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.

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.