Simeprevir, Sofosbuvir, and the Limitations of the COSMOS

[flyinlynn]

Interesting article looks like my cohort in the Cosmos trial was 7 patients prior non responders with cirrhosis. So 6 of 7 cleared or 84%

http://blogs.jwatch.org/hiv-id-observations/index.php/simeprevir-sofosbuvir-and-the-limitations-of-the-cosmos/2014/07/31/

[HectorSF]

Lynn, I have already talked with my hepatologist about treating either with Dacatavir and Sovaldi or the AbbVie combo should I fail this Sovaldi, Olysio + ribavirin treatment fail. Of course even if I do get cured I will be following hep C treatment so I can continue to help our transplant folks who need to treat either with cirrhosis pretransplant or post liver transplant as I am doing now.

Dr. Norah Terrault, my hepatologist, is speaking on the subject of "Interferon-free Treatment in the Transplant Setting"  at our annual UCSF Transplant Conference tomorrow and she will be at a special AASLD Hepatitis C meeting in Manhattan Friday and Saturday. So I will be aware of all of the data for the soon to be available hep C treatments and our hepatitis C clinic's protocols for treating different infectious populations.

You can always send me a message any time you want to know what the latest developments are, at least at our transplant center, where we treat folks with advanced liver disease in the hopes of clearing the virus either to stop the need to a transplant our prevent recurrence post transplant.

I recently norah speak at the The World Transplant Congress here in San Francisco about a month ago with Dr. Paul Kwo and surgeon Jean C. Emond, MD. And of course treatment in compensated cirrhotics is one of the hottest issues in the transplant community now that we have options and more on their way soon.

Here is some of the hopeful news that Dr. Kwo speaks of for us "hear to treat" folks...pretransplant cirrhotics as well as post transplant folks.

"Although the landscape for treating HCV in the transplantation setting has evolved dramatically during the past 6 months, we are still learning about best practices for managing HCV in this setting.

I will be gathering with my colleagues, Norah Terrault, MD, MPH, and Jean C. Emond, MD, in San Francisco, California, during the World Transplant Congress for a symposium addressing the key challenges and opportunities for managing HCV in transplant patients.

Are New HCV Therapies Ready for Use in Transplant Patients?
Paul Y. Kwo, MD - 7/10/2014  

December 2013 marked the first drug approval from a new class of direct-acting antiviral (DAA) agents, the nucleotide polymerase inhibitors. Sofosbuvir was approved for use in combination therapy both with and without interferon. For genotype 1 patients, clinical trials demonstrated overall SVR rates of 90% when sofosbuvir was combined with peginterferon and ribavirin for 12 weeks and 70% SVR rates when sofosbuvir was given with ribavirin for 24 weeks. For genotype 2 and 3 patients, SVR rates were more than 85% with the interferon-free combination of sofosbuvir and ribavirin for 12-24 weeks. In addition, the approval of a once-daily protease inhibitor simeprevir has allowed clinicians to remove interferon and ribavirin from the equation in genotype 1 infection by combining sofosbuvir and simeprevir for 12-24 weeks; a regimen associated with SVR rates > 90% in genotype 1 individuals.

The Arrival of DAA Therapy in the Pretransplantation Setting

"The prescribing information for sofosbuvir also included an indication for use in the pretransplantation setting when combined with ribavirin for cirrhotic patients with hepatocellular carcinoma, who meet Milan criteria. The regimen is given and virus suppressed for up to 24-48 weeks in an effort to eradicate virus prior to transplantation and prevent reinfection of the graft after transplantation. In our pretransplantation clinic, we are now able to suppress HCV viremia prior to transplantation with sofosbuvir and ribavirin in those with mild decompensation or with hepatoma. Whether suppression prior to transplantation will be the best strategy remains to be seen as it is not always possible to predict the timing of transplantation, especially without living related transplants. However, most patients we have treated tolerate this approach well, and we are noting that some patients have experienced clinical improvement that has allowed them to come off the transplantation list. Certainly longer-term follow-up will be required to see if this trend continues. I am interested to see if this approach can be applied to individuals who require orthotopic liver transplantation without hepatocellular carcinoma and who have Child-Turcotte-Pugh scores greater than 7; data evaluating this approach are still needed."

