Learning CFS: Dr. Lerner on his Longterm Antiviral Treatment
Study (05/10) by Cort Johnson
Our clinic has treated hundreds of people who are now leading normal lives
Background:
Dr. Lerner had quite a career before CFS. A check of
his research record revealed over five decades of infectious disease work
focusing on Coxsackie virus, herpes simplex virus, pseudomonas, interferon,
Staphylococcus, Mycoplasma, enteroviruses, myocarditis, etc.
A contributing author to one of the seminal works in the medical field -
“Harrison’s Principal’s of Internal Medicine” - he’s published over 150 papers
over the past fifty years.
In 1986 he began having troubles with dizziness and severe
fatigue. A visit to the Cleveland Clinic found his heart was found
to be grossly dilated. 10 years later he’d figured out
how to treat himself recovered.In the meantime he did a 180
degree career turn and plunged, largely working alone, into wilderness of ME/CFS
research. His first post-CFS paper in 1989 “A new continuing fatigue syndrome
following mild viral illness” proposed that mild heart abnormalities involving
T-waves in a group of post viral patients would be amplified greatly upon
exercise and recommended that these patients not exercise vigorously.
A 1993 paper cinched the T-wave problem and documented what he called
a ‘subtle cardiac dysfunction’ that showed up response to normal
everyday tasks. In a 1997 paper he proclaimed that “CFS is a persistent
nonpermissive herpes virus infection of the heart”.A small
2001 study finding that antiviral therapy was indeed effective in CFS provided
still more evidence for his theory.
In 2002 he documented a finding that would lay the foundation for
his subsequent work - the presence of early gene products (for cytomegalovirus)
in a subset of patients with CFS. 2002 would bring another
successful small antiviral trial - this time using valacyclovir for 6 months in
patients with Epstein-Barr virus infection. In 2004 he again
documented the presence of early gene products in ME/CFS; this time to
Epstein-Barr virus.He cemented his non-permissive infection
hypothesis later that year when he demonstrated that abnormal heart wall motion
and other problems were assoc
iated with incomplete replication of both viruses
in CFS.
A 36 month followup of his patients in 2007 indicated further progress on all
fronts; the heart problems continued to decline, antibody levels
felland he reported that many patients resumed normal
activities. A 2008 paper validated the effectiveness of his Energy Point Index
Score in measuring fatigue in ME/CFS.
Now Dr. Lerner has published his largest and most comprehensive study to date.
While Dr. Lerner is an acknowledged pioneer in the antiviral field on CFS his
theory’s have yet to gain acceptance outside of the immediate CFS community.
Attempts to gets grants - not a problem at all in his pre-CFS career
- have failed.. Will this paper finally translate
into federal dollars for funding antiviral trials?Will it
result in increased funding in this area? Only time will tell.
Did he regret turning his back on such a fertile career and journeying into the
‘desert’ of CFS research? With no funding publications came much less frequently
post-CFS but Dr Lerner had no regrets at all saying ‘the work has been so
fascinating that I just couldn’t stop”.He is clearly very
excited about the possibilities present in the field.
The Study : Dr. Lerner’s study
presents a culmination of his work with patients over the last ten years.
This is not your typical 25 or 50 patient treatment trial. Virtually
everyone he saw in his clinic over the past 10 years is in it. The study
involved examining patient records every three months for the past 10 years -
that’s ten years of replicated data. Ultimately it involved 7,000 patient visits
that generated 35,000 fields of data.
While this is not the placebo controlled, double blinded treatment trial the
research community loves it’s clearly dense with replicated data.
Findings: the paper presents some startling findings
- Long term
antiviral therapy was effective - very effective - in many of his
patients. Many of them, while not completely cured, are able
to work and lead normal lives again - an astounding finding in this field.
Some are completely cured.
-
About
25% did not respond- a finding that may be related to the
limited duration of their treatment.
-
While Dr.
Lerner’s protocol can and often does work for longer duration patients -
duration of illness does make a difference in treatment response
-
About
30% of his patients had, in addition to herpesvirus infection, another related
infections such as Lyme disease, Babesia or Streptococcyus.
The fact that these patients improved but not to the extent of herpesvirus only
patients has profound implications for how to treat both ME/CFS and Lyme disease
and other infected patients.
