Pharmacogenomics of hepatitis C infections: Personalizing therapy

Abstract

It is a widely held view that drug response genes have not proved as useful in clinical practice as anticipated at the start of the genomic era. An exception is in the treatment for chronic hepatitis C virus (HCV) genotype 1 infection with pegylated interferon α and ribavirin. In 2009, four independent genome-wide analyses identified IL28B polymorphisms that predict drug response in chronic hepatitis C (CHC). This discovery had immediate clinical impact. First, the IL28B genotype could be used to personalize therapy. In the 2 years since discovery, most of the more than 100,000 CHC patients commencing therapy for CHC in the West will have considered IL28B genotype testing. Second, the discovery has supported clinical trials for the use of the protein encoded by the gene known as interferon lambda. Third, it is expected that new insights into HCV pathogenesis will follow from studies of how IL28B affects HCV viral clearance and, ultimately, this will lead to new therapeutic strategies for CHC. This review discusses how IL28B genotyping is now used in personalizing therapy and, with the dramatically changing clinical landscape in CHC, with the advent of direct-acting antivirals, the prospects ahead.

Full text

IL28B and hepatitis C
 e recent rapid increase in knowledge of genetic
variability and the decrease in the cost of genotyping
were expected to lead to an explosion in the number of
new diagnostic tests to predict drug response [1].  is
has not happened, largely because drug response pheno-
types, like many other phenotypes, are probably the net
eff ects of numerous common genetic variants of small
eff ect, and uncommon interacting variants of unknown
eff ect size. A striking exception is the prediction of res-
ponse to pegylated interferon α and ribavirin (PegIFN/R)
for the treatment for chronic hepatitis C (CHC). Four
independent genome-wide analysis studies published at
the end of 2009 and in early 2010 identifi ed variants of
the same single gene as predicting drug response [2-5].
 is gene, IL28B, encodes a recently discovered inter-
feron: interferon λ3.  e discovery was particularly excit-
ing because the closely related interferon λ1 had just
been shown to have promise as an alternative to inter-
feron α in phase 1 clinical trials for CHC [6].
CHC aff ects more than 180 million people or about 3%
of the world’s population [7].  e majority of these are in
Asia, the Middle East, Brazil and Indonesia; but there are
also more than 10 million in the USA, Europe and Aus-
tralia (Figure 1). Of those exposed to the virus, about a
quarter spontaneously clear infection [8], while the
majority develop chronic disease [9,10]. Disease progres-
sion in CHC is typically insidious, but a proportion will
develop end-stage liver disease resulting in morbidity and
mortality from liver failure and hepatocellular cancer.
 e genome-wide analysis studies were performed in
diff erent geographic locales (Australia, Japan, Europe,
USA) and in diff erent ethnic populations (European,
Japanese, African Americans, Hispanics), but all identi-
fi ed only the SNPs around IL28B as associated with drug
response, providing independent replication, and con-
fi rming that the data are robust and valid. In slightly over
2years since these reports, several hundred studies have
been published on IL28B and hepatitis C, underlying the
impact of this discovery on investigations of hepatitis C
virus (HCV) pathobiology.
 e importance of IL28B for hepatitis C infection and
the practice of hepatology is fourfold. First and foremost,
it marks host genetic variation as an important player in
the outcome of infection, bringing to the fore the era of
personalized medicine. From a clinical perspective, geno-
typing for polymorphisms near the IL28B gene have
impacted on decision making with regard to who to treat
and when to treat with PegIFN/R, but also for the new
direct-acting antiviral (DAA)-based therapies and
interferon-free regimens [11,12]. From the perspective of
pathogenesis, the discovery has led to important new
Abstract
It is a widely held view that drug response genes have
not proved as useful in clinical practice as anticipated
at the start of the genomic era. An exception is in
the treatment for chronic hepatitis C virus (HCV)
genotype 1 infection with pegylated interferon α
and ribavirin. In 2009, four independent genome-
wide analyses identi ed IL28B polymorphisms that
predict drug response in chronic hepatitis C (CHC).
This discovery had immediate clinical impact. First, the
IL28B genotype could be used to personalize therapy.
