Learning CFS: the Lerner Antiviral Treatment Trial Succeeds
- Thread starter Phoenix Rising Team
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I think the ramifications of this study are much larger than many of us realize. Will reserve further comment for later, except that this article will make it much easier for a CFS patient to get in to an Infectious Disease doctor if they have a co-infection, or to investigate whether or not they have any co-infections which could thus be treated along the protocol in this study which might result in a good deal of 'recovery' for many of us. A wonderful development indeed!
He reported that Vistide (brand name)/Cidofiovir (generic) - was effective against HCMV but that he uses it only for the patients who have not responded to the standard protocol after at least 1 year because it can affect the kidneys.
Is standard protocol using the Valtrex? Is this effective for HHV-6 and HHV-5 as well as EBV. The article isnt quite clear?
Do you know Cort, what he means by Standard Protocol?
Thanks
Is standard protocol using the Valtrex? Is this effective for HHV-6 and HHV-5 as well as EBV. The article isnt quite clear?
Do you know Cort, what he means by Standard Protocol?
Thanks
Hmmm, I think there is nothing wrong with the 'science' of this study, once you categorize it correctly. But it is a weak design statistically, an uncontrolled clinical trial. However, this is a perfectly valid way to design a study, if your goal is to show treatment cohort data.
The conclusions that can be drawn in any research area are commensurate with the study design. In other words, since this is not a randomized treatment study, there is less confidence in using this to advise patients. You can't state the treatment effect without a control group, for example, and side-effects and treatment risks are more difficult to identify with such a small N. And I think medical professionals are not likely to change their views on CFS based on a study like this.
However, this type of clinical study is a good door-opener for further research, there is clear evidence that some patients improve, which is rare enough in CFS studies. Are they improving more than a control group of CFS patients trying to get well using other methods would? Hard to say without controls. But still, a good doctor who understands the limits of this type of study and does not mind careful patient monitoring might be able to use this as a basis for an experimental treatment.
I must say I am disappointed this is not a stronger research design, but still glad to see this, some possibilities here, more pieces to the puzzle. And that claimed statistic of 74% patients returning to near normal life? Hello, is that real? If so this may be one of the more important articles published about CFS. Even with the weak study design.
The conclusions that can be drawn in any research area are commensurate with the study design. In other words, since this is not a randomized treatment study, there is less confidence in using this to advise patients. You can't state the treatment effect without a control group, for example, and side-effects and treatment risks are more difficult to identify with such a small N. And I think medical professionals are not likely to change their views on CFS based on a study like this.
However, this type of clinical study is a good door-opener for further research, there is clear evidence that some patients improve, which is rare enough in CFS studies. Are they improving more than a control group of CFS patients trying to get well using other methods would? Hard to say without controls. But still, a good doctor who understands the limits of this type of study and does not mind careful patient monitoring might be able to use this as a basis for an experimental treatment.
I must say I am disappointed this is not a stronger research design, but still glad to see this, some possibilities here, more pieces to the puzzle. And that claimed statistic of 74% patients returning to near normal life? Hello, is that real? If so this may be one of the more important articles published about CFS. Even with the weak study design.
I totally agree Shane, here in Canada, they don't do fancy herpes virus test, they just tell ya that most people are positive anyways :tear::worried:
I wonder what dr Lerner thinks of XMRV and how it could align with XMRV and Dr Mikovits' work? I think it would be great to have a cohort antiretrovirals + antivirals or antiretrovirals only. Oh and probably a placebo cohort but who wants to be on a sugar pill?
HI Kurt,
This is TOTAL speculation, but if I were to guess I would say that you had subclinical ME or CFS and that the flu triggered it into the full illness.
Dr Lerners research wasn't that low profile to some. My doctors practice was trying to organise a clinical trial in Australia to replicate the results. While we could probably get the drugs for free, we would have to pay cash for labwork, or at least preliminary labwork, and so I was priced out of the possibility. This was all attempted without any grants or funding.
Bye
Alex
This is TOTAL speculation, but if I were to guess I would say that you had subclinical ME or CFS and that the flu triggered it into the full illness.
Dr Lerners research wasn't that low profile to some. My doctors practice was trying to organise a clinical trial in Australia to replicate the results. While we could probably get the drugs for free, we would have to pay cash for labwork, or at least preliminary labwork, and so I was priced out of the possibility. This was all attempted without any grants or funding.
