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Chu TW, Kulkarni R, Gane EJ, Roberts SK, Stedman C, Angus PW, et al. Effect of IL-28B genotype on early viral kinetics during interferon-free treatment of patients with chronic hepatitis C. Gastroenterology 2012;142:790-795. (Reprinted with permission.)

Abstract

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  2. Abstract
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BACKGROUND & AIMS: Although interleukin 28B (interferon, lambda 3) (IL28B) genotype affects the response of patients with chronic hepatitis C to peginterferon and ribavirin, little is known regarding its effect on response to direct-acting antivirals in interferon-free combinations. We analyzed the effects of IL28B genotype on the viral kinetic (VK) response to an interferon-free combination of the nucleoside polymerase inhibitor mericitabine (RG7128) and the hepatitis C virus (HCV) protease inhibitor danoprevir. METHODS: We performed a double-blind, dose escalation study of patients with chronic HCV genotype 1 infection who were interferon treatment naive or had not responded to previous therapy with peginterferon and ribavirin. Patients were sequentially assigned to 1 of 7 cohorts then randomly assigned to groups that received up to 13 days of treatment with mericitabine (500 or 1000 mg, twice daily) plus danoprevir (100 or 200 mg, every 8 hours, or 600 or 900 mg, twice daily) or placebo. Eighty three of 87 patients were genotyped for the IL28B single nucleotide polymorphism rs12979860. VKs were analyzed only in patients who received 13 days of treatment, at optimal doses, using a biphasic model to describe first and second-phase slopes of viral decay during therapy. RESULTS: At day 14 (the end of interferon-free treatment), the mean reduction in the serum level of HCV RNA was slightly greater in patients with the CC polymorphism (5.01 log10 IU/mL) than those without (4.59 log10 IU/mL). Modeling revealed that patients with the CC polymorphism had slightly better early VKs, most apparent in the β-phase of viral decay. A mixed effect on the α-phase was observed, which was reduced in magnitude but prolonged in patients with CC, who also had better on-treatment response to peginterferon and ribavirin during follow up. CONCLUSIONS: IL28B genotype appears to affect early VKs in patients with chronic hepatitis C receiving interferon-free treatment.

Comment

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  2. Abstract
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In 2009 the identification of IL28B single nucleotide polymorphisms (SNPs) as predictors of increased sustained virological response (SVR) in response to pegylated interferon and ribavirin generated a lot of excitement in the hepatitis C (HCV)-treating community.1 It also became clear that IL28B had important power in predicting spontaneous HCV clearance.2IL28B predicts responses in HCV genotype 1 more than genotypes 2 or 3, although this effect has varied between studies.3-5 Principally, the addition of direct-acting antiviral agents (DAAs), however, to pegylated interferon (PegIFN) and ribavirin (RBV) has seemed to limit the role of IL28B in predicting response to triple therapy including either of the HCV protease inhibitors boceprevir or telaprevir. SVR rates among patients with the beneficial IL28B CC SNP at rs12979860 in the ADVANCE registration trial of PegIFN/RBV/telaprevir 12 weeks were 90%, whereas those among CT or TT patients were 71%-73%.6 Similarly in SPRINT-2, the response-guided therapy arm of PegIFN/RBV/boceprevir produced 81% SVR among CC, 55%-65% among CT or TT.7 These differences between IL28B genotypes, while present, were not statistically significant, and it has not been clear how IL28B genotyping will influence either further clinical trial development or clinical practice. Recent national guidelines on the use of IL28B describe it as a test that may be obtained if treating providers and patients feel that it will help to guide their decision making.8, 9

The study by Chu et al.10 forms part of the refinement of IL28B clinical effects in the setting of DAA use, and suggests that IL28B SNPs may play a fundamental role in HCV antiviral responses even using interferon-free treatment regimens. The study represents a post-hoc analysis of the 13 day HCV RNA kinetics in five of the seven arms of the INFORM-1 study.11 Both treatment-naïve and treatment-failure patients (null responders, partial responders, and relapsers) were included in the study arms, and they received different doses of RG 7128 (mericitabine, a nucleoside polymerase inhibitor) and danoprevir (a protease inhibitor) without pegylated interferon or ribavirin. HCV loads were checked daily for the first week and also at days 10, 13, and 14 during this therapy. Most of the analyses compared the 12 IL28B CC patients to the 33 non-CC patients.

