JC viremia: does JC virus negative mean virus negative?

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.