hiv-associated neurocognitive disorder (hand)

HIV-ASSOCIATED NEUROCOGNITIVEDISORDER (HAND)

Dr. Patrick Li

Queen Elizabeth HospitalHong Kong

Background

• HIV is neurotropic and invades the nervous system from the time of primary infection

• HIV-associated dementia is an AIDS-defining illness• Recognition of minor and asymptomatic

neurocognitive impairment in HIV-infected persons• Overall prevalence of HIV-associated neurocognitive

disorders (HAND) has not decreased with cART• HAND is associated with increased mortality and

morbidity

Chiodi F, et al. Brain Pathology 1991;1:185–91Gray F, et al. Brain Pathol 1996;6:1–15

7th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

Typical features of HIV-associated dementia

Cognitive impairment

o Mental slowness or loss of mental staminao Memory problemso Poor concentration and comprehension

Behavioural abnormalities

o Apathyo Lethargyo Diminished emotional responseo Reduced gregariousnesso Depressiono Agitation/increased irritability

Motor dysfunction

o Unsteady gaito Poor balanceo Incoordinationo Abnormal toneo Tremors

Navia BA, et al. Ann Neurol 1986;19:517–24


No alternative

cause

Delirium absent

Acquired impairment in ≥ 2 cognitive

abilities

Interferes with daily

functioning

Asymptomatic Neurocognitive Impairment (ANI) ✔ ✔ ✔ No

Mild Neurocognitive Disorder (MND) ✔ ✔ ✔ Mild

HIV-Associated Dementia (HAD) ✔ ✔ Marked Marked

Antinori A, et al. Neurology 2007;69:1789–99

Spectrum of HAND


Heaton RK, et al. Neurology 2010;75:2087–96

Asymptomatic Neurocognitive

Impairment

HIV infection without cognitive

impairment

Mild Neurocognitive

Disorder

HIV-Associated Dementia

CHARTER Study (n=1,555 HIV-infected adults)52% had NP impairment: HAD 2%, MND 12%, ANI 33%

Neuropsychological impairmentin the era of cART


Prevalence of HAND in cART era

• Asia-Pacific (2008)1: 12% (0-23% in 10 sites; 63% on cART)• Switzerland (2010)2: 69% (aviremic for median of 48 months)• Botswana (2010)3: 38% (98% on cART)• Malawi (2010)4: 14% (75% on cART)• South Africa (2010)5: 23.5% (48% on cART)• Thailand (2010)6: 37.5% (2NN Cohort)• Singapore (2012)7: 22.7% (91% on cART)

1. Wright E, et al. Neurology 2008;71:50–6; 2. Simioni S, et al. AIDS 2010;24:1243–50;3. Lawler K, et al. J Int AIDS Soc 2010;13:15; 4. Patel VN, et al. J Int J STD AIDS 2010; 21:356–8;

5. Joska JA, et al. AIDS Behav 2010; 14:371–8; 6. Pumpradit W, et al. J Neurovirol 2010;16:76–82;7. Chan LG, et al. BMJ Open 2012;2:e000662


Prevalence of HAND and CDC stage

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

HIV- CDC-A CDC-B CDC-C

Perc

ent i

mpa

ired

Grant (1987)HNRC-500 (1995)CHARTER (2010)

Grant I, et al. Ann Intern Med 1987;107:828–36Heaton RK, et al. J Int Neuropsychol Soc 1995;1:231–51

Heaton RK, et al. Neurology 2010;75:2087–96


Risk of HAND is increasedwith lower CD4 nadir

Ellis RJ, et al. AIDS 2011;25:1747–51

0 200 400 600 800 1000

0.2

0.3

0.4

0.5

0.6

0.72

1.5

1

0.75

0.5

CD4 nadir (cells/µL)

Pro

babi

lity

of im

pairm

ent

Odds of im

pairment

HAND eligible

All subjects


Impact/consequences of HAND

• Poorer survival1,2

• Diminished self-care ability and quality of life3

• Deterioration in work performance, higher unemployment rate4

• Suboptimal drug adherence5,6

• Impaired driving, increased accident risk7

• Significant personal, economic and societal burden

1. Sevigny JJ, et al. Arch Neurol 2007;64:97–102; 2. Vivithanaporn P, et al. Neurology 2010;75:1150–8;3. Heaton RK, et al. J Int Neuropsychol Soc 2004;10:317–31; 4. Heaton RK, et al. Psychosom Med 1994;56:8–17;