Bye
Alex
Hi Gerwyn
Issues about bias are always a concern, it is a point worth noting. However, there is also the issue that ME or CFS only attract something like 1% of the funding other diseases of the same scope seem to get, so everyone has to find ways to do their research on a limited budget. Dr. Lerner's approach was detailed series of case studies, not a random placebo controlled trial. Thi s is actually more usefull than an RCT when you are still investigating the underlying science, because much much more is uncovered, and you have lots more data to mine for hypotheses. An RCT is obviously the next step, however.
You comments do however imply that it could be risky to presume this works without serious consideration, and I agree with this. Given the cost and difficulties, plus potential side effects, careful thought is always waranted.
The claim that nobody made it past 7 on his energy scale is wrong. I recall that many made it to 10, I will have to go back and check the paper again. It is, instead, that he stopped antivirals at 7, but patients then continue to recover.
I think the scale is also inclusive - 7 includes AT LEAST everything in 6, 5, 4 etc.
Bye
Alex
Issues about bias are always a concern, it is a point worth noting. However, there is also the issue that ME or CFS only attract something like 1% of the funding other diseases of the same scope seem to get, so everyone has to find ways to do their research on a limited budget. Dr. Lerner's approach was detailed series of case studies, not a random placebo controlled trial. Thi s is actually more usefull than an RCT when you are still investigating the underlying science, because much much more is uncovered, and you have lots more data to mine for hypotheses. An RCT is obviously the next step, however.
You comments do however imply that it could be risky to presume this works without serious consideration, and I agree with this. Given the cost and difficulties, plus potential side effects, careful thought is always waranted.
The claim that nobody made it past 7 on his energy scale is wrong. I recall that many made it to 10, I will have to go back and check the paper again. It is, instead, that he stopped antivirals at 7, but patients then continue to recover.
I think the scale is also inclusive - 7 includes AT LEAST everything in 6, 5, 4 etc.
Bye
Alex
long term Guinea pigs
Hi Jackie
Nearly every long term patient I have talked to is more than willing to be test subjects, and many like me are actively looking for studies. The test subects aren't the problem, its the fact that nobody has decent funding.
Bye
Alex
PS I am currently in a non-pharmacolocial study now, and was passed over for a study early this year presumably because I am house bound - and this in Australia where there is far less money for research than the USA. Studies exist, but are usually limited in scope.
Hi Jackie
Nearly every long term patient I have talked to is more than willing to be test subjects, and many like me are actively looking for studies. The test subects aren't the problem, its the fact that nobody has decent funding.
Bye
Alex
PS I am currently in a non-pharmacolocial study now, and was passed over for a study early this year presumably because I am house bound - and this in Australia where there is far less money for research than the USA. Studies exist, but are usually limited in scope.
types of test
Hi Kati,
The type of test is critical. I agree that a simple antibody test is close to useless, but a viral titre test is very different, and according to Dr Lerner's paper is critical to monitoring progress. I think he also implies that those with highest titre are harder to treat, and recovery wont happen until viral titre is essentially zero.
I would really like to know how many of his subjects are XMRV+ and XMRV-, and see an analysis based on this distinction.
bye
alex
Hi Kati,
The type of test is critical. I agree that a simple antibody test is close to useless, but a viral titre test is very different, and according to Dr Lerner's paper is critical to monitoring progress. I think he also implies that those with highest titre are harder to treat, and recovery wont happen until viral titre is essentially zero.
I would really like to know how many of his subjects are XMRV+ and XMRV-, and see an analysis based on this distinction.
bye
alex
I totally agree Shane, here in Canada, they don't do fancy herpes virus test, they just tell ya that most people are positive anyways :tear::worried:
Hi Kati,
there is the real risk that placebo controlled studies would be TOTALLY useless. I have seen scientific studies collapsed because every patient knew who was on placebo and who wasn't - the downfall of modern communications. I very much doubt that patients wouldn't know what group they were in within a few weeks to months. However, using "usual care" instead of a placebo could be usefull.
I totally agree with the idea of antitretroviral plus antiviral. It is very much worth studying, and we might find that non responders suddenly get better etc. Unitl this is tired, we wont know for sure.
Bye
Alex
there is the real risk that placebo controlled studies would be TOTALLY useless. I have seen scientific studies collapsed because every patient knew who was on placebo and who wasn't - the downfall of modern communications. I very much doubt that patients wouldn't know what group they were in within a few weeks to months. However, using "usual care" instead of a placebo could be usefull.
