After attending this presentation, learners will be able ... · HIV infiltrates the CNS early (days -week) ... Nat. Rev. Immunol. (2010) * ... HIV meningitis (acute HIV -1 infection):

Dennis Kolson, MD, PhDProfessor of Neurology

University of Pennsylvania

Philadelphia, Pennsylvania

Update on Neurologic Complications in

Persons With HIV Infection: 2017

FORMATTED: MM/DD/YY

Chicago, Illinois: May 10, 2017

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Slide 3 of 34

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 era

neuropathy

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

Slide 4a of 34

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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 era

neuropathy

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

Slide 4b of 34

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

Infection meningitis symptoms

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 and

cell death)

Endothelial Lumen

Blood Brain Barrier

HIVMONOCYTE

Glutamate

QUIN, ROS,Ntox, PAF, TNF- , &

gp120, Tat

CD4+ T lymphocyteHIVHIV

Slide 5 of 34

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Slide 6 of 34

Acute neurological complications of HIV infection:• meningitis

• Acute Inflammatory Demyelinating Neuropathy (AIDP)

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Early neurological complications of HIV infection prior to

initiation of antiretroviral therapy/ART

• IRIS

• meningitis• Acute IDP

• HAND (less severe) • Chronic IDP

• DSPN • PML

Slide 7 of 34

HIV-associated neurocognitive disorders (HAND)

Distal Symmetric Polyneuropathy (DSPN)

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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

Slide 8 of 34

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HIV meningitis (acute HIV-1 infection):

• 25-50% of patients with clinical/subclinical meningitis

• duration ~ 2 weeks/self-limited

• occasional cranial nerve sx: facial droop or diplopia

• CSF: lymphocytes (5-70/mm3) in ~ 30% of acute infections

Protein (<70 mg/dl)

IgG index

• PATIENT WILL BE SERONEGATIVE!!!

Early neurologic complications of HIV-1 infection:

meningitis

Slide 9 of 34

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• IRIS

• meningitis• Acute IDP

• HAND (less severe) • Chronic IDP

• DSPN • PML

Early neurologic complications of HIV-1 infection:

Acute Inflammatory Demyelinating Polyneuropathy (AIDP)

Slide 10 of 34

HIV-associated neurocognitive disorders (HAND)

Distal Symmetric Polyneuropathy (DSPN)

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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)

Slide 11a of 34

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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)

Slide 11b of 34

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Slide 12 of 34

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

• meningitis• Acute IDP

• HAND (less severe) • Chronic IDP

• DSPN • PML

Slide 13 of 34

HIV-associated neurocognitive disorders (HAND)

Distal Symmetric Polyneuropathy (DSPN)

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• CSF: < 50 cells/ul

• elevated protein

• indistinguishable from idiopathic CIDP

Symptoms &

signs TreatmentNatural history• 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

Robinson-Papp, Muscle & Nerve. (2009)

Kaku M, Curr Opin HIV AIDS. (2014)

Later neurological complications of HIV infection:

Chronic inflammatory demyelinating polyneuropathy (CIDP)

Peripheral nerve onion-bulb in CIDP

Slide 14 of 34

*http://emedicine.medscape

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• CSF: < 50 cells/ul

• elevated protein

• indistinguishable from idiopathic CIDP

Symptoms &

signs TreatmentNatural history• weakness

• mild sensory

• 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

Robinson-Papp, Muscle & Nerve. (2009)

Kaku M, Curr Opin HIV AIDS. (2014)

Later neurological complications of HIV infection:

Chronic inflammatory demyelinating polyneuropathy (CIDP)

Peripheral nerve onion-bulb in CIDP

Slide 14b of 34

*http://emedicine.medscape

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• IRIS

Later neurological complications of HIV infection:

Distal symmetric polyneuropathy (DSPN)

• meningitis• Acute IDP

• HAND (less severe) • Chronic IDP

• DSPN • PML

• meningitis • HAND (less severe) • Chronic IDP

Slide 15 of 34

HIV-associated neurocognitive disorders (HAND)

Distal Symmetric Polyneuropathy (DSPN)

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Robinson-Papp, Muscle & Nerve. (2009)

Kaku M, Curr Opin HIV AIDS. (2014)

• Capsaicin (8% top.)

‘proved’ effective

Neurontin

Lamictal

(weak evidence)

• modify ART regimen

‘

Later neurological complications of HIV infection:

Distal symmetric polyneuropathy (DSPN)

Symptoms &

signs TreatmentNatural history

• 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)

‘

Slide 16a of 34

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

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Robinson-Papp, Muscle & Nerve. (2009)

Kaku M, Curr Opin HIV AIDS. (2014)

• Capsaicin (8% top.)

