6-2 ars final au edited final hiv 17 chi dr kolson build ... · hiv infiltrates the cns early...

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Dennis Kolson, MD, PhDProfessor of Neurology

University of PennsylvaniaPhiladelphia, Pennsylvania

Update on Neurologic Complications in Persons With HIV Infection: 2017

FORMATTED: MM/DD/YY

Chicago, Illinois: May 10, 2017

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Financial Relationships With Commercial Entities

Dr Kolson has no relevant financial affiliations to disclose. (Updated 05/04/17)

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Learning Objectives

Recognize and list the early neurologic manifestations of acute HIV infection

Describe the chronic neurologic manifestations and potential management options for neurologic complications of HIV infection in individuals on suppressive antiretroviral therapy

To describe the rationale for adjunctive neuroprotective strategies for cognitive impairment in individuals on suppressive antiretroviral therapy

After attending this presentation, learners will be able to:


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• HAND prevalence remains ~ 40%

BUT

• less severe HAND: encephalitis & dementia now ~2%

• neuropathy prevalence < 30% with newer ARTs

HAND

Post-ART eraneuropathy

Neurological complications of chronic HIV infection are less severe with use of antiretroviral therapy/ARTPre-ART era

HIV-encephalitis (HIVE)HIV-associated neurocognitive disorders (HAND)

• HIV-associated neurocognitive disorders (HAND) ~ 40%

• severe HAND: HIV encephalitis & dementia ~20%

• neuropathy prevalence ~ 30%

HIV encephalitisHAND

neuropathy

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HIV infiltrates the CNS early (days-week) after systemic HIV Infection potential CNS reservoir

Adapted from Gill & Kolson, Crit. Rev. Immunol. (2013).

NEURON

ASTROCYTE

MACROPHAGE

proinflammatorycytokines/chemokines

ACTIVATEDMACROPHAGE/

MICROGLIA

viral replication

NMDA Receptor Excitotoxins

Glutamate Regulation

Neuronal Injury(loss of synapses

and dendrites

Endothelial Lumen

Blood Brain Barrier

HIV MONOCYTE

GlutamateQUIN, ROS,Ntox, PAF, TNF- , &

gp120, Tat

CD4+ T lymphocyteHIVHIV

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CD4+ T lymphocyte

?

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CNS compartmentalization in as early as 4 months & throughout course

Independent HIV replication in infiltrating lymphocyte population (pleocytosis)

Entering virus is exclusively R5, T lymphocyte-tropic

Little initial independent HIV replication in endogenous CNS cell population (macrophages), which begins to emerge during the first two years of infection, suggesting establishment of a macrophage reservoir)

Compartmentalization occurs in state of pleocytosis & higher viral loads

Presumably from replication in a CNS pool established by infiltrating T lymphocytes

Two ways to increase CSF viral load (early infection)

Influx of infected T lymphocytes carrying virus into the CNS

Replication in the CNS pool established by infiltrating T lymphocytes (compartmentalization)

Sturdevant, PLOS Path. (2015)


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What are the neurological complications of acuteHIV infection?

• meningitis • Acute Inflammatory Demyelinating Neuropathy (AIDP)

Early neurological complications of HIV infection prior to

initiation of antiretroviral therapy/ART

• IRIS

• meningitis• Acute IDP

• HAND (less severe) • Chronic IDP• DSPN • PML

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HIV-associated neurocognitive disorders (HAND)Distal Symmetric Polyneuropathy (DSPN)

Early HIV infection (days 10-20) is associated with symptoms of meningitis in ~25% of individuals*

Meningitis (~25%)

McMichael AJ, Nat. Rev. Immunol. (2010)

*Typically HIV antibody ELISA negative at this time

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• IRIS



Early neurologic complications of HIV-1 infection:Acute Inflammatory Demyelinating Polyneuropathy (AIDP)

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Early neurologic complications of HIV-1 infection:Acute inflammatory Demyelinating Polyneuropathy (AIDP)

http://emedicine.medscape

• CSF: < 50 cells/ul• elevated protein• indistinguishable from GBS

Symptoms & signs TreatmentNatural history

• weakness

• mild sensory sx.

• pain

• respiratory

• autonomic

• ankle reflexes absent

• plasmapheresis

• IVIG

• corticosteroids

• response rates probably similar to HIV-negative patients

• AIDP: (rare)

• most often at seroconversion (20-30d)

• progresses rapidly over days to < 4 weeks

Robinson-Papp, Muscle & Nerve. (2009)Kaku M, Curr Opin HIV AIDS. (2014)

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Chronic neurological complications of HIV infection:• Chronic Inflammatory Demyelinating Neuropathy (CIDP)

• Distal Symmetric Polyneuropathy (DSPN)

• HIV-associated neurocognitive disorders (HAND)


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• IRIS

Later neurological complications of HIV infection after initiation of antiretroviral therapy/ART



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• CSF: < 50 cells/ul• elevated protein• indistinguishable from idiopathic CIDP


• weakness

• mild sensory sx.