Interferon-Free Options in Posttransplantation Patients

"The phase II COSMOS study combining sofosbuvir with simeprevir (without interferon or ribavirin) has demonstrated that SVR may be achieved in traditionally difficult-to-treat patient populations, including those with previous null response to peginterferon and ribavirin as well as those with F3 or F4 fibrosis. Although there are few data currently evaluating this regimen after transplantation, neither sofosbuvir nor simeprevir have meaningful drug–drug interactions with the calcineurin inhibitors tacrolimus and cyclosporine, and therefore, our center and others are now combining these 2 direct-acting antivirals after transplantation. We have found this gives genotype 1 HCV–infected posttransplantation patients a treatment option that removes agents that were difficult to tolerate due to the immunosuppression and poor tolerance of cytopenias."

Sofosbuvir combined with ribavirin is another option after transplantation that has demonstrated SVR rates of more than 70% in one study and, in another study, has shown efficacy as a salvage strategy for those with the dreaded complication of fibrosing cholestatic hepatitis C.

"The combination regimen of ABT-450/ritonavir/ombitasvir plus dasabuvir and ribavirin, which is expected to become available for the treatment of HCV infection later this year, has also been evaluated in genotype 1 HCV liver transplantation recipients with recurrent infection. Among evaluable patients at the time of interim analysis, 96% had achieved SVR. Alterations in calcineurin inhibitors were required but were manageable."

"These findings make me believe that the future for patients with advanced liver disease and posttransplantation hepatitis C infection is indeed bright. In fact, I think it is likely that with successful eradication of hepatitis C with therapies that are well tolerated, the hepatitis survival for orthotopic liver transplant for hepatitis C will match survival in those who are not HCV infected."

Be well.
Hector

[Dbzc2]

Lynn, I heard the second go around for our group is better.  What my doc said months ago is that the S&O should have been approved for 24 weeks the first go around!  I thought round 2 was going to be 24 weeks but he said no.  12 weeks.

Here I am reading all of this and any minute my results could finally pop up! I know they have to be released by my doc, so I'm a bit paranoid that they are holding back for fear of how upset I'll be.  To be honest, ever since it took a full six weeks for me to go to non-detected and I got the "new" label SLOW responder, I have not felt right about stopping the meds so soon!  My chances when I ended treatment where already not great for a SVR!

Thanks Hector for all the info. The two drugs I no longer can tolerate, and that was when I had zero cirrhosis, are interferon and ribavarin.  I can't do any of the treatments that have ribavarin.  So I have to hope the new pills will do the job, eventually.  I didn't know any of this stuff when I started the S&O treatment!  I've only had cirrhosis less than a year! I did three previous treatments (no cirrhosis), and still, with 1A responded, but NEVER a sustained response.  

This summer, It did get to the point that my doc said I might be doing treatments to give my liver a break and try to keep the cirrhosis at bay. (With portal hypertension and a bunch of side effects, it seems I have a really pissed off liver or virus?)

Anyway, I will do whatever I get approved for...it's that or deal with worsening cirrhosis, which I do not want to have to do!  Although, and why I've been so nervous, I feel those nasty side effects building again.  My results, any day now, I guess will be interesting? As in if I have a SVR, then it's cirrhosis I'm already dealing with, or If I do not have a SVR it's the virus that's messing with my cirrhosis.  

On S&O  I could not think, and I felt like I had lost me? Like my brain shut down?  About two weeks after I finished the treatment, I could think again!  I really do not want to do that again, but I now feel like it's okay and I can do whatever is necessary.  

I am encouraged by those who do sustain a response. I am given courage by those who don't sustain a response.  So either way. I'm so glad I get to read new articles, read info people (like Hector) are kind enough to seek out and share.  By  myself, (this past June), I was completely and utterly lost!  I do not feel lost now.

(I am getting a bit manic about getting the results! But at least whatever they are, I know more about what to do.)  

Great info and Lynn, just do whatever you can.  I think giving our livers a break does help. Hector is right.