5. Woods SP, et al. Arch Clin Neuropsychol 2008;23:257–70; 6. Hinkin CH, et al. Neurology 2002;59:1944–50;7. Marcotte TD, et al. J Clin Exp Neuropsychol 2006;28:13–28


HAND predicts an increasedrisk of death

Vivithanaporn P, et al. Neurology 2010;75:1150–8

60

70

80

90

100

0 5 10 15 20

Years since HIV diagnosis

Sur

viva

l (%

)Without HAND

(n=1549)

HAND(n=102)


Problem with recognition of HAND• Vast majority of patients with HAND have mild or

no symptoms• Patients may not volunteer symptoms from lack of

awareness or insight• ID physicians caring for HIV/AIDS patients may not

have relevant training for diagnosis and management of HAND

• Practical difficulties with routine screening for HAND in busy clinic settings

• Limited access to formal neuropsychological testing


Screening instruments for HAND

• Mini-Mental State Examination• HIV Dementia Scale• International HIV Dementia Scale• Montreal Cognitive Assessment (MoCA)• Medical Outcomes Study HIV Health

Survey (MOS-HIV)• Other screening protocols


HAND screening instrumentsBenefits Limitations

MMSE – Familiar to most clinicians– Quick to perform (10 minutes)

– Not sensitive to HIV-related cognitive impairment

HDS – Validated for HAND– Quick to perform (10 minutes)

– Validated in Caucasian population– Needs training for testing anti-

saccadic eye movements– Less sensitive for milder forms of

HAND

IHDS – Validated for HAND– Quick to perform (5 minutes)– Validated in different cultures– Requires less training

– Less sensitive for milder forms of HAND

MoCA – Quick to perform (10 minutes)– Translated into 35 languages– Freely available online

– One recent study showed 63% sensitivity and 71% specificity for HAND

MOS-HIV

– Easy to perform, can be done by patients in waiting room

– Translated into many languages– Evaluates functional status and

quality of life

– Only identifies symptomatic disease

– Subjective reporting of symptoms

Valcour V, et al. Clin Infect Dis 2011;53:836–42Overton ET, et al. J Neurovirol 2013:19:109–16

Grooved Pegboard (GP)

• Requires minimal operator training• Measures

– Manipulative dexterity– Visual-motor coordination– Performance and speed in fine motor tasks

• Administered to dominant and non-dominant hands• Trial time allowed: 5 minutes• Several scores may be recorded:

– (1) Time (in seconds) to perform each trial from start to end– (2) No. of unintentional “drops” of peg from time of pick-up to correct

placement in hole during each trial– (3) No. of pegs correctly placed in the holes in each trial

Klove H. Med Clin N America 1963;47:1647–58Lafayette Instrument Grooved Pegboard Test User’s Manual; Lafayette, USA


Trail Making Test B (TMT-B)

• Measures – Visual attention– Information processing– Psychomotor speed – Executive functioning

• Average completion time: 75 seconds• Results reported as time (in seconds) required to complete

the task (higher score = greater impairment)

Average Deficient Rule of Thumb75 seconds > 273 seconds Most in 3 minutes

Lezak MD. Neuropsychological Assessment. 4th ed. New York: Oxford University Press (2004)Reitan RM. Percept Mot Skills 1958;8:271–6


Digit Symbol Substitution Test (DSST)

• Tests – Visual acuity & attention– Psychomotor speed– Information processing

• Also incorporates an element of memory testing

• Score is based on number of symbols correctly coded in90 seconds

• Score usually ranges between 0–76: lower scores = greater impairment

Lezak MD. Neuropsychological Assessment. 4th ed. New York: Oxford University Press (2004)DW. WAIS-R manual 1981, New York: Psychological Corporation


Patients with neurocognitive impairment

• Neurological examination for focal signs• Referral for full neuropsychological assessment

(IHDS or MoCA as alternative to facilitate diagnosis)• Evaluation for confounding factors• Investigation for other treatable causes• Neuroimaging• CSF examination: opportunistic infection; CSF HIV

RNA level


Co-morbidities/confounding factors• Co-infections

– Hepatitis B/C, toxoplasma, CMV, cryptococcus, tuberculosis,malaria, meningitis

• Medications– Drugs with CNS effects, psychotropic medications, adverse effects of cART

• Aging• Substance use

– Alcohol, opiates• Psychiatric disorders

– Mood and anxiety disorders, depression, bipolar disorders, personality disorders, schizophrenia

• Systemic/Metabolic disorders– Anaemia, diabetes, dyslipidaemias, B12 deficiency


