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New Features of PML in the HAART and natalizumab era


HIV/Neurology Center. Beth Israel Deaconess Medical Center. Harvard Medical School ... HIV/Neurology Center. Renaud Du Pasquier. Xin Dang. Christian Wuethrich ... – PowerPoint PPT presentation

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Title: New Features of PML in the HAART and natalizumab era

New Features of PML in the HAART and natalizumab
  • Igor J. Koralnik, M.D.
  • HIV/Neurology Center
  • Beth Israel Deaconess Medical Center
  • Harvard Medical School

  • Who's afraid of JC virus ?

Classical AIDS-associated PML in the pre-HAART
  • CD4 T cell counts lt 200 ml
  • non-enhancing white matter lesions on MRI,
    without edema and mass effect
  • detectable JCV DNA by PCR in CSF
  • Absence of inflammatory infiltrates in brain
  • Progressive evolution and fatal outcome in few

Good prognostic markers in PML
  • Inflammatory infiltrates in PML lesions
    (Richardson 75)
  • PML heralding AIDS, CD4 gt 300/ml (Berger 98)
  • Faint peripheral contrast enhancement of lesions
    on MRI (Berger 98)
  • Low JCV viral load in CSF (Taoufik 98,
    Yiannoutsos 99)
  • Presence of JCV-specific CD8 Cytotoxic T
    Lymphocytes in blood (Koralnik 01,02, Du Pasquier
  • Elevated mI/Cr ratio in PML lesions on MRS
    (Koralnik 03)

Unifying Hypothesis
  • PML can be contained if
  • Sufficient number of CD4 T cells
  • presence of JCV-specific CD8 cytotoxic T
    lymphocytes in the blood
  • these CD8 T cells infiltrate the brain lesions
    and destroy JCV-infected cells
  • This inflammatory reaction
  • causes a break-down of the blood-brain-barrier
    and contrast enhancement on MRI
  • decreases viral replication in the brain and JCV
    VL in CSF

Atypical presentation of PML in the HAART era
  • HIV-infected patients with CD4 T cell counts lt
    200 ml, high plasma HIV VL
  • Initiation of HAART
  • good immunologic and virologic response
    increased CD4, decreased HIV VL
  • paradoxical development of an inflammatory form
    of PML
  • manifestation of IRIS ?

Immune reconstitution inflammatory syndrome
  • Also known as immune restoration disease (IRD),or
    immune reconstitution syndrome (IRS)

- preexisting infection, clinically silent -
recovery of the immune system - local
inflammatory reaction - paradoxical
deterioration in clinical status
Classical manifestations of IRIS
  • CMV retininis
  • mycobacterium avium complex lymphadenitis
  • cryptococcal meningitis
  • may occur also in HIV-negative individuals after
    discontinuation of immunosuppressive therapy
  • may require treatment with steroids

How frequent is PML/IRIS ?
  • Retrospective study of 39 PML patients (31 HIV
    and 8 HIV-) since 1996
  • JCV PCR in CSF or brain biopsy
  • PML presentation in context of increased CD4
    counts, decreased HIV VL on HAART, or with signs
    of inflammation on neuroimaging studies or biopsy
  • 5/39 patients (13 ) (4 HIV/1HIV-)

Contrast enhancement on MRI
Contrast enhancement and CD8 T cell infiltrates
(pt 5)
PML/IRIS case reports
  • 3 HIV pts with PML 5-8 w after HAART
    (Mayo et al. AIDS 98)
  • 1 HIV pt with enhancing PML lesions
    (Kotecha et al. Am J Med 98)
  • 4 HIV pts with enhancing PML lesions (Collazos
    et al. AIDS 99)
  • 3 HIV with PML soon after HAART. Two treated
    with steroids. Inflammation in brain bx of 4/9
    PML pts on HAART vs 1/19 HAART naïve pts
    (Miralles et al. AIDS 01)

PML/IRIS case reports (cont.)
  • 2 HIV pts with PML 4w - 4mo after HAART.
    (Safdar et al CID 02). Transient response to
    steroids but fatal outcome in both
  • JCV CSF PCR neg in CSF
  • Biopsy lymphocytic infiltrates, gliosis
    and giant multinucleated histiocytes,
    c/w viral encephalitis
  • No histological features of PML
  • No report of IHC or ISH for JCV or HIV
  • JCV PCR on DNA from biopsy tissue
  • Are these cases PML ?