I totally agree with the idea of antitretroviral plus antiviral. It is very much worth studying, and we might find that non responders suddenly get better etc. Unitl this is tired, we wont know for sure.
Bye
Alex
I read in this thread (sorry can't find it) that Dr Lerner didn't like the idea of giving a placebo to a group of patients because he believes so strongly that his therapy is effective, and that that is why he hasn't done a randomised, controlled trial (RCT).
Dr Lerner is following established medical ethics. In funded research trials at least (probably all), any doctor running (or even agreeing to participate in) an RCT is ethically obliged to be in "equilibrium" about whether the treatments being compared are equally effective (there's a special term that I've forgotten - it's something like "clinical equilibrium"). In practice this rule is sometimes broken (junior doctors can be dragooned into taking part in the trial by their superiors regardless of the junior doctors' views). But no doctor should set up a trial if they believe they will be withholding an effective treatment from patients in the control arm.
The usual research process is to note the effectiveness of a new treatment in a bunch of patients (like Dr L has done here) and if there are big effects, run a small RCT and then a big one. However, if a therapy has so huge an effect that its effectiveness is blindingly obvious, my understanding is that no RCT is necessary; indeed, it would be unethical (because you are withholding a clearly effective treatment from patients). Think of Vitamin C for rickets or something - the effects so obvious that you'd be nuts not just to start treating patients.
Indeed, some RCTs are stopped early if effects become obvious partway through; large trials have regular points at which the data are assessed to see if help or harm has been established early (after X number of patients have been treated).
I haven't read Dr Lerner's study in enough detail or understand medical stuff well enough to know if a trial looks unnecessary - but I thought it would help the discussion to be aware of the issues surrounding whether/how/why RCTs are done. An RCT may be the gold standard but if a treatment effect is huge, it may be unnecessary and hence unethical.
Of course, other doctors may require RCT evidence before they'll believe in efficacy; then we're into a different ball game but RCTs are possible where both active & placebo treatment groups get treated, just one gets treated earlier than the other (e.g. for one, treatment starts immediately; for the other, they get a placebo for the first six months and time to reach a certain level of improvemen is the outcome measure).
Dr Lerner is following established medical ethics. In funded research trials at least (probably all), any doctor running (or even agreeing to participate in) an RCT is ethically obliged to be in "equilibrium" about whether the treatments being compared are equally effective (there's a special term that I've forgotten - it's something like "clinical equilibrium"). In practice this rule is sometimes broken (junior doctors can be dragooned into taking part in the trial by their superiors regardless of the junior doctors' views). But no doctor should set up a trial if they believe they will be withholding an effective treatment from patients in the control arm.
The usual research process is to note the effectiveness of a new treatment in a bunch of patients (like Dr L has done here) and if there are big effects, run a small RCT and then a big one. However, if a therapy has so huge an effect that its effectiveness is blindingly obvious, my understanding is that no RCT is necessary; indeed, it would be unethical (because you are withholding a clearly effective treatment from patients). Think of Vitamin C for rickets or something - the effects so obvious that you'd be nuts not just to start treating patients.
Indeed, some RCTs are stopped early if effects become obvious partway through; large trials have regular points at which the data are assessed to see if help or harm has been established early (after X number of patients have been treated).
I haven't read Dr Lerner's study in enough detail or understand medical stuff well enough to know if a trial looks unnecessary - but I thought it would help the discussion to be aware of the issues surrounding whether/how/why RCTs are done. An RCT may be the gold standard but if a treatment effect is huge, it may be unnecessary and hence unethical.
Of course, other doctors may require RCT evidence before they'll believe in efficacy; then we're into a different ball game but RCTs are possible where both active & placebo treatment groups get treated, just one gets treated earlier than the other (e.g. for one, treatment starts immediately; for the other, they get a placebo for the first six months and time to reach a certain level of improvemen is the outcome measure).
G
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Gerwyn
You have such a soft touch
I wonder what Dr. Fitzgerald at the Dept of Medical Education at the University of Michigan Medical School - the guy who did the statistical analysis would say about that - an utter waste of his precious time?
The assessments were self-reported - hopefully in a fuller trial they'll focus more on antibody levels, etc - but the instrument - the EPIS - has been validated against other fatigue severity indexes - it works You've got to measure functionality somehow.....and its going to be self-report.
