Mark Gudesblatt, MD

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88% (22 of 25) sera from natalizumab-associatedPML cases were JCV-seropositive. 7 Thethree patients with PML who were JCV-seronegativewere tested during plasma exchange.Seronegativity during plasma exchange mightreflect not seronegativity but the eliminationof anti-JCV antibodies from circulation, hencecausing a false-sero negative state. These threepatients were subsequently tested with theGorelik assay and were seropositive. 29 Tyler 5suggested that findings from these two studiesmay indicate potential use of JCV antibodytesting for estimating risk of natalizumabassociatedPML development. However, becauseof very high prevalence of JCV seropositivityin the general population, JCV antibodytesting may be of limited use in predictingPML development among seropositive individuals.Indeed, there is almost no risk of PMLdevelopment in JCV-seronegative individuals.Antibody testing may be useful in excludingthe risk of PML development in JCV-seronegativeMS patients treated with natalizumab orother monoclonal antibodies.Clinical OutcomesCurrently, there are no proven therapiesor vaccines available for the treatment andprevention of PML. Although early observationalstudies demonstrated promising resultswith cidofovir in improving survival ofHIV-positive patients with PML in combinationwith cART, subsequent studies have concludedthat cidofovir therapy has no significanttherapeutic benefit. 8 Similarly, while oneretrospective study suggested that cytarabinemay stabilize PML in a subset of HIV-negativepatients, subsequent studies failed to show asurvival benefit. Drugs such as mirtazapineand mefloquine have shown some promisein anecdotal or small case studies, but furtherstudies are warranted to prove their beneficialeffect against PML. In the absence of effectiveantiviral pharmacotherapy targetingPML, restoring the host’s adaptive immuneresponse against JCV remains the currentmanagement objective—achieved mainly bytreatment with cART in HIV-positive patientsand by reducing immunosuppressive or immunomodulatingdrugs where possible inHIV-negative individuals.A few HIV/AIDS patients after the initiationof cART and almost all cases of PML associatedwith natalizumab after discontinuation oftherapy may develop PML-IRIS. 2,8 In PML-IRIS,although the recovering immune system maycontrol JCV replication, it can also aggravateCNS inflammation and may accentuate theclinical picture. 2 Inflammation can also lead tosignificant neurological deficits, mass effectswith herniation, and other catastrophic effects,including death. The use of steroids can be beneficialin such severe cases and, when appropriatelymanaged, PML-IRIS has been reportedin multiple instances to lead to prolonged survivaland even improvement in PML-relatedneurological deficits. Vermersch et al 11 recentlyreported a 71% survival rate in natalizumab-treatedPML patients, attributed in partto aggressive corticosteroid management ofIRIS and rapid diagnosis once symptoms wereidentified. The use of steroids remains controversialbecause, as immunosuppressants, steroidsmight increase replication of HIV in HIVpositivepatients or alter treatment regimensin HIV-negative patients who have cancer orautoimmune disease. 8 While short-term discontinuationof cART may reduce the symptomsof PML-IRIS in HIV-positive patients,even short-term interruption of the therapycan increase HIV mutation rate, resulting infuture drug resistance.Survival RatesThe onset of PML is insidious, but in the absenceof treatment disease progression is usuallyrapid, with death ensuing in three to sixmonths after diagnosis. With the advent ofcART in the mid-1990s, however, HIV-positivepatients are living longer. 8 Several studies havedemonstrated that cART significantly prolongslife span of AIDS-associated PML caseswith one-year survival being 50% or more,while it was 5% or less in patients not receivingcART. 26,30-35While PML-IRIS appears to be more commonand more severe in patients with natalizumab-associatedPML than it is in patientsS22 July 2011 • Clinical Reviews of JCV and PML
