Hi Mike,

I’m also a bit on the fence on this one. I appreciate you are trying to reach people stuck behind enemy lines. But it would be a real pity if all your ground-work gets lost if the famous Joy-To-The-World deletes your thread.

Do you have to push the big red G-button so soon?

Cheers,

Vororo

Hi folks,

Here is my (non-medical) understanding of RAVs.

Imagine a world in which Big Pharma executives were paid an annual bonus in which all their crisp $100 dollar bills were glued together? Probably they would figure out a way to make a super-sized tailor-made pocket that would be just right for their juicy bonus.

But what if we could change the juicy bonus by just a bit, without telling anyone in advance?

Each different NS5A inhibitor is a small molecule with a slightly different shape, but each is capable of blocking a key active site or “pocket” on the NS5A protein. Usually a RAV (resistance associated variant) has some kind of mutation in the amino acid composition of the protein near the active site. For example Q30R means the usual “Q” has mutated to “R” which causes the shape of the active site to change and the inhibitor to fit the pocket less well (or not at all). As far as the virus is concerned, the trick is to make such a change without also knocking out its original biological function (whatever that is for NS5A). The nasty thing about Hep-C is it mutates rapidly, and this is how it escapes our immune systems. But most mutations are away from any active pockets, because otherwise the mutated form just wouldn’t work any more. So the trick for the virus to survive a drug molecule is to find a mutation on the drug’s target site that does not also render the protein useless.

From Jonathan’s story, it seems that the Q30R mutation allows the virus to survive elbasvir (NS5A inhibitor), and taking that with grazoprevir (a NS3/4A inhibitor) alone is not enough to kill the virus.

Sofosbuvir blocks a “pocket” on NS5B, and that protein seems to be more essential to the virus (or its harder for the virus to make an escape mutant in the NS5B pocket that survives).

But the point I really want to make is that a virus protein might escape one drug, but it can still be clobbered by another one which fits the pocket in a slightly different way – with or without the mutation. So in Jonathan’s case, a different NS5A inhibitor from elbasvir could still work on his NS5A RAV.

As there are lots of new antivirals coming on-line, this means lots more possible combination treatments. But it then becomes a question of doing many clinical tries to see which actually work.

If you follow that kind of argument through, the best Hep-C treatment would use a triple combination – whack NS5A, NS5B, and one of the others like NS3A or NS4A all at the same time. There’s no way a virus can simultaneously mutate all three proteins in the space of a few weeks! Result? No more virus despite the RAVs. It then just comes down to a question of cost … How many DAAs can we afford to throw into the deadly mix for a cost-effective treatment?

Big Pharma is often accused as producing lots of “me too” drugs, just to make more money. But for anti-virals, as long as the new molecule fits the pocket in a slightly different way, this could end up being a real advantage as far as alternative treatments are concerned.

And of course, each new alternative *should* bring down the cost. But as we all know, the Mutant-Executives who work in Big Pharma have figured out how to escape the rules of the market and still keep their fat bonus pockets full.

Still, the more DAAs, the better…

This is great news for Australians… And crucially, the article states:

“The move will make Australia one of the first countries in the world to publicly subsidise the drugs for their entire population, no matter what a patient’s condition is or how they contracted the disease.”

A quick calculation – let’s suppose the govt will pay Gilead 50 000 per patient: 230 000 * 50 000 = 11 500 000 000 (11.5 BIllion). Therefore, assuming a spend of 1 Billion per year, it will take 11.5 years.

Of course, not all of this money goes to Gilead, so add a few more years. And of course prices will come down so subtract a few years (and/or dollars).

Conclusion?

1. The Australian Govt will finally cover everyone who is really sick. Great News!!

2. Its reasonable to suppose there will be prioritisation of patients in the first few years, which is completely fair, given the cost.

3. For everyone else who wants treatment now, they will still need to look to generics, e.g. with fixHepC

But Wait A Minute!

Who wants to bet on whether the Australian Government will source from Gilead or from the generics?

If its from Gilead, guess what kind of “voluntary” anti-generic deal Gilead will try to slip in ???

Oh, shit… Now is the time for everyone in Australia to do some very heavy lobbying !!! .

We live in dangerous times.

Hi GAJ,

Your last post has set me thinking about how far we should go about posting messages here from other HepC forums.

Knocking ignorant moderators seems to be fair game, but I have a feeling that reproducing some-one else’s post in full (even if you disagree with it) is crossing a line somewhere. Why not just post a link to it or quote an extract without the e-mail address?

Well, no offence intended, but that’s just my 2-cents…

Cheers,

Me, I’m swallowing about 2 Kalashnikovs per day in US prices.

Ooh, you guys are really mean!!

Just for the record, here is how it played out…Now you see it, … now you dont!

(sorry I missed the last few posts)