11/6/2010

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HIV Brain Injury

Victor Valcour MD

Associate ProfessorDivision of Geriatric Medicine and Department of

Neurology/UCSF

Overview

• The neuropathology of HIV

• HIV Dementia – a current snapshot

• Scenarios of rapid progression

– Immune Reconstitution Inflammatory Syndrome

(IRIS)

– CNS escape

– Acute infection

HIV Dementia

Recommended ReadingEllis, Langford, and Masliah. HIV and antiretroviral therapy in the

brain: neuronal injury and repair. Nature Reviews 2007

HIV characteristics

– Primate lentiviruses recognize CD4 as a receptor protein

• Immunosepression due to depletion of t-helper cells

– Regulatory genes - neurotoxicity

• vif, vpr, vpu, tat, rev, nef, env

– Env polymorphisms resulting

in clade specificity

• Implications for international setting

• Unclear neuropathogenesis by clade

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Critical role of inflammation

• Histopathological

hallmarks

– Perivascular monocytes

• Identified with CD14 and

CD45 markers

• Consistently the most

highly infected cells

– Multinucleated Giant

Cell

Brew et al 1998

Blood Brain Barrier

Capillary lumen

(5) Altered integrity of the BBB facilitating further transmigration of infected M/MФ

(3) Impacts brain cells leading to cognitive dysfunction

(2) Transfer of HIV into the brain - infection establishment in perivascular macrophages

(4) Neuronal dysfunction and death

(1) HIV-infected monocytes, some activated

Cellular co-receptors required for infection (e.g. CD4) – thus, neurons not thought to have substantial infection

CD4

cells

Plasma

HIV

RNA

Time

weeks months years

viral set-

point

HIV in human hosts(aseptic) meningitis,

radiculitis, myelitisdementia,

myelopathy,

neuropathy

opportunistic

infections

Clinical Features

Cognition

Memory loss

Concentration

Mental slowing

Comprehension

Behavior

Apathy

Depression

Agitation, mania

Motor

Unsteady gait

Poor coordination

Tremor

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Clinical CharacteristicsPresenting symptoms

0

10

20

30

40

50

60

70

Memory Gait MentalSlow ing

Depression Tremors Behavioralchanges

Apathy OtherNormal MC/MD HAD

0

5

10

Uni

fied

Par

kins

on D

isea

se R

atin

g S

cale

M

otor

Exa

m M

ean

(95%

CI)

Older

All

Younger

Valcour 2008 J Neurovirology

Neuropsychological deficit

Prominent motor part of advanced disease

Advanced disease

Clinical Features of HAD MRI findings

• Absence of opportunistic

infection

• Periventricular white matter

hyperintensities

• Atrophy

A 79 year old male with HIV

Dementia

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Dementia among HIV patients1996 - Post-HAART realities

1980

40

30

20

10

0

50

35

25

15

5

45

1985 1990 1995 2000 2005

survival

Cognitive Impairment despite HAART

0

0.25

0.5

0.75

1

HIV- CDC-A CDC-B CDC-C

Pro

po

rtio

n Im

pai

red

(1987)Grant

(1995)HNRC-500

(2007)CHARTER

Pre- ARV

Pre-HAART

HAART

Grant et al. 2009

Conference on Retroviruses and Opportunistic Infections

17%

Moderately

Impaired

22% Mildly

Impaired

21% Developed

impairment after 48

weeks of HAART

Brain Impairment and HIV

Robertson K, et al. AIDS. 2007

39% Impaired

HIV infectionHIV Asymptomatic

Neurocognitive

Impairment

Mild

Neurocognitive

Disorder (NMD)

HIV-associated

Dementia

(HAD)

Cognitive Impairment in HIV

Neurology 2007

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Functional consequences of cognitive

impairment in HIV

Heaton et al JINS 2004

Diagnostic Transitions from Baseline to Year 1

• There is considerable movement in the MCMD and HAD arms

• Approximately one-third of HAD patients improve and 18% of MCMD patients decline at one year

60.98%

21.95%

17.07%

17.65%

38.24%

41.18%

2.94%

10.71%

17.86%

53.57%

17.86%

3.57%

28.57%

67.86%

0%

100%

Normal(N=37)

NP Abnormal(N=53)

MC/MD(N=39)

HAD(N=30)

Baseline Diagnosis

Normal NP Abnormal MC/MD HAD

Year 1 Diagnosis as a % of Baseline

Diagnosis

CD68 expression in hippocampusElevated despite viral control with HAART

Anthony, Bell, et al. J Neuropath Exp Neurol 2005

VAMC ID Rounds Feb 2009 Gonzalez-Scrano et al. 2005

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HIV DNA in CD14+ cellsCorrelation to HAD HAART naïve Thais

