Aa
Harvoni - Baseline NS5A Resistance
Hi All,
The Gilead ION2 study found that:
"Baseline NS5A RAVs were overrepresented in patients who experienced relapse in the Phase 3 studies"
For those who have done or are currently on 12 weeks Harvoni, excluding a Gilead trial, did anyone get tested for baseline NS5A resistance before starting tx?
If you did, where did you get the test done?
Thanks
dointime
The Gilead ION2 study found that:
"Baseline NS5A RAVs were overrepresented in patients who experienced relapse in the Phase 3 studies"
For those who have done or are currently on 12 weeks Harvoni, excluding a Gilead trial, did anyone get tested for baseline NS5A resistance before starting tx?
If you did, where did you get the test done?
Thanks
dointime
I found this part of the link that you posted, disturbing.
"Recommended regimen for patients in whom previous treatment with any HCV nonstructural protein 5A (NS5A) inhibitors has failed (including daclatasvir plus sofosbuvir, ledipasvir/sofosbuvir, or paritaprevir/ritonavir/ombitasvir plus dasabuvir).
For patients with minimal liver disease, deferral of treatment is recommended, pending availability of data."
You raise the very important issue that some people will have their treatment deferred when RAV testing is introduced. You might well have had NS5A and NS3 RAVs from the Olysio but you still got the chance for retreatment and you were successful. That might change in the future for others in your situation.
Based on these guidelines, if I fail with 12 weeks Harvoni then even with no RAV testing my retreatment would be deferred pending availability of data. I already have NS3 resistance and would end up with NS5A RAVs as well. This would make my future choices of tx limited and currently not foreseeable.
These are sobering thoughts on what the near future holds for people who fail first time with current standard of care that includes an NS5A. Many thanks for posting this link. I will be looking very carefully at my options in the light of this new information.
dointime
"Recommended regimen for patients in whom previous treatment with any HCV nonstructural protein 5A (NS5A) inhibitors has failed (including daclatasvir plus sofosbuvir, ledipasvir/sofosbuvir, or paritaprevir/ritonavir/ombitasvir plus dasabuvir).
For patients with minimal liver disease, deferral of treatment is recommended, pending availability of data."
You raise the very important issue that some people will have their treatment deferred when RAV testing is introduced. You might well have had NS5A and NS3 RAVs from the Olysio but you still got the chance for retreatment and you were successful. That might change in the future for others in your situation.
Based on these guidelines, if I fail with 12 weeks Harvoni then even with no RAV testing my retreatment would be deferred pending availability of data. I already have NS3 resistance and would end up with NS5A RAVs as well. This would make my future choices of tx limited and currently not foreseeable.
These are sobering thoughts on what the near future holds for people who fail first time with current standard of care that includes an NS5A. Many thanks for posting this link. I will be looking very carefully at my options in the light of this new information.
dointime
I read the links and it looks like had I been tested and found to have resistance the current recommendation is pretty much what was done with me can't really blame my doctor these change were just released 8/7
http://www.hcvguidelines.org/node/73#gt1-ns5a
RETREATMENT OF PERSONS IN WHOM PRIOR THERAPY HAS FAILED
"For patients with cirrhosis or other patients who require retreatment urgently, testing for resistance-associated variants that confer decreased susceptibility to NS3 protease inhibitors and to NS5A inhibitors is recommended. The specific drugs used in the retreatment regimen should be tailored to the results of this testing as described below. Treatment duration of 24 weeks is recommended and, unless contraindicated, weight-based RBV should be added"
http://www.hcvguidelines.org/node/73#gt1-ns5a
RETREATMENT OF PERSONS IN WHOM PRIOR THERAPY HAS FAILED
"For patients with cirrhosis or other patients who require retreatment urgently, testing for resistance-associated variants that confer decreased susceptibility to NS3 protease inhibitors and to NS5A inhibitors is recommended. The specific drugs used in the retreatment regimen should be tailored to the results of this testing as described below. Treatment duration of 24 weeks is recommended and, unless contraindicated, weight-based RBV should be added"
With my treatment history being a multiple null responder to interferon /ribavirin, with cirrhosis who relapsed after Sovaldi and Olysio I would not be entirely surprized if I did have a resistance factor possibly NS5A
Yes my doctor did use the argument no point in testing it would not change our treatment protocol.
