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HCV treatments and IL28B genetic variations:  CC, CT, and TT alleles

Feb 11, 2012 - 0 comments
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IL28B genotypes

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HCV treatment

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CC CT TT alleles

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Interleukin 28B

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interferon lambda3



Below is some information regarding the IL28B (Interleukin 28B; interferon lambda3) genetic variations found on the human interferon gene on chromosome 19.  Research indicates that these variations may be a predictor regarding the effectiveness of interferon treatments for Hep C.  There are 3 variations of the IL28B genotypes:  CC, CT, and TT.  Although patients with the CC allele appear to have the best response to current treatments, people with CT and TT alleles also have demonstrated improved responses with the addition of the new DAAs.  ERVR and achievement of virological milestones are still considered to be the best predictors for SVR.
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1.  Telaprevir-Based HCV Treatment Benefits All IL28B Genotypes

Caroline Helwick

May 24, 2011 (Chicago, Illinois) — The direct-acting protease inhibitor telaprevir, given in combination with pegylated interferon plus peginterferon/ribavirin (PR), increased the chance of sustained viral response (SVR) across all interleukin (IL) 28B genotypes of hepatitis C virus (HCV), results of a substudy of the ADVANCE trial have shown.

The findings were reported here at Digestive Disease Week 2011 by Ira Jacobson, MD, chief of the division of gastroenterology and hepatology at New York–Presbyterian Hospital/Weill Cornell Medical Center, and Vincent Astor Distinguished Professor of Medicine at Weill Cornell Medical College in New York City. Dr. Jacobson is also principal investigator for the ADVANCE study.

"Single-nucleotide polymorphisms near the IL28B gene have been strongly associated with the likelihood of SVR in genotype 1 HCV patients treated with PR. During our evaluation of an exploratory diagnostic test that characterizes genetic polymorphisms near the IL28B gene, we investigated the impact of the IL28B genotype on SVR rates in the telaprevir-based regimens," Dr. Jacobson said.

The 3 variations of the IL28B genotype have been associated with a person's response to hepatitis C treatment with PR, Dr. Jacobson noted. In this study, substantial improvements were observed in SVR, or viral cure, across all IL28B genotypes — CC, CT, and TT — for patients treated with telaprevir-based combination therapy, he reported.
In ADVANCE, patients were randomized to receive telaprevir (for 8 weeks or 12 weeks) in combination with PR, followed by PR alone, for a total of either 24 weeks or 48 weeks of treatment. In the response-guided regimen, eligibility for the shorter treatment duration was based on having undetectable HCV at weeks 4 and 12.

The IL28B allele distribution in a sample of 454 patients for whom genotyping was available was consistent with previous reports for treatment-naïve patients: 49% had the CT genotype, 33% had the CC genotype, and 18% had the TT genotype.

The SVR rates in these 454 white patients were 78% for the 12-week telaprevir-based regimen, 65% for the 8-week telaprevir-based regimen, and 38% for the control group treated only with PR.

Patients with the CC allele were the most likely to achieve an SVR, which reached 90% with the 12-week regimen and 84% with the 8-week regimen. In the CC allele population receiving only PR, 68% achieved an SVR. In the other 2 allele subsets receiving 12 weeks of telaprevir, SVR was achieved by 71% of CT patients and 73% of TT patients; in those receiving PR only, SVR was achieved by 25% of CT patients and 23% of TT patients.

"You see that the largest increment in SVR occurred in patients with the T allele," Dr. Jacobson pointed out. Rates exceeded 70%, compared with 25% or less with PR only.

With the 8-week regimen, SVR rates were 57% and 59%, respectively, compared with 25% and 23%, respectively, for the PR regimen in these genotype subsets.

Telaprevir-based regimens also improved rapid viral responses (RVRs) and extended (e)RVR rates across all IL28B genotypes, meaning they had undetectable HCV RNA at weeks 4 and 12. The eRVR rate in the 12-week group was higher than in the placebo group for CC patients (78% vs 15%), for CT patients (57% vs 2%), and for TT patients (45% vs 0%).

