Welcome to I-TECH HIV/AIDS Clinical Seminar Series

HIV and the Nervous System, Part 3Christina M. Marra, MD

June 18, 2009

JW

• 57 yo man brought in by friend to ED – “Not himself” X past 3 weeks

• Decline in self-care and increasingly forgetful– Apartment messy– Recently lost job, car repossessed– Got lost while driving– Needs to be cued to eat, drink, dress, undress

• Complains of difficulty concentrating, dizziness, weight loss, depression

JW Pre-morbid Function

• Four years of college

• Program assistant for public health system

• Traveled to China and Tibet for his 50th birthday

• Occasional tobacco, rare alcohol, no other recreational drugs

JW PMH

• B3 HIV– “Fearful of antiretrovirals”– Nadir CD4 74 (2 mo prior), VL 103,000 copies/ml

• Hx neurosyphilis treated with IV PCN, 1987• Peripheral neuropathy• Hx B12 deficiency

JW Medications

• Atripla – Poor adherence

• Vitamin B12

• Bactrim DS one table PO q day

JW Exam

• Afebrile, thin, normal general medical examination

• Neurological examination– MMSE score 22 – Variably oriented – Fluent speech– Brisk ankle reflexes, right Babinski

JW Laboratory Data

• Serum RPR non-reactive

• TSH normal

• Negative toxicology screen

• Normal electrolytes

• Plasma HIV RNA 33,900 copies/ml

JW Laboratory Data

• CSF– 10 WBC, all mononuclear– Protein 99 mg/dl – Cryptococcal Ag negative– CSF-VDRL nonreactive– CMV, HSV, VZV, JCV PCRs negative– Beta-2 microglobulin 4.5– CSF HIV RNA 55,000 copies/ml

JW T1 and FLAIR MR

JW FLAIR MR

JW Follow up

• Admitted to nursing facility• Restarted Atripla

– Plasma HIV RNA undetectable 1 month later– CD4 remains ~100 cells/ul 7 months later

• Living independently• Driving• Still having trouble with math

Approach to Diagnosis

Meningeal Sx/Signs Nonfocal Parenchymal Sx/Signs Focal Parenchymal Sx/Signs

Syndrome

Approach to Diagnosis

HIV dementiaCMV encephalitis

NeurosyphilisDrugs, metabolic

Most Common Etiologies

CD4+ T cell countToxicology screen, TSH, B12

ConsiderationsTests

Nonfocal Parenchymal Sx/Signs

Cognitive Motor Behavioral

Forgetfulness Poor balance Apathy, social withdrawal

Decreased concentration

Leg weakness Depression

Confusion Irritability

Slow thinking Psychosis, mania

Clinical Features of HIV Dementia

“HAND”: HIV Associated Neurocognitive Disorder

Disorder NP Tests No NP Tests

HIV Dementia

Moderate NP impairment

Major functional decline

Moderate MSE impairment

Major functional decline

Risk Factors for HIV Dementia

• CASCADE (Bhaskaran K et al. Ann Neurol 2008;63:213)

– 23 cohorts Europe, Canada, Australia– Pre-1997 to 2006– 15,380 subjects– 222 HIV Dementia– Total follow-up 83,388 person-yrs

Current CD4 and HIV Dementia

CD4 Stratum Relative Risk

> 350 1

200-349 3.47

100-199 10.19

0-99 39.03

Adjusted for calendar period

HIV Dementia Epidemiology

Dore GJ. AIDS 2003;17:1539

• Infectious– Serum CrAg, TPPA

– Imaging

– CSF CMV PCR, HIV RNA, B-2-microglobulin, VDRL

• Non-infectious– Medication history– Tox screen

• Metabolic encephalopathy– Electrolytes, B12, TSH

HIV Dementia Evaluation

JW T1 and FLAIR MR

PML T1 and FLAIR MR

ADC Treatment

• Potent ARV– Does good CNS penetration matter?

CNS Penetration-Effectiveness Rank

Better=1 Intermediate=0.5 Worse=0NRTIs Abacavir, ABC Emtricitabine, FTC Didanosine, ddI

Zidovudine, AZT Lamivudine, 3TC Tenofovir, TDFStavudine, d4T Zalcitabine, ddC

NNRTIs Delavirdine, DLV Efavirenz, EFVNevirapine, NVP

PIs Indinavir, IDV Amprenavir-r, APV-r Amprenavir, APVIndinavir-r, IDV-r Atazanavir, ATZ Nelfinavir, NLFLopinavir-r, LPV-r Atazanavir-r, ATZ-r Ritonavir, RTV

Saquinavir, SAQSaquinavir-r, SAQ-rTipranavir-r, TPV-r

FusionInhibitors

Enfuvirtide, T20

Letendre et al, Archives of Neurology, 2008

P = 0.03

34%

18% 18%

12% 11% 8%

23%

CPE and CSF HIV RNA

ACTG 736

• 101 patients starting or changing potent ARVs– 0, 12, 24 weeks

• Plasma HIV RNA• CSF HIV RNA• Neuropsychological performance

• Data analyzed for 79 patients

NP Performance in Cognitively Impaired

Characteristic Estimate P Value

Entry NPZ4 0.86 <0.001

Number of ARV Agents -0.38 0.001

CPE rank > 2 -1.08 <0.001

CNS Escape

Venkataramana A et al. Neurol 2006;67

EC

• 38 yo man brought in by friend to clinic – “Not himself” X past 11 months

• Began with change in personality– Less reserved

• Decline work performance– Fired from job

• Little insight

EC Pre-morbid Function

• BA degree in zoology

• Laboratory soil analyst

• No tobacco, occasional alcohol, no other recreational drugs

EC PMH

• A1 HIV– No ARVs– CD4 530, plasma HIV RNA 13,000

copies/ml

• No medications

EC Exam

• Afebrile, thin, normal general medical examination

• Neurological examination– MMSE score 30 – Trouble following examination instructions– Mild left sided weakness

