Is IL28B Testing A Threat To Telaprevir Or To Patients ?

Update Jan 2011
Hepatitis C: Proposed Treatment Guidelines
 
In Jan/2011 medscape published a proposed guide for physicians ;"Hepatitis C: New Direct-acting Antivirals in Development : Treatment Guidelines" which is highlighted here on the blog.

A quick summary;
Owing to the side-effect cost of DAAs and the risk of development of drug-resistant viral strains, it will be necessary to guide treating physicians through a growing maze of confounding factors. These will likely not only include new drugs but also important predictive tests and relevant mutation analysis.

One such predictive test is the IL28B genetic polymorphism, which has recently been reported to be associated with SVR by three separate groups [Ge et al. 2009; Suppiah et al. 2009; Tanaka et al. 2009].

The IL28B genotype will become a commercially available polymerase chain reaction assay in 2010 and may be helpful for decisions using SOC treatment. It is unknown if the C/C, C/T, and T/T alleles of IL28B will be associated with response rates to DAAs and this information will need to be carefully collected in ongoing trials.

In this proposed system;

Class I
patients would be those with a very high chance of SVR with SOC therapy for 24 weeks, that is, treatment naïve, interferon-tolerant patients with genotype 2/3, or genotype 1 infection with low viral loads or the C/C IL28B allele [Thompson et al. 2009].

As these patients would have an 80–90% probability of cure without the risk of additional side effects or the additional cost of DAAs, they might be well served to be treated with current SOC alone. These patients represent approximately 20–25% of the US population with HCV [Ghany et al. 2009].

Class II
Patients might be those who are treatment naïve, interferon-tolerant with genotype 1 who have high viral loads and/or have C/T or T/T IL28B alleles. These patients would be less likely to have an SVR with current SOC but would have approximately a 75–80% chance of an SVR with the addition of an NS3/4 protease inhibitor followed by consolidation therapy for a total of 24 weeks (if an RVR is attained). The added cost of DAA therapy and the risk of side effects would need to be considered in these patients, who represent the majority of the US HCV population (40–50%) [Ghany et al. 2009].

Class III
Patients would be those requiring 48 weeks of total therapy in order to attain an SVR with SOC and protease inhibitor therapy, such as relapsers and nonresponders of all genotypes, and those in Class I who do not attain an RVR. It would be important to establish a limit on exposure to protease inhibitor therapy in this group as many who are interferon refractory would not clear virus permitting the emergence of resistance. Although this period will require refinement in the future it appears to be 12 weeks based on the data we have presented herein. These patients are prevalent in practices but actually do not represent a majority of the infected population, certainly no more than 20%. It would be anticipated that half of these patients would not attain an SVR based on the data seen in treatment-failure patients Table 2.

Class IV
Patients would include Class IIIs who do not become undetectable by week 12, interferon-intolerant patients and all treatment failures from treated Classes I and II. This could be up to 30% of the US population infected with HCV based on the SVR rates proposed above. These patients would probably be best served by waiting for the availability of combination therapy with an NS3/4 protease and either an NS5B polymerase, an NS5A inhibitor, a cyclophilin inhibitor, or another interferon-free combination regimen.

The goal of therapy in these patients would be viral eradication but this is not likely to be an attainable outcome for most. Instead, viral suppression with cessation of histological injury will likely be the new goal in these patients. As such, the risks for resistance and the cost of long-term therapies will need to be major considerations in this population Table 3.

Full  text; ,
Hepatitis C: New Direct-acting Antivirals in Development : Treatment Guidelines .
Abstract and Introduction
Protease Inhibitors
Polymerase Inhibitors
Ribavirin Analogues
Other Direct-acting Antiviral Drugs
Other Novel Compounds
Treatment Guidelines Conclusions
Is IL28B Testing A Threat To Telaprevir Or To Patients ?
Dec 2010

On the blog and website IL28B testing has been an important hot topic over the last year. It will change the way we treat hepatitis C. 

People who carry a particular allele of the IL28B gene have a good chance of reaching SVR = (Sustained Virologic Response) when treating with standard of care= (peginterferon and ribavirin) therapy. ..

The question is will these people need a protease inhibitor?