• pain

• respiratory

• autonomic

• ankle reflexes absent

• plasmapheresis

• IVIG

• response rates probably similar to HIV-negative patients

• CIDP: >1 year- later stages of HIV infection

• up to 30%of CIDP patients are HIV+*

• progresses over > 8 weeks

• relapses and remissions


Later neurological complications of HIV infection:Chronic inflammatory demyelinating polyneuropathy (CIDP)

Peripheral nerve onion-bulb in CIDP

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*http://emedicine.medscape

• IRIS

Later neurological complications of HIV infection:Distal symmetric polyneuropathy (DSPN)



• meningitis • HAND (less severe) • Chronic IDP

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• Capsaicin (8% top.)‘proved’ effective gabapentin lamotrigine

(weak evidence)

• modify ART regimen

‘

Later neurological complications of HIV infection:Distal symmetric polyneuropathy (DSPN)


• Symmetric, distal, sensory (axonal +/- demyelinating)

Pain predominates• burning• hyperalgesia

• tightness• numbness• preserved proprioception

• prevalence ~ 30%• occurs with or without

ART use

• ART associated(d-drugs):

d4T (Stavudine)ddI (didanosine)ddC (zalcitabine)

‘

Stocking/glove distribution of pain in DSPN

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http://emedicine.medscapeSimpson, Neurol. (2008),

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Question #1

A 40 year old diabetic man presents to the ED with ascending weakness and mild numbness of the lower extremities (one week), and now he cannot walk. Two weeks prior he presented with a severe headache and neck stiffness; CSF showed a mild lymphocytosis. He had mentioned recent high-risk behavior, but was seronegative then. He is now seropositive for HIV infection. Among the following, which is most likely?

1. Diabetic Neuropathy

2. Distal Symmetric Polyneuropathy (DSPN)

3. Acute Inflammatory Demyelinating Polyneuropathy (AIDP)

4. Spinal cord infarction

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Question #1

A 40 year old diabetic man presents to the ED with ascending weakness and mild numbness of the lower extremities (one week), and now he cannot walk. Two weeks prior he presented with a severe headache and neck stiffness; CSF showed a mild lymphocytosis. He had mentioned recent high-risk behavior, but was seronegative then. He is now seropositive for HIV infection. Among the following, which is most likely?

1. Diabetic Neuropathy

2. Distal Symmetric Polyneuropathy (DSPN)

3. Acute Inflammatory Demyelinating Polyneuropathy (AIDP)

4. Spinal cord infarction

Later neurological complications of HIV infection: Immune Reconstitution Inflammatory Syndrome (IRIS)




• IRIS

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Initiation of cART (1-6 months): CNS syndrome (mild or severe) resulting from heightened immunologic and/or inflammatory response against opportunistic pathogens (or other antigens associated with HIV suppression by cART)

• robust inflammatory CNS infiltration (MRI detection)

• CNS IRIS in ~1-30% of pts. initiating cART

• rapid decline of viral load

- greatest risk with CD4 <50 and VL >100K

• most commonly associated with crypto meningitis, TB, PML

Johnson, Ann NY Acad Sci (2010)Johnson, Curr Opin HIV AIDS (2014)


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Slide 23 of 34HIV-associated CNS IRIS

Zafiri et al. New Microbiologica. (2013)

57 yo HIV+ man, off ART x 3 years, then re-start:3 weeks right hemiparesis, slurred speech

CD4 T cells24 99/mm3

CSF:56 cells/ul64 mg/dl prot.

Admission: stroke 24 days post-ART: IRIS

31 days post-ART: IRIS

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Slide 24 of 34HIV-associated CNS IRIS in PML patient Slide 20 of 34

Vendrely A, Acta Neuropathol. (2005)

52 yo HIV+ man, ART naïve x 16 years, admitted for sub-acute cognitive decline

cART started:CD4 T cells117 284/mm3

JC virus confirmed at autopsy

Before ART

1 mo. post-ART

• Supportive Care CSF drainage (Crypto), Abscess drainage (needle aspiration)

• Treatment for any underlying opportunistic infection• Anti-inflammatory treatment

NSAIDs Corticosteroids: severe cases

• 2-3wks, then taper • Investigational/Anecdotal treatments

None yet proven• Pausing HAART

reserved for severe, life-threatening symptoms risks of immunodeficiency & resistance


Management:

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Later neurological complications of HIV infection: Progressive Multifocal Leukoencephalopathy (PML)




