Aa
Telaprevir Abstracts AASLD 2007
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)
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)
In light of today's discussion of Boceprevir, I thought I'd bump up the AASLD Telaprevir Abstracts previously posted, for review, analysis, and maybe into simplification by into a chart or something by those here so invloved and inclined. Something I was planning on doing but haven't gotten around to yet.
-- Jim
-- Jim
Hi Jim,
probably Vertex does not think it could help people without a HCV infection. This kind of studies are done for safety reasons, not to show efficacy. I think they just work on the typical registration programm needed for new chemical entities (see below *). This includes safety data for special patient groups, eg. those with hepatic impairment, renal impairment, geriatric people, children (!) and so on. Perhaps they do it step by step and want to get a restricted marketing authorisation first, but to get it as soon as possible. This is good for most of us.
About cirrhosis and Prove 3: What does the Informed Consent or study protocol write about inclusion and exclusion criteria of Prove 3? Would be nice to know the wording
exactly.
* From a European Guideline (should be similiar worldwide):
http://tinyurl.com/2ystnu
Additional information on special populations
Available relevant information on special populations such as renal/hepatic impairment, geriatric or paediatric patients should be presented here.
Renal/hepatic impairment
Dosage adjustments in specific patient groups should be stated e.g. regarding:
• renal insufficiency; the dose recommendation should relate as precisely as possible to the cutoff values for biochemical markers of renal impairment clinical studies and to the results of these studies.
• liver disease, specified according to the patients included in studies, for instance ‘alcoholrelated cirrhosis’ and the definitions used in the studies, for instance Child-Pugh score/grade of the patients, and
• other concomitant diseases.
probably Vertex does not think it could help people without a HCV infection. This kind of studies are done for safety reasons, not to show efficacy. I think they just work on the typical registration programm needed for new chemical entities (see below *). This includes safety data for special patient groups, eg. those with hepatic impairment, renal impairment, geriatric people, children (!) and so on. Perhaps they do it step by step and want to get a restricted marketing authorisation first, but to get it as soon as possible. This is good for most of us.
About cirrhosis and Prove 3: What does the Informed Consent or study protocol write about inclusion and exclusion criteria of Prove 3? Would be nice to know the wording
exactly.
* From a European Guideline (should be similiar worldwide):
http://tinyurl.com/2ystnu
Additional information on special populations
Available relevant information on special populations such as renal/hepatic impairment, geriatric or paediatric patients should be presented here.
Renal/hepatic impairment
Dosage adjustments in specific patient groups should be stated e.g. regarding:
• renal insufficiency; the dose recommendation should relate as precisely as possible to the cutoff values for biochemical markers of renal impairment clinical studies and to the results of these studies.
• liver disease, specified according to the patients included in studies, for instance ‘alcoholrelated cirrhosis’ and the definitions used in the studies, for instance Child-Pugh score/grade of the patients, and
• other concomitant diseases.
Do you know why they think Telaprevir will help people with hepatic impairment who don't have Hep C?
As to Telaprevir studies for people with Hepatitic Impairment WITH Hep C, "FullOfHope" has posted above that he has stage 4 and is currently enrolled in Prove 3 and all appears to be going well.
-- Jim
As to Telaprevir studies for people with Hepatitic Impairment WITH Hep C, "FullOfHope" has posted above that he has stage 4 and is currently enrolled in Prove 3 and all appears to be going well.
-- Jim
Yes, cirrhotics were excluded in Prove 1 and 2 and for the most part in Prove 3 too (as stated above).
Quote: Maybe I'm missing something but did you read the "EXCLUSION criteria" section. It included: Tested positive for HIV, Hepatitis C, Hepatitis B
****************************************
Hi Jim, no you are missing nothing. To my knowledge this is the very first study of Telaprevir in subjects with hepatic impairment and safety studies in subjects with hepatic impairment from Hepatitis C will follow even later.
Or do you know any telaprevir-studies on hepatic impairment from Hepatitis C?
I would be very interested to get the link. Thank you in advance.
Didn't Vertex select more or less "healthy" hep c patients for the Prove 1 and 2?
I have some discussions about this in mind, but do not remember well...
****************************************
Hi Jim, no you are missing nothing. To my knowledge this is the very first study of Telaprevir in subjects with hepatic impairment and safety studies in subjects with hepatic impairment from Hepatitis C will follow even later.
