Valganciclovir research paper - Jose Montoya & Andreas Kogelnik

[Sasha]

I know valcyte definately helped me and when i came off i crashed within 8 weeks. The quick fall has shown me how much it helped as many symptoms have returned or intensified since i stopped. I think for those who respond, the issue maybe how to maintain this improvement when off valcyte. I think this is where they need to look into ways of improving immune function.

My impression from reading the studies of the clinicians' records is that for many people, the improvement maintains in the long term. It's a while since I've read the studies so my memory of that could be wrong. As with so many things with ME, I wonder if there's a range of responses from zero to temporary to almost permanent.

 

[Sparrowhawk]

This is disappointing to see but thanks for the link.

This doesn't seem to square at all though with what Dr. Kogelnik told me two months ago his experience was with Valcyte which was that 30% approx of his patients got much better (though no indication of how long they held that effect); about a third of his patients saw some benefit, and it may not have lasted. And a third could have been taking nothing. Eg noresponse. I've been going along considering Valcyte because of that 30% shot, now I'm not sure it's worth three potential toxicity. SOC I know it worked for you and your daughter and that's part of what made me continue to consider this option.

 

[SOC]

I know valcyte definately helped me and when i came off i crashed within 8 weeks. The quick fall has shown me how much it helped as many symptoms have returned or intensified since i stopped. I think for those who respond, the issue maybe how to maintain this improvement when off valcyte. I think this is where they need to look into ways of improving immune function.

I think Dr Lerner believes that longer treatment is needed to get at deep tissue infection, so if you stop too soon, the remaining areas of active infection just keep spreading and you start to feel sick again.

 

[SOC]

SOC I know it worked for you and your daughter and that's part of what made me continue to consider this option.

I seems likely to me that those who respond to Valcyte are a subset of PWME. The fact that 3 people in my extended family responded well (2 fully functional, 1 greatly improved) to Valcyte suggests that we have something in common -- genetics, the same virus, who knows? We were at 3 different levels of illness -- one mild, one moderate, and one severe. We had a range of HHV-6 titres from barely high to very high, so that doesn't seem to be common factor. Daughter and I have different immune abnormalities -- she has low NK cell number and function, I have high NK cell function but low CD8+ cell count -- so that is not the commonality.

It seems likely at this point that ME/CFS will turn out to be multiple illnesses classed under one heading. Perhaps one of those groups responds to Valcyte. If Dr Kogelnik's numbers are right, two thirds (67%) of his patients have a positive response, which sounds like a big subgroup, but it's not all of us.

I'm one who didn't achieve full functionality with Valcyte. I'd take it again for the same amount of improvement.

 

[Legendrew]

I think Dr Lerner believes that longer treatment is needed to get at deep tissue infection, so if you stop too soon, the remaining areas of active infection just keep spreading and you start to feel sick again.

I'm not sure I agree with this considering that many of the viruses implicated infect neurones.

I seems likely to me that those who respond to Valcyte are a subset of PWME. The fact that 3 people in my extended family responded well (2 fully functional, 1 greatly improved) to Valcyte suggests that we have something in common -- genetics, the same virus, who knows? We were at 3 different levels of illness -- one mild, one moderate, and one severe. We had a range of HHV-6 titres from barely high to very high, so that doesn't seem to be common factor. Daughter and I have different immune abnormalities -- she has low NK cell number and function, I have high NK cell function but low CD8+ cell count -- so that is not the commonality.

It seems likely at this point that ME/CFS will turn out to be multiple illnesses classed under one heading. Perhaps one of those groups responds to Valcyte. If Dr Kogelnik's numbers are right, two thirds (67%) of his patients have a positive response, which sounds like a big subgroup, but it's not all of us.

I'm one who didn't achieve full functionality with Valcyte. I'd take it again for the same amount of improvement.

The improvement rate Dr Kogelinik discusses is likely inflated through the exclusionary testing which he likely does meaning those he treats have already been divided into a subgroup who are more likely to respond. I think the results from his recent trial likely reflect the more likely outcome in the general ME population IE a smaller subset benefit. It's definitely worth further work though - i'm very intrigued to see the results for his multi-arm approach to a rituximab trial get underway - especially how the rituximab in conjunction with valcyte fares compared to rituximab alone.

 

[Sasha]

The improvement rate Dr Kogelinik discusses is likely inflated through the exclusionary testing which he likely does meaning those he treats have already been divided into a subgroup who are more likely to respond.

What exclusionary testing does he do?

 

[heapsreal]

Proper sub grouping improves the risk to benefit ratio and will improve the overall success rate of the treatment. In the future these treatments would more likey be approved as a treatment for cfs me if they can predict more accurately who will respond. For us in Australia could mean that the cost of a drug like valcyte would be covered by the health system here. Also maybe better treatments will be found.