Best wishes, dbz

[flyinlynn]

Many good thoughts there Hector.

I like to say no one is getting out of this place alive.

I have an appointment to discuss Sovaldi/ Ledipasvir in November but from what you posted I don't know what is best. I just wish I could do interferon ribavirin and sovaldi ledipasvir for 24 weeks if that would do it to stomp this darned thing into the ground

Genotype 1a
3 null responder (interferon monotherapy, and interferon/Ribavirin)
never treated with telaprevir or boceprevir
Cirrhosis DX 1/08
edema & varicies banded
Meld 7 Child A


Good luck and all the best to you on your current treatment hope you are on the good side of the data this go round. I hope it is your last dance with the dragon.

Lynn

[patra_]

Well said, Hector!!!

All we can do, is all we can do.

Be well!

[Giddyup5]

Nice one Hector, wishing you a better tommorrow always. I was lucky enough to cure on Sovaldi Olysio and ribaviron although I had previous treatments and cirrhosis . I hope you do as well, I was always aware that it it'S not a not 100 percent cure.
Lynn, science is working every day to find your cure. I was told if I did not obtain svr that they would go ahead with the ledipasvir. Hang in there!

[HectorSF]

Thank you Lynn. And again I am very sorry that the treatment failed you and you dealing with the distress and disappointment of having your hopes that this was the end of having to deal with your hepatitis C.

Here are some of my thoughts (my two cents worth) on cirrhotics and other “hard to treat” folks and our new and soon to be coming treatments.

In the article you referenced the doctor is pointing out the limitations of the COSMOS Phase 2 trials. Something which has been noted in every medical article published about this treatment but largely ignored in all of the media hype headlines that get constantly repeated as a panacea for all infected people. For those who have little liver disease, are treatment naive, or genotype 2 the data lives up to the hype with SVR rates in the 90% + range. But unfortunately that is not the case for all of us who are infected. Once we look behind the headlines and the 100% cure rate hype… we see that real story is much more complex for us "harder to treat" patients. For those of us with cirrhosis, treatment experienced, folks.

If we look at SVR rates in cirrhotics with our current treatments the clinical trials SVR rates have been and continue to be in the 80%-90% range at best.  Whether it is Sovaldi + peg-interferon + ribavirin,  Sovaldi + ribavirin or Sovaldi and Olysio. (The only exception is for genotype 2 cirrhotics with a SVR rate of 92% if memory serves me which is consistent with being an easier to treat genotype. Conversely for genotype 3, treatment experienced cirrhotics the data for 24 weeks of treatment is very poor. 60%.

Genotype 1s current treatments:

NEUTRINO - SOVALDI + Peg-IFN alfa + RBV - 12 weeks - cirrhotics
SVR 80% (43/54)
Genotype 1, Metavir F3/F4 fibrosis, IL28B non-C/C, HCV RNA >800,000 IU/mL
SVR 71% (37/52)

COSMOS - Simeprevir/Sofosbuvir 12 weeks - cirrhotics
SVR 86%
Simeprevir/Sofosbuvir + Ribavirin 12 weeks - cirrhotics
SVR 91%

By the way, the next so-called "Miracle Cure" hype of Sovaldi and Ledipasvir.  The SVR rates are consistent with current treatments. In the ION 2 12-week arms SRV was 82% with Ribavirin and 86% without the addition of Ribavirin. (With 24 weeks of treatment SVR was 100%).
Also note: " The number of patients with cirrhosis was fairly small—only 22 in each arm—so this may need further study." Jordan J. Feld, MD, MPH
So again we see cirrhotics under represented in the trials which makes these numbers less than reliable in real world use.

Is there hope for us hard to treat folks? YES. The data from trials of cirrhotics and post transplant patients show more efficacy, though no 100% cure... the AbbVie (ABT-450/r/ABT-267 + ABT-333 + RIBAVIRIN) combo for example. But again it depends on each patient’s particulars (your “host factors”), genotype  1a or 1b, if and how you failed peg-interferon and Ribavirin treatment (null-responder, relapser etc.). All this trial data is available for anyone interested. So again based on your particular host factors, you and your doctor will choose the best available treatment for your particular situation until a newer/more effective treatment comes along.

