Genetics and hepatitis C: It’s good to be ‘CC’
ABSTRACTThe interleukin-28B (IL28B) gene contains a single-nucleotide polymorphism at location rs12979860 that affects both the natural history of hepatitis C virus infection and the patient’s response to treatment, particularly interferon-based regimens with or without protease inhibitors.
KEY POINTS
- In IL28B, the rs12979860 location can be occupied by either cytosine (C) or thymine (T). The CC genotype is more favorable than the CT or TT genotype.
- Testing for the IL28B polymorphism is currently available and allows for better outcomes through proper selection of treatment, particularly with interferon-based treatment.
- Although newer therapies have shifted toward regimens that do not use interferon, the IL28B polymorphism remains clinically significant, especially in light of the potentially prohibitive costs of the newer regimens, and for patients in whom these treatments are contraindicated.
IL28B POLYMORPHISM AND LIVER TRANSPLANTATION
Hepatitis C virus infection always recurs after liver transplantation, with serious consequences that include cirrhosis and liver failure. Recurrent hepatitis C virus infection has become an important reason for repeat transplantation in the United States.
Results of treatment with pegylated interferon and ribavirin for recurrent hepatitis C after liver transplantation have been disappointing, with response rates lower than 30% and significant side effects.31 Identifying the factors that predict the response to therapy allows for better selection of treatment candidates.
Similar to the way the IL28B genotype predicts response to antiviral therapy in the nontransplant setting, the IL28B genotypes of both the recipient and the donor are strongly and independently associated with response to interferon-based treatment in patients with hepatitis C after liver transplantation. The IL28B CC genotype in either the recipient or the donor is associated with a higher rate of response to pegylated interferon and ribavirin combination therapy after liver transplantation.30,32 For example, the response rate to therapy after liver transplantation reaches 86% in CC-donor and CC-recipient livers, compared with 0% in TT-donor and TT-recipient livers.
Additionally, the IL28B genotype of the recipient may determine the severity of histologic recurrence of hepatitis C, as indicated by progressive hepatic fibrosis. A recipient IL28B TT genotype is associated with more severe histologic recurrence of hepatitis C.33
These data suggest that CC donor livers might be preferentially allocated to patients with hepatitis C virus infection.
IL28B AND OTHER FACTORS IN HEPATITIS C VIRUS INFECTION
Although it is tempting to think that the IL28B polymorphism is the sole predictor of response to antiviral therapy, it is but one of several known factors in the virus and the host.
While IL28B polymorphisms are the most important predictor of sustained virologic response with an interferon-based regimen, a rapid virologic response (undetectable viral load at 4 weeks) had superior predictive value and specificity in one study.34 In fact, for patients with chronic hepatitis C infection who achieved a rapid virologic response with pegylated interferon and ribavirin, the IL28B polymorphism had no effect on the rate of sustained virologic response. However, it did predict a sustained virologic response in the group who did not achieve rapid virologic response.
In a study of patients with acute hepatitis C infection,35 jaundice and the IL28 rs12979860 CC genotype both predicted spontaneous clearance. The best predictor of viral persistence was the combination of the CT or TT genotype plus the absence of jaundice, which had a predictive value of 98%.
IL28B AND THE FUTURE OF HEPATITIS C VIRUS THERAPY
New oral agents were recently approved for treating hepatitis C. As of November 2014, these included simeprevir, sofosbuvir, and ledipasvir.
Simeprevir is a second-generation NS3/4A protease inhibitor approved for use in combination with pegylated interferon and ribavirin. A recent phase 3 trial evaluating simeprevir in patients who had relapsed after prior therapy found sustained virologic response rates to be higher with simeprevir than with placebo, irrespective of IL28B status.36 This finding was similar to that of a trial of telaprevir.16
Sofosbuvir is a nucleotide analogue NS5B polymerase inhibitor that becomes incorporated into the growing RNA, inducing a chain termination event.37 In phase 3 trials,38,39 researchers found an initial rapid decrease in viral load for patients treated with this agent regardless of IL28B status.
In the NEUTRINO trial (Sofosbuvir With Peginterferon Alfa 2a and Ribavirin for 12 Weeks in Treatment-Naive Subjects With Chronic Genotype 1, 4, 5, or 6 HCV Infection),38 which used sofusbuvir in combination with interferon and ribavirin, the rate of sustained virologic response was higher in those with the favorable CC genotype (98%) than with a non-CC genotype (87%).
In COSMOS (A Study of TMC435 in Combination With PSI-7977 [GS7977] in Chronic Hepatitis C Genotype 1-Infected Prior Null Responders to Peginterferon/Ribavirin Therapy or HCV Treatment-Naive Patients),39 which used a combination of simeprevir, sofosbuvir, and ribavirin, the rate of sustained virologic response was higher in those with the CC genotype (100%) than with the TT genotype (83%; Table 1).
These new medications have radically changed the landscape of hepatitis C therapy and have also unlocked the potential for developing completely interferon-free regimens.
Other new interferon-free regimens such as ledipasvir, daclatasvir, and asunaprevir promise high rates of sustained virologic response, which makes the utility of testing for IL28B polymorphisms to predict sustained virologic response very much diminished (Table 1).40,41 However, these new drugs are expected to be expensive, and IL28B polymorphisms may be used to identify candidates who are more likely to respond to pegylated interferon and ribavirin, particularly in resource-poor settings and in developing countries. Additionally, patients who have contraindications to these newer therapies will still likely need an interferon-based regimen, and thus the IL28B polymorphism will still be important in predicting treatment response and prognosis.
IL28B WILL STILL BE RELEVANT IN THE INTERFERON-FREE AGE
The IL28B polymorphism is a strong predictor of spontaneous clearance of hepatitis C virus and responsiveness to interferon-based therapy, and testing for it has demonstrated a great potential to improve patient care. IL28B testing has become available for clinical use and may optimize the outcome of hepatitis C treatment by helping us to select the best treatment for individual patients and minimizing the duration of therapy and the side effects associated with interferon-based antiviral medications.
As newer therapies have shifted toward interferon-free regimens that offer very high sustained virologic response rates, the usefulness of IL28B polymorphism as a clinical test to predict the response rate to antiviral therapy is minimized substantially. It may remain clinically relevant in resource-poor settings and in developing countries, especially in light of the potentially prohibitive costs of the newer regimens, and for patients in whom these treatments are contraindicated. This does not minimize the lesson we learned from the discovery of the IL28B gene and the impact on our understanding of the pathogenesis of hepatitis C virus infection.