In the 2years since discovery, most of the more than
100,000 CHC patients commencing therapy for CHC in
the West will have considered IL28B genotype testing.
Second, the discovery has supported clinical trials for
the use of the protein encoded by the gene known
as interferon lambda. Third, it is expected that new
insights into HCV pathogenesis will follow from studies
of how IL28B a ects HCV viral clearance and, ultimately,
this will lead to new therapeutic strategies for CHC. This
review discusses how IL28B genotyping is now used
in personalizing therapy and, with the dramatically
changing clinical landscape in CHC, with the advent of
direct-acting antivirals, the prospects ahead.
© 2010 BioMed Central Ltd
Pharmacogenomics of hepatitis C infections:
personalizing therapy
David R Booth*
1
, Golo Ahlenstiel
2
and Jacob George
2
R E VI E W
*Corresponding author: david.booth@sydney.edu.au
1
Institute for Immunology and Allergy Research, Westmead Millennium Institute,
University of Sydney, Australia
Full list of author information is available at the end of the article
Booth et al. Genome Medicine 2012, 4:99
http://genomemedicine.com/content/4/12/99
© 2012 BioMed Central Ltd

knowledge, with type III interferons recognized as the
predominant interferon produced by HCV infection in
humans and chimpanzees and that best correlates with
induction of interferon-sensitive genes (ISGs) [13]. Finally,
from a therapeutic perspective, the type III interferons
might have a specifi c role in therapy, with the down-
stream signaling pathways and their modulation an
attractive target for drug development.
Given that humans and HCV, and their ancestors, have
co-evolved over millennia in diff erent ethnogeographic
contexts and have been subject to divergent selection
pressures, it is to be expected that both organisms will
develop genetic variations that improve survival. For
humans, the fact that some individuals but not others
spontaneously clear virus suggests that innate and
adaptive immune response variations determine the
outcome of infection. Viral genomic variation allows for
evasion of the host immune response and in this context,
suboptimal host responses predispose to the develop-
ment of chronic infection. Interferons play a major role in
the response to viral infections, including to HCV specifi -
cally, in both humans and chimpanzees [14-17]. Type I
interferons, IFNα and IFNβ, are produced in response to
signaling through viral recognition receptors, and utilize
the same receptor.  e type II interferon (IFNγ) is pro-
infl ammatory, regulating the direct T-cell and other
responses.  e three type III interferons (IFNλ 1 to 3) are
transcribed from a gene cluster on chromosome 19, are
highly homologous, and upregulate the same set of genes
as type I interferons, but through a diff erent receptor
[18]. It follows that host genetic variation, particularly in
innate response pathways, will likely contribute to
predict ing outcome to treatment with interferon-based
regimes. Likewise, viral genomic variation may explain
treatment failure in some individuals.
 is review will focus on the pharmacogenetic applica-
tions of IL28B genotyping, the only genetic variant
currently used diagnostically to predict drug response.
 e eff ectiveness of this genotyping for prediction of
therapeutic response and clinical management for dual
therapy (PegIFN/R) and triple therapy (PEGIFN/R and
DAA) for the diff erent viral subtypes will be discussed.
Also discussed are the other genes that have been
implicated in prediction for HCV treatment, and other
diseases and therapies that might be aff ected by the
IL28B genotype.
Prediction of response to PegIFN/R therapy
The need for prediction of drug response
HCV is mostly spread by blood-blood transmission:
typically through transfusion before screening for HCV
was mandatory, shared needles in the context of injecting
drug use, and use of non-sterile medical devices. If the
virus is not cleared spontaneously, it establishes chronic
infection of the liver, leading to fi brosis and loss of liver
function, some 15 or more years after onset. At this
Figure 1. Global prevalence and genotypes of hepatitis C. Prevalence data are derived from Shepard et al. (2005) [28] and Te et al. (2010) [27].
Genotype data are from Shepard et al. (2005) [28] and Te et al. (2010) [27]. The pie chart diameter is Ln (number infected with hepatitis C virus) in
the most populous areas of the world. The location of pie charts is approximate, based on the limited studies (reviewed in [27,28]). Colors in the
pie charts represent HCV genotypes: 1, blue; 2, red; 3, green; 4, purple; 5, light blue; 6, orange. Approximately 30 million sub-Saharan Africans have
chronic hepatitis C, with widely variant genotypes around the continent.