Interview (any misrepresentations of Dr. Lerner's thoughts are my own)
The CFS Community is a large and many
people think a very varied one. I asked Dr. Lerner what percentage of patients
that he saw fit into this herpesvirus/other pathogen infected
subset?
Dr. Lerner replied that he thought about 90% of the patients that see him have
this kind of pathogen involvement and that the reason the medical community
doesn't get it about the pathogen prevalence in ME/CFS is that
they're basically looking in the wrong place; if they start looking in the right
place - that is, if they start looking for signs of ‘non-permissive infection’
he believes these results would show up in spades across the community.
In fact, Dr. Lerner believes that even he may be missing
some significant pathogen involvement because we still don't have a test for
early gene products of HHV6. He noted that Dr. Kondo in Japan is trying to
develop an antibody test for these. Once that test is developed it's possible
that the rate of HHV-6 infection in his cohort - which is quite low - could jump
dramatically.
It’s possible, however, that Dr. Lerner’s reputation as an antiviral specialist
has caused a more pathogenic subset of patients to make its way to him so it’s
unclear at this point what percentage the CFS community it applies to. That fact
demonstrates how desperately the CFS community needs studies that assess the
prevalence of early herpesvirus gene products in CFS (as well as Borrelia,
Babesia, etc). . Ironically, the one group that’s been in a position to do this
- theCDC’s CFS research program in the Rickettsial and Viral
Diseases branch, no less -has virtually ignored pathogens in
CFS for over the past decade.
Interlude I: ‘A Non-Permissive Infection’
In general a virus needs to do four things to spread an infection in the body.
- penetrate a
cell
- use
the cells machinery to build more viruses
- l
eave the cell
and move into the bloodstream
- find another
cell it can infect and start the process all over again.
Problems with the second step of the process - using the cells machinery to
create more viruses - are where non-permissive infections show up.
Once they’re inside a cell viruses create a series of gene products or building
blocks that are then pieced together to form the complete virus . In a
nonpermissive infection the building block process gets stopped leaving the
cells littered with bits of viral gene products. Dr. Lerner believes the
herpesviruses in people with ME/CFS are able to create about a quarter of the
building blocks needed to produce a new virus. He believes these viral gene
products interfere with cell metabolism, weakening it and eventually probably
causing it to die.
Most viral tests look for antibodies to proteins found on the envelope of the
virus. This makes sense in an normal infection because the immune
system is usually interacting with the proteins on the outside surface the
virus. But if the virus is pumping out hordes of early gene products such tests
will miss any evidence of infection.
You must've had wide range of
responses.The average patient basically went from being out of bed for 4-6 hours
a day (ie being in bed from 18-20 hours a day) to been able to maintain a 40
hour work week as well as light housekeeping or social activities. That’s an
amazing functional shift.Since responders were classified as
anyone who shifted at least one level upwards on the EIPS this suggests that
some people must have shifted all the way to nine or 10; not only are they able
to work but they are completely well, able to exercise without relapse, etc. Is
that true?
Oh absolutely. I’ve got people who are up to 8 or 9 or 10; fully recovered able
to exerciseand participate fully in life. I have all kinds
of people who are not as well but are living normal lives now, marrying when
they couldn't marry before, working when they couldn't work
before. It’s been extraordinarily satisfying.
This study demonstrated
that people who’ve been ill longer are, indeed, more difficult to treat. Do you
know what’s going on here? Are their antibody titers not going down
- is it more difficult to knock out the virus or are they less likely to
heal after the virus has been knocked down? If the antibody titers are not going
down does this mean has made its way to parts of the body antivirals have
trouble getting at?
Dr. Lerner said that ‘viral load’ is a critical point and he pointed to what he
described as a wonderful study showing that total viral load does diminish over
time with Valtrex. He stated that ‘viral load’ (the number of viral particles
present in the body) may be a function of duration for some patients; ie
the longer the patient has been ill the higher their viral load. As a rule of
thumb if
somebody has been ill for three years or less they generally begin to
respond within six months of starting antiviral therapy. Other patients will
take longer; at the Clinic they suggest that patients be treated for at least a
year before they assess how effective treatment is.
This is not to say that people who have been ill for seven or 10 or 15 years do
not respond to this treatment; Dr. Lerner said many long-duration patients do
respond to this treatment - but as a group they don’t respond as quickly and, of
course, some don't respond at all. About 25% of his patients were classified as
nonresponders.
