Aa
Resistance in 2-DAA combos
Following on from the discussion on resistance in another thread, I found this study.
http://www.pharmasset.com/assets/1/Page/ALam_combo_studies_invitro_7977_938_June10.pdf
"Selection study in replicon cells treated with the nucleotide analogs PSI-7977 and PSI-352938 did not select for resistance over a 120-day time period. Combining VX-950 plus HCV-796 selected for dually resistant HCV replicons within 46 days. Results suggest that combination therapies using complementary NS5B nucleotide analogs could provide a significant barrier to resistance selection that might not be seen with a combination of a protease inhibitor and a non-nucleoside inhibitor."
I think it is an important study because it is showing that if you don't get the 2-DAA combo right you could be looking at dually resistant mutations within 46 days of tx. The viral superbugs already! From experience with HIV we know that multiple drug resistance does emerge eventually, but it is the 46 days that I find such a shocker, such a short time.
The good news is that the 2 NS5B nucleotide analogs used in the study did not produce any resistant mutations within 120 days of tx.
Anyhow, this wrecks my previous complacency about 2-DAA combos being the magic bullet. We are going to have to be very cautious about resistance with these combos - I presume even when there is SOC in the mix but poor ifn response.
dointime
PS - and thanks to willbb for waking me up.
http://www.pharmasset.com/assets/1/Page/ALam_combo_studies_invitro_7977_938_June10.pdf
"Selection study in replicon cells treated with the nucleotide analogs PSI-7977 and PSI-352938 did not select for resistance over a 120-day time period. Combining VX-950 plus HCV-796 selected for dually resistant HCV replicons within 46 days. Results suggest that combination therapies using complementary NS5B nucleotide analogs could provide a significant barrier to resistance selection that might not be seen with a combination of a protease inhibitor and a non-nucleoside inhibitor."
I think it is an important study because it is showing that if you don't get the 2-DAA combo right you could be looking at dually resistant mutations within 46 days of tx. The viral superbugs already! From experience with HIV we know that multiple drug resistance does emerge eventually, but it is the 46 days that I find such a shocker, such a short time.
The good news is that the 2 NS5B nucleotide analogs used in the study did not produce any resistant mutations within 120 days of tx.
Anyhow, this wrecks my previous complacency about 2-DAA combos being the magic bullet. We are going to have to be very cautious about resistance with these combos - I presume even when there is SOC in the mix but poor ifn response.
dointime
PS - and thanks to willbb for waking me up.
Recently I spoke with a PharmD professor that is doing research on the DAAs and asked her about the futility rule with telaprevir. The 1,000 copies ruled seems rather arbitrary. The answer was yes it is arbitrary. In the trials there were a few that had viral loads of 100 or 200 and they went on to SVR. 1,000 was chosen to ensure that all those that might have a chance to clear are given the opportunity. She seemed convinced that those with several hundred copies or more did not have an adequate INF response and would not clear.
Blessings
Eric
Blessings
Eric
what did your VL drop with tela look like? I'm not sure there's reason to assign a number like 10% but believe your Dr's point about it not being a good bet sounds right.
In rough terms, when you started triple say 99% of your viral variants were susceptible to the PI and 1% wasn't. The PI took care of stopping replication among the 99% "wild-type" (no such concept as PI non-response) but the ifn/rbv was incapable of eliminating the 1% and they multiplied and grew. By restarting soc you'd be betting that the improvement in ifn response due to alinia,SamE or whatever now made it capable of dealing with the 1% it couldn't deal with before and the 99% handled by the PI. Could certainly happen but, as a stage 2, waiting for quad therapy sounds a better bet. Best wishes.
In rough terms, when you started triple say 99% of your viral variants were susceptible to the PI and 1% wasn't. The PI took care of stopping replication among the 99% "wild-type" (no such concept as PI non-response) but the ifn/rbv was incapable of eliminating the 1% and they multiplied and grew. By restarting soc you'd be betting that the improvement in ifn response due to alinia,SamE or whatever now made it capable of dealing with the 1% it couldn't deal with before and the 99% handled by the PI. Could certainly happen but, as a stage 2, waiting for quad therapy sounds a better bet. Best wishes.
If one 'fails' a 4 week trial of telaprevir, and as a result now has resistant issues, does that mean that it would be futile to attempt SOC in the near future?...whilst throwing all at the body to get the uptake of interferon going, including things like alinia into the mix. Doctor seemed to think there was around a 10% chance. Am a stage 2, CT, la.
I don't know that taking particular tests are the patients choice unless you want to pay out of pocket. I did so when the genotyping first came out, it was $700. You are right about the uncertainty dointime but if you are not inclined to interferon treatments, it seems a reasonable uncertainty, esp. if all arms get meds. They do not do controlled, double blind studies on Hep C anymore. That is, everyone gets something.
Here's my thinking on this. The 4-week lead in is not useful in this case because if at that point your ifn response was found to be poor then the fact that you have started tx would disqualify you from the trial which is for tx naive only. Same goes if you do incivek and you don't pass the futility rule at 4 weeks. So while the IL28B test is not the holy grail, it is the only indicator you can get on your ifn response while keeping all your options open.
If the IL28B test were to show that you are a cc then you get lucky, as that would be a really good indicator of success with the triple therapy in 6 months. The triple would then, in my opinion, be your best choice. Other than that I would not say.
All trials, by definition, are unknown quantities for which we have insufficient information to make informed choices. They are all, to some extent, a leap in the dark. I have tried to highlight in this thread some of the ramifications of failing a DAA trial, and advised that they be taken into account when deciding on whether to do it or not. I don't think that speculating on the success of a phase2 trial is helpful. If you do the trial then you should at least be clear in your own mind, no matter what you hope for, that the outcome is uncertain.
Best,
dointime
If the IL28B test were to show that you are a cc then you get lucky, as that would be a really good indicator of success with the triple therapy in 6 months. The triple would then, in my opinion, be your best choice. Other than that I would not say.
All trials, by definition, are unknown quantities for which we have insufficient information to make informed choices. They are all, to some extent, a leap in the dark. I have tried to highlight in this thread some of the ramifications of failing a DAA trial, and advised that they be taken into account when deciding on whether to do it or not. I don't think that speculating on the success of a phase2 trial is helpful. If you do the trial then you should at least be clear in your own mind, no matter what you hope for, that the outcome is uncertain.