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point, the patient with symptoms will present to a
clinician. To avoid the risk of liver failure or hepato-
cellular carcinoma, the patient needs to clear virus. e
standard of care treatment in most of the world is
PegIFN/R, which is very expensive (about US$20,000 per
year). Treatment of the most common viral genotype
requires 48 weeks of injection with weekly pegylated
interferon α, and daily ribavirin tablets. Most patients
report flu-like symptoms and neuropsychiatric adverse
reactions, but improved therapies are now becoming
available. As disease progression is relatively slow, patients
are very keen to know if they are likely to benefit from
currently available therapy, or if they should wait for the
new, probably more expensive, therapies.
For PegIFN/R, IL28B genotyping can predict the
chance of achieving a sustained viral response (SVR) or,
as explained below, the likelihood of failing to achieve an
SVR. e rs12979860 SNP CC genotype predicts res ponse,
and the CT and TT genotypes predict non-response [2].
e rs8099917 SNP TT genotype predicts response, and
the GT and GG genotypes predict non-response [3,4]. In
east and north Asians, the rs12979860 and rs8099917
SNPs can be used interchangeably in prediction because
of the high degree of linkage disequilibrium, meaning
that an rs129798690 C is virtually always inherited with
an rs8099917 T. In patients of European descent, differing
results are obtained with regard to the positive predictive
value (PPV) for the SNPs. Based on 941 previously un-
treated patients of European descent with genotype 1
CHC and known treatment response examined for
rs12979860 and rs8099917, the rs12979860 CC had a
higher PPV for treatment success (64% versus 55% for
rs8099917). In contrast, when the PPV for treatment
failure was considered, then rs8099917 GG had a higher
PPV (73% versus 69% for rs12979860) [13]. ese data
indicate differential effects of the SNPs, most likely at the
haplotype level (discussed below). In Europeans, an
rs12979860 T can be on an allele with rs8099917 G
(haplo type 2; Table 1), with the highest prediction of
non-response. Or, it can be on an allele with rs8099917 T
(haplotypes 3, 5 and 6), which does not increase the risk
of treatment failure. Consequently, of the 50% of
rs12979860 CTs, those whose T occurs with rs8099917 G
have a poor chance of response (30%), while those with
rs8099917 T have a better than average chance of res-
ponse (Figure2) [19,20].
e responses in Figure 2 are from cross-sectional
cohorts, reflective of the clinical situation. It is important
to note that PPVs for success are higher in clinical trial
cohorts, where adherence to regimes is monitored. In the
study by Ge et al. [2], 82% of people of European descent
cleared virus if rs12979860 CC genotype, 42% if hetero-
zygotes, and 33% if TT genotype. In people of African
descent, rs8099917 is not in linkage disequilibrium with
rs12979860 and does not predict response. e SNP
rs12979860 does predict response, so that 53% of those
with CC clear the virus, 19% of heterozygotes clear the
virus, and 17% of those with TT clear the virus. For the
same genotype, clearance in African Americans is much
lower, and the basis for this has yet to be explained. One
possibility is genetic variation in another gene, with
human leukocyte antigen C (HLA-C) genotype being one
candidate [21].
The IL28B haplotypes
From the genome-wide analysis studies there were
several polymorphisms mapping to the IL28B haplotype
block associated with treatment-induced genotype 1
HCV clearance. rs12979860 is located 3 kb upstream of
the IL28B gene, while rs8099917 is located 8.9 kb from
the start of transcription of IL28B and 16 kb from the
start of transcription of IL28A [2-4].
