Hi mcmaklin,

I have no idea if and when any "trials" (that may be suitable for you), may come to you, in Poland. I am thinking ... if you were able to go to the UK for some reason to suss things out, maybe you could possibly let your fingers do some walking and check it out/suss it out, if you can be in a trial in another country -  how hard it might be for you to BE in Germany for a trial?

The idea is straw-grabbing and a long-shot, but, leave no stone unturned. Sof/vel/vox may be coming, but no one knows if and when (in reality). It might be worth asking your Polish doc, again, how soon he thinks sof/vel/vox might be coming to you and him in Poland.

1)  First, you would need to know IF indeed Germany (or one of the other country "locations") ARE even actually holding this trial, or if the trial is already pre-committed/finished. (Would this area in Germany be close or far for you?) Is this concept even possible, legally/logistically? Find out if it REALLY IS recruiting, or not. That would be the first thing - IS there a trial?

2)     You and your Polish doc would have to carefully determine if this MK-3682B triple really would be best for you. If so, then perhaps he could even be of assistance in asking for an appointment for you, on your behalf, to be assessed by the German trial doc. (Could you re-locate to Germany for a trial)? I have no idea if ANY of this is feasible in any way in the EU. But you have nothing to lose for your efforts in exploring it or considering it.

3)      You would have to do some sleuthing/phoning/inquiring/research of the trial location in Germany (verify the specific doctors/facility doing it) to find out if they are even doing intake or have any seats available. (I only picked Germany as I figured it might be closest to you).

4)   If there was even a "chance" (that any of these factors are possible), then you would need an appointment with the German doc running that trial, to see if he would accept you.

I had to do the same thing to ensure I got into my trial - I sussed it out (and it wasn't easy to find things out), but I did determine that I had found and landed myself in the right place, I had maneuvered myself into the right facility, with an appointment with the right doc, in the right "line-up" for an assessment, and in the end I successfully managed to get myself into a trial that had only 5 possible seats! Granted, it was easier for me than you, as it was within my own country and province and was only about a 5 hour drive away. My change in doctors, my inquiries, my angst, the waiting, the efforts, the travelling back and forth, was all well worth it to me in the end.

Pablo (UK) had to do some maneuvering to get a seat in his trial too.

Keep looking, sussing and exhausting possible options. C.

Pasted - from the NCT details: (just google up what you can on this "contact", do some sleuthing around first, and just find out what you can about this "location" before contacting them)

And there is a mistake here because Pibrentasvir and Glacaprevir should be 493/530 I guess?

Mamaklin,

Canuck and others are a better guide for current protocols.  

I can only add that difficulties I had with ribavirin earlier this year (with sovaldi)  earlier did go away after treatment. I was unsure while I was on it, but I made it and it was worth it in the end.

Keep gathering information.  You want to get this right.

Courage!

Cheddy

Dear Canuck,

Thank You so much For your help. I am reading everything but sometimes it is all upsetting so I need to give it a break. 

I am very thankful that you are thinking of me.

For the information from a private consultation at Prof:

"He has genotype 1b 

infection. He has been unlucky to have not responded to the triple NS3, NS5A and non-

nucleotide NS5B Viekirax plus Exviera regimen. He would now require a regimen that does 

not share cross resistance or possesses potent activity against the L31 resistance-

associated substitution. Sofosbuvir plus velpatasvir plus voxilaprevir come to mind or 

ABT-533 496 (now known as glecaprevir and pibrentasvir, possibly with Sofosbuvir or 

possibly a Merck next generation regimen including MK-3682(a NS5B polymerase inhibitor, 

grazoprevir (a protease inhibitor) and ruzasvir (NS5A inhibitor) would be suitable"

I am not sure when and how. I hope there will be trials in London or in Poland.

2. Another thing that I am VERY concerned is adding Ribavirin- do I really need it? There are not so many trial results of those with L31M and 1b. I have even now a dry mucosa. Are there after Riba any sides that last forever after treatment? In patients treated without interferon?

Are there some other NS5a variants I should test? I know I do not have Y93H.

