Valcyte: does it work because of its antiviral or immunomodulatory properties (or both)?

[OnlyInDreams]

I wonder how much brincidofovir will cost though. Will it be priced beyond the reach of many ME/CFS patients?

Also, will brincidofovir work as well as Valcyte for treating ME/CFS?

If Valcyte's anti-inflammatory effects (it's a potent microglial inhibitor) and its immunomodulatory effects are part of why Valcyte helps ME/CFS, and if brincidofovir does not possess these mechanism of action, then brincidofovir may not replace Valcyte.

I have no idea what the cost will be. I know that Chimerix has a 30 year patent on the drug. So in terms of pricing, Chimerix is totally in control. Hopefully they won't be too greedy.

As for mechanism of action, they are quite similar in that they both preferentially inhibit viral DNA polymerases.

Here are some bits of info in regards to mechanism of action:

Cidofovir is a nucleotide analogue which inhibits viral DNA polymerase and is effective against human cytomegalovirus (CMV) infection. It is phosphorylated to its active form by cellular enzymes. With the long intracellular half-life of its metabolites, cidofovir can be administered weekly during induction and every other week during maintenance therapy.

Acting as an antiviral agent by preventing the replication of CMV, cidofovir targets viral DNA polymerase and prevents transcription. Because the viral polymerase is 8 to 600 times more sensitive than human DNA alpha, beta, and gamma polymerases, the active ingredient, cidofovir diphosphate, is able to specifically target viral replication processes.

Cidofovir is a monophosphate nucleotide analogue. After undergoing cellular phosphorylation to its diphosphate form, it competitively inhibits the incorporation of deoxycytidine triphosphate into viral DNA by viral DNA polymerase. Incorporation of the drug disrupts further chain elongation [1]. Unlike nucleoside analogues such as acyclovir or ganciclovir, cidofovir is not phosphorylated (and hence activated) by a viral kinase.


Notice how the administration of maintenance therapy is every other week! So you would take the pill bi-weekly!

Another key point is the main difference between Valcyte and Brincidofovir, which is the fact that Brincy is not phosphorylated by the virus. So it does not require activation on the part of the virus to incorporate (embed) itself into the viral DNA. The implication here is that Brincy would be less susceptible to drug resistance in the event of viral DNA mutation. Because when the genes are mutated, then activation on the part of the virus may not occur. At least, that's my understanding of it.

I don't believe that Valcyte's anti-inflammatory effects are what ultimately resolve the core problem with ME/CFS folks. That may treat symptoms, but not the root, which is viral DNA replication. Brincy seems to mitigate viral DNA replication in a superior, safer fashion when compared to Valcyte.

 

[Hip]

It's certainly going to be very interesting to see if brincidofovir does bring major benefits to ME/CFS patients when it becomes available at the end of 2016.

 

[redaxe]

The only downside to Brincy that I have read of comes from one of Cort's articles
http://www.cortjohnson.org/blog/201...t-pridgen-testing-kristin-loomis-talks-pt-ii/

Quoting
"Still, brincidofovir is not a magic bullet because like the other three drugs available to treat HHV-6 (cidofovir, foscarnet and ganciclovir/valganciclovir) it has no activity against the virus when it is “semi-latent” (active enough to throw off chemokines and cytokines) but not replicating. This class of drugs can only prevent replication. In other words they can put out the fire, but can’t help with the smoldering coals. That may be one reason why longer treatment periods seems to work better in these patients. The smoldering coals will eventually die down."

So it seems like it will be better and safer than Valcyte but not a perfect magic bullet. But as some have pointed out if the cost is not too high, and it is safe than there is no good reason why we shouldn't be able to stay on it for long periods of time.

 

[Hip]

Quoting
"Still, brincidofovir is not a magic bullet because like the other three drugs available to treat HHV-6 (cidofovir, foscarnet and ganciclovir/valganciclovir) it has no activity against the virus when it is “semi-latent” (active enough to throw off chemokines and cytokines) but not replicating.

If the theory that some subtypes of ME/CFS may be due to partial reactivation of Epstein-Barr virus is correct, then brincidofovir may not help these cases much at all.

 

[OnlyInDreams]

"Still, brincidofovir is not a magic bullet because like the other three drugs available to treat HHV-6 (cidofovir, foscarnet and ganciclovir/valganciclovir) it has no activity against the virus when it is “semi-latent” (active enough to throw off chemokines and cytokines) but not replicating.

I don't think there will ever be a perfect magic bullet for ME/CFS. Because all forms of the herpes virus are able to hide & remain latent, evading the immune system. It will always try to act on opportunities to rear its ugly head when we're the most vulnerable (stress, weakened immune system, etc). That's why we will have to medicate for the rest of our lives. Which is why it's so important to have a drug that is effective and non-toxic. Eventually, those smoldering coals will die off too. That's the icing on the cake.

If the theory that some subtypes of ME/CFS may be due to partial reactivation of Epstein-Barr virus is correct, then brincidofovir may not help these cases much at all.

Brincidofovir was designed to treat CMV. It is also very effective against HHV6 because the two are so similar. For EBV, you could just take Valtrex, which is also non-toxic.