Haplotypes are groups of SNPs that are inherited
together, so that the presence of one variant tags the
presence of others; for example, a ‘C’ at rs12979860
indicates that the SNP at rs12980275 is an ‘A’ (Table1).
ese two SNPs are currently used for IL28B genotyping
tests. ey were identified on genotyping chips loaded
with haplotype-tagging SNPs, and as such any SNPs,
including many not on the chips, that are also only on the
haplotypes they tag could be as good for predicting
response. e haplotype with the highest association
with response failure is haplotype 2, tagged by rs8099917
‘G’. e other haplotypes do not appear to have equal
effects on response. e ‘T’ that predicts response failure
for rs12979860 is on haplotype 2, but also on haplotypes
3 and 6, which affect drug response less.
e rs12979860 C allelic frequency varies significantly
across populations, about 70% in northern Europeans,
more than 90% in north and east Asians, and about 30%
in African populations where it is the minor allele
(Table2). is difference in allelic frequency for the most
part underlies the ethnic-specific differences in response
rates to PegIFN/R, accounting for the better response of
Asians, and about half the difference in SVR rates
between African Americans and Americans of European
ancestry [2].
Better SNPS for prediction from the haplotypes?
ere may be better SNPs in the IL28B region, tagging a
less common haplotype. An unbiased approach to
discover new and better SNPs near the IL28B gene for
response prediction, not limited by the genome-wide
analysis study SNP design, is through next-generation
sequencing technologies. Smith et al. [20] approached
this using massively parallel sequencing of pooled DNA
from 100 responders and 99 non-responders, and
validated this in a cohort of 905 patients. Long-range
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PCR was used to amplify a continuous 100kbp region of
DNA containing the IL28A, IL28B and IL29 genes. Only
SNPs in the IL28B linkage disequilibrium block predicted
drug response. Two SNPs, rs4803221 (homozygote minor
allele PPV of 77%) and rs7248668 (PPV 78%), predicted
failure to respond better than the rs8099917 (PPV 73%)
and rs12979860 (PPV 68%) SNPs. e best SNPs tagged a
single common haplotype, haplotype 2, and genotypes
predicted lack of response better than alleles.
Final decisions on the best SNP(s) may follow from
identification of the functional haplotype or SNP,
although haplotype tagging SNPs will likely be as effective
for prediction as any causal SNP they are in complete
linkage disequilibrium with. At this stage, haplotype 2
appears to be the causal haplotype. e African American
non-response haplotype, currently best tagged by
rs12979860 T, with less significant P values as SNPs up-
stream and downstream are sampled, likely contains the
functional SNP(s) [2,22]. e SNP found to best predict
response in the study by Smith et al. [20] was rs4803221,
which is in the CpG region of the proximal promoter
with rs12979860. It will be interesting to establish if the
subsection of Africans with rs12979860 T and rs4803221
G have the lowest response. Other further refinements
may follow from discovering rarer SNPs of bigger effects
that may have been tagged by the haplotype SNPs. It is
also possible that there are non-SNP genetic variants in
this region causing the functional effect(s).
e underlying mechanism for the effect of host and
viral genomes in predicting treatment response to
PegIFN/R therapy is still unknown. Two early studies
identified lower expression of the non-responder allele in
whole blood from healthy controls [3,4]. Subsequent
attempts to identify differential regulation of IL28B by
the alleles in blood, immune cells or hepatocytes have not
been conclusive, although there is a strong correlation of
the IL28B non-responder allele with high expression of
interferon-stimulated genes in infected hepatocytes but
not uninfected hepatocytes, and evidence for lower
expression of ISGs in immune cells of biopsies of infected
liver tissue [23-25]. African American haplotypes are
shorter and so ideal for narrowing down the potential
functional SNPs on the functional haplotypes. is indi-
cates the causal variant lies 5’ of rs12979860 and 3’ of
rs12980275, encompassing the proximal promoter and
coding region of the gene. Exonic changes on the non-
responder haplotype do not affect function in trans-
formed cells [23,26]. e TA repeat polymorphism on the
non-responder allele affects expression in the proximal
promoter region of transformed cells [26]. Responder
IL28B alleles and wild-type core 70 mutations are
associated with improved early viral kinetics. However,
the mechanism for these effects is uncertain, possibly
through effects on hepatic type III interferon and ISG
induction. Indeed, raised ISG induction in hepatic biop-
sies of CHC patients is tightly correlated with the
Figure 2. IL28B rs12979860 and rs8099917 genotypes and frequency in Europeans. Blue bars show the percentage of patients with sustained
viral response (SVR). Yellow diamonds show the percentages of the chronic hepatitis C population with the genotype combinations shown.
