c3 neurological complications and treatment of hiv clifford

HIV and the Brain:HIV and the Brain:Update 2010Update 2010

David B. Clifford, MDMelba and Forest Seay Professor

Washington University in St. Louis

HIV-1 Associated Neurologic Problems

HIV-1 Associated Neurologic Problems

• Primary HIV-associated conditions– HIV-associated

neurocognitive disorder and dementia

– Myelopathy– Peripheral

neuropathy– Myopathy

Selected Secondary Problems

• Toxoplasma encephalitis

• PML

• Syphilis

HIV-Associated Dementia (HAD)

Formerly AIDS Dementia Complex

• Occurs with low CD4• Progressive – untreated death

in 6 months• Correlates at least moderately

to active viral replication (in CNS)– CSF VL high

• Correlates to immune activation markers

• Pathology: Multinucleated giant cells

Approved Antiretroviral Agents 1987 - 2010

87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07

Nucleoside RTI

Non-Nucleoside RTI

Protease InhibitorFusion InhibitorCCR Inhibitor

Integrase Inhibitor

RTG

MVC

T-20SQV NFV LPV/r

SQV.sgc APV

RTV

IDV

ATV

RFV

TPV

DRV

NVP EFV

DLV

ZDV DDI

DDC

d4T

3TC

3TC/ZDV

ABC

ABC/3TC/ZDV

TDF

3TC/ABC

FTC/TDF

TDF/FTC/EFV

ETR

Neurocognitive Impairment in the Pre-ARV, Pre-HAART and HAART Eras

0%

25%

50%

75%

100%

HIV- CDC-A CDC-B CDC-C

Pe

rce

nt

Imp

air

ed

Grant 1987 HNRC-500 1995 CHARTER 2008

Frascati Classification of HIV-Associated Neurocognitive Disorders (HAND)

• ANI = Asymptomatic neurocognitive impairment

• MND = Mild neurocognitive disorder

• HAD = HIV-1 associated dementia

Neurocognitive Impairment in the Neurocognitive Impairment in the Pre-HAART and Post-HAART ErasPre-HAART and Post-HAART Eras

Modified from Ellis et al, Nat Rev Neurosci 2007 and Grant et al., CROI 2009

Incidence but not prevalence of HIV-associated neurocognitive disorders (HAND) has declined with HAART

Cognitive Dysfunction in HIV

HAND in HAART Era• Occurs at higher CD4 counts• Course stable or oscillating, still

under investigation• Occurs with undetectable

plasma VL, generally CSF VL also controlled (?almost)

• Poorer correlation to immune activation markers

• Pathology: minimal changes in brain

Letendre et al, 16th CROI 2009, Abstract 484b

Cognitive Dysfunction in HIVAIDS Dementia (now HAD)

Pre-HAART

HAND (ANI/MND)

Post=HAART

DiagnosisCHARTER Neurocognitive Test Battery

• Verbal Fluency– Letter Fluency– Category Fluency

• Speed of Information Proc.– WAIS-III Symbol Search– WAIS-III Digit Symbol– Trail Making Test Part A

• Attention/Working Memory– Paced Auditory Serial Addition Test - 50– WAIS-III Letter-Number Sequencing

• Motor– Grooved Pegboard

• Abstraction/Executive– Wisconsin Card Sorting Test 64– Trail Making Test Part B

• Learning and Memory– Hopkins Verbal Learning Test-R– Brief Visuospatial Memory Test-R– Story Memory Test – Figure Memory Test

Everyday Functioning: Patient’s Assessment of Own Functioning Inventory

Activities of Daily Living Scale

International HIV Dementia Scale

•International HIV Dementia Scale •Naming four objects•Fingertapping•“Luria” psychomotor learning task•Recall of names

Sacktor et al. Neurology 2003 60;1:A186-187

CogState

http://library.cogstate.com/public/Brochures/12_Minute%20Brochure%20REV6_LowRes.pdf

CROI 2010, Winston, et al

Executive Function

DiagnosisNPZ -4 used in ACTG

• Trail making A and B• Symbol digit test• Hopkins Verbal

Learning test

Robertson, et al, ALLRT

Cognitive ScreeningMontreal Cognitive Assessment (MoCA)

• Broad balanced test• Online and free• Bedside scoring• Being assessed in

comparison with tools currently used that require licenses, and norming

http://www.mocatest.org/

What causes HAND now?

