BARCELONA, Spain — A
quantitative test for antibodies to the JC virus (JCV) stratifies
antibody-positive patients with multiple sclerosis (MS) for their risk
of contracting progressive multifocal leukoencephalopathy (PML) if they
receive natalizumab (Tysabri, Biogen Idec). However,
some risk remains even with low antibody levels, and some patients who
harbor the virus have proven negative for antibodies, studies show.
Presenting
preliminary results of a study here at the 23rd Meeting of the European
Neurological Society, Barry Ticho, MD, PhD, vice president of clinical
development at Biogen Idec in Cambridge, Massachusetts, commented
to Medscape Medical News, "What it would indicate to us right now is
that the current levels [of risk] that are ascribed to patients who are
JC antibody-positive may not be uniform across that group for those
who've not had prior immunosuppressive use."
After
2 years of therapy, the risk for PML is approximately 5 per 1000
patients without prior immunosuppressant use. But "there's a population
that ranges between 30% and almost half of the [antibody-positive]
patients who may be at substantially lower risk of PML than is currently
ascribed," he said.
PML
is an opportunistic viral disease causing inflammation of the white
matter of the brain. It is usually fatal. JC virus is normally kept in
check by the immune system, but immunosuppressive therapies can
compromise this ability. Natalizumab is thought to act by blocking the
ability of inflammatory immune cells to migrate across the blood-brain
barrier.
In
the present study, anti-JCV antibody levels were determined by using
the second-generation Stratify(Biogen Idec) JCV enzyme-linked
immunosorbent assay (ELISA). Data were from antibody-positive patients
from postmarketing sources and natalizumab clinical trials. The ELISA
yields an anti-JCV antibody index, which is an optical density
measurement of antibody level and is a corollary to antibody titer.
Higher JCV Antibody Levels Precede PML Diagnosis
Patients
who were diagnosed with PML (n = 71) had significantly higher JCV
antibody index values more than 6 months before the diagnosis compared
with patients without a PML diagnosis (n = 2522) (P < .001).
Differences in antibody indices occurred only in comparison of patients
with (n = 19) and those without (n = 176) a PML diagnosis who had not
had prior immunosuppressive therapy; values were higher for patients
later diagnosed with PML (P < .001).
For
patients with no prior immunosuppressive exposure, antibody index
values allowed estimation of PML risk according to the duration of
exposure to natalizumab. Patients with lower antibody levels remained at
substantially lower PML risk over the course of natalizumab therapy
compared with patients with higher antibody levels.
"We
know that currently some physicians after 2 years of natalizumab
treatment in their antibody-positive patients will take the patients off
of drug because of a fear of PML," Dr. Ticho said. "Perhaps for
patients who have lower antibody index levels there is another analysis
of the benefit-risk that has to be made with respect to both the disease
course that those patients have and the fact that their risk of PML may
actually be lower than expected right now."
Patients With Low Antibody Levels Still at Risk
Dr.
Ticho also noted that some antibody-negative patients seroconvert over
time, with an expectation of increased PML risk. "Our data would
indicate that depending on what index level they have after they change
from negative to positive the change in their PML risk may not be nearly
as dramatic as people are expecting," such as going from a risk of 1
per 10,000 to an expected risk of 1 per 500. "But now we see that maybe
they're only going from a risk of 1 per 10,000 to maybe a risk of 1 per
1000 or even less."
By
18 months of natalizumab treatment, 96% of 553 previously
antibody-negative patients remained negative (87%) or seroconverted to a
low antibody index level. The current recommendation is to test
patients every 6 months for antibody levels.
Dr.
Ticho cautioned that the data are still preliminary and the hypothesis
of risk based on antibody levels needs further validation.
Session
moderator Ludwig Kappos, MD, professor of neurology and clinical
neuroimmunology at the University of Basel and chair of the Department
of Neurology at University Hospital in Basel, Switzerland, commented
to Medscape Medical News that the study provides a further step in
defining the risk of PML and is important for that reason, "but it does
not eliminate the risk. You have to understand how the risk is and
perhaps also to tailor the other additional measures of surveillance,
but it is of course not eliminating the risk."
He
said that up to now, tests have shown only whether a patient was
positive or negative for antibody, but by judging antibody levels on a
continuum and with thresholds for risk, "it shows at least a part of
those who are positive may still have a reasonable risk that you would
perhaps be ready to take regarding the efficacy of taking the drug and
the alternatives." Thus, such a test may open a path for some of the
positive patients to get back to or to continue receiving natalizumab
therapy.
"Even
with more precise risk calculations," Dr. Kappos said, "it's still an
individual decision between the treating physician and the patient if
they stop treatment or not."
Evolution of JCV Antibody Testing
JCV antibody testing has evolved over the past few years. In 2010, researchers reported development
of an ELISA to detect antibodies in serum and plasma, with the hope
that the test could be used to confirm the absence of antibodies and
therefore facilitate natalizumab treatment of patients at low risk for
PML.
The
present risk stratification efforts based on the amount of antibody
further refine the risk but are not perfect. Patients with low levels of
antibody are still at some risk. And a report in
the June 6 New England Journal of Medicine showed that in 1 series, one
third of patients with MS who tested negative for anti-JCV antibodies
had active JCV viremia. However, it is not practical to test for JCV in
the clinic at this time. full story: http://www.medscape.com/viewarticle/806294
23rd Meeting of the European Neurological Society. Abstract #O228. Presented June 9, 2013.