Another significant finding was that the nonresponders didn't take the drugs for
as long as the responders which suggested that some people simply needed to be
on the drugs longer for the treatment effects to show up.
Interlude II: the Necessity of Long Term Drug Therapy
EBV replicates when the B cells it is found in divide -
this is how it spreads from the original cell into the new cell.
It reactivates - ie grows inside those cells - using an entirely
different procedure.
The primary treatment for EBV (either acyclovir or valtrex) is able to stop EBV
reactivation; that is it is able to reach into the cell and stop the process
which EBV uses to grow in the cell. Neither are able to stop EBV from
replicating when the B cells its infected divide.
This is a problem because patients with high viral loads have many, many of
their B cells infected with EBV, each of which is potentially a little
time bomb waiting to go off if their immune system gets suppressed again.
This could result in the classic get better, relapse, get better, relapse
scenario that occurs as their stop EBVreactivation then allow it to reactivate
as their systems get overwhelmed. Each time EBV reactivates enough to spread
outside the cell the patients viral load increases (Dr. Lerner
believes the herpesvirus infections in CFS are a mixture of
permissive/nonpermissive infections).
Even if they knock EBV reactivation down are these people doomed to carrying
increasingly high loads of EBV? Not necessarily. Because B-cells
die off over time EBV is always in a race to keep infecting new cells before the
cells it is present in die off. This means that if Valtrex can keep EBV
reactivation down then as the infected B-cells die off the number of EBV
infected cells should slowly decline over time.
This is what Cohen found
in the paper
Dr. Lerner liked very much. The
decline in infected cells after Valtrex administration was slow, however; after
a year only a modest decline has occurred. This ‘modest decline’ could be why
really long-termantiviral therapy is sometimes necessary.
Cohen estimated that it would take6 years of Valtrex administration every day
to eradicate EBV from the B-cells (and 11 years to eradicate it completely from
the body). Higher doses would work more quickly. Fortunately it’s more important
to reduce EBV activity than to completely eradicate it. Most healthy people are,
after all, infected with EBV and most patients should not require such long term
treatment.
(Some healthy people do in fact carry high loads of EBV without any problem.
These people, however, are able to hold EBV in check; if Dr. Lerner is right
many CFS patients cannot).
I wondered about side effects from such
long term therapy?
Dr. Lerner said it’s important to be very careful with dosing but with an EBV
infection it's as simple as making sure that the patient is drinking enough water.
With HMCV infection he has to be very careful with liver functioning tests since
the antiviral can damage the liver but even so he’s had no really serious side
effects.
One of the most significant findings was
that unless physicians look for the full range of pathogens treatments for
anyone pathogen may be not effective. About 30% of his patients had
herpesviruses plus either Borrelia or Babesia and the patients with those
infections simply did not thrive on a standard antivirals. Of course the same
case can be made for Lyme patients; many patients undergo long antibiotic
regimes but Dr. Lerner’s results suggest that if they have a herpes virus
infection they most likely will not satisfactory results from antibiotic
therapy. I asked him if he was surprised to see this subset popout. This finding
could have profound implications for both sets of patients.
Dr. Lerner replied that he was ‘very, very surprised’ to see this pathogen+
group stick out. This was not a small subset of CFS patients - about 30% of his
patients had ‘parasitic’ as well as ‘opportunistic’ infections. Most of these
were Lyme disease
(2/3rds Borrelia burgdorfii) with the rest either Babesia and/or Anaplasma (rickettsia) and/or streptococcal infections.These patients tended to be
sicker (EIPS 3.1-4.0) and while after two and half years of treatment their EIPS
scores were significantly improved (EIPS 5.3) they were still sick enough to be
diagnosed with ME/CFS.
Dr. Lerner noted that the data is not so ‘bleak’ as it appears in the paper and
that further directed treatment improved their outcomes considerably. Dr.
Lerner’s assessment of the ‘bleakness’ of their treatment outcomes surprised me
given their progress and surely reflected his high expectations; most physicians
would be happy to see a jump from an EPIS score somewhere in the three’s (in bed
about 20 hours a day) to the fives (performing with difficulty a sedentary job
). That kind of outcome is rarely seen in CFS treatment trials but Dr. Lerner
clearly wanted to see more.
