TOPIC: Genotype 1b relapsed after Viekira+Exviera

Hello. My story.
I have finished  Abbvie Trial Viekira Pack no Riba Nov 2015. I have HCV genotype 1b, TT, F1, upon start 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 after treatment  I was undetected. 4WEEKS EOT RELAPSED , 14Dec2016 VL 27000 IU.mL, Feb 2016 VL 24296 IU/mL, May 2016 VL 106675 IU/mL - ALT63 ASPAT 61, GGTP circa 90 - 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.

For now I am waiting probably for retreatment in trials (no data yet) with ABT 450/530 Combo + Sofosbuvir + Riba 12 weeks

1, Is anyone here 1b who relapsed?
2. I have been told that for me probably ABT-450 for L31M works very well and would be great to have it
3. I am afraid of side effects after all this combo with sofosbuvir and especially Riba
4,Am I the first one taking Abbvie (whichever) with Sofosbuvir?

Hello,

Sorry to hear you have relapsed

1) ?
2) Daclatasvir works for L31M, ledipasvir does not. ABT-493 is the NS3/4A inhibitor and ABT-530 is the NS5A and it is the current state of the art - but only available via a trial.
3) No, QUEST-1 was salvage of patients like you had failed V-pak (and other DAA regimens) www.infohep.org/Treatment-intensificatio...atment/page/3014990/

1. Thank you - is it possible you give me a source that ledipasvir does not work for L31M please?

2. I am wondering why ombitasvir in Viekira+Esviera did not work for L31M?

3. You probably meant ABT450 not ABT-493?

1) www.sciencedirect.com/science/article/pii/S0168827813002092

In addition, daclatasvir has been demonstrated to be 2-fold more active against the L31M substitution as compared with ledipasvir [53]

Follow it from there if you like.

2) Because Dasabuvir is a weak NS5B inhibitor compared to Sofosbuvir. Sofosbuvir mono-therapy produces about 70% SVR which is pretty incredible. Sofosbuvir + V-pak + Riba would almost certainly work, and as noted before was the salvage regimen used by Abbvie in QUEST-1

3) No I meant ABT-493. www.worldhepatitisalliance.org/latest-ne...pes-surveyor-studies

Thank you for you knowledge. Yes, my mistake - I am waiting for ABT 493/530 with Sofo and Riba in trials.

Do you think it is a good idea? And probably to not risk adding Riba which I am really afraid of is necessary?

ad 2. Dasabuvir weak inhibitor - I have NS5A resistant variants probably not not NS3 variants. I was taking VPack+Exviera in trials phase 3, standard approved doses. I was asking for Ombitasvir. May it all mean that if I took Harvoni at that time I would also relapse?

Why do people add Sofosbuvir to ABT493/530?

There are 3 target sequences with good drugs that block them in HCV. NS3/4A, NS5A and NS5B. In HIV we started with AZT and resistance was rapid. Adding ddI or ddC improved things and now the standard of care is 3 or 4 drugs targeting 3 or 4 different bits of that unstable RNA virus.

V-pak is already targeting NS3/4A, NS5A and NS5B +/- the non specific effect of Ribavirin for GT1a. The observations from QUEST-1, C-SWIFT and trials of SOF+DCV + either Asunaprevir or Simpeprevir show better results with a 3 target strategy in line with logical expectations. More targets mean resistance requires resistance to all drugs on the same RNA sequence. The chances of a single replication cycle generating a RAV are about 1:1000 to 1:10,000. Let's say 1:1000. So to get 2 RAVs in the one sequence the chances are 1:1000 x 1:1000 - one in a million. Three RAVS - 1 in a billion. So more targets (as a strategy) works better than stronger drugs. Nothing wrong with stronger drugs, it's just that extra drugs raise the bar to resistance more.

The combination of ABT-493, ABT-530 and Sofosbuvir would provide best in class inhibition of the 3 targets. I don't know if anyone is actually doing it, and the who would be Abbvie for salvage of people who failed the 2 drug combination (just as QUEST-1 was salvage for V-pak failures - mostly).

In GT1 SOF+LDV and SOF+DCV are just about strong enough that RBV provides limited benefit. A modest 2% improvement in SVR rate on a 12 week treatment for a GT1 past treatment failure. RBV will probably always provide a slight benefit (it's a different mechanism, so different target0, but that benefit may be so small it's not worthwhile, for example the V-pak -RBV used for GT1b. The results would almost certainly be slightly better +RBV but 98% is viewed as good enough to skip it.