"Most eRVR patients achieved an SVR in all groups," he added, including 95% of the CC group, 92% of the CT group, and 80% of the TT group receiving 12 weeks of telaprevir plus PR. "Patients with an eRVR were highly likely to achieve SVR as well."

Nonattainment of eRVR was associated with lower SVR rates across all IL28B genotypes, with the largest decrement in CT/TT patients, the study found.

Andrew Muir, MD, clinical director of hepatology at Duke University Medical Center, Durham, North Carolina, told Medscape Medical News that these findings confirm that all patients benefit from the addition of telaprevir, regardless of their IL28B genotype.

When it became clear that the CC genotype is associated with higher response rates, patients who learned they had the CT or TT genotype tended to have concerns, Dr. Muir said. "These findings change that discussion a lot," he noted. "Those patients now see that they can benefit from treatment as well."

The other value of the study is the finding that a patient is more likely to benefit from a shorter course of treatment if he or she [has genotype] CC," he added. "This may be relevant to some patients — that is, it may make a difference in their enthusiasm for treatment. It's important to have this information in your discussions with patients."

Telaprevir was just approved by the US Food and Drug Administration for the treatment of HCV.

Dr. Jacobson reports receiving grant and research support, consulting fees, and other financial benefit from Vertex Pharmaceuticals. Dr. Muir reports financial relationships with Anadys, Genentech, Idera, Medtronic, Merck & Co, Pharmasset, Santarus, Scynexis, Three Rivers Pharmaceuticals, Vertex, and ZymoGenetics.

Digestive Disease Week (DDW) 2011: Abstract 904. Presented May 10, 2011.

http://www.medscape.com/viewarticle/743298

2.  Limited use of interleukin 28B in the setting of response-guided treatment with detailed on-treatment virological monitoring

Alessandra Mangia
Alexander J. Thompson
Rosanna Santoro
Valeria Piazzolla
Massimiliano Copetti
Nicola Minerva
Daniela Petruzzellis
Leonardo Mottola
Donato Bacca
John G. McHutchison

Article first published online: 21 JUL 2011
DOI: 10.1002/hep.24458

"A SNP upstream of the IL28B gene is associated with pegylated-interferon-alfa-induced viral clearance in HCV-1 patients. We studied, in a well characterized cohort of patients randomised to standard vs response-guided therapy, whether the favourable CC-type allows shortening of treatment duration. Association with viral kinetics, SVR and predictors of response were also analysed.

In the original study, 696 patients were randomized to either standard or variable therapy of 24,48 or 72 weeks according to first undetectable HCV-RNA.

Association between IL28B determined by genotyping rs12979860 and EOT response and SVR by treatment arm was tested; baseline predictors of response analyzed by MLR.

454 patients were evaluated. The frequency of IL28B-type was CC=29%,CT=53%,TT=18%. CC-type was strongly associated with RVR (CC=51%,CT=42% and TT=7%,P=0.0001) as well as higher rates of week-8 and 12 response. CC-type was associated with SVR in both arms (70% and 69%,P =1.0). In patients with RVR, SVR was high and IL28B-type was not associated with SVR (84%/87%/86%, for CC/CT/TT, P=0.92). In RVR patients, there was no significant difference in SVR or relapse rates after 24 or 48 weeks by IL28B-type. Among non-RVR, CC-type was associated with SVR at higher rate than CT/TT, both in standard (52%vs35%,13%, P=0.017) and variable (63%vs41%,29%, P=0.010). However, when week-8 and 12 responders were considered separately, IL28B-type was no longer predictive of SVR. Few CC patients remained viremic beyond week-8 to allow the analysis of relationships between IL28B-type and extended treatment.

Conclusions:
In HCV-1 patients, the favourable CC-type strongly predicted for higher rates of on-treatment virological milestones and SVR. However, achievement of on-treatment virological milestones was the critical factor in determining outcome. IL28B-type appeared to have limited potential for response-guided treatment strategies.

http://onlinelibrary.wiley.com/doi/10.1002/hep.24458/full


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