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.
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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