In case you missed it -Easy to understand from
Medscape- text/slides "Understanding resistance in Hepatitis C infection" CME-transcript
From CCO new data presented at the 2011AASLD
meeting " HCV Resistance "- Covers Boceprevir,Telaprevir
(TMC435) and BI 201335,MK-5172,
GS-7977 (formerly PSI-7977) Plus Ribavirin and Daclatasvir Plus Asunaprevir)
Hepatitis C virus resistance to protease inhibitors
Hepatitis C has always been extremely difficult to treat effectively because the virus evolves so quickly and develops resistance to drugs that are used to treat it. The new protease inhibitors can elicit resistance even in patients who follow dosing regimens. Today on the blog is data covering HCV resistance to protease inhibitors, which include abstracts, links to expert analysis from CCO, and a patient video on hepatitis C Drugs and Resistance. Also a summary of the AASLD guidelines for treating HCV published today in the October issue of Hepatology.
Those guidelines are available on this blog , or in this months issue of Hepatology and in a PDF format.
An easy to understand article was published in July by HCV Advocate. In the article "Resisting Resistance" written by Ms. Lucinda K. Porter, RN , viral resistance and the importance of taking the new protease inhibitors as directed is discussed.
The importance of stopping therapy in patients who do not experience SVR or a breakthrough has been stressed in the new guidelines. Patients with inadequate viral response are unlikely to achieve SVR, and may develop resistance.
Here is a summary of the recommendations
From the 2011 practice guideline by the American Association for the Study of Liver Diseases
View Full Guidelines HereRecommendations:
1. The optimal therapy for genotype 1, chronic HCV infection is the use of boceprevir or telaprevir in combination with peginterferon alfa and ribavirin (Class 1, Level A).
Class 1 Conditions for which there is evidence and/or general agreement that a given diagnostic evaluation procedure or treatment is beneficial, useful, and effective
Level A Data derived from multiple randomized clinical trials or meta-analyses
2. Boceprevir and telaprevir should not be used without peginterferon alfa and weight-based ribavirin (Class 1, Level A).
Class 1 Conditions for which there is evidence and/or general agreement that a given diagnostic evaluation procedure or treatment is beneficial, useful, and effective
Level A Data derived from multiple randomized clinical trials or meta-analyses
For Treatment-Naïve Patients:
3. The recommended dose of boceprevir is 800 mg administered with food three times per day (every 7-9 hours) together with peginterferon alfa and weight-based ribavirin for 24-44 weeks preceded by 4 weeks of lead-in treatment with peginterferon alfa and ribavirin alone (Class 1, Level A).
Class 1 Conditions for which there is evidence and/or general agreement that a given diagnostic evaluation procedure or treatment is beneficial, useful, and effective
Level A Data derived from multiple randomized clinical trials or meta-analyses
4. Patients without cirrhosis treated with boceprevir, peginterferon, and ribavirin, preceded by 4 weeks of lead-in peginterferon and ribavirin, whose HCV RNA level at weeks 8 and 24 is undetectable, may be considered for a shortened duration of treatment of 28 weeks in total (4 weeks lead-in with peginterferon and ribavirin followed by 24 weeks of triple therapy) (Class 2a, Level B).
Class 2a Weight of evidence/opinion is in favor of usefulness/efficacy
Level B Data derived from a single randomized trial, or nonrandomized studies
5. Treatment with all three drugs (boceprevir, peginterferon alfa, and ribavirin) should be stopped if the HCV RNA level is more then 100 IU/mL at treatment week 12 or detectable at treatment week 24 (Class 2a, Level B).
Class 2a Weight of evidence/opinion is in favor of usefulness/efficacy
Level B Data derived from a single randomized trial, or nonrandomized studies6. The recommended dose of telaprevir is 750 mg administered with food (not low-fat) three times per day (every 7-9 hours) together with peginterferon alfa and weight-based ribavirin for 12 weeks followed by an additional 12-36 weeks of peginterferon alfa and ribavirin (Class 1, Level A).