Hey Mcmaklin,

More, on Merck products.

A Merck trial of "MK-3682B".

MK-3682B is the combined products of NS 3/4A Grazo, and their new NS5B MK-3682, and their NS5A Ruz  (with or without riba).

ClinicalTrials.gov Identifier: NCT02613403

https://clinicaltrials.gov/ct2/show/study/NCT02613403?show_locs=Y#locn

Says it IS still "recruiting", but IS old now.

This trial differs from the last Merck "RUZ" trials we were discussing (prior posts), in that, the varying arms in this one (with and without riba) are 16 to 24 weeks, AND, it is only for GT1's and GT3's who have previously failed on dac, ledi or grazo/elba. For the folks who have previously failed on sofa/riba or sof/riba/interferon, and some in conjunction with other daas, (who are NOT excluded in the trial) they seem to be mainly for the GT3's and 1's? Regardless, in how I may be misreading how far "inclusion" goes (as far as including other daas and riba/interferon relapsers), I think the relapsers must be GT1's or 3's? Other than in the USA, the only trial countries listed are France, Germany, Spain and Sweden.

Too bad this one is perhaps "not quite fitting" the right picture for our friend from Poland (who I would rather not see having to do riba if it could be avoided). With the very good results showing up from Mercks new "double" - NS5B (MK-3682) and their new NS5A (Ruz), I wish I could find a trial of this double (with the NS3/4A grazo added) as a possible "choice" consideration (if it was a trial that fits his parameters and if it was a trial that did not exclude him).

I wish Gilead (with their sof/vel/vox), and Merck (with their MK-3682B triple) would hurry up in coming out with their pan-rescue-triplets for relapsers!

Hey mcmaklin,

I am thinking of you and wondering if you have exhausted looking at the "merits" of Merck products, just in case a triple "trial" might exist, or, (perhaps) if one might yet happen with Merck products ... say, before a rescue product like Gileads (sof/vel/vox) triplet becomes easily available.

Here is some "associated" reading, about their products and some of the promising results from Mercks - Grazo (NS3/4A) /  RUZ (their new NS5A) / MK-3682 (their new NS5B).

Note: I am NOT talking about the OLD Merck product Zepatier-  elba (NS5A) / grazo NS3/4A (with or without riba), but of their "newer drug line-up for a riba-free triple. Mercks new MK-3682 would be their own NS5B answer to compete with sof. And I am assuming their new RUZ is outperforming their old elba as a NS5A

2016 - Part B of C-CREST-1 & 2 - Safety and efficacy of the fixed-dose combination regimen of MK-3682 (their new NS5B)/ grazoprevir (NS3/4A)/ MK-8408 (their new NS5A-RUZ) with or without ribavirin in non-cirrhotic or cirrhotic patients with chronic HCV GT1, 2 or 3 infection

2016 - SVR24 data from the phase 2 C-CREST 1 and 2 studies -  High efficacy of an 8-week drug regimen of grazoprevir/MK-8408/MK-3682 in HCV genotype 1, 2 and 3-infected patients

2015 -  Part A of C-CREST-1 & 2 - Phase 2 - randomized, open-label clinical trials of the efficacy and safety of grazoprevir and MK-3682 (NS5B polymerase inhibitor) with either elbasvir or MK-8408 (NS5A Inhibitor) in patients with chronic HCV GT1, 2 or 3 infection.

VIDEO: C-CREST-1 trial shows fixed-dose combo effective at 8 weeks ...

www.healio.com Hepatology Hepatitis C

Merck & Co., Inc. - Merck Announces Findings for Investigational Triple ...

investors.merck.com/investors/.../2016/Merck...C...1.../default.aspx

 I could be wrong, but I think this might be the only "current" recruiting trial (ClinicalTrials.gov Identifier: NCT02956629).  It is for a wider number of differing GT's, BUT, this triple includes riba! along with MK-3682 (their "new" NS5B) / RUZ (their new NS5A). It does not include NS3/4A grazo.

