Hi folks, the information/links provided here today is meant to provide you with a bit of information before you begin treating with one of these new HCV agents.
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Below is an excerpt from this weeks medscape abstract/study : Hepatitis C: New Direct-acting Antivirals in Development : Treatment Guidelines. Listed is the approximate cost of treating with the new inhibitors, using a proposed system/class scale. The system includes "treatment guidelines" using pre-testing with the IL28B genotype test. I have added a summary of these alleles and response rates for anyone who hasn't yet read up on the whole "allele" phenomenon.
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The Test
You may have ran across the buzz words "IL28B" and "allele". The new test is called IL28B genotype test, however this "genotype" test is not the same terminology used to describe the different (genotypes or strains) of HCV. The term "CC genotype" is used to describe the variation of IL28B gene. In the future this test may be used before treatment begins.
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What is the test for ?
The test is exciting, as it may be predictive to treatment response. Currently people who are waiting to treat HCV are curious about the test, with the majority wanting to be tested to find out if they have the good "CC" allele. However, as mentioned below researchers/physicians are still waiting to see how these alleles will be associated with response rates to these new drugs. Although at this time insurance companies are not covering the cost of the test. In the future if the test proves to be beneficial through the ongoing trials that may/should change.
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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.
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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 recognized as "C" and "T"
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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.
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What Is T/T or "TT" ?.
The same is true in Hepatitis C Patients who have the T/T pattern or two "T" alleles .
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What Does This Mean To The Hepatitis C Patient?.
Hepatitis C Patients With The C/C pattern or two "C" alleles have the best response to HCV therapy
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As for the T/T pattern or two "T" alleles they have the least response to therapy. .
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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
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The bottom line.........
TT - Poorest response to Hepatitis C treatment.
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.
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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 recognized as "C" and "T"
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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.
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What Is T/T or "TT" ?.
The same is true in Hepatitis C Patients who have the T/T pattern or two "T" alleles .
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What Does This Mean To The Hepatitis C Patient?.
Hepatitis C Patients With The C/C pattern or two "C" alleles have the best response to HCV therapy
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As for the T/T pattern or two "T" alleles they have the least response to therapy. .
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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
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The bottom line.........
TT - Poorest response to Hepatitis C treatment.
CC - Best response to Hepatitis C treatment.
CT - Somewhere in between TT and CC alleles.
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Also this blogger made a little video which you may find less...boring then this blog entry.
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Also this blogger made a little video which you may find less...boring then this blog entry.
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With good news.... comes bad news, the concern is that if a person has the bad "TT" allele, the insurance companies may refuse to pay for treatment. Another controversy, or should I say speculation could come from Merck.
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What controversy?
The drug company Merck who is behind boceprevir seems to have the intellectual rights to IL28B genotype testing. In clinical trials boceprevir had a four week lead in with standard of care. (patients started with four weeks of pegylated interferon/riba before adding boceprevir). 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 ?
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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 ?
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This isn't a bad way to go, why add a third drug if its not needed. However, where does that leave telaprevir ?
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That brings me to this, yesterday on the blog in an entry entitled "New Future Hepatitis C Treatments: Interferon-sparing combinations " it was noted;
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"The addition of a protease inhibitor to pegylated interferon plus ribavirin is associated with increase in efficacy and shortened duration of therapy in patients with HCV Genotype1 and is likely to become the new standard-of-care. However, triple therapy will not be suitable for patients with non-1 HCV infection. "
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At this point it appears that genotype 1s will be treating with the new drugs. We can only wait to see if the other genotypes will also be using the new agents. A prudent assumption could be that this applies to only naive 2 and 3 genotypes; people who are treating for the first time, as discussed in the "Treatment Guidelines" below.
Genotype 3's noted in the post ;
"Moreover, although telaprevir has similar antiviral activity against HCV Genotype 2, this agent has no effect in patients with HCV Genotype 3 infection."
I assume this is the small study they were referring too.
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Also mentioned in the "New Future Hepatitis C Treatments: Interferon-sparing combinations " data was that "Genotype 1" patients who do not respond to this new triple therapy will have developed resistance to protease inhibitors.