Class 1 Conditions for which there is evidence and/or general agreement that a given diagnostic evaluation procedure or treatment is beneficial, useful, and effective
Level A Data derived from multiple randomized clinical trials or meta-analyses
7. Patients without cirrhosis treated with telaprevir, peginterferon, and ribavirin, whose HCV RNA level at weeks 4 and 12 is undetectable should be considered for a shortened duration of therapy of 24 weeks (Class 2a, Level A).
Class 2a Weight of evidence/opinion is in favor of usefulness/efficacy
Level A Data derived from multiple randomized clinical trials or meta-analyses
8. Patients with cirrhosis treated with either boceprevir or telaprevir in combination with peginterferon and ribavirin should receive therapy for a duration of 48 weeks (Class 2b, Level B).
Class 2b Usefulness/efficacy is less well established by evidence/opinion
Level B Data derived from a single randomized trial, or nonrandomized studies
9. Treatment with all three drugs (telaprevir, peginterferon alfa, and ribavirin) should be stopped if the HCV RNA level is more then 1,000 IU/mL at treatment weeks 4 or 12 and/or detectable at treatment week 24 (Class 2a, Level B).
Class 2a Weight of evidence/opinion is in favor of usefulness/efficacy
Level B Data derived from a single randomized trial, or nonrandomized studiesFor treatment-experienced patients:
10. Re-treatment with boceprevir or telaprevir, together with peginterferon alfa and weight-based ribavirin, can be recommended for patients who had virological relapse or were partial responders after a prior course of treatment with standard interferon alfa or peginterferon alfa and/or ribavirin (Class 1, Level A).
Class 1 Conditions for which there is evidence and/or general agreement that a given diagnostic evaluation procedure or treatment is beneficial, useful, and effective
Level A Data derived from multiple randomized clinical trials or meta-analyses
11. Re-treatment with telaprevir, together with peginterferon alfa and weight-based ribavirin, may be considered for prior null responders to a course of standard interferon alfa or peginterferon alfa and/or weight-based ribavirin (Class 2b, Level B.)
Class 2b Usefulness/efficacy is less well established by evidence/opinion
Level B Data derived from a single randomized trial, or nonrandomized studies
12. Response-guided therapy of treatment-experienced patients using either a boceprevir- or telaprevir-based regimen can be considered for relapsers (Class 2a, Level B for boceprevir; Class 2b, Level C for telaprevir), may be considered for partial responders (Class 2b, Level B for boceprevir; Class 3, Level C for telaprevir), but cannot be recommended for null responders (Class 3, Level C).
Class 2a Weight of evidence/opinion is in favor of usefulness/efficacy
Class 2b Usefulness/efficacy is less well established by evidence/opinion
Class 3 Conditions for which there is evidence and/or general agreement that a diagnostic evaluation, procedure/treatment is not useful/effective and in some cases may be harmful
Level B Data derived from a single randomized trial, or nonrandomized studies
Level C Only consensus opinion of experts, case studies, or standard-of-care
13. Patients re-treated with boceprevir plus peginterferon alfa and ribavirin who continue to have detectable HCV RNA more then 100 IU at week 12 should be withdrawn from all therapy because of the high likelihood of developing antiviral resistance (Class 1, Level B).
Class 1 Conditions for which there is evidence and/or general agreement that a given diagnostic evaluation procedure or treatment is beneficial, useful, and effective
Level B Data derived from a single randomized trial, or nonrandomized studies
14. Patients re-treated with telaprevir plus peginterferon alfa and ribavirin who continue to have detectable HCV RNA > 1,000 IU at weeks 4 or 12 should be withdrawn from all therapy because of the high likelihood of developing antiviral resistance (Class 1, Level B).
Class 1 Conditions for which there is evidence and/or general agreement that a given diagnostic evaluation procedure or treatment is beneficial, useful, and effective
Level B Data derived from a single randomized trial, or nonrandomized studiesViral Resistance and Monitoring
15. Patients who develop anemia on protease inhibitor-based therapy for chronic hepatitis C should be managed by reducing the ribavirin dose (Class 2a, Level A).
