Transcript Effect of IL28B Genotype on Early Viral Kinetics During

Gastroenterology
Volume 142, Issue 4, April 2012, Pages 790–795
Tom W. Chu
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DrMohammad Sadrkabir
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Host interleukin 28B (interferon, lambda 3) (IL28B)
genotype is the most important baseline predictor of
sustained virologic response (SVR) after treatment
with peginterferon plus ribavirin in patients with
chronic hepatitis C virus genotype 1 infection.
Patients with a CC genotype at the rs12979860 locus
on chromosome 19 had a 2- to 3-fold greater rate of
SVR when treated with peginterferon plus ribavirin
than patients with the less favorable TT genotype.
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Several classes of direct-acting antiviral agents
(DAAs) are under development, and it is expected
that, when used in combination with peginterferon
plus ribavirin, these new drugs will increase SVR
rates and decrease the required duration of therapy
for many patients with chronic hepatitis C.
Unfortunately, treatment with interferon-containing
regimens is associated with significant adverse
effects in a large proportion of patients.
Consequently, interferon-free combinations of DAAs
have become an area of considerable clinical
interest.
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To this end, we recently showed in the
INterferon-Free regimen fOR the Management
of HCV (INFORM-1) study that a dual oral
combination regimen composed of the
nucleoside polymerase inhibitor mericitabine and
the HCV protease inhibitor danoprevir produced a
rapid and substantial viral load decline that was
maintained throughout 2 weeks of treatment.
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A host IL28B polymorphism has also been shown
to affect the spontaneous clearance of HCV
infection; thus, it is conceivable that genetic
variation at this locus may also influence the
outcome of treatment with interferon-free
regimens.
For this reason, we conducted an exploratory
analysis to determine the effect of host IL28B
genotype on the early viral kinetic response to
mericitabine and danoprevir in patients enrolled
in the INFORM-1 study.
 Patients and Methods
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INFORM-1 was a randomized, double-blind,
placebo-controlled, dose-escalation trial in patients
with chronic hepatitis
Briefly, patients from 6 centers in Australia and New
Zealand were enrolled into 1 of 7 cohorts.
Patients who received 13 days of combination
therapy in cohorts C–G are the subject of this
analysis.
Patients randomized to cohort B received lower
doses of both mericitabine and danoprevir and had
lower viral declines over the 13 days than the
subsequent cohorts and are excluded from the
analyses.
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Serum HCV RNA levels were (lower limit of
quantification, 43 IU/mL; lower limit of detection, 15
IU/mL) at baseline; at days 1, 2, 3, 4, 5, 6, 7, 10, and
13 of treatment with mericitabine plus danoprevir;
study day 14 (washout); and at weeks 4 (study day
42) and 12 (study day 98) of treatment with
peginterferon plus ribavirin.
All patients enrolled in INFORM-1 were considered
for inclusion in this genetic analysis.
A total of 83 out of 87 patients in the intention-totreat population consented to donate DNA. These
samples were subsequently genotyped at the
rs12979860 locus by direct sequencing of regions in
and upstream of the IL28B gene.
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Viral load profiles were constructed for each
patient over 13 days of combination therapy with
mericitabine plus danoprevir.
To assess the effect of treatment and IL28B
genotype on the viral kinetics, viral decay profiles
were fit to a nonlinear mixed effect model :
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HCV RNA measurements made at 12 and 16 hours
postdose on day 3 and day 4 were ignored because
they create an artificial saw-tooth pattern,. Seven
data points qualified as rebound (a data point
qualified as a rebound if it occurred after the nadir of
the viral decay trajectory and was > 0.5 log10 higher
than the HCV RNA measurement at the nadir) and
were excluded.
Thus, a total of 600 data points on 45 subjects across
15 time points on 13 days of dosing were considered
for model fitting and parameter estimation.
Seventy-two of these data points were below the
limit of quantification and imputed as 40 IU/mL.
 Results
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Host IL28B genotype was determined by direct
sequencing for 83 out of 87 patients who received at
least 1 dose of study medication.
One-third of treatment-naive patients had a CC
genotype (21 of 63). The remaining two-thirds of
treatment naive patients carried the T allele (34
[54%] had the CT genotype, and 8 [13%] had the TT
genotype).
Only 2 (20%) of the 10 previous partial responders
and none (0%) of the 10 previous null responders to
peginterferon plus ribavirin had a CC genotype.
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Mean baseline serum HCV RNA levels were similar in
patients with the CC genotype (6.49 ± 0.48 log10
IU/mL) and in those with non-CC genotypes (6.31 ±
0.61 log10 IU/mL).
Robust viral load reductions were seen in patients
with CC, CT, and TT genotypes in the 5 cohorts (C, D,
E, F, and G; n = 45) that received 13 days of active
treatment with both drugs (Figure 2) and in the
subset of patients in the 2 highest dose cohorts (F
and G, n = 15) (Figure 3).
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The mean reduction in serum HCV RNA level began
to differentiate at day 7 in patients with CC versus
the non-CC genotypes and continued through the
end of treatment.
A 0.37–0.66 log10 (IU/mL) greater mean reduction
was observed for patients with the CC genotype
within each dose group.Therefore, dosing did not
appear to be associated with the differential viral
load decline observed between patients with CC
versus non-CC genotypes at rs12979860 (after
excluding the group B with the lowest doze
regimens).
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A higher proportion of patients with the CC
genotype had undetectable HCV RNA levels at the
end of interferon-free treatment overall (50% vs
27%, respectively, P = .174) and in the highest dose
cohorts (100% vs 33%, respectively, P = .077)
Viral clearance rates between patients were higher
overall in CC versus non-CC genotypes on treatment
with peginterferon plus ribavirin during the followup phase of the trial (week 4: 83% vs 27%,
respectively, P = .001; and week 12: 92% vs 64%,
respectively, P = .134).
 Discussion
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This small post hoc analysis suggests that IL28B
genotype has an influence on early viral kinetics
during treatment with an interferon-free DAA
regimens.
Our data suggest that the relative reduction in viral
load between CC and non-CC patients is not
associated with dosing, although the numbers of
patients in these 2 subgroups are too small to make
a definitive statement. Future studies of interferonfree regimens should determine whether there is an
interaction between the doses of the DAAs and
IL28B genotype.
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Based on these data, determination of IL28B
polymorphism may be important for analysis of
treatment outcomes in clinical trials of interferon-free
regimens. These results, however, need to be confirmed
in larger studies and with different combinations of
direct-acting antivirals and in longer studies to
determine the ultimate impact of these kinetic
differences on SVR.
As expected and seen in other studies, patients with the
CC genotype had more robust antiviral responses in
comparison with the non-CC genotype after stopping
mericitabine plus danoprevir and continuing subsequent
treatment with peginterferon plus ribavirin.
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IL28B genotyping will continue to play an important
role in determining the likelihood of response to
treatment with peginterferon plus ribavirin and to
emerging triple (single DAA plus
peginterferon/ribavirin) and quadruple (2 DAAs plus
peginterferon/ribavirin) antiviral regimens.
However, the importance of IL28B genotype on
response to future interferon-free combination DAA
regimens remains to be determined with analyses of
larger and longer duration studies with interferonfree therapy required.
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