Date: March 1, 2010
Author: Walter Armstrong
The race is on - medicine's "problem child"
From almost any angle, CFS presents a vexing picture. No cause—not even
a single biomarker—has been identified. Symptoms are as diverse as they
are unpredictable, including debilitating fatigue, post-exertion malaise,
and an enduring flu-like state ranging from aches and pains to severe
headaches, cognitive disturbances, paralysis, and myriad complications.
"CFS defies the established structure of medical disease," says Kimberly
McCleary, who has headed the CFIDS Association of America for 20 years.
"Many doctors still don't 'believe' in it. They treat a single symptom
without seeing the whole. Or, worse, they dismiss it as a psychological
problem." In turn, a fierce mistrust of not only the medical profession
but the federal research establishment is endemic in the CFS community.
Conspiracy theories abound.
Some 200,000 Americans have been diagnosed with CFS, while anywhere from
1 million to 4 million may suffer from it, according to the CDC. Average
life expectancy is about 55, with suicide the third most frequent cause
of death. Depression is rampant. "CFS is not a death sentence - it's a
life sentence," is a CFS community truism. Meanwhile, skeptics persist
in dismissing it as "yuppie flu" and "shirker syndrome."
Yet recent studies show that most CFS patients did not experience clinical
depression prior to getting sick. And increasing diagnoses of pediatric
and adolescent cases reveal that kids who fall victim to the disease
include many high achievers, whose parents can trace the onset of the
illness to a routine infection of unusual severity or duration. Still, the
CDC's sole treatment recommendation is cognitive-behavioral therapy. The
agency's longtime CFS program head was finally axed in February, following
years of public criticism by doctors for favoring a research focus on early
sexual abuse rather than the search for pathogens.
The tenacity of its "disputed diagnosis" status has earned CFS the dubious
distinction as the only orphan disease with literally millions of "silent
sufferers." Pharma's longstanding disinterest in CFS is predictable, given
the disease's unforgiving uncertainties. "I don't blame the drug industry
- CFS is medicine's 'problem child,'" says virologist Suzanne Vernon, the
CFIDS Association's scientific director. "If so many doctors do not recognize
CFS, how can a drugmaker sell a treatment?"
CFS presents a kind of Gordian Knot to any pharma wishing to brave clinical
trials: the lack of a biomarker confounds diagnosis; the lack of quantitative
measurements of fatigue—the telltale symptom—confounds evaluation of a drug's
efficacy; the presence of such diverse symptoms confounds validation of data.
"The drug industry works best on a 'bug and drug' model, and CFS has been
slow to deliver a target," says McCleary. Early on, hopes were high that basic
science would uncover a single virus behind CFS's devastating immune-system
collapse - as took place in HIV. Academic research into the human retrovirus
HTLV-II yielded especially promising preliminary results in 1991, raising
patients' hopes, but replication studies foundered and funding was cut.
Until now, pharma's contribution to CFS treatment has been largely limited to
the off-label use of a panoply of drugs, such as stimulants, sedatives,
antidepressants, and anti-migraine medications to treat symptoms. However,
with the success of Lyrica and Cymbalta for fibromyalgia (another "disputed
diagnosis") drugmakers may find themselves inching into the CFS market.
Pharma may in fact stand to gain considerably by investing in CFS R&D.
Expert consensus is that CFS is actually a suite of diseases, with some
overlapping symptoms but many differences—and multiple causes. Advanced
research is identifying biological trends, including chronic low-grade
immune activation, latent activation of infections, and specific
abnormalities in cognition, metabolism, and blood pressure. Deeper forays
into CFS pathogenesis could yield finds that apply to many other conditions.
"CFS is a huge opportunity for pharma," says Moore. "The market is big,
the bar is low, and they don't need a home run. Even incremental
improvements to quality of life would be fantastic."
Unfortunately, the first CFS drug to face FDA review bombed in December:
Hemispherx's sloppy NDA for Ampligen, an antiviral and immune booster in
experimental use since the late '80s, contained 15-year-old data that "did
not provide credible evidence of efficacy." The drug, which requires twice-
weekly IVs and costs thousands of dollars a month, appears to work well in
about 15 percent of patients. "This is the right drug in the wrong hands,"
says McCleary. "They cut too many corners."