Targeted screening for HAND• Higher awareness and index of suspicion• Routinely asking about cognitive, behaviour or motor

symptoms from patients, significant others, or observation during consultation

• “Red flags” such as older age, low nadir CD4, previous CNS opportunistic infection, not on cART, HCV co-infection

• Use of screening tool such as MoCA to identify patients requiring comprehensive neuropsychological testing


Observed clues for HAND

• Decreased precision and clarity of history• Circumstantiality• Perseveration• Word finding difficulty, paraphrasia• Paucity of details and absence of imagery• Emotional lability• Decreased concern about limitations• Decreased drug adherence


Assessment of functional impairment

• Self-report or by informant• Cognitively related instrumental ADLs• Shopping, food preparation, laundry, housekeeping,

transport, use of telephone• Medication management, financial management,

work performance or efficiency• Increased need for assistance


www.europeanaidsclinicalsociety.org


EACS guidelines for HAND diagnosis

EACS Guidelines Nov 2012[www.europeanaidsclinicalsociety.org]

Abnormal

Screening for NCI:3 questions

Neurological examinationBrain MRI

CSF examination

HAND diagnosis(HAD, MND)

IADL questionnaire

Abnormal

NP Examination

Abnormal

Additional causes of NCI other than HIV excluded

Normal

Normal

Normal

Repeat 3questionsafter 2 yrs

All patients without highlyconfounding conditions

Clear symptoms and/orsigns of NCI and no highly

confounding conditions

3 questions1. Do you experience frequent memory loss (e.g. do you forget the occurrence of special events even the more recent ones, appointments, etc.)?2. Do you feel that you are slower when reasoning, planning activities, or solving problems?3. Do you have difficulties paying attention (e.g. to a conversation, a book, or a movie)?

Possible reasons for HAND prevalence

• Confounding conditions• Immune restoration• CNS penetration of ARV• Toxicity of ARV• “Legacy” effect• Ageing effect


Management for HAND

• Exclude and manage reversible causes• Optimisation of ART regimen:

– Achieve full viral suppression in blood and CSF– Genotypic resistance testing– CPE score of ART regimen

• Consider possibility of antiretroviral toxicity• Adjunctive therapy so far not proven effective• Medication adherence management• Cognitive rehabilitation• Support to activities of daily living


EACS treatment guidelines for HAND

Start plasma and CSFGDR-guided ART

Consider inclusion ofpotentially

CNS-active drugs

Repeat 3 questionsafter 6 months

If CSF VL > 50 c/mLConsider repeating after

3–6 months


If CSF VL > 50 c/mLConsider repeating after

3–6 months


Repeat CSF after 3–6 months


Optimise ART by plasma(CSF, if VL > 50c/mL)

GDR testingConsider inclusion ofpotentially CNS-active

drugs

Optimise ART by CSFGDR testing

Include potentiallyCNS-active drugs

Continue ongoing ARTConsider inclusion ofpotentially CNS-active

drugsReconsider other causes

of NCI

Plasma VL > 50 c/mL CSF VL > 50 c/mLPlasma VL < 50 c/mL

CSF VL < 50 c/mLPlasma VL < 50 c/mL

Off ART On ART

HAND diagnosis(HAD, MND)

EACS Guidelines Nov 2012 [www.europeanaidsclinicalsociety.org]

BHIVA recommendationson HAND8.4.2 When to start ART• We recommend patients with symptomatic HIV-associated neurocognitive

disorders start ART irrespective of CD4+ lymphocyte count (1C)

8.4.3 What to start• We recommend patients with HIV-associated NC disorders start standard

combination ART regimens (1C)

8.4.4 Modification of antiretroviral therapy• In patients with ongoing or worsening NC impairment despite ART we

recommend the following best practice management– Re-assessment for confounding conditions– Assessment of CSF HIV RNA, CSF HIV genotropism and genotyping of CSF

HIV RNA– In subjects with detectable CSF HIV RNA, modifications to antiretroviral

therapy should be based on plasma and CSF genotypic and genotropism results

BHIVA guidelines for the treatment of HIV-1 positive adults with antiretroviral therapy 2012


‘Potentially CNS-active drugs’

• ARV drugs with either demonstrated clear CSF penetration when studied in healthy HIV-infected populations (concentration above the IC90 in > 90% examined patients)

or• Proven short-term (3–6 months) efficacy on cognitive

function or CSF viral load decay when evaluated as single agents or in controlled studies in peer-reviewed papers



‘Potentially CNS-active drugs’

