Aa
Holkira Pak failure?
Hello there
Just wanted to know which meds or treatment the group would consider as best overall effective treatment for hep c genotype 1a, compensated cirrhosis, (previous null responder to interferon and ribaviron)
Just wanted to know which meds or treatment the group would consider as best overall effective treatment for hep c genotype 1a, compensated cirrhosis, (previous null responder to interferon and ribaviron)
Here is one more, it won't copy and paste so follow the link and scroll down to the article titled "What the heck are RAV's", it is about half way down the page.
http://hcvadvocate.org/news/NewsUpdates_pdf/Advocate_2015/advocate1015.pdf#WhatAreRAVs
http://hcvadvocate.org/news/NewsUpdates_pdf/Advocate_2015/advocate1015.pdf#WhatAreRAVs
forgot the link
http://www.clinicaloptions.com/Hepatitis/Treatment%20Updates/HCV%20Resistance%20Alert/Clinical%20Thoughts/CT1.aspx
http://www.clinicaloptions.com/Hepatitis/Treatment%20Updates/HCV%20Resistance%20Alert/Clinical%20Thoughts/CT1.aspx
How I Use Resistance Testing to Guide Management of Patients With Chronic Hepatitis
Mark S. Sulkowski, MD - 9/15/2015
Recently, I have begun to hear many questions from colleagues and trainees regarding the use of resistance testing in the management of HCV-infected patients. To be honest, my answers to their questions are not always straightforward, as this is a rapidly evolving area of discussion in the field and I am confident that my opinion will evolve along with the data.
When Resistance Testing Is Recommended
That said, the AASLD/IDSA guidance has now highlighted at least one patient population for whom resistance testing with commercially available assays can be used to guide treatment decisions: Persons for whom treatment is urgent and previous treatment with NS5A inhibitors has failed to achieve cure. This would include previous exposure to such regimens as ledipasvir/sofosbuvir, ombitasvir/paritaprevir/ritonavir plus dasabuvir, and daclatasvir plus sofosbuvir. We know from follow-up data of patients treated in clinical trials that resistance associated variants (RAVs) against any of the available DAAs are likely to be detected upon on-treatment virologic breakthrough or posttreatment relapse with the exception of the nucleotide analogue NS5B inhibitor sofosbuvir. More importantly, we know that variants that are associated with resistance to NS5A inhibitors, including ledipasvir, ombitasvir, and daclatasvir, are likely to be stable and detectable for as long as 2 years after treatment.
Based on these data, updated AASLD/IDSA guidance recommends that, if treatment is urgent, patients who are not cured after receiving an NS5A inhibitor should undergo testing for the presence of resistance associated variants in the NS5A region and NS3 region (selected by protease inhibitors which target NS3, such as paritaprevir and simeprevir). Per the guidance, such patients who have no NS5A RAVs can be treated with 24 weeks of ledipasvir/sofosbuvir and ribavirin, those with NS5A RAVs but no NS3 RAVs can be treated with 24 weeks of simeprevir plus sofosbuvir and ribavirin, and those with both RAVs should be treated in clinical trial settings only.
The utility of testing for RAVs in the NS5B polymerase region is much less clear. Resistance to nucleotide analogues that target the NS5B active site (ie, sofosbuvir) is rare, and data indicate that retreatment with sofosbuvir-containing regimens is feasible in patients for whom a previous sofosbuvir-containing treatment has failed. Given the rarity of resistance to the NS5B active site, resistance testing is not routinely recommended. Currently, dasabuvir is the only other NS5B inhibitor available; however, it is a nonnucleoside inhibitor that targets domains of the NS5B polymerase distinct from sofosbuvir. Dasabuvir is used only with the NS5A inhibitor ombitasvir and the protease inhibitor paritaprevir, against which RAVs are more common. Thus, the results of NS5B inhibitor resistance testing would be unlikely to change the treatment decision.