The principal finding of the study was that at day 14 the mean reduction in HCV RNA was slightly greater among patients with the CC genotype (5.01 log10 IU/mL) compared with patients with CT or TT genotypes (4.59 log10 IU/mL), although this difference was not quite statistically significant (Mann-Whitney P = 0.08) (Fig. 1). The mean reductions at day 7 (4.21 log10 IU/mL versus 3.97 log10 IU/mL, respectively) were greater in CC patients (Mann-Whitney P = 0.04). These data suggest that, even in a small group of somewhat heterogeneous patients treated with dual DAA interferon-free therapy for only 2 weeks, the CC genotype affected viral kinetics. The authors then took the additional step of modeling the viral kinetic profiles during this therapy and found that CC patients had a less brisk, but more sustained, first phase (α) decline than CT and TT patients, and that the second phase decline (β) was more brisk among CC patients, eventually leading to a somewhat greater HCV RNA decline.

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Figure 1. Mean change in serum HCV RNA between study days 1 and 14 by rs12979860 genotype in all patients (n = 45) who received 13 days of dual oral combination therapy with mericitabine plus danoprevir in the INFORM-1 study (from Chu et al.).

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These data are intriguing, and strengthen the case for the continued acquisition of IL28B genotype data among patients in current clinical trials using interferon-free combination regimens. Certainly viral kinetic data are available across most studies and provide interesting, although incomplete, snapshots of the HCV clearance process. Additional insights are likely to be gained from evaluating HCV decline in response to different DAA-containing regimens. Recently published analysis of HCV RNA decline during RG7128 monotherapy in prior treatment failures found that ∼40% of patients exhibited a “monophasic” slow first-phase decline throughout 14 days of therapy, a pattern not generally seen using interferon-based therapies.12 The slope of HCV RNA decline was also significantly dose-related in this study. This study illustrates the fact that individual DAA agents are likely to produce unique patterns of HCV RNA decline, and that when they are combined with other DAA agents, additive, synergistic, or even inhibitory interactions may be seen, and these effects may be reflected to some degree in changes in HCV RNA decline. Also, interpretation of a DAA regimen's HCV RNA decline “signature” based on early Phase 2 dose optimization studies is likely premature, in part due to the small sample size in these studies.

Two other recent studies also describe the distribution of IL28B SNPs in differential responses to interferon-free regimens, but highlight the crucial differences in DAA responses between HCV subtypes 1a and 1b. These include the SOUND-2 study13 and the study of daclatasvir/asunaprevir by Lok et al.14 SOUND-2 evaluated BI 201335, a second-generation protease inhibitor administered once daily, in combination with BI 207127, a nonnucleoside HCV NS5B polymerase inhibitor, generally given with ribavirin in treatment-naïve patients with HCV genotype 1.13 Patients infected with HCV genotype 1a who were IL28B non-CC had a poor response rate (12-week SVR 32%-42%), whereas genotype 1a IL28B CC patients and all genotype 1b patients had similarly good response rates (12-week SVR 62%-82%). Lok et al. studied genotype 1-infected prior partial/null responders to pegylated interferon and ribavirin. Among 11 patients treated for 24 weeks with the NS5A replication complex inhibitor daclatasvir and protease inhibitor asunaprevir alone, SVR was achieved in four patients, failure of SVR in seven. Two of the patients who experienced SVR were infected with HCV genotype 1b (thus, a 50% SVR rate among genotype 1b patients, compared to 22% SVR among patients with genotype 1a). Only one of 11 patients was IL28B genotype CC, so IL28B genotype did not have a large effect on SVR.

The mechanisms by which IL28B SNPs exert their effects upon treatment-induced SVR remains unknown. The current weight of the rapidly expanding clinical evidence suggests that IL28B genotypes will likely continue to play some role in predicting SVR using interferon-free regimens, although they may play less of a role than HCV genotype 1 subtype, and possibly more so with some combinations of DAA therapy than others. As further work continues to be done to understand exactly how IL28B genotype acts on viral clearance, the mechanisms behind these relationships will become clearer.

References

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  2. Abstract
  3. Comment
  4. References
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