Valcour J Leukocyte Biol 2010

Aging with HIV infection

The New York Times, 2007

The Honolulu Advertiser, 2003

Tau expression in hippocampus

Elevated despite viral control with HAART

Anthony, Bell, et al. J Neuropath Exp Neurol 2006

Prevalence of Dementia

0

10

20

30

40

50

60

70

80

55 60 65 70 75 80 85 90

Age

% of population

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Immune Reconstitution

Inflammatory Syndrome (IRIS)

Recommended reading:Johnson and Nath Neurological complications of immune

reconstitution in HIV-infected populations. Annals of the New York

Academy of Sciences 2010

IRIS – Clinical Presentation

• Profound immune response - often to previously

unrecognized or subclinical pathogens

• Two main categories:

– Simultaneous (“Unmasking”): inflammatory immune

response against an opportunistic pathogen previously

uncontrolled or untreated

– Delayed (“Paradoxical”): inflammatory immune response

against an antigen previously controlled or treated

IRIS – Clinical Presentation

• Some speculation that autoimmune phenomenon

can underlie some IRIS

– Emergence of clear autoimmune phenomenon have been

described (Guillain-Barre, Graves Disease)*

– Independent t-cell mediated encephalitis without

identified pathogen

• Descriptions of paradoxical worsening with

treatment of other infections prior to HAART

– can occur with TB, MAI leprosy treatment - confirms that

the response is due to immune reconstitution – not HAART

*Chen et al, Medicine 2005

CNS-IRISDefining Features

1. Worsening of neurological status after HAART

2. Deterioration of or new radiological findings

suggestive of inflammation

3. Occurring in the context of HIV control

– decrease in plasma HIV viral load of > 1 log appears to be

a better marker than CD4 count recovery

4. Symptoms not explained by: (1) newly acquired disease;

(2) ARV side effects; (3) usual course of other illnesses

5. If biopsy - histopathology confirms T cell

lymphocytic infiltration

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CD4

cells

Plasma

HIV

RNA

Time

weeks months years

viral set-

point

HIV in human hosts

HAART

CD4

cells

Plasma

HIV

RNA

Time

weeks months

viral set-

point

Timing of IRIS

Viral load

CD4

CD8

4 -20 weeks, increasing freq.

Most cases occur within the first 3 months of therapy

Risk Factors

• Severe immune suppression - low CD4 count at

HAART initiation (nadir)

– Implications for populations with delayed diagnosis (aged,

women, international settings)

• Known presence opportunistic infections

• High initial viral load and rapid decline in viral load

(likely a better predictor than rate of CD4 rise)

• Possibly genetic risks

– polymorphisms in cytokine and MHC genes

• Unclear association: timing of HAART c/t OI treatment

Epidemiology of IRIS

• Systemic IRIS

– 15-35% of individuals initiating HAART

• CNS-IRIS

– 0.9% of adults (1.5% if CD4 T cell count <200)

– Most common CNS-IRIS is caused by the JC virus (PML- IRIS)

– Other pathogens

• Viruses: Herpes Viruses [VZV, CMV (retinitis), EBV, HSV 1 and 2], parvovirus,

BK virus, HTLV 2,

• Fungal pathogens: Cryptococcus neoformans, Candida

• Bacterial pathogens: Mycobacterium (M. tuberculosis, M. leprae, M. avium)

• Parasitic pathogens: Toxoplasma gondii

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Clinical Course of CNS IRIS

• Varies greatly based on severity and underlying

pathogen

• Severity

– Asymptomatic – only radiological changes are noted

– Symptomatic, with recovery – clinical deterioration and

imaging confirmation

– Catastrophic – severe neurological deficits can lead to

coma, herniation, death

• PML IRIS associated with high rate of mortality

(>40%) and long-term morbidity

Radiology of PML-IRIS

• Confluent, bilateral, asymmetric, white matter changes

• Similar to chronic PML

– Key differentiation = presence of inflammation: additional peripheral enhancement and/or mass effect

Johnson and Nath, Ann NY Acad Sci 2010

Histopathology and biomarkers

• Biomarkers needed

– Cytokines? (IL-6); Genetic?

