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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
N Engl J Med. Author manuscript; available in PMC 2013 December 6.
Published in final edited form as:
PMCID: PMC3771634

JC Viremia in Natalizumab-Treated Patients with Multiple Sclerosis

Eugene O. Major, Ph.D., Elliot Frohman, M.D., Ph.D., and Daniel Douek, M.D., Ph.D.

To the Editor: We analyzed plasma samples for the presence of JC virus antibodies and viral DNA. The samples were obtained from separate cohorts of patients with multiple sclerosis who received monthly infusions of natalizumab. Blood samples were obtained from 26 patients immediately before the first infusion (the baseline) and for several months during the first year of treatment. Blood samples also were obtained from 23 patients once after more than 24 months of treatment. Antibody titers and viral DNA1 were measured by means of an enzyme-linked immunosorbent assay with the use of JC viruslike particles (the Biogen Stratify assay uses similar viruslike particles).2 We also used an ultrasensitive quantitative polymerase-chain-reaction (PCR) assay specific for JC virus DNA.1 Our procedures were certified in accordance with the Clinical Laboratory Improvement Amendment. 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 patients with multiple sclerosis.

Overall, 17 of the 49 patients (35%) had viremia at some time. Ten of 26 patients in whom treatment was initiated had viremia; 4 were seronegative (antibody titer, <2560) and 6 were seropositive (antibody titer, ≥2560).1 Of these patients, 4 had viremia at baseline and 3 were seropositive. Seven of 23 patients 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.

Fisher’s exact test was used to determine a statistical difference between the treated patients who had viremia and healthy volunteers (P = 0.003) (Table 1). We observed a range in viral titers from 13 to 510 copies of JC virus DNA per milliliter (mean, 43 copies per milliliter) in patients 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%).

Table 1
Plasma Viremia in Patients with Multiple Sclerosis Who Were Treated with Natalizumab.*

Although viremia by itself is not a predictor of the risk of PML, the observation that viremia can occur in patients with negative test results for antibodies to the JC virus raises other issues. The relatively high percentage of patients who had viremia and were seronegative appears to be greater than the false negative rate identified previously.2 In some of these patients, the same blood sample showed T-cell responses to JC virus proteins but a seronegative test result.3

To establish risk-stratification algorithms for PML in patients 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.4,5 The observation that some patients had viremia and were seronegative provides support for a more comprehensive risk-mitigation strategy involving periodic monitoring over the course of the treatment intervention.


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Contributor Information

Eugene O. Major, National Institute of Neurological Disorders and Stroke Bethesda, MD.

Elliot Frohman, University of Texas Southwestern Medical Center Dallas, TX.

Daniel Douek, National Institute of Allergy and Infectious Diseases Bethesda, MD.


1. Ryschkewitsch CF, Jensen PN, Monaco MC, Major EO. JC virus persistence following progressive multifocal leukoencephalopathy in multiple sclerosis patients treated with natalizumab. Ann Neurol. 2010;68:384–91. [PMC free article] [PubMed]
2. Bloomgren G, Richman S, Hotermans C, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med. 2012;366:1870–80. [PubMed]
3. Perkins MR, Ryschkewitsch CF, Liebner JC, et al. Changes in JC virus specific T cell responses during natalizumab treatment and in natalizumab-associated progressive multifocal leukoencephalopathy. PLoS Pathog. 2012;8(11):e1003014. [PMC free article] [PubMed]
4. Trampe AK, Hemmelmann C, Stroet A, et al. Anti-JC virus antibodies in a large German natalizumab-treated multiple sclerosis cohort. Neurology. 2012;78:1736–42. [PubMed]
5. Major EO, Ryschkewitsch CF, Jensen PN, et al. Persistence of JCV in natalizumab treated MS patients who developed PML. Ann Neurol. 2011;69:430.