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mallani


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RE: Musings
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Hi all,

Just a bit more about the antiproteases. Some are on ViekiraPak so are exposed to ABT-450, and Merck's MK-5172 will shortly enter the playing field.

Our virus's protease is a serine protease- that just means that serine is the amino-acid at the enzyme's active site. It is closely related to trypsin, one of the most powerful digestive enzymes produced by the pancreas. This was recognised way back in 1989 and work was started to block this enzyme. The earliest clinical trials of an antiprotease were in 2002, when BILN-2061 (ciluprevir) was trialled. I remember reading the early results and started to get hopeful. This was very effective against the Genotype 1  wild-type virus but hopeless once resistant variants emerged (usually after 3-4 weeks). The next trial was using VX-950. This was even more effective in reducing the viral load to zero, but again, it could not cope with the resistant variants. Many different antiproteases were trialled, prior to the FDA approval of Victrelis and Incivek in 2011.

The structure of the viral protease is the problem. It's shallow and easily transformed.

Victrelis and Incivek were only used with Peg. and Ribavirin to cope with the mutations. Since Peg/Riba have a dreadful list of side effects, getting an accurate picture of the side effects of Victrelis and Incivek was not easy. By looking at other serine proteases, researchers hoped that these may explain side effects. Serine proteases are everywhere in the body,and they co-ordinate various physiological functions, like digestion, blood clotting, reproduction and immune response. Victrelis was noted to cause a more profound anaemia than that of Riba alone, and gut disturbances including the dreadful dysgeusia (metallic taste in mouth) were common. Skin rashes were not common, and if present were probably due to Riba. Incivek caused dreadful skin problems, and up to 30 % of patients had to stop treatment due to the rash. Anorectal issues, anal fissures etc. were also common. It was not possible to directly blame these side effects on individual serine proteases.

Olysio was the next antiprotease. Skin hypersensitivity and nausea were the main side effects. The RAV's were just as much of a problem, so again, Peg/Riba was used. When Sovaldi became available, they were used together so some patients could drop the Peg/Riba.

Now we have ABT-450 in ViekiraPak. Same problem potential RAV's, this time avoided by including another 2 DAA's.

All of the antiproteases are metabolised by the enzyme pathway CYP3A, so there is a wide potential for drug interections. These are now well known and listed.

So, although it's the oldest known viral replication site, blocking it is not without problems. Cheers.



__________________

Geno 1b, IL28B CT,  x3 prior relapser,  ex-cirrhotic, 75 yo, did 48 weeks with Victrelis/Peg./Riba.  VL 1.28m at start, UNDET. at 8 ,12 ,16 ,24 ,30  and 48 weeks.  EOT 15 Feb 2013 , UNDET. at EOT + 28 weeks. SVR!  Still Undet. at EOT +5 years

Malcolm
Tig


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This has been a very thought provoking and educational thread thus far. Excellent topic Testiva! The discussion has been more than interesting. Thanks for the explanation on the related actions Malcolm. If you wrote that from memory, I kneel in amazement! Your knowledge continues to serve all of us well. It's very appreciated.

Tig



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Tig

68yo GT1A - 5 Mil - A2/F3 - (1996) Intron A - Non Responder, (2013) Peg/Riba/Vic SOT:05/23/13 EOT:12/04/13 SVR 9+ years!

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Zlikster


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Cheers Malcolm for explanation,

hence Sofosbuvir (as NS5B inhibitor) + GS-5816 (as NS5A inhibitor) are in my view the silver bullet regarding HCV and possible sidefx from tx. Not sure how Gilead will call that combo, but it's the one i look forward the most.

Long term sx from first gen of DAAs that inhibit NS3-4A like Boceprevir, Telaprevir,etc are yet to be known. Those drugs have been for how long now, 4th or 5th year since in active use? Not to mention that ABT-450 has to be boosted with Ritonavir which on it's own has plenty of sx.

anyways, can't wait for SOF+GS-5816 combo :) i am putting my money it's THE pangenotype antihcv combo that will be least harmful and most effective. Glad Gilead signed (already!) deal for generic version of that combo to be produced in India.

best



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GT 3 dg. 08-2012 / FibroScan: 5 kPa F1 / FibroTest: F0-1 A1 / SoC TX: PegInt 120mcg+Riba 1000mg UND from w8 relapse EOT+4w
01-2016 Sof+Dac+Riba UND from w8, SVR24!
mallani


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Hi Testiva,

Good to see you thinking outside the box.