Had I been tested and was positive for NS5A would they not have treated me?
Or would they treat me as I was treated? With 24 weeks of Harvoni and we later added ribavirin for 15 of those weeks which my doctor felt maybe would have been better to have had the ribavirin from the start.
All I can say is mayhe my odds were 85% but at least I fell on the right time of the stats this time being SVR12 on 7/27/15
Yes my doctor did use the argument no point in testing it would not change our treatment protocol.
Had I been tested and was positive for NS5A would they not have treated me?
Or would they treat me as I was treated? With 24 weeks of Harvoni and we later added ribavirin for 15 of those weeks which my doctor felt maybe would have been better to have had the ribavirin from the start.
All I can say is mayhe my odds were 85% but at least I fell on the right time of the stats this time being SVR12 on 7/27/15
I just found this:
http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/Vienna%202015/Clinical%20Thoughts/CT1.aspx
"The move from interferon-based therapy to direct-acting antiviral (DAA)–agent therapy has introduced a relatively new concept to hepatitis C virus (HCV) therapy and has added another acronym, RAVs (resistance-associated variants), to our treatment lexicon. However, despite advice from our HIV-experienced colleagues, most hepatologists have been reluctant to accept the need for pretreatment-resistance testing.
The biggest argument against pretreatment-resistance testing has been that it will not change clinical management. The very high sustained virologic rates (SVR) achieved in almost all populations treated with ledipasvir/sofosbuvir or ombitasvir/paritaprevir/ritonavir with dasabuvir (plus or minus ribavirin) might suggest that resistance testing is not necessary. However, new data presented at the recent European Association for the Study of the Liver (EASL) meeting in Vienna could suggest otherwise, at least for some patients.
The Impact of Baseline NS5A Inhibitor RAVs
The major issue to consider is NS5A inhibitor RAVs. Unlike the RAVs associated with sofosbuvir and most protease inhibitors (PIs), NS5A inhibitor RAVs tend to be very fit, allowing them to persist long term after failed NS5A inhibitor therapy. Perhaps more importantly, these RAVs occur spontaneously in 15% to 20% of treatment-naive patients with genotype 1 HCV infection and at even higher rates in patients infected with other genotypes. NS5A inhibitors are a component of all approved interferon-free regimens—except the sofosbuvir plus simeprevir regimen—and all regimens in development. The initial claims that baseline NS5A inhibitor resistance is not important are coming under scrutiny as more data emerge.
When an NS5A inhibitor is combined with another DAA having a low barrier to resistance, baseline resistance has a huge effect. For instance, in the HALLMARK DUAL trial, in which patients with genotype 1b HCV infection were treated with daclatasvir (an NS5A inhibitor) and asunaprevir (an NS3 PI), the SVR12 rate fell from 90% in the overall population to just 40% in the 15% of patients who had baseline NS5A inhibitor RAVs.
When NS5A inhibitors are combined with other DAAs having a high barrier to resistance, NS5A inhibitor resistance is less of a concern but remains an issue. In an analysis presented by Christophe Sarrazin at EASL, of the cirrhotic patients treated with ledipasvir/sofosbuvir ± ribavirin in select phase 2/3 trials, only 86% of the 13% of patients with genotype 1a HCV infection having baseline NS5A inhibitor RAVs achieved SVR12; patients with no detectable RAVs achieved a 98% SVR12 rate. This analysis found that the lowered SVR12 rate was attributed primarily to the existence of high-level (> 100-fold) NS5A RAVs among treatment-experienced (but NS5A inhibitor–naive) patients, and the SVR12 rate was only 67% in this subset of patients. Notably, the patients in this study were all cirrhotic; these patients are traditionally harder to cure. Baseline RAVs may only be an issue when the regimens are “stressed,” as with cirrhotic, treatment-experienced patients.
