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Hep C Discussion Forum -> Hep C News -> Potential Resistance Pathways for Sofosbuvir
Post Info TOPIC: Potential Resistance Pathways for Sofosbuvir
Dzdayscomin


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RE: Potential Resistance Pathways for Sofosbuvir
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Groupergetter wrote:

I wonder if we will ever know the true % of relapse for those taking Sovaldi? 

 We will here that's for sure, id have to say we are a pretty good sample of folks from all corners of at least the States where it's available. 

Maybe we start a sticky thread for those that have relapsed just to keep track and limit the commentary to just the answer.

 

Not my board but it would be better than all us fogheads trying to remember who did.

Just an idea



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Huey


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Groupergetter wrote:

I wonder if we will ever know the true % of relapse for those taking Sovaldi? 

 Got a majic  8  ball?



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  HCV Genotype 3a , now Psot-Tx was on S/riba. First VL was 5.8 mil on 7-5-13 then "und" at 3.8 weeks. 06/13/14 still und. off meds 3 days back on 7/29 Last pill 08/10/14 SVR+4

 
Groupergetter


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I wonder if we will ever know the true % of relapse for those taking Sovaldi? 



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1b  Int/Riba relapse @ 48 weeks.  Stop tx Peg Int/Riba 12 weeks ill. Relapse S/O 6/23/14 :(   Started Harvoni 11/12/14  EOT 4/28/15.  EOT+4 UND :)  SVR! 8/4/15  :)     Thankful for every morning.
Tig


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Isis,

Since you're able to find hard to locate government databases, how about you take a look into those lost IRS emails? Keep an eye on the driveway for any dark sedans and people wearing dark sunglasses with earwig radiosets...  JK! wink

Tig



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mallani


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Hey Isiscat,

LOVE that letter to Gilead. I'm also impressed you were able to find it. Thanks.



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Geno 1b, IL28B CT,  x3 prior relapser,  ex-cirrhotic, 75 yo, did 48 weeks with Victrelis/Peg./Riba.  VL 1.28m at start, UNDET. at 8 ,12 ,16 ,24 ,30  and 48 weeks.  EOT 15 Feb 2013 , UNDET. at EOT + 28 weeks. SVR!  Still Undet. at EOT +5 years

Malcolm
Isiscat2011


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Thank you, Matt.  What a nice thing to say.  The information available to the public, or even to the FDA for that matter, is limited.  

As with any billion dollar industry pharma keeps its cards close to the vest.  If only it wasn't about profits and brilliant scientists could all work together for the common good.  Imagine what we could accomplish.  Maybe someday, huh?



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Matt Chris


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Hey Isiscat

Great work on digging up that NDA correspondence between the FDA & Gilead.

Public records are there to be found if we just know where to look.

Its outstanding to have a bright lawyer to help us navigate the FDA

Thanks matt



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61 year old Geno type A1, F4 Cirrhotic, started 24 weeks on Harvoni 12-17-14 ,EOT-5 week = UND, 8-31-15 =UND , SVR-24 Baby YES! 
Huey


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What I think will happen, is Gilead will sell Sovaldi right before the dirt comes out, That is why they are in shush a hurry to get there 11 B back.

  There will be lawsuits just like bend over America BOA but the culprits will have sold the outfit to a small S corp and leave them, the new owners with all the liability.  They will file chapter 13 and taxpayers flip the bill.



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  HCV Genotype 3a , now Psot-Tx was on S/riba. First VL was 5.8 mil on 7-5-13 then "und" at 3.8 weeks. 06/13/14 still und. off meds 3 days back on 7/29 Last pill 08/10/14 SVR+4

 
Isiscat2011


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Gator Man wrote:

It seems to me that we are near a 100% SVR rate if the right DAA combos and Tx duration are tailored to the specific needs of the patients. On the other hand, some of us were/are not in a position to wait for better clinical data and have to treat with the information available. 

