Telaprevir/Great Weekend Folks

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Telaprevir/Great Weekend Folks

Tina J & F Blog

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Good weekend folks, I am so excited about the good news coming from the liver meeting or (EASL) "European Association for the Study of Liver" in Vienna, Austria.

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We have some results on our website from different internet sources

including presentations directly from the EASL website.

..I haven't been this excited since I found out I was SVR and dreamt I was Madonna.

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I'm talking about the real Madonna kids, back when she still had the "American accent" not that new "English accent".

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You know, before she kissed Britney, but after she divorced Mr. Penn.

What am I so enthusiastic about ?

Telaprevir !

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Telaprevir seems to cure this disease in a large amount of us who have previously failed treatment. Telaprevir is one HCV protease inhibitor making it's way through the new drug pipeline. The news coming out of the EASL is good for anyone who will be treating in the next year , but especially promising for people re-treating.

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We all know to many people who haven't cleared the virus yet, they're waiting for the magic bullet. .Treating with Telaprevir along with Pegylated interferon and Ribavirin might just be it. This treatment regimen has increased the rate of SVR over 50 percent in previous treated persons , depending on the type of previous treatment failure they had. For those of us who are genotype 1 (most difficult to treat) who did not achieve (SVR) the first time you treated with Interferon-based therapy, you too have more then a 50 percent chance to reach SVR treating with the HCV Protease inhibitor telaprevir plus Pegylated Interferon/Ribavirin according to what Vertex presented this April to the "EASL 2010" in Vienna.

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Would you like to see the stats ?

They got me more energized then watching Clooney shave.

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First let's define the different treatment response terms used in clinical practice. Because all of this can get pretty technical for anyone who is new to treatment and HCV. I still get Null Responder confused with Non-responder, always have, always will.

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From The Body

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Treatment Response:

Response to hepatitis C treatment is measured by change in HCV viral load at different time points. Since it is a common practice to release interim data from HCV treatment trials, it is important to understand what these terms mean, so that interim results can be properly interpreted. It is important to consider the threshold of detection of the test used to measure HCV viral load, since these thresholds vary widely. The most sensitive tests can detect >5 copies IU/mL.

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RVR (Rapid Virological Response):

RVR means that there is no detectable hepatitis C virus in the blood after 4 weeks of treatment. An RVR is a good indication of SVR, but it is not as accurate for predicting who is unlikely to have SVR. Therefore, HCV treatment should not be discontinued if there is no RVR. RVR is mainly used in research.

EVR (Early Virological Response):

EVR means that hepatitis C viral load has dropped by 99% (2 logs), or is undetectable after 12 weeks of HCV treatment. An EVR is a good predictor of the ultimate response to HCV treatment. If a person does not have an EVR, their chance of SVR is very low (1-4%). Usually, HCV treatment is discontinued in people who do not have an EVR

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ETR (End-of-Treatment Response):

ETR means that there is no detectable hepatitis C virus in the blood at completion of HCV treatment. The ETR is usually higher than the SVR rate, because the hepatitis C virus may reappear in a person's blood after completion of HCV treatment.

Null Responder:

A null responder is someone who achieves little or no decrease in hepatitis C viral load during HCV treatment. Null responders are highly unlikely to respond to re-treatment with an interferon-based regimen.

Non-responder:

Often referred to as a "treatment failure," a non-responder is someone who does not have an EVR or, if they stay on treatment for 24 weeks, does not ever have a 2-log (99%) drop in hepatitis C viral load or undetectable HCV RNA during hepatitis C treatment.Partial Responder: A partial responder is someone who experiences at least a 2-log decrease in hepatitis C viral load during HCV treatment. Partial responders are more likely to respond to re-treatment than non-responders or null responders.

Relapsers: The term relapser refers to someone who has had an EVR or ETR, but whose virus rebounded after they completed HCV treatment. People who had a relapse after completing HCV treatment are more likely to achieve SVR after re-treatment than partial responders, non-responders, or null responders.

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Partial Responders

Virologic response occurs before 24 weeks of treatment, but is not maintained at the end of treatment

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SVR= Sustained Virologic Response:

SVR means that there is no hepatitis C virus detectable in the blood six months after a person completes HCV treatment. Many experts regard SVR as a cure, and it is an indication of long-term remission. SVR rates are always lower than response rates from earlier time points.

