Where did you come across chinese firms manufacturing these API’s”?

See this for links to the latest about this combo: http://hepatitiscnewdrugresearch.com/grazoprevirelbasvir.html

It is only phase 2 stuff, so not at scale.

Grazoprevir (an NS3/4A protease inhibitor) and elbasvir (an NS5A inhibitor) and it is being used with Ribavirin.

It would be comparable to using Simeprevir (NS3/4A) and Ledipasvir/Daclatasvir (NS5A).

It is missing the secret sauce of Sofosbuvir’s pan genotypic log 4.5 kill rate.

Merck show real decency with their $4.50 Gardasil vaccine price to the 3rd world compared to their $130 1st world price which of course looks nothing like Gilead’s pricing structure. It would be great if they could get 95% + cure rates (preferably without Riba) but it’s still an open question because the trials are still small.

Hi Jonathan,

Let’s start by saying I don’t have any practical experience treating DAA recurrence so this is only a combination of book knowledge and background knowledge. I would advise taking your specialist’s advice, but here are some things to consider.

NS5A RAVs don’t necessarily render NS5A inhibitors useless because resistance is invariably relative. Here is what it looks like on a petri dish:

The white disc contain antibiotic and the clear area around them gives a visual of how effective they are (or how resistant the bacteria are to being killed). The antibiotic concentration falls off with distance from the disc and where you see the bugs growing is where the antibiotic falls below the MIC (Minimum Inhibitory Concentration).

So if I was 1a I would have 12 weeks of Sofosbuvir+Daclatasvir+Simeprevir and I would be considering increasing the 12 towards 24 weeks on the basis is 8 weeks works for F0, 12 weeks for F1-3, and 24 weeks for F4 it is probably more like

F0 8 weeks
F1 12 weeks
F2 16 weeks
F3 20 weeks
F4 24 weeks

The trials divided people into cirrhotic and non cirrhotic and found the 12 vs 24. This was to make 2 statistical buckets rather than 4 buckets without enough n.

Fibrosis is a spectrum from none to lots so if we need lots of treatment time for high fibrosis we “probably” would be better to use a bit more than 12 weeks for F2 and F3. Can’t prove it. Can’t show you evidence, but makes logical sense to me.

It’s not directly applicable to you but the recent trial n=468 for F3/F4 GT3 patients failed to show any benefit for 24 weeks Sof+Dac+Riba versus Sof+Dac alone. http://fixhepc.com/media/kunena/attachments/391/CCO.pdf

From theAASLD guidelines:
http://www.hcvguidelines.org/full-report/retreatment-persons-whom-prior-therapy-has-failed

“Recommended regimen for patients in whom previous treatment with any HCV nonstructural protein 5A (NS5A) inhibitors has failed (including daclatasvir plus sofosbuvir, ledipasvir/sofosbuvir, or paritaprevir/ritonavir/ombitasvir plus dasabuvir).
For patients with minimal liver disease, deferral of treatment is recommended, pending availability of data.

For patients with cirrhosis or other patients who require retreatment urgently, testing for resistance-associated variants that confer decreased susceptibility to NS3 protease inhibitors and to NS5A inhibitors is recommended. The specific drugs used in the retreatment regimen should be tailored to the results of this testing as described below. Treatment duration of 24 weeks is recommended and, unless contraindicated, weight-based RBV should be added.”

Jonathan asked:
“My specialist has suggested a 12 week course of sofosbuvir/simeprevir/ribavirin – what are your thoughts? Any alternative options that may have greater efficacy?

His specialist is in line with the AASLD recommendations for his case if he is cirrhotic:
“For patients who have NS5A inhibitor RAVs detected and who do not have NS3 inhibitor RAVs detected, treatment with simeprevir, sofosbuvir, and RBV for 24 weeks is recommended.

So, even given that resistance is relative, what do you know that allows you to say with any degree of confidence that an NS5A in the combo would have greater efficacy than ribavirin against NS5A RAVS?

dt

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…

Hi dt,

Yes, lots of unanswered questions. Also, its difficult to separate the marketing from the medicine. It seems to me that making a treatment guideline about whether or not someone is “treatment-naive” (for NS5A or anything else) only makes sense if there is only one treatment for each target protein. And this is not the case now. But the report you cite says there is just not enough data to really know.

As Dr James said before, Jonathan’s treatment did not involve the usual sofosbuvir. So unless he wants to be a guinea-pig again, probably his next treatment should be sofosbuvir+X, where X is not grazoprevir or elbasvir.

Unless, elbasvir is some kind of “me-too” version of ledipasvir or daclatasvir, I’d guess its probably OK to try the usual Sof+Dac or Sof+Led combo. The received medical advice is Sof+Led for GT-1: http://fixhepc.com/getting-treated/genotype-specific-hepc-treaments.html.

Just looking at the pictures, they all look like quite different but vaguely similar molecules. But these pictures are only 2D chemical representations, and not how they might look in a 3D.

https://en.wikipedia.org/wiki/Elbasvir
https://en.wikipedia.org/wiki/Daclatasvir
https://en.wikipedia.org/wiki/Ledipasvir

Sorry, Jonathan. I’m not trying to plan your future here!

Heck, I’m not a Dr, so I stop now…