Are IL28B Gene Variations Associated with Outcomes in People with Hepatitis B?

IL28B gene patterns may influence response to interferon therapy for hepatitis B, but this is not as straightforward as it is for hepatitis C, according to a set of studies presented at the recent American Association for the Study of Liver Diseases "Liver Meeting" (AASLD 2010) in Boston. Two analyses suggested that people with the protective rs12979860 C/C pattern were more likely to achieve sustained virological suppression with interferon, but less likely to experience HBeAg seroconversion. A third study, however, found no link between rs12979860 pattern and hepatitis B or HIV persistence or progression.

In 2009, researchers first reported that specific variations known as single nucleotide polymorphisms (SNPs) in the IL28B gene region -- which encodes interleukin 28, also known as interferon lambda -- were associated with spontaneous clearance of genotype 1 hepatitis C virus (HCV) and response to interferon-based therapy for chronic infection. Different teams have identified several associated SNPs, but one known as rs12979860 is implicated most often.

Each individual carries 2 copies of the relevant gene on chromosome 19. Among people with hepatitis C, individuals with the C/C gene pattern -- meaning they carry 2 copies of the "C" variant, or allele -- are more likely to respond well to interferon alfa plus ribavirin. People with the T/T pattern have the least favorable response, while those carrying 1 "C" and 1 "T" allele fall somewhere in between.

Hepatitis B Treatment Response

In the first study presented at the AASLD meeting, Bart Takkenberg and Hendrik Reesink from the University of Amsterdam investigated whether the rs12979860 SNP linked to hepatitis C outcomes is also associated with outcomes among patients with chronic hepatitis B virus (HBV) infection treated with a combination of pegylated interferon plus adefovir (Hepsera).

The investigators determined IL28B gene patterns for 96 chronic hepatitis B patients -- 45 hepatitis B "e" antigen (HBeAg) positive and 51 HBeAg negative -- with HBV DNA viral load > 20,000 IU/mL at baseline who were treated with pegylated interferon alfa-2a (Pegasys) plus adefovir for 48 weeks, followed by a 24-week post-treatment follow-up period.

The researchers saw no significant association between rs12979860 SNP pattern and viral load or hepatitis B surface antigen (HBsAg) status at baseline. Among patients who completed treatment, there were also no significant differences in overall outcomes between the different rs12979860 groups. There was a trend toward a greater likelihood of sustained virological response (SVR, defined as HBV DNA < 2000 IU/mL) among HBeAg negative patients with the favorable C/C pattern (57%) compared to those with C/T or T/T (36% combined). In contrast, HBeAg seroconversion among initially HBeAg positive patients was somewhat less common in the C/C group (22% vs 54%, respectively). Rates of HBsAg loss were similar.

Finding significant links between IL28B gene patterns and treatment outcomes might require larger studies, the researchers suggested, "as the heterogeneity of HBV patients, viral genotypes, and definitions of outcome make [hepatitis B] more challenging for evaluation of host genetics" than hepatitis C.

HBV Genotype D

In the second study, Pietro Lampertico from Universita degli Studi di Milano in Italy and colleagues looked at the association between the same rs12979860 SNP and outcomes among 101 HBeAg negative chronic hepatitis B patients. Most (92%) had HBV genotype D and about half had liver cirrhosis. Just under half (48) had the C/C pattern, 42 had C/T, and 11 had T/T.

Participants were treated with either conventional or pegylated interferon alfa for 12-24 weeks, and followed for 11 years on average post-treatment. During follow-up 21% experienced HBsAg clearance and 15% achieved HBs antibody response. Here, HBsAg clearance rates differed significantly across IL28B patterns: 36% of T/T patients, 29% of C/C patients, and just 7% of C/T patients.

In a univariate analysis, baseline HBV DNA, ALT level, and IL28B pattern were significantly associated with HBsAg clearance, but not patient age, sex, cirrhosis, or HBV genotype. In a multivariate analysis, baseline HBV DNA < 6 log copies/mL, ALT > 150 IU/mL, and the rs12979860 C/C pattern (odds ratio 3.9; P = 0.025) remained significant predictors.

"IL28B polymorphism may represent an additional pretreatment predictor of interferon response in HBeAg negative, genotype D patients with chronic hepatitis B," the researchers concluded.


Finally, Fuat Kurbanov from Johns Hopkins University School of Medicine and colleagues assessed the link between the rs12979860 SNP and outcomes of acute HBV infection, susceptibility to HIV infection, and HIV disease progression.

The researchers looked at participants from prospective cohorts of individuals infected with or at risk for HBV or HIV, including the Multicenter AIDS Cohort Study (MACS), the ALIVE cohort, and 2 hemophilia cohorts. The HBV analysis included 384 individuals who cleared HBV and 226 who developed persistent infection. The HIV study included 1036 HIV seroconverters and 291 people who were at high risk but remained HIV negative. Consistent with other studies, the "C" allele was more common among whites than blacks (69% vs 44%).

The researchers observed no difference in "C" allele frequency between people who experienced HBV recovery and those who developed persistent infection (65% vs 64%, respectively). In an adjusted multivariate analysis, the C/C, C/T, and T/T gene patterns were not associated with outcomes of HBV infection. There was still no difference when results were stratified by race or HIV status. Similarly, there were no differences in rs12979860 SNP patterns between people who became HIV positive and those who remained HIV negative, nor was there an association with HIV disease progression.

"We found that the SNP upstream of IL28B, which is strongly associated with HCV outcome, has no association with HBV recovery, HIV infection, or HIV disease progression," the investigators concluded. "Additional studies are needed to understand the mechanisms underlying the beneficial effects of this SNP in HCV but not in HIV or HBV infections."

Investigator affiliations:

Abstract LB-21: Departments of Hepatology, Pathology, and Clinical Epidemiology & Biostatistics, Medical Microbiology and Karl Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands; KIT Biomedical Research, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands; Department of Virus Diagnostic Services, Sanquin, Amsterdam; Translational Medicine-Virology, Pharma Research and Early Development, Roche Pharmaceuticals, Nutley, NJ.

Abstract 237: 1st Division of Gastroenterology, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico, Universita degli Studi di Milano, Milano, Italy; INGM Istituto Nazionale Genetica Molecolare , Milano, Italy.

Abstract 1408: Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD; Laboratory of Experimental Immunology, SAIC Frederick, Inc., NCI-Frederick, Frederick, MD; Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD; Division of Blood Diseases and Resources, National Heart Lung and Blood Institute, Bethesda, MD; University of California, Los Angeles, CA; University of California, San Francisco, CA, United States.



B Takkenberg, A de Niet, R Benayed, H Reesink, and others. Association between treatment outcome and rs12979860 polymorphism in HBeAg positive and negative chronic hepatitis B patients treated with Peginterferon alfa-2a (Pegasys) and Adefovir (Hepsera); An interim analysis. 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2010). Boston, October 29-November 2, 2010. Abstract LB-21.

P Lampertico, M Vigano, C Cheroni, and others. Genetic variation in IL28B polymorphism may predict HBsAg clearance in genotype D, HBeAg negative patients treated with interferon alfa. 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2010). Boston, October 29-November 2, 2010. Abstract 237.

F Kurbanov, MP Martin, Y Qi, CL Thio, and others. An IL28B SNP that is associated with HCV outcome is not associated with HBV or HIV outcome. 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2010). Boston, October 29-November 2, 2010. Abstract 1408.