This one does say it is recruiting, BUT, it IS OLD (from early 2016) - and, I think WAS the phase 2 discussed in results above, and, it is a "double" only. MK-3682 (their new NS5B) and RUZ (their new NS5A). It also does not include NS3/4A grazo.  - ClinicalTrials.gov Identifier: NCT02759315.

The Merck triple trial(s) that were of interest to me would have been the new NS5B MK-3682/ RUZ/ and Grazo triplet.

This is may add NOTHING to the thinking, but, here is some more (January and July 2016) Zepatier info that Merck put out on their elba/grazo product.

Zepatier's Product Monograph - Index

www.merck.ca/assets/en/pdf/products/ZEPATIER-PM_E.pdf

In the first pages, it shows in which circumstances, they DO recommend adding sof or riba to their elba/grazo regime (GT3's are included)..

INDICATIONS AND CLINICAL USE ZEPATIER® (elbasvir/grazoprevir) is indicated for the treatment of chronic hepatitis C (CHC) genotypes 1, 3, or 4 infection in adults as follows:

Without ribavirin:  

in genotype (GT) 1 or 4 treatment-naïve (TN) and peginterferon alfa + ribavirin (PR) treatment-experienced (TE) relapsers (12 weeks)

in GT1 protease inhibitor (PI)/PR-TE relapsers (12 weeks)

in GT1b TN, non-cirrhotic patients (8 weeks)

in GT1b PR- or PI/PR-TE on-treatment virologic failures (12 weeks)

With ribavirin:

in GT1a PR- or PI/PR-TE on-treatment virologic failures (16 weeks)

in GT4 PR-TE on-treatment virologic failures (16 weeks)

With sofosbuvir:

in GT3 TN patients (12 weeks)

According to this one (above), sof is only added for treatment-naïve (TN) GT3's, and, treatment-experienced (TE) relapser GT1b's get 12 weeks of Zepatier alone (no riba).

The Zepatier cure rates do seem high, even in the TE's, but of the (very limited) reading I have done, I am still partial to Epclusa with VOX as a "rescue therapy" for any relapser. But, when will people ever be able to get their hands on this sof/vel/vox rescue therapy triple, easily, anytime soon?!

In the link (below) that Tig showed (noted as updated by FDA Jan. 2016), it shows regimes limited to GT1's and GT4's only (no GT3's, nor the sof use for the 3's are shown here). It DOES show (on the other hand) riba use with elba/grazo for GT1b relapsers, but I cannot clarify the "footnote" symbols (TE on PI's), - (see footnote symbols highlighted in red below) -  I am thinking perhaps this is what NHS is saying ... "is that you would have to have been unsuccessful on a interferon/riba (PI) based regime first" ... before you could get Zepatier with riba the second time around. You did not have riba, nor interferon with your first treatment failure.

(From Tig's link) ... Dosage Regimens and Durations for ZEPATIER in Patients with Genotype 1 or 4 HCV with or without Cirrhosis Patient Population Treatment Duration.

Genotype 1a: Treatment-naïve or PegIFN/RBVexperienced* without baseline NS5A polymorphisms(#) ZEPATIER 12 weeks.

Genotype 1a: Treatment-naïve or PegIFN/RBVexperienced* with baseline NS5A polymorphisms(#) ZEPATIER + ribavirin 16 weeks. 

Genotype 1b: Treatment-naïve or PegIFN/RBVexperienced* ZEPATIER 12 weeks.

Genotype 1a or 1b: PegIFN/RBV/PI-experienced(##) ZEPATIER + ribavirin 12 weeks.

Genotype 4: Treatment-naïve ZEPATIER 12 weeks.

Genotype 4: PegIFN/RBV-experienced* ZEPATIER + ribavirin 16 weeks.

*Peginterferon alfa + ribavirin. (#)Polymorphisms at amino acid positions 28, 30, 31, or 93. (##)Peginterferon alfa + ribavirin + HCV NS3/4A protease inhibitor.

I don't think anyone is going to prescribe Sovaldi and Zepatier, at least not commonly. Sovaldi NS5B would mitigate the RAV's at NS5A, but again, the cost to administer both, along with Grazoprevir NS3/4a, would be prohibitively expensive for the penny pinchers. 

