General Survey re: Anti-virals

[Gingergrrl]

"Oh, and heapsreal, your idea of pushing the virus to go lytic and then attack it is exactly what they do for EBV lymphomas. Its a brutal business, though, and not one Id be willing to risk. I'll try to find some links to articles."

@Woolie can you explain what this means (in a non science version for dummies .)

 

[Woolie]

@Gingergrrl

Here's an article about the tumour stuff.

http://jvi.asm.org/content/78/4/1893.full

This is how I think it goes from memory: Herpes viruses like EBV can exist in two different states or "phases", latent and lytic. In their latent phase, they hide in various cells (especially B lymphocytes) in a way that most other viruses can't - so the cells don't carry any markers that the immune system can detect, and they can't be touched. They can persist in the body indefinitely. In their lytic phase they release virus particles from the cell which then penetrate other cells, recruiting new hosts.

But there's more to the latency phase - the virus hijacks some of the cell's machinery, making the B cells less effective at fighting infections in general. Apparently, they inhibit the production of certain substances that you need for effective immune function, and stimulate the overproduction of others - some of which cause flu-like symptoms when produced in large amounts (doesn't that sound a bit like MECFS?). Then they wait for an opportunity to go into the lytic phase –so they can infect new people - usually when the immune system is busy fighting some other infection and so already under stress (doesn’t that also sound like MECFS?).

But there’s more. The viruses’ host cells can also split to create copies of themselves, preserving the entire viral contents inside. So these viruses don't even need to go into the lytic phase to reproduce themselves. Very nasty. And finally, they can make their host cells live longer than they normally would - even forever in some cases. They call these "immortal cells" and they are the stuff of which tumours are made.

Tumours (lymphomas) caused by these immortal EBV-infected cells and hard to treat because the latently infected cells are hard to kill without also killing healthy cells. So one approach to treatment is to get the cells to go into the lytic phase. Then they burst open and release their contents, killing themselves in the process. At the same time, you treat with really strong antivirals to prevent the virus particles from actually entering new cells.

 

[josephine2]

Hi- on generic: Famciclovir 500mgs daily - mfg is Macleods
Taking it approximately 20 days and feel dizzy, nausea but afraid to stop. My EBV titers were so high and alsohave mycoplasma pneu - so took azythrom. for that until the GI. was too much. Right now with bad sinus infection and miserable and wonder if this is some response to antiviral or some resistant bacteria. Last week tried Levoquin for sinus (because 20 years ago I tolerated it) WHOA - couldn't even get past 2 pills with that stuff. So now just in bed like the old days.

 

[heapsreal]

@Gingergrrl

Here's an article about the tumour stuff.

http://jvi.asm.org/content/78/4/1893.full

This is how I think it goes from memory: Herpes viruses like EBV can exist in two different states or "phases", latent and lytic. In their latent phase, they hide in various cells (especially B lymphocytes) in a way that most other viruses can't - so the cells don't carry any markers that the immune system can detect, and they can't be touched. They can persist in the body indefinitely. In their lytic phase they release virus particles from the cell which then penetrate other cells, recruiting new hosts.

But there's more to the latency phase - the virus hijacks some of the cell's machinery, making the B cells less effective at fighting infections in general. Apparently, they inhibit the production of certain substances that you need for effective immune function, and stimulate the overproduction of others - some of which cause flu-like symptoms when produced in large amounts (doesn't that sound a bit like MECFS?). Then they wait for an opportunity to go into the lytic phase –so they can infect new people - usually when the immune system is busy fighting some other infection and so already under stress (doesn’t that also sound like MECFS?).

But there’s more. The viruses’ host cells can also split to create copies of themselves, preserving the entire viral contents inside. So these viruses don't even need to go into the lytic phase to reproduce themselves. Very nasty. And finally, they can make their host cells live longer than they normally would - even forever in some cases. They call these "immortal cells" and they are the stuff of which tumours are made.