The problem, as you have discovered, is that even 98% means that 2 out of every 100 people will fail to SVR.

I have relapsed after Viekira and Exviera in November 2015, genotype 1b.


Now I am waiting for Vosevi which I hope to get in October. I am still thinking if I should not take Ribavirin additionally. I do not want to take it.


1. How many people from the forum where taking Vosevi for genotype 1b? Do you know anyone, any real-time data? If you know anyone on the forum please let me know.
 
2. I am trying to explain WHY Viekira+Exviera did not work for the L31M. Is it supposed not to work for this well? 

3. There is a table down in my letter from my blood tests after treatment- what does it mean
Ombitasvir    |substitution on scored position  |       31M
Does it mean that Ombitasvir that I was taking did not work for this?



From my findings:
NS-3 condones covered 1-181
NS3 region (w.r.t M58335) - S7A, V48I, A66G, P86Q, K87A, P89S, F147L, V170l
Ns3 region (w.r.t H77) - I35V, T42S,T61S, R62K, I64L, S66G, V71I,I72T, P86Q, Q89S, , S91A, I132V, A147L, L153I, N174S, L175M
 



Resistance Analysis
Drug     | Predicition | Scored mutations
Asunaprevir | suspecitble | none
Boceprevir | susbstituion on second position.   |   170I
Grazoprevir | suspectible | none
Paritaprevir| suspectible |none
Simeprevir| substitution on scored position   |  170l
Telaprevir |substitution on scored position | 170I
 
 

NS5A condons covered. 1-104
NS5A Region (w.r.t. D90208). - K6R, S17A, L31M, L34V, L37F,  G49A, Q54H, K68R, S101A
NS5A region (w.r.t. H77) I8V, E14T, S17A, K24Q, A25S, M28L, Q30R, L31M, I34V, V37F, R44K, G49A, R56T, H58P, E62Q, K68R, T71S, R78K, R81S, M83T, S85H, L101A
 
Resistance Analysis
Drug         |     Prediction                                      |     Scored mutations
Daclatasvir   | reduced suspectibility                  |      31M
Elbasvir        |  resistant                                 |            31M
Ledipasvir  |    suspectible                              |          31M
Ombitasvir    |substitution on scored position  |       31M
 
Velpatasvir      supsectible                                       none

AND MY HISTORY:
Compl. Viekira+Exviera no Riba Nov2015. 1b,TT,F1, 1400000U start of treatm. After 2 weeks 120U. After a month below possib of detect. After 3 months UND.3EOT UND. 4wEOT RELAPSED,14Dec2016 VL 27000 IU.mL,Feb 2016 VL 24296 IU/mL,  May 2016 VL 106675 IU/mL .L31M in NS5A.Y93H not pres. No NS3 D168/A/F/H/N/Y

Your L31M provides resistance to the NS5A in Viekira (Ombitasvir) leaving you with only the Paritaprevir (NS3/4A) and Dasabuvir (NS5B) to do the job. Dasbuvir is significantly inferior to Sofosbuvir and clearly not up to the task in you.

You should be easy to retreat and could retreat now with Viekira + Sofosbuvir (that's what we use) but Vosevii would be equivalent if you can get it.

www.aidsmap.com/Treatment-intensificatio...atment/page/3014995/

If you fail Vosevii you will probably be incurable unless you could get Maviret and add Sofosbuvir and Ribavirin. So it's probably best to take your consultant's advice on this one.

The retreatment success rate with Vosevii is "only" 96%. Nobody wants to be in the 4% but 1 in 25 patients will be, regardless of what they want. While Ribavirin might not add much not taking it and then relapsing again would leave you wondering... what if?

Hi mcmak,

I was pretty hard to treat and relapsed after a significant treatment of Sof/Dac then Sof/Led. My next treatment was the Viekira Pak, Solvadi and Ribavirin. I know we all need different cocktails. Ribavirin gave me a few more side affects than the other medications but nothing that I couldn't handle. I just felt that I wanted to throw everything I had at the retreatment and it worked for me.

Relapsing just sucks. I really wish you well in sorting out the best approach.

Coral