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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)
see my profile interest
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
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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
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