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SVR-12:

SVR-12 means that there is no hepatitis C virus detectable in the blood 12 weeks after completion of HCV treatment. Although it has not been prospectively validated, many experts agree that relapse (meaning the emergence of detectable hepatitis C virus in blood after completion of treatment) is most likely to occur within 12 weeks. However, FDA and other regulatory agencies require 24 weeks of post-treatment follow-up before a person is considered to have achieved an SVR.

HCV Treatment History: /

There is a growing population of people who did not have a sustained virological response from HCV treatment. They are sometimes referred to as "treatment failures," but the term "treatment-experienced" is preferable, although both are not sufficiently specific.It is important to know how treatment-experienced people responded to their first course of treatment, and the regimen that they were treated with, because these factors help to predict the likelihood of SVR from re-treatment. People initially treated with standard interferon, or standard interferon plus ribavirin, may achieve SVR when re-treated with pegylated interferon and ribavirin. Sometimes, HCV re-treatment trials study a mixed population of relapsers, partial responders, non-responders, and null responders, which makes it difficult to interpret the results.

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Now that we know all that stuff, this stuff will be much easier to read.

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Drum Roll Please ........

Here's The Stats :

Telaprevir

Almost all prior relapsers achieved SVR, prior null responders had the lowest odds of successful treatment.

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59 Percent of Patients Overall Achieved SVR with Telaprevir-Based Regimens in Study 107

After Not Achieving SVR with at Least One Prior Course of Treatment for HCV Infection

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-56% of prior treatment null responder patients achieved SVR with a 48-week telaprevir-based regimen--

97% of prior treatment relapsers and 55% of prior treatment partial responders achieved SVR with 24-week or 48-week telaprevir-based regimens-

Click Below For the Full Results from EASL 2010:

Telaprevir-Based Regimens in Study 107

Isn't this just the best news ! This time it's good news for all genotypes and anyone who treated before. I know it's so hard to re-treat this disease. Treatment is no picnic, that's for sure.

But, if I had to go back on treatment I would recite this quote over and over. It's from the movie with Scarlet Madonna and .

"As God is my witness, as God is my witness they’re not going to lick me! I’m going to live through this and when it’s all over, I’ll never have HCV again! No, nor any of my friends. If I have to lie, steal, cheat or Re-Treat ! As God is my witness, I’ll never test positive again!"

Hey, we all need some sort of distraction on treatment. ________________________________

The much awaited other drug is NS3 HCV protease inhibitor Boceprevir . Treating with Boceprevir will include treating with pegylated interferon and Ribavirin.

However the results below presented at the EASL in Vienna,

show treating with or without ribavirin.

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From HIV and Hepatitis.com

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HCV Protease Inhibitor Boceprevir Demonstrates Durable Sustained Response with No Late Relapse

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SUMMARY: Genotype 1 chronic hepatitis C patients treated with the Merck/Schering-Plough's investigational NS3 HCV protease inhibitor boceprevir plus pegylated interferon (with or without ribavirin) achieved durable sustained response with no evidence of viral rebound or adverse events lingering after completion of therapy, according to a late-breaker poster presented this week at the 45th Annual Meeting of the European Association for the Study of the Liver (EASL 2010) in Vienna

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By Liz Highleyman

Sustained virological response (SVR) to hepatitis C therapy -- defined as continued undetectable HCV viral load 6 months after completion of treatment -- is generally considered a "cure," though a small proportion of patients treated with interferon-based therapy may experience late viral relapse after this point.J. Vierling from St. Luke's Episcopal Hospital in Houston and colleagues looked at long-term outcomes among participants who received boceprevir plus pegylated interferon alfa-2b (PegIntron), with or without ribavirin, in previous Phase 2/3 clinical trials.The researchers analyzed blood samples from 604 patients, including formerly treatment-naive individuals and those who did not respond to a prior course of pegylated interferon plus ribavirin, after up to 3 years post-therapy. Most participants (nearly 90%) were white and the average was about 50 years.The extended follow-up cohort consisted of 520