In XAND Land
Into this bleak landscape last October blazed an unpredictable claim by an
obscure researcher from a little-known institute that the cause of CFS may
have been discovered: a human retrovirus called xenotropic murine leukemia
virus–related virus (XMRV). Biochemist Judith Mikovits at the Whittemore
Peterson Institute (WPI) in Reno, NV, along with colleagues at the National
Cancer Institute and the Cleveland Clinic, reported in the journal Science
that DNA from the mouse-derived retrovirus were found in 67 out of 101
blood samples of CFS patients. Testing of 300 additional samples was said
to hit 98 percent. What's more, 3.7 percent of the 218 control samples also
The media predictably amplified the remarkable, if preliminary, findings
into a "cause-of-CFS" story, and WPI was only too happy to oblige. "This
is the breakthrough that we have been hoping for. Now we have scientific
proof that this infectious agent is a significant factor in CFS," Annette
Whittemore, WPI founder and president, proclaimed in the initial press
release, which also announced that WPI had renamed CFS as XMRV-associated
neuro-immune disorder (XAND).
WPI did not discover the XMRV virus, however. That distinction goes to
scientists at the Cleveland Clinic and the University of California San
Francisco, who in 2005 detected this fourth human retrovirus in the
cancerous prostate tissue of 40 percent of men with a particular defective
gene. WPI's Mikovits made the opportune leap from prostate cancer to CFS
when she learned of the high incidence of lymphoma among the original Lake
Tahoe cohort. XMRV seemed a possible culprit because it decimates natural
killer blood cells, the immune defense against cells infected by HTLV-I.
In addition, some CFS patients carry the same genetic mutation as men with
prostate cancer who tested positive for XMRV. The working hypothesis at
WPI is that XMRV indirectly causes CFS by inflicting so potent an assault
on the immune system that it reactivates other viral infections and a
chronic inflammatory response. "XMRV is the sort of agent that could create
that effect on the immune system," Daniel Peterson, WPI's medical director
and the co-discoverer of the original Lake Tahoe outbreak, told The New
York Times in a piece headlined "A Big Splash by an Upstart Medical Center."
WPI was founded in 2006 by Whittemore and her husband, Harvey, a prominent
Nevada couple whose daughter, Andrea, 31, has lived with a severe case of
CFS for 20 years. Frustrated by Andrea's marginalization by doctors and by
the lack of leadership, funding, and research at CDC, Annette Whittemore
invested $5 million to launch her own research institute at the University
of Nevada Medical School in Reno.
A flurry of activity followed on the heels of the discovery. Other
researchers raced to confirm the WPI study. Patients flocked to the Internet
for more information: Was XMRV fatal? How was it transmitted? Could they get
tested for it? The answer to the last question was yes. A diagnostic test
for the virus was already being marketed at $650 a shot by VIP Dx, which
just happens to be owned by Annette and Harvey Whittemore. "Leaving aside
the issue of who's right and who's wrong, the original paper did not
establish the virus [causes CFS] and didn't establish it as a viable
marker," Tufts University retrovirologist John Coffin, who wrote the
editorial accompanying the original Science study, told the journal.
Nevertheless, VIP Dx reported a six-to-eight-week backlog for results.
In general, patients' emotions bordered on the euphoric. Cort Johnson,
whose Phoenix Rising Web site is one of the most trusted sources of
information in the CFS community, says, "Patients are starved for good
news. A discovery like this excites researchers, brings in funding, and
gives patients hope—something they haven't had for many years." Meanwhile,
the nation's handful of CFS specialists tried to temper patients'
expectations with YouTube educational lectures on XMRV and its potential
For public health officials, the most alarming data point was XMRV's 3.7
percent prevalence rate in the control group. Extrapolating a worst-case
scenario led to the prospect that as many as 10 million Americans could
be carrying an infectious retrovirus already linked to two serious
diseases. In January, a federal task force was convened to safeguard the
nation's blood supply, an operation that could take a year or more,
according to member Suzanne Vernon. Then again, a little public panic has
its upside. "As we saw in the early years of HIV, fear among the general
population at least gets the money flowing," says Moore.
A Pharma Screening
XMRV is exactly the kind of bug that hooks Big Pharma. "Two of the
world's biggest drug companies contacted us the day our Science paper
appeared," says Judith Mikovits. "By showing that XMRV is an infectious
agent, we think we've convinced them to become interested in this
target." Although Mikovits refused to disclose the identity of the two
companies - "for fear that patients might seek out the treatments
before studies" - she said that both were already screening HIV
antiretroviral compounds in WPI cell lines for a hit.
Given the similarities among human retroviruses, an HIV drugmaker may
already possess an effective anti-XMRV agent—if not a drug already on
the market, then one of the thousands of marginally variant molecules
made in the painstaking process of discovery—and currently gathering
dust. Two classes of HIV drugs are in the running.