• Co-morbidities• Virus• Inflammation• Perfusion/Vascular

Is this all due to non-HIV- associated co-morbidities?

• Contribution of other factors to cognitive performance– ?trauma

– ?drugs

– ?hepatitis

– ?psychiatric dx/rx

Neurocognitive Impairment by Co-Morbidity Status

0

10

20

30

40

50

60

70

80

Total Minimal Moderate Severe

% im

pair

men

t

Damaged brain may heal poorlyCD4 Nadir

• Legacy of prior damage

• Nadir CD4 count– CHARTER analysis

suggest significant impact of nadir <350

– Data too limited to test higher nadirs

• Implies earlier rx could be helpful CROI 2010, Poster 429,

Ellis, et al

CNS HIV ANTIRETROVIRAL THERAPY EFFECTS RESEARCH | WWW.CHARTERRESOURCE.UCSD.EDU

Slide 22

Correlates of CSF Viral Loads in 1,221

Volunteers of the CHARTER Cohort

Scott Letendre, Chelsea FitzSimons, Ronald J. Ellis, David Clifford, Ann C. Collier, Benjamin Gelman, Christina Marra, Justin McArthur, J.

Allen McCutchan, Susan Morgello, David Simpson,

Florin Vaida, Robert Heaton, and Igor Grant for the CHARTER Group

CROI 2010, #172

CROI 2010, #172


Slide 23

Distribution of CSF Viral Loads

Off ART On ART


Slide 24Correlates of Detectable CSF Viral Loads

842 Volunteers Taking ARTDirection Uni Multi

Plasma Viral Load Higher < 0.001 < 0.001

CD4+ Cell Count < 200 < 0.001 0.03†

No. Past Antiretrovirals Larger 0.003 -

Duration Current Regimen Shorter < 0.001 -

Ethnicity Non-White < 0.001 0.003

Adherence < 95% < 0.001 0.09

Age Older 0.03 -

CPE Rank Lower 0.007 < 0.001


Slide 25

CNS Penetration-Effectiveness Ranks2010 4 3 2 1

NRTIs Zidovudine Abacavir Lamivudine DidanosineEmtricitabine Stavudine Tenofovir

ZalcitabineNNRTIs Nevirapine Delavirdine Etravirine Efavirenz PIs Indinavir-r Darunavir-r Atazanavir Nelfinavir

Fosamprenavir-r

Atazanavir-r Ritonavir

Indinavir Fosamprenavir SaquinavirLopinavir-r Saquinavir-r

Tipranavir-rEntry Inhs Vicriviroc Maraviroc EnfuvirtideIntegrase Inhs Raltegravir


Slide 26CNS Penetration-Effectiveness Ranks

CPE 2008 Ranks CPE 2010 RanksCross-Sectional Analysis

p = 0.008n = 467

Letendre S, et al. Arch Neurol 2008; 65:65-70


Slide 28

Conclusions

Plasma viral load was the strongest correlate of CSF viral load, emphasizing the importance of systemic HIV suppression for control of HIV in the nervous system » Without ART, higher CSF VLs also correlated with older age and more

advanced current and past immunosuppression» With ART, detectable CSF VLs were associated with worse adherence,

worse estimated antiretroviral penetration, and non-white ethnicity » The mechanisms by which age and ethnicity influence CSF VL are

unknown Among people not taking ART, worse global

neurocognitive performance was associated with having CSF VLs that were at least as high as plasma VLs

Does CPE have a downside?

• A5170 found stopping ARV resulted in cognitive improvement

• ACTG 736 results suggested poorer performance in better penetrating regimens

• Elevated penetration could cause increased toxicity

A B

C D

CROI 2010, Liner et al,Poster 435

A=Control, B=ATV, C=EFV (dendrites), D=EFV(neuron loss)

MAP-2

~60% still have elevated neopterin and IgG Index after 4 yrs HIV rx

Brain Perfusion

Multicenter AIDS Cohort• After accounting for education,

depression and race

• Carotid intima-media thickness (IMT) and GFR associated with psychomotor speed

• IMT associated with memory

• HIV serostatus not associated with poorer cognitive performance overall

• In HIV+, HIV detection in plasma associated with poorer memory

Cardiovascular Risks Associated with Poor Cognitive Performance

in SMART Study

• Traditional HIV associated risk factors were not associated with baseline NP performance

• CVD risk factors were associated with poorer baseline performance

CROI 2010

HIV Indirectly Contributes to Cognitive Impairment?

