TOPIC:

You can read about NS5A RAVs here:

www.ncbi.nlm.nih.gov/pmc/articles/PMC3961994/

Resistance is relative and some RAVs are more resistant than others. They do not confer Sofosbuvir resistance which is what you really don't want.

James,

According to the DAA drug interaction charts ledipasvir/sofosbuvir should not be co-administered with simeprevir. However, sofosbuvir/daclatasvir/simeprevir can be co-administered. Any ideas as to why that may be the case?

Cheers

James,

FYI - the attached presentation from AASLD conference in San Fransisco is of relevance to our discussion.

Cheers

Summary

Coadministration with ledipasvir/sofosbuvir has not been studied and is not recommended. Coadministration of simeprevir (150 mg once daily) and ledipasvir alone (30 mg once daily) to 22 subjects increased ledipasvir Cmax and AUC by 81% and 92%. Simeprevir Cmax and AUC increased by 161% and 169%. Coadministration of simeprevir (150 mg once daily) and sofosbuvir alone (400 mg once daily) increased sofosbuvir AUC and Cmax by 3.16- and 1.91-fold, respectively when compared to historical data. The AUC of GS-331007 (the main metabolite) increased by 9%, but Cmax decreased by 31%. Simeprevir AUC and Cmax decreased by 6% and 4%, respectively.

Description

Concentrations of ledipasvir, sofosbuvir and simeprevir are increased when simeprevir is co-administered with ledipasvir/sofosbuvir. Co-administration is not recommended. Coadministration of simeprevir (150 mg once daily) and ledipasvir (30 mg once daily) increased simeprevir Cmax and AUC by 161% and 169%; ledipasvir Cmax and AUC increased by 81% and 92%. Coadministration of simeprevir and sofosbuvir decreased simeprevir Cmax and AUC by 4% and 6%, increased sofosbuvir Cmax and AUC by 91% and 216%, and decreased GS-331007 Cmax by 31% but increased AUC by 9%.
Harvoni Summary of Product Characteristics, Gilead Sciences Ltd, November 2014.

Concentrations of ledipasvir and simeprevir are increased when simeprevir is coadministered with ledipasvir. Coadministration of simeprevir (150 mg once daily) and ledipasvir (30 mg once daily) to 22 subjects increased ledipasvir Cmax and AUC by 81% and 92%. Simeprevir Cmax and AUC increased by 161% and 169%. Coadministration of ledipasvir/sofosbuvir with simeprevir is not recommended.
Harvoni US Prescribing Information, Gilead Sciences, October 2014.

As per the party line Sof+Led+Sim increase blood levels. This could be managed with dose reduction but would be experimental.

100% cure and pan genotypic profile of Sof+Dac+Sim makes it a very attractive option.

The only problem with Simeprevir is that it is even more diabolical to make than ledipasvir and more or less unavailable as a generic. We have some but it was triple the price of ledipasvir.

It is there for retreatment but people will be paying over 3x the price of Sof+Dac chasing the last few % if used as the first line treatment.

James,

My specialist has informed me that I could add daclatasvir to the treatment regimen but that its efficacy would be severely impaired due to pre-existing NS5A RAV's (which include L31M and now Q30R following relapse after 12 weeks of elbasvir/grazoprevir in a clinical trial). He also stated that I need to add RBV and that treatment needs to be for 24 weeks which presents a major problem - I don't have access to 24 weeks of simeprevir!

You mentioned in a previous post that you have some simeprevir available for retreatment purposes but it is expensive. My question is would I be able to access 12 weeks of simeprevir and what would the cost be to do so?

Thanks

Knowing his original post here is somewhat dated - I can not help but wonder if Jonathan successfully pursued retreatment. Hopefully he will comment when he comes back online.

My situation is somewhat similar - Viekira/RBV failure (as previously posted). And my gastroenterologist is also directing me towards the AASLD recommendation for retreatment with simeprevir/sofosbuvir and RBV.

It seems there may not be an experience based consensus for DAA retreatment - maybe because it is all too new. In lieu of a better recommendation - I am inclined to follow my GI's advice.

I do see that Mesochem lists simeprevir on their website - not sure what that means in terms of real-world availability.

Will explore this and other possible retreatment options during my upcoming GP2U appointment.

J

J. Eugene, I have not recommenced retreatment as yet but hopefully will do so within the next few weeks. I am awaiting the results of resistance studies, and a subsequent appointment with my gastroenterologist, before commencing retreatment.

Do you have any data on your baseline or treatment emergent RAV's? That information is important because it will determine your retreatment options.

hepatitiscnewdrugs.blogspot.com/2016/03/...ug-zepatier.html?m=1

Jonathan

I did not have HCV drug resistance testing performed prior to my therapy (Viekira/RBV) - hence no baseline data for RAVs.

Subsequent HCV drug resistance testing by LabCorp (Monogram Biosciences) shows an NS5A Q30R RAV and resistance to both ledipasvir and ombitasvir. Without prior testing - I have no way to be sure that this RAV is treatment emergent.

While taking Viekira/RBV - I did experience early viral suppression. Started with a modest 500k VL that went to undetected within 12 days and remained undetected through the 12 week course of therapy. AST/ALT also dropped from ~ 60/100 to a remarkable 13/11 within the first 12 days of therapy - the lowest numbers I had seen in over 40 years.

Side effects during treatment were negligible - if even present. Actually felt much better during treatment than before - or certainly after.

The success was short lived. Testing at EOT plus 12 weeks showed a 2,240k VL and LFTs headed back to pretreatment levels.