Both HIV and XMRV replicate by virtue of reverse transcriptase, the
enzyme that links their viral RNA to the host cell's DNA. Reverse-
transcriptase blockers were the first victory Big Pharma scored against
HIV. Ironically, in the February Virology, Mayo Clinic researchers
reported that after testing 10 HIV drugs against XMRV in vitro, the
virus was susceptible only to AZT, a nucleoside reverse-transcriptase
inhibitor (NRTI) notorious for its toxicity. "No CFS patient wants
to go near AZT," says Mikovits.
Other RTs (or experimental versions) that may show promise include
Bristol-Myers Squibb ddI and d4T, GlaxoSmithKline's Ziagen, and
Gilead's Emtriva and Viread. Merck's first-in-class integrase
inhibitor, Isentress, may work "because of its broad-spectrum
activity," according to Coffin. In the best case, an already-approved
antiretroviral will reveal XMRV-busting prowess, allowing the
drugmaker to bypass safety and other early tests and advance straight
into humans. "If one of the drugmakers currently screening candidates
gets lucky, we could start a clinical trial in a month," says
Veteran advocates like Kimberly McCleary do a double-take at the news
that two global pharmas are on the trail of CFS. "Now what we need is
a race between them to see which can be first to market," she says.
WPI and Full Disclosure
When XMRV was first discovered in 2005, pharma held back because it
was reported that the virus appeared to be inactive in prostate cancer
cells. But Abbott Diagnostics jumped at the challenge of developing
assays to detect XMRV. Last month, Abbott HIV Global Surveillance
Program's John Hackett reported early progress on several fronts. But
the main takeaway was that detecting XMRV in human blood samples is
proving far more difficult than the WPI study had led anyone to
expect. Using their new assay that can detect three different antibody
proteins, the Abbott team found XMRV in only three of 2,851 random
human samples. That's good news for the general population - a .01
percent extrapolated prevalence rate—but bad news for CFS patients.
Nor is Abbott alone in judging XMRV hard to find. Since January, three
confirmation studies - two British, one Dutch - have reported results,
and none found the retrovirus in either their CFS blood samples or
their controls. As doubt is increasingly cast on WPI's theory that
XMRV causes CFS, arguments have raged across the Atlantic. Accusations
of sloppiness, bias, and even fraud have been hurled, mostly by Judith
Mikovits and WPI's defenders. Old suspicions of patients have
When asked for a more considered opinion, others choose their words
carefully. "Validation and confirmation are not coming as fast as one
might like, that's for sure," says John Coffin. "If you can't establish
a disease association, then there is less interest in developing a drug,
obviously." Coffin also notes that uncertainty remains about whether or
not the virus is replicating. "If it does so, like HIV, then an
antiretroviral would be very effective. But if not, as it appears in
prostate cancer, a drug would not make any difference."
Writing on the CFIDS Association of America's Web site, Suzanne Vernon
made a valiant effort to keep hope in the causal hypothesis flickering
by emphasizing that none of the three studies is a "proper and robust
replication study." And she concluded by throwing down the gauntlet:
"Until methods are standardized and the scientific community is provided
information about the specific characteristics of the CFS subjects who
tested positive in the Science paper, be prepared to read more negative
studies. Hopefully the Science investigators will make this information
available before interest in XMRV being associated with CFS fades."
Given the great diversity in CFS symptoms, disclosure of the medical
histories and clinical conditions of the high number of WPI's XMRV-
infected CFS patients is critical. "Of course, this would generate more
questions, but a cleaner association is needed," Vernon says. "I don't
know why WPI won't provide this."
So far, Mikovits has refused to budge. "No additional medical histories
or anything about the patient population would shed any light on XMRV,"
Sleuthing on her own, Vernon was able to uncover some suggestive
information about the 32 CFS patient samples about which WPI originally
reported assay results. Only 12 tested positive on more than one assay
(WPI ran four assays); of those 12, four had been diagnosed with cancer.
Another 13 of the total 67 XMRV-positive CFS samples also had cancer.
Whether XMRV is a cause or a passenger or merely a geographical
coincidence of a particular CFS outbreak remains to be learned. But one
thing is clear: With its big discovery, the upstart medical center has
made more than a big splash. WPI has placed CFS - and itself - at the
center of the perfect storm. "I knew how serious a retrovirus is,"
Annette Whittemore told the Times. "I was very concerned, knowing the
implications. My second thought was, 'Of course, it was going to be
something serious like that. Look at my daughter and how ill she is.'"
(c) 2010 Advanstar Communications, Inc.