I don't see how level four - out of bed - sitting, standing or walking four to six hours a day (or to put it another way being in bed from 18-20 hours/day)
could be construed as more active than level 7 - out of bed 14 hours a day plus working at a job. They're going from in bed 18-20 hours a day to being in bed 10 hours a day PLUS they're working. That sounds like progress! :victory:
I was a bit confused by the scale at first. The scales is not saying that people are walking 6 hours a day; the scale is saying that they are doing one of three activities either sitting, standing or walking 6 hours a day; they have to be doing something if they're out of bed.( I suppose he would have putting swimming in there as well or cycling...).those are just activities people do when they're not in bed
Valacyclovir was the main drug tested; famiciclovir got very little testing; I don't see how that effects the main findings.
Look at Figure 3 - the EIPS score steadily went up and up; the first three years showed the greatest benefit overall. The first 6 months there was typically little improvement; after two years most people had gained two functional levels! and then the average person went up another one - you just don't see that. Of course some people only gained a little bit but that also meant that some people zoomed up there to wellness.
I wonder what Dr. Fitzgerald at the Dept of Medical Education at the University of Michigan Medical School - the guy who did the statistical analysis would say about that - an utter waste of his precious time?
The assessments were self-reported - hopefully in a fuller trial they'll focus more on antibody levels, etc - but the instrument - the EPIS - has been validated against other fatigue severity indexes - it works You've got to measure functionality somehow.....and its going to be self-report.
I don't see how level four - out of bed - sitting, standing or walking four to six hours a day (or to put it another way being in bed from 18-20 hours/day)
could be construed as more active than level 7 - out of bed 14 hours a day plus working at a job. They're going from in bed 18-20 hours a day to being in bed 10 hours a day PLUS they're working. That sounds like progress! :victory:
I was a bit confused by the scale at first. The scales is not saying that people are walking 6 hours a day; the scale is saying that they are doing one of three activities either sitting, standing or walking 6 hours a day; they have to be doing something if they're out of bed.( I suppose he would have putting swimming in there as well or cycling...
).those are just activities people do when they're not in bedValacyclovir was the main drug tested; famiciclovir got very little testing; I don't see how that effects the main findings.
Look at Figure 3 - the EIPS score steadily went up and up; the first three years showed the greatest benefit overall. The first 6 months there was typically little improvement; after two years most people had gained two functional levels! and then the average person went up another one - you just don't see that. Of course some people only gained a little bit but that also meant that some people zoomed up there to wellness.
4
Out of bed sitting, standing, walking 4–6 hours
per day
5
Perform with difficulty sedentary job 40 hours a
week, daily naps
Recovery
6
Daily naps in bed, may maintain a 40-hour
sedentary work week plus light, limited
housekeeping and/or social activities
5 gives a diagnosis of CFS and 6 does not.There is no objective difference between the two.There was no statistical tests actually carried out.you cant perform statistics on subjective parameters.dr Lerner decided that an improvement of 1 on his scale was significant.According to his own data a move from 5 to 6 would be considered significant.I submit that the only difference between 5 and 6 is the wording
There is a lot more to this illness than fatigue.
If his hypothesis was to test that ebv causes CFS then i,m afraid that
i the evidence he presented does not support that hypothesis----no mention of PEM or any statistical treatment of any kind Normal is an EIPS level above 5
His view is contrary to many published studies who have found that EBV is either not present or not causative
He should have used the null hypothesis as all scientific studies do
If you decide before hand that a change of one ona sunjective scale of 1 to 10 is significant a change of 1 will give an enormously low p value without any significan clinical benefit.
I am only applying scientific criteria for analysing a clinical study.