Or do you know any telaprevir-studies on hepatic impairment from Hepatitis C?
I would be very interested to get the link. Thank you in advance.
Didn't Vertex select more or less "healthy" hep c patients for the Prove 1 and 2?
I have some discussions about this in mind, but do not remember well...
Thank you and I hope the best for your son and you as well.
FYI, I think my exclusion was based on low platelets.
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
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
That's wonderul and hopefully some encouragment for Nick that they appear to be accepting stage 4's.
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.
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.
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
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
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
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
The trial Drofi posted is not for those with Hep C, or so it appears. And yes, cirrhosis can be reversed like fibrosis, according to more recent thinking. Of course no guarantees.
Thank you for posting the results. Would you please post a link as well? I tought we would not hear from VRTX until Nov 2nd.
Thank you,
Ludwig
Thank you,
Ludwig
In Prove 1 cirrhotics were excluded. I'm almost certain they were excluded in Prove 2 as well. Travelmom's daughter is in Prove 3 and has cirrhosis, but I think she was given a special exception because of her age. Not sure but I think pretty much all VX testing to date has more or less excluded cirrhotics, so I doubt there's any real data available to demonstrate how well TV+SOC works in those with cirrhosis. But child24, I'm sure Telaprevir would help those with cirrhosis, there's no reason why it's powerful antiviral effectiveness wouldn't help them get cured too (as long as ribavirin is included, of course).
Maybe I'm missing something but did you read the "EXCLUSION criteria" section. It included: Tested positive for HIV, Hepatitis C, Hepatitis B
----------------------------
----------------------------
to my knowledge Vertex so far has not done studies with cirrhosis patients. This kind of examination is just on the way: http://tinyurl.com/2jf9bp
Thanks for posting the info Jim....I didn't realize that a side of TVR is anemia, perhaps that is why they had some no riba study people, but that appears to have not worked out to well..Pro
Some crisp charts would have been nice, but maybe they're reserving that for the full presentations. So meanwhile, I'll probably sit down with pencil and paper and chart out the different scenarios unless someone (hopefully) beats me to the punch.
Have only glanced at them so far but will read more later, but honestly haven't been following the trials as closely as I used to. You might also want to look for some more professional commenatry on sites like this: http://www.hivandhepatitis.com/
If they don't already, I'm sure they will soon have an AASLD 2007 section.
If they don't already, I'm sure they will soon have an AASLD 2007 section.
Final Results of Patients Receiving Peg-Interferon-Alfa-2a (Peg-IFN) and Ribavirin (RBV) After a 14-Day Study of the Hepatitis C Protease Inhibitor Telaprevir (VX-950), With Peg-IFN
C. J. Weegink1; N. Forestier2, 3; P. L. Jansen1; S. Zeuzem2, 3; H. W. Reesink1
1. Academic Medical Center, Amsterdam, Netherlands.
2. J.W.Goethe University Hospital, Frankfurt a.M., Germany.
3. Saarland University Hospital, Homburg/Saar, Germany.
Purpose: Telaprevir (TVR, VX-950) is a highly-selective peptidomimetic inhibitor of the hepatitis C virus (HCV) NS3●4A protease that is designed to block HCV replication. This 14-day study was designed to explore the viral kinetics and safety during dosing with TVR in combination with peginterferon-alfa-2a (Peg-IFN). Here we report the final results of patient status after stopping follow-on standard therapy with Peg-IFN and ribavirin (RBV).
Methods: The VX04-950-103 clinical study randomized twenty treatment-naïve patients with chronic genotype 1 hepatitis C infection to three dosing arms. Eight patients received TVR (750 mg as tablets q8h) with Peg-IFN on Days 1 and 8, and eight patients received TVR alone. Four patients received Peg-IFN alone on Days 1 and 8. At the completion of the 14-day study, off-study therapy with Peg-IFN and RBV was offered to all patients. Nineteen of 20 patients began therapy within 5 days of completing the 14-day dosing period. The patient who refused post-study Peg-IFN/RBV was in the TVR-alone group.