0
5
10
15
20
25
30
35
0
10
20
30
40
50
60
70
Percentage of CHC
Percentage of SVR
rs12979860 CT CT
rs8099917
CC TT TT
GGGT GTTT TT
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non-responder haplotypes, and provides slightly better
prediction of SVR [24,25].
Prediction of clearance for dierent HCV genotypes
HCV viruses are classified into six genotypes, with geno-
type 1 being the most widespread (China, Europe, America,
Australia) and common [27,28], the least susceptible to
PegIFN/R treatment, and for which prediction from
IL28B genotype is most useful.
e role of viral genomes in predicting the response to
treatment is contentious. Viral genotype and load are
important and established predictors of response. Most
studies of viral mutations have been from Japan and in
persons infected with HCV genotype 1b, where amino
acid substitutions at positions 70 and 91 of the HCV core
protein and substitutions in the interferon sensitivity
determining region (ISDR) of the NS5A protein have
been shown to be associated with treatment outcome.
e role of IL28B polymorphisms and the above substi tu-
tions were recently reported from 817 Japanese patients
with genotype 1b CHC [29]. In that report, IL28B
rs12979860 CC, core amino acid 70 substitution (non-
arginine; odds ratio (OR) 0.53, P = 0.016), age and viral
load were predictive of SVR, while IL28B CC genotype,
core amino acid 70 substitutions (P=0.0013), ISDR sub-
stitutions (P=0.0019), viral load GGT, ALT and platelet
count were predictive of a rapid virological response
(RVR).
e role of IL28B SNPs in predicting the outcome of
PegIFN/R treatment of infection with genotypes 2 to 6 is
controversial. ese other genotypes are more responsive
to therapy, with around 80% of those infected with
genotype 2 clearing virus on treatment [30]. IL28B geno-
type is correlated with success, but only improves
prediction by around 5%. Mangia et al. [31], using a
cohort of 268 Caucasian patients with HCV genotype 2
or 3 infection treated with combination therapy, found
that IL28B SNPs were associated with SVR principally in
those that did not achieve an RVR. In subsequent studies,
IL28B SNPs have been associated with RVR and variably
with SVR. Genotype 3, the most common type in India
and Pakistan, is thought to be similarly susceptible to
PegIFN/R to genotype 2, but clearance success in these
different clinical settings has yet to be established.
Genotype 4 is thought to be cleared with intermediate
efficacy between genotypes 1 and 2/3. It is the most
common type in the many millions infected in the Middle
East, with near 20% prevalence in the population of Egypt.
In a single small study of genotype 4 infected patients,
IL28B genotype was shown to influence RVR, SVR and
SVR in non-RVR patients [32]. Genotype 6 is the most
common form in the many millions infected in Southeast
Asia, and genotype 5 the most common in southern
Africa [27,28]. All genotypes are found in Africa, where
at least 30 million are thought to be infected, but where
genotypes and treatment responses are not well
characterized.
Post-treatment prediction of response
For HCV genotype 1, within 24h of first injection, there
is a rapid, IL28B genotype-dependent, reduction of HCV
viral load [33]. By week 4, undetectable HCV (RVR)
Table 1. Common SNPs across the IL28B gene region and their haplotypes
Haplotype
Location SNP 1
a
2
b
3 4
a
5 6
5’ rs7248668 G A G G G G
5’ rs8099917
c
T G T T T T
5’ rs8109886 C A A A A A
5’, CpG rs4803221 C G C C C G
5’, CpG rs12979860
c
C T T C T T
Exon 2 rs8103142 T C C T C C
Intron 2 rs11881222 A G G A A G
3’ rs688187 G A A G A A
3’ rs8105790 T C C T T C
3’ rs12982533 T C C T T C
3’ rs12980275 A G G A A G
OR (95% CI) 0.70 2.20 1.04 0.60 0.79 1.49
(0.57-0.85) (1.72-2.80) (0.75-1.43) (0.43-0.83) (0.39-1.60) (0.62-3.56)
%CEU (CHC) 43.2 23.8 10.3 9.8 1.9 1.4
a
Highest sustained viral response.
b
Causal haplotype; lowest sustained viral response.
c
SNPs currently used for genotyping to decide CHC treatment. Odds ratio (OR)
and percentage of haplotypes in chronic hepatitis C (CHC) in patients of European descent (CEU) are from Smith et al. [20]. CI, condence interval.
