We examined whether prediagnostic John Cunningham virus (JCV) antibodies and viremia are predictors of progressive multifocal leukoencephalopathy (PML) in 83 PML cases and 240 human immunodeficiency virus (HIV) disease-matched controls. JCV viremia was not predictive of PML, but some patients showed higher anti-JCV immunoglobulin G (IgG) responses 6 months prior to diagnosi

Clifford, David B.

Hirsch, Hans H.

Jacobson, Lisa

Khanna, Nina

Koralnik, Igor J.

Li, Xiuhung

Margolick, Joseph B.

Nath, Avindra

Shah, Keerti V.

Tan, Chen S.

Viscidi, Raphael P.

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H I V / A I D S B R I E F R E P O R TJC Virus Antibody and Viremia asPredictors of Progressive MultifocalLeukoencephalopathy in HumanImmunodeficiency Virus-1–InfectedIndividualsRaphael P. Viscidi,1,a Nina Khanna,2,3 Chen S. Tan,4,5 Xiuhung Li,6Lisa Jacobson,6 David B. Clifford,7 Avindra Nath,8 Joseph B. Margolick,9Keerti V. Shah,9 Hans H. Hirsch,2,3,a and Igor J. Koralnik4,5,a1Department of Pediatrics, Johns Hopkins University School of Medicine,Baltimore, Maryland; 2Division of Infectious Diseases and Hospital Epidemiology,and 3Institute for Medical Microbiology, Department of Biomedicine, University ofBasel, Basel, Switzerland; 4Department of Medicine, and 5Department ofNeurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts;6Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health,Baltimore, Maryland; 7Department of Neurology, Washington University School ofMedicine, Saint Louis, Missouri; 8Department of Neurology, Johns HopkinsUniversity School of Medicine, and 9Department of Molecular Microbiology andImmunology, Johns Hopkins Bloomberg School of Public Health, Baltimore,MarylandWe examined whether prediagnostic JC virus (JCV) anti-bodies and viremia are predictors of progressive multifocalleukoencephalopathy (PML) in 83 PML cases and 240 humanimmunodeficiency virus (HIV) disease-matched controls.JCV viremia was not predictive of PML, but some patientsshowed higher anti-JCV immunoglobulin G (IgG) responses6 months prior to diagnosis.Progressive multifocal leukoencephalopathy (PML) is a de-myelinating disease of the central nervous system caused bylytic infection of oligodendrocytes with JC polyomavirus(JCV). PML occurs in immunosuppressed individuals withAIDS or hematological malignancies, transplant recipients, andpatients treated with immunomodulatory medications forautoimmune diseases [1–3].Clinically useful predictors for PML are lacking. We thereforeperformed nested case-control studies within the Multicenter-AIDS and the Swiss-HIV (human immunodeficiency virus)cohort studies (MACS and SHCS) to examine whether JCV-specific virological and serological markers are predictors ofPML.METHODSThe study was approved by the institutional review board (IRB)at each participating center and each MACS location.Study PopulationsTwo nested case-control studies were performed using archivedsamples from the MACS, a prospective study of HIV/AIDS inhomosexual men in the United States begun in 1984, and theSHCS, a prospective study of HIV-1 infected Swiss adults ini-tiated in 1988. Demographic and clinical data, plasma, serum,and peripheral blood mononuclear cells (PBMC) were col-lected every 6 months for 2.5 years prior to PML diagnosis, andadditionally for 1 year after diagnosis in the SHCS. Thirty PMLpatients fromMACS were diagnosed between 1985 and 1996 bybrain histology in 16 (53%), radiographic and clinical signs in 9(30%), and clinical diagnosis in 5 (17%) patients. Cases werematched with 81 HIV-seropositive participants, who did notdevelop PML. In the SHCS, 53 patients were diagnosed withPML between 1995 and 2006 by brain histology in 7 (13%),detection of JCV by polymerase chain reaction (PCR) in ce-rebral spinal fluid in 18 (34%) and radiographic and clinicalsigns in 28 (53%) patients. Cases were matched with 149 HIV-seropositive participants. Criteria for matching are described insupplementary materials.JCV PCR AssaysPlasma and PBMC samples were tested by quantitativePCR (QPCR) for JCV DNA (as described elsewhere [4] andsupplementary materials).JCV Serology AssaysA virus-like particle-based enzyme-linked immunosorbent assay(ELISA) was used to detect antibody to JCV capsids (as de-scribed elsewhere [5] and supplementary materials).Statistical AnalysisConditional logistic regression, with adjustment for age andCD41 T-cell counts at diagnosis, was used to investigate theReceived 8 