In the C-EDGE TE trial, which was presented at EASL and evaluated treatment-experienced patients who received the second-generation PI/NS5A inhibitor combination of grazoprevir/elbasvir, SVR12 rates fell to 52% in those harboring baseline NS5A variants associated with > 5-fold change in elbasvir susceptibility. With both the ledipasvir/sofosbuvir and grazoprevir/elbasvir combinations, the effects of NS5A inhibitor resistance was largely overcome by extending therapy and/or adding ribavirin. While it is valuable to have potentially simple solutions to overcome baseline RAVs, introducing these strategies requires planning.
Resistance in Patients Who Have Failed DAA Regimens
Data indicate that resistance will be a greater challenge among patients for whom DAA combinations fail to achieve SVR. A small study from EASL evaluated 24 weeks of retreatment with ledipasvir/sofosbuvir among patients for whom 8 or 12 weeks of ledipasvir/sofosbuvir had failed to achieve SVR. In this analysis, retreatment with ledipasvir/sofosbuvir was more likely to fail among patients with baseline NS5A RAVs. In addition, of the 12 patients not achieving SVR with retreatment, 4 were found to have sofosbuvir RAVs, including the S282T variant. The S282T variant is normally so unfit that it cannot replicate to high levels; however, its emergence in this study suggests that unfit variants continue to evolve during treatment, selecting for so-called compensatory mutations that enhance their replication fitness. Perhaps the addition of ribavirin or use of an alternative regimen would have resulted in better SVR rates in this study; again, these scenarios require planning.
My Practice Moving Forward
Extending therapy, adding ribavirin, or choosing alternative regimens for those with baseline RAVs makes sense. The cost of RAV testing is less than the price of 1 pill for most DAAs and certainly much less expensive than overtreating the majority of patients. If this testing will help us to make rational decisions to optimize retreatment strategies or even refine first-line therapy, we should embrace it. Unfortunately, resistance testing is not yet widely available, and there is poor standardization of results reporting with commercially available tests. As a result, although we are doing testing in our research lab to better understand the importance of RAVs, I have not yet been able to introduce it into my clinical practice. Our biggest challenge moving forward is likely to be overcoming the resistance to resistance testing. "
http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/Vienna%202015/Clinical%20Thoughts/CT1.aspx
"The move from interferon-based therapy to direct-acting antiviral (DAA)–agent therapy has introduced a relatively new concept to hepatitis C virus (HCV) therapy and has added another acronym, RAVs (resistance-associated variants), to our treatment lexicon. However, despite advice from our HIV-experienced colleagues, most hepatologists have been reluctant to accept the need for pretreatment-resistance testing.
The biggest argument against pretreatment-resistance testing has been that it will not change clinical management. The very high sustained virologic rates (SVR) achieved in almost all populations treated with ledipasvir/sofosbuvir or ombitasvir/paritaprevir/ritonavir with dasabuvir (plus or minus ribavirin) might suggest that resistance testing is not necessary. However, new data presented at the recent European Association for the Study of the Liver (EASL) meeting in Vienna could suggest otherwise, at least for some patients.
The Impact of Baseline NS5A Inhibitor RAVs
The major issue to consider is NS5A inhibitor RAVs. Unlike the RAVs associated with sofosbuvir and most protease inhibitors (PIs), NS5A inhibitor RAVs tend to be very fit, allowing them to persist long term after failed NS5A inhibitor therapy. Perhaps more importantly, these RAVs occur spontaneously in 15% to 20% of treatment-naive patients with genotype 1 HCV infection and at even higher rates in patients infected with other genotypes. NS5A inhibitors are a component of all approved interferon-free regimens—except the sofosbuvir plus simeprevir regimen—and all regimens in development. The initial claims that baseline NS5A inhibitor resistance is not important are coming under scrutiny as more data emerge.