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predicts clearance better than IL28B genotype, and
response-guided therapy, where the time on treatment is
determined from the decline in viral load, is based on
viral load changes. Even using triple therapy, where
PegIFN/R is augmented with telaprevir, for those with
the non-responder genotype who do not achieve an RVR,
the chances of clearing virus by the end of therapy is 0%,
and 59% for those who do achieve RVR; whereas for
those homozygous for the responder genotype, 16% will
not clear virus if they have not achieved RVR, whereas
84% will clear if they have achieved RVR [34].
Combining RVR, HCV genotype and IL28B genotype
may prove useful in guiding therapy where cost is limiting
or dependent on time on therapy, particularly in the new
era of DAAs (see below).
Other host genes and the prediction of viral clearance
It is striking that in all the genome-wide analysis studies
to date, and including genes from the MHC region, only
IL28B reaches genome-wide statistical significance.
Certain genetic variants are not amenable to SNP chip
analysis. ese include the MHC region variants and
deletion variants such as CCR5 delta 32. In a recent
report, Suppiah et al. [21] studied the combined effect of
IL28B SNPs with HLA-C, and their ligands, the killer
immunoglobulin-like receptors in predicting treatment-
induced clearance (n = 417) or failure (n = 493) in
Caucasian patients with genotype 1 CHC. e rs8099917
non-responder G allele was associated with failure to
clear on treatment (OR 2.19, P=1.27×10
-6
, 1.67 to 2.88)
and absence of spontaneous clearance (OR 3.83,
P = 1.71 × 10
-14
, 2.67 to 5.48), as was rs12979860, with
slightly lower ORs. e HLA-C C2C2 genotype was also
over-represented in patients who failed treatment
(P = 0.024). e prediction of non-response improved
from 66% using IL28B to 80% using both IL28B and
HLA-C (OR 3.78, P = 8.83 × 10
-6
, 2.03 to 7.04). Using
logistic regression, the combination rs8099917, G*/C2C2
was shown to be partially due to genetic interaction and
not just an additive effect, consistent with the known role
of HLC-C in the pathogenesis of HCV infection. is
combination is present in about 20% of the Caucasian
population, and captures a higher percentage of non-
responders than using homozygote non-responders alone
(Table3). While the data need replication, the combi na-
tion of IL28B and HLA-C SNPs appears to improve
diagnostic accuracy and clinical utility. Natterman et al.
[35] found that prediction of spontaneous clearance in a
German cohort was improved using both CCR5delta32
and IL28B rs12979860 SNP. It remains to be seen if these
two genes interact in predicting SVR.
Impact of other clinical parameters with IL28B genotype
Clinical and genomic data can be combined for predict-
ing response to combination therapy with PegIFN/RBV
in genotype 1 CHC [36]. More recently, serum IP10 [37],
25 hydroxyvitamin D3 and SNPs in the vitamin D binding
protein [38], and hepatic ISG expression [23-25] have
been shown to be additional factors predicting the out-
come of therapy. However, while these markers in
combination improve diagnostic utility, large-scale pros-
pective trials are unlikely to eventuate given the rapid
development of DAA-based regimens.