This describes the situation in a nutshell.  Aahhhh.......to be an F-1 and have the luxury of time.  

Having said that, the FDA needs to sit on Gilead with a bit more conviction to get some answers.  It lets these guys get away with practically anything.  

And, alas, we are the test bunnies.  :)  

 

P.S.  This assumes the new DAAs are capable of eliminating the RAVs problem.  The other possibility is that there is no eliminating them in some people.... the super-strain emerges.  An awful thought. 



-- Edited by Isiscat2011 on Wednesday 27th of August 2014 03:31:31 PM

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Isiscat2011


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mallani wrote:

Now, we need to know whether Daclatasvir and/or Ledipasvir are active against the RAV's described. Actually, we need a complete list of RAV's with responses to different DAA's, including antiproteases like MK-5172. Also we need to know the expected lifespan of these RAV's- it wouldn't help to reuse Sovaldi if these are still present. That's the way to develop a 'superbug' strain of the virus. Ah, so much to learn.

 The FDA sent a letter instructing Gilead to determine the phenotypic susceptibility of Sovaldi against the following NS5B substitutions: 

Genotype 1a:

L159F 

L159F + L320F 

LI59F + C316N 

C316N, H, and F 

L320F, S282R, and L320F + S282R 

D61G 

D61G + N62H, D and N 

___________________________________

Genotype 1b

L159F 

L159F+L320F 

L159F+C316N 

C316N, H, and F 

E440G 

____________________________________

Genotype 2b

L159F 

L159F+L320F 

L159F+C316N 

______________________________________________

Genotype 3a

L159F 

L159F+L320F 

L159F+C316N 

K211R 

V321A 

P540L

TS42A

 

http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2013/204671Orig1s000ltr.pdf __________________________________________________

This doesn't give us the answers but it indicates that the FDA is aware of the RAVs problem and wants to take a closer look.  The FDA instructed Gilead to file its findings by August, 2014.  Hopefully, Gilead will also disclose how effective Ledipasvir is at defeating these substitutions. 



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Diagnosed in 2011, Incivek triple in 2011, tx discontinued, Genotype 1a, CT, VL 7mill, cirrhosis dx in 2012, age 67, waiting for new DAAs.
Gator Man


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Isiscat2011 wrote:
mallani wrote:

I wish Gilead would come clean and release all their data on Sovaldi relapses.

 

The polymorphisms described should be cleaned up by the extra drugs. Extending treatment time may help with cirrhotics, who need the extra perfusion/exposure to drugs.

 ...

There is clearly a need for additional studies on hard to treat groups: cirrhotics, relapsers and RAV's, and particularly patients that have more than one of these complications. We also have limited data on Riba's effectiveness with various DAA combos and whether the Sx are worth dealing with versus any benefit. You are absolutely correct Malcolm, we need to get away from the one size fits all approach to Tx. It seems to me that we are near a 100% SVR rate if the right DAA combos and Tx duration are tailored to the specific needs of the patients. On the other hand, some of us were/are not in a position to wait for better clinical data and have to treat with the information available. My Tx decision was based entirely on incomplete COSMOS data. Length of Tx and the inclusion of Riba were decisions based more on getting insurance approval than clinical trial results. Limited trial results were in part based on Gilead's lack of cooperation with using Olysio with Solvaldi for more studies, despite urging from the FDA.



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Geno 1b, compensated cirrhotic, 54 yo, prior null responder. Pre tx VL approx 595,000, tx with Sovaldi/Olysio (no Riba) started 1/8/14. VL 40 @ 2 weeks, UND @ 4 weeks. Still UND @ EOT + 1 year.

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mallani


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I'm assuming that the article in Hepatology was referring to treatment with Sovaldi with Riba/ +or - Interferon.

The polymorphisms described should be cleaned up by the extra drugs. Extending treatment time may help with cirrhotics, who need the extra perfusion/exposure to drugs.