When an NS5A inhibitor is combined with another DAA having a low barrier to resistance, baseline resistance has a huge effect. For instance, in the HALLMARK DUAL trial, in which patients with genotype 1b HCV infection were treated with daclatasvir (an NS5A inhibitor) and asunaprevir (an NS3 PI), the SVR12 rate fell from 90% in the overall population to just 40% in the 15% of patients who had baseline NS5A inhibitor RAVs.
When NS5A inhibitors are combined with other DAAs having a high barrier to resistance, NS5A inhibitor resistance is less of a concern but remains an issue. In an analysis presented by Christophe Sarrazin at EASL, of the cirrhotic patients treated with ledipasvir/sofosbuvir ± ribavirin in select phase 2/3 trials, only 86% of the 13% of patients with genotype 1a HCV infection having baseline NS5A inhibitor RAVs achieved SVR12; patients with no detectable RAVs achieved a 98% SVR12 rate. This analysis found that the lowered SVR12 rate was attributed primarily to the existence of high-level (> 100-fold) NS5A RAVs among treatment-experienced (but NS5A inhibitor–naive) patients, and the SVR12 rate was only 67% in this subset of patients. Notably, the patients in this study were all cirrhotic; these patients are traditionally harder to cure. Baseline RAVs may only be an issue when the regimens are “stressed,” as with cirrhotic, treatment-experienced patients.
In the C-EDGE TE trial, which was presented at EASL and evaluated treatment-experienced patients who received the second-generation PI/NS5A inhibitor combination of grazoprevir/elbasvir, SVR12 rates fell to 52% in those harboring baseline NS5A variants associated with > 5-fold change in elbasvir susceptibility. With both the ledipasvir/sofosbuvir and grazoprevir/elbasvir combinations, the effects of NS5A inhibitor resistance was largely overcome by extending therapy and/or adding ribavirin. While it is valuable to have potentially simple solutions to overcome baseline RAVs, introducing these strategies requires planning.
Resistance in Patients Who Have Failed DAA Regimens
Data indicate that resistance will be a greater challenge among patients for whom DAA combinations fail to achieve SVR. A small study from EASL evaluated 24 weeks of retreatment with ledipasvir/sofosbuvir among patients for whom 8 or 12 weeks of ledipasvir/sofosbuvir had failed to achieve SVR. In this analysis, retreatment with ledipasvir/sofosbuvir was more likely to fail among patients with baseline NS5A RAVs. In addition, of the 12 patients not achieving SVR with retreatment, 4 were found to have sofosbuvir RAVs, including the S282T variant. The S282T variant is normally so unfit that it cannot replicate to high levels; however, its emergence in this study suggests that unfit variants continue to evolve during treatment, selecting for so-called compensatory mutations that enhance their replication fitness. Perhaps the addition of ribavirin or use of an alternative regimen would have resulted in better SVR rates in this study; again, these scenarios require planning.
My Practice Moving Forward
Extending therapy, adding ribavirin, or choosing alternative regimens for those with baseline RAVs makes sense. The cost of RAV testing is less than the price of 1 pill for most DAAs and certainly much less expensive than overtreating the majority of patients. If this testing will help us to make rational decisions to optimize retreatment strategies or even refine first-line therapy, we should embrace it. Unfortunately, resistance testing is not yet widely available, and there is poor standardization of results reporting with commercially available tests. As a result, although we are doing testing in our research lab to better understand the importance of RAVs, I have not yet been able to introduce it into my clinical practice. Our biggest challenge moving forward is likely to be overcoming the resistance to resistance testing. "
Well ok I stand corrected lol
I was an interferon Ribavirin failure with cirrhosis and was not tested prior to treating with Sovaldi Olysio but then again it was my only option for treatment in Spring of 2014 and I needed to treat.