Utilizing Resistance Testing in Practice: A Case Example
Of course, recommendations are only helpful if they can be applied to the care of real patients in clinical practice. A recent patient from my clinic is one such example. The case patient was a 54-year-old man with genotype 1a HCV infection and compensated cirrhosis who had a null response to treatment with peginterferon/ribavirin years before the availability of DAAs. He was subsequently treated with ledipasvir/sofosbuvir and ribavirin for 12 weeks and had an outstanding initial drop in HCV RNA. However, he unfortunately experienced relapse after stopping therapy. HCV drug resistance testing revealed a mutation in the NS5A region at position 93 (Y93H) that confers decreased susceptibility to ledipasvir (and ombitasvir and daclatasvir). However, testing of the NS3 protease domain revealed no Q80K mutation, suggesting that simeprevir would be active in this patient.
Case Treatment Decision
Based on the presence of an NS5A RAV but absence of NS3 RAVs, we elected to retreat this patient with sofosbuvir and simeprevir plus ribavirin for 24 weeks.
Why 24 weeks? Because longer therapy appears to decrease the risk of HCV relapse in patients with cirrhosis.
Why add ribavirin? Because ribavirin appears to decrease the emergence of HCV variants resistant to the DAAs in this regimen.
Can we anticipate insurance challenges? Based on this being the recommended approach in national guidelines, I expect insurance would cover this regimen for our patient.
Mark S. Sulkowski, MD - 9/15/2015
Recently, I have begun to hear many questions from colleagues and trainees regarding the use of resistance testing in the management of HCV-infected patients. To be honest, my answers to their questions are not always straightforward, as this is a rapidly evolving area of discussion in the field and I am confident that my opinion will evolve along with the data.
When Resistance Testing Is Recommended
That said, the AASLD/IDSA guidance has now highlighted at least one patient population for whom resistance testing with commercially available assays can be used to guide treatment decisions: Persons for whom treatment is urgent and previous treatment with NS5A inhibitors has failed to achieve cure. This would include previous exposure to such regimens as ledipasvir/sofosbuvir, ombitasvir/paritaprevir/ritonavir plus dasabuvir, and daclatasvir plus sofosbuvir. We know from follow-up data of patients treated in clinical trials that resistance associated variants (RAVs) against any of the available DAAs are likely to be detected upon on-treatment virologic breakthrough or posttreatment relapse with the exception of the nucleotide analogue NS5B inhibitor sofosbuvir. More importantly, we know that variants that are associated with resistance to NS5A inhibitors, including ledipasvir, ombitasvir, and daclatasvir, are likely to be stable and detectable for as long as 2 years after treatment.
Based on these data, updated AASLD/IDSA guidance recommends that, if treatment is urgent, patients who are not cured after receiving an NS5A inhibitor should undergo testing for the presence of resistance associated variants in the NS5A region and NS3 region (selected by protease inhibitors which target NS3, such as paritaprevir and simeprevir). Per the guidance, such patients who have no NS5A RAVs can be treated with 24 weeks of ledipasvir/sofosbuvir and ribavirin, those with NS5A RAVs but no NS3 RAVs can be treated with 24 weeks of simeprevir plus sofosbuvir and ribavirin, and those with both RAVs should be treated in clinical trial settings only.
The utility of testing for RAVs in the NS5B polymerase region is much less clear. Resistance to nucleotide analogues that target the NS5B active site (ie, sofosbuvir) is rare, and data indicate that retreatment with sofosbuvir-containing regimens is feasible in patients for whom a previous sofosbuvir-containing treatment has failed. Given the rarity of resistance to the NS5B active site, resistance testing is not routinely recommended. Currently, dasabuvir is the only other NS5B inhibitor available; however, it is a nonnucleoside inhibitor that targets domains of the NS5B polymerase distinct from sofosbuvir. Dasabuvir is used only with the NS5A inhibitor ombitasvir and the protease inhibitor paritaprevir, against which RAVs are more common. Thus, the results of NS5B inhibitor resistance testing would be unlikely to change the treatment decision.
