Should Clinical Trials of antivirals remain on the table in ME/CFS

The news that the authors of a 2009 Science paper linking a retrovirus, XMRV, with Chronic Fatigue Syndrome (ME/CFS) have partially retracted their paper went viral in the last 48 hours. This had been building for months as negative XMRV study followed negative study as other researchers attempted to replicate the results of Lombardi et al and failed. But the original researchers stuck to their guns supported by a large group of patients desperate for answers. Many viruses have been associated with subgroups of patients and many researchers continue to suspect an infectious connection, so why was a retrovirus specifically so appealing? After all, most people would rather not have a disease caused by a retrovirus.

One possible answer lies in clinical trials . Thanks in part to the retrovirus HIV, scientists have gained a great deal of knowledge about retroviruses in the past 30 years and have developed many ways to treat them in the years. CFS clinicians knew that there are already antivirals in the arsenal to combat retroviruses. Indeed in early 2010 University of Utah retrovirologist Dr. Ila Singh and colleagues published “Raltegravir Is a Potent Inhibitor of XMRV, a Virus Implicated in Prostate Cancer and Chronic Fatigue Syndrome” after testing forty-five compounds, including twenty-eight drugs approved for use in humans, against XMRV replication in test tubes (in vitro). Some patients and their clinicians began using anti-retrovirals on the basis of supposedly having tested positive for XMRV. But, as meaningful as the results might be to the individual patients such interventions are not a basis for clinical extrapolation to entire populations.

Enter the scientists – A year ago Dr. Andrew L. Mason of the University of Alberta and colleagues editorialized that perhaps it was time to begin clinical testing of such drugs in CFS thus working in reverse from intervention to etiological agent.

Their reasoning was this:

" …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 pepticulcer disease was only accepted after Barry Marshall showed that bacterial eradication with antibiotics cured peptic ulcer disease. 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. Trials using acombination 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."

Their caveats for conducting clinical trials in patients with CFS:

· Potential benefits of treatment should outweigh the risks – the severity of the disease in the subgroup studied would be a variable for example.

· Studies should be conducted as randomized controlled trials with meaningful and

· feasible endpoints using robust therapies.

In other words clinical interventions should not be based on anecdotal evidence although anecdotal evidence can serve as a starting point for determining whether a trial is justified. Dr. Mason and colleagues concluded, "At this juncture, studies to establish proof of principle are justified to determine whether safe antiviral regimens can impact on CFS."

The question remains, even if XMRV is not a causative pathogen in CFS, does the reasoning of these scientists still hold? After all, as immunologist and CFS expert Dr. Nancy Klimas told the New York Times yesterday, “Internationally recognized experts have looked at the immune data and concluded that there very well may be a pathogen or pathogens involved in the persistence of this illness.” And, although done with considerably less fanfare, there have been successful pilot studies of antivirals in CFS patient subgroups with herpesvirus infections. If, as many CFS researchers believe, CFS can be caused by multiple viruses as is the case with the common cold then such a process could be long and complicated. Researchers would first have to agree on who does and does not have the disease, then sort subsets by pathogen or maybe even combinations of pathogens as antivirals are virus specific, and then study in the potential of antivirals in inhibiting the growth of the suspected virus(es) in those subgroups. And just for fun funguses, toxins, and bacteria could be proven to be part of the mix in some subsets as well further complicating the process.

The process of science is and always has been, one part knowledge, two parts guesswork and whole lot of dead ends – not the clean cut answer for which patients might wish. But will one dead end be considered a reason to take no as a final answer? Unlikely.

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Since this article was written, journalist Scott James wrote an excellent column for the New York Times about CFS patients taking HIV drugs . Issues raised were whether manufacturers of such drugs are promoting off-label prescribing of such drugs for CFS patients and whether a shortage of HIV drugs for HIV patients with reduced financial means was the result of CFS patients competing for the same free drugs or people taking HIV drugs as preventative measures.

The problem, as stated in Mr. James' column, is there are no hard numbers on the number of CFS patients being prescribed HIV drugs and thus no objective means to determine the scale of the situation. In an email Mr. James stated, "Since my story was published more people have come forward to me to tell me that they've also taken HIV drugs for CFS. I've also had people tell me that their doctors have prescribed HIV drugs experimentally for all sorts of conditions, including arthritis." Also responding in an email, HIV and CFS clinician and research Dr. Nancy Klimas said, "I doubt that there are many CFS patients on antiretrovirals. Most doctors asked their patients to wait until the XMRV observations were confirmed and clinical trials begun. In my own practice very few were tested and I wrote no prescriptions for antiretrovirals. I think this was the norm."

This underscores the need for clinical trials rather than individual experimentation.