Vertex as monotherapy

Why can't telepravir work as monotherapy?

[HCA]

Rapidly reduces viral level when tested as a monotherapy,but does not eliminate.
Virus quickly rebounds back up again.

[mremeet]

What HCA said is right, pretty much any protease or polymer inhibitor (PI) like VX950 will only knock the virus down temporarily by itself. Anyone who is infected with HCV has a variety of "breeds" or viral genetic variations within them. There is a huge population of viral particles within most of us, somewhere around a trillion copies. Although the vast majority of viral particles will usually be quickly eliminated after being exposed to the PI, a select few remain capable of reproducing while in the presence of the PI (which normally would inhibit or stop reproduction). These few are of a different genetic makeup than the bulk of the remaining population. So what usually happens is that shortly after taking the PI monotherapy (like VX950), the viral load sharply declines very rapidly. This initial decline eliminates nearly all of the vulnerable virus (i.e. the majority), but it selectively allows the resistant strains to survive, albeit in small initial numbers. Once the primary (non-resistant) population has been eliminated by the effects of the PI, the PI resistant strains continue to replicate largely unhindered and produce more and more of their offspring - which share its same exclusively PI resistant genetic attributes.

Finally it gets to the point where the non-resistant population is gone, leaving only the ever increasing resistant strains to then populate the sudden void left in the "ecosystem" (i.e. your body and liver). The viral population then begins to rapidly rebound because it's rapidly shifting to exclusively resistant strains, which are unaffected by the PI. Couple this fact with the very high reproductive rate of HCV (i.e. a few hours). This shows up as a sharp initial viral decline, followed by a gradual rebound to baseline levels, usually taking about 2-4 weeks (from what I've usually seen).

So that's why these drugs always have to be dosed with at least one other drug that has a differing anti-viral mechanism. Right now interferon and ribavirin are what's being used. Hopefully they'll also eventually be able to combine different PI's together to produce an effective anti-HCV cocktail without the use of interferon or ribavirin. Which will hopefully result in a much shorter, more humane and more effective treatment than what is currently offered via IFN/riba.

[GrandOak]

Initial trials were performed as monotherapy pharmacutical and found to be ineffective for the reasons given.

I can't recall if it also demonstrated resistance mutation or just the ineffectiveness because it only addresses one of the replication factors used by the virus.  For some reason I'm thinking the later which is why trials shifted as an additional meds for the tx cocktail.

[Hepatitis Researcher]

Not only will monotherapy rapidly lead to resistance and rebound, even under continuous dosing - with some delay - but from there on you could not use this drug as part of a promising combotherapy, since the resistance mutant has been archived and will rapidly resurge under selective pressure. This scenario works only too well with all the HIV and HBV drugs and it will play out in the HCV arena as well. So beware of loosing the possibly single trump card by playing it out naively.
The Alinia report a few dowm shows you the same scenario, very much expected. It does not at all mean that this could not have done wonders as part of a combo.

[ChrisDDD]

That was a very helpful explanation, seriously.  Thank you!

[GrandOak]

Thanks for the clarification.  I seemed to recall seeing abstracts to that effect when I was researching this med during tx, but could remember for sure and didn't have the info right at hand nor a reference to it.

I seem to still endure reside brain fog from 10 months of tx even though it's been 3 months of no meds.  

I seem to recall that these proteases or polymers being studied also are geared towards stopping or slowing viral replication not eradication and that Interferon is still the only known agent capable of killing the virus.

Perhaps with your insights into the R&D world that you are aware of anything being considered as possible alternatives to it which is as or more effective in eradication without mutation.  Inquiring minds are desiring to know and I for one would appreciate hearing about them.

[Hepatitis Researcher]

There were actually resistance mutations found to almost all Vertex Monotherapy participants. Some high, some lower level resistance mutations, after only 8 weeks duration.