January 6, 2010
XMRV retrovirus replication: Round up 2 Patient organisation responses
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Patient representation organisation statements
UK patient organisations
Action for M.E. | 6 January 2010
Link between XMRV and CFS?
New UK research claims there’s no link between XMRV and CFS.
Research published today from Imperial and King’s College London announces that they have been unsuccessful in finding the XMRV retrovirus in a sample of British patients with chronic fatigue syndrome.
Last year, as reported on our website, the Whittlemore Peterson Institute in America found that 68 out of 101 patients with the illness appeared to be infected with the virus, compared to 8 out of 218 healthy controls.
The recent UK study analysed tissue samples from 186 patients with CFS using sensitive molecular testing techniques, but found no evidence that they had the XMRV virus.
In a press release issued by Imperial College, Professor Myra McClure, one of the authors of the study, said:
“Our research was carried out under rigorous conditions – we looked at samples from well-studied patients, and we used very sensitive testing methods to look for the virus. If it had been there, we would have found it. The lab in which we carried out the analysis had never housed any of the murine leukaemia viruses related to XMRV, and we took great care to ensure there was no contamination.
“We are confident that our results show there is no link between XMRV and Chronic Fatigue Syndrome, at least in the UK. The US study had some dramatic results that implied people with the illness could be treated with anti-retrovirals. Our recommendation to people with Chronic Fatigue Syndrome would be not to change their treatment regime, because our results suggest that anti-retrovirals would not be an effective treatment for the condition,” added Professor McClure.
Sir Peter Spencer, Action for M.E. says:
“Action for M.E. is disappointed to hear about these findings but no single small-scale study can be conclusive and the fact remains: American researchers found XMRV virus in 68 out of 101 people with chronic fatigue syndrome. Were those samples contaminated – or were those people susceptible to XMRV because they had CFS?
“What we need is more research involving large numbers of carefully characterised patients at a number of sites, preferably using fresh, not stored, blood samples. We also need studies on large numbers of both healthy people and people with other conditions.
“250,000 British men, women and children have this devastating illness. They need answers, better treatments and a cure.”
ME Association | 6 January 2010
ME Association statement – XMRV: UK research group fails to replicate American findings
Failure to detect the novel retrovirus XMRV in chronic fatigue syndrome.
Erlwein O et al. Public Library of Science/PLoS ONE open access journal: January 2010.
In October 2009, an American research group published a paper in Science which reported that they had found evidence of a new retrovirus called XMRV (xenotropic murine leukaemia virus-related virus) in a very high percentage (68/101) of people with ME/CFS – whose diagnosis met with both 1994 CDC/Fukuda research criteria and the Canadian clinical criteria. This compared to only 8/218 positive tests in the healthy controls.
The MEA has provided regular website updates on these findings and offered to help fund further research studies which would attempt to replicate these findings. Our latest XMRV update can be found here.
A number of research groups both here and abroad are now carrying out XMRV replication studies using stored blood samples.
The first study to be reported in the medical literature comes from a very reputable virology/infectious disease group at Imperial College in London. The group obtained stored blood samples from patients who have been attending the King’s College Hospital ME/CFS service.
The virologists examined 186 blood samples from the KCH patients who met Fukuda/CDC criteria for CFS using sensitive molecular testing techniques. DNA (viral genetic material), which was extracted from the blood samples, was screened for XMRV provirus and for the closely related murine leukaemia virus (MLV) by nested PCR (polymerise chain reaction)using specific oligonucleotide primers. PCR is a highly sensitive method that can locate tiny viral fragments. No molecular evidence of XMRV or MLV sequences was found in any of the ME/CFS samples.
These results clearly represent a major difference in scientific opinion on the possible role of XMRV in ME/CFS.
Among the explanations that could be relevant are:
1 The use of different types of ME/CFS patients in the two studies. The American patients had ‘severe disability’, were diagnosed using both CDC/Fukuda and Canadian clinical criteria, and were obtained from a small group of private physicians who take a very biomedical approach to ME/CFS. The UK sample, who had ‘high levels of disability’, were diagnosed using only Fukuda/CDC criteria and came from King’s College Hospital in London – an NHS tertiary referral centre that specialises in behavioural interventions.