‘proved’ effective

Neurontin

Lamictal

(weak evidence)

• modify ART regimen

‘

Later neurological complications of HIV infection:

Distal symmetric polyneuropathy (DSPN)

Symptoms &

signs TreatmentNatural history

• 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

Slide 16b of 34

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

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Later neurological complications of HIV infection:

Immune Reconstitution Inflammatory Syndrome (IRIS)

• meningitis• Acute IDP

• HAND (less severe) • Chronic IDP

• DSPN • PML

• meningitis • HAND (less severe) • Chronic IDP

• IRIS

Slide 17 of 34

HIV-associated neurocognitive disorders (HAND)

Distal Symmetric Polyneuropathy (DSPN)

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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 pathogen (or other antigen

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)

Later neurological complications of HIV infection:

Immune Reconstitution Inflammatory Syndrome (IRIS)

Slide 18a of 34

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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 pathogen (or other antigen

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)

Later neurological complications of HIV infection:

Immune Reconstitution Inflammatory Syndrome (IRIS)

Slide 18b of 34

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Slide 19 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 cells

24 99/mm3

CSF:

56 cells/ul

64 mg/dl prot.

Admission: stroke 24 days post-ART:

IRIS

31 days post-ART:

IRIS

Slide 19 of 34

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HIV-associated CNS IRIS in PML patientSlide 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 cells

117 284/mm3

JC virus

confirmed at

autopsy

Before ART

1 mo. post-ART

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Later neurological complications of HIV infection:

Progressive Multifocal Leukoencephalopathy (PML)

• meningitis• Acute IDP

• HAND (less severe) • Chronic IDP

• DSPN • PML

• meningitis • HAND (less severe) • Chronic IDP

• IRIS

Slide 22 of 34

HIV-associated neurocognitive disorders (HAND)

Distal Symmetric Polyneuropathy (DSPN)

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Later neurological complications of HIV infection:

Progressive Multifocal Leukoencephalopathy (PML)

Symptoms & signs TreatmentNatural history

• 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

Slide 23 of 34

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Later neurological complications of HIV infection:

Progressive Multifocal Leukoencephalopathy (PML)

Symptoms & signs TreatmentNatural history

• 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

Slide 23b of 34

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Later neurological complications of HIV infection:

Progressive Multifocal Leukoencephalopathy (PML)

Note lesions restricted to white matter

Slide 24 of 34

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Later neurological complications of HIV infection:

Progressive Multifocal Leukoencephalopathy (PML)

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

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

typical PML: no enhancement

Slide 25 of 34

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• IRIS

• meningitis • HAND

• DSPN • PML

Later neurological complications of HIV infection:

HIV-associated neurocognitive disorders (HAND)

Slide 26 of 34

HIV-associated neurocognitive disorders (HAND)

Distal Symmetric Polyneuropathy (DSPN)

• Acute IDP

• Chronic IDP

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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

Slide 27 of 34

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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/ul

began ART after severe immunosuppresion;

white matter lesions + brain atrophy

Slide 28 of 34

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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?

Slide 29a of 34

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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?

Slide 29b of 34

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HIV-associated neurocognitive disorders (HAND)

Distal Symmetric Polyneuropathy (DSPN)

• IRIS

• meningitis• Acute IDP

• HAND (less severe) • Chronic IDP

• DSPN • PML

• meningitis • Chronic IDP

Neuropathy (less severe)

HAND

Neurological complications of HIV can persist in ART-treated

individuals and require adjunctive therapies to limit morbidity

Slide 30 of 34

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Slide 33 of 34

Thank you!

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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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Dr Kolson Suggested Readings

Activity #: HIV 17 CHI (F)

05-04-17

Page: 1

SUGGESTED READINGS

1. Hellmuth J, Fletcher JL, Valcour V, et al. Neurologic signs and

symptoms frequently manifest in acute HIV infection. Neurology.

2016;87(2):148-154.

Ref ID: 15078

2. Johnson T, Nath A. Neurological complications of immune

reconstitution in HIV-infected populations. Ann N Y Acad Sci.

2010;1184:106-120.

Ref ID: 15079

3. Johnson TP, Nath A. New insights into immune reconstitution

inflammatory syndrome of the central nervous system. Curr Opin HIV

AIDS. 2014;9(6):572-578.

Ref ID: 15080

4. Kaku M, Simpson DM. HIV neuropathy. Curr Opin HIV AIDS.

2014;9(6):521-526.

Ref ID: 15081

5. Pavlovic D, Patera AC, Nyberg F, Gerber M, Liu M. Progressive

multifocal leukoencephalopathy: current treatment options and

future perspectives. Ther Adv Neurol Disord. 2015;8(6):255-273.

Ref ID: 15082

6. Robinson-Papp J, Simpson DM. Neuromuscular diseases associated

with HIV-1 infection. Muscle Nerve. 2009;40(6):1043-1053.

Ref ID: 15083

7. Saylor D, Dickens AM, Sacktor N, et al. HIV-associated

neurocognitive disorder - pathogenesis and prospects for

treatment. Nat Rev Neurol. 2016;12(5):309.

Ref ID: 15084

8. Schutz SG, Robinson-Papp J. HIV-related neuropathy: current

perspectives. HIV AIDS (Auckl ). 2013;5:243-251.

Ref ID: 15085

9. Simpson DM, Brown S, Tobias J. Controlled trial of high-

concentration capsaicin patch for treatment of painful HIV

neuropathy. Neurology. 2008;70(24):2305-2313.

Ref ID: 10401