small German Telaprevir Study

1: Hepatology. 2007 Aug 6

Telaprevir and pegylated interferon-alpha-2a inhibit wild-type and resistant genotype 1 hepatitis C virus replication in patients.

Kieffer TL, Sarrazin C, Miller JS, Welker MW, Forestier N, Kwong AD, Zeuzem S.
Vertex Pharmaceuticals Inc., Cambridge, MA.
Telaprevir (VX-950) is an orally active, specifically targeted antiviral therapy for hepatitis C virus (HCV) that has been shown to profoundly reduce plasma HCV RNA in genotype 1 patients. Using a highly sensitive sequencing assay that detects minor populations of viral variants (>/=5%), mutations were identified that conferred low-level (V36M/A, T54A, or R155K/T) or high-level (A156V/T and 36/155) resistance to telaprevir in vitro. We report a detailed kinetic analysis of these variants in 16 patients given telaprevir or telaprevir + pegylated interferon-alpha-2a (PEG-IFN-alpha-2a) for 14 days. In 4 patients who had a viral rebound on telaprevir alone, the R155K/T and A156V/T variants were detected during the initial steep decline in HCV RNA. During the rebound phase, the R155K/T and A156V/T variants were replaced by V36(M/A)/R155(K/T) double mutant variants. In the remaining 12 patients given telaprevir alone or with telaprevir/PEG-IFN-alpha-2a, the A156V/T variant was detected in some patients, but viral levels continued to decline in all patients. Conclusion: These studies suggest that the initial antiviral response to telaprevir is due to a sharp reduction in wild-type virus, which uncovers pre-existing telaprevir-resistant variants. In patients given telaprevir alone, viral rebound can result from the selection of variants with greater fitness. However, the combination of telaprevir and PEG-IFN-alpha-2a inhibited both wild-type and resistant variants. In the present study, every patient who began PEG-IFN-alpha-2a and ribavirin after the 14-day dosing period had undetectable HCV RNA levels at 24 weeks, indicating that telaprevir-resistant variants are sensitive to PEG-IFN-alpha-2a and ribavirin. (HEPATOLOGY 2007.).
PMID: 17680654

[Jesser]

This is way above my head...but I am going to ask a question and probably make
myself look stupid anyway.  If every patient who began had VX950/INF/Riba after 14-day
dosing (2 weeks) had undetectable...then.. I am/was in the PROVE 3 study
started 5/3/07...at 4 weeks my Doctor stated "I made the protocol can
move on"...then...at 7 1/2 weeks Doctor called and stated"Stop all medication protocol
has changed to must be undetectable at week 4"...
QUESTION..."Do you think I was in the placebo group?"
Thanks for your help,
Jesser

[dointime]

This study used a small sample.  In a larger population it has been shown that not everybody gets to UND at 24 weeks, some people fall out because of severe sides and some people develop resistance to the triple therapy.  

I hope you were in the placebo group because then you still have a first try with VX to come somewhere up the line.  Good luck,

dointime

[drofi]

Hi,
I agree with dointime. The results are promissing again, not a drawback for Telaprevir, but UND is not what we want, what we want is SVR. UND without SVR is laboratory-cosmetics, nothing more. The clinical data from the PROVE studies have to show the numbers of SVR.
Your question: Nobody will know the the true group before unblinding. You could be a nonresponder to VX too.
Btw, in Germany we say "There are no stupid questions, only stupid answers".

All the best, drofi

[drofi]

from my understanding  the numbers in the abstract describe the mutations of the virus, which are the reason for the resistance.
Example: T54A means the aminoacid Threonin at position 54 was changed to Alanin.
Research like this will be the key to next generation protease inhibitors AFTER Telaprevir.

[Jesser]

Thanks Guys (Guy & Gal),
I just have so many questions and I know I won't get answers until I'm unblinded.
Patience - is not my strong suit :) I really appreciate and want to thank you both
for helping me.  All the best, Jesser