Friday, 14 June 2013

JC viremia: does JC virus negative mean virus negative?

Will the latest JCV lab study prove to be due to contamination? #MSBlog #MSResearch

"The following study may, or may not, be important. These investigators' find JC virus, the cause of PML, in blood sample of MSers who do not have antibodies to the virus. This implies the antibody test is not good enough to detect carriers of the virus and imply that these MSers are potentially at increased risk of PML."
"I am sceptical of the results. Why? Simply because our immune systems are so good at detecting and responding to viruses that the results are not credible. Our immune systems seldom lie; they may forget when we get older or when we hit them with an immunosuppressant sledgehammer, but they seldom ignore foreign  agents in such a systematic way."

"In addition, this study is not supported by other studies published in the literature on this topic. Therefore this study needs to be reproduced by not one but several laboratories."
"I would like to see what efforts these investigators went to make sure their results were not due to contamination. When using an ultra-sensitive PCR assay that detects viral DNA positive results can be due to contamination. I wonder if the authors' sequenced the DNA of these viruses to make sure they were not a common laboratory contaminant. Quite recently a very high profile publication on JCV and PML was published in the New England Journal of Medicine and when the so called isolates were sequenced they were all from a laboratory strain of the virus implying the results were due to contamination. The latter is a problem that can happen in the best labs in the world."


"I won't let this study change clinical practice. The data on PML risk stratification using the JCV serology seems to be holding up."

"What is clear is that we urgently need other highly-effective treatments in the same zone as natalizumab, that are not associated with an increased risk of PML, to provide MSers with alternative choices. The sooner alemtuzumab and ocrelizumab get the clinics the better; both these drugs will be as effective as natalizumab and are unlikely to have a significant PML risk."

Major et al. JC viremia in natalizumab-treated patients with multiple sclerosis. N Engl J Med. 2013 Jun 6;368(23):2240-1.

These investigators analyzed plasma samples for the presence of JC virus antibodies and viral DNA. The samples were obtained from separate cohorts of MSers who received monthly infusions of natalizumab. Blood samples were obtained from 26 MSers immediately before the first infusion (the baseline) and for several months during the first year of treatment. Blood samples also were obtained from 23 MSers once after more than 24 months of treatment. Antibody titers and viral DNA were measured by means of an enzyme-linked immunosorbent assay with the use of JC virus-like particles (the Biogen Stratify assay uses similar virus-like particles).They also used an ultrasensitive quantitative polymerase-chain-reaction (PCR) assay specific for JC virus DNA. The Laboratory of Molecular Medicine and Neuroscience has provided quantitative PCR results that have confirmed the diagnosis of progressive multifocal leukoencephalopathy (PML) in approximately half the 370 cases of PML in natalizumab-treated MSers.

Overall, 17 of the 49 MSers (35%) had viremia at some time. Ten of 26 MSer in whom treatment was initiated had viremia; 4 were seronegative (antibody titre, <2560) and 6 were seropositive (antibody titer, ≥2560). Of these MSers, 4 had viremia at baseline and 3 were seropositive. Seven of 23 MSers who received more than 24 infusions had viremia and 2 were seronegative. One blood sample was obtained from each of the 18 healthy volunteers; 6 were seronegative, 12 were seropositive, and none had detectable viral DNA.

They observed a range in viral titers from 13 to 510 copies of JC virus DNA per milliliter (mean, 43 copies per milliliter) in MSers in the initial year of treatment and from 21 to 126 copies (mean, 40 copies per milliliter) in those who received more than 24 infusions. Of the 17 persons with viremia, 11 were seropositive (65%) and 6 were seronegative (35%).

Although viremia by itself is not a predictor of the risk of PML, the observation that viremia can occur in MSers with negative test results for antibodies to the JC virus raises other issues. The relatively high percentage of MSers who had viremia and were seronegative appears to be greater than the false negative rate identified previously. In some of these MSers, the same blood sample showed T-cell responses to JC virus proteins but a seronegative test result.

To establish risk-stratification algorithms for PML in MSers who receive potent immunomodulatory therapies, a single measurement of viral activity such as a test for antibodies to JC virus may be useful but not sufficient to assess risk. The observation that some MSers had viremia and were seronegative provides support for a more comprehensive risk-mitigation strategy involving periodic monitoring over the course of the treatment intervention.

CoI: multiple

Other posts of interest on PML

Multiple Sclerosis Research: ENS HOT TOPIC: JCV titres and PML risk
09 Jun 2013
With polyomaviruses, higher levels of antibodies have been correlated with increased viral burden and increased disease risk. It is not known whether JCV Ab levels correlate with PML risk in natalizumab-treated MSers.

Multiple Sclerosis Research: PML Update: May 2013
05 Jun 2013
"Biogen-Idec the company that helped develop and market natalizumab are concerned that my monthly PML update is too complicated for MSers to understand. I have therefore tried to simplify the slide deck. This is a work in ...

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Multiple Sclerosis Research: Case report: nipping PML in the bud
23 Feb 2013
Case report: nipping PML in the bud. #MSBlog: If you are natalizumab, or Tysabri, and are worried about PML this post if for you! Epub: Lindå H, von Heijne A.Presymptomatic diagnosis with MRI and adequate treatment ...

Guest post: FUMADERM and PML – can we make conclus...
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"In response to the intense interest on the blog concerning Fumaderm and PML and its possible implications for BG12, we invited Professor Doctor Ralf Gold to contribute a guest post on this topic! I hope it answers some of ...

Multiple Sclerosis Research: PML and fumarates
20 Jan 2013
Clarification: I have just found out that the case report below and the third case in the BfArM's ADR Database (10130944) are the same case. Therefore there has only been 4 reported cases of PML on Fumaderm, one of which ...

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