Tumours (lymphomas) caused by these immortal EBV-infected cells and hard to treat because the latently infected cells are hard to kill without also killing healthy cells. So one approach to treatment is to get the cells to go into the lytic phase. Then they burst open and release their contents, killing themselves in the process. At the same time, you treat with really strong antivirals to prevent the virus particles from actually entering new cells.

Do u know of any other ways to bring these viruses out of latency other then the drugs mentioned in the article?
It sounds like an interesting concept, it would be good to be able to get these viruses when they are latent too??

 

[heapsreal]

Hi- on generic: Famciclovir 500mgs daily - mfg is Macleods
Taking it approximately 20 days and feel dizzy, nausea but afraid to stop. My EBV titers were so high and alsohave mycoplasma pneu - so took azythrom. for that until the GI. was too much. Right now with bad sinus infection and miserable and wonder if this is some response to antiviral or some resistant bacteria. Last week tried Levoquin for sinus (because 20 years ago I tolerated it) WHOA - couldn't even get past 2 pills with that stuff. So now just in bed like the old days.

Thats sux, i think alot of the time sinus infections are very under rated unless your the sufferer. They can really knock you down and greatly increase cfs symptoms. Sometimes the simple things work like low dose of doxycycline and slowly increase the dose and at the same time continually rinsing sinuses with saline sprays or something similar?

Its hard to see the effects of antivirals when u have another ongoing bacterial infection going on?

 

[Woolie]

Do u know of any other ways to bring these viruses out of latency other then the drugs mentioned in the article?
It sounds like an interesting concept, it would be good to be able to get these viruses when they are latent too??

Heapseal, I had a look at some more articles, alas quite a few were beyond my grasp. The only medications I saw identified for inducing the lytic cycle were the really nasty ones used in chemo. Most commonly described was bortezomib - check out the side effects on wikipedia! Plus, you'd want to be really sure you didn't end up infecting more cells in the process.

 

[heapsreal]

Heapseal, I had a look at some more articles, alas quite a few were beyond my grasp. The only medications I saw identified for inducing the lytic cycle were the really nasty ones used in chemo. Most commonly described was bortezomib - check out the side effects on wikipedia! Plus, you'd want to be really sure you didn't end up infecting more cells in the process.

Yes saw the chemo drugs which is why i asked if u have heard of any other ways.

Generally when im off av's i can get a good read on when the viruses reactivate going by symptoms and then hit them hard for a few weeks. My last 'crash' i didnt get a good read on it, i think because i was trialling some valtrex, in the past this hasnt worked for me, but it may have worked enough to put me off being able to read my symptoms. So my delay in hitting it hard with famvir(also thought the valtrex would have helped) is probably the reason why i crashed harder then i have for awhile and recovering slower than previously. Generally 2-3 days of viral symptoms i start back on famvir, this last episode was a couple of weeks, too long.

Im not sure if using av's on an as need basis is another way that could work and getting at the viruses 'better' and reducing latent viral load. I do think though initially people need to stay on av's long term at first before using them on an as needs basis??

Im also looking at using interferon inducers with the antivirals in this as needs manner. Long term use their effects seem to wear off, ie my experience with cycloferon, although it does work well initially for the first couple of weeks?

 

[Gingergrrl]

Hi- on generic: Famciclovir 500mgs daily - mfg is Macleods
Taking it approximately 20 days and feel dizzy, nausea but afraid to stop. My EBV titers were so high... Last week tried Levoquin for sinus (because 20 years ago I tolerated it) WHOA - couldn't even get past 2 pills with that stuff. So now just in bed like the old days.

@josephine2 Thanks and was just curious about your dosage as I take 1500 mg of Famvir per day for high EBV titers, too. As far as the Levaquin, you did the right thing to stop after two pills and it is one of the most dangerous meds on the market. There are definitely alternative antibiotics that you can request.

Heapseal, I had a look at some more articles, alas quite a few were beyond my grasp.

@Woolie, thanks for trying to explain all that (re: viruses) and it was above my grasp as well!

 

[Woolie]

Yes saw the chemo drugs which is why i asked if u have heard of any other ways.