with HIV-associated PML, recent studies suggestthat early recognition and treatment ofmonoclonal antibody-associated PML-IRISimproves prognosis. 10,11Higher CD4+ T-cell count, contrast enhancementon radiographic imaging and neurologicalrecovery, 8,35-37 and low JCV load inthe CSF 8,30,38-40 are all associated with longersurvival in HIV-associated PML patients. In a1998 study of biopsy-proven, AIDS-associatedPML, nearly 43% of the long-term survivors(≥12 months) had CD4 T-lymphocyte countsgreater than 300 cells/mm 3 versus 4.3% of theshort-term survivors (≤12 months). 36 Radiographicimaging demonstrated contrast enhancementin 50% of the long-term survivorscompared with only 9% of the short-term survivors,whereas neurological recovery and radiographicimprovement were seen only in thelong-term survival group (71.4%).Subsequent study on HAART-treated HIVassociatedPML cases corroborated thesefindings. 37 The two patients who died afterthree months had more extensive white matterchanges on their initial MRI studies thanthe two long-term survivors, and follow-upimaging revealed progressive destructive diseasein the short-term survivor group. The twolong-term survivors, both of whom were aliveat the time the study’s findings were reported(at 22 and 43 months’ survival, respectively),had evidence of development of a mass effecton follow-up MRI, and the studies of oneof the two patients demonstrated temporaryenhancement, suggesting to the investigatorsthat such findings in the early phase of treatmentmay represent positive predictive factorsfor longer-term survival.More recently, the presence of JCV-specificCD8+ cytotoxic T-lymphocytes (CTLs) in patientswith PML was associated with a trendtoward longer survival. 35 In a study reportingthe clinical outcomes of 60 patients with PML,73% of whom were HIV-positive, Marzocchettiand colleagues 35 found that PML patients withdetectable CTLs within three months of diagnosishad an estimated probability of survivalat one year of 73% versus 46% for those withoutCTLs, rates that could be juxtaposed with theone-year estimated survival of HIV-positiveand HIV-negative patients with PML—52% and58%, respectively. Meanwhile, the estimatedone-year survival rate of HIV-positive patientswith PML who had a CD4 count greater than200/microL at the time of PML diagnosis was67% versus 48% for those with a CD4 count lessthan 200/microL, but this trend toward longersurvival in the former group was found by theinvestigators to be less pronounced than thepresence of CTLs.The magnitude of the JCV load in the CSFhas been examined in several studies andfound to be inversely correlated with survival.8,30,38-40 Taoufik and colleagues 38 measuredJCV load in CSF of 12 AIDS-associated PMLpatients using quantitative PCR and demonstrateda significant inverse correlationbetween JCV load in CSF and survival time(P < .01). Patients with high JCV loads diedwithin eight months after the onset of PMLand within three months after JCV quantitation;whereas patients with low virus loadswere still alive at the end of the study, withsurvival times greater than 19 months afterthe beginning of PML and 13 months afterCSF sampling. These results suggested thatCSF JC virus load determination may be usefulin monitoring anti-JCV therapies in PML.Subsequently, Yiannoutsos and colleagues 39estimated JCV burden in CSF samples from15 AIDS-associated biopsy-proven PML patientsby semiquantitative PCR and demonstratedthat lower viral load was predictive oflonger survival (median survival from entry,24 weeks) compared with a high JCV burden(7.6 weeks). Similarly, Garcia De Viedma andcolleagues 40 in 2002 also found an inverse correlationbetween JCV load in CSF and survivaltime—patients with JCV load greater than4.68 log had shorter survival than those withlower viral load. These results were virtuallyidentical to those of a multicenter analysis of57 HIV-positive PML patients treated with andwithout HAART, in which a baseline JCV DNAload of less than 4.7 log helped predict longersurvival among HAART-treated patients. 30Probability of survival at one year in this latterstudy was .46 with HAART and .04 without it.Clinical Reviews of JCV and PML • July 2011 S23
Page 1 and 2: A SUPPLEMENT TO NEUROLOGY REVIEWSCl
Page 3 and 4: An Overview of JC Virusand Progress
Page 5 and 6: cation. Although PML is generally c
Page 7 and 8: JCV exposure than those who are not
Page 9 and 10: 39. Weber F, Goldmann C, Krämer M,
Page 12 and 13: diseases, which represent an autoim
Page 14: tainment of JCV in the CNS as well
Page 17 and 18: Progressive MultifocalLeukoencephal
Page 19 and 20: TABLE 2 Different forms of PMLClass
Page 21: characteristic brain changes on mag
Page 25 and 26: Natalizumab, the first monoclonal a
Page 27: 22. Lebwohl M, Tyring SK, Hamilton

Mark Gudesblatt, MD

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