Understanding HAND

Dr Edwina Wright MD PhDThe Burnet Institute

World AIDS Conference,Melbourne July 2014

Understanding HAND

Launch of the HAND Toolkit, Alzhemier’s Victoria

HIV-1 Associated Neurocognitive Disorders: HAND

1. Updated Research Nosology for HIV-associated Neurocognitive Disorders, Antinori et al, Neurology 2007

Mild Neurocognitive Disorder (MND)Mild symptoms but still working and activeImpairment: same as ANI

HIV-Associated Dementia (HAD)Significant impairment ADLsImpairment ≥ two domains, ≥2SD below the mean formatched controls

Asymptomatic Neurocognitive Impairment (ANI)Asymptomatic Impairment ≥ 2 domains, ≥ 1SD below the mean for matched controls

HAND occurs in ≈ 20% of untreated HIV+ people with CD4+ cells < 200/mm3

Is a diagnosis of Minor Neurocognitive Disorder important?

• Associated with increased risk for:– Mortality – Job loss – Driving ability decline – Poor medication

adherence in more severe neurocognitive impairment

– Risk of HAD

www.genomicseducation.ca/. ../health/HIV.asp; (Albert et al, 1995 ; Wilkie et al 1998;Sacktor et al 1996; Mayeux et al 1993; Price et al 1999; Marcotte et al, 1999; Hinkin et al, 2002; Stern et al, 2001; Cherner et al, 2002)

HAND: Synopsis

Pathogenesis

Navia et al, Ann Neurol 1986. www.goasiapacific.com. Gonzalez-Scarano et al, Nat Rev Immunol 2005. http://www.med.harvard.edu/AANLIB/ medcine, plosjournals.org. Ferrando et al, AIDS 1998. Price et al, AIDS 1999. Cohen RA, AIDS 2001. Cysique et al, Arch Neurol 2004. Letendre et al, Annals Neurol 2004. Letendre et al, Arch Neurol 2008. Cysique et al, Neurology 2009. Cysique, Waters, Brew. BMC Neurol 2011. Bell, Anthony, Simmons. Current HIV Research, 2006 www.emedicine.com/NEURO/topic447.htm ; www.pulitzer.org/.../ works/africa1.html

TreatmentCART vs no cART or mono/dual therapy improves cognitive function

cART with 3 or more drugs with effective CSF penetration appears superior in patients with HAND.

Clinical

Diagnosis of Exclusion

Caudate, Globus pallidus, Putamen





HAND: Synopsis

Clinical


ClinicalCognitive impairmentForgetfulness, loss of concentration,

confusion and slowing of thought

Motor symptomsLoss of balance, clumsiness, change in

handwriting, tremor, unsteady gait

Behavioural changesApathy, social withdrawal, loss of interest

in hobbies, world events and their own well-being

Some patients present with mania

Navia et al, Ann Neurol 1986 . Tross et al, AIDS 1988. Mijch et al, J Neuropsychiatry Clin Neurosci 1999. Brew, Oxford Press 2001


1.Navia et al, Ann Neurol 1986. 2. www.goasiapacific.com. 3 Gonzalez-Scarano et al,Nat Rev Immunol