TURQUOISE-II Results

GT1a 88.6% (n=124/140)
     New to therapy (treatment naive) 92.2% (n=59/64)
GT1a treatment-experienced
     Prior null responders         80.0% (n= 40/50)
     Prior relapsers                93.3% (n= 14/15)
     Prior partial responders   100.0% (n= 11/11)
GT1b 98.5% (n=67/68)
     New to therapy (treatment naive) 100.0% (n= 22/22)
GT1b treatment-experienced
     Prior null responders 100.0% (n=14/14)
     Prior relapsers            100.0% (n=25/25)
     Prior partial responders   85.7% (n= 6/7)

Which brings us back to the main question. So why are us treatment experienced cirrhotics and other "hard to treat" folks treating with Sovaldi and Olysio treatment? …Because it is simply THE BEST treatment currently available for many of us, even with all of its limitations.

• It the ONLY 12 week, all oral, treatment that not only eliminates peg-interferon but for some, also eliminates Ribavirin as well. Why is this important? First because peg-interferon has the well documented risk of causing decompensation in cirrhotics and more rarely, liver failure. Not something we want to risk. Making a patient liver disease worse when we are trying to help them get better and possibly avoid transplant if at all possible. A case of possibly doing more harm than good. A few of my friends have ended up needing liver transplants sooner because peg-interferon based treatments. It is unfortunately but it was the only option available to them at the time.
• Secondly cirrhotics on average have MORE side effects from treatments and more medically SERIOUS side effects. Whether from peg-interferon which we know can cause dangerously low platelet counts in cirrhotics and when combined with Ribavirin can also cause dangerously low red and white blood counts. For all of cirrhotics who have treated with these interferon based treatments we know this only too well. We all have our horror stories about our 24 or 48 weeks of "treatment".

For us cirrhotics (and other “hard to treat” folks) treating with Sovaldi and Olysio with or without Ribavirin for 12 weeks.... we have for the very first time...
1. A treatment that we can complete (very few have to stop treatment due to side effects)
2. While being undetectable, typically for about 8 weeks, at least temporarily are stopping further damage to our liver
3. And probably most importantly, this treatment provides us with the best known change of SVR

Compared to the previous and forgotten 14% cure rate of cirrhotics treating with peg-interferon + Ribavirin only a relatively few years ago or the PI treatments that a large number of cirrhotics couldn't even finish due to the increased in side effects. We with cirrhosis and other "hard to treat" patients have come light years from where we were even last year. While for some folks we are close to a cure, for cirrhotics we are getting closer but still have a ways to go before we see cure rates close to 100%.

If we look at the data for all of us we see hep C treatments have never been more effective and safe.

So now I am treating with Sovaldi, Olysio + Ribavirin. Why? Because I want to stop any further damage to my new post transplant liver, first. That we know these new treatments do.  After a little more than a week of treatment I am undetectable. So the first goal of treatment has been achieved. Will I be cured? Who knows? I hope so, but I am not putting all of my eggs in that basket. While I know that for genotype 1b and IL28B CC like myself, all were cured in the COSMOS trials who had cirrhosis, showing the treatment is very effective. Olysio being more active against 1b virus, COSMOS was only a PHASE 2 trial. Which excluded folks post transplant folks like me as well as those who failed PI treatment. So the data doesn’t exactly apply. And as pointed out in the article, only a very SMALL group of people treated in these trials. ONLY 27 people with cirrhosis treated with the Sovaldi, Olysio + Ribavirin treatment. And ONLY 14 people treated with Sovaldi and Olysio. Not the scores or hundreds we typically see in Phase 3 trials. Which is now why there are ongoing Phase 3 trials to get a more accurate assessment of how these two treatments really work in patients, including cirrhotics, so Janssen can get FDA approval for this treatment. As we all know, this treatment is “off label” because of the lack of data.
...

[hepcandme]

that was an interesting piece

I sent it to my doc. He Loves it when I send him stuff (not!)

thanks for posting