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.
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.
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