TOPIC:

I am gen 1b, with fiboscan 15.I have spent hours reading reports from various trials.My specialist says no comparaitive studies have been done and does not really know.
There is also a paper presented at the last EASL conference which presents prelimerary results from a combination of sof plus sim plus declat amongst cirrhotic patients.Which appears to be very successful,but there are no followup results of this Impetus 2 trial.
www.natap.org/2015/EASL/EASL_30.htm
I am able to access (at a cost) any of these 3 alternatives.Since my specialist appears not to know,I would be very grateful for any opinions
on this.

As you note the data is currently inadequate to be definitive. With 15 kPA on your fibroscan you are F4 and with that the cirrhosis sub groups are the ones most applicable to you. 24 weeks of treatment will be required.

On first principles we observe with HIV there has been a progression from 1 to 2 to 3 (or more) medications and HAART - Highly Active Anti Retroviral Therapy. Given HIV and Hep C are similar there are probably useful lessons but it is still experimental.

Looking to mechanisms:

• Sofosbuvir is a pan genotypic RNA polymerase inhibitor
• Daclatasvir is a pan genotypic NS5A inhibitor
• Ledipasvir is an NS5A inhibitor
• Simeprevir is an NS3/4A inhibitor
• Ribavirin is a guanosine analog (fake RNA component)

Failure to clear represents the selection of resistance. The way I explain it to patients is like this:

• You have 1000 soldiers and you shoot them all with a machine gun
• 100 were wearing bullet proof vest so you walk along with a sword and chop their heads off
• 10 "idiots" put their vests on wrong, covering their necks so you drop rocks on their heads
• 1 "idiot" put the armour plate meant for the front of the vest on his head....

Each drug has what is known as a log kill. A log kill of 1 kills 9:10, 2 kills 99:100

Log kill reflects the fact that for any one drug there are typically some survivors and the next drug's job it to "take them out". It makes sense that the next drug should use a different mechanism to taking Ledipasvir + Daclatasvir would not make much sense because either one can inhibit NS5A for GT1b.

If all of Sofosbuvir + Daclatasvir + Simeprevir were available it's hard to argue that would not be gold class.

If you want to go totally experimental Ribavirin has been shown to provide impressive results in cirrhotics with Sof + Dac so HAART in Hep C might end up as: Sof+Dac+Sim+Riba.

The fundamental problem with small trials is the margin of error. At n=100 this is +/-10% so the 96.6% you might read should really be 96.6% +/- 10%. In other words the confidence intervals of the various options overlap making it impossible to be definitive.

Your priority is more about starting than choice because fibrosis is progressive but regresses in the face of reduced or zero viral load. The more fibrosis you have the harder it will be to get to cure.

Thank you for this most useful and informative reply Dr James.Could I trouble you for a further opinion?
In fact I can probably go "Gold Standard"
Courtesy of Greg Jefferys and Rachel at Mesochem I have had 3 months supply of Sofosbuvir,Declatasvir,and Ribavirin sitting in the fridge
for 6 weeks now,while I'm shunted between my GP and Specialist with endless delays for appointments.
Simeprevir is available on the PBS,so a triple or quadruple attack is not totally out of the question.
I note in the Impetus 2 trial all partisipants had much higher fibroscan readings,yet a 100% positive result was achieved at 3 months with the triple combination.You mention 24 wks as mandatory in my case but is this dependent on the combination?For 24 wks therapy I will have to try and access another 3mnths supply,which might not still be available if Big Pharma has its way.
I should mention that I am 75yrs old,but not done yet.I recently completed a 600km mountain bike ride with some very steep hills.
Earlier in the year I climbed Mt Agung in Bali,Mt Ranjani in Lombok,and Mt Fansipan in Vietnam.My most tangible problem is knees.

Hi Miko,

My personal experience: I've been treated with Simeprevir+interferon+ribavirin. The Simeprevir side effects were by far the worst. I thought I was going to die. Once I finished the Simeprevir part of the course, the interferon side effects were, in comparison, just mildly unpleasant.

Also, no bike riding on Simeprevir. After the first week, every time I went out, my skin started peeling off, and I grew big, red blisters on my eyeballs. After the second week, I was bed ridden. On top of that, the treatment was totally ineffective.

On the other hand, maybe Simeprevir will work for you.

Your priority is more about starting than choice because fibrosis is progressive but regresses in the face of reduced or zero viral load. The more fibrosis you have the harder it will be to get to cure.

There is not perfect choice. Take the Sof+Dac tomorrow. Continue to think about the other options while you get better.

You've heard from someone who has had Sim. I have no idea, never used it. Could be bad luck could be common.

Thank you Dr James.I just wish someone like you was supervising my treatment.Unfortunately you live at the opp end of the continent.
I hope you eventually get the peer recognition you deserve for your humantarian efforts.

PKQ.Your post on Simeprevir scares the living daylights out of me.It does not seem to tally with the reported results of trials.But then they are often drug company sponsored.
Is there anyone else out there reading this that has had a similar experience with Simeprevir?