemia through increasing oxidative stress.
- This study also identified genetic variants with biologically-relevant roles that approached genome-wide significance for predicting ribavirin-induced anemia. GYPC, influencing red blood cell (RBC) stability, is associated with an 8-fold lower risk. IFR7 and RASGRP3 increase RBC production and are associated with 4-fold lower and 3-fold lower risks respectively.
- The presence of a variant in ITPA that reduces oxidative stress, leads to an 8-fold decrease in the risk of ribavirin-induced anemia.
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