March 2011; accepted 29 June 2011.aR. P. V., H. H. H., and I. J. K. contributed equally to the study.Correspondence: Raphael P Viscidi, MD, Johns Hopkins Hospital, Blalock Bldg Rm 1105, 600N Wolfe St, Baltimore MD 21287 (rviscid1@jhmi.edu).Clinical Infectious Diseases 2011;53(7):711–715 The Author 2011. Published by Oxford University Press on behalf of the Infectious DiseasesSociety of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.1058-4838/2011/537-0013$14.00DOI: 10.1093/cid/cir507HIV/AIDS d CID 2011:53 (1 October) d 711temporal relationship between PML and levels of log-transformedimmunoglobulin (Ig) G, IgA, and IgM optical density values,serostatus, and plasma JCV DNA copy number.RESULTSStudy PopulationWithin each study, demographic characteristics of cases andcontrols were similar (Table 1). MACS participants were men,while one-fifth of SHCS patients were women. Intravenous druguse was more common in SHCS (39.6%) than in MACS(12.6%). One case in MACS received combined antiretroviraltherapy (cART), but 30 (57%) cases in SHCS were treated withcART. Within SHCS, cases and controls were well matched atentry and at PML diagnosis, while median CD41 T-cell countsofMACS cases at the time of PML diagnosis were lower than thatof controls (139 cells/uL vs 171 cells/uL, P 5 .01).Serological StudiesAmong the 83 PML cases and 230 controls, JCV IgG seropre-valence was 58% and 49%, respectively, 1–1.5 years beforediagnosis, and did not differ substantially during other 6-monthintervals before PML diagnosis. IgA seroprevalence among casesand controls 1–1.5 years before diagnosis was 16% and 11%,while IgM seroprevalence was 2.2% and 3.4%, respectively. AfterPML diagnosis, IgG seroprevalence increased to 96% in the6 months following diagnosis, while IgA and IgM seroprevalenceincreased to 50% and 12.5%, respectively (analysis restricted toSHCS). Among subjects with 2 or more IgG measurements,8 cases (15.1%) and 15 controls (9.4%) seroconverted. Fluctu-ating serostatus was observed in 8.6% of controls and 11.3% ofcases. Treatment with cART had no effect on JCV-specific capsidIgG and IgM levels, whereas a trend for IgA seropositivity wasseen (adjusted odds ratio [OR], 3.1, 95% confidence interval[CI], .99–9.74, P 5 .052).The distribution of IgG, IgA, and IgM seroreactivity to JCVcapsids during 6-month time intervals prior to PML diagnosis isshown in Figure 1. Six months prior to diagnosis, median (in-terquartile range) IgG levels for cases and controls were 0.23(0.13, 0.40) and 0.18 (0.08, 0.35), respectively, and the mediandifference between matched case-control sets was 0.06 (20.11,0.23). Controlling for CD41 T-cell count and age, a 1 log10Table 1. Characteristics of Study PopulationsMACS SHCSVariable Cases (n 5 30) Controls (n 5 81) Cases (n 5 53) Controls (n 5 149)Gender, N (%)Male 30 (100%) 81 (100%) 33 (77%) 118 (79%)Female 0 (0%) 0 (0%) 10 (23%) 31 (21%)Age, median (IQR) 39 (36, 44) 40 (36,51) 39 (34, 43) 38 (35, 43)Race/ethnicity, N (%)White 29 (97%) 79 (98%) 44 (83%) 129 (87%)Black 0 (0%) 2 (2%) 1 (2%) 8 (5%)Other/unknown 1 (3%) 0 (0%) 8 (15%) 12 (8%)Ever IV drug use, N (%)No 26 (87%) 71 (88%) 32 (60%) 70 (47%)Yes 4 (13%) 10 (12%) 21 (40%) 79 (53%)Ever smoking, N (%)No 7 (23%) 31 (38%) NA NAYes 23 (77%) 50 (62%) NA NAYears on study, median (IQR) 6.6 (4.0, 8.4) 7.1 (4.9, 9.3) 4.6 (0.25, 7.8) 6.4 (1.8, 9.7)PML diagnostic criteriaHistological/virological 16 (53%) NA 25 (47%) NAClinical/radiographic 14 (47%) NA 28 (53%) NACalendar Yr Dx, median (IQR) 1991 (1989, 1994) NA 1999 (1997, 2002) NAEntry CD4, median (IQR) 549 (363, 631) 483 (375, 636) 274 (90, 440) 216 (105, 430)CD4 at Dx, median (IQR) 139 (87, 206) 171 (90, 280) 139 (44, 257) 120 (57, 218)cART in 2 yrs before PMLNo 29 (97%) 81 (100%) 23 (43%) NAYes 1 (3%) 0 (0%) 30 (57%) NAAbbreviations: cART, combined antiretroviral therapy; IQR, interquartile range; MACS, Multicenter AIDS Cohort Study; NA, not available; SHCS, Swiss HIV CohortStudy.712 d CID 2011:53 (1 October) d HIV/AIDSincrease in JCV capsid-specific IgG level in cases comparedwith controls was associated with a 75% increase in the oddsof developing PML (hazard ratio [HR], 1.75, 95% CI, 1.19–2.58, P 5 .0046). The association of IgG with risk of PML wasobserved in the combined analysis of 83 PML cases and in the53 SHCS cases, but only a non-significant trend was seen inthe 30 MACS cases. IgA and IgM levels were not associatedwith risk of PML. Comparable results were obtained when