 

[leokitten]

My issue with this comment is the part where you said Valcyte will have to be taken in cycles "for the rest of your life". There is a worthy alternative to Valcyte, it just isn't available yet. Brincidofovir has been given "Fast track" designation and is currently enrolling folks for the Phase 3 SUPPRESS trial. Assuming everything goes as planned with the trials, I read that Brincy will become commercially available in either Q4 2016 or Q1 2017. This drug has the expectation of being 65x more potent than Valcyte AND completely non-toxic, no cancer risk what-so-ever. It will effectively replace Valcyte as a treatment method for CMV and HHV6 (as wells and dozens of other viral infections). So your near future targeted therapy has been identified and is being vetted as we speak.

My plan is to stay on Valcyte until Brincy is released. I think that the cancer risk of taking Valcyte until late 2016 / early 2017 is low. And then I will stay on Brincy for the rest of my life, no breaks.

If you haven't heard of Brincidofovir, you can visit the drug maker's website:

www.chimerix.com

I think you need to read the entire thread @OnlyInDreams, we have been discussing here the possibility/theory that Valcyte could have more of it efficacy in ME/CFS due to its immunomodulating/immunosuppressive properties than its antiviral properties. I mentioned that if this turns out to be true then we would have to take it in cycles for the rest of our lives because like all current autoimmune medications it doesn't cure the disease and must be taken forever.

I have written multiple posts here on PR informing people on brincidofovir, its clinical trials and its eventual replacement for CMV/HHV-6 infection. In fact when people switch to brincidofovir this will be a an excellent test examining the possible underlying cause(s) of ME/CFS. Brincidofovir I believe does not have any significant immunomodulating/immunosuppressive action and as you stated has a much stronger antiviral action than Valcyte.

So if people get worse after switching or have less symptom relief then this will add to the evidence that ME/CFS being an autoimmune disease, if they get much better then this will add to the evidence that ME/CFS is an infection-driven disease. The underlying cause could also be a bit of both, if the viruses are actually causing the autoimmunity, but none of us will care to know if we do get better anyway

 

[leokitten]

If the theory that some subtypes of ME/CFS may be due to partial reactivation of Epstein-Barr virus is correct, then brincidofovir may not help these cases much at all.

This is not true, brincidofovir is a conjugated lipid and prodrug of cidofovir, it becomes cidofovir in the cell, and cidofovir has strong antiviral activity against EBV and pretty much all dsDNA viruses.

 

[leokitten]

I wonder how much brincidofovir will cost though. Will it be priced beyond the reach of many ME/CFS patients?

It will definitely be priced beyond reach of ME/CFS patients that don't have insurance. It's the first drug of its type, using Chimerix's conjugated lipid technology.

Also, will brincidofovir work as well as Valcyte for treating ME/CFS?

If Valcyte's anti-inflammatory effects (it's a potent microglial inhibitor) and its immunomodulatory effects are part of why Valcyte helps ME/CFS, and if brincidofovir does not possess these mechanism of action, then brincidofovir may not replace Valcyte.

It's going to be an excellent real-world experiment to help elucidate the underlying causes of ME/CFS. Brincidofovir I believe does not have any significant immunomodulating/immunosuppressive action and has a much stronger antiviral action than Valcyte. So if people get worse after switching or have less symptom relief then this will add to the evidence that ME/CFS being an autoimmune disease, if they get much better then this will add to the evidence that ME/CFS is an infection-driven disease. The underlying cause could also be a bit of both, if the viruses are actually causing the autoimmunity, but none of us will care to know if we do get better anyway

 

[Hip]

So if people get worse after switching or have less symptom relief then this will add to the evidence that ME/CFS being an autoimmune disease, if they get much better then this will add to the evidence that ME/CFS is an infection-driven disease.

The immunomodulatory effects of Valcyte may be causing the immune system to better fight of the virus, so if people get worse after switching from Valcyte to brincidofovir, this might be due to a resurgence of the virus.

 

[Hip]

This is not true, brincidofovir is a conjugated lipid and prodrug of cidofovir, it becomes cidofovir in the cell, and cidofovir has strong antiviral activity against EBV and pretty much all dsDNA viruses.

Possibly that's right, although since cidofovir is an inhibitor of viral DNA replication, perhaps its effectiveness against partial EBV reactivation may depend on how just much replication takes places during this partial reactivation.

 

[redaxe]

No.

Sorry for asking for more details if you don't mind answering.

How long have you had CFS for?
and have you ever been tested by a CFS specialist for HHV6, EBV and CMV?

 

[IreneF]

Sorry for asking for more details if you don't mind answering.

How long have you had CFS for?
and have you ever been tested by a CFS specialist for HHV6, EBV and CMV?

I was diagnosed about 10 years ago. I am regularly tested for HHV-6 and EBV by Dr. Montoya.

 

[redaxe]

I was diagnosed about 10 years ago. I am regularly tested for HHV-6 and EBV by Dr. Montoya.

I wonder if Rituximab needs to be combined with long term Valtrex. Theoretically if you destroy all the malfunctioning B cells with chemotherapy but you still have some unsuppressed EBV activity that remaining EBV may continue to attack new B cells.
That is one hypothesis that Cort Johnson has also discussed that EBV can trigger autoimmunity by hijacking B cells. You can kill off those B cells but unless the virus is suppressed it's only a temporary solution.
Just like killing infected humans that are bitten by zombies but leaving the zombies in the community to continue attacking more healthy people