I would be happy to post the criteria if that would be useful
The lowest scores the patients had was 4 the maximum 6.The differences between 5 and 6 are not clinically significant.In 6 the wording is may hold down a job(a subjective assessment) not can which is an objective one
If you look at the graphs the error bars overlap so the differences as a whole are not statistically significant.They have chosen an arbitary end point when the responses clearly fluctuated over time
People with the kind of infections in Lerners study are ill.An EBV infection does put people in bed.A person with an EBV infection will easily qualify for a diagnosis of CFS under the FUKUDA criteria particularily if the Dr in question believes that EBV causes CFS.Unfortunately it does not mean that they have CFS in any objective sense.People with these infections get better over time without any interventions.This is why a placebo arm is essential .This is the only way of judging the effect of the treatment.Splitting the population into two kinds of CFS based on the type and pattern of infection they were shown to have has no scientific basis what soever.It is based on the assumption that all people with infections have CFS.From that point the study becomes a self fulfilling prophesy.The study fulfills none of the objective requiements ofa scientific clinical study
Dr.Lerner on XMRV:
"I am delighted with Dr. Mikovitz's findings concerning XMRV in the bloods of CFS patients. The more we understand of the science of CFS the better our care for our patients will be. I look forward to the confirmation of the XMRV findings from another investigator(s) in another laboratory(s).
There is unequivocal evidence that EBV, HCMV and HHV-6 are etiologic in CFS. Illness disappears upon antiviral treatment and CFS patients remain well. If XMRV findings are confirmed, they will coordinate our better understanding for treatment of CFS. We look forward to the science."
Source: http://chronicfatigue.about.com/b/2009/11/03/chronic-fatigue-syndrome-dr-lerner-on-ampligen-xmrv.htm
Additionally: http://www.cfsviraltreatment.com/personal_statement/index.html from Dr.Lerner's site http://www.cfsviraltreatment.com/
"I am delighted with Dr. Mikovitz's findings concerning XMRV in the bloods of CFS patients. The more we understand of the science of CFS the better our care for our patients will be. I look forward to the confirmation of the XMRV findings from another investigator(s) in another laboratory(s).
There is unequivocal evidence that EBV, HCMV and HHV-6 are etiologic in CFS. Illness disappears upon antiviral treatment and CFS patients remain well. If XMRV findings are confirmed, they will coordinate our better understanding for treatment of CFS. We look forward to the science."
Source: http://chronicfatigue.about.com/b/2009/11/03/chronic-fatigue-syndrome-dr-lerner-on-ampligen-xmrv.htm
Additionally: http://www.cfsviraltreatment.com/personal_statement/index.html from Dr.Lerner's site http://www.cfsviraltreatment.com/
Brilliant work Cort thanks for letting us know. Bits of the "jigsaw" all coming together now.
G
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Gerwyn
no alex the final finding was 6 + 0r minus 1.2.Dr lerners avowed intent was to show that EBV caused CFS.This was not achieved.without a placebo arm it is impossible to say whether the drug treatments caused any benefit that would not have occured anyway because the infectious phase of the pathogens in question is self limiting.I have no doubt that the patients inquestion were ill anyone with that pathology would be.Everyone with that pathology in terms of viral infection would eventually recover anyway.
thanks so much for this story
Thanks for the link to the complete paper. Lerner tested his patients for viruses, then used antivirals to treat them, while monitoring all patients very closely -- every 4 weeks. The effectiveness of the treatment varied, depending how many viruses were found in the patient.
Now we learn the success of the treatment, which is great. The only part that made me gasp was the comment this costs $1,000 per month! Yikes.
Oh, I want to get better! Even if 4 years sick, for me, was a year in the last century. Stop getting worse, that would be great.
Lerner has had more success than Montoya. I hope he and Montoya, or some 3rd party, can see the reasons why. Montoya had spectacular success in his first small group of patients, a paper that grabbed much interest, and I thought, got him resources for a slightly larger study. Is there a very basic logic here, treat virus infected patients with anti viral drugs? Carefully, as the drugs are potent.
I love the good news to know these people have better lives, more function in their day. Thank you!
Thanks for the link to the complete paper. Lerner tested his patients for viruses, then used antivirals to treat them, while monitoring all patients very closely -- every 4 weeks. The effectiveness of the treatment varied, depending how many viruses were found in the patient.
Now we learn the success of the treatment, which is great. The only part that made me gasp was the comment this costs $1,000 per month! Yikes.
Oh, I want to get better! Even if 4 years sick, for me, was a year in the last century. Stop getting worse, that would be great.
Lerner has had more success than Montoya. I hope he and Montoya, or some 3rd party, can see the reasons why. Montoya had spectacular success in his first small group of patients, a paper that grabbed much interest, and I thought, got him resources for a slightly larger study. Is there a very basic logic here, treat virus infected patients with anti viral drugs? Carefully, as the drugs are potent.
I love the good news to know these people have better lives, more function in their day. Thank you!