The bigger question is will insurance companies pay to treat with telaprevir/boceprevir or a protease inhibitor in these individuals who have the good "CC" allele; best response to Hepatitis C treatment ?

The concern is these patients may be started on standard of care without the option of a protease inhibitor. This is only in theory and until  the FDA approval of  telaprevir/ boceprevir we can only speculate.

What about those people who carry the TT allele; which has the poorest response to treatment.

This group of people will more than likely be offered a protease inhibitor.

What will the final treatment protocol be when IL28B testing becomes standard ?  

 If you remember in the boceprevir RESPOND-2 study all patients underwent a 4-week lead-in phase of standard therapy (peginterferon/ribavirin for four weeks) before adding boceprevir.

(Hold that thought we will return to boceprevir in a moment) ,

Think about this, before starting treatment with boceprevir you're tested for IL28B and you have the good allele "CC".
You begin therapy; after four weeks on standard therapy you have an early response (RVR) .

Could a pattern begin to emerge in that people tested prior to treatment for IL28B (having "CC") and who achieve a four week early response be kept on standard therapy,  do these individuals need a protease inhibitor?

Will insurance companies seize the opportunity to cut costs by refusing to pay for a protease inhibitor for these people? Especially in the event of socialized medicine or standardized care.

In published data 30% of patients carrying the "CC" allele stand a very good chance of being cured with standard of care. The buzz is that the FDA is working with Vertex in order to understand the impact of IL28B genotype on anti-viral activity .

Another factor is Merck who is behind boceprevir seems to have the intellectual rights to IL28B testing. ..

 LabCorp Gains Rights to Merck & Co.'s IL-28B Polymorphism IP for HCV Therapy Predictive Test

http://www.genengnews.com/
 Merck & Co. has granted LabCorp a nonexclusive license to use the IL-28B polymorphism in a commercial test to help predict an HCV patient's response to peginterferon alpha-based therapy. Merck will receive an up-front fee from LabCorp plus royalties on sales of tests covered under the deal. LabCorp has already developed an in vitro assay to identify the IL-28B polymporphism in HCV patients. An association between the polymorphism and peginterferon alpha response was identified by Merck and collaborating scientists through a genome-wide association study of nearly 1,700 HCV genotype-1 patients, the firm points out. The IL-28B link with HCV therapy identified through the Ideal study was first reported last year, and full data from the trial was published in Gastroenterology in May. Merck says it plans to provide a limited number of nonexclusive licenses to the IL-28B polymorphism to established diagnostics companies. Global sales of the firm's peginterferon alfa-2b HCV therapy Pegintron were $186 million in the first quarter of 2010.

This brings us back to "Merck's boceprevir" and their four week lead in with standard of care.
I can't say what this all means to us folks, maybe nothing. However, if IL28B testing becomes standard could physicians be persuade by insurance companies to use boceprevir over telaprevir ? It could happen because the protocol for boceprevir thus far is the four week lead in.

So the analogy goes like this ?

1-IL28B testing

2-Test shows the "CC" allele (good allele)

3-Start with standard of care

4-Four week early response (RVR) continue on with Standard of care

5-No early response....add boceprevir ?

Where does that leave telaprevir?

Where does that leave us ?

Well, possibly it could mean standard of care in those people with a good ol' gene.

Understanding The IL28B Gene and Testing

What is a gene?
A gene is the basic physical and functional unit of heredity. Genes, which are made up of DNA, act as instructions to make molecules called proteins. In humans, genes vary in size from a few hundred DNA bases to more than 2 million bases. The Human Genome Project has estimated that humans have between 20,000 and 25,000 genes.

Every person has two copies of each gene, one inherited from each parent. ..

Most genes are the same in all people, but a small number of genes (less than 1 percent of the total) are slightly different between people. .
Alleles are forms of the same gene with small differences in their sequence of DNA bases. These small differences contribute to each person’s unique physical features.

How is the IL28B gene related to Hepatitis C ?
Variations in the IL28B gene have recently been linked to better treatment response among people with chronic hepatitis C virus.