EC Laboratory Data

• Serum RPR 1:128

• TSH normal

• Negative toxicology screen

• Normal electrolytes

• Plasma HIV RNA 12,247 copies/ml

EC Laboratory Data

• CSF– 78 WBCs, all mononuclear– Protein 120 mg/dl – Cryptococcal Ag negative– CSF-VDRL 1:128– CMV, HSV, VZV, JCV PCRs negative– Beta-2 microglobulin ND– CSF HIV RNA ND

EC FLAIR MR

Two HIV+ Patients

• EJ– 42 yo woman presented Sept 6, 2006– HIV diagnosed in 1999

• CD4 293 cells/ul• Plasma HIV RNA 29,600 copies/ml

– Hepatitis C– Burning pain and numbness in feet for 4 months

• Began with stopping potent ARVs

– Progressive weakness

Two HIV+ Patients

• RM– 53 yo man under my care since 1990– Biopsy proven PML– Undetectable plasma HIV RNA and CD4 > 500

cells/ul X years– Type II DM X 4 years– Burning pain and numbness in feet for 2 years

DSPN in HIV

• Most common neurological complication of HIV

• Increasing in prevalence

• ARV-related– D-drugs (didanosine, stavudine)– ? PIs– Clinically indistinguishable from HIV DSPN

HIV DSPN

• Subjective– Numbness– Pain– Burning– Cramping– Unsteadiness

• Objective– Symmetrical– Lower extremities

involved before upper– Loss of pinprick,

temperature, vibration– Absent or reduced ankle

reflexes– Mild intrinsic foot

weakness

Stavudine and Neuropathy

• Sacktor et al. (Neurology 2009;72)

– 102 HIV+ beginning stavudine-lamivudine-nevirapine in Uganda

– Baseline • Pain in feet in 37% • Neuropathy signs in 43%

– Loss or diminished ankle reflexes– Diminished pin sensitivity in feet– Decreased vibration sensation at great toes

Stavudine and Neuropathy

• Sacktor et al. (Neurology 2009;72)

– Six months, previously asymptomatic• Pain in feet in 38%• Neuropathy signs in 31%

– Six months, previously symptomatic• No pain in feet in 22%• No neuropathy signs in 23%

PIs and DSPN

• Ellis et al. (Ann Neurol 2008;64)

– 1159 patients in CHARTER– 58% neuropathy

• Loss or diminished ankle reflexes• Diminished pin sensitivity in feet• Decreased vibration sensation at great toes• Symmetrical in all instances

– 58% with neuropathy were symptomatic

PIs and DSPN

Odds Ratio P-value

Age per 10 yr 2.40 <0.001

CD4 nadir per 100 cells 0.75 <0.001

D-drug exposure 2.57 <0.001

Log plasma HIV RNA 0.81 <0.001

Duration HIV per 5 yr 1.50 <0.001

Ellis et al. Ann Neurol 2008;64

PIs and DSPN

Ellis et al. Ann Neurol 2008;64

HOPSImmunodeficiency

+ Toxic DrugsBetter immunity + ?Fewer Toxic Drugs

Lichtenstein et al. Clin Infect Dis 2005;40

HIV DSPN

• Some other causes of neuropathy in HIV– Dapsone– INH– Vincristine, other chemotherapy– Ethambutol– Thalidomide– Megadose B6 – B12 deficiency– Alcohol– Diabetes

Neuropathy Work-up

• EMG, NCV– Large fiber

• QST– Small fiber

• ENFD– Small fiber

• Labs– SPEP, immunofixation– B12, B6, folate– TSH– TPPA– HbA1c– Cryoglobulins– ESR, CRP

DSPN Treatments

• Gabapentin +/- SR morphine

• Pregabalin

• Lidocaine patches

• Duloxetine

• Amitriptyline

• High dose capsaicin patch

• Cannabis

Capsaicin Patch

• Simpson et al. (Neurology 2008;70)

– Three doses high concentration capsaicin vs. low dose control

– 12 weeks– 203 treated, 73 controls– > 30% pain reduction in 34% vs. 18%– No dose response

Capsaicin Patch

Cannabis

• Abrams et al. (Neurology 2007;68)

– Smoked marijuana• 32 mg delta-9-THC/cigarette 3 times per day X

5 days

– Matched control cigarettes– 25 patients per group– > 30% pain reduction in 52% vs. 24%

Pain Intensity

Abrams et al. Neurology 2007:68

Welcome to I-TECH HIV/AIDS Clinical Seminar Series

Next session: July 9, 2009Dr. Nina Kim

HIV and Hepatitis

Welcome to I-TECH HIV/AIDS Clinical Seminar Series

Next session: July 9, 2009Listserv:

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