participants from the SPRINT-1 treatment-naive trial, of whom 269 patients achieved SVR and 104 were treatment failures. Another 357 patients were from Study PO3659 looking at prior non-responders, of whom 21 achieved SVR and 205 were treatment failures. In addition, 5 patients were included from another prior non-responder study, PO4887.HCV RNA was detected using the Roche Taqman assay with a lower limit of detection of 29 IU/mL and resistance mutations were detected by population sequencing of the HCV NS3 protease region (codons 1-181).ResultsAmong the 290 patients who achieved SVR, no cases of late relapse were confirmed.1 person was confirmed to have been re-infected with HCV based on genotype/subtype sequence.29 patients (5%) experienced serious adverse events during extended follow-up, similar to those previously described during initial follow-up.A total of 18 boceprevir

resistance mutations were identified, including:R155K, 64%;T54S, 54%;V36M, 54%;T54A, 22%;All others: <> "No latent serious adverse events or laboratory abnormalities related to prior treatment were observed over follow-up period." "Specific resistance mutations to boceprevir declined at different rates, V36M declined fastest; T54S and R155K declined at similar rates," they continued. "Variation in the rate of mutational decline likely reflects the relative fitness of the mutants." /

Advanced Liver Therapies/St. Luke's Episcopal Hospital, Houston, T; Merck Research Laboratories, Kenilworth, NJ; Alamo Medical Research, San , TX; Mount Vernon Endoscopy Center, andria, VA; Henry Ford Hospitals, Detroit, MI; Indianapolis Gastroenterology Research Foundation, Indianapolis, IN; South Florida Center of Gastroenterology, Wellington, FL; Liver Specialists of Texas, Houston, TX; Weill Medical College of Cornell University, New York, NY; Medical Center, University of California, Sacramento, C; Liver and Intestinal Research Centre, Vancouver, BC, Canada' LSU Medical Center; Louisiana State University, Shreveport, Baton Rouge, LA; Hospital Saint ph, Marseill, France; Hospital Vall d'Hebron, Barcelona, Spain; Digestive Disease Associates, Baltimore, MD; Kelsey Research Foundation, Houston, TX. 4/16/10 Reference JM Vierling, R Ralston, EJ Lawitz, and others. Long-term outcomes following combination treatment

with boceprevir plus Peg-Intron/ribavirin (P/R) in patients with chronic hepatitis C, genotype 1 (CHC-G1). 45th Annual Meeting of the European Association for the Study of the Liver (EASL 2010). Vienna, Austria. April 14-18, 2010. (Abstract). http://www.hivandhepatitis.com/2010_conference/easl/docs/0416_2010_c.html

HCV Drug ResistanceLiz HighleymanA new approach to hepatitis C treatment – specifically targeted antiviral therapy for hepatitis C, or “STAT-C†– promises to improve the likelihood of achieving a cure for hard-to-treat patients. But these new therapies also come with a drawback: HCV can develop drug resistance, making them less effective.HCV Replication and MutationThere are two basic approaches to fighting HCV: strengthening the body’s immune response and attacking the virus directly. Interferon-based therapy uses a manufactured version of a natural cytokine to boost immune function. HCV does not develop resistance to interferon over time.STAT-C drugs block specific steps of the viral lifecycle. For example, HCV protease inhibitors (such as telaprevir and boceprevir) interfere

with an enzyme encoded by the NS3/4A gene that processes proteins before they can be assembled into new virions (virus particles). HCV polymerase inhibitors disrupt the action of another enzyme, encoded by the NS5B gene, that copies viral genetic material. (The HCV lifecycle and how drugs work is explained more fully in the December 2009 HCV Advocate.)Drug resistance can develop when a virus mutates, or changes its genetic code. HCV replicates very rapidly – at an estimated rate of 1012 virions per day – and is prone to errors as it copies its genetic material. The genetic code of mutated HCV is essentially an altered blueprint. Viral proteins consist of a chain of building blocks called amino acids. When the altered blueprint is used to make new proteins and enzymes, the directions call for insertion of a wrong amino acid.For example, the NS3 protease enzyme produced by mutated HCV might have the usual amino acid valine (V) replaced