Cheers

 

[Legendrew]

What exclusionary testing does he do?

I can't say for certain but i'm sure I remember reading somewhere that he does tests for viral antibody titres - surely if these are lower it would be unlikely that you would respond to antiviral therapy (presuming that the antiviral action is what makes people feel better of course.)

 

[Sasha]

I can't say for certain but i'm sure I remember reading somewhere that he does tests for viral antibody titres - surely if these are lower it would be unlikely that you would respond to antiviral therapy (presuming that the antiviral action is what makes people feel better of course.)

I've read in his earlier paper that he treats according to high IgG titres but having read all the ME Valcyte papers, I can't see much relationship, if any, between initial titres above their threshold and response to treatment. Also, high IgG titres aren't generally accepted as evidence of current (as opposed to past) infection. This is making me wonder if Valcyte is operating via a different mechanism and if they haven't really identified a subset at all - maybe a random sample of PWME would do just as well (or badly). Or maybe high IgG's to individual viruses are an indirect measure of general immune function.

It's a bit of a mess.

 

[heapsreal]

I've read in his earlier paper that he treats according to high IgG titres but having read all the ME Valcyte papers, I can't see much relationship, if any, between initial titres above their threshold and response to treatment. Also, high IgG titres aren't generally accepted as evidence of current (as opposed to past) infection. This is making me wonder if Valcyte is operating via a different mechanism and if they haven't really identified a subset at all - maybe a random sample of PWME would do just as well (or badly). Or maybe high IgG's to individual viruses are an indirect measure of general immune function.

It's a bit of a mess.

testing is a mess but i think if the doc can put a few tests together then it could hint at an active infection. I think if one has borderline viral titres, t cell markers and has low nk function then theres a good chance that those viruses are causing issues. The only real way to know is to try and treat the infections and see if improvement occurrs.
Im not sure if viral titres are an indication of severity either and then when one is on antiviral treatment, titre levels can be even more confusing as some can start to feel better but tests show titres going up. I think all this shows they need better viral testing??

 

[Sparrowhawk]

Dr. K. did pages of initial tests on me, including viral antibodies, immune function indicators, cell counts, and nk cell function test. Given those results he then wanted to do viral blood levels for my big three (hhv6, CMV, ebv), and he said if any of them were high then I should consider antivirals asap. They all turned out to be below detectable levels so he said I could do what, at the time, was my preference: waiting to see if I could get better with rest and nutrition/supplementation. Basically Montoya looked at all the tests Dr. K. had done and checked all the boxes -- said he couldn't think of anything else that would make sense to test (not surprising because they essentially are coming out of the same root approach) and they both said "see you again in six months."

 

[Sparrowhawk]

My impression from reading the studies of the clinicians' records is that for many people, the improvement maintains in the long term. It's a while since I've read the studies so my memory of that could be wrong. As with so many things with ME, I wonder if there's a range of responses from zero to temporary to almost permanent.

Yes that last is my impression, of course Valcyte hasn't been in use long enough to track lifelong "permanent" but if you consider 5 years healthy as a standard, that may be true for some subset of those who tried it.

 

[Sparrowhawk]

Circling back to this thread after having found and read the great interview here:
http://thoughtsaboutme.com/2011/04/...ting-chronic-fatigue-syndrome-and-immunology/

I am just not getting the contrast between the paper that started this thread, and his comments below. Am I missing something? The papers basically "meh" about the effects of Valcyte. Yet below, and when I spoke with him a few months ago, he seemed to be saying 30% or better efficacy. Confused here.

Dr. K. then talked a bit about the placebo-controlled Valcyte study at Stanford. Valcyte is a relatively new antiviral, but it’s about to go off patent. There have been some “good treatment successes” in treating CFS with it. It targets largely the herpes virus family. According to Dr. K., the initial data from the Stanford trial was underwhelming. But over time, it turned out that there were some consistent changes across the patients. Most of the patients continued to improve after the range of the study period. Patients were taking Valcyte for six months. They were evaluated at six months and one year. Many of them reported that they had gotten back, or close, to their healthy levels only after the one-year mark. A lot of them are not tracked anymore because Stanford lost touch with them.

Dr. K. thinks that several hundred if not several thousand of CFS patients have been trying Valcyte in the US and that nobody has been tracking those patients. He said tongue in cheek that Roche must be very happy that Stanford did that trial because it probably prompted many CFS patients to try it.

Dr. K. said that there is a possibility that the very strong patient-reporting outcomes of the initial (uncontrolled) Stanford study were the result of a selection bias because patients were not selected at random. Self-reported pre-treatment activity levels were at an average of 10%, which Dr. K. called “pretty lousy.” Those patients reported that they were at 90 % after 6 months of Valcyte. Dr. K. called this outcome “pretty amazing.”