Results: At week 12 of therapy, all 8 patients in the TVR/Peg-IFN group and 5 of 7 patients in the TVR alone group had undetectable HCV RNA. At week 24, all 15 patients who received TVR had undetectable HCV RNA(<10 IU/mL). Ten patients (6/8 TVR/Peg-IFN and 4/7 TVR alone) chose to stop Peg-IFN/RBV treatment at week 24 and 5 patients chose to continue Peg-IFN/RBV for a total of 48 weeks. All groups were followed for the subsequent 24 weeks. In patients who had received TVR-based therapy for 14 days before starting off-study Peg-IFN/RBV therapy, 7/10 patients treated for a total of 24 weeks and 2/5 patients treated for a total of 48 weeks achieved a sustained viral response (SVR) One patient, treated for 48 weeks, was lost to follow-up. From the group who received Peg-IFN alone before 48 weeks of Peg-IFN/RBV therapy, 1/4 patients achieved SVR. The side effect profile observed during the post-study dosing was consistent with the expected profile of Peg-IFN/RBV therapy. Sequence analysis of the 5 patients who relapsed after TVR-based therapy is in progress.
Conclusions: SVR was achieved in 9 of 15 patients treated for 14 days with TVR or TVR/Peg IFN followed by Peg-IFN/RBV therapy for a total of 24 or 48 weeks. These results suggest that TVR-based regimens may increase SVR rates compared to current therapies. Large Phase 2 clinical studies of TVR-based regimens are now ongoing to evaluate this hypothesis and the possibility of shortening the duration of therapy.
C. J. Weegink1; N. Forestier2, 3; P. L. Jansen1; S. Zeuzem2, 3; H. W. Reesink1
1. Academic Medical Center, Amsterdam, Netherlands.
2. J.W.Goethe University Hospital, Frankfurt a.M., Germany.
3. Saarland University Hospital, Homburg/Saar, Germany.
Purpose: Telaprevir (TVR, VX-950) is a highly-selective peptidomimetic inhibitor of the hepatitis C virus (HCV) NS3●4A protease that is designed to block HCV replication. This 14-day study was designed to explore the viral kinetics and safety during dosing with TVR in combination with peginterferon-alfa-2a (Peg-IFN). Here we report the final results of patient status after stopping follow-on standard therapy with Peg-IFN and ribavirin (RBV).
Methods: The VX04-950-103 clinical study randomized twenty treatment-naïve patients with chronic genotype 1 hepatitis C infection to three dosing arms. Eight patients received TVR (750 mg as tablets q8h) with Peg-IFN on Days 1 and 8, and eight patients received TVR alone. Four patients received Peg-IFN alone on Days 1 and 8. At the completion of the 14-day study, off-study therapy with Peg-IFN and RBV was offered to all patients. Nineteen of 20 patients began therapy within 5 days of completing the 14-day dosing period. The patient who refused post-study Peg-IFN/RBV was in the TVR-alone group.
Results: At week 12 of therapy, all 8 patients in the TVR/Peg-IFN group and 5 of 7 patients in the TVR alone group had undetectable HCV RNA. At week 24, all 15 patients who received TVR had undetectable HCV RNA(<10 IU/mL). Ten patients (6/8 TVR/Peg-IFN and 4/7 TVR alone) chose to stop Peg-IFN/RBV treatment at week 24 and 5 patients chose to continue Peg-IFN/RBV for a total of 48 weeks. All groups were followed for the subsequent 24 weeks. In patients who had received TVR-based therapy for 14 days before starting off-study Peg-IFN/RBV therapy, 7/10 patients treated for a total of 24 weeks and 2/5 patients treated for a total of 48 weeks achieved a sustained viral response (SVR) One patient, treated for 48 weeks, was lost to follow-up. From the group who received Peg-IFN alone before 48 weeks of Peg-IFN/RBV therapy, 1/4 patients achieved SVR. The side effect profile observed during the post-study dosing was consistent with the expected profile of Peg-IFN/RBV therapy. Sequence analysis of the 5 patients who relapsed after TVR-based therapy is in progress.
Conclusions: SVR was achieved in 9 of 15 patients treated for 14 days with TVR or TVR/Peg IFN followed by Peg-IFN/RBV therapy for a total of 24 or 48 weeks. These results suggest that TVR-based regimens may increase SVR rates compared to current therapies. Large Phase 2 clinical studies of TVR-based regimens are now ongoing to evaluate this hypothesis and the possibility of shortening the duration of therapy.
hey jim can you give us your take on this in laymans terms? i'm not to good at understanding these studies. as usual thanks for the great info
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