What Are Alleles?
Alleles are corresponding pairs of genes located at specific positions in the chromosomes. Together, alleles determine the genotype of their host organism. .
For example, the alleles for eye color are found on chromosomes 15 and 19, and depending on which alleles someone has, he or she may have blue, brown, green, gray, or hazel eyes, and sometimes a mixture of these traits is present. Source

What Are "C" and "T" Alleles ?
As mentioned above a person inherits two copies of each gene; one from each parent to make up each allele. The IL28B rs12979860 SNP has two alleles or variations which are regonized as "C" and "T". .

Then What Is C/C or "CC" ?
In Hepatitis C patients who have the C/C pattern simply means that they have two copies of the "C" allele.

Then What Is T/T or "TT" ?
The same is true in Hepatitis C Patients who have the T/T pattern or two "T" alleles .

What Does This Mean To The Heptitis C Patient?
Hepatitis C Patients With The C/C pattern or two "C" alleles have the best response to HCV therapy..
As for the T/T pattern or two "T" alleles they have the least response to therapy. .

What If A Person Has The C/T pattern?
The C/T pattern would mean the person has one copy of each allele. These people would fall somewhere in between.

Summarize All Of This Please
TT - Poorest response to Hepatitis C treatment.
CC - Best response to Hepatitis C treatment.
CT - Somewhere in between TT and CC alleles.

Non-genetic and genetic factors play a part in determining whether PEG-IFNalpha/RBV therapy will work. Recent research has identified several inherited variations near the interleukin 28B (IL28B) gene that could eventually help doctors identify those people with hepatitis C for whom the standard treatment is doomed to fail.
See: Response to Hepatitis C Treatment

** Note: It has been proven that people of European descent more commonly have the C/C pattern this may explain why white patients infected with HCV respond better then black patients.

Is There A Test For The IL28B Gene?
LabCorp Launches Interleukin 28B Polymorphism (IL28B) Genotype Test to Support Individualized Treatment Decisions for Patients with Hepatitis C Viral Infection.
Service Announcement >> .

As reported On Feb 25 2011
Scripps Health ;IL28B Genetic Testing to Hepatitis C Patients Now Available

From HCV Advocate Note:
The term CC genotype used to describe the variation of IL28B is not same as the term used for different strains of HCV (called genotypes)–numbered 1 through 6. ..

 
(IL28B) Genotype Test 
Likeihood Of Achieving SVR

LabCorp Launches Interleukin 28B Polymorphism (IL28B) Genotype Test
to Support Individualized Treatment Decisions for Patients with Hepatitis C Viral Infection.
Service Announcement >> 
Science 29 October 2010: Vol. 330 no. 6004 p. 579

Gene Variants Affect Hepatitis C Treatment, But Link Is Elusive

Jessica Wapner*
Summary
A year ago, three groups independently found that patients with a particular variant of a gene called IL28B tend to fare better than others in battling hepatitis C virus (HCV). The finding promised new insights into the complex interplay between the immune system and HCV, which is estimated to infect 4 million people in the United States and 170 million worldwide. A diagnostic test for the IL28B variants recently became available. It is helping to guide decisions on whether, and when, patients begin treatment with the current therapy, a combination of pegylated interferon-α and the antiviral drug ribavirin. And there are hints that the IL28B polymorphisms may play a similar role in responses to treatment with two new drugs that are expected to be approved early in 2011. So far, however, research to determine why different versions of the gene provide different levels of protection against HCV and different responses to treatment has yet to yield any answers.

The content requires a AAAS member subscription to this site or Science Pay per Article purchase
Read the Full Text

"IL28B gene, which predict spontaneous hepatitis C virus clearance and response to interferon-based therapy" .

Nov 20 2010
/
Do IL28B Gene Variations Affect Liver Disease Progression in People with Hepatitis C?

SUMMARY: Variations in the IL28B gene, which have been shown to predict spontaneous hepatitis C virus (HCV) clearance and response to interferon-based therapy, may also play a role in liver disease progression, according to a set of studies presented at the recent American Association for the Study of Liver Diseases "Liver Meeting" (AASLD 2010) in Boston. Some investigators found that the unfavorable rs12979860 T/T gene pattern was associated with worse liver fibrosis, but others did not observed this link

IL28B Gene Patterns and Liver Transplant Outcomes in Hepatitis C Patients
SUMMARY: Variations in the IL28B gene, which are associated with spontaneous hepatitis C virus (HCV) clearance and response to interferon, also appear to influence the speed of HCV recurrence, treatment response, and complications after liver transplantation, according to 2 studies presented at the recent American Association for the Study of Liver Diseases "Liver Meeting" (AASLD 2010) in Boston. Transplant outcomes were linked not only to the IL28B pattern of the recipient, but also variations in the new donor liver.