Best,
dointime
Graham R. Foster, FRCP, PhD:
Poordad and colleagues[7] conducted a retrospective analysis of the boceprevir phase III studies, SPRINT-2[8] and RESPOND-2,[9] investigating the potential correlation between IL28B genotype and SVR in patients with genotype 1 HCV infection treated with boceprevir plus peginterferon/ribavirin or peginterferon/ribavirin alone (Capsule Summary). The relative impact of IL28B genotype and treatment regimen on SVR rates differed between treatment-naive patients in SPRINT-2 and patients with previous treatment failure in RESPOND-2. Among treatment-naive patients with the IL28B CC genotype, SVR rates were high at 78% with peginterferon/ribavirin alone and 82% with boceprevir plus peginterferon/ribavirin. However, among treatment-naive patients with the IL28B CT or TT genotype, SVR rates were substantially higher with boceprevir-based therapy vs peginterferon/ribavirin alone. In patients with the CT genotype, response rates were 65% with response-guided therapy and 71% with 48-week therapy including boceprevir vs 28% with peginterferon/ribavirin alone. In those with the TT genotype, corresponding rates were 55%, 59% and 27%. Therefore, an encouraging finding from this analysis was that the differences in SVR rates according to IL28B genotype observed in treatment-naive HCV genotype 1 patients treated with peginterferon/ribavirin alone were substantially, although not fully, mitigated by the use of triple therapy with boceprevir plus peginterferon/ribavirin.
By contrast, SVR rates were substantially higher with boceprevir-based therapy vs peginterferon/ribavirin alone in treatment-experienced patients with the IL28B CC or CT genotype. In patients with the CC genotype, response rates were 79% with response-guided therapy and 77% with 48-week therapy including boceprevir vs 49% with peginterferon/ribavirin alone. In those with the CT genotype, corresponding rates were 61%, 73% and 17%. Among treatment-experienced patients with the IL28B TT genotype, there was a trend toward a lower SVR rate with response-guided boceprevir-based therapy vs 48-week boceprevir-based treatment: 55% with response-guided therapy and 72% with 48-week therapy including boceprevir vs 50% with peginterferon/ribavirin alone.
The IL28B CC genotype was determined to be predictive of SVR in both studies according to a multiple stepwise logistic regression model (P < .001 for SPRINT-2; P = .025 for RESPOND-2). However, when response to the 4-week peginterferon/ribavirin lead-in phase was added to the model, IL28B genotype was no longer a significant predictor of SVR.
It is important to assess the validity and applicability of these findings. The patient numbers in some of the subgroups are relatively low as not all of the patients in the trials were available for IL28B genotyping. The trials were designed before the predictive value of IL28B genotype had been discovered; therefore patients had to provide additional consent to be included, and IL28B genotyping data were available for only 63% of the population. However, despite this limitation, the trend is fairly clear: boceprevir improved SVR rates in nearly all of the IL28B genotype subgroups, with the exception of treatment-naive patients harboring the CC genotype (who exhibited high SVR rates regardless of regimen) and previously treated patients with the TT genotype who received response-guided boceprevir plus peginterferon/ribavirin. It still remains to be determined whether patients with the IL28B TT genotype can achieve SVR rates as high as patients with the CC genotype with boceprevir-based therapy. The suggestion from this analysis is the rates are not quite as high, but they are still a great deal higher with boceprevir-based treatment than with peginterferon/ribavirin alone.
Paul Y. Kwo, MD:
I would echo the point that IL28B genotype data from retrospective analyses such as this one must be interpreted with caution. The SVR rate of 78% among treatment-naive patients with the IL28B CC genotype receiving peginterferon/ribavirin alone is reasonably consistent with what has been observed in other studies, although somewhat higher than the rate observed in the large IDEAL analysis by Thompson and colleagues,[10] possibly due to the small sample size. The results showed that treatment-naive patients with the IL28B CC genotype did not derive substantial benefit from the addition of boceprevir to standard peginterferon/ribavirin, yet treatment-naive patients with the CT or TT genotype did derive a substantial benefit. This pattern was markedly different from that observed among patients with previous treatment failure where the addition of boceprevir improved SVR rates regardless of IL28B genotype.
Stefan Zeuzem, MD:
Regarding the limitations imparted by retrospectively assessing IL28B genotype, it is also possible that the results may be biased because patients who were lost to follow-up could not be queried for consent. As a result, the analysis may include a slight selection bias toward compliant patients and potentially toward patients with SVR. Future studies that include IL28B genotyping as an enrollment criterion will be much more informative.
Paul Y. Kwo, MD:
That is a legitimate question to ask in a country with limited resources because SVR rates are high with peginterferon/ribavirin alone among treatment-naive patients with the CC genotype. However, it is important to consider that patients with the CC genotype are much more likely to be able to undergo a shorter treatment duration if a DAA agent such as boceprevir is included in the regimen. In the current study, 89% of treatment-naive patients and 82% of treatment-experienced patients with the IL28B CC genotype were eligible for short-duration therapy with boceprevir plus peginterferon/ribavirin. That is a very encouraging take-home message from this presentation. Although it would be preferable not to withhold boceprevir, in a country where treatment is truly limited because of constrained resources, it would not appear to be an unreasonable strategy if the DAA agent is unaffordable. In regions such as Asia, where SVR rates are already very high due to the high prevalence of the IL28B CC genotype, it may be difficult to improve SVR rates further and if resources are limited, continuing to treat with peginterferon/ribavirin alone might be a strategy that is cost effective. It depends on the prevalence of the CC genotype.
Paul Y. Kwo, MD:
The data from the SPRINT-2 and RESPOND-2 analysis do convincingly suggest that knowing that a patient has the IL28B CC genotype will allow us to counsel him or her that there is a high likelihood that they will be receiving shorter-duration therapy.
Paul Y. Kwo, MD:
Regarding the relative predictive value of IL28B genotype and response to the 4-week peginterferon/ribavirin lead-in, IL28B genotype was no longer a significant predictor of SVR when the lead-in response was included in the analysis. That result is not surprising because IL28B genotype predicts peginterferon/ribavirin sensitivity; it is not perfect, but it is the first genetic tool in the era of personalized medicine that has allowed the prediction of a patient’s ability to clear HCV quickly during peginterferon/ribavirin-based therapy. The 4-week peginterferon/ribavirin lead-in, however, provides a real-time assessment of a patient’s peginterferon/ribavirin responsiveness, and therefore, it is not surprising that the impact of IL28B genotype is no longer evident when response to the 4-week lead-in is considered.