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Listed below is an excerpt from medscape/entitled: Hepatitis C: New Direct-acting Antivirals in Development : Treatment Guidelines. Listed in the excerpt is the approximate cost of treating with the new inhibitors, using a proposed system/class scale. The system includes pre-testing with the IL28B genotype test. However, as mentioned below researchers/physicians are still waiting to see how these alleles will be associated with response rates to these new drugs. I have added a summary of these alleles and response rates for anyone who hasn't yet read up on the whole allele phenomenon.
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Updated; As reported On Feb 25 2011
Updated; As reported On Feb 25 2011
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The abbreviations used in medscapes article are as follows;
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CC, IL28B allele genotype C/C;
CT, IL28B allele genotype C/T;
IT, interferon tolerant;
TT, IL28B allele genotype T/T.
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From Medscape..............
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Hepatitis C: New Direct-acting Antivirals in Development : Treatment Guidelines
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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.
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.
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One such predictive test is the IL28B genetic polymorphism, which has recently been reported to be associated withSVR by three separate groups [Ge et al. 2009; Suppiah et al. 2009; Tanaka et al. 2009].
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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.
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In Tables 2 and 3, a simple classification system is proposed that might permit physicians to solidify decisions regarding therapy.
In Tables 2 and 3, a simple classification system is proposed that might permit physicians to solidify decisions regarding therapy.
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Table 2. A proposed classification system for the treatment of hepatitis C virus in the direct-acting antiviral era.
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Class I: treatment naïve, IT, G2/3, G1 low viral load, and/or CC allele (20–25% of US patients)
Class I: treatment naïve, IT, G2/3, G1 low viral load, and/or CC allele (20–25% of US patients)
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Class II: treatment naïve, IT, G1 high viral load, or CT/TT allele (40–50% of US patients)
Class II: treatment naïve, IT, G1 high viral load, or CT/TT allele (40–50% of US patients)
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Class III: G1/4 and G2/3 relapsers and nonresponders to current standard of care who become RNA undetectable by week 12 of treatment (20% of US patients)
Class III: G1/4 and G2/3 relapsers and nonresponders to current standard of care who become RNA undetectable by week 12 of treatment (20% of US patients)
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Class IV: Class IIIs who do not become undetectable by week 12, interferon-intolerant patients and all treatment failures from treated Classes I–III (30% US patients assuming 5% from Classes I and III, and 10% from Class II)
Class IV: Class IIIs who do not become undetectable by week 12, interferon-intolerant patients and all treatment failures from treated Classes I–III (30% US patients assuming 5% from Classes I and III, and 10% from Class II)
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CC, IL28B allele genotype C/C; CT, IL28B allele genotype C/T; IT, interferon tolerant; TT, IL28B allele genotype T/T.
CC, IL28B allele genotype C/C; CT, IL28B allele genotype C/T; IT, interferon tolerant; TT, IL28B allele genotype T/T.
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Table 3
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*Costs assume US $25,000/year for standard of care, likely use of growth factors for extended duration therapy, and costs of direct-acting antivirals less then us $25,000/regimen.
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Abbreviations
SOC, standard of care;
SVR, sustained virologic response.
AWP ; average wholesale cost;
NS5B pol, NS5B HCV polymerase inhibitor;
PI, NS3/4 hepatitis C virus protease inhibitor;
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Class I SOC×24 weeks SVR=80–90% Cost=US $25,000 (AWP)
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Class II PI+SOC×24 weeks SVR=80% Cost less then US $50,000*
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Class III PI+SOC×48 weeks SVR=70–75% Cost more then US $50,000 but less then US $100,000*
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Class IV PI+NS5B pol+other agents SVR=nil (lifetime suppression) Cost less then US $100,000*
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In this proposed system;
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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].
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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].
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Class II
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].
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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.
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Class IV
Class IV
patients would include Class IIIs who do not become undetectable by week 12, interferon-intolerant patients and all treatment failures fromtreated 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.
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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.
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Links for the full abstract and text;
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Abstract and Introduction
Protease Inhibitors
Polymerase Inhibitors
Ribavirin Analogues
Other Direct-acting Antiviral Drugs
Other Novel Compounds
Treatment Guidelines
Abstract and Introduction
Protease Inhibitors
Polymerase Inhibitors
Ribavirin Analogues
Other Direct-acting Antiviral Drugs
Other Novel Compounds
Treatment Guidelines
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