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Info on Viral Breakthrough with Triple Therapies

Feb 04, 2012 - 0 comments

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Here is some info on Viral Breakthrough with Triple Therapies.

1. Virologic Response Definitions With PegIFN/RBV-Based Therapy

Viral breakthrough:  HCV RNA detectable at any time during treatment after being undetectable

“A Practical Guide for the Use of Boceprevir and Telaprevir for the Treatment of Hepatitis C
Source: The Future of HCV Therapy With the Advent of Direct-Acting Antiviral Agents”
By: Nezam H. Afdhal, MD, FRCPI, Geoffrey M. Dusheiko, MD, FCP(SA), FRCP, Xavier Forns, MD, Donald M. Jensen, MD, Fred Poordad, MD

2. Management of virological breakthrough on protease inhibitors:

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 than a 1 log increase in serum HCV RNA above nadir is observed (Class 1, Level A).

“An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases”, By: Marc G. Ghany, David R. Nelson, Doris B. Strader, David L. Thomas, Leonard B. Seeff

Article first published online: 26 SEP 2011, DOI: 10.1002/hep.24641

3. 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. 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. 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
HCV Genotype 1 Subtype Telaprevir                 Boceprevir
1a                 V36M, R155K, or combination V36M, T54S, R155K
1b                 V36A, T54A/S, A156S/T T54A, V55a, A156S, I/V170A

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.

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 than 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 than 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.

“A Practical Guide for the Use of Boceprevir and Telaprevir for the Treatment of Hepatitis C
Source: The Future of HCV Therapy With the Advent of Direct-Acting Antiviral Agents”,
By: Nezam H. Afdhal, MD, FRCPI, Geoffrey M. Dusheiko, MD, FCP(SA), FRCP, Xavier Forns, MD, Donald M. Jensen, MD, Fred Poordad, MD

4. Resistance mutations within Hep C virus NS3 protease gene after treatment with telaprevir or boceprevir

“Analysis 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.  Journal of Clinical Virology, 2011 Dec;52(4):321-7. Epub 2011 Sep 15.

Telaprevir and boceprevir are highly selective hepatitis C virus (HCV) NS3/4A protease inhibitors in phase 3 development. Viral breakthrough during mono- and triple-therapies with PEG-interferon and ribavirin and relapse is associated with resistance.

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.

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.

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.

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