theanalysis was restricted to the 36 PML cases confirmed histo-logically and/or virologically and their 114 controls. Antibodiesto JCV capsid increased post PML diagnosis. The medianIgG level was higher in SHCS cases compared with controlsduring the first 6-month interval (0.54 vs 0.24, P , .0001) andthe 6–12 month interval (0.68 vs 0.23, P ,.001) after diagnosis(Figure 2).Virological StudiesJCV DNA was detected by QPCR in plasma from 14 (17%) of83 cases and 28 (12%) of 230 controls. The median detectablelevel of JCV DNA was 168 copy numbers per mL of plasma(interquartile range, 108–364). Detecting JCV viremia prior todiagnosis was not associated with a risk of developing PML.Of 42 subjects with viremia at 1 or more visits, 12 (29%) wereseronegative at all visits. Six (26%) of 23 PML cases had de-tectable JCV DNA in PBMC samples during the 2 years priorto the diagnosis of PML, and the corresponding number forcontrols was 15 (17%) of 90 patients (P 5 .36).DISCUSSIONWe combined data from 2 nested case-control analyses toexamine risk factors for development of PML in HIV-infectedpatients. Our study population of 83 PML cases is large forthis rare disease. A striking finding was that JCV viremia didnot have any diagnostic use for the risk of developing PML inthe 2 years before diagnosis. The frequency of JC viremia inour study (13.4%) was lower than that reported for HIV-positive patients in some studies, which ranged between 20%and 40% [6–8].The prevalence of IgG to JCV capsids and the level of an-tibody did not differ between cases and controls during any6-month time window between 2.5 and 0.5 years before PMLdiagnosis. However, in the 6 months immediately precedingdiagnosis of PML, the level of JCV capsid antibody was ele-vated in cases compared with controls, as reported elsewhere[9]. The association was largely due to the contribution of53 cases from the SHCS. We cannot rule out that undefinedtechnical and clinical factors, such as sample size, storageconditions, or the use of cART, contribute to this difference.The temporal proximity to the diagnosis of PML suggests thatthis association may reflect underlying disease. In a previousstudy in MACS, higher titers of JCV IgG were associated withJCV viruria but not to a diagnosis of PML [10] In total, 25%of HIV-positive individuals who developed PML were sero-negative on 1 or more visits during the 2 years prior to di-agnosis. It is not clear if seronegative patients were trulynegative or if they had levels of antibodies too low to be scoredas positive by our assay. In total, 29% of patients with JCVviremia were seronegative, supporting the notion that theFigure 1. Distribution of IgG, IgA, and IgM absorbance values of serafrom PML cases and HIV disease matched controls in the MACS andSHCS at time intervals before the diagnosis of PML. The summarystatistics of each distribution are displayed in a box plot. The length of thebox corresponds to the interquartile range with the upper boundary of thebox representing the 75th percentile and the lower boundary the 25thpercentile. The horizontal clear line in the box represents the medianvalue. The 10th and 90th percentiles are shown by the small bar at theend of the line extending downward or upward, respectively, from thebox. Each outlier value is shown individually by a solid line. The number ofoutliers that are not displayed in the graph space is indicated at the top ofeach graph. The number of samples contributing to each distribution isindicated at the bottom of the figure.HIV/AIDS d CID 2011:53 (1 October) d 713assay was not very sensitive in the setting of advanced HIVinfection. We speculate, therefore, that an increase in JCV IgGactivity may reflect recent exposure to JCV antigen, which, ina severely immunosuppressed patient, might also indicate anincreased risk of developing PML, while a stable IgG titer doesnot preclude subsequent development of PML.One limitation of our study is the use of samples that hadbeen kept frozen for long periods of time. It is possible thatdegradation of viral DNA precluded efficient amplification ofJCV sequences. The JCV seroprevalence was lower in MACS(42%) than SHCS (67%) and lower than that reported in otherpopulations [11, 12]. Nevertheless, the absence of viremia beforePML diagnosis is consistent with models of pathogenesis, whichhypothesize that PML is caused by reactivation in the braineither from virus resident in the brain or from virus in cells thattraffic