IL28B Gene Variation Linked to Spontaneous Clearance and Treatment Response in HIV/HCV Coinfected People

		SUMMARY: A human genetic variation previously shown to predict hepatitis C prognosis in people with HCV alone may play a similar role in HIV/HCV coinfected individuals, according to a set of studies presented at the 17th Conference on Retroviruses and Opportunistic Infections (CROI 2010) last month in San Francisco. The IL28B non-risk genotype associated with both spontaneous HCV clearance and response to interferon-based hepatitis C treatment was less common among people of African descent, perhaps helping explain disparities in treatment outcomes.

By Liz Highleyman

The IL28 gene encodes interleukin 28, also known as interferon lambda, a cytokine (chemical messenger) with antiviral activity. Discovery of the link between IL28B and hepatitis C prognosis -- initially in people with HCV monoinfection -- has "revolutionized way we think about treatment and management issues in the past six months," said Ken Sherman from the University of Cincinnati, who moderated a HIV/hepatitis coinfection session largely devoted to IL28B.

Andri Rauch (Photo by Liz ighleyman)

Andri Rauch from University Hospital Bern (abstract 162) began with an overview of the recent discovery of the IL28 phenomenon. The fact that people respond so differently despite receiving the same hepatitis C treatment, he noted, "strongly point to host genetic determinants for the control of HCV infection."

Researchers identified IL28B by scanning the human genome to look for differences between people who responded well and those who did not respond to interferon-based therapy. They initially examined genes already known to play role in immune control of HCV; when these were not confirmed, they performed genome-wide association studies (looking at the full set of genes from multiple individuals) to broaden their search.

Rauch and colleagues analyzed participants in the Swiss Hepatitis C Cohort, while other teams looked at genotype 1 hepatitis C patients in the U.S. (white and African-American participants in the IDEAL trial), Australia, and Japan.

All the research groups saw an association between favorable treatment response and single nucleotide polymorphisms (SNPs) in the IL28 gene near the "B" subunit that encodes interferon lambda-3. This finding was "very consistent" among 4 studies published during the past 6 months, all looking at HIV negative individuals, Rauch said.

Each research group identified several relevant SNPs, but one -- rs8099917, dubbed the "risk allele" -- was common to all of them, while 2 other (rs12980275 and 12979860) were also implicated.

Alleles are natural variations of a gene. In simple terms, for example, the eye color gene has blue and brown alleles (in actuality, eye color is controlled by multiple genes); the IL28B gene has risk and non-risk alleles. Because people inherit 1 copy of every gene from each parent, they may end up with either 2 copies of the risk alleles, 2 copies of the non-risk version, or 1 of each. The combination is known as the genotype: risk, non-risk, or mixed.

Across the studies, people who achieved sustained virological response (SVR) to interferon-based therapy were about half as likely to have the risk genotype as non-responders. This genotype was even less common among people who spontaneously cleared HCV without treatment.

Furthermore, the risk genotype occurred with higher frequency among people of African descent, intermediate frequency among Europeans, and lower frequency among Asians, which Rauch said "explains at least in part ethnic differences seen in HCV recovery rate both natural and with therapy."

IL28B and HIV/HCV Coinfection

At the same session, 3 research groups reported results from studies looking at IL28B in HIV/HCV coinfected people.

Jacob Nattermann and colleagues (abstract 164) determined IL28B genotypes for 192 coinfected individuals of European ethnicities treated with pegylated interferon alfa, including 74 with acute HCV infection and 118 with chronic hepatitis C. In addition, 156 HCV monoinfected people and 136 healthy individuals with neither virus served as control subjects.

Looking at the rs12979860 SNP, they found that IL28B genotype distribution did not differ significantly across the groups based on infection status. Among coinfected individuals, those with the non-risk genotype were more likely to achieve SVR than those with the risk genotype or mixed genotype. However, this effect was not as strong as that shown for HCV monoinfected people, and was significant only for chronic but not acute hepatitis C infection.

Norma Rallon and colleagues (abstract 165), in contrast, found a strong link between the same rs12979860 SNP and treatment response in HIV/HCV coinfected individuals (90 sustained responders, 74 non-responders, and 24 with spontaneous HCV clearance). Here, 75% of people with spontaneous clearance had the non-risk genotype compared with 46% of those who developed chronic infection.

With regard to treatment outcomes, among patients who achieved SVR, 75% had the non-risk genotype while 38% did not. But the association was only significant for HCV genotype 1 (65% vs 30%, respectively), with a trend for genotype 4 (67% vs 25%), but not for genotype 3 (86% vs 81%).

The researchers also looked a matrix of predictors of good treatment response including rs12979860 non-risk genotype, HCV genotype 3, low baseline HCV viral load, and lack of advanced liver fibrosis. Within a total study population of 164 patients, those with zero positive predictors had a 12% chance of achieving SVR, while those with 3 or more had a 100% likelihood of treatment success.