• Histopathology

– Inflammatory cells:

• Predominantly CD8 t cells, typically in the perivascular

spaces

• macrophages, CD4+ t cells also present

– Brain biopsy sensitivity and specificity: 64-96%

and 100% in PML-IRIS

IRIS Treatment

• No published randomized trials to direct

recommendations

• Exclude non-IRIS possible explanations

– Drug toxicities, interactions, poor HAART

adherence, other diseases with progression

• Continue HAART

– No guarantee that the condition will not recur

once HAART is resumed

– Likely and increased risk of HIV and OI progression

if HAART is stopped

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IRIS Treatment – use of steroids

• Catastrophic cases

– Despite lack of published data, likely needed, high

doses

• Symptomatic cases - Use of steroids is

controversial

– Inflammatory response likely beneficial to

controlling pathogen

– In non-HIV diseases, use of adjuvant steroids

accepted

CSF Escape

Case

• 45 year old male from Dublin with chronic

well-controlled HIV infection

• Presents with acute exacerbation of

depression requiring hospitalization

• Psychomotor slowing, depressed affects,

markedly decreased response times

Blood Brain Barrier

Capillary lumen

(5) Altered integrity of the BBB facilitating further transmigration of infected M/MФ

(3) Impacts brain cells leading to cognitive dysfunction

(2) Transfer of HIV into the brain - infection establishment in perivascular macrophages

(4) Neuronal dysfunction and death

(1) HIV-infected monocytes, some activated

HAART

?

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CompartmentsAntiretrovirals: CNS Penetration-Effectiveness

Courtesy: S. Letendre, UCSD

poor better

NRTI didanosine emtricitabine abacavir

tenofovir lamivudine zidovudine

zalcitabine stauvudine

NNRTI efavirenz delavirdine

nevirapine

PI nelfinavir amprenavir amprenavir-r

ritonavir atazanavir indinavir-r

saquinavir atazanavir-r lopinavir-r

tipranavir-r indinavir

enfuviride

CPE and CSF viral load

Letendre et al 2008 Arch Neurol

Proportion with detectable virus in CSF

HAART with higher BBB penetration

CompartmentsCSF viral load and cognition

Improved control of CSF HIV RNA relates to greater

improvements in cognitive performance

Ellis et al Ann Neurol 2004

Acute meningoencephalitis

Case Series

• Case series – 3 cases

– Suppressed plasma HIV

RNA presenting with acute

meningoencephalitis

– All had detectable virus in

CSF ( 7059, 180,692, and

11,227 copies/ml)

– All had MRI changes

– All responded to change in

ARVs

Representative T2 image

Wendel and McArthur CID 2003

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Subacute Neurological SyndromesCase Series

Age CD4 Months

VL<50

Neurological symptoms ARVs CSF HIV

RNA

Plasma

HIV RNA

50 592 36 Persistent headache TDF/FTC/ATZr 12,885 147

49 190 11 Memory disorder, cerebellar ataxia AZT/3TC/IDVr/T20 845 <50

43 400 18 Cerebellar dysarthria, cerebellar ataxia 3TC/ABC/ATV/IDVr 1190 <50

50 432 68 Tactile allodynia TDF/FTC/fAPRr 870 78

36 107 75 Glasgow Coma Score of 3 3TC/ABC/TDF/DRVr 5035 <50

47 631 64 Persistent Headache DRVr 580 <50

44 544 14 Memory d/o, cerebellar ataxia, pyramidal

syndrome

FTC/ABC/ATVr 558 <50

53 360 12 Lower limb dysesthesia and hypoesthesia 3TC/AZT/ABC/EFV 1023 <50

68 147 12 Memory d/o, left lower limb dysesthesia 3TC/DDI/TDF/NVP 586 <50

68 534 18 Temporospatial disorientation, cerebellar

ataxia

3TC/AZT/ATV 880 <50

56 593 10 Memory d/o, cerebellar dysarthria LPVr 6099 483

Canestri et al CID 2010

Subacute Neurological SyndromesCase Series

• All but one had CSF pleocytosis and/or

elevated protein levels

• resistance-associated mutations seen in 7 of 8

CSF strains that were genotyped

• Optimization of HAART in response to

resistance mutations identified or to increase

CSN penetration effectiveness resulted in

suppression of HIV RNA in CSF and clinical

improvement for all

Canestri et al CID 2010

Practical implications

• All cases presented with sub-acute symptom

progression - ? Approach for the 50% of

subjects with chronic impairment

– Current published studies are mixed

• Provides no basis for using neuro-HAART in

asymptomatic patients

An approach to impairment in HIV

Lancet Neurology 2005

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Acute HIVCD4

cells

Plasma

HIV

RNA

Time

weeks months years

viral set-

point

HIV in human hosts(aseptic) meningitis,

radiculitis, myelitis

Laboratory Staging of Acute HIVLaboratory Staging of Acute HIVLaboratory Staging of Acute HIVLaboratory Staging of Acute HIV----1 Infection1 Infection1 Infection1 Infection

Fiebig et al., AIDS 2003

Fiebig 1 (5 days)Fiebig 2 (10 daysFiebig 3 (14 days)

