Many people infected with the hepatitis C virus are not cured despite gruelling therapy. A human genetic variant that predicts successful treatment has been identified. So is personalized therapy now a possibility?
A staggering 170 million people are persistently infected with the hepatitis C virus (HCV), including 1–1.7% of people in the United States and roughly the same proportion in the European Union1. HCV infection causes a slowly progressive liver disease that can lead to cirrhosis over several decades. People can be infected by one of several genetic types of HCV, each of which varies in its sensitivity to therapy. Genotype 1 HCV is the most difficult to treat, with clearance occurring in only about 50% of infected people during therapy. On page 399 of this issue, Ge et al.2, as part of David Goldstein's group, report the identification of a variant, or polymorphism, in the human genome that is significantly associated with virus clearance during treatment. Two independent studies, one by Suppiah et al.3 and the other by Tanaka et al.4, report similar findings in Nature Genetics.
The only approved treatment for HCV infection is weekly injection of polyethylene glycol-conjugated interferon-α plus daily oral ribavirin. Interferon is thought to work by stimulating the body's natural defences against virus infection; the mechanism of action of ribavirin is not completely understood. The 48-week treatment course is often poorly tolerated, so new approaches are needed that enhance the effectiveness and shorten the duration of therapy, while targeting the longest antiviral courses to the most appropriate patients.
Ge and colleagues2 tackled this problem by applying a relatively new methodology in genetics, the genome-wide association study (GWAS). These types of study test the association of a characteristic of interest, usually a disease, with typically hundreds of thousands of single nucleotide polymorphisms (SNPs) — variations in one of the three billion nucleotide base pairs that make up the human genome. If, for instance, the variant SNP is found to be significantly more common in people with a disease than in a disease-free control group, the variant is considered to be associated with that disease. The power of GWAS to detect such associations derives from the large number of variants that are screened and the many people included in these studies.
Ge et al.2 analysed 1,137 patients with HCV infection who were enrolled in a clinical trial to test the relative effectiveness of two commercial interferon preparations5. They identified several SNPs near the IL28B gene on chromosome 19 that were significantly more common in the patients that responded to interferon therapy than in non-responders. Across a multi-ethnic population, approximately 80% of patients who carry two copies of the advantageous variant cleared the virus during interferon therapy and remained virus-free for a period of 24 weeks post-treatment. Patients who meet these initial criteria for response rarely experience a resurgence of virus and are widely considered to be cured.
Ge and colleagues' results2 are independently confirmed by two GWAS published online in Nature Genetics3,4. Suppiah et al.3 and Tanaka et al.4 characterize an overlapping group of SNPs in the same region of chromosome 19 in responders from different populations — Suppiah et al. studying HCV-infected patients of European origin, and Tanaka et al. studying a group of Japanese patients.
Although all of the identified variants in the three studies lie in or near the IL28B gene, none of them has an obvious effect on the function of this gene, which encodes interferon-λ3, a growth factor with similarities to the interferon-α preparations used as treatment. The interferon-λ proteins have lower antiviral activity than interferon-α in laboratory experiments6, but despite this, interferon-λ3 may contribute to virus clearance either spontaneously or during drug treatment. A study by Thomas and colleagues published online in Nature7 reports that the same variant described by Ge et al.2 is also associated with spontaneous clearance of HCV, that is, in the absence of drug treatment. And a related interferon-λ protein encoded by the IL29 gene was shown to reduce the amount of HCV virus in the body when given to genotype-1-infected patients8.
An important finding from Ge and colleagues' work2 is the population distribution of the advantageous SNP, which is significantly more frequent in the Caucasian and Asian populations than in African Americans. About 30–50% of Sub-Saharan Africans carry this variant, compared with about 90% of Chinese and Japanese people9. Clinicians have long struggled to explain the relatively poorer outcomes among HCV-infected African Americans in trials of interferon and ribavirin therapy. Using a standard definition of treatment response, African Americans clear the virus roughly half as frequently as Caucasians10, and some of this difference now seems to be explained by population differences in the incidence of the advantageous IL28B genotype.
The question remains, however, as to how readily these and other observations from GWAS can be translated into meaningful changes in patient care. The field of human genetics has described many associations between specific mutations and medically important outcomes, but rarely have these observations resulted in new therapies to treat disease or in major shifts in existing treatments. This failure is exemplified by the lack of clinical benefit that followed the cloning in 1989 of the gene responsible for cystic fibrosis11 — the first example of the use of molecular genetics to discover the cause of an otherwise poorly understood condition. Although some progress has been made in treating patients with cystic fibrosis, in the ensuing 20 years neither of the two newly approved drugs for this condition were developed using knowledge of the gene mutations that cause it. Apart from a few well-characterized beneficial mutations (for example, those resulting in resistance to HIV infection12), genetics has been an inefficient tool for drug discovery.
So, although these findings2,3,4 raise the tantalizing prospect of a more personalized approach to treating HCV by tailoring treatment to patients who are most likely to benefit, the reality is more sobering. Diagnostic testing to identify likely responders to interferon may be a future possibility, but clinical decision-making will be clouded by the fact that the effect of the advantageous variant is not absolute — not all carriers of the variant clear the virus, nor do all patients lacking the variant fail to benefit from treatment. Furthermore, there is currently no alternative to interferon therapy for the HCV-infected population.
Although the amount of genetic information available to researchers across various disciplines has expanded, advances in data collection have historically failed to translate into equivalent advances in medical innovation (Fig. 1). And although GWAS can probe the subtler effects of a larger number of gene variants, little attention has been paid to the black box that stands between most genetic discoveries and the promise of personalized treatments. A challenge for the future will be to apply genetic tools in a way that accelerates drug and diagnostics development, including better integration of genetic studies into the drug-development process, a reduced emphasis on modest genetic contributions to a disease, and a focus on the role of genetic variation in maintaining health as a blueprint for designing new drugs.
Ge, D. et al. Nature 461, 399–401 (2009).
Suppiah, V. et al. Nature Genet. doi:10.1038/ng.447 (2009). | Article |
Tanaka, Y. et al. Nature Genet. doi:10.1038/ng.449 (2009). | Article |
McHutchison, J. G. et al. N. Engl. J. Med. 361, 580–593 (2009).
Sheppard, P. et al. Nature Immunol. 4, 63–68 (2003).
Thomas, D. L. et al. Nature doi:10.1038/nature08463 (2009). | Article |
Shiffman, M. L. et al. Proc. 44th Annu. Meet. Eur. Assoc. Study Liver (EASL), Copenhagen, abstr. 520 (2009).
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Conjeevaram, H. S. et al. Gastroenterology 131, 470–477 (2006).
Riordan, J. R. et al. Science 245, 1066–1073 (1989).
Fatkenheuer, G. et al. Nature Med. 11, 1170–1172 (2005).
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