This first, uncontrolled trial was followed up with the placebo-controlled trial of Valcyte. Some people didn’t respond to Valcyte at all. It seems that people are either going to respond to it or not. According to Dr. K., the duration of the treatment was and still is in question. How long do patients need for their immune systems to recover? He likened it to cardiac surgery after which you wouldn’t expect the patient to get off the operating table and go jog. He said that there is a long rehab process, the duration of which depends on the health of the patient before the surgery, comorbidities and the level of support and stress after the surgery.

In terms of antibody levels, some of the patients in the trial had some really high HHV-6 and EBV numbers. One of the patient’s EBV VCA IgG was 10,240, which is something you would never see in the general population where you normally see numbers between 140 and 180. A year after the six-month treatment with Valcyte, only half of the patients dropped their antibody levels.

Dr. K. didn’t say anything about some patients actually feeling worse in the long run after taking Valcyte.

 

[heapsreal]

Circling back to this thread after having found and read the great interview here:
http://thoughtsaboutme.com/2011/04/...ting-chronic-fatigue-syndrome-and-immunology/

I am just not getting the contrast between the paper that started this thread, and his comments below. Am I missing something? The papers basically "meh" about the effects of Valcyte. Yet below, and when I spoke with him a few months ago, he seemed to be saying 30% or better efficacy. Confused here.

So its either going to work or its not. I guess it comes down to a good diagnosis then or luck. If we look at dr lerners work, thise with hhv6 etc that dont respond he says have an underlying bacterial infection, so those non responders may need their doc to investigate deeper.

The other question is how long does one stay on valcyte before their immune system recovers, well for me its now over 12 months and im sure many others. We need a good drug to get our immune system going as well to use along side valcyte.

Good news valcyte is going generic, anyone know when that is??

cheers!!!

 

[Sparrowhawk]

Looks like it goes generic in 2015? http://www.drugs.com/availability/generic-valcyte.html

 

[Hip]

(The following wdb quote comes from this thread).

They measured 16 different outcomes, 14 of which showed no significant difference and 2 of which showed a small significant improvement. Overemphasising the two exceptions is textbook p-hacking.

Dr Martin Lerner's and Prof Jose Montoya's Antiviral Protocols for Herpesvirus-Associated ME/CFS

Table III (shown below) from Montoya's 2013 paper indicates that it was mental fatigue and cognitive function which improved the most with Valcyte.

Table III from Prof Montoya's Valcyte 2013 Study

Montoya used a total daily dose of 900 mg of Valcyte. However, I think Prof Montoya ended this Valcyte trial rather prematurely at 6 months, before the full benefits had time to manifest, and they mention this in the paper: "findings in this study suggest that clinical trials using longer courses of VGCV [Valcyte] and a larger sample size are warranted."

A flaw in Montoya's study was the ME/CFS severity scale he used to measure the outcome, which was the Multidimensional Fatigue Inventory (MFI‐20). This is a bad scale, because it is purely subjective. It does not measure objective changes, and so cannot accurately measure improvements in ME/CFS.

Whereas Lerner used a more objective severity scale, his Energy Index Point Score. So Lerner's study was better at accurately quantifying the improvements.


In Dr Lerner's 2010 study on Valtrex (valacyclovir) and Valcyte (valganciclovir) for herpes family infections in ME/CFS, he treated patients for up to 6 years with Valtrex and/or Valcyte, using Valtrex (1,000 mg four times daily) for active EBV infections, and/or Valcyte (900 mg in the morning and another 450 mg twelve hours later) for active HHV-6 or cytomegalovirus infections. Ref: 1

Note that Valtrex 500 mg twice daily is equivalent in efficacy to acyclovir 200 mg five times daily. Ref: 1

So presumably Valtrex 1000 mg four times daily is equivalent in efficacy to acyclovir 800 mg five times daily.

If you look at Table 3 (shown below) in the Lerner study, which shows the average improvement in ME/CFS patients' Energy Index Point Score (EIPS), you see that it takes around 2 years of treatment before you get 2-point increase on this EIPS scale (the row I highlighted in green indicates the 2 year point). Note that each row of table 3 represents a three month interval.

Table 3 from Dr Lerner's 2010 Valcyte and Valtrex Study

So this table 3 shows that the full benefits of Valcyte and Valtrex only appear after around 2 years of treatment. If you continue to take these antivirals for longer than 2 years, the table shows slight further improvements can be achieved, but the bulk of the improvements in health are achieved in the first two years of treatment.

So anyone considering taking Valcyte and Valtrex for herpes infections really needs to think in terms of committing to 2 years of treatment, if they want to obtain the full benefits.