Poordad and colleagues[7] conducted a retrospective analysis of the boceprevir phase III studies, SPRINT-2[8] and RESPOND-2,[9] investigating the potential correlation between IL28B genotype and SVR in patients with genotype 1 HCV infection treated with boceprevir plus peginterferon/ribavirin or peginterferon/ribavirin alone (Capsule Summary). The relative impact of IL28B genotype and treatment regimen on SVR rates differed between treatment-naive patients in SPRINT-2 and patients with previous treatment failure in RESPOND-2. Among treatment-naive patients with the IL28B CC genotype, SVR rates were high at 78% with peginterferon/ribavirin alone and 82% with boceprevir plus peginterferon/ribavirin. However, among treatment-naive patients with the IL28B CT or TT genotype, SVR rates were substantially higher with boceprevir-based therapy vs peginterferon/ribavirin alone. In patients with the CT genotype, response rates were 65% with response-guided therapy and 71% with 48-week therapy including boceprevir vs 28% with peginterferon/ribavirin alone. In those with the TT genotype, corresponding rates were 55%, 59% and 27%. Therefore, an encouraging finding from this analysis was that the differences in SVR rates according to IL28B genotype observed in treatment-naive HCV genotype 1 patients treated with peginterferon/ribavirin alone were substantially, although not fully, mitigated by the use of triple therapy with boceprevir plus peginterferon/ribavirin.
By contrast, SVR rates were substantially higher with boceprevir-based therapy vs peginterferon/ribavirin alone in treatment-experienced patients with the IL28B CC or CT genotype. In patients with the CC genotype, response rates were 79% with response-guided therapy and 77% with 48-week therapy including boceprevir vs 49% with peginterferon/ribavirin alone. In those with the CT genotype, corresponding rates were 61%, 73% and 17%. Among treatment-experienced patients with the IL28B TT genotype, there was a trend toward a lower SVR rate with response-guided boceprevir-based therapy vs 48-week boceprevir-based treatment: 55% with response-guided therapy and 72% with 48-week therapy including boceprevir vs 50% with peginterferon/ribavirin alone.
The IL28B CC genotype was determined to be predictive of SVR in both studies according to a multiple stepwise logistic regression model (P < .001 for SPRINT-2; P = .025 for RESPOND-2). However, when response to the 4-week peginterferon/ribavirin lead-in phase was added to the model, IL28B genotype was no longer a significant predictor of SVR.
It is important to assess the validity and applicability of these findings. The patient numbers in some of the subgroups are relatively low as not all of the patients in the trials were available for IL28B genotyping. The trials were designed before the predictive value of IL28B genotype had been discovered; therefore patients had to provide additional consent to be included, and IL28B genotyping data were available for only 63% of the population. However, despite this limitation, the trend is fairly clear: boceprevir improved SVR rates in nearly all of the IL28B genotype subgroups, with the exception of treatment-naive patients harboring the CC genotype (who exhibited high SVR rates regardless of regimen) and previously treated patients with the TT genotype who received response-guided boceprevir plus peginterferon/ribavirin. It still remains to be determined whether patients with the IL28B TT genotype can achieve SVR rates as high as patients with the CC genotype with boceprevir-based therapy. The suggestion from this analysis is the rates are not quite as high, but they are still a great deal higher with boceprevir-based treatment than with peginterferon/ribavirin alone.
Paul Y. Kwo, MD:
I would echo the point that IL28B genotype data from retrospective analyses such as this one must be interpreted with caution. The SVR rate of 78% among treatment-naive patients with the IL28B CC genotype receiving peginterferon/ribavirin alone is reasonably consistent with what has been observed in other studies, although somewhat higher than the rate observed in the large IDEAL analysis by Thompson and colleagues,[10] possibly due to the small sample size. The results showed that treatment-naive patients with the IL28B CC genotype did not derive substantial benefit from the addition of boceprevir to standard peginterferon/ribavirin, yet treatment-naive patients with the CT or TT genotype did derive a substantial benefit. This pattern was markedly different from that observed among patients with previous treatment failure where the addition of boceprevir improved SVR rates regardless of IL28B genotype.
Stefan Zeuzem, MD:
Regarding the limitations imparted by retrospectively assessing IL28B genotype, it is also possible that the results may be biased because patients who were lost to follow-up could not be queried for consent. As a result, the analysis may include a slight selection bias toward compliant patients and potentially toward patients with SVR. Future studies that include IL28B genotyping as an enrollment criterion will be much more informative.
Paul Y. Kwo, MD:
That is a legitimate question to ask in a country with limited resources because SVR rates are high with peginterferon/ribavirin alone among treatment-naive patients with the CC genotype. However, it is important to consider that patients with the CC genotype are much more likely to be able to undergo a shorter treatment duration if a DAA agent such as boceprevir is included in the regimen. In the current study, 89% of treatment-naive patients and 82% of treatment-experienced patients with the IL28B CC genotype were eligible for short-duration therapy with boceprevir plus peginterferon/ribavirin. That is a very encouraging take-home message from this presentation. Although it would be preferable not to withhold boceprevir, in a country where treatment is truly limited because of constrained resources, it would not appear to be an unreasonable strategy if the DAA agent is unaffordable. In regions such as Asia, where SVR rates are already very high due to the high prevalence of the IL28B CC genotype, it may be difficult to improve SVR rates further and if resources are limited, continuing to treat with peginterferon/ribavirin alone might be a strategy that is cost effective. It depends on the prevalence of the CC genotype.
Paul Y. Kwo, MD:
The data from the SPRINT-2 and RESPOND-2 analysis do convincingly suggest that knowing that a patient has the IL28B CC genotype will allow us to counsel him or her that there is a high likelihood that they will be receiving shorter-duration therapy.