The Association Between IL-28B Genotype and Expression of Interferon-Stimulated Genes for Predicting Response to Peginterferon/Ribavirin in Hepatitis C

By confirming the predictive value of IL-28B genetic variation and extending understanding of the relationship between IL-28B genotype and hepatic ISG expression, this study yields some important clinical implications. Whereas measurement of pretreatment hepatic ISG expression is difficult and impractical, the findings suggest that determination of a patient’s IL-28B genotype can, to some degree, capture the same information that would be obtained from ISG measurement, which can then be used to predict the response to peginterferon/ribavirin treatment. It is widely anticipated that a blood test to assess IL-28B genotype via SNP analysis will be commercially available in some regions (eg, the United States) in the second half of 2010.
Full Article
http://www.clinicaloptions.com/Hepatitis/Journal%20Options/Collections/2010%20JO%20Hepatitis%20Volume%204/Articles/Honda_Gastroenterol_2010/Commentary.aspx


Treatment of Hepatitis C in 2011

Based on current data and ongoing clinical trials using DAA, I have attempted to speculate about the treatment of chronic HCV infection in 2011.

The year 2011 will open with our current standard of care: peginterferon and ribavirin. Between now and 2011, a declining number of patients will likely be treated with peginterferon and ribavirin because of the desire to delay treatment until a DAA is available.

Futhermore, patients will likely be tested for the IL-28B haplotype; only those with the CC allele, and a high chance to achieve SVR, are likely to be treated with peginterferon and ribavirin. Patients with mild fibrosis may also opt to defer therapy because they have a low likelihood of developing significant fibrosis over the next several years. During this time, I anticipate more uniform application of the concepts of response-guided therapy. Patients who achieve RVR will be treated for 24 weeks, patients with cEVR will be treated for 48 weeks, and STR patients will be treated for 72 weeks. We will be more prepared to modify the doses of peginterferon and ribavirin to limit adverse events in patients who have already become HCV RNA undetectable. The use of epoetin-α will be limited to only those patients who become anemic very rapidly (within the first 1 to 2 months of treatment). This limitation will be especially true if IL-28B testing determines that the patient has a high chance for SVR.

It is anticipated that the first DAA will be approved by the US Food and Drug Administration by mid-late 2011

*UpdateIL28B) Test 
. At that time, patients will be treated with triple therapy: peginterferon, ribavirin, and a DAA. About 80% of patients will achieve RVR and SVR of 70% is anticipated. The treatment duration will be reduced for all patients with RVR to 24 to 28 weeks, depending on whether a “lead-in” strategy using peginterferon and ribavirin is adopted. Relapse will be less than 5%; the remaining 10% of patients will simply be unable to tolerate the side effects of one or more of these three medications and will prematurely discontinue treatment. Patients who become HCV RNA undetectable after week 4 will be treated for 48 weeks. Patients who do not become HCV RNA undetectable by treatment week 8 to 12 will likely stop treatment. It remains to be determined if patients who do not achieve SVR with triple therapy could be more effectively treated after 2011 with a combination of DAAs.

Interleukin-28B Haplotype
From : Treatment of Hepatitis C in 2011It has long been hypothesized that host genetics play an important role in the ability to achieve SVR. This hypothesis was recently confirmed with the identification of a single nucleotide polymorphism (SNP) that has a high positive predictive value for SVR. This SNP is located near the gene that codes for interleukin (IL)-28B and is associated with a twofold increased likelihood of achieving SVR in patients infected with HCV genotype 1 regardless of race, sex, or other baseline factors [27 •]. The SNP that favors SVR is the CC haplotype, which is observed most frequently in the Asian population and least frequently in African Americans.

