Hepatitis C-Why IL28B Genotype Remains Important With DAA Regimens

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Why IL28B Genotype Remains Important With DAA Regimens

Raymond T. Chung MD - 11/1/2012
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One of the most interesting questions attending the remarkable pace of new therapies for patients with chronic hepatitis C is to what extent  IL28B genotype plays a role in management—both now and in the future.

IL28B: Still Important With PI Therapy
How do I currently use IL28B genotype in my practice? In the era of peginterferon/ribavirin plus protease inhibitor therapy, IL28B can be used to provide an increment of additional data that may assist with decision making. For the patient who needs to be treated (advanced fibrosis) or who really wants to be treated, I will not be deterred from starting therapy, so the test has limited value. On the other hand, for the patient with more limited disease in whom we could justifiably defer therapy, the finding of a CC genotype may persuade the patient toward giving treatment a try, particularly given the high likelihood of being able to abbreviate treatment to 24 weeks. If it’s clear that the patient has no inclination to consider interferon-containing therapy, then again the test has little value.

IL28B With Investigational Therapies
Given the postulated mechanisms of direct-acting agents (DAAs)—offering a stranglehold on virus replication by means of blocking enzymes or proteins that contribute to the replication machinery—the use of DAAs should “level the playing field” by halting replication until it’s extinguished. Under this scenario, we might then expect the contribution of IL28B genotype to be rendered either irrelevant or minimally relevant, given that it was discovered due to its relationship with interferon responsiveness. However, in recent phase II DAA studies, IL28B status still mattered in predicting outcome in genotype 1 patients being treated with interferon-free regimens. I found this to be somewhat unexpected but quite revealing about the role of this polymorphism in dictating outcome.

Contribution of HCV Subtype
How might IL28B be contributing to success under these circumstances? Let’s drill down somewhat deeper. In SOUND-C2, a study of the combination of a protease inhibitor plus nonnucleoside polymerase inhibitor with or without ribavirin, it appeared that in subtype 1b patients, responsiveness was excellent across the board, regardless IL28B status. By contrast, those subtype 1a patients with non-CC IL28B genotypes did poorly compared with those with the CC genotype who performed as well as the 1b subjects. This suggests to me that genotype 1 may need to be cleaved further into 1a/1b subtype distinctions for future clinical trials, and I can envision that DAA regimens may even be tailored to HCV subtype. In current practice, we routinely obtain subtype information with our genotype assays, so no additional information generally needs to be requested. However, subtype has less bearing presently on the decision to treat with current regimens, since overall SVR rates with these regimens are not terrifically different between subtypes.

The findings also suggest that HCV subtype 1a is an inherently more difficult-to-treat virus and that the right innate immune “equipment”—in this case, represented by IL28B genotype—is essential to maximize response for this group of patients. These data further imply to me that IL28B status does matter even in the absence of exogenous interferon. In the case of a virus with a low barrier to resistance development, such as HCV subtype 1a, the strength of the innate response coupled with antiviral therapy becomes critical. This might be reflected in an enhanced ability to respond to locally produced interferon and to minimize breakthrough of resistant viral variants. By contrast, in the case of HCV subtype 1b, where there is a generally higher barrier to virally encoded resistance, the DAA regimen alone may suffice, given the lower hurdle presented to the regimen. 

Of course, these hypotheses are nothing more than that until we understand more precisely how IL28B genotype functionally produces its phenotype. Until then, we are left stratifying for subtype and IL28B in upcoming trials. Of course, the development of regimens that present ever higher barriers to resistance, including those that contain nucleotide polymerase inhibitors, may overcome these concerns at the end of the day. 

Your Thoughts
How about you? Are IL28B testing and HCV subtyping an important part of your practice workup when making decisions about HCV therapy? Do you see this changing in the future?

Raymond T. Chung, MD, is Director of Hepatology, Vice Chief of Gastroenterology, Massachusetts General Hospital and Associate Professor of Medicine, Harvard Medical School, Boston, Massachusetts. 

Dr. Chung has disclosed that he has received funds for research support from Gilead Sciences, Mass Biological, Pfizer, and Romark.

Topics: HCV