Paul Y. Kwo, MD:
Regarding the relative predictive value of IL28B genotype and response to the 4-week peginterferon/ribavirin lead-in, IL28B genotype was no longer a significant predictor of SVR when the lead-in response was included in the analysis. That result is not surprising because IL28B genotype predicts peginterferon/ribavirin sensitivity; it is not perfect, but it is the first genetic tool in the era of personalized medicine that has allowed the prediction of a patient’s ability to clear HCV quickly during peginterferon/ribavirin-based therapy. The 4-week peginterferon/ribavirin lead-in, however, provides a real-time assessment of a patient’s peginterferon/ribavirin responsiveness, and therefore, it is not surprising that the impact of IL28B genotype is no longer evident when response to the 4-week lead-in is considered.
Graham R. Foster, FRCP, PhD:
In a retrospective, exploratory subanalysis of the REALIZE study, Pol and colleagues[3] evaluated the relationship between IL28B genotype and SVR among patients infected with genotype 1 HCV who received telaprevir-based triple therapy following previous peginterferon/ribavirin treatment failure (Capsule Summary). As discussed previously, the REALIZE study enrolled treatment-experienced patients with previous relapse, partial response, or null response to peginterferon/ribavirin therapy.[1] Patients were randomized to 2 treatment arms involving 12 weeks of triple therapy with telaprevir plus peginterferon/ribavirin with or without a lead-in phase of peginterferon/ribavirin followed by 32-36 weeks of peginterferon/ribavirin (arms pooled for current analysis) or to a third arm of 48 weeks of peginterferon/ribavirin alone. As expected, SVR rates were higher among patients with IL28B CC vs CT or TT genotype in the peginterferon/ribavirin arm (29% vs 13% to 16%). In the telaprevir-based arms, SVR rates were high across all IL28B genotypes (CC: 79%; CT: 60%; TT: 61%), and although the rates were numerically higher with the IL28B CC genotype relative to non-CC genotypes, IL28B genotype was not significantly associated with SVR in a 2-step multivariate analysis (CC: P = .169; TT: P = .792). Within previous response subgroups, SVR rates with telaprevir-based therapy were also similar across IL28B genotypes. Among this subgroup of REALIZE participants for whom IL28B genotype data were available, previous relapsers experienced the highest SVR rates to telaprevir-based therapy (85% to 88%) relative to previous partial responders (58% to 71%) and previous null responders (29% to 40%), who had the lowest SVR rates.
In my opinion, the clinical take-home message from this study is that in patients with previous peginterferon/ribavirin treatment failure who are considering a telaprevir-based regimen, there is little to be gained by assessing the IL28B genotype because its ability to predict the likelihood of response is relatively muted with telaprevir. Thus, I would not recommend ordering an IL28B genotype in our case patient. There may be individual patients whose decision whether to undergo retreatment might differ based on a 60% vs 80% likelihood of achieving SVR, but I suspect that with such high SVR rates, the majority of patients in the more favorable previous response categories (ie, previous relapsers or partial responders) would want to undergo retreatment rather than base the decision on their IL28B genotype.
Paul Y. Kwo, MD:
I agree completely with Dr. Foster. When patients come to the clinic after failing peginterferon/ribavirin therapy with good viral kinetic history and want to know their IL28B genotype, I tell them that there is little value in obtaining this information because we already know that they responded poorly to peginterferon/ribavirin. Therefore, if they previously experienced a < 2 log10 IU/mL HCV RNA decrease, it is irrelevant whether they have a favorable or unfavorable IL28B genotype because their clinical interferon response phenotype is poor.
The analysis is strengthened by the high proportion of participants who consented to genetic testing, which provides confidence that these data are valid.
The role of IL28B in predicting SVR to telaprevir-based therapy among treatment-naive patients infected with genotype 1 HCV was also reported at the EASL 2011 meeting in a retrospective analysis of the ADVANCE trial conducted by Jacobson and colleagues.[4] The ADVANCE study was a placebo-controlled phase III trial in which 1088 treatment-naive patients with genotype 1 HCV infection were randomized to the following 3 treatment arms: telaprevir plus peginterferon/ribavirin for 12 weeks followed by peginterferon/ribavirin alone for 12 or 36 weeks; telaprevir plus peginterferon/ribavirin for 8 weeks followed by peginterferon/ribavirin alone for 16 or 40 weeks; or peginterferon/ribavirin for 48 weeks (Capsule Summary).[5] In both telaprevir-containing arms, the duration of treatment with peginterferon/ribavirin after completing triple therapy was determined by whether patients did or did not achieve extended rapid virologic response during triple therapy.
In the current analysis, IL28B genotype was assessed in deidentified samples from patients treated in the ADVANCE trial; as a result of requirements for the deidentification procedure, only samples from white patients were available. Although the analysis is limited by the fact that samples from only 42% of the ADVANCE population were available for IL28B determination and only white patients were included, the results showed that the addition of telaprevir to peginterferon/ribavirin increased SVR rates across all IL28B genotypes, with the largest increases observed among patients with the IL28B CT or TT genotype. The SVR rates among patients with the CC genotype were 90% with 12 weeks of telaprevir-based therapy, 84% with 8 weeks of telaprevir-based therapy, and 64% with peginterferon/ribavirin alone. Among patients with the CT genotype, SVR rates were 71% with 12 weeks of telaprevir-based therapy, 57% with 8 weeks of telaprevir-based therapy, and 25% with peginterferon/ribavirin alone. Finally, for patients with the TT genotype, SVR rates were 73% with 12 weeks of telaprevir-based therapy, 59% with 8 weeks of telaprevir-based therapy, and 23% with peginterferon/ribavirin alone. However, as noted previously, these results should be interpreted with great caution as they are based on a very limited dataset. For example, the SVR rate among all white patients treated in the peginterferon/ribavirin control arm of the ADVANCE study was 46%; however, the SVR rate was only 38% among the subset of white patients in this arm with IL28B data available.