Generally when im off av's i can get a good read on when the viruses reactivate going by symptoms and then hit them hard for a few weeks. My last 'crash' i didnt get a good read on it, i think because i was trialling some valtrex, in the past this hasnt worked for me, but it may have worked enough to put me off being able to read my symptoms. So my delay in hitting it hard with famvir(also thought the valtrex would have helped) is probably the reason why i crashed harder then i have for awhile and recovering slower than previously. Generally 2-3 days of viral symptoms i start back on famvir, this last episode was a couple of weeks, too long.

Im not sure if using av's on an as need basis is another way that could work and getting at the viruses 'better' and reducing latent viral load. I do think though initially people need to stay on av's long term at first before using them on an as needs basis??

Im also looking at using interferon inducers with the antivirals in this as needs manner. Long term use their effects seem to wear off, ie my experience with cycloferon, although it does work well initially for the first couple of weeks?

@heapsreal, this is a really interesting approach! Like you, I also have a crash-recover-crash sort of pattern, and can "feel" the different phases. Plus, I'm encouraged that you've had such success using famvir, suggesting there really must be something in it.
Oh, another lytic inducer I saw in my readings was arsenic Needless to say, I'm not going there!

 

[minkeygirl]

@Woolie I've bad great luck with famvir too. I had a huge crash in August. It took me a month to realize it was a stress related reactivation

I had been taking 500 mgs famvir so upped it to 750. I had almost immediate relief but 2 days later I felt bad again.

I upped to 1000 mgs and within 2 days I felt hugely better. I stayed at 1000 mgs for a month then dropped down to 750 and I'm still ok.

My plan is when I know I have something stressful coming up (dentist appt) I'll up to 1000 and get them before they get me!

I had also been rotating immune mods for a year but unlike @heapsreal i never noticed anything specific from them.

I've been off for a few days because I got clobbered from arbidol. I'll try again with 1/2 cap.

 

[JT1024]

Looks like Famciclovir has positive effects when used in conjunction with Celebrex. (See below ********) I've been on Valtrex and Celebrex but suspected the dosage wasn't right. I had enormous improvement when Valtrex was added to the Celebrex. Looking forward to seeing my Dr. again very soon.

*********

Results of Dr. Pridgen's Phase 2 clinical trials were revealed at today's American College of Rheumatology conference today in Boston. From the title below, it appears Famciclovir prevailed over other antivirals tested. Can't wait to hear more about this. Hopefully, a publication or presentation will be forthcoming.

http://www.acrannualmeeting.org/wp-...4-ACR_ARHP-Annual-Meeting-Program-Book-v2.pdf

A Combination of Celecoxib and Famciclovir Is Efficacious in the Treatment of Fibromyalgia: Results of a Phase IIa Randomized, Double-Blind, Placebo-Controlled Study
William Pridgen1, Carol Duffy2, Judith Gendreau3 and R Michael Gendreau3, 1Innovative Med Concepts, Tuscaloosa, AL, 2University of Alabama, Tuscaloosa, AL, 3 Gendreau Consulting, LLC, Poway, CA

 

[Woolie]

@Gingergrrl @heapsreal

A late addition to this forum, but one that gives me renewed hope that antivirals will be effective in the long term, even if there is little or no active infection. The article reports a reduction in the number of latently EBV-infected B cells in healthy people after long-term antiviral use.

So if healthy people, with presumably mostly latent infection, can still benefit in this way, then we will probably benefit at least as much if not more.


Long-Term Administration of Valacyclovir Reduces the Number of Epstein-Barr Virus (EBV)-Infected B Cells but Not the Number of EBV DNA Copies per B Cell in Healthy Volunteers
http://jvi.asm.org/content/83/22/11857.full
Abstract: Epstein-Barr virus (EBV) establishes a latent infection in B cells in the blood, and the latent EBV load in healthy individuals is generally stable over time, maintaining a “set point.” It is unknown if the EBV load changes after long-term antiviral therapy in healthy individuals. We treated volunteers with either valacyclovir (valaciclovir) or no antiviral therapy for 1 year and measured the amount of EBV DNA in B cells every 3 months with a novel, highly sensitive assay. The number of EBV-infected B cells decreased in subjects receiving valacyclovir (half-life of 11 months; P= 0.02) but not in controls (half-life of 31 years; P= 0.86). The difference in the slopes of the lines for the number of EBV-infected B cells over time for the valacyclovir group versus the control group approached significance ( P= 0.054). In contrast, the number of EBV DNA copies per B cell remained unchanged in both groups ( P= 0.62 and P= 0.92 for the control and valacyclovir groups, respectively). Valacyclovir reduces the frequency of EBV-infected B cells when administered over a long period and, in theory, might allow eradication of EBV from the body if reinfection does not occur.