by alanine (A) at position 107 of the chain – designated V107A. (See below for list of amino acids letter codes.)Amino AcidsAlanine AArginine RAsparagine NAspartic Acid DCysteine CGlutamic Acid EGlutamine QGlycine GHistidine HIsoleucine ILeucine LLysine KMethionine MPhenylalanine FProline PSerine SThreonine TTryptophan WTyrosine YValine VIn many cases, proteins containing the wrong amino acids do not work properly. This can make mutant HCV less “fit†than wild-type (non-mutated) virus, so it stays at a very low level or dies out. But in other cases, a “wrong†amino acid turns out to be right for the virus, giving it an evolutionary advantage. In fact, this is how viruses manage to survive constant attack by the

immune system.Mechanisms of ResistanceOne such advantage is drug resistance – mutations that allow the virus to keep replicating despite the presence of a drug. Amino acid substitutions in the HCV protease or polymerase enzyme can change the protein’s shape and interfere with a drug’s action. For example, a small structural change to the shallow binding pocket of the NS3 protease makes it difficult for a protease inhibitor to fit in and perform its intended function.HCV polymerase inhibitors are of two types, nucleoside analogs – which act as defective building blocks when the virus tries to copy its genetic material – and non-nucleoside inhibitors, which work by other mechanisms. The HCV NS5B polymerase has at least five sites that are potential drug targets.Ribavirin, which is used with pegylated interferon to help prevent HCV relapse, is also a nucleoside

analog, but it has additional mechanisms of action, and resistance due to viral mutation has not been a concern in hepatitis C treatment.The emergence of drug resistant mutations sometimes occurs randomly as HCV mutates to evade immune defenses, so an individual who has never been treated may harbor some strains, or quasispecies, that are naturally resistant (known as primary resistance). Most genetic screening studies have detected protease and polymerase resistance mutations at rates of <1% color="#660000">Resistance StudiesExperience treating hepatitis B and HIV led researchers to suspect that using single directly targeted anti-HCV agents – known as monotherapy – would likely promote resistance. As such, resistance testing is part of hepatitis C drug development from the earliest laboratory studies through the final clinical trials.One or more amino acid substitutions that reduce antiviral potency have

been identified for all the HCV protease and polymerase inhibitors currently in development. At the outset, STAT-C agents used as monotherapy may rapidly and dramatically decrease HCV RNA. But before long – days to months, depending on the specific agent – viral load may start to rise again (known as viral breakthrough), indicating that drug-resistant variants are gaining the upper hand.But drug resistance does not necessarily lead to treatment failure. Even when a mutant virus is less susceptible, a drug still may be potent enough to keep replication under control. Sometimes multiple mutations must coexist to cause a notable decrease in effectiveness. And because HCV treatment is relatively short – typically 24-48 weeks – it does not present the risk of long-term resistance after taking a drug for years (as with hepatitis or even for life (as with HIV).In the November 10, 2009 advance online edition of the Journal of Viral

Hepatitis, A.J.V. and J.G. McHutchison presented an overview of HCV drug resistance, including data from laboratory studies and clinical trials.Because HCV is difficult to grow in vitro, most laboratory studies use models called replicons that may not respond to drugs exactly like whole virus in the body. Genotypic tests, which examine viral gene sequences for substitutions known to confer resistance, do not always reflect what happens when HCV variants are exposed to drugs in the laboratory (phenotypic testing), which in turn may not predict clinical outcomes in patients.Nevertheless, some clear patterns have emerged. As noted, the structure of the NS3 protease allows HCV to easily evade protease inhibitors, especially with mutations at positions 155 and 156. For HCV genotype 1, the A156S/T/V and R155K/Q/T substitutions confer resistance to telaprevir, boceprevir, and RG7227 (ITMN-191), especially when additional mutations

including V36M and T54A are also present. Other mutations confer resistance primarily to specific drugs, for example V170A for boceprevir and D168V/A for RG7227.Current polymerase inhibitor candidates produce smaller viral load decreases than protease inhibitors, but they also promote less resistance. Nucleoside analogs such as RG7128 appear to have a particularly high barrier to resistance. Among the non-nucleosides, most agents target only one binding site, and there appears to be no cross-resistance – and perhaps even synergy – between drugs targeting different sites.To date, no mutations have been found to confer resistance to both protease and polymerase inhibitors, though researchers have produced replicons that simultaneously carry separate protease and polymerase mutations. Fortunately, HCV with protease and/or polymerase resistant mutations appears to remain as responsive as wild-type virus to standard therapy with pegylated