In a retrospective, exploratory subanalysis of the REALIZE study, Pol and colleagues[3] evaluated the relationship between IL28B genotype and SVR among patients infected with genotype 1 HCV who received telaprevir-based triple therapy following previous peginterferon/ribavirin treatment failure (Capsule Summary). As discussed previously, the REALIZE study enrolled treatment-experienced patients with previous relapse, partial response, or null response to peginterferon/ribavirin therapy.[1] Patients were randomized to 2 treatment arms involving 12 weeks of triple therapy with telaprevir plus peginterferon/ribavirin with or without a lead-in phase of peginterferon/ribavirin followed by 32-36 weeks of peginterferon/ribavirin (arms pooled for current analysis) or to a third arm of 48 weeks of peginterferon/ribavirin alone. As expected, SVR rates were higher among patients with IL28B CC vs CT or TT genotype in the peginterferon/ribavirin arm (29% vs 13% to 16%). In the telaprevir-based arms, SVR rates were high across all IL28B genotypes (CC: 79%; CT: 60%; TT: 61%), and although the rates were numerically higher with the IL28B CC genotype relative to non-CC genotypes, IL28B genotype was not significantly associated with SVR in a 2-step multivariate analysis (CC: P = .169; TT: P = .792). Within previous response subgroups, SVR rates with telaprevir-based therapy were also similar across IL28B genotypes. Among this subgroup of REALIZE participants for whom IL28B genotype data were available, previous relapsers experienced the highest SVR rates to telaprevir-based therapy (85% to 88%) relative to previous partial responders (58% to 71%) and previous null responders (29% to 40%), who had the lowest SVR rates.
In my opinion, the clinical take-home message from this study is that in patients with previous peginterferon/ribavirin treatment failure who are considering a telaprevir-based regimen, there is little to be gained by assessing the IL28B genotype because its ability to predict the likelihood of response is relatively muted with telaprevir. Thus, I would not recommend ordering an IL28B genotype in our case patient. There may be individual patients whose decision whether to undergo retreatment might differ based on a 60% vs 80% likelihood of achieving SVR, but I suspect that with such high SVR rates, the majority of patients in the more favorable previous response categories (ie, previous relapsers or partial responders) would want to undergo retreatment rather than base the decision on their IL28B genotype.
Paul Y. Kwo, MD:
I agree completely with Dr. Foster. When patients come to the clinic after failing peginterferon/ribavirin therapy with good viral kinetic history and want to know their IL28B genotype, I tell them that there is little value in obtaining this information because we already know that they responded poorly to peginterferon/ribavirin. Therefore, if they previously experienced a < 2 log10 IU/mL HCV RNA decrease, it is irrelevant whether they have a favorable or unfavorable IL28B genotype because their clinical interferon response phenotype is poor.
The analysis is strengthened by the high proportion of participants who consented to genetic testing, which provides confidence that these data are valid.
The role of IL28B in predicting SVR to telaprevir-based therapy among treatment-naive patients infected with genotype 1 HCV was also reported at the EASL 2011 meeting in a retrospective analysis of the ADVANCE trial conducted by Jacobson and colleagues.[4] The ADVANCE study was a placebo-controlled phase III trial in which 1088 treatment-naive patients with genotype 1 HCV infection were randomized to the following 3 treatment arms: telaprevir plus peginterferon/ribavirin for 12 weeks followed by peginterferon/ribavirin alone for 12 or 36 weeks; telaprevir plus peginterferon/ribavirin for 8 weeks followed by peginterferon/ribavirin alone for 16 or 40 weeks; or peginterferon/ribavirin for 48 weeks (Capsule Summary).[5] In both telaprevir-containing arms, the duration of treatment with peginterferon/ribavirin after completing triple therapy was determined by whether patients did or did not achieve extended rapid virologic response during triple therapy.
In the current analysis, IL28B genotype was assessed in deidentified samples from patients treated in the ADVANCE trial; as a result of requirements for the deidentification procedure, only samples from white patients were available. Although the analysis is limited by the fact that samples from only 42% of the ADVANCE population were available for IL28B determination and only white patients were included, the results showed that the addition of telaprevir to peginterferon/ribavirin increased SVR rates across all IL28B genotypes, with the largest increases observed among patients with the IL28B CT or TT genotype. The SVR rates among patients with the CC genotype were 90% with 12 weeks of telaprevir-based therapy, 84% with 8 weeks of telaprevir-based therapy, and 64% with peginterferon/ribavirin alone. Among patients with the CT genotype, SVR rates were 71% with 12 weeks of telaprevir-based therapy, 57% with 8 weeks of telaprevir-based therapy, and 25% with peginterferon/ribavirin alone. Finally, for patients with the TT genotype, SVR rates were 73% with 12 weeks of telaprevir-based therapy, 59% with 8 weeks of telaprevir-based therapy, and 23% with peginterferon/ribavirin alone. However, as noted previously, these results should be interpreted with great caution as they are based on a very limited dataset. For example, the SVR rate among all white patients treated in the peginterferon/ribavirin control arm of the ADVANCE study was 46%; however, the SVR rate was only 38% among the subset of white patients in this arm with IL28B data available.
good point about the resistance clock running while waiting, up to a couple of weeks, for the w4 PCR to come in. This can be avoided by having a w2 test and, if this doesn't look on target, arranging a quick turn around w4. For those counting on quad therapy that includes Vic/Inci in case triple doesn't deliver, the sooner you stop the PI the less resistance selection you'll have to overcome in the future.
I also think we should be cutting our Drs some slack in making these decisions. How the h*ll are the poor guys supposed to predict the unknown? There is scant information available on the impact of resistance selection and none on triple re-tx. Asking them to roll the dice for us doesn't increase our odds of winning.
I also think we should be cutting our Drs some slack in making these decisions. How the h*ll are the poor guys supposed to predict the unknown? There is scant information available on the impact of resistance selection and none on triple re-tx. Asking them to roll the dice for us doesn't increase our odds of winning.
i went back and looked at the total number of subjects that had the il28 test in study 108 and also received 12 weeks of telaprevir. the number was 140 so there may not be a significant difference between the three il28 genotypes. for all three genotypes combined the SVR was 78%.
dointime - thank you for your informative posts. so if someone is tt they might be better off with the study curiouslady is considering? and if cc curiouslady might be better served by triple therapy with teleprevir?
in study 108 the 12 week telaprevir study found that with the least favorable genotype, tt, 73% achieved SVR and in the most favorable genotype, cc, 90% got to svr.
personally i would let the biopsy tell me what to do. if i had little or no scarring i might take a chance on the study, assuming i really wanted to treat soon. if i were a 3 or 4 i would take the bird in the hand any day.
blessings
eric
in study 108 the 12 week telaprevir study found that with the least favorable genotype, tt, 73% achieved SVR and in the most favorable genotype, cc, 90% got to svr.
personally i would let the biopsy tell me what to do. if i had little or no scarring i might take a chance on the study, assuming i really wanted to treat soon. if i were a 3 or 4 i would take the bird in the hand any day.
blessings
eric
Wow. Thanks for the suggestion about the added test. I didn't know there was anything beyond finding out about the genotype. I will ask about the IL28B. Of course, it probably cost an arm and a leg if it is new and may not be considered standard with insurers.