The antiproteases, like Olysio, Victrelis, Incivek and ABT-450, block the viral protease found at site NS-3 and it's co-factor NS-4A. This protease splits the virus into 4 separate fragments. A protease is just an enzyme that splits proteins by severing polypeptide bonds. There are many proteases in the human body. NS-3 is a serine protease, so all serine proteases may be blocked by the DAA antiproteases. Most of these are found in the gut and produced by the pancreas. Non-serine proteases are not affected. Some of the side effects of the antiproteases may be blamed on this action but the mechanism is not fully understood. Once we stop taking our antiprotease, all serine proteases return to normal.

The NS-5A and NS-5B viral structures are not found elsewhere in the human body. They are only found in the HCV. This may explain why blockers of these sites cause few side effects. Cheers.



__________________

Geno 1b, IL28B CT,  x3 prior relapser,  ex-cirrhotic, 75 yo, did 48 weeks with Victrelis/Peg./Riba.  VL 1.28m at start, UNDET. at 8 ,12 ,16 ,24 ,30  and 48 weeks.  EOT 15 Feb 2013 , UNDET. at EOT + 28 weeks. SVR!  Still Undet. at EOT +5 years

Malcolm
Rubye


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Ditto to what Greg says.



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UNDETECTED 5/4/15 - 16 weeks after EOT, 1st treatment - Sovaldi and Olysio, Geno 1a, 67 year old with compensated cirrhosis, over 40 years with HCV.
Greg D


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Thanks for your thoughts. I, for one, have found them extremely thought provoking.

I know there is something else at play here in post treatment besides just normal aging. As a layperson all I have is the 'feeling' that something has profoundly changed and I may never return to where I left off, prior to treatment. It's hard to explain but it's similar to the 'feeling' one gets when he knows he's being watched.

That being said, I am still better off now than I would have been if I hadn't been treated, however we, as a human race, strive for the perfect silver bullet and that's what makes us search and search and search for better ways. It's very cool that we have that instinctive drive. This is what will eventually make future treatments less invasive. Unfortunately you don't get to the next step until you take the step before, there's no getting around it.

Thanks Testiva.



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60 yo (2013), genotype 2b, started 28 week tx Sept.14, 2013. Triple Therapy (ribavirin, victrelis, peginterferon), VL 235k prior to tx, UND right through. EOT March 29, 2014. EOT24 Sept. 15, 2014 and EOT + ONE YEAR April 1, 2015 UND.... SVR!

 
skewedButNotBroken


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It would be quite naive to believe that the hep c virus is the only biological function to use the NS3/4A and NS5B pathways. In fact, I will postulate that billions of biological processes use these pathways. When they are inhibited with drugs such as Olysio and Sofosbuvir, the body must immediately find alternate methods to conduct its necessary processes to sustain life. The virus, on the other hand, (as a general rule) dies off en mass.

I do not believe that the human body will ever use these pathways again. That's why even though the virus is cleared many people never feel the way that they anticipated that they would.Why? The body has been biologically altered and in a sense has re-wired itself. The body is an amazing thing and will strive to survive even if it means fundamentally altering itself in a drastic way such as growing new arteries or veins that have been clogged, etc, 

I would bet that there is no scientific evidence that once the NSA/4A and NS5B pathways have been inhibited that these pathways open back up again. It's analogous to a river that changes course due to a blocked pathway. Once the new pathway has be created the forces of nature keep the river flowing in it's new path.

Cheers,



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Diag. with hep c in 1992; A3:F2;  GT 1a; IL28B CT; VL 900k, ALT 150, AST 100 on 8/5/2014; SOT 9/5/2014  S/O ---VL 127 after 6 days; VL detected on day 18 but < 15.; --> UND @ EOT+ 1 year SVR!
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