 

[Gingergrrl]

@Woolie do you think the above study would also apply to Famvir or only Valtrex?

 

[Woolie]

@Gingergrrl, I can see no reason why not, as I understand it, Lerner considers them to be largely interchangeable as EBV antivirals (and some say, maybe even better?). Maybe someone who knows more about these drugs might want to comment?

Here's something else encouraging I found out (have lots of time at the moment, stuck in bed in a crash).

Antiherpes antivirals (valtrex, famvir, valcyte, visitide, etc.) work by latching on to a substance called thymidine kinase (I'll call it TK). This substance is produced by cells as they transition from EBV latency to the lytic phase. There are three stages to the transition process: 1) early-immediate (or IE); 2) early; and 3) late. The thymidine kinase/TK is produced at the second stage - which is oddly called "early". The virus particles themselves aren't released until the late stage. This seems to me to be good news, as it means you don't have to produce active virus particles in order to benefit from antivirals. All you need is for some of the cells to get to the second stage of the transition process some of the time.

Another encouraging thing I discovered was that when these antivirals attach to the TK, they don't just stop the cell from producing virus particles, they actually kill the cell. Some of the stuff I read - which was mainly about valcyte - also suggested that when this type of cell killing happens, there is also a "bystander effect", meaning other cells in the proximity also get killed. So you get a bigger result than you'd expect. Which also seems to me good news! Not sure how much of this translates to valtrex and famvir, though, but I expect the same basic mechanism could be at play.

Not sure how much of this makes sense, even for those currently without brain fog... happy to clarify (at least as far as my own dodgy incomplete knowledge allows).

 

[heapsreal]

Interesting. I was under the belief that antivirals didn't work on latent infections, so that is good to know. Also interesting about killing the viral infected cells, maybe when people feel bad initially on avs it is because of a viral die off? ?

Cheers

 

[Woolie]

Interesting. I was under the belief that antivirals didn't work on latent infections, so that is good to know. Also interesting about killing the viral infected cells, maybe when people feel bad initially on avs it is because of a viral die off? ?

Cheers

@heapsreal, yes, now the idea of "die-off" with AVs doesn't sound so out there, does it?

I've been on valtrex for 9 months now. One change I've noticed is that when I do have a major crash (bedridden, severe flu like symptoms for 7-10 days), I now also get gut wrenching stomach cramps and severe diarrhea. Thought it was a coincidence, but maybe not - maybe the crashes are the times when this kind of AV-induced cell killing is at its peak?

 

[Butydoc]

@heapsreal, yes, now the idea of "die-off" with AVs doesn't sound so out there, does it?

I've been on valtrex for 9 months now. One change I've noticed is that when I do have a major crash (bedridden, severe flu like symptoms for 7-10 days), I now also get gut wrenching stomach cramps and severe diarrhea. Thought it was a coincidence, but maybe not - maybe the crashes are the times when this kind of AV-induced cell killing is at its peak?

Hi Woolie,

This sounds very interesting. Can you provide me with the reference concerning antivirals and die off. I wasn't aware that these drugs caused this type or reaction to the infected cells. Maybe this could explain the "Herx" reaction that many people experience on antivirals.

Best,
Gary

 

[Woolie]

@Butydoc, I was afraid someone would ask this, should have kept better notes!

Here are some of the articles I looked at, most from cancer journals, but the parts about the mechanisms of the antivirals are not cancer-specific. (Notice they're all about valcyte, I'm figuring the mechanism might be the same for all the antiherpes AVs, but not sure).