Interferon Lambda

Although its mechanism is not yet known, Rauch suggested that the risk variant of the IL28 gene may produce interferon lambda that has less effect on interferon-stimulated genes, and thus induces a weaker response against HCV. Natterman's group found that people with HIV had lower blood levels of interferon lambda than HIV negative individuals with acute HCV, chronic HCV, or HCV uninfected.

Pegyalated Interferon lambda as a hepatitis C treatment is undergoing clinical trials. In a Phase 1b study reported at the American Association for the Study of Liver Diseases (AASLD) meeting this past fall, researchers found that interferon lambda had efficacy similar to that of the current standard HCV therapy, pegylated interferon alpha (Pegasys or PegIntron), but with fewer adverse side effects.

Experts believe, however, that rs8099917 and the other risk SNPs are not themselves the actual cause of poor response, but rather are linked to and serve as markers for the causal gene(s).

Julia di Iulio and others from Rauch's team (abstract 163) sought to determine the actual causal genetic region tagged by the rs8099917 risk allele. They performed recombinant DNA mapping on 4 types of people:

	Individuals with the risk genotype who developed chronic infection;
	Individuals with the non-risk genotype who spontaneously cleared HCV;
	Individuals with the non-risk genotype who nevertheless developed chronic infection;
	Individuals with the risk genotype who nevertheless cleared infection.

The first 3 groups included 15 people each, but the last configuration was uncommon and the researcher could only find 2 such patients. All were HIV/HCV coinfected except for 6 people in the third group who had HCV alone.

The investigators identified 12 haplotypes (sets of genes that occur together), clustering into 2 families. Most people who cleared HCV had Type I haplotypes, while most who developed chronic infection had Type II haplotypes. The rs8099917 marker SNP was highly associated with the latter, but having a Type II haplotype was associated with chronic infection even in people who lacked the marker SNP. Within the second family, they identified 4 candidate SNPs that might be responsible for poor response.

Clinical Implications

During the session, researchers discussed the clinical relevance of these findings for people with hepatitis C. Some suggested that IL28 genotypic testing might help guide treatment decisions, since it could show who is most likely to respond and therefore spare others futile therapy.

However, an audience member expressed concern that such a test might be used as a rationale for providers to deny treatment or for insurers to refuse payment. At an accompanying press conference, Rauch said, "It's part of a puzzle...It will certainly not be the only thing on which we base the decision to treat or not."

The discovery also introduces a potential confusion with regard to terminology. These human IL28B genotypes should be confused with HCV genotypes (1, 2, 3, 4, etc), which also predict treatment response. Speaking about a "favorable genotype" or "high-risk genotype" now has 2 distinct meanings.

Abstract 162: University Hospital Bern, Switzerland.

Abstract 163: University Hospital Lausanne and University of Lausanne, Switzerland; University Hosp Bern and University of Bern, Switzerland; University Hospital Geneva, Switzerland.

Abstract 164: University of Bonn, Germany; Private Practice, Berlin, Germany; Praxiszentrum Kaiserdamm, Berlin, Germany; ICH, Hamburg, Germany; St Vincent's Clin Sch, Australia; Hosp Univ Germans Trias i Pujol, Autonomos Univ of Barcelona, Spain; University of Pavia IRCCS, San Matteo Hosp, Italy.

Abstract 165: Hosp Carlos III, Madrid, Spain; Duke Clinical Research Institute, Durham, NC; Institute for Genome Science and Policy, Durham, NC.

3/12/10

Reference

A Rauch. The interleukin 28B gene and HCV recovery. 17th Conference on Retroviruses & Opportunistic Infections (CROI 2010). San Francisco. February 16-19, 2010. Abstract 162.

J di Iulio, P-Y Bochud, M Rotger, and others. Association of IL28B haplotypes with chronic HCV infection in HIV/HCV co-infected individuals. 17th Conference on Retroviruses & Opportunistic Infections (CROI 2010). San Francisco. February 16-19, 2010. Abstract 163.

J Nattermann, M Vogel, A Baumgarten, and others. Genetic variation in IL28B and treatment-induced clearance of HCV in HCV/HIV co-infected patients. 17th Conference on Retroviruses & Opportunistic Infections (CROI 2010). San Francisco. February 16-19, 2010. Abstract 164.

N Rallon, S Naggie, J Benito, and others. Strong association of a single nucleotide polymorphism located near the interleukin-28b gene with response to hepatitis C therapy in HIV/HCV co-infected patients. 17th Conference on Retroviruses & Opportunistic Infections (CROI 2010). San Francisco. February 16-19, 2010. Abstract 165.