You could possibly make a more informed decision if you got an IL28B test. Your likely ifn response is relevant to this decision.
Good luck
dointime
Good luck
dointime
I see, haven't really kept up with the most recent polymerase trials. There is no doubt in my mind future treatment will not include interferon and it may be so refined that ribavirin is no longer required either. In this phase of the polymerase trials that exclude interferon it's a matter of risk vs reward and that's a tough call.
There is no interferon on Pharmasset and the Riba is for 24 weeks if that is the arm you get randomized to. It is the Polymerase agents that are emphasized.
12 weeks only of daily Incivek - RVR = 6 mo. total treatment time.
You will have side effects with the PI's recently released or the Pharmasset trial drugs but with Incivek it is stopped after 12 weeks regardless. An option might be a 4 week lead in with SOC and add either Victrelis or Incivek according to SOC response. In my opinion a bird in the hand (Victrelis or Incivek) is worth two in the bush.
You will be effected by the drugs regardless of what drugs you choose and there is no way to gauge the degree it will effect you until you take the plunge. You might be able to schedule throw up time but you can't schedule fatigue or anemia or the myriad of other side effects that can happen. If you commit to treatment you take what comes a day at a time and the primary focus is beating the virus. Lifestyle changes may be necessary when trying to achieve that and if you absolutely cannot be flexible maybe it isn't a good time to treat now.
You will have side effects with the PI's recently released or the Pharmasset trial drugs but with Incivek it is stopped after 12 weeks regardless. An option might be a 4 week lead in with SOC and add either Victrelis or Incivek according to SOC response. In my opinion a bird in the hand (Victrelis or Incivek) is worth two in the bush.
You will be effected by the drugs regardless of what drugs you choose and there is no way to gauge the degree it will effect you until you take the plunge. You might be able to schedule throw up time but you can't schedule fatigue or anemia or the myriad of other side effects that can happen. If you commit to treatment you take what comes a day at a time and the primary focus is beating the virus. Lifestyle changes may be necessary when trying to achieve that and if you absolutely cannot be flexible maybe it isn't a good time to treat now.
Thanks Spectda, very sobering.
To all on this thread: Here is my dilemna. I am treatment naive and have the choice of going into a trial (Pharmasset - PSI 7977 +BMS 79002 and Riba) or getting SOC with triple therapy right off the bat.
I must continue to work at a job which requires maximum alertness but is home based. Little or no family support. I cannot be taking time off but my morns are free for vomiting. Research is being conducted at a major University hospital. I am genotype 1a, blood tests normal with FLD. I am over 60. Signs look good for no cirrohsis but biopsy will tell the story.
The trial is randomly assigned but open. The relevant arms are PSI 7977 add BMS after 7 days and both for 6 months; PSI 7977 and BMS for 6 months; PSI+BMS+Riba 1000mg for 6 months. Once assigned you cannot switch.
The director of hepatology says they like that study. There is no control arm so everyone gets meds. But if I don't clear in one arm or if I have severe sides, I cannot then be reassigned to another.
They will give me SOC if I fail (he is unconcerned about resistence).
Which would you pick if you were in my shoes all things considered?
To all on this thread: Here is my dilemna. I am treatment naive and have the choice of going into a trial (Pharmasset - PSI 7977 +BMS 79002 and Riba) or getting SOC with triple therapy right off the bat.
I must continue to work at a job which requires maximum alertness but is home based. Little or no family support. I cannot be taking time off but my morns are free for vomiting. Research is being conducted at a major University hospital. I am genotype 1a, blood tests normal with FLD. I am over 60. Signs look good for no cirrohsis but biopsy will tell the story.
The trial is randomly assigned but open. The relevant arms are PSI 7977 add BMS after 7 days and both for 6 months; PSI 7977 and BMS for 6 months; PSI+BMS+Riba 1000mg for 6 months. Once assigned you cannot switch.
The director of hepatology says they like that study. There is no control arm so everyone gets meds. But if I don't clear in one arm or if I have severe sides, I cannot then be reassigned to another.
They will give me SOC if I fail (he is unconcerned about resistence).
Which would you pick if you were in my shoes all things considered?
My last three biopsies
diagnosed 1998 and stopped drinking (didn't drink heavily prior)
1rst tx 2010
1999-stage 0 (about 20 years after infection)
2004-stage 0 (about 25 years after infection)
2010-stage 2/3 (very close to bridging) (about 31 years after infection)
diagnosed 1998 and stopped drinking (didn't drink heavily prior)
1rst tx 2010
1999-stage 0 (about 20 years after infection)
2004-stage 0 (about 25 years after infection)
2010-stage 2/3 (very close to bridging) (about 31 years after infection)
Fibrosis progression is not linear. It is certainly good news that you had little progression over five years, but that does not mean that you definitely won't progress over the next 5 years. There are many variables such as age and lifestyle, just to mention a couple.
I wonder if I should even get another biopsy. Last one was 2005. There won't be any treatments for me due to autoimmune problems. I believe docs can see if you have cirrhosis based on blood tests? My ALT AST PT PTT Fibrinogen, GGT ALK Platelets, Albumin are normal. I have a high VL. What do you think?
I have been weighing the need for a biopsy and do appreciate the advise on this. The reasons I had tentatively decided to hold off on a biopsy are as follows:
-liver biopsies in 2000 and again in 2005 were both stage 1 indicating slow progressive disease (according to hep doc).
-my liver panel, and platelets are always in normal range (APRI 0.3 = likely minimal fibrosis)
-Recent abdominal CT showed mild hepatosplenomegaly (common with chronic viral infections), but it didn't show any liver fibrosis (although they weren't looking for fibrosis specifically).
-My hepatologist won't do a biopsy because they are not going to tx me having been a null responder with SOC in 2005. They may only be treating the null responders who are now at stage 4. They seem very concerned about the resistance issue. Anyhow, they don't think I have progressed at all, and they are basing that on the above information, and palpation. Of course I could, and very well may get a biopsy elsewhere. It's my out of state internist who wants to do the Tx.