Acute HIV InfectionImpact on the brain

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Procedures

Main

Clinical PhlebotomyQuestionnairesLeukopheresis

Gut

Colon biopsySemen, anal,cervical

Days 0, 2, 3, 5, 7, 10Wks 2, 4, 8, 12, 16, 20, 24 then every 24 wks till 96 wks

Wks 0, 24, 96 D 0, 3, 7, wks 2, 4, 12, 24, 48, 72, 96

Genital

Compartment (optional)

MRI/MRSLPNP test

Wks 0, 6, 12, 24, 48, 96LP wks 0, 24, 96

Neuro

Acute Retroviral Syndrome (ARS)

Symptoms N(%)Fever 8(72.7)Oral ulcer 5(45.4)Sore throat 5(45.4)

Headache 4(36.4)Myalgia 4(36.4)Anorexia 4(36.4)Diarrhea 4(36.4)Skin rash 4(36.4)Adenopathy 2(18.2)Arthalgia 2(18.2)Genital ulcer 1(9.1)Oral candidiasis 1(9.1)Vaginal candidiasis 1(9.1)

Of 11 subjects, 9 subjects (82%) had ARS

Characteristics and neurological profile

of acute HIV infected subjects at enrollment

ID Age/ge

nder

Risk Fiebig HIV RNA CD4/CD8 Subtype ARS

symptoms

Headache

(yes or no)

CSF cell count

1 28yr/F Hetero III 794,947 341/264 CRF01_AE Yes No RBC=0,WBC=02 28yr/M MSM III 1,069,278 426/238 NT Yes Yes RBC=0,WBC=103 30yr/M MSM III 302,722 740/917 NT Yes

No RBC=10,WBC=304 30yr/F Hetero IV 571,082 463/1227 CRF01_AE Yes No RBC=10,WBC=505 46yr/M Hetero III 258,559 525/245 CRF01_AE Yes Yes RBC=8,WBC=06 25yr/M MSM II 150,633 269/203 NT No No Not done7 23yr/M MSM II 285,651 218/191 CRF01_AE Yes No RBC=1,WBC=08 24yr/M MSM III 81,978 428/500 B No Yes RBC=2,WBC=19 25yr/M MSM III 48,421 381/998 NDY Yes No RBC=0,WBC=0

10 25yr/M MSM III >750,000 298/426 NDY Yes No RBC=1,WBC=011 25yr/M MSM II 276,124 311/271 NDY Yes Yes RBC=10,WBC=0

All had normal CSF protein and sugar

HIV CNS penetration during acute

Infection

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Early inflammation in Acute HIV

Cho/Cr

Feib

ig 1

&2 : B

G

Feib

ig 3

&4 : B

G

Contro

l : B

G

0.15

0.20

0.25

0.30

0.35

MRS Feibig

MRS – Basal Ganglia CSF Cytokines before and after megaHAART

Major unanswered Questions

• Our there founder viruses in CSF that may

uncover aspects of neurotropism

• Do CNS outcomes depend on early immune

responses

• Is there a CNS impact of treatment within the

first weeks of infection

Conclusions

• HIV-related brain injury remains frequent

despite HAART

• There is evidence that on-going brain

inflammation may be occurring

– Infiltration of macrophages at autopsy

– Circulating HIV DNA

Conclusions

• HIV can present as a rapidly progressive

dementia syndrome

– Immune Reconstitution Inflammatory Syndrome

• In association with opportunistic infection

• Autoimmune phenomenon

– CNS escape syndromes

– Acute HIV

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A B

C D

Top

Thank you

Research support

R01 NS061696 (Monocyte HIV DNA and HIV

Dementia)

K23AG032872 (Brain Impact of Aging with HIV)

R21-MH086341 (Neurological Complications of

Acute HIV Infection)

UCSF AIDS Research Institute (NeuroImaging

Correlates to Dementia in HIV over 60)

UCSF-Gladstone Center for AIDS Research

(NeuroImaging Correlates to Dementia in

HIV over 60)

Hillblom Foundation (Cognitive Impact of Insulin

Resistance in Aging HIV Patients)

P50 AG023501 (UCSF Alzheimer’s Disease

Research Center)

Disclosures: Dr. Valcour has provided consultative services to GlaxoSmithKline, Merck, and Abbott

Special Thanks:

Krista Nicolas

Edgar Busovaca

Stephanie Chaio

Lauren Wendelken

Howard Rosen, Bruce Miller and the Memory and

Aging Center Staff

Cecilia Shikuma, Bruce Shiramizu and the Hawaii

Center for AIDS

Jintanat Ananworanich and the Southeast Asia

Research Collaboration with Hawaii (SEARCH,

www.SEARCHThailand.org)

Jerome Kim and the US Army HIV Research team

Our research subjects in California, Hawaii and

Thailand