interferon plus ribavirin.Preventing and Overcoming ResistanceThe surest way to prevent drug resistance is by completely halting viral replication, or even better, eradicating HCV altogether. With current drugs, however, many people continue to have some level of ongoing viral replication.Another way to overcome resistance is combination therapy. In order to evade the action of multiple drugs, HCV would have to develop simultaneous mutations, which typically reduces viral fitness in other ways.Learning from the setbacks of hepatitis B and HIV treatment, researchers understand the benefits of using STAT-C agents in combination regimens from the outset, rather than adding additional drugs after resistance develops. Given how quickly resistance can emerge, the U.S. Food and Drug Administration now limits clinical trials of direct antiviral agents to three days of

monotherapy.Several studies have demonstrated that combining HCV protease inhibitors with pegylated interferon/ribavirin delays the emergence of resistance. In the PROVE trials, however, about 25% of participants who took telaprevir plus pegylated interferon without ribavirin developed resistance. Some trials start with a pegylated interferon/ribavirin “lead-in†period to drive down viral load before adding the direct antiviral agent.Researchers are exploring combinations of STAT-C agents that work by different mechanisms in the hope of one day eliminating pegylated interferon/ribavirin. In the first such clinical trial (INFORM-1), presented last fall at the 2009 annual meeting of the American Association for the Study of Liver Diseases (AASLD), S. Le Pogam and colleagues showed that over 14 days, the protease inhibitor RG7227 plus the polymerase inhibitor RG7128 produced potent antiviral activity. Viral load declined by as much as 5

logs and no resistant mutations were detected, even in one patient in a low-dose arm who experienced viral breakthrough.Using another novel approach, L. Delang and colleagues recently demonstrated that adding statin drugs (usually used to manage high cholesterol) to HCV protease and polymerase inhibitors enhanced antiviral activity and reduced emergence of resistant mutations.In the coming years, hepatitis C therapy is likely to increasingly resemble HIV treatment, using complementary oral drugs that target different steps of the viral lifecycle. As such, it will draw on lessons from that field, such as the importance of good adherence, frequent viral load monitoring, and resistance testing to guide selection of the drugs most likely to be effective.For more information see:Hepatitis C Basics: New HCV Antivirals and Drug Resistance.HCV Treatment: Interferon and Ribavirin.Selected ReferencesL. Delang et al. Statins potentiate the in vitro anti-hepatitis C virus activity of selective hepatitis C virus inhibitors and delay or prevent resistance development. Hepatology 50(1): 6-16. July 2009.S. Gaudieri et al. Hepatitis C virus drug resistance and immune-driven adaptations: relevance to new antiviral therapy. Hepatology 49(4): 1069-1082. April 2009.T. Kuntzen et al. Naturally occurring dominant resistance mutations to hepatitis C virus protease and polymerase inhibitors in treatment-naive patients. Hepatology 48(6): 1769-1778. December 2008.S. Le Pogam et al. Combination therapy with nucleoside polymerase R7128 and protease R7227/ITMN-191

inhibitors in genotype 1 HCV infected patients: interim resistance analysis of INFORM-1 cohorts A-D. 60th Annual Meeting of the American Association for the Study of Liver Diseases. Boston. October 30-November 1, 2009. Abstract 1585.M.F. McCown et al. The hepatitis C virus replicon presents a higher barrier to resistance to nucleoside analogs than to nonnucleoside polymerase or protease inhibitors. Antimicrobial Agents & Chemotherapy 52(5): 1604-1612. May 2008.A.J.V. and J.G. McHutchison. Antiviral resistance and specifically targeted therapy for HCV (STAT-C). Journal of Viral Hepatitis 16(6): 377-387. November 10, 2009 [Epub ahead of print].http://www.hcvadvocate.org/news/newsLetter/2010/advocate0210.html#3 ;,

Another women I am a huge fan of is Liz Highleyman, I follow her on twitter. Is that sick ?

I hope you all have a wonderful weekend .

Tina

http://Hepatitis Cnewdrugs.blogspot.com/2010/04/telaprevirgreat-weekend-folks_17.html