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Modeling probability of additional cases of natalizumab-associated JCV sero-negative progressive multifocal

Robert L Carruthers1, Tanuja Chitnis, Brian C Healy

  • 1Department of Neurology, Harvard Medical School, Boston, MA, USA.

Multiple Sclerosis (Houndmills, Basingstoke, England)
|November 6, 2013
PubMed

Insights

Determining progressive multifocal leukoencephalopathy (PML) risk in natalizumab patients requires assessing John Cunningham virus (JCV) serologic status. This study models PML risk in JCV sero-negative patients, addressing uncertainties in current testing.

Area of Science:

  • Neurology
  • Immunology
  • Virology

Background:

  • John Cunningham virus (JCV) serologic status is crucial for assessing progressive multifocal leukoencephalopathy (PML) risk in patients treated with natalizumab.
  • Recent cases of PML in JCV sero-negative patients and concerns about the JCV serologic test's false negative rate raise questions about the adequacy of current PML risk assessment.
  • The lack of a gold standard for diagnosing prior JCV exposure makes definitive characterization of the JCV serologic test's performance impossible.

Purpose of the Study:

  • To develop a predictive model for PML risk specifically in natalizumab-treated patients who are JCV sero-negative.
  • To quantify the potential number of JCV-exposed but sero-negative individuals and estimate the expected PML cases within this population.
  • To establish a probabilistic framework for evaluating the adequacy of current PML risk understanding in JCV sero-negative patients.

Main Methods:

  • Utilized patient numbers from a prior study (13,950 JCV sero-positive, 11,414 sero-negative).
  • Applied a range of potential sensitivities and specificities for the JCV serologic test to estimate false negative rates.
  • Incorporated varying rates of PML development in sero-negative individuals and employed the binomial function to calculate probabilities of observed PML cases.

Main Results:

  • The model allows for the calculation of the number of JCV-exposed, sero-negative patients based on assumed test characteristics.
  • It estimates the expected number of PML cases in this population under different PML incidence assumptions.
  • Probabilistic outcomes are generated to assess the likelihood of observed PML cases occurring by chance.

Conclusions:

  • The proposed model provides a method to evaluate the adequacy of PML risk assessment in JCV sero-negative natalizumab patients.
  • It enables the establishment of a threshold for the number of PML cases that would suggest current risk understanding is insufficient.
  • This approach aids clinicians in interpreting PML risk in the context of JCV serologic test limitations.
Keywords:
JC Virusdisease modifying therapiesmultiple sclerosisnatalizumabprogressive multifocal leukoencephalopathy

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