Class 2a Weight of evidence/opinion is in favor of usefulness/efficacy
Level A Data derived from multiple randomized clinical trials or meta-analyses
16. Patients on protease inhibitor-based therapy should undergo close monitoring of HCV RNA levels and the protease inhibitors should be discontinued if virological breakthrough more then a 1 log increase in serum HCV RNA above nadir) is observed (Class 1, Level A).
Class 1 Conditions for which there is evidence and/or general agreement that a given diagnostic evaluation procedure or treatment is beneficial, useful, and effective
Level A Data derived from multiple randomized clinical trials or meta-analyses
17. Patients who fail to have a virological response, who experience virological breakthrough, or who relapse on one protease inhibitor should not be re-treated with the other protease inhibitor (Class 2a, Level C).
Class 2a Weight of evidence/opinion is in favor of usefulness/efficacy
Level C Only consensus opinion of experts, case studies, or standard-of-care
Role of IL28B Testing in Decision to Treat and Selection of Therapeutic Regimen
18. IL28B genotype is a robust pretreatment predictor of SVR to peginterferon alfa and ribavirin as well as to protease inhibitor triple therapy in patients with genotype 1 chronic hepatitis C virus infection. Testing may be considered when the patient or provider wish additional information on the probability of treatment response or on the probable treatment duration needed (Class 2a, Level B).
Class 2a Weight of evidence/opinion is in favor of usefulness/efficacy
Level B Data derived from a single randomized trial, or nonrandomized studies
From CCO Published Sept 2011
On-Treatment Management: Futility Rules and Prevention of Resistance
Viral resistance with boceprevir and telaprevir occurs because of the selection of preexisting variants during the course of therapy, as a result of failure to eradicate infection on triple combination treatment.[54] In pooled analyses of subjects who had on-treatment failure or relapse during clinical trials with boceprevir or telaprevir, HCV variants emerged, which have been shown to carry several NS3 amino acid substitutions that reduce viral susceptibility to boceprevir and telaprevir (Table 10).[51,53] Extensive cross-resistance exists between the 2 drugs, one of several reasons why they should never be used together. Patterns of treatment-emergent amino acid substitutions were genotype 1 subtype specific.
Resistance was found to be more frequent among previous null responders and among those with subtype 1a HCV. The emergence of different substitutions among the subtypes can be explained by a different genetic barrier to resistance between subtype 1a and subtype 1b. For example, coding for R155K requires a single-nucleotide change in subtype 1a (AGG → AAG) but 2 nucleotide changes in subtype 1b (CGG → AAG). Thus, R155K is more likely to preexist in subtype 1a than in subtype 1b. The higher failure rates of boceprevir- or telaprevir-based therapy that are observed in treatment-experienced patients are owing to a poorer response to pegIFN/RBV than in treatment-naive patients, resulting in the subsequent outgrowth of resistant variants selected by boceprevir or telaprevir.
Table 10. Most Frequent Treatment-Emergent Substitutions During Boceprevir- or Telaprevir-Based Therapy
The clinical implications of treatment failure to boceprevir- or telaprevir-based therapy are unknown. In theory, the persistence of resistant variants could lead to patients being ineligible for, or unresponsive to, future regimens that incorporate PIs into novel regimens. Several lines of evidence and reasoning provide reassurance on this issue. First, HCV is not known to be capable of archiving its genome as do HIV or hepatitis B virus. Data suggest that after treatment withdrawal, treatment-emergent substitutions decline in relative abundance over time and that wild-type virus regains its predominance in the majority of cases.[55-57]
However, this may take 2-3 years, and subtype 1a tends to return to wild type more slowly. Moreover, the diversity of antiviral agents under development may overcome whatever adverse impact viral variants that are resistant to boceprevir or telaprevir might confer. Ultimately, trials in patients who have failed boceprevir or telaprevir therapy will be critical in addressing this question.