2 There may be different prevalence rates for XMRV in different countries and it is interesting to note that German researchers were unable to replicate the American results in relation to the presence of XMRV in patients with prostate cancer.
3 The UK and USA laboratories used slightly different techniques for investigating the presence of XMRV and there may have been differing levels of risk in relation to the possibility of laboratory XMRV contamination.
Comment from Dr Charles Shepherd, honorary medical adviser to the ME Association:
“The ME Association has taken a cautious and open-minded view about the initial XMRV findings and offered to help fund further research into what could be a very significant finding. Although these UK results are clearly questioning the validity of the American findings, no single study can be regarded as being conclusive. So we believe it is important to wait for the results of further replication studies before drawing any firm conclusions about the possible role or pathogenicity (disease-causing ability) of XMRV in ME/CFS. In the meantime, there seems little point in people with ME/CFS spending large sums of money in arranging private tests for XMRV. And in our current state of uncertainty it would not be appropriate for doctors to start prescribing antiretorviral treatment to people with ME/CFS”.
Invest in ME | 6 January 2010
STATEMENT by INVEST in ME
BBC NEWS ARTICLE “Research finds no proof that a virus is the cause of ME”
The perennial problem of trials such as this from ICL and those funded by the Medical Research Council is that they do not use well defined patient cohorts which can negate the research results.
To replicate a research study the patient samples used and the methodology have to be the same and in this case it appears that there are differences in both compared to the study published online 8 October, 2009 by the Science magazine.
The organisations in USA who discovered the XMRV retrovirus used the Canadian Guidelines to select patients for their research and Invest in ME feel the Canadian Guidelines should be used for all research.
Those who portray ME as a somatoform illness are fully aware that using patients who do not fit strict selection criteria will obviously skew results. We therefore have serious doubts about the the results of the ICL research.
If the correct patient cohorts are not participating in the trials or different methods are used then this will affect the results.
The result of finding no sign of XMRV would point to a different methodology to that used in the research published by the Science magazine in which 3.7% of controls tested positive.
The work performed by the Whittemore-Peterson Institute (WPI) and the National Cancer Institute and the Cleveland Clinic is of the highest quality and has been validated by Science magazine.
Much more research is underway and the results from the first XMRV replication trials such as these from ICL prove little.
People with ME and their families should expect these “false” results to be publicised early, especially as ME has been ignored by the government and research organisations for generations. However, the new XMRV research has changed the landscape for good and patients and carers can look forward to a new era of ME/CFS research based on the biomedical basis for the illness.
Proper science is now finally being performed.
Those who have delayed or stopped high quality biomedical research into ME from being performed in the past, and those who continue to downplay the significance of the new research from WPI, will not be in a position to continue this denial for much longer.
The WPI have promised more exciting news which we can expect to hear at the forthcoming 5th Invest in ME International ME/CFS Conference on 24th May in London.
Invest in ME remain convinced that the WPI research is of monumental importance to the future of research into ME and we look forward to the future and the momentum in biomedical research into ME which the XMRV research has generated.
Invest in ME
The BBC article is available – click here
The PLoS One article is here
Documented involvement of Viruses in ME/CFS
5th Invest in ME International ME/CFS Conference 2010
The Proof is Out There – the WPI research – click here
US patient organisations
CFIDS Association of America | 6 January 2010
XMRV Negative Results Emphasize Need for Robust Replication Study
Suzanne D. Vernon, PhD
A study testing for evidence of XMRV infection in CFS patients in the United Kingdom has reported negative results. This is the first publication following the article in the top-ranked journal Science from researchers at the Whittemore Peterson Institute, the National Cancer Institute and Cleveland Clinic that garnered worldwide attention from the media and scientific community. The new report, published Jan. 6, 2010, in the open access online journal PLoS ONE, failed to detect XMRV in CFS, but should not be considered a valid attempt to replicate the findings described by Lombardi et al., in the Oct. 8, 2009 Science article.