But as now there are more options it makes sense to check for Q80K as that effects treatment choice.
Before I treated with Sovaldi Olysio I had not treated with an NS5A. This year when I treated with Harvoni I now was prior treated with an NS5A, Olysio, but again no other option existed for me except not to treat at all so testing would be at least in my case a moot point or a reason to deny me any treatment.
I was an interferon Ribavirin failure with cirrhosis and was not tested prior to treating with Sovaldi Olysio but then again it was my only option for treatment in Spring of 2014 and I needed to treat.
But as now there are more options it makes sense to check for Q80K as that effects treatment choice.
Before I treated with Sovaldi Olysio I had not treated with an NS5A. This year when I treated with Harvoni I now was prior treated with an NS5A, Olysio, but again no other option existed for me except not to treat at all so testing would be at least in my case a moot point or a reason to deny me any treatment.
Great answer Jimmy, thanks for posting. Brings much needed clarity to the situation, whether I agree with the guidelines or not.
dointime
dointime
FYI
http://www.hcvguidelines.org/full-report/monitoring-patients-who-are-starting-hepatitis-c-treatment-are-treatment-or-have
Accessed August 8, 2015
red box only go to link to read changes made on this section on August 7, 2015. in yellow including below the box for more details
"The following monitoring is NOT routinely recommended prior to or during therapy.
Routine monitoring for HCV drug resistance–associated variants during therapy is NOT recommended, with 2 exceptions:
For patients with HCV genotype 1 infection whose prior treatment with a nonstructural protein 5A (NS5A) inhibitor–containing regimen failed and who have cirrhosis or require urgent retreatment, pretreatment testing for resistance-associated variants that confer decreased susceptibility to NS3 protease inhibitors and to NS5A inhibitors is recommended (for further details, see Retreatment section)
For patients with HCV genotype 1a infection with cirrhosis who are treatment naive or whose prior treatment with PEG-IFN and RBV failed and who are being considered for treatment with simeprevir and sofosbuvir, pretreatment testing for the Q80K NS3 variant is recommended (for further details, see Initial Treatment or Retreatment sections)
Rating: Class IIb, Level C
http://www.hcvguidelines.org/full-report/monitoring-patients-who-are-starting-hepatitis-c-treatment-are-treatment-or-have
Accessed August 8, 2015
red box only go to link to read changes made on this section on August 7, 2015. in yellow including below the box for more details
"The following monitoring is NOT routinely recommended prior to or during therapy.
Routine monitoring for HCV drug resistance–associated variants during therapy is NOT recommended, with 2 exceptions:
For patients with HCV genotype 1 infection whose prior treatment with a nonstructural protein 5A (NS5A) inhibitor–containing regimen failed and who have cirrhosis or require urgent retreatment, pretreatment testing for resistance-associated variants that confer decreased susceptibility to NS3 protease inhibitors and to NS5A inhibitors is recommended (for further details, see Retreatment section)
For patients with HCV genotype 1a infection with cirrhosis who are treatment naive or whose prior treatment with PEG-IFN and RBV failed and who are being considered for treatment with simeprevir and sofosbuvir, pretreatment testing for the Q80K NS3 variant is recommended (for further details, see Initial Treatment or Retreatment sections)
Rating: Class IIb, Level C
Hi Lynn,
Many thanks for your info.
Given the lack of response to my question I think you are right, it is only done by clinical trial. That is what I needed to know.
Congratulations on your SVR. You went through a lot to get there. The virus doesn't make it easy for many of us,
best wishes,
dointime
Many thanks for your info.
Given the lack of response to my question I think you are right, it is only done by clinical trial. That is what I needed to know.
Congratulations on your SVR. You went through a lot to get there. The virus doesn't make it easy for many of us,
best wishes,
dointime
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