I accessed the articles via my University so not sure if they are available freely, happy to supply copies if you would like.

Would love your thoughts on all this as a professional!

Israel, B. F., & Kenney, S. C. (2003). Virally targeted therapies for EBV-associated malignancies. Oncogene, 22(33), 5122-5130. (review article)
The relevant bit: "Tumor cells containing the lytic (but not latent) type of EBV infection express virally encoded kinases (BGLF4 and the viral thymidine kinase) that induce phosphorylation of the prodrug, GCV, converting it to its active cytotoxic form (Moore et al., 2001). Phosphorylated GCV inhibits not only the virally encoded DNA polymerase, but also inhibits the host cell DNA polymerase and is thus cytotoxic (Tiberghien, 1994; Conners, 1995). Furthermore, phosphorylated GCV can be transferred into nearby cells, thus inducing 'bystander' killing (Freeman et al., 1993; Chen et al., 1995; Conners, 1995).

Feng, W. H., Hong, G., Delecluse, H. J., & Kenney, S. C. (2004). Lytic induction therapy for Epstein-Barr virus-positive B-cell lymphomas. Journal of virology, 78(4), 1893-1902.
The relevant bit: "EBV manifests two distinct phases in its life cycle: latency and lytic replication. During latency, EBV expresses a limited number of viral genes, which are involved in tasks such as stimulating cell proliferation, inhibiting apoptosis, blocking viral lytic replication, and assuring accurate and equal partitioning of the episomal viral genome to daughter cells (31, 43). However, during the lytic replication phase of the EBV life cycle, many more viral genes are expressed which encode proteins involved in viral DNA replication and viral particle synthesis. In addition, during the lytic form of infection, two virally encoded kinases, the EBV thymidine kinase (EBV-TK) and the BGLF4 gene product, which phosphorylate the prodrug GCV and convert it into its active cytotoxic form (11, 33, 37, 41, 53), are expressed. Phosphorylated GCV inhibits not only the virally encoded DNA polymerase but also the cellular DNA polymerase, leading to premature termination of the nascent DNA and cell death (14, 23, 34). In addition, phosphorylated GCV can be transferred to adjacent cells, thus inducing “bystander” killing (23). Lytic EBV infection also confers sensitivity to the cytotoxic effects of zidovudine (AZT), possibly by inducing AZT phosphorylation (10, 28, 41, 52). However, GCV and AZT are not generally effective for treating EBV-positive tumors because most tumor cells are infected with the latent form of EBV and therefore do not express the kinases which activate these drugs."

Young, L. S., & Rickinson, A. B. (2004). Epstein–Barr virus: 40 years on. Nature Reviews Cancer, 4(10), 757-768.
The relevant bit: “Other approaches are based on the induction of the EBV lytic cycle, either by pharmacological agents or by delivery of EBV immediate-early genes, thereby inducing virus-encoded kinases (EBV thymidine kinase and BGLF4, a protein kinase) that phosphorylate the nucleoside analogue gancyclovir to produce its active cytotoxic form”.

 

[Gingergrrl]

@Woolie Thank you for doing all this research and sharing it with us. I am so curious to hear what @Butydoc thinks of it and everyone else with strong science backgrounds. I am now wondering if Valcyte would have been a better choice for me than Famvir but I just don't think I would have tolerated it and would have gotten all the dangerous side effects (as I always do.)

 

[heapsreal]

(Notice they're all about valcyte, I'm figuring the mechanism might be the same for all the antiherpes AVs, but not sure).

Some of the studies you mention are valacyclovir which is valtrex not valcyte, valgancyclovir is valcyte.

Long-Term Administration of Valacyclovir Reduces the Number of Epstein-Barr Virus (EBV)-Infected B Cells but Not the Number of EBV DNA Copies per B Cell in Healthy Volunteers

So the above study is talking about valtrex, so i would take it that valtrex and famvir would have direct killing effect of ebv??

Easy to get the generic name of valtrex and valcyte mixed up.