Note that on the EIPS scale:
Level 4 = Out of bed sitting, standing, walking 4 - 6 hours per day (the rest of the day in bed).

Level 6 = Daily naps in bed, may maintain a 40 hour sedentary work week plus light, limited housekeeping and/or social activities.

Dr Lerner found that 75% of the patients he treated increased their Energy Index Point Score by at least 1 point. So most patients do have some response.

When the patient only had EBV infections, they were treated with Valtrex (or Famvir) 1,000 mg every six hours. If the patient had HHV-6 or cytomegalovirus, they were give Valcyte 450 mg x 3 daily.



Dr Lerner also performed a blinded placebo-controlled study in 2007 on Valtrex (or Famvir) for the subset of ME/CFS patients who only have active Epstein-Barr virus infections. This trial showed even better and faster results, with patients making an average of a 3-point increase on the Energy Index Point Score scale (for example, as a result of antiviral treatment, an average patient may go from level 4 to level 7 on this scale); and most of the improvement occurs within the first year on Valtrex.

If you look at Table V (shown below) from the Lerner 2007 study, you can see the gradual increase the patients' EIPS score that took place over time. The left hand column shows how many months the patients had been taking the antivirals, and the right hand column shows the patients' average EIPS score, which you can increases as the months go by.

Table V from Dr Lerner's 2007 Valtrex Study

Dr Lerner says usually the benefits of Valtrex or Famvir only begin to become noticeable after around 3.5 months of treatment. Ref: 1

Phoenix Rising article on Dr Lerner's antiviral studies.


For Dr John Chia's quasi-study on the efficacy of oxymatrine for treating ME/CFS associated with chronic active enterovirus (coxsackievirus B and echovirus) infections, see this post.

​

 

[me/cfs 27931]

In Dr Lerner's study on Valtrex and Valcyte for herpes family infections in ME/CFS, he treated patients for up to 6 years with Valtrex and/or Valcyte (depending on which herpes viruses were active in the patients), using doses of Valtrex 1,000 mg four times daily, and/or Valcyte 450 mg three times daily.

Interesting. OMI had me go from Valtrex 6g/day to 1g/day after 7 months. But this chart says Dr. Lerner uses 4g/day.

I have noticeably more symptoms below 2g/day Valtrex, and am now trying to convince my primary care doctor to increase the dose again.

Unfortunately, insurance won't cover Valcyte, although OMI recommended it.

ETA: Thanks @Hip. Your info will come in handy when talking with my primary care doc.

 

[cb2]

I dont understand the Enegry Index Point system
it seems
Level 4 Out of Bed.. walking 4 to 6 hours a day? really? what about being stuck in the recliner? to me that is pretty much the same as "bed"

Level 6 daily naps? how do you have daily naps when you are working a 40 hour week , + light housekeeping and or social activities? how do you go to the grocery and or do "heavy " house keeping ?

i guess i am at a level zero, except i spend most of my time in a recliner rather than the bed -- so that means i am "out of bed"

(The following wdb quote comes from this thread).

Note that on the EIPS scale:
Level 4 = Out of bed sitting, standing, walking 4 - 6 hours per day (the rest of the day in bed).

Level 6 = Daily naps in bed, may maintain a 40 hour sedentary work week plus light, limited housekeeping and/or social activities.

​

 

[gbells]

A problem is the Lehrner's study was uncontrolled while Montoyas was controlled so you don't know if the fatigue improvement really was significant. While Montoya's was shorter, he didn't see any improvement in fatigue at all. If the effect was there it should have showed up. That is why the Montoya research is a better study.

 

[Hip]

A problem is the Lehrner's study was uncontrolled

That's true, but Lerner's is the only study which ran for a long time.

Lerner found that it takes 4 months before the benefits of Valcyte even begin to appear. So at 4 months you will only see the first small inklings of improvement. Thus for Montoya to terminate his Valcyte study at only 6 months was a mistake; he should have run the study for a least 18 months say.

Note also that in terms of antibody blood tests for herpesviruses, Montoya used different study inclusion criteria to Lerner's. Dr Lerner's theory is that ME/CFS is caused by an abortive herpesvirus infection, and thus the testing criteria he used were based on detecting such abortive infections.

A PR forum poll found Valcyte moved 50% of patients trying it up at least one level on the ME/CFS scale of: very severe, severe, moderate, mild, remission.



You might like to read this list of recovery and improvement stories, which includes several cases of improvement or recovery from Valcyte.

Note in particular the recovery by @OnlyInDreams in that list: this is an interesting case, because he recovered as a result of taking Valcyte, but when he stops taking it, the ME/CFS returns (and he tested this more than once).