Tuesday, January 11, 2011

XMRV Proof of Principle Studies = Clinical Trials Now

Are ME/CFS patients first and foremost lab animals or patients?

Apparently, it depends on your point of view.

With the news that XMRV, a newly discovered retrovirus may contribute to or be the cause of chronic fatigue syndrome, or myalgic encephalomyelitis, as it is called by the World Health Organization, some patients, doctors and researchers called for clinical trials of the drugs already developed for HIV/AIDS.

Courgnaud et al, Department of Medicine, University of Alberta, Edmonton, AB, Canada wrote, in a commentary on the Alter/Lo paper in PNAS:

"As we currently lack postulates to prove a causal association with a prevalent agent and a chronic disease with genetic predisposition, it would also be appropriate to conduct interventional studies. Indeed, the Helicobacter pylori hypothesis of peptic ulcer disease was only accepted after Barry Marshall showed that bacterial eradication with antibiotics cured peptic ulcer disease (21). Studies to gain proof of principle have been performed with antivirals in other chronic, idiopathic diseases linked to retroviral infection, such as primary biliary cirrhosis associated with mouse mammary tumor virus, another possible murine zoonosis (22). Trials using a combination of reverse transcriptase inhibitors led to significant improvements in clinical, histological, and biochemical outcomes in these patients, albeit with some evidence of viral resistance to therapy (23). Such studies are now feasible for CFS, because reverse-transcriptase inhibitors, such as
tenofovir and emtracitabine, and the integrase inhibitor raltegravir can inhibit XMRV (24). The caveats for conducting clinical trials in patients with CFS and MLV infection are that the potential benefits of treatment should outweigh the risks; also, studies should be conducted as randomized controlled trials with meaningful and feasible endpoints using robust therapies. At this juncture, studies to establish proof of principle are justified to determine whether safe antiviral regimens can impact on CFS and to determine whether xenotropic or polytropic MLV is causally associated with this debilitating disease."

On the other side of the argument Mary Kearney and Frank Maldarelli, HIV Drug Resistance Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland declared that :

“Such pressures are not justification for testing of therapies in an uncontrolled manner. Indeed, because they are of no help whatsoever to other patients, physicians, pharmaceutical companies, or regulatory agencies, such uncontrolled therapy works directly against the goal of providing effective therapy to the million or more individuals experiencing these serious conditions.”

OK, so some researchers, pharmaceutical companies and regulatory agencies have decided to wait and see. To them , the one million or more people who have CFS are to be the source of lab samples to be tested. Some researchers have predicted it will be at least ten years before treatment could become available. Others are still contesting whether XMRV is the cause of disease, or whether it is even a human pathogen.

In the meantime, physicians who have been trying to help CFS patients for decades look at this research and ask themselves and their patients, what have we got to lose?

Dr. Ila Singh has already found that three drugs developed for HIV/AIDS treatment are also effective in the lab against XMRV and the related MLVs that further research has found in CFS patients.

Physicians have been prescribing drugs “off label”, or for conditions the drug wasn’t developed or approved for, since forever.

When selecting a drug to prescribe for any ailment the physician never knows whether it will work for her/his patient until the patient tries it.

It wouldn’t be the first time a disease was proven to exist by its response to treatment. Barry Marshall, PhD, proved peptic ulcers were caused by bacteria, not stress, by infecting himself with that bacteria and then curing himself with antibiotics. He got a Nobel Prize in Medicine for it.

Physicians are ethically obligated to do the best they can for the individual before them. They tend to see patients as people who need treatment rather than potential contributors of lab samples. If they and the patient, after assessing the risks of the treatment and the risks of doing nothing, decide to try antiretroviral drugs, there is nothing unethical or zealous about it. They can do the same monitoring for these patients that they would do if the patient were HIV positive instead of XMRV positive. They can discontinue therapy if there are warning signals indicating they should.

A physician’s first responsibility is to the patient, not to research, regulatory agencies or pharmaceutical companies. To withhold reasonable treatment in an attempt to advance science would be unethical.

Haven't both medicine and research progressed past the "Tuskegee Mentality"?

From 1932 to 1972, when public outcry stopped the program, patients infected with syphilis were "observed" but not treated by the US Public Health Service in Tuskegee AL. At some point the CDC was created and took over the study.

From the CDC's account of the experiment:

[1969 CDC reaffirms need for study and gains local medical societies' support (AMA and NMA chapters officially support continuation of study).

1972 First news articles condemn studies.

1972 Study ends.

1973 Congress holds hearings and a class-action lawsuit is filed on behalf of the study participants.

1974 A $10 million out-of-court settlement is reached and the U.S. government promised to give lifetime medical benefits and burial services to all living participants. The Tuskegee Health Benefit Program (THBP) was established to provide these services.]

In 1947 penicillin was found to effectively treat syphilis, but it was not offered to the men in the study. Reminiscent of Nazi medical experiments, it was decided to observe the men until they died, do autopsies on them and pay for their burial.

From 1946-48 the US did the same thing in Guatemala except that it purposefully infected prisoners and mental patients with syphilis.

It bears repeating: A physician’s first responsibility is to the patient, not to research, regulatory agencies or pharmaceutical companies. To withhold reasonable treatment in an attempt to advance science, however misguided that attempt might be or however highly approved it might be by other researchers, would be unethical.

Prisoners and mental patients may lose their civil rights but they never lose their human rights, even as those rights are being abused. Persons with ME/CFS have long had their human rights abused and arguably, their civil rights as well. But more about that in another post.


  1. Yep. It's all well and good for scientists to advocate prudence, but people are desperate and clinical trials for antivirals don't exactly constitute throwing random stuff at the wall and seeing what sticks.

    Fingers crossed.

  2. Diagnostics has been a common and intended use of medications for a very long time. It's a very effective diagnostic tool. If the potential benefits outweigh the potential hazards, withholding the medication is not motivated by care for the patient. And, it disregards the oath of first doing no harm.