Prediction of clearance for HIV-HCV co-infection
Because HCV and HIV are both blood-borne viruses,
where risks of infection are increased by similar practices,
co-infection is common. In these cases, two studies have
indicated a higher risk of mortality for the rs12979860
CC genotype on antiviral treatment for HIV. In one study,
Table 2. Common SNPs across the IL28B gene region have very dierent minor allele frequencies in the major ethnic
groups
Location SNP OR %CEU %CHI %YRI
5’ rs7248668 2.24
b
17 7 6
5’ rs8099917
c
1.91
b
17 8 6
5’ rs8109886 0.67
a
43 7 80
5’, CpG rs4803221 2.24
b
17 7 18
5’, CpG rs12979860
c
1.99
b
32 8 60
Exon 2 rs8103142 1.50
b
27 4 56
Intron 2 rs11881222 2.02
b
30 7 31
3’ rs688187 1.94
b
32 7 59
3’ rs8105790 1.63
b
17 7 19
3’ rs12982533 2.01
b
31 8 39
3’ rs12980275 1.79
b
31 8 51
a
Minor allele predicts treatment success.
b
Minor allele predicts treatment failure.
c
SNPs currently used in genotyping to decide treatment for CHC. %, Percentage of
SNPs in major ethnic groups. CEU, European; CHI, Han Chinese; YRI, Yorubi Africans. SNP frequencies are from the 1000 Genome Project pilot genotyping data.
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the rs12979860 CC genotype was associated with 54%
higher mortality risk compared with TT genotype in
HIV-HCV co-infected individuals [39]. In another, the
increased risk was 80% [40]. e authors in the latter
study speculated that this was due to higher baseline
plasma HIV viremia and possibly altered immune recon-
stitution associated with interferon λ expression. Vispo et
al. [41] found evidence that IL28B genotype predicted
clearance of HCV genotype 1a, but not 1b, in HIV/HCV
co-infection. Dayyeh et al. [42] have suggested that
therapy should be delayed in those with non-responder
genotypes and HCV genotype 1 infection, depending on
the baseline viral load.
Association of host genetic variants with other treatment
adverse reactions
e major adverse reactions to treatment with PegIFN/R
are IFN-induced neutropenia and leucopenia, and
ribavirin-induced hemolysis. Two genome-wide analyses,
one in Japanese [43] and one in Europeans [44], found
that SNPs at the inosine triphosphatase (ITPA) locus pre-
dicted ribavirin-related hemolysis. No genetic variants
were identified associated with neutropenia or leucopenia.
Association of host genetic variants with other viral
diseases and drug responses
To date, no association of IL28B genotype with clearance
or response to treatment of other flaviviruses (a group
that includes arboviruses such as dengue and West Nile
virus) has been reported. is may await interrogation of
appropriate cohorts. It may also represent different tro-
pisms of these viruses, to tissues not so dependent on
expression of the IL28 receptor. Other RNA viruses, such
as influenza, do infect tissues that express the receptor,
and so may be affected by IL28B genotype - this has yet
to be established. Although IL28B was not associated with
clearance of HIV [45] or hepatitis B [45,46], the IL28B
genotype can affect clearance of hepatitis B on interferon
therapy in European and Chinese cohorts [47,48].
Type 1 interferons are used to treat autoimmune diseases
such as multiple sclerosis, and antibodies to interferon α
are used to treat systemic lupus erythamotosis, as well as
many other inflammatory and autoimmune conditions
[18]. It has also yet to be established if the IL28B genotype
affects response to interferons in these diseases.
Prediction of response with DAAs
erapy for HCV infection is currently undergoing a
radical transformation with the advent of oral medica-
tions: the DAAs. e first two to receive US Food and
Drug Administration (FDA) approval are the NS3
protease inhibitors boceprevir and telaprevir. ese have
cure rates substantially higher (about 70 to 80%) than
dual therapy with PegIFN/R (<50%), and may allow
reduction in treatment duration [49,50] (Table 4). To
minimize the risk of viral resistance, both are used with a
PegIFN/R pre-treatment. For both, IL28B genotype
predicts SVR. For telaprevir, cure rates (SVR) vary from
90% for rs12979860 CCs, to 73% for TTs. Clearance at
8 weeks for boceprevir/PegIFN/R was achieved for 89%
of CCs and 52% of CT/TTs; and at 4 and 12weeks (no
HCV detected at both time points) for 72% of CCs and
52% of CT/TTs. Many more DAAs are in late-stage
clinical trials and producing very promising results [51].
ey have been so rapidly taken up, especially in the
USA, that triple therapy is now considered the new
standard of care treatment for genotype 1 HCV there
[12]. Dual therapy remains the standard of care treatment
for other viral genotypes.
