IL28B Genotyping in the Management of Chronic HCV

Michael Charlton

MBBS, FRCP

Hepatology Director and Medical Director of Liver
Transplantation, Mayo Clinic, Rochester, MN

Dr. Charlton is a council member of the International Liver Transplantation Society. He is also a member of AASLD’s practice guidelines writing group and the United Network for Organ Sharing’s Liver and Intestinal Organ Transplantation Committee.

IL28B Genotyping in the Management of Chronic HCV

"There are exciting data regarding IFN-free treatment protocols with combinations of direct-acting antivirals and RBV. Whether IL28B polymorphism will remain relevant in the context of IFN-free treatment protocols is not known and seems unlikely."

In the years following the identification of hepatitis C virus(HCV), the efficacy of interferon (IFN)- and ribavirin(RBV)-based therapies reached a peak of approximately 45 percent for the most prevalent HCV genotype, genotype 1.

Predicting response to IFN, bound to polyethylene glycol(PEG) or otherwise, and RBV has been frustrating. Profound differences in the frequency of virological cure(sustained virological response [SVR]) following IFN- and RBV-based therapy exists between ethnic groups. Among patients within an ethnic group, the likelihood of SVR could not be predicted accurately by any single or combination of host or virological parameters.

As the treatment of HCV infection is both expensive and difficult, with frequent toxicities, estimating the likelihood of success is important. Virological factors that influence response to treatment include viral genotype (the most predictive single factor) and viral load
(view table at http://www.gastro.org/charlton83).

Patients infected with HCV genotype 1 who are treated for 48 weeks with pegylated IFN (PEG-IFN) and RBV have an approximately 40 to 54 percent1 likelihood of achieving an SVR, whereas patients with genotypes 2 or 3 virus have an SVR rate of approximatley 65 to 82 percent. Host characteristics predictive of response to treatment include ethnicity, gender, age, weight, insulin resistance, hepatic steatosis and liver fibrosis stage.

In 2009, Ge et al3 reported that variation in and near the IL28B gene is strongly predictive of response to treatment of chronic HCV infection with PEG-IFN and RBV. The p value for the association of rs12979860 with SVR was approximately 10,2, 4 with an associated 2.5-fold higher relative rate of SVR among non-Hispanic Caucasian subjects carrying the responsive C/C genotype compared to the T/T genotype. The C/C genotype is also associated with higher likelihood of SVR in Hispanics, Asians and African Americans. IL28B genotype accounts for essentially all of the variability in SVR between ethnic groups. IL28B genotype is also highly predictive of spontaneous clearance of acute HCV infection and outcomes following liver transplantation.

How should IL28B genotyping, which costs about $300, be incorporated into current treatment algorithms now that addition of a protease inhibitor, boceprevir or telaprevir to PEG-IFN and RBV is the new standard of care in the treatment of genotype 1 HCV infection? Is there a role for IL28 genotyping in non-1 genotypes or acute HCV infection?  I present my interpretation and a rational possible approach.

Genotype 1 (and possibly 4)

If the decision of whether or not to treat HCV infection is dependent upon likelihood of SVR, IL28B genotyping should be considered (view figure at http://www.gastro. org/charlton83). In patients in whom treatment is planned, IL28B genotyping can be useful in guiding duration of treatment with PEG-IFN and RBV, as the C/C genotype confers a nine-fold increase in likelihood of rapid virological response (RVR).

Among those who do not achieve RVR, patients with C/C genotype are more than five times as likely to achieve SVR. Adding boceprevir and telaprevir to PEG-IFN and RBV reduces, but does not eliminate, the association between IL28B genotype and treatment outcome. In treatmentnaïve patients with HCV genotype-1 infection, IL28B genotype continues to be significantly predictive of SVR.

As the protease inhibitors do not significantly increase efficacy among patients who achieve RVR or patients with IL28B C/C genotype, a case could be made for performing IL28B genotyping to identify patients who are likely to achieve SVR without protease inhibitors.

IL28B C/C genotype patients who do not achieve RVR could have boceprevir added to PEG-IFN and RBV, thus still adhering to the response-guided triple therapy protocol for boceprevir, which includes a four week lead-in phase of boceprevir-free therapy. Telaprevir is also effective with a PEG RBV lead-in. Such an approach might maximize patient-specific likelihood of response while potentially limiting cost.

The potential for cost savings may be magnified if generic PEG-IFNs become available (an event that is hard to predict for biologic agents). The benefit of the protease inhibitors in patients with IL28B C/C genotype is to allow shorter treatment duration while maintaining SVR rates above 80 percent, not to increase SVR. Non-CC IL28B genotype patients clearly benefit from the addition of protease inhibitors, with SVR rates doubling among treatment-naïve patients when compared to PEG-IFN and RBV alone.

There are exciting data regarding IFN-free treatment protocols with combinations of direct-acting antivirals and RBV. Whether IL28B polymorphism will remain relevant in the context of IFN-free treatment protocols is not known and seems unlikely.

Genotypes 2 and 3

IL28B genotype has been only variably and modestly predictive of SVR for patients with HCV genotypes 2 and 3, for whom SVR rates are 65 to 82 percent.

IL28B genotyping thus has little role in decision making regarding treatment initiation. Although IL28 genotype predicts SVR at 24 weeks in patients without RVR, the role for IL28B genotyping is not clear at a practical level.

While it is possible that IL28B genotyping may be of utility in determining optimal duration of antiviral therapy in patients with HCV genotypes 2/3 (e.g., 24 weeks for C/C and 48 for non-C/C), the data are too weak to make a firm practice recommendation

References

1. McHutchison JG, Lawitz EJ, Shiffman ML, Muir AJ, Galler GW, McCone J, Nyberg LM, Lee WM, Ghalib RH, Schiff ER, Galati JS, Bacon BR, Davis MN, Mukhopadhyay P, Koury K, Noviello S, Pedicone LD, Brass CA, Albrecht JK, Sulkowski MS.
Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection.
N Engl J Med 2009;361:580-9
2. Mangia A, Thompson AJ, Santoro R, Piazzolla V, Tillmann HL, Patel K, Shianna
KV, Mottola L, Petruzzellis D, Bacca D, Carretta V, Minerva N, Goldstein DB,McHutchison JG.
An IL28B polymorphism determines treatment response of hepatitis C virus genotype 2 or 3 patients who do not achieve a rapid virologic response.
Gastroenterology  2010;139:821-7, 827 e1.
3. Ge D, Fellay J, Thompson AJ, Simon JS,Shianna KV, Urban TJ, Heinzen EL, QiuP, Bertelsen AH, Muir AJ, Sulkowski M, McHutchison JG, Goldstein DB.
Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance.
Nature 2009;461:399-401.

June/July 2012 issue of AGA Perspectives

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