Resistance and Treatment Failure are really the same thing. 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 vests 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....
Log Kill Rates
Each DAA (Direct Acting Antiviral) drug has what is known as a log kill. A log kill of -1 kills 9 out of 10, a log kill of -2 kills 99 out of 100, etc
Sofosbuvir has a log kill of something like -4.5 which means it kills about 31999 out of 32000 viruses
www.medscape.com/viewarticle/811157
Ledipasvir has a log kill of -3 which means it kills 999:1000
www.ncbi.nlm.nih.gov/pubmed/24320933
Daclatasvir has a log kill of -3.3 which means it kills 1999:2000
Ribavirin has a log kill of only -0.5 which means it kills about 2 out of 3 viruses
www.ncbi.nlm.nih.gov/pmc/articles/PMC3002526/
I can't find data for log kill for Simeprevir (pointers welcome).
Log kill reflects the fact that for any one drug there are typically some survivors and the next drug's job is to "take them out". It makes sense that the next drug should use a different mechanism so taking Ledipasvir + Daclatasvir would not make much sense because either one can inhibit NS5A for GT1.
You don't get entirely additive benefits. Some of the viruses present will be killed by more than one method so the extra killing power goes to waste.
The goal of therapy is to reduce the number of viruses to absolute zero or very close. We know in chimpanzees that 1-10 virions (single virus units) is typically not enough to cause infection but > 100 almost always does cause infection.
www.ncbi.nlm.nih.gov/pubmed/14554088
How resistance happens
As mentioned in
Understanding Hep C and the new DAAs
the Hep C virus is like a mini photocopier. The thing is it's not a very good one. While it does make decent copies we all know a copy of a copy of a copy can end up blurry. With HCV that means it mutates into many "imperfect" forms.
Almost all of these imperfect copies are defective and die. Some however still work, although maybe not as well as "mum" or "dad" or really "the clone master" that originally entered the body.
In viruses we see rapid Darwinian evolution - survival of the fittest. If I can't breed as fast as you, then you have more clones and before we know it I'm a small minority group subject to persecution.
Now enter a DAA. All of a sudden the playing field changes. Whereas before putting on my bullet proof jacket just so worked great, now perhaps it does not and the small minority groups that mutated a little have a great advantage.
Enter a second DAA - it's job is to kill these ones off.
Enter a third DAA - it's job is to pick off any survivors....
Looking to the future
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.
If all of Sofosbuvir + Daclatasvir + Simeprevir were available it's hard to argue that might not be gold class.
If you wanted 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.
A word of warning
All drugs have side effects. For all genotypes there are proven combinations with excellent results. Sometimes less is more so my advice is go with the evidence and take the recommended combination(s). If that means you're cirrhotic and Ribavirin is suggested please take that or if you really don't want to make sure you extend to 24 weeks.