-I don't care to have another needle run through my liver unless absolutely necessary. I think it can cause scaring as well. I also know that the biopsy, although the most accurate of all tests, can be invalid.
In spite of the reasons for passing on a biopsy at this time, the reasons for having it done are quite obvious as well....if I'm over stage 2, I should have my out of state internist do the Tx even though I am a previous null responder with SOC....maybe. I'm still not sure on this, and this is why I am appreciating the feedback.
-liver biopsies in 2000 and again in 2005 were both stage 1 indicating slow progressive disease (according to hep doc).
-my liver panel, and platelets are always in normal range (APRI 0.3 = likely minimal fibrosis)
-Recent abdominal CT showed mild hepatosplenomegaly (common with chronic viral infections), but it didn't show any liver fibrosis (although they weren't looking for fibrosis specifically).
-My hepatologist won't do a biopsy because they are not going to tx me having been a null responder with SOC in 2005. They may only be treating the null responders who are now at stage 4. They seem very concerned about the resistance issue. Anyhow, they don't think I have progressed at all, and they are basing that on the above information, and palpation. Of course I could, and very well may get a biopsy elsewhere. It's my out of state internist who wants to do the Tx.
-I don't care to have another needle run through my liver unless absolutely necessary. I think it can cause scaring as well. I also know that the biopsy, although the most accurate of all tests, can be invalid.
In spite of the reasons for passing on a biopsy at this time, the reasons for having it done are quite obvious as well....if I'm over stage 2, I should have my out of state internist do the Tx even though I am a previous null responder with SOC....maybe. I'm still not sure on this, and this is why I am appreciating the feedback.
I think that it is invalid to compare the SOC timing with the triple therapy timing for stopping. If we are talking about telaprevir for example, it is just so much faster at cutting down the wild type virus, so it is not reasonable to have the same expectations as for SOC.
So if somebody has a viral load of >1000IU/mil at week 4 with the triple then that has a different implication for the success of the tx than if the tx were SOC alone. What I think is missing in the recommended triple tx regime are PCR's at week1, 2, and 3. It is quite possible to become UND in the first 4 weeks and already be having a breakthrough by the week4 PCR. That is what happened to me. In that case you would know that your viral population consists of a majority of selected out resistant mutations which are on the rise despite the presence of SOC. That would be valid grounds for stopping.
" The thing is, you have no idea if the virons that are left are resistant virons or wild type. None. They don't know and they don't want to take the chance, I presume."
I think that they do know from the monotherapy trials of VX950 that virions left by week 4 are mostly resistant mutations. What is perhaps hard to appreciate when we are used to SOC is just how very fast a drug like telaprevir works. It just decimates the wild type virus in a matter of days. So before you are even near the 4 week mark the only question left to be answered is whether SOC and your ifn response can effectively do the mopping up of the resistant mutations. If you are still >1000 at 4 weeks then the answer to that is probably no. However if somebody wanted to hang in there and bet on SOC finishing the job then that's a debatable choice much like for SOC at the 12 week mark. It just comes so much faster because adding the PI to the mix is like adding nitro.
dointime
So if somebody has a viral load of >1000IU/mil at week 4 with the triple then that has a different implication for the success of the tx than if the tx were SOC alone. What I think is missing in the recommended triple tx regime are PCR's at week1, 2, and 3. It is quite possible to become UND in the first 4 weeks and already be having a breakthrough by the week4 PCR. That is what happened to me. In that case you would know that your viral population consists of a majority of selected out resistant mutations which are on the rise despite the presence of SOC. That would be valid grounds for stopping.
" The thing is, you have no idea if the virons that are left are resistant virons or wild type. None. They don't know and they don't want to take the chance, I presume."
I think that they do know from the monotherapy trials of VX950 that virions left by week 4 are mostly resistant mutations. What is perhaps hard to appreciate when we are used to SOC is just how very fast a drug like telaprevir works. It just decimates the wild type virus in a matter of days. So before you are even near the 4 week mark the only question left to be answered is whether SOC and your ifn response can effectively do the mopping up of the resistant mutations. If you are still >1000 at 4 weeks then the answer to that is probably no. However if somebody wanted to hang in there and bet on SOC finishing the job then that's a debatable choice much like for SOC at the 12 week mark. It just comes so much faster because adding the PI to the mix is like adding nitro.
dointime
Although they may not be including and providing personal sequencing data in the decision making process to the patients as they should and we all wish they would, my impression is that they are quite clear from trial data that failure with triple tx is associated with resistant vairants, not wildtype. Maybe I am misinterpreting the information but this is what I understood.
Personally I believe that the 1000 iu/ml threshold after 4 weeks of a pi is quite liberal and in the absence of personal sequencing information the only exception for continuing would be altering/tayloring treatment as Lynda607 suggested and/or if the patient is out of time because of their disease progression. To me this still all points to using a lead in with all but relapsers.
As other's mentioned, we need qualified specialists to be treating people with these powerful drugs who are able to offer individualized therapy and make these decisions which have much more serious implications then with soc alone. We don't have PCPs prescribing chemo to my knowledge, why are they treating people in the first place?
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM252562.pdf
"In a regimen of telaprevir, Peg-IFN, and RBV, the primary role of telaprevir is to inhibit wild-type virus and variants with lower-levels of resistance to telaprevir. The primary and complementary role of Peg-IFN and RBV is to clear any remaining telaprevir-resistant variants.
Clinical virology results from clinical studies of telaprevir in combination with Peg-IFN and RBV have shown a clear and consistent resistance profile across HCV genotype 1 patient populations (treatment-naive and prior Peg-IFN/RBV treatment-failure). Sequence analyses in patients not achieving an SVR with a telaprevir-based regimen consistently identified amino acid substitutions at 4 positions in the NS3•4A protease region that were associated with decreased sensitivity to telaprevir, consistent with the mechanism of action for telaprevir: V36A/M, T54A/S, R155K/T, A156S/T/V, and V36M+R155K. Phenotypic characterization of these HCV NS3 variants determined that lower-level resistance to telaprevir (3- to 25-fold decrease in IC50 to telaprevir in a replicon-based assay) was conferred by V36A/M, T54A/S, R155K/T, and A156S, and higher-level resistance to telaprevir (>25-fold decrease in replicon IC50) was conferred by A156T/V and V36M+R155K. Telaprevir-resistant variants are less fit than wild-type virus and are sensitive to Peg-IFN, RBV, and polymerase inhibitors in vitro.