With an extra DAA added to Sovaldi, it would be hoped the extra DAA could handle these polymorphisms. Now, we need to know whether Daclatasvir and/or Ledipasvir are active against the RAV's described. Actually, we need a complete list of RAV's with responses to different DAA's, including antiproteases like MK-5172. Also we need to know the expected lifespan of these RAV's- it wouldn't help to reuse Sovaldi if these are still present. That's the way to develop a 'superbug' strain of the virus. Ah, so much to learn.



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Geno 1b, IL28B CT,  x3 prior relapser,  ex-cirrhotic, 75 yo, did 48 weeks with Victrelis/Peg./Riba.  VL 1.28m at start, UNDET. at 8 ,12 ,16 ,24 ,30  and 48 weeks.  EOT 15 Feb 2013 , UNDET. at EOT + 28 weeks. SVR!  Still Undet. at EOT +5 years

Malcolm
Matt Chris


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Thanks Wayne

I read this also, but we all should understand that beating HCV has never had its successes in a mono mode, beating HCV requires multiple tier attack with a minimum of two or more agents to box in and control the polymorphisms.

Isiscat one reason that Gilead extended treatment was a early trialist that had developed  Rav's at the end of a 12 week treatment.  Gilead next put him back on extended treatment and he cleared after the treatment. Seems like Gilead is not really sure or willing to reveal what they know or should I say what they don't know. If the percent of possible relapse is 2%-4% they are likely still in a good place, but time will tell.

matt        



-- Edited by Matt Chris on Wednesday 27th of August 2014 06:02:50 AM



-- Edited by Matt Chris on Wednesday 27th of August 2014 06:03:50 AM

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61 year old Geno type A1, F4 Cirrhotic, started 24 weeks on Harvoni 12-17-14 ,EOT-5 week = UND, 8-31-15 =UND , SVR-24 Baby YES! 
Isiscat2011


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mallani wrote:

I wish Gilead would come clean and release all their data on Sovaldi relapses.

YES.  Can I get an AMEN?  

So, extending tx wouldn't help once the Sovaldi created RAVs show up?    



-- Edited by Isiscat2011 on Wednesday 27th of August 2014 05:19:35 AM

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Diagnosed in 2011, Incivek triple in 2011, tx discontinued, Genotype 1a, CT, VL 7mill, cirrhosis dx in 2012, age 67, waiting for new DAAs.
mallani


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Hi Wayne,

Thanks for posting this. It confirms my comments from Feb 16th. in my '' Understanding Sovaldi' post.

I wish Gilead would come clean and release all their data on Sovaldi relapses.

http://hepcfriends.activeboard.com/t56748030/understanding-sovaldi/



__________________

Geno 1b, IL28B CT,  x3 prior relapser,  ex-cirrhotic, 75 yo, did 48 weeks with Victrelis/Peg./Riba.  VL 1.28m at start, UNDET. at 8 ,12 ,16 ,24 ,30  and 48 weeks.  EOT 15 Feb 2013 , UNDET. at EOT + 28 weeks. SVR!  Still Undet. at EOT +5 years

Malcolm
Isiscat2011


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Thanks for posting this, Wayne.  Do you know if the resistance problem can be mitigated (or eradicated) by increasing the tx duration or would that not make any difference?



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Diagnosed in 2011, Incivek triple in 2011, tx discontinued, Genotype 1a, CT, VL 7mill, cirrhosis dx in 2012, age 67, waiting for new DAAs.
OldenSlow


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"SOF has a high barrier to resistance; however, low frequency NS5B substitutions associated with treatment failure were identified that may contribute to resistance of this important drug for chronic HCV infection."

http://hepatitiscnewdrugs.blogspot.com/2014/08/clinical-evidence-and-bioinformatics.html

 

 

 



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66 y/o male - Geno 1b - F4 cirrhotic dx 2001 - 16 wk treatment w/ Sovaldi/Olysio/Riba - Und @ EOT+24 SVR

 
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