Covered most of this in my first post on this forum a week ago - sorry to be repetitive here.

By simply following the AASLD recommendations for retreatment - or those outlined in the article Dr. Freeman recently posted (authored by Dr. Jordan Feld just last month) - I would be back to watchful waiting in the hope that new medicines and treatment protocols would soon appear.

Having waited for decades - and coming so close while experiencing a wonderful but brief respite - I suppose my desire to try another therapy is understandable - even if misguided. My GI is willing to support my decision to go forward with the simeprevir/sofosbuvir + RBV .... I have to admit to second thoughts though. Have read a number of articles covering the increase of RAVs with unsuccessful retreatment protocols.

You mentioned undergoing additional resistance testing - curious as to your strategy. I was thinking about another NS5A resistance assy that includes daclatasvir (Quest Diagnostics) - not sure if it would be helpful - will discuss it with the treating physician should I go forward.

Stalled here at the moment.

All the best

J.

Wow. Good luck to you, sir. Keep us abreast.

J,

It seems that you are in a very similar boat to me. Prior to treatment I had NS5A resistance at L30M and treatment emergent RAV's at Q30R. Unfortunately, various studies suggest that NS5A treatment-emergent RAVs persist for a long period of time (but NS3 RAV's disappear after 12 to 18 months) and obviously present a challenge for clinicians (and patients).

Your physician's suggestion is consistent with the advice that I have been given from my gastroenterologist ie sofosbuvir/simeprevir plus ribavirin for 24 weeks. Retreatment with a different class of DAA, addition of RBV and treat for a longer period.

I am awaiting results for NS3 simeprevir resistance tests just to make sure prior to recommencing treatment. I would suggest that for peace of mind and prior to retreatment, you need to undertake testing for simeprevir resistance, in particular Q80K. You didn't mention whether this had been undertaken in your post.

Notwithstanding, that I have NS5A resistance I will probably include daclatasvir into the DAA treatment regime and "throw everything but the kitchen sink at it" because I don't want to go through another relapse and the detrimental psychological impact. It is a lot of treatment but better to be safe than sorry!

Jonathan

Jonathan

Have read your posts here and am very sorry that you too failed to achieve SVR - our cases are indeed similar.

Interesting that you had NS5A resistance testing done before your GZP/EBR therapy – suppose it was part of the Merck trial.

And yes – I had NS3/4A resistance tested. Luckily – against the four readily available protease inhibitors – there were no RAVs detected (note that treatment significant baseline NS3 RAVs are rare). Dodged the prevalent Q80K (present in > 40% of GT 1a patients here) – so it looks like the effectiveness of simeprevir will not be impaired. Have read that there is no clear impact of Q80K on extended simeprevir/sofosbuvir therapy anyway.

I too have also read about the durability of treatment emergent NS5A RAVs. Unlike the NS3 mutations (such as Q80K that fade in ~ 72 weeks) – treatment emergent NS5A RAVs (like Q30R) soldier on well past 96 weeks (the extent of most tests to date). This is another reason that the next course of treatment after DAA failure needs to be carefully chosen.

You have probably studied most of the retreatment options by now. I see that Dr. Freeman just posted a link to another current AASLD hosted article on the subject. The bottom line seems the same on most I have read.

Curious as to your thought on adding daclatasvir to your gastroenterologist’s AASLD based treatment recommendation. It looks like a recent recommendation I have seen for “desperation time” where both serious NS3 and NS5A RAV’s are present (R155, A156, D168). Would be extremely cautious about throwing everything in the mix – though I can understand the desire to do so.

The more I read on retreatment – the more inclined I am to wait awhile longer – maybe just a year. There are a number of potent NS5A inhibitors on the horizon that look very promising. And those existing emergent RAV’s should be easier to deal with by then just with time alone. Will see - waiting isn't my strong suit.

I wish you the best Jonathan - please keep us posted on your progress. Greatly looking forward to your success story.

And I need to add this for others who are seeking treatment ..

The success rate in achieving SVR with existing DAA therapies of the type available here-and-now is remarkably high - have witnessed it first-hand. Only a very few of us are unfortunate enough to miss on the first attempt – and with the advances in HCV DAA therapies coming so quickly now – there will soon be a day where we are all free of this.

Have been reluctant to post about my lack of success this go-round - concerned that others might become overly worried when they really shouldn’t be. Most everyone will beat this now first try – and I will catch up with them soon.

Probably before I wear-out the new set of tires on my motorcycle – California coast and sunny days ahead.

J.

J,

Thanks for your kind words. I too wish you all the best and please keep me informed of your deliberations. I totally understand your view to wait before undertaking retreatment but I need to get on with my life and want to put this behind me as soon as possible. I firmly believe that this DAA regime will do the trick! I have attached a study (without RBV) which had some impressive results (albeit small sample size and some G1b's) - hence my desire to start as soon as it is practical to do so - waiting, waiting, waiting.....
In respect of adding daclatasvir into the mix there is no doubt that its efficacy will be significantly reduced but it adds a little more potency into the therapy. It was actually a suggestion by Dr James Freeman and I discussed it with my gastroenterologist who is happy that I include it into the regimen. I thought that I may be able to get away with not having RBV but he also said that RBV does seem to impact on the emergence of resistance during therapy and that I should include to increase my chances (albeit minor) and continue for 24 weeks.
I will keep you informed of progress.

Jonathan

Jonathan

Curious about your progress - please check your PM

J.