The panel underscored the importance of assessing the indications for treatment (particularly in null responders—weighing risk of treatment failure and resistance with need for therapy), adherence to stopping rules to minimize the risk of emergence of resistant variants, and any potential impact on future treatment options. For both drugs, the stopping rules put forth in the prescribing information have been harmonized for treatment-naive and treatment-experienced patients. Of note, the HCV RNA cutoffs used for boceprevir and telaprevir stopping rules differ.
For all patients treated with boceprevir, the following futility rules should be employed:
If HCV RNA is ≥ 100 IU/mL at Week 12, all 3 medications should be discontinued.
If the patient has confirmed, detectable HCV RNA at Week 24, all 3 medications should be discontinued.
For all patients treated with telaprevir, the following futility rules should be employed:
If HCV RNA is more then 1000 IU/mL at treatment Week 4 or 12, all 3 medications should be discontinued.
If HCV RNA is detectable at Week 24, pegIFN/RBV should be discontinued.
Experts note that providers should be confident with strictly applying these stopping rules when making decisions about the continuation or discontinuation of boceprevir or telaprevir. If, for instance, a patient has an HCV RNA level slightly above the level recommended in the stopping rules, the experts suggest that clinicians adhere to the stopping rule and discontinue boceprevir or telaprevir, rather than continuing the patient on triple therapy to see if they will respond at a later time point. Some experts believe that pending further experience, continued pegIFN/RBV (in the absence of boceprevir or telaprevir) could be considered for treatment-naive patients with HCV RNA declines that are highly robust but fail to qualify for continuation by the new stopping rules together with frequent HCV RNA monitoring to ensure the HCV RNA continues to decline. In these cases, at a minimum, the usual stopping rules for pegIFN/RBV should be followed. In addition, some have suggested that, albeit not recommended in the label, Week 2 HCV RNA be measured to provide context to the Week 4 HCV RNA level (for example, to assess whether HCV RNA more then 1000 IU/mL at Week 4 of telaprevir represents a viral breakthrough). Publication of data demonstrating the negative predictive value of the new futility rules, along with additional experience with boceprevir and telaprevir, may shed further light on whether there is any role for continuing therapy if the thresholds of HCV RNA incorporated into the new futility rules are exceeded.
Both boceprevir and telaprevir must not be administered as monotherapy and must be administered together with both pegIFN and RBV. If pegIFN or RBV is discontinued for any reason, boceprevir or telaprevir must also be discontinued. Boceprevir and telaprevir must not be dose reduced. Boceprevir and telaprevir must not be stopped and then restarted. The importance of adherence should be emphasized to patients to ensure the greatest potential for treatment success and to minimize potential for treatment failure and subsequent resistance development.
Currently, there is no evidence to support switching from one PI to the other if treatment is not successful. The safety and efficacy of switching to the other PI because of a drug-specific adverse event also has not been established. Likewise, a patient for whom one PI was not successful should not be retreated with a regimen containing the other PI.
Panel Recommendations
Stopping rules for boceprevir- or telaprevir-based regimens should be strictly adhered to.
Fear of resistance should not be a reason to withhold telaprevir or boceprevir from a patient who is expected to benefit from therapy because resistance can be minimized as long as stopping rules are adhered to and it does not necessarily disqualify patients from future therapeutic options.
Please See The Featured Content Practical Guide for PI-Based HCV Therapy
Review guidance from experts on the optimal use of boceprevir and telaprevir for the treatment of HCV.
CCO does require free registration, however treatment updates including interactive virtual presentations by HCV experts is the best gateway to understanding the new drugs and the importance of adherence to Hepatitis C therapy. More @ CCO
Sept 15 2011
AbstractAnalysis of long-term persistence of resistance mutations within the hepatitis C virus NS3 protease after treatment with telaprevir or boceprevir
Klinikum der Goethe Universität, Medizinische Klinik 1, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
Universitätsklinikum Homburg, Klinik für Innere Medizin 2, Kirrberger Str., Homburg/Saar, Germany
Received 16 May 2011; revised 20 July 2011; Accepted 16 August 2011. Available online 15 September 2011.