How did ‘parasitic’ infections show up in a disease mostly characterized by
‘opportunistic’ infections? Dr. Lerner could only speculate that the
opportunistic infections had weakened the immune system enough to allow
parasitic infections to gain entry.
The New Mantra -
Data Mining, Data Mining, Data Mining
- The ‘pathogen plus’ finding illustrated how important data mining is when
you're dealing with large amounts of data. The ability to tease out the
herpesvirus plus patients had huge implications for the outcome of this study;
if Dr. Lerner’s crew hadn't statistically separated the pathogen plus group out
the positive effects in the pure herpesvirus group would have partially
disappeared. - This is a problem that presumably occurs in many studies. When
you treat a ‘wastebasket disorder’ such as CFS as if it was a single disorder
then the good responders are washed out by the non-responders which allows lower
common denominator treatments like CBT (which would probably be somewhat
effective in any chronic illness) to gain prominence.
In any case Dr. Lerner’s paper illustrates just how important ‘data mining’ is
in uncovering patterns in complex, poorly characterized diseases like chronic
fatigue syndrome and he’s fortunate to have a dedicated crew of volunteers with
the skills necessary to do this kind of work. Providing Dr. Bateman with the
tools to better mine her data was one reason the Phoenix Rising Fundraiser for
the Fatigue Consultation Clinic took place.
It’s not surprising therefore that data mining plays such a key role in large
data-rich enterprises such as the CFIDS Associations creation of its BioBank and
DataBank and Research Network. Several of the CFIDs Associations
current research projects use innovative techniques to mine large amounts data
from multiple systems in order to find patterns that explain. Both the CFIDS
Association and Whittemore Peterson Institute’s Biobanks should provide
researchersopportunities to examine patient samples for
factors like Dr Lerner has found.
What about when the responders go off the
anti-retrovirals? They seem, on average, to be able to hold a job but exercise
still seems to be problematic for many of them. Are they able to maintain their
health off the antivirals? At some point do they need to do another round of
antivirals? What is their prognosis post viral treatment?
Dr. Lerner stated that when his patients get well they tend to stay
well. About 30% of them get up to eight or nine on the EIPS Scale and stay
there. There's another group there needs some ongoing viral suppression. He
noted that he was on Valtrex for six years and is now off them entirely.
The Heart of It All?
“CFS is a persistent nonpermissive herpesvirus infection of the heart"
The heart infection Dr. Lerner proposes is present is unusual; in most heart infections the
heart is grossly inflamed when dying cells explode into the bloodstream where
their fragments attract hordes of immune cells that then touch off
the inflammation seen in myocarditis or a typical heart
infection.
In the nonpermissive infection Dr. Lerner envisions incomplete
herpesvirus gene products disturbing heart cell functioning. Many of the
infected cells probably do die off when the cell, recognizing that it’s been
irrevocably damaged, flips on its suicide program but they do so at a rate that
leaves them largely hidden from the immune system and inflammation is low.
The heart replaces these cells with fibrous tissue - which means the damage is
permanent. Stopping the infection, however, stops the slide to further damage to
the heart and substantial recovery can occur - as evidenced by the improvement
on the heart tests Dr. Lerner regularly gives.Patients may
or may not fully recover their full extent of physical function - but after a
point its not clear how much it matters.Dr. Lerner pointed
to himself as an example; after 10 years of illness he probably sustained some
permanent damage but it’s hard now to tell where; not many 80+ year olds are
running a full-time medical practice, regularly traveling to international
conferences, etc.
How do EBV and HCMV get
carried to the heart when they’re present in a nonpermissive infection; ie if
the herpesviruses are unable to create copies of themselves how are they getting
out of the B cells and into the heart cells? In this paper Dr.
Lerner stated that he believes that parts of the infection are permissive
and that low levels of complete herpesvirus particles that are intermittently
being carried to the heart; thus producing a smoldering infection that burns at
a low heat.
What percentage of your patients have
orthostatic intolerance (problems standing)? Does that clear up as well and if
so do you have any idea what herpesviruses are doing to cause that problem? How
about low blood volume?
Orthostatic intolerance(OI) - was a key symptom for Dr.