There are other treatments coming available, Epclusa for example, with and without Voxilaprevir, is a consideration. 

EPCLUSA

"Genotype 1: Among the 75 genotype 1 subjects who had baseline NS5A RAPs, one subject (1%) with Q30R, L31M and H58P polymorphisms at baseline and compensated cirrhosis relapsed."

I will probably wait for other option- I have asked if they concider to add Ribavirin not asking even for Sofosbuvir (this is what EASL Recommendation says) so they redirected me to figure on page 13 where there are options for treatment experienced but after interferon and riba. I told them they are wrong. Now waoting what they say.

I would also ask if your consultant with the NHS is aware of your L31M status. I'm aware of it impacting the effectiveness of treatment on Genotype 1A, not 1B. Your NS3/4a status appears clear, but I think I'd ask if they think Ribavirin would be warranted in your case. I may consider the 16 week protocol if that's an option. Again, this would be determined by an accurate RAV determination. 

Hey Mak,

Yes, it's a good protocol and if you can get it, I think you should do well. There isn't a lot of information on retreatment following new DAA failures, but the trials did investigate the RAV status of people having failed a combination of them and Interferon/Riba. The results were good. I would be curious to know what RAV's (current) you might have now that you're post treatment with Viekira/Exviera. Might be some differences since April. Is that something they might investigate? I would ask. 

Here's some additional information on Zepatier in PDF:      ZEPATIER

Greetings,

I was looking at ZEPATIER after I had failed and before I settled on Harvoni.

Pretty much the same success rate;

"The study group included subjects with HCV genotype 1 or 4 infection with or without HIV-1 co-infection who had failed prior treatment with peginterferon and ribavirin. Subjects received either Zepatier for 12 weeks or Zepatier with ribavirin for 16 weeks. 94% of those with genotype 1 infection who received Zepatier alone achieved SVR, and 97% of those who received Zepatier with ribavirin achieved SVR."

http://www.rxeconsult.com/healthcare-articles/Zepatier-elbasvir--grazoprevir-Dosage-Side-Effects-Cost-Cure-Rates-And-Prescribing-Information-For-Hepatitis-C-1046/2

Pretty good stuff and if it were me I would jump on it.

http://lloydwright.org/messages/Zepatier-beats-Harvoni-Sovaldi-hep-C-clinical-data

JimmyK

Hello, I have been offered re-treatment from NHS Elbasvir/Grazoprevir.

I know I should add Sofosbuvir and Ribavirin.

As I have L31M would you recommend me to wait for other drugs form Abbvie or Gilled? 

I know nothing about ZEPATIER, and is it a good solution for me?

thank you

------

I am 41 y.o.   I RELAPSED.  I have finished  3 months of Abbvie Trial Viekira Pack (Ombitasvir/Paritaprevir,Ritonavir + Dasabuvir) no Ribavrin in November 2015. 

Trial name: M14-423  TOPAZ-I -   ABT-450/ Ritonavir/ ABT-267/  ABT-333  without Ribavirin

I have HCV genotype 1b since blood transfusion in 1975 (as my twin sister who managed to cure with Harvoni) , TT, F1-F2.

In trials:  Upon start of  treatment I had 1400000 units of virus. After 2 weeks 120 units. After a month below the possibility of detection. After 3 months no virus.  3 weeks EOT  I was undetected,  4WEEKS EOT RELAPSED , 

14 Dec2015 VL 27000 IU.mL,  Feb 2016 VL 24296 IU/mL- ALT 33, AST 32

May 2016 VL 106675 IU/mL - ALT63 ASPAT 61, GGT circa 90.   September 2016 AST = 71,7  ALT = 66

20 October 2016 VL 3,9mln (Epsom)

8 November 2016 VL only 214016 IU/mL

I was testing for RAVs: as checked in April 2016 I have L31M in Region NS5A .

 Y93H not present in referral sequence AY045702.

 Additionally confirmed to be present Q54H.

 In region NS3 there are no mutations D168/A/F/H/N/Y