Telaprevir Abstracts AASLD 2007

[jmjm530]

Telaprevir resistance mutations in patients with hepatitis C who relapsed after sequential therapy with telaprevir, peg-interferon alfa 2a and ribavirin
N. Forestier1, 2; S. Susser2; M. W. Welker2; C. J. Weegink3; H. W. Reesink3; S. Zeuzem1, 2; C. Sarrazin1, 2
1. Internal Medicine I, J. W. Goethe University Hospital, Frankfurt, Germany.
2. Internal Medicine II, Saarland University Hospital, Homburg, Germany.
3. Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, Netherlands.


Introduction: Telaprevir (TVR) is a highly selective inhibitor of the hepatitis C virus (HCV) NS3/4A protease with highly effective blocking of HCV replication in patients with hepatitis C. Mutations have been identified in the NS3 protease gene at positions 36, 54, 155 and 156 conferring resistance to TVR in vitro and in vivo. For single resistance mutations an inverse correlation of resistance level and viral fitness has been described while combined mutations (i.e. V36/R155) display relative high resistance with compensatory effects on replication efficiency. Little is known about persistence of TVR resistance mutations in patients treated sequentially with TVR, peg-interferon and ribavirin (RBV). Methods: Fifteen patients received either TVR monotherapy or TVR peg-interferon alfa 2a combination therapy for 2 weeks followed by peginterferon alfa 2a plus RBV standard combination therapy for 24 or 48 weeks. In the present study, we performed amplification and clonal sequencing (approx. 50 clones per patient and time point) of the HCV NS3 protease gene in 5 patients who relapsed so far. All 5 patients were tested HCV RNA negative during therapy but relapse with increasing HCV RNA concentration was observed after the end of standard combination treatment for 24 or 48 weeks. Results: While in 2 patients no mutations conferring resistance to TVR were detected during different time points after relapse, in 3 patients known TVR resistance mutations within the NS3 protease gene were detected. Patient 1 with initial TVR monotherapy, 48 weeks of standard therapy, and relapse at week 4 after treatment discontinuation (433.000 IU/ml) showed mutations at positions V36 (100% of clones) and R155 (100% of clones). In patient 2 with initial TVR monotherapy, 24 weeks of standard treatment and relapse at week 4 (viral load pending) only single isolates with resistance mutations were observed at position V36 (2%) and A156 (2%). Finally, patient 3 received initially combination therapy followed by 48 weeks of standard treatment. In this patient relapse was detected at follow up week 8 (1.400 IU/ml) and resistance mutations were detected at position V36 (84% of clones) only. In both patients who received TVR monotherapy mutations at positions V36, T54, R155 and A156 were observed during the initial 2 weeks of treatment. Conclusion: In patients treated with TVR with and without peginterferon alfa 2a for 2 weeks followed by standard therapy with peginterferon and RBV for 24 or 48 weeks mutations conferring resistance to TVR can be detected after relapse. The significance of TVR resistance mutations for the probability of relapse has to be investigated in future studies.

(MORE TO FOLLOW)

[somuchmore]

Thank you for the input. I verily hope you do well and your liver starts to recover after tx.

What genotype are you? (genotype 1a or 1b?)
Had you failed earlier tx of interferon-based? (which or both interferon std or peg?)

with reference to text from Vertex June, 12 2007 post on their site.

"Vertex today announced that it has completed patient enrollment in the PROVE 3 clinical trial with more than 440 patients. PROVE 3 is a Phase 2b clinical trial of telaprevir in patients with genotype-1 HCV who have not achieved SVR with a previous interferon-based treatment."

I do not see where there will be much about prove 3 in Boston Nov. 2-6, 2007. Therefore, those like me who have not been capable of getting into the trials are very interested in any input about expected result once FDA allows us to do the treatment.

Thanks

[jmjm530]

That's wonderul and hopefully some encouragment for Nick that they appear to be accepting stage 4's.

[FullOfHope77]

Thanks for posting as it was greatly appreciated... btw, I'm Stage 4 (cirrosis) and in Prove 3 study at week 19 and so far so good.

[JRenquist]

Thanks so much for posting this.  I can't wait for you to translate it into English.  I don't really understand it, but it seems very positive?  Also , it seems that all of the patients were genotype 1, whereas in other trials other, more easily treated genotypes were included; comparing this to them is apples and oranges, right.  S.

[susan400]

Elaine,

Amanda was in Group C - no Riba.  I know this, because Jodi (Travelmom) talked to me about it since I was also in the a Group C - no Riba group.  I don't feel like I'm speaking out of line here, since I believe she's said to us on the boards here, before about Amanda not having the Ribavirin.    

I hope that answers your question....

Susan

[jmjm530]

Don't think you can direct link. If you want to see these abstracts (and more) from the source, go to the AASLD web site and register:

https://www.aasld.org/eweb/DynamicPage.aspx?webcode=07am

Then go to "abstacts", then "abstract viewer".

Good luck, not a very intuitive site but you should find what you want with a little patience.

-- Jim