Lerner when he became ill as it is for many ME/CFS patients. Some ME/CFS
researchers think the autonomic nervous system plays the key role in OI but Dr.
Lerner’s focus is on the heart. Over the years he’s documented several heart
problems in his patients including aberrant Holter Monitor tests and abnormal
cardiac wall motion findings.He believes that a heart
weakened by these unusual infections beats more rapidly (the tachycardia in
POTS) and ineffectively and this causes many of the problems many CFS patients
have in standing up.
He noted that these problems to clear up in the patients
who respond to antiviral treatments. He starts patients with these problem but these problems on
fludrocortisone acetate, atenolol and/or digoxin - each of which was able to be discontinued
as the EIPS values rose.
Low blood volume - Dr. Lerner believes the low blood volume found in
ME/CFS patients is an extraordinarily interesting finding but exactly what’s
causing it is unclear. He did note that it could be protective in nature as it's
easier for the heart to function if there's less pressure.
I wondered about other markers? There are
lots of interesting immune and endocrine findings in CFS. Where
any of these correlated with drops in antibody levels? Can Dr. Lerner see, for
instance, the immune system or endocrine system readjusting itself?
Dr. Lerner acknowledged the importance of immune dysfunction in CFS but said he
is not following any other immune markers in the illness and this makes sense.
He is, after all, primarily a doctor treating his patients - most of whom have
to pay for an expensive and long-term treatment regime (@$1,000/month) out of
pocket. Without federal funding it’s hard to see how any physician can regularly
collect nonessential data. Certainly one would think that immune functioning
would be a part of any federally funded pathogen study
The current crop of drugs went a long way
but they didn’t work for some people, are expensive and require
long treatment regimes; there’s still much work to be done on the antiviral
front. I asked Dr. Lerner if he saw promise in any new or upcoming drugs?
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.
He felt Marabavir is an interesting drug on the horizon. It still needs to
be tested further but initial in vitro testing indicated it was effective
against both HCMV and EBV and its safety profile looks very promising (which
means that it may be able to be given in larger doses. Many drugs are a
trade-off between side effects and effectiveness. If given in large enough
quantities many drugs can kill off pathogens; the problem is that they can kill
if the patient as well. Any ideal drug would be a drug safe enough to be able to
give it in large enough quantities to quickly kill off the pathogens without
harming the patient.)
Dig Deeper!
Discuss the Paper Here
Dig Deeper! Valtrex in
ME/CFS
Dig Deeper!
The Lerner
Antiviral Treatment Paper
Dig Deeper: A Four Part Series on EBV In ME/CFS
Future Work; I didn't specifically ask
Dr. Lerner about his future work but it's clear that he's very excited about the
progress being made in the field and he’s actively pursuing his ideas. He said
he plans to submit studies that will help to solidify the idea that
‘non-permissive’ viruses play a key role in ME/CFS (or as he says it ‘the
chronic fatigue syndrome’).He hopes that a multi-center
treatment trial will be done
The Martin Lerner Foundation
- before the interview got started Dr. Lerner first acknowledged the
people who created the Martin Lerner Foundation for the study of Chronic Fatigue
Syndrome. It’s absolutely accurate to say that this paper would
not have been created without their help. He first acknowledged Kim and Carol
Gill, whom, if my notes are correct, created the Foundation in order to promote
Dr. Lerner’s work. They and Jim Eddington spent a year and a half in the office
developing the study. James Fitgerald at the Department of Medical Education at
the University of Michigan Medical School did the statistics. Safadin
Beqaj assisted in the creation of the paper . Ann Cavanaugh, the volunteer
Communications Director for the Center (another CFS patient), was my liason.
In the end Dr. Lerner saw and treated his patients while a group of skilled
volunteers snatched up his data, inputted it and then analyzed it and, in the
end, presented it to him and that’s how this paper came about. He was very
gratified by their work as should we all be.
Conclusion: This is not the paper
that will cause the traditional medical community to turn its standard treatment
approach to CFS on its head but it hopefully is the paper that will spur the
creation of federally funded treatment trials and more research into the effects
herpesvirus have on ME/CFS. This study cries out to put Dr. Lerner's protocol to
the test with double
blinded, placebo-controlled, multicenter treatment trials and it is Dr. Lerner’s
hope that is just what will happen.