to the brain.Interest in prediagnostic markers of PML has been triggeredby the recent development of PML in multiple sclerosis andCrohn’s disease patients treated with natalizumab, and psoriasispatients treated with efalizumab [3]. The selective impairment inT-cell activation and trafficking caused by these drugs differsfrom immunosuppression seen in AIDS. Therefore, while it isnot clear if the findings of our study are readily applicable topatients treated with these drugs, the study does suggest thatmonitoring these patients for JCV viremia is unlikely to predictwho will develop PML.Supplementary DataSupplementary materials are available at Clinical Infectious Diseases on-line (http://www.oxfordjournals.org/our_journals/cid/). Supplementarymaterials consist of data provided by the author that are published tobenefit the reader. The posted materials are not copyedited. The con-tents of all supplementary data are the sole responsibility of the authors.Questions or messages regarding errors should be addressed to the author.NotesAcknowledgments. Data in this manuscript were collected by theMulticenter AIDS Cohort Study (MACS) with centers (Principal Inves-tigators) at the Johns Hopkins Bloomberg School of Public Health (JosephB. Margolick, Lisa P. Jacobson), Howard Brown Health Center, FeinbergSchool of Medicine, Northwestern University, and Cook County Bureau ofHealth Services (John P. Phair, Steven M. Wolinsky), University of California,Los Angeles (Roger Detels), and University of Pittsburgh (Charles R. Rinaldo).Web site located at http://www.statepi.jhsph.edu/macs/macs.html.The members of the Swiss HIV Cohort Study are M. Battegay,E. Bernasconi, J. Bo¨ni, HC. Bucher, Ph. Bu¨rgisser, A. Calmy, S. Cattacin,M. Cavassini, R. Dubs, M. Egger, L. Elzi, M. Fischer, M. Flepp, A. Fontana,P. Francioli (President of the SHCS, Centre Hospitalier UniversitaireVaudois, CH-1011- Lausanne), H. Furrer (Chairman of the Clinical andLaboratory Committee), C. Fux, M. Gorgievski, H. Gu¨nthard (Chairmanof the Scientific Board), H. H. Hirsch, B. Hirschel, I. Ho¨sli, Ch. Kahlert,L. Kaiser, U. Karrer, C. Kind, Th. Klimkait, B. Ledergerber, G. Martinetti,B. Martinez, N. Mu¨ller, D. Nadal, M. Opravil, F. Paccaud, G. Pantaleo,A. Rauch, S. Regenass, M. Rickenbach (Head of Data Center), C. Rudin(Chairman of the Mother & Child Substudy), P. Schmid, D. Schultze,J. Schu¨pbach, R. Speck, P. Taffe´, P. Tarr, A. Telenti, A. Trkola, P. Vernazza,R. Weber, S. Yerly.We wish to thank Nadine Doppler from the institute for MedicalMicrobiology for technical assistance.Figure 2. Distribution of absorbance values of IgG in sera from PML cases and HIV disease matched controls in the SHCS at time intervals before andafter the diagnosis of PML. Data are represented in box plots as described in the legend to Figure 1.714 d CID 2011:53 (1 October) d HIV/AIDSFinancial support. This work was sponsored in part by grants fromthe Neurologic AIDS Research Consortium (U01 NS322228 to D. C. andI. J. K., R01 NS 041198, NS 047029, and K24 NS 060950); Johns HopkinsNIMH Center (5P30MH075673 to A. N.); and a Biogen Idec researchgrant (to I. J. K.). The MACS is funded by the National Instituteof Allergy and Infectious Diseases, with additional supplemental fundingfrom the National Cancer Institute (UO1-AI-35042, 5-MO1-RR-00052[GCRC], UO1-AI-35043, UO1-AI-35039, UO1-AI-35040, UO1-AI-35041).This study has been supported by the Swiss HIV Cohort Study and theSwiss National Science Foundation (SHCS project Nr. 512).Potential conflict of interest. D. C. has received fees for the following:consultancy from Biogen Idec, Genentech, Millennium, Genzyme, BMS,and Pfizer; expert testimony from Biogen Idec; payment for lectures orspeakers bureaus from GSK, Millennium, Biogen; development of edu-cational presentations from Millennium; travel/meeting expenses fromBiogen Idec. A. N. has received fees for consultancy from Biogen andDiogenix. All other authors report no potential conflicts.All authors have submitted the ICMJE Form for Disclosure of PotentialConflicts of Interest. 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JC Virus Antibody and Viremia as Predictors of Progressive Multifocal Leukoencephalopathy in Human Immunodeficiency Virus-1-Infected Individuals

JC Virus Antibody and Viremia as Predictors of Progressive Multifocal Leukoencephalopathy in Human Immunodeficiency Virus-1-Infected Individuals

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