• IRIS

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• papovavirus (JC virus) activation in the brain

• white matter (myelin) damage, early in occipital areas

• ~4% of all untreated patients

• ~1% in ART-treated patients

• Death within ~1 year in 90%

• hemiparesis

• memory loss

• slurred speech

• seizures

• visual sxs., blind spots

• sensory disturbances

up to 60%

~30-60%

~20-40%

~15-30%

~25%

~20%

• None effective

• ?inhibit JC virus

• ?reconstitute immune system

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Note lesions restricted to white matter

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atypical PML: patchy enhancement in HIV+, 30 y.o. man

atypical PML: ring enhancementHIV+, 25 y.o. man

typical PML: no enhancement

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• IRIS

• meningitis • HAND• DSPN • PML

Later neurological complications of HIV infection: HIV-associated neurocognitive disorders (HAND)

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• Acute IDP• Chronic IDP

HIV associated neurocognitive disorders (HAND) have similar prevalence but decreased severity post-ART

Saylor, Nature Reviews Neurology (2016)

HAND sub-groups

ANI: Asymptomatic neurocognitive impairment

MND: Mild neurocognitive disorder

HAD: HIV-associated dementia

• functional impairment in certain ADLs• affects ~20% of virally suppressed patients

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HIV-associated neurocognitive disorders (HAND)

Later neurological complications of HIV infection: HIV-associated neurocognitive disorders (HAND)

• 1/3 have MRI evidence of white matter abnormality, with or without brain atrophy

46 year old man, HIV+ for ~20 years, CD4 nadir 50+ cells/ulbegan ART after severe immunosuppresion; white matter lesions + brain atrophy

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• Using ART regimens with higher CNS penetration?

multiple (conflicting) reports suggest no benefit

ART drugs may directly induce oxidative stress and neuronal damage

• Intensification of ART regimens with additional classes of antivirals?

* recent studies of Maraviroc (CCR5 blocker) suggest possible benefit

additional studies underway

• Adjunctive therapies in addition to ART?

focus on controlling neuroinflammation & oxidative stress

How to reduce residual HAND impairment in ART- treated individuals?

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* Gates, AIDS (2016)

HAND Diagnosis

NCNNeurocognitively Normal

HANDHIV-associated neurocognitive disorders

HIVEHIV-encephalitis

Gill et al. J Clin Invest (2014)

Heme oxygenase-1 protein reduction in the prefrontal cortex correlates with clinical dysfunction (HAND)


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• IRIS



• meningitis • Chronic IDP

Neuropathy (less severe)

HAND

Neurological complications of HIV can persist in ART-treated individuals and require adjunctive therapies to limit morbidity

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Question #2

A 34 year old woman came to the ED with a 3-4 day history of confusion & disorientation, which were worsening. She stated that she was diagnosed with HIV infection more than 3 years ago, when she was diagnosed with a brain infection (she was unclear what type). She started, then discontinued ART and re-started it only ~2 months ago. Her physical examination confirmed altered mental status. Her MRI showed a gadolinium-enhancing lesion of the parietal lobe, no meningeal enhancement. Cryptococcal antigen was negative.

1. HIV-associated neurocognitive disorders (HAND)

2. Immune Reconstitution Inflammatory Syndrome (IRIS)

3. HIV meningitis

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Question #2

A 34 year old woman came to the ED with a 3-4 day history of confusion & disorientation, which were worsening. She stated that she was diagnosed with HIV infection more than 3 years ago, when she was diagnosed with a brain infection (she was unclear what type). She started, then discontinued ART and re-started it only ~2 months ago. Her physical examination confirmed altered mental status. Her MRI showed a gadolinium-enhancing lesion of the parietal lobe, no meningeal enhancement. Cryptococcal antigen was negative.

1. HIV-associated neurocognitive disorders (HAND)

2. Immune Reconstitution Inflammatory Syndrome (IRIS)

3. HIV meningitis

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Thank you!

Kolson Lab: Univ. of Pennsylvania

• Alexander Gill, MD, PhD student

• Colleen Kovacsics, PhD student• Yoelvis Garcia-Mesa, PhD

• Rolando Garza, BS• Patricia Vance, BS

Penn Center for AIDS Research

• Ron Collman, MD (Director)

University of Texas Medical Branch

• Ben Gelman, MD, PhD

University of North Carolina, Chapel Hill

• Kevin Robertson, PhD

AcknowledgementsSlide 32 of 34


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Dennis Kolson, MD, PhDProfessor of Neurology

University of PennsylvaniaPhiladelphia, Pennsylvania

Update on Neurologic Complications in Persons With HIV Infection: 2017

FORMATTED: MM/DD/YY



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