However, enthusiasm for these regimens is tempered
by the substantially lower cure rates (about 30%) in
previous PegIFN/R null responders. In all those failing
single DAA-based therapy, future treatment with multiple
DAA-based combinations with or without PegIFN/R may
be compromised by the development of drug resistance.
Further, HCV eradication using single DAA-based strate-
gies, particularly in previous treatment failures, appears
to be IL28B genotype dependent. In this context, predict-
ing non-response rather than success is paramount since
the former should perhaps have therapy deferred until
multiple DAA-based combinations become available. e
present results therefore provide a strong rationale for
the use of IL28B SNPs such as rs4803221 in combination
with the HLA-C genotype, such that those with non-
response genotypes are considered for future regimens
rather than single DAA-based therapy.
Table 3. Combining HLA-C and IL28B genotypes to improve
prediction
Genotype % of CHC % of NSVR % with NSVR
HLA-C IL28B
rs8099917
Any GG(1) 6 10 73
Any G* 48 57 64
C2C2 Any 17 32 20
C2C2 G*(2) 8 12 80
b
(1)+(2) 12 18
a
77
a
rs12979860
Any TT(3) 15 19 68
Any T* 68 79 63
C2C2 Any 17 21 64
C2C2 T*(4) 13 18 73
(3)+(4) 26 33 70
CHC, chronic hepatitis C; NSVR, non-sustained viral response.
a
Slightly lower
prediction percentage, but identies a higher percentage of NSVR.
b
Best
prediction. Data from Suppiah et al. [21].
Booth et al. Genome Medicine 2012, 4:99
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Page 7 of 10

Conclusion
Internationally, in the next few years, hundreds of
thousands to millions of people with HCV are likely to
consider therapy to clear virus, and consideration of
IL28B genotype may aid in pre-treatment choice of
therapy. As discussed above, such testing can predict the
difference between a 15% chance of clearance (for
example, for those with HCV genotype 1a and HIV co-
infection, or those with rs8099917 GG and HLA-C C2C2
genotypes) to 100% chance of clearance (rs12979860 CC
on DAA), depending on the treatment chosen, HCV
geno type and HIV co-infection status. is decision will
also be greatly affected by the cost of therapeutic options,
with vastly different parameters in western countries,
Asia, the Middle East and Africa. To the armory of
information already obtained will come a need to gather
more for the new therapeutic options and for the vastly
different clinical settings in the different parts of the
world. Specifically, new genetic variants (SNPs, inser-
tions, deletions, gene copy number variants, even RNA
isoforms) may identify the few who fail to respond to the
triple therapies. Next-generation sequencing studies to
identify viral variants that resist particular therapies will
be needed. Clinical management may need to be guided
by monitoring of the emergence of such viral variants
and the rebound of viral load.
Abbreviations
CHC, chronic hepatitis C; DAA, direct-acting antiviral; HCV, hepatitis C virus;
HLA-C, human leukocyte antigen C; ISDR, interferon sensitivity determining
region; ISG, interferon sensitive gene; kb, kilobase; OR, odds ratio; PegIFN/R,
pegylated interferon and ribavirin; PPV, positive predictive value; RVR, rapid
viral response; SNP, single nucleotide polymorphism; SVR, sustained viral
response.
Competing interests
DB and JG have patent applications for using IL28B and HLA-C to predict drug
response.
Acknowledgements
This work was funded by an Australian National Health and Medical Research
Council Project Grant, a MS Senior Research Fellowship to DB, and the Robert
W Storr Bequest to the Sydney Medical Foundation.
Author details
1
Institute for Immunology and Allergy Research, Westmead Millennium
Institute, University of Sydney, Australia.
2
Storr Liver Unit, Westmead
Millennium Institute, University of Sydney, Australia.
Published: 26 December 2012
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doi:10.1186/gm400
Cite this article as: Booth DR, et al.: Pharmacogenomics of hepatitis C
infections: personalizing therapy. Genome Medicine 2012, 4:99.
Booth et al. Genome Medicine 2012, 4:99
http://genomemedicine.com/content/4/12/99
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