The PLoS ONE paper by Otto Erlwein, Steve Kaye, Myra O. McClure, Jonathan Weber, Gillian Wills, David Collier, Simon Wessely and Anthony Cleare is titled, “Failure to Detect the Novel Retrovirus XMRV in Chronic Fatigue Syndrome.” The investigators tested peripheral blood DNA from 186 routine clinic attendees who met 1994 (Fukuda) CFS case definition criteria and were well-characterized from participation in prior neuroendocrine and cognitive behavioral therapy studies. These 186 CFS patients were reported to be unwell for a median of four years with high levels of fatigue and disability.
This team of researchers used a special type of DNA “xeroxing” called nested polymerase chain reaction (PCR) reaction to amplify specific segments of the XMRV proviral DNA from the genomic DNA obtained from these 186 CFS subjects. In essence, they were looking to see if XMRV genetic material had integrated into human genetic material, which is a key characteristic of retroviral infection. The experiment included positive, negative and contamination controls, but did not test any samples taken from healthy subjects. The samples were coded so that the origin of the DNA was not known to the person conducting the PCR assays. XMRV was not detected in any of the 186 samples.
Can this study be considered comparable to the results published by Lombardi et al., in Science? In short, no. Both studies included CFS patients defined by the 1994 case definition criteria, but this is where the comparability ends. Here are some of the ways the PLoS ONE and Science methods differ:
The blood was collected from CFS patients in different types of blood collection tubes.
The genomic DNA was extracted and purified using different techniques.
The amount of genomic DNA included in the amplification assay was different.
Different primer sequences were used that amplified different regions of the XMRV proviral DNA.
The conditions of the PCR amplification assay were different – from the numbers of cycles, to the type of polymerase used.
Should these differences affect an investigator’s ability to detect XMRV? To a microbiologist with experience handling samples and studying various infectious agents (as I am), these variances in procedure could make the difference between detecting XMRV or not.
It very well could be true that XMRV is not present in the U.K. as Erlwein, et al. suggest in their discussion, but it is also possible that the technique used in the PLoS ONE paper was suboptimal due to the different methods employed, when compared to the original experiments conducted by Lombardi, et al.
The U.S. Department of Health and Human Services Blood XMRV Scientific Research Working Group is conducting a rigorous study to detect XMRV. Multiple laboratories will standardize methods to optimize sensitive detection of XMRV proviral DNA and viral RNA and then, once methods are standardized, these same laboratories will test coded panels of blood samples obtained from healthy blood donors and CFS patients. We look forward to the results of this study and urge that it be completed expeditiously, especially in light of this report from the U.K. In the meantime, be prepared to read about more studies with conflicting findings. Rather than simply accept or dismiss new information, we will help make sense of why discrepant results occur.
Perhaps the most important statement in the PLoS ONE paper is the acknowledgement by this group of investigators that CFS is an incapacitating organic disease affecting millions of people worldwide. Once XMRV detection methods are optimized and made widely available, we encourage this group of researchers to take another look at XMRV as a possible explanation for the organic basis of CFS in the U.K.
Erlwein O, Kaye S, McClure MO, Weber J, Willis G, Collier D, Wessley S, Cleare A. (2010) Failure to detect the novel retrovirus XMRV in chronic fatigue syndrome. PLoS ONE 5(1):e8519. doi:10.1371/journal.pone.0008519
Lombardi VC, Ruscetti FW, Gupta JD, Pfost MA, Hagen KS, Peterson DL, Ruscetti SK, Bagni RK, Petrow-Sadowski C, Gold B, Dean M, Silverman RH, Mikovits JA. Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Science 8 October 2009. 1179052.
Suzanne D. Vernon, PhD, earned her doctorate in virology at the University of Wisconsin at Madison and worked in public health research on infectious diseases at the U.S. Centers for Disease Control and Prevention for 17 years before joining the CFIDS Association of America’s staff as scientific director in 2007. She has more than 70 peer-reviewed scientific publications on topics including human immunodeficiency virus, human papillomavirus, cervical cancer and chronic fatigue syndrome. Dr. Vernon has initiated and participated in numerous international and multidisciplinary research collaborations and she now leads the CFIDS Association’s research program. The CFIDS Association of America is the nation’s largest philanthropic supporters of CFS research.
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