Blood Products Advisory Committee Mulls XMRV Information

Fran Lowry

July 27, 2010

July 27, 2010 — The US Food and Drug Administration (FDA) Blood Products Advisory Committee yesterday heard briefings from a number of public health agencies and other experts on whether the recently discovered human retrovirus xenotropic murine leukemia virus–related virus (XMRV) poses a threat to the nation's blood supply.

The committee also heard how laboratories from the National Cancer Institute (NCI), the Centers for Disease Control and Prevention (CDC), the Blood Systems Research Institute, and the FDA are working to develop state-of-the-art assays to speed recognition of the virus and facilitate screening of potential blood donors.

The panel was treated to a rehash of conflicting studies — some showing an association with XMRV and prostate cancer and chronic fatigue syndrome (CFS), and others showing zero association between the gammaretrovirus and these diseases.

Indira Hewlett, PhD, from the FDA's Division of Emerging and Transfusion Transmitted Diseases, Office of Blood Research and Review, briefed the panel on the conflicting studies that linked — or did not link — XMRV with prostate cancer and CFS.

In one study, XMRV was detected in 7 of 11 prostate cancer patients with a genetic predisposition for prostate cancer; in another, 6% of 334 prostate cancer patients were found to be positive for XMRV by polymerase chain reaction (PCR), and 23% were found to be positive for XMRV by immunohistochemistry. "Taken together, these findings suggest an association of XMRV with prostate cancer," Dr. Hewlett said.

In CFS, one study (Science. 2009;326:585-589) showed that XMRV could be detected in 67% of patients with CFS vs 3.7% of healthy control patients, using PCR and serology testing.

Horns of a Dilemma

However, other studies have yielded negative results for both prostate cancer and CFS, and these have placed researchers and policy makers on the horns of a dilemma.

The possibility of potential transfusion transmission of XMRV comes from experiments with rhesus macaque monkeys — intravenous inoculation showed disseminated infection and low but detectable transient viremia between 4 and 14 days, Dr. Hewlett told the committee. Seroconversion occurred between 11 and 14 days, with titers peaking around day 95. In addition, XMRV was isolated from lymphoid cells, reproductive tissue, and a number of organs.

"These findings lend support to potential transfusion transmission of XMRV and suggests that there is a need for additional studies using well-standardized assays," Dr. Hewlett said.

Because of the potential for transmission of XMRV during blood transfusions, the Canadian government has decided to err on the side of caution by mandating that all patients with CFS refrain from donating blood, Peter Ganz, MD, from Health Canada, Ottawa, told the panel.

Caution in Canada

The Canadians have been ultracautious ever since the "tainted blood" scandal of the mid-1980s, which saw a number of people become infected with HIV through blood transfusions, Dr. Ganz said.

Blood from donors with CFS who were asymptomatic was accepted in Canada until April 2010, but now 90% of these would-be donors are indefinitely referred. The remaining 10% are from the province of Quebec, which still allows donors to give blood as long as they feel well.

"In Canada, one of our overarching guiding principles with regard to blood safety is the precautionary principle, which means that authorities must act, even if there is only a theoretical risk of harm," he said.

Robert Silverman, PhD, who was part of the team that first reported the potential link between XMRV and prostate cancer and CFS, presented those data again and also told the panel about possible ways that the virus infects humans.

Dr. Silverman told the panel that XMRV is found in semen and that its infectivity is enhanced by androgen and inhibited by antiandrogens.

Evidence Mixed for Disease Links

Of the 12 studies on XMRV and prostate cancer, 9 found evidence of the virus at some level. In CFS, the evidence has been less: Only 1 study of the 5 that have been done found a link between XMRV and this debilitating disease.

Dr. Silverman suggested that laboratory contamination, geographical distribution, sequence variants, clinical criteria for patient selection (particularly with CFS), and lack of standardized screening methods and positive control human participants are factors that could be responsible for large differences in the detection rate.

"XMRV is associated with prostate cancer and CSF in humans in some, but not all, studies. All individuals are at risk, regardless of the RNA cell genotype. XMRV establishes both acute and chronic persistent disseminated infection in primates — the prostate epithelium is an early target, the stroma a late target, CD4 and other blood cell types are infected," he told the panel.

In addition, "XMRV growth is fueled by androgen, which is a possible oncogenic mechanism, XMRV might be transmitted by blood transfusion, and there is now donor deferral for people with CFS in 3 countries," he said.

Knowledge Still Emerging

In spite of these observations, Dr. Silverman cautioned that knowledge about the infectious nature of XMRV is still emerging. "We need to let science do its work. Any causal link to human disease remains to be established."

R. Michael Hendry, DSC, from the CDC in Atlanta, Georgia, followed Dr. Silverman's presentation. He told the panel that, in direct and complete contrast to Dr. Silverman's experience, the CDC was unable to find any evidence of infection with XMRV in their population of CFS patients by any means, including using Western blot or ultrasensitive PCR assays.

"Many people have alluded to differences in patient population, complexities of defining [CFS], lab methods, and strain differences, to explain the contrasting results; however, our results do not support an association of XMRV with the majority of [CFS] patients," he said.

Stuart Le Grice, PhD, from the NCI Frederick Laboratory, Frederick, Maryland, described how he and his colleagues have been working to develop a single-copy assay for XMRV DNA, RNA, and serology, based on the assay that was developed for HIV.

"The HIV single copy that was developed at the NCI is regarded as the gold standard assay. We now believe that we have an equivalent assay for XMRV."

Dr. Le Grice and his team have also developed a cell line, dubbed the Derse cell line, which can detect XMRV in as little as 3 days.

He said that the XMRV assay that his lab has developed has been transferred to labs in Sweden, Australia, Vietnam, and South Africa to prove its utility. "Developing an assay is one thing, but transferring it to a laboratory where it can be reproduced is clearly important when we are talking about single copy assay. Contamination is a huge problem, and the ability to transfer these reagents is very important," he noted.

Dr. Le Grice added that the aim of the NCI is to make sure that the assays they have developed are as valid as possible. "Our goal is to develop a series of assays that we feel confident in and to test those head to head with other assays. I think that is really important at the moment. We should start with 6 assays in house, and if we have a problem, I think it is important to sit amongst ourselves and try to understand where those problems are before we disagree with anybody else's assay."

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