Abstract
Background
Telaprevir and boceprevir are highly selective hepatitis C virus (HCV) NS3/4A proteaseinhibitors in phase 3 development. Viral breakthrough during mono- and triple-therapies with PEG-interferon and ribavirin and relapse is associated with resistance.
Objectives
Potential persistence of resistance mutations during long-term follow-up should be analyzed.
Study design
Clonal sequence analysis of the NS3-protease gene was performed at long-term follow-up in HCV genotyp-1 infected patients who received telaprevir or boceprevir within phase-1b studies for comparison with resistant variants present directly after the end-of-treatment.
Results
After a median follow-up of 4.2 years in 28 of 82 patients HCV-RNA was still detectable. Resistance variants were detected in two of 14 telaprevir- and in four of 14 boceprevir-treated patients.
For telaprevir patients two low-level (V36M, V36A) and one high-level (A156T) mutation associated with resistance were detected at low frequencies (4–9% of the clones). In five boceprevir-treated patients four low level mutations (V36A, T54A/S, V55A) were observed at low frequencies (1–10%) while in one patient additionally a combined variant (T54S + R155K) was detected at 94%. Presence of resistant variants at long-term follow-up was not predictable by variants detected at the end-of-treatment. In one patient a V55A variant which was dominant already at baseline was still detectable at long-term follow-up.
Conclusions
In the majority of patients after short-term treatment with telaprevir or boceprevir wild-type NS3-protease isolates are detectable by clonal sequencing at long-term follow-up. Detectable resistance mutations in single patients are not predictable by initial frequencies of variants.
2011
From Natap
HCV Protease Inhibitor Resistance - New Monogram Resistance Assay: this report contains relevant information related to HCV telaprevir & boceprevir resistance and the new assay
More From CCO
Expert AnalysisFrom Podium to Practice: Clinical Impact of New Data From EASL 2011
Source: CCO Independent Conference Coverage of the 2011 Annual Meeting of the European Association for the Study of the Liver*
By: Graham R. Foster, FRCP, PhD, Paul Y. Kwo, MD, Stefan Zeuzem, MD
Analyses of Treatment-Emergent Telaprevir- or Boceprevir-Resistant HCV Variants
The key take-home message for the treating physician is: if the patient is not responding well, stop. treatment early and do not persist with ineffective therapy. Minimizing exposure to futile therapy may turn out to be very important to protect future treatment options.
***Free registration is required
From Nature
Published online 31 March 2011 Nature doi:10.1038/news.2011.199
New drugs for hepatitis C on the horizon
Early studies showed that although a protease inhibitor given on its own was very effective initially, it often led to resistant strains of the virus in a matter of days, Gordon says. Even with interferon and ribavirin, resistance "remains a concern," he says. To keep it to a minimum, "clinicians must follow such patients very closely during therapy because if the viral level starts to rise after initially declining, then the protease inhibitor must be stopped to prevent the development of even more resistant strains."
Aug 8 2011
Hepatitis C-New Protease Inhibitor (NS3/4A) Drug Resistance Test
LabCorp and Monogram Biosciences are pleased to announce the launch of HCV GenoSure NS3/4A, a protease inhibitor drug resistance assay for the clinical management of patients with hepatitis c.
Aug 19 2011
In Case You Missed It
Patient video;New hepatitis C Drugs and Resistance
Some new copies of HCV carry mutations, meaning they are slightly different from the original virus. Some mutated virus can keep multiplying even when you are taking anti-HCV medications. When this happens, the drug will stop working. This is called “developing resistance” to the drug. Resistance can develop quickly. It is very important to take antiviral medications according to instructions, on schedule, and not to skip or reduce doses. If your HCV viral load is too high after 4 weeks of treatment, your doctor might decide that you should stop taking telaprevir to avoid having your HCV develop resistance
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