Cognitive Normal

CognitiveImpaired

Carotid IntimaThickening

HIV AgeHBPDMLipids

Arterial spin labeling (ASL) measures cerebral blood flow (CBF)

Tag by Magnetic Inversion

Wait

Acquire image

1:

Control

Wait

Acquire image

2:

Control - Tag CBF (mL/100mL/min)

Ances,Abst 157CROI2009

Effects of HIV and Aging on rCBF

Ances et al. , JID, Feb 2010

Age (years old)

Cross sectional: Global and Regional Cross sectional: Global and Regional rCBF Are Affected by HAARTrCBF Are Affected by HAART

35.0

45.0

55.0

65.0

75.0

0 1 2

Box Plot

Group

Glo

bal_

rCBF

HIV+Naive

HIV+Meds

HIV-Controls

(n=26) (n=26) (n=13)

P < 0.05

P < 0.01

P < 0.05 P < 0.05 P < 0.05

P < 0.05

Longitudinal: HAART Affects Longitudinal: HAART Affects HIV Viral Load and Global rCBFHIV Viral Load and Global rCBF

HIV Causes Synaptodendritic Injury HIV Causes Synaptodendritic Injury Leading to Reduction in rCBFLeading to Reduction in rCBF

NormalSynapto- dendritic Density

HIV

NormalCerebral

Blood Flow

Disruption or Loss of Synapto-dendritic communication

ReducedCerebral

Blood Flow

HAART

Masliah et al,Ann Neurol 1997

Masliah et al,Ann Neurol 1997

Modifiable Risk Factors

• Smoking• Diet

– Glucose– Lipids

• Rest• Exercise

– Physical– Mental

Conclusions• Cognitive functions remain impaired in many

optimally treated HIV patients• Optimal therapy should avoid low nadir CD4,

optimize HIV control, minimize chronic immune activation, and optimize cerebral perfusion

• Healthy lifestyles as well as HIV control should contribute to better neurologic outcomes

History

• 34 yo woman from Liberia• AIDS, off Rx, CD4 <50• Extrapulmonary tuberculosis in elbow and leg

for several years• Hepatitis B• Cardiomyopathy• Positive serum RPR• Presents with headache 10/09

Extrapulmonary TBC – 2008Clavicle

Aspiration of lesion yields AFB

CT Brain – October 2009

History 2

• Workup non-diagnostic– CSF benign– CSF PCR negative for EBV, toxo, JC HSV– CSF cultures negative

• Neurosurgery unwilling to biopsy brain• Treated for TBC with four drugs, taken

intermittently• Presents 01/2010 worsening

– Control right hand poor, decreased feeling in right hand

Lab Eval 2010

• CSF– 15 cells (lyms)– Glucose 70 mg/dl, protein 56 mg/dl– Toxo PCR positive, EBV negative

• Plasma– Neg histoplasma, coccidio– RPR 1:4, FTA negative

Toxoplasma Encephalitis

Toxoplasma Strains

Type IIMost commonly cause toxoplasmosis

Type I : Rarer but pathologic

Type IIIRarely assoc with dx

Signs/Sx of Toxoplasmosis

• Headache• Fever• Confusion• Hemiparesis, other

focal signs• Posterior fossa

syndrome• Seizures• ICP elevation

Therapy for Toxoplasma encephalitis

• Initiation of HAART at appropriate time

• Primary prevention– If CD4 < 200 use

primary prophylaxis

– Same as for P. jerevicii

TE Therapy

• Sulfadiazine/Pyrimethamine/Folinic Acid– Pyrimethamine 200 mg po loading dose, then 75 mg

PO qd

– Sulfadiazine 1.5 grams q 6 h

– Folinic acid 5-10 mg qd PO

• Problems– Sulfa allergies

– Crystalluria

– Oral Pill burden

TE Therapy

• Alternative for sulfadiazine: Clindamycin 150-300 mg q6h IV/PO– Allergies– GI toxicity

Co-trimoxizole as therapy

• Anecdotal experience and case reports• Pilot study: Torre et al (Italian

Collaborative Study Group), Antimicrob Agents and Chemoth 1998; 1346-9.

