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Gastroenterology Volume 142, Issue 4, April 2012, Pages 790–795 Tom W. Chu.

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Presentation on theme: "Gastroenterology Volume 142, Issue 4, April 2012, Pages 790–795 Tom W. Chu."— Presentation transcript:

1 Gastroenterology Volume 142, Issue 4, April 2012, Pages 790–795 Tom W. Chu

2  DrMohammad Sadrkabir

3  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.

4  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.

5  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.

6  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.

7  Patients and Methods

8  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.


10  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-to- treat 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.

11  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 :

12  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.

13  Results

14  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.

15  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).Figure 2Figure 3



18  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).



21  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 follow- up phase of the trial (week 4: 83% vs 27%, respectively, P =.001; and week 12: 92% vs 64%, respectively, P =.134).


23  Discussion

24  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 interferon- free regimens should determine whether there is an interaction between the doses of the DAAs and IL28B genotype.

25  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.

26  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 interferon- free therapy required.


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