Genetics and hepatitis C: It’s good to be ‘CC’

What a difference a single nucleotide can make! The human genome contains more than 3 billion base pairs. Yet having a different nucleotide in only one pair can make a big difference in how we respond to a disease or its treatment.

Specifically, in hepatitis C virus infection, people born with the nucleotide cytosine (C) at location rs12979860 in both alleles of the gene that codes for interleukin 28B (the IL28B CC genotype) can count themselves luckier than those born with thymine (T) in this location in one of their alleles (the CT genotype) or both of their alleles (the TT genotype). Those with the CC genotype are more likely to clear the virus spontaneously, and even if the infection persists, it is less likely to progress to liver cancer and more likely to respond to treatment with interferon.

Here, we review the IL28B polymorphism and its implications in treating hepatitis C.

GENETIC POLYMORPHISM AND HUMAN DISEASE

Of the 3 billion base pairs of nucleotides, fewer than 1% differ between individuals, but this 1% is responsible for the diversity of human beings. Differences in genetic sequences among individuals are called genetic polymorphisms. A single-nucleotide polymorphism is a DNA sequence variation that occurs in a single nucleotide in the genome. For example, two sequenced DNA fragments from different individuals, AAGCCTA and AAGCTTA, contain a difference in a single nucleotide.

Genetic variations such as these underlie some of the differences in our susceptibility to disease, the severity of illness we develop, and our response to treatments. Therefore, identifying genetic polymorphisms may shed light on biologic pathways involved in diseases and may uncover new targets for therapy.¹

Genome-wide association studies have looked at hundreds of thousands of single-nucleotide polymorphisms to try to identify most of the common genetic differences among people and relate them to common chronic diseases such as coronary artery disease,² type 2 diabetes,³ stroke,⁴ breast cancer,⁵ rheumatoid arthritis,⁶ Alzheimer disease,⁷ and, more recently, hepatitis C virus infection.⁸

HEPATITIS C VIRUS: A MAJOR CAUSE OF LIVER DISEASE

Hepatitis C virus infection is a major cause of chronic liver disease and hepatocellular carcinoma and has become the most common indication for liver transplantation in the United States.⁹

This virus has six distinct genotypes throughout the world, with multiple subtypes in each genotype. (A genotype is a classification of a virus based on its RNA.⁹) In this review, we will focus on genotype 1; hence, “hepatitis C virus” will refer to hepatitis C virus genotype 1.

Our knowledge of the biology, pathogenesis, and treatment of hepatitis C has been advancing. Originally, fewer than 50% of patients responded to therapy with the combination of pegylated interferon and ribavirin,^10,11 but since 2011 the response rate has increased to approximately 70% with the approval of the protease inhibitors telaprevir and boceprevir, used in combination with pegylated interferon and ribavirin.^12–15

Unfortunately, interferon-based treatment is often complicated by side effects such as fatigue, influenza-like symptoms, hematologic abnormalities, and neuropsychiatric symptoms. An accurate way to predict response would help patients make informed decisions about antiviral treatment, taking into account the risk and possible benefit for individual patients.

GENETIC POLYMORPHISM AND HEPATITIS C VIRUS INFECTION

Genome-wide association studies have identified single-nucleotide polymorphisms in the IL28B gene that are associated with differences in response to hepatitis C treatment.⁸

Studying 565,759 polymorphisms in 1,137 patients, researchers at Duke University identified a single-nucleotide polymorphism at location rs12979860 in IL28B (Figure 1) that was strongly associated with response to combination therapy with pegylated interferon and ribavirin.⁸ The chance of cure with this standard treatment is twice as high in patients who are homozygous for cytosine in this location (the CC genotype) than in those who are heterozygous (CT) or homozygous for thymine in this location (the TT genotype) (Table 1).

Adding one of the new protease inhibitors, telaprevir or boceprevir, to the standard hepatitis C treatment substantially improves the cure rates in all three IL28B genotypes, but especially in people with CT or TT, in whom the response rate almost triples with the addition of one of these drugs. Those with the CC genotype (who are more likely to be cured with pegylated interferon and ribavirin alone) also achieve an increase (although minimal) in cure rates when a protease inhibitor is included in the regimen (TABLE 1).^13–15 Thus, it remains unclear if adding a protease inhibitor to pegylated interferon plus ribavirin in patients with the IL28B CC genotype translates into added effectiveness worth the additional cost of the protease inhibitor in previously untreated patients.

Additionally, the effect of the IL28B genotype on telaprevir-based triple therapy has been disputed in more recent studies. In a subgroup analysis of the results of a trial that evaluated telaprevir in the treatment of hepatitis C, researchers found that sustained virologic response rates were significantly higher in the telaprevir group, and this was similar across the different IL28B polymorphisms.¹⁶

The favorable IL28B CC genotype is associated with higher rates of rapid virologic response to antiviral therapy.^13–15 Of note, almost all patients who achieve a rapid virologic response do well, with a high rate of sustained virologic response even after a shorter duration of therapy (24 vs 48 weeks). Therefore, in addition to predicting response to interferon before starting treatment, the IL28B CC genotype may also identify patients who need only a shorter duration of therapy.

Interestingly, the C allele is much more frequent in white than in African American populations, an important observation that explains the racial difference in response to hepatitis C therapy.⁸

Two other research groups, from Asia and Australia, performed independent genome-wide association studies that identified different single-nucleotide polymorphisms (eg, rs8099917) in the same IL28B gene as predictors of response to treatment in patients with hepatitis C virus infection.^17,18 These findings may be explained by linkage disequilibrium, which means that these single-nucleotide polymorphisms are found more frequently together in the same patient due to their proximity to each other. In this review, we will focus on the rs12979860 polymorphism; hence “IL28B genotype” will refer to the single-nucleotide polymorphism at rs12979860, unless otherwise specified.

The favorable CC genotype is less common in African Americans than in patients of other ethnicities.¹⁹ Moreover, although IL28B CC is associated with a better response rate to interferon-based antiviral therapy across all ethnicities, those of African American descent with the CC genotype are less likely to achieve a sustained virologic response than white or Hispanic Americans.⁸