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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)
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
I know, haven't read most of them myself yet :)
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