PML/IRIS series
  • Review of 118 cases in Spain (Berenguer et al CID
  • 36 PCR or bx proven and 64 possible PML
  • 10/118 (8) PML 3-13 w after HAART. 2/10
    enhancing lesions
  • 8/118 (7) treated with steroids
  • Only CD4 gt 100 associated with good outcome
  • Review of 43 cases of PML in Italy (Cinque et al
    JNV 03)
  • 8/43 (19) PML 3-9w after HAART. 4/8 fatal outcome

PML in 2 MS and 1 Crohns pt rx with natalizumab
  • Humanized monoclonal ab against a4b1 integrins
  • Given once/month iv. Biological activity up to 3
  • Prevents lymphocyte and monocyte trafficking in
    brain, gut and other organs
  • Promising rx of MS and Crohns Disease (Affirm
    and Sentinel trial)
  • Voluntary withdrawal on 2/28/05

Natalizumab Crohns/PML
Natalizumab Crohns/PML (2)
Natalizumab MS/PML case 1
  • PML 20 months after natalizumab/INF b-1a
  • Cavitary lesions, death in 3 months
  • Extensive PML lesions in cerebral hemispheres and
    brainstem at autopsy
  • Absence of inflammatory infiltrates
  • NO MS lesions found

Natalizumab MS/PML case 1 (2)
Natalizumab MS/PML case 1 (3)
Natalizumab MS/PML case 2
  • PML 2 years after natalizumab/INF b-1a
  • Incidental PML lesion seen in MRI
  • IRIS 3 months after d/c natalizumab, associated
    with clearance of JCV from blood and decrease in
    JCV CSF viral load
  • Transient worsening of T2 hyperintense lesions
    on MRI and of neurological function
  • Improvement concomitant with ARA-C rx
  • Surviving 8 months after PML onset with severe
    neurologic deficits

(No Transcript)
Natalizumab MS/PML case 2 (3)
Immunopathogenicity of PML/IRIS ( hyp. 1)
  • Latent subclinical infection of glial cells by
    JCV in some patients. Expression of early T ag
    but not capsid proteins
  • HAART induces increase in CD4 T cells, which
    help CD8 T cells attack latently JCV-infected
    glial cells in the brain
  • Symptomatic inflammatory PML, which is
    detrimental to the patient and should be treated
    with steroids

hyp. 1 (cont.)
  • JCV PCR in brain of 4/13 HIV pts without
  • PML (Quinlivan et al. JID 92)
  • JCV ISH in brain of 4/10 elderly HIV-negative
    individuals without PML (Mori et al.Ann Neurol
  • JCV PCR in brain of 68 HIV-negative patients
    (Whyte et al)
  • But
  • At least 4 published negative studies
  • presence of DNA alone not sufficient to trigger
    immune response
  • block in lytic cycle of JCV never been
    demonstrated in vivo

Immunopathogenicity of PML/IRIS ( hyp. 2)
  • Cytokine-mediated mechanisms
  • variation of INF-a and IL-12 after onset of
    HAART implicated in increased Hep C VL and crypto
    meningitis (DeSimone et al. Ann Int Med 00)
  • HAART induces a decrease of HIV VL, which in turn
    lower cytokines levels and may promote JCV
    reactivation (within CNS, or from kidneys and
    lymphoid organs)

Immunopathogenicity of PML/IRIS ( hyp. 3)
  • PML develops during decreased immunosurveillance
    on natalizumab
  • Rush of T lymphocytes in PML lesions after d/c
    natalizumab creates intense inflammatory reaction
  • Incidental development of productive, yet
    subclinical infection of oligos by JCV around
    time of HAART onset
  • Immune reconstitution concomitant to PML
    development leads to an inflammatory reaction in
    PML lesions which is beneficial and should not be
    treated with steroids

PML/IRIS questions
  • If inflammatory reaction is beneficial, why do
    some patients still have a fatal outcome ?
  • Multiple factors associated with survival
  • timing of response to HAART, size and location
    of the lesions, JC CSF VL, structure of JCV
    regulatory region, size of pool of memory CTL
  • Inflammation may betoo little too late
  • Inflammation may be detrimental in some cases

Practical issue in PML/IRIS steroid treatment
  • Challenge in diagnosis of inflammatory PML
  • Edema and mass effect are rare
  • Many cases of PML/IRIS appear to have a favorable
  • Steroids are immunosuppressants
  • Steroids may promote JCV replication (CRE
  • Steroids should be reserved in cases with major
    neurological worsening or with clinical or
    radiological signs of impending brain herniation

  • Division of Viral Pathogenesis (BIDMC)
  • Marcelo Kuroda
  • Jörn Schmitz
  • Michelle Lifton
  • Patrick Autissier
  • Kristi Martin
  • Norman Letvin
  • HIV/Neurology Center
  • Renaud Du Pasquier
  • Xin Dang
  • Christian Wuethrich
  • Yiping Chen
  • Marco De Lima
  • Jims Jean-Jacques
  • Luz-Andrea Pfister
  • Yue Zheng
  • Funding NINDS RO1 041198 and 047029, R21 046243
    and 051124 Harvard CFAR, Harvard Center for
    Neurodegeneration and Repair, Milton Fund