Utilizing Resistance Testing in Practice: A Case Example
Of course, recommendations are only helpful if they can be applied to the care of real patients in clinical practice. A recent patient from my clinic is one such example. The case patient was a 54-year-old man with genotype 1a HCV infection and compensated cirrhosis who had a null response to treatment with peginterferon/ribavirin years before the availability of DAAs. He was subsequently treated with ledipasvir/sofosbuvir and ribavirin for 12 weeks and had an outstanding initial drop in HCV RNA. However, he unfortunately experienced relapse after stopping therapy. HCV drug resistance testing revealed a mutation in the NS5A region at position 93 (Y93H) that confers decreased susceptibility to ledipasvir (and ombitasvir and daclatasvir). However, testing of the NS3 protease domain revealed no Q80K mutation, suggesting that simeprevir would be active in this patient.
Case Treatment Decision
Based on the presence of an NS5A RAV but absence of NS3 RAVs, we elected to retreat this patient with sofosbuvir and simeprevir plus ribavirin for 24 weeks.
Why 24 weeks? Because longer therapy appears to decrease the risk of HCV relapse in patients with cirrhosis.
Why add ribavirin? Because ribavirin appears to decrease the emergence of HCV variants resistant to the DAAs in this regimen.
Can we anticipate insurance challenges? Based on this being the recommended approach in national guidelines, I expect insurance would cover this regimen for our patient.
http://www.hepatitiscnewdrugresearch.com/hcv-resistance-to-new-and-experimental-drugs.html
Ok, so my understanding is that you aren't resistant from the beginning. You develop resistance as you go along in the treatment. Sometimes resistance is caused by patients who miss doses. Sometimes it is caused by using the drug as monotherapy when two or more drugs are needed to protect against resistance. Sometimes it is because you have certain mutations that "fight" against a particular drug.
I wish I could do a better job explaining. I am not a scientist, far from it. So I often do not understand the actual explanations and just have to go with the bottom line(conclusion) when I hear it from someone I respect in the field. I have heard a few virologists talk about the weakness of the resistance problems with the DAA's....something about the wild type virus taking over and getting rid of the resistant virus and they believe it takes about two years.
I am hoping someone a lot smarter than I will come along and explain this in layman's terms to all of us.
I wish I could do a better job explaining. I am not a scientist, far from it. So I often do not understand the actual explanations and just have to go with the bottom line(conclusion) when I hear it from someone I respect in the field. I have heard a few virologists talk about the weakness of the resistance problems with the DAA's....something about the wild type virus taking over and getting rid of the resistant virus and they believe it takes about two years.
I am hoping someone a lot smarter than I will come along and explain this in layman's terms to all of us.
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Per the American Association for the Study of Liver Diesase (AASLD)
HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C
RETREATMENT OF PERSONS IN WHOM PRIOR THERAPY HAS FAILED
http://www.hcvguidelines.org/full-report/retreatment-persons-whom-prior-therapy-has-failed
here is the recommendation for his situation
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 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.
For patients with cirrhosis or other patients who require retreatment urgently, testing for RAVs that confer decreased susceptibility to NS3 protease inhibitors (eg, Q80K) and to NS5A inhibitors should be performed using commercially available assays prior to selecting the next HCV treatment regimen. For patients with no NS5A inhibitor RAVs detected, retreatment with ledipasvir/sofosbuvir and RBV for 24 weeks is recommended. For patients who have NS5A inhibitor RAVs detected and who do not have NS3 inhibitor RAVs detected, treatment with simeprevir, sofosbuvir, and RBV for 24 weeks is recommended. For patients who have both NS3 and NS5A inhibitor RAVs detected, retreatment should be conducted in a clinical trial setting, as an appropriate treatment regimen cannot be recommended at this time.
Hi me again
Basically if he has failed 24 weeks of Holkira pak (paritaprevir/ritonavir/ombitasvir plus dasabuvir) he will need to be tested for his resistance factors to treatment to best determine where to go from here
The tests would be to see if he tests positive for (technical stuff) the Q80K polymorphism a NS3 protease inhibitor and for NS5A protease inhibitors.
If he tests negative for the NS5A he should be treated for 24 week of Harvoni with Ribavirin.
If he tests positive for NS5A but not the NS3 Q80K he could be treated with Simeprevir (Olysio) and Sofosbuvir (Sovaldi) with Ribavirin for 24 weeks
If he tests positive for both NS3 and NS5A we would need to look for a clinical trial or wait for new medicines to be approved