The frequency of the CC haplotype in various racial/ethic populations is directly related to the rate of SVR. Being either TT or a TC heterozygote at this locus is associated with a significant reduction in SVR.

It is already envisioned that all patients will have IL-28B testing performed before initiating peginterferon and ribavirin once such a test is commercially available. Patients with the CC haplotype have a high likelihood to achieve SVR and should be encouraged to remain on treatment. In contrast, patients with either the TC or TT haplotype have a low likelihood for SVR and probably will be taken off treatment early if they do not exhibit RVR or cEVR. Whether this gene will be useful in predicted SVR to triple combination therapy with a DAA, peginterferon, and ribavirin remains to be determined.



IL28B Genomic-Based Treatment Paradigms for Patients With Chronic Hepatitis C Infection: The Future of Personalized HCV Therapies

Am J Gastroenterol advance online publication

5 October 2010;

doi: 10.1038/ajg.2010.370Paul J Clark MD 1, Alex J Thompson MD, PhD 1 and John G McHutchison MD 11 Duke Clinical Research Institute and Division of Gastroenterology, Duke University Medical Center, School of Medicine, Duke University, Durham, North Carolina, USACorrespondence: Paul J. Clark, MD, Division of Gastroenterology, Duke Clinical Research Institute, Duke University Medical Center, PO Box 17969, Durham, North Carolina 27715, USA.

E-mail: paul.clark@duke.edu Received 5 April 2010;

Accepted 16 August 2010; Published online 5 October 2010.

Abstract

Genome-wide association studies (GWAS) have recently identified host genetic variation to be critical for predicting treatment response and spontaneous clearance in patients infected with hepatitis C virus (HCV). These important new studies are reviewed and their future clinical implications discussed. Single-nucleotide polymorphisms in the region of the IL28B gene on chromosome 19, coding for the interferon (IFN)-λ-3 or IL28B gene, are strongly associated with treatment response to pegylated IFN and ribavirin in patients infected with genotype 1 HCV.

The good response variant is associated with a twofold increase in the rate of cure.

Allele frequencies differ between ethnic groups, largely explaining the observed differences in response rates between Caucasians, African Americans and Asians. IL28B polymorphism is also strongly associated with spontaneous clearance of HCV.

The biological mechanisms responsible for these genetic associations remain unknown and are the focus of ongoing research. Knowledge of a patient's IL28B genotype is likely to aid in clinical decision making with standard of care regimens. Future studies will investigate the possibility of individualizing treatment duration and novel regimens according to IL28B type.

Source

Aug 2010
Assay is Commercially Available for Patient Testing and Clinical Trials

The test is now available for patient testing through LabCorp Centers of Excellence, Monogram Biosciences and The Center for Molecular Biology and Pathology (CMBP). The test is also available through Esoterix Clinical Trials Services for clinical trials. LabCorp has licensed global rights to this marker from Merck.

Laboratory Corporation of America® Holdings (LabCorp®) (NYSE: LH) announced today the nationwide availability of a genetic test to detect the presence of a single polymorphism within the IL-28B gene that has been reported to help predict a person’s response to certain hepatitis C virus (HCV) therapies.

The importance of the IL-28B genetic polymorphism was first reported in the journal Nature (September 2009) by scientific teams from Merck and Duke University. Specific variants in this gene have been associated with an approximately 2-3 fold greater rate of sustained viral suppression in response to treatment with combination pegylated interferon alfa/ribavirin therapy among patients infected with HCV genotype 1 with a CC genotype as compared with either the CT or TT genotypes. HCV genotype 1 is the most common form of the virus, accounting for approximately 70 percent of HCV cases in the U.S.

Aug 2010 “This test represents an important addition to the management and treatment of HCV infections, and complements the current company test portfolio for this disease,” indicated Dr. Mark Brecher, LabCorp’s Chief Medical Officer. “The ability to detect the polymorphism within the IL-28B gene may help predict the response to treatments, leading to an improvement in patient care and a reduction in treatment costs.”

The test is now available for patient testing through LabCorp’s Centers of Excellence, Monogram Biosciences and The Center for Molecular Biology and Pathology (CMBP). The test is also available through Esoterix Clinical Trials Services for clinical trials. LabCorp has licensed global rights to this marker from Merck.