• Agents with demonstrated clear CSF penetration– NRTIs: ZDV, ABC– NNRTIs: EFV, NVP– Boosted PIs: IND/r, LPV/r, DRV/r– Other classes: MAR

• Drugs with proven “efficacy”– NRTIs: ZDV, d4T, ABC– Boosted PIs: LPV/r



CNS Penetration-Effectiveness (CPE)score ranking 2010

CPE Score

Drug Class 4 3 2 1NRTIs Zidovudine Abacavir

EmtricitabineDidanosineLamivudineStavudine

TenofovirZalcitabine

NNRTIs Nevirapine DelavirdineEfavirenz

Etravirine

Protease Inhibitors

Indinavir/r Darunavir/rFosamprenavir/r

IndinavirLopinavir/r

AtazanavirAtazanavir/r

Fosamprenavir

NelfinavirRitonavir

SaquinavirSaquinavir/rTipranavir/r

Entry/Fusion Inhibitors

Maraviroc Enfuvirtide

Integrase Inhibitors

Raltegravir

/r = ritonavir boosted1. Letendre S. Top Antivir Med 2011;19:137–42

2. Tozzi V, et al. J Acquir Immune Defic Syndr 2009;52:56–63


CPE score and CSF viral load control

Letendre S. Top Antivir Med 2011;19:137–42

0.0

0.1

0.2

0.3

0.4

0.5

0.6

≤3 4 5 6 7 8 ≥9Revised CPE rank

Pro

porti

on d

etec

tabl

e C

SF

vira

l loa

dP<0.0001

n=615

9%11%13%

18%

22%

39%43%


• Does use of ART regimen with high CNS penetration enhance neurocognitive performance in patients with HAND who are initiating or changing ART?

• Planning committee provided list of suitable ART regimens to primary physician based on viral susceptibility

– Rated as CNS-targeted vs. non-CNS-targeted ART based on CNSpenetration effectiveness ranking

– Patients assessed for neurocognitivefunction (measured via global deficitscore [GDS]) 16 weeks after startingregimen

In patients with HAND, no neurocognitive benefit of CNS-targeted vs. standard ART


Ellis R, et al. CROI 2013. Abstract 20. Reproduced from the CCO website

Outcome at week 16 CNS-T(n=26)

Non-CNS-T(n=23)

P value

Mean change in adjusted GDS (SD) -0.14 (0.54) -0.07 (0.43) 0.76

HIV-1 RNA <50 c/mL, %• Plasma• CFS

5468

8287

0.650.17

Screened (N=326)

Randomized (n=59)

Not eligible (n=196)Other exclusions (n=171)

Non-CNS-T arm (n=30)

Non-CNS-T arm (n=23)

Reached endpoint (n=19)

CNS-T arm (n=29)

CNS-T arm (n=26)

Reached endpoint (n=23)

Lost to follow-up

Protocol violationITT

Neurotoxicity of antiretroviral agents

• In vitro study of antiretroviral neurotoxicity using ratforebrain cultures

• Dendritic beading and dendritic tree simplification• Some toxic concentrations overlapped concentrations

currently seen in the CSF• Level of toxicity was generally modest at clinically relevant

concentrations• Highest neurotoxicities associated with abacavir, efavirenz,

etravirine, nevaripine and atazanavir; lowest with darunavir, emtricitabine, tenofovir and maraviroc

Robertson K, et al. J Neurovirol 2012;18:388–99


Low prevalence of neurocognitiveimpairment in early diagnosed and managed

HIV-infected persons• HIV+ patients categorized as earlier (<6 years of HIV, no

AIDS-defining conditions, and CD4 nadir >200) or later stage patients (n = 100 in each group); both groups diagnosed early with access to care

• 50 matched HIV-ve control• Neurocognitive impairment was diagnosed among 19%

HIV+ patients: similar prevalence among earlier and later stage patients (18% vs. 20%, p = 0.72); similar to HIV- patients

Crum-Cianflone NF, et al. Neurology 2013;80:371–9


Caveats

• Long-term implications of ANI uncertain• Natural course of different categories of HAND with

and without cART uncertain• The concept of CNS penetration by ART influencing

the efficacy in treating HAND is yet to be validated in large scale prospective RCTs


Summary

• HAND is common, important and under-recognised• High index of suspicion and routine screening can

facilitate early diagnosis• Intervention available to manage HAND• More research necessary to develop and validate

simple screening tool, determine the natural history of HAND, and optimal treatment


hiv-associated neurocognitive disorder (hand)

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