Predominant baseline resistance to telaprevir is rare (< 1% to 2.7%) and does not necessarily preclude achieving an SVR with a T/PR regimen. On-treatment virologic failure during telaprevir treatment is associated with higher-level telaprevir-resistant variants, and occurs more frequently in genotype 1a compared to 1b. On-treatment virologic failure rates on T/PR
Page 5 of 147
Telaprevir NDA 201-917 FDA Advisory Committee Briefing Document Vertex Pharmaceuticals
are low in treatment-naive patients, and prior relapser patients, but are higher for prior nonresponders patients. Relapse is generally associated with wild-type or lower-level resistant variants. Overall, TVR-resistant variants were observed in 12% of treatment-naïve patients (Study 108; T12/PR arm) and 22% of treatment-experienced patients, after therapy with a telaprevir-containing regimen. Resistant variants were observed in the majority of subjects who did not achieve an SVR. Resistant variants tend to be replaced by wild-type virus over time in the absence of telaprevir selective pressure."
Personally I believe that the 1000 iu/ml threshold after 4 weeks of a pi is quite liberal and in the absence of personal sequencing information the only exception for continuing would be altering/tayloring treatment as Lynda607 suggested and/or if the patient is out of time because of their disease progression. To me this still all points to using a lead in with all but relapsers.
As other's mentioned, we need qualified specialists to be treating people with these powerful drugs who are able to offer individualized therapy and make these decisions which have much more serious implications then with soc alone. We don't have PCPs prescribing chemo to my knowledge, why are they treating people in the first place?
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM252562.pdf
"In a regimen of telaprevir, Peg-IFN, and RBV, the primary role of telaprevir is to inhibit wild-type virus and variants with lower-levels of resistance to telaprevir. The primary and complementary role of Peg-IFN and RBV is to clear any remaining telaprevir-resistant variants.
Clinical virology results from clinical studies of telaprevir in combination with Peg-IFN and RBV have shown a clear and consistent resistance profile across HCV genotype 1 patient populations (treatment-naive and prior Peg-IFN/RBV treatment-failure). Sequence analyses in patients not achieving an SVR with a telaprevir-based regimen consistently identified amino acid substitutions at 4 positions in the NS3•4A protease region that were associated with decreased sensitivity to telaprevir, consistent with the mechanism of action for telaprevir: V36A/M, T54A/S, R155K/T, A156S/T/V, and V36M+R155K. Phenotypic characterization of these HCV NS3 variants determined that lower-level resistance to telaprevir (3- to 25-fold decrease in IC50 to telaprevir in a replicon-based assay) was conferred by V36A/M, T54A/S, R155K/T, and A156S, and higher-level resistance to telaprevir (>25-fold decrease in replicon IC50) was conferred by A156T/V and V36M+R155K. Telaprevir-resistant variants are less fit than wild-type virus and are sensitive to Peg-IFN, RBV, and polymerase inhibitors in vitro.
Predominant baseline resistance to telaprevir is rare (< 1% to 2.7%) and does not necessarily preclude achieving an SVR with a T/PR regimen. On-treatment virologic failure during telaprevir treatment is associated with higher-level telaprevir-resistant variants, and occurs more frequently in genotype 1a compared to 1b. On-treatment virologic failure rates on T/PR
Page 5 of 147
Telaprevir NDA 201-917 FDA Advisory Committee Briefing Document Vertex Pharmaceuticals
are low in treatment-naive patients, and prior relapser patients, but are higher for prior nonresponders patients. Relapse is generally associated with wild-type or lower-level resistant variants. Overall, TVR-resistant variants were observed in 12% of treatment-naïve patients (Study 108; T12/PR arm) and 22% of treatment-experienced patients, after therapy with a telaprevir-containing regimen. Resistant variants were observed in the majority of subjects who did not achieve an SVR. Resistant variants tend to be replaced by wild-type virus over time in the absence of telaprevir selective pressure."
http://www.clinicaloptions.com - register with them ( free ) - from there you can select hep hiv oncology - they keep you posted with email updates - sorry i took so long
"That gives the resistant mutations, if there are any, possibly up to 6 weeks to run, not 4 weeks. I'm not sure how much difference that makes but I wanted to highlight the misnomer that the mutations only get 4 weeks to run if there is a discontinuation of tx. "
That's one way to look at it. The other way, I suppose, is that the resistant mutations are not as fit as wild type. So it also potentially gives a little more time for them to be killed off as well. The thing is, you have no idea if the virons that are left are resistant virons or wild type. None. They don't know and they don't want to take the chance, I presume.
The difficulty I have with cutting off at >1000IU/mil , depending how much greater you are, is that under SOC/PR treatment, nobody would stop at that point. You'd keep going aiming for an EVR, as the SVR rates are still quite good for EVR. Best for RVR, but still good for EVR. So my concern with stopping at that point, across the board for anyone with a viral load of >1000IU/mil, is that my personal opinion is that a certain number of those people could have potentially achieved SVR and not have been left with potential resistant virons. Some hepatologists may proceed beyond that on an individual basis but my concern is that a number of GI's will not and will stay strictly with that stopping rule and I'm not even sure where that stopping rule comes from. Anyone?
Trish
That's one way to look at it. The other way, I suppose, is that the resistant mutations are not as fit as wild type. So it also potentially gives a little more time for them to be killed off as well. The thing is, you have no idea if the virons that are left are resistant virons or wild type. None. They don't know and they don't want to take the chance, I presume.
The difficulty I have with cutting off at >1000IU/mil , depending how much greater you are, is that under SOC/PR treatment, nobody would stop at that point. You'd keep going aiming for an EVR, as the SVR rates are still quite good for EVR. Best for RVR, but still good for EVR. So my concern with stopping at that point, across the board for anyone with a viral load of >1000IU/mil, is that my personal opinion is that a certain number of those people could have potentially achieved SVR and not have been left with potential resistant virons. Some hepatologists may proceed beyond that on an individual basis but my concern is that a number of GI's will not and will stay strictly with that stopping rule and I'm not even sure where that stopping rule comes from. Anyone?
Trish
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