• Randomized pilot study• Suggests T-S may be reasonable alternative

to P-S, but lacked power to demonstrate noninferiority

Mortality of AIDS Defining Complications

CROI 2007,Abstract 80,Mocroft et al

Data derived from15 HIV cohort studies including >30K subjects

Graber et al, CROI 07 Abstract 525, also identifies PML as one of the conditions in which HAART has had the least impact on mortality hazard ratio

Progressive Multifocal Leukoencephalopathy

• Acquired demyelinating CNS disease

• JC virus is etiologic agent• ~5% of untreated HIV

deaths• Disease exclusively in

immunocompromised • Remains problem in

HAART era, and in other populations

• Worldwide distribution

Clinical Aspects of PML• Signs and symptoms dependent

on lesion location– Motor sx

– Seizures (20%)

– Behavioral signs

• Progressive over weeks to a few months

• Generally have dominant clinical focus that progresses and is consistent with MR lesion visualized

PML Survival in HAART Era

0.2

5.5

.75

1

0 26 52 78 104 130 156 182 208 234 260weeks

Kaplan-Meier survival estimate with 95%CI

(n=168 PML-related deaths in 372 patients with 465 PY follow up)

1-year cumulative proportion surviving: 0.56 (95%CI 0.50-0.61)36.1 PML-related deaths/100 PY

DeLuca, et al, 12th CROI

PML IRIS

Vendrely, et al Acta Neuropathol (2005) 109:449-455

•HIV associated PML with cognitive presentation

•Brisk increase of CD4 117 to 300 and drop in HIV VL

•Clinical state continued to progress

•Biopsy performed

CSF PCR Performance

Marzocchetti et al, J. Clin Microbiol, 2005

Therapeutic Approaches

– Immune reconstitution– Adjunctive therapy

• Cytosine arabinoside• Cidofovir• 5HT2a inhibitors (mirtazepine)• Mefloquine

Mefloquine (Larium)

• Antimalarial drug– 11 million people have taken

since 1984

• Toxicity– Psychiatric sx: anxiety,

paranoia, depression, hallucinations, psychotic behavior

– Increased risk of sz in epilpetics

– Prolong QTc with quinine derivatives

• Clinical trial now in progress

Case History

• 67 yo married WM

• 3 wks increasing severe leg and back pain

• HIV discovered 3 mo previously

• CD4 75

• Atripla started 2 mo ago

Exam

• Articulate lawyer complaining of radicular pain to legs

• Reflexes increased

• No distal sensory loss

Localization

• Peripheral nerve?– Wrong history

– Wrong exam

– No other risks identified

• Spinal cord ?– radicular– Brisk reflexes suggest

UMN finding

– Radicular suggests root

– Babinski

• MR scan ordered to rule out compressive lesion

• B12/folate• Copper• HTLV-1• Records checked

– NO RPR

Syphilis

• ++RPR 1:128• +FTA• CSF inflammatory

with +VDRL• PCN treatment

resulted in prompt improvement

Neurosyphilis and HIV

• Concurrent syphilis and HIV exposure not rare

• Course to neurosyphilis may be accelerated in HIV

• IRIS and syphilis may explain this presentation

• Treatment may be more difficult • Care to consider syphilis, and treat

aggressively with close followup important

Neurologic Complications in HIV

• Primary – Cognitive

– Peripheral nerve

• Secondary– Toxoplasma

– PML

– Syphilis

• Diagnosis important• All are now treatable• Ongoing

investigations promise better outcomes

Washington University AIDS Trials Group

Thanks!

• CHARTER investigators• Igor Grant

• Ann Collier

• Ben Gelman

• Justin McArthur

• David Simpson

• Susan Morgello

• Scott Letendre

• Ron Ellis

• NARC investigators

• ACTG investigators

• Washington U – STL– Turner Overton

– Beau Ances

– Mary Gould

– Mengesha Teshome

• Patients and families

c3 neurological complications and treatment of hiv clifford

Documents

hiv hand

hivassociated dementia

hiv aids dementia

prevalence of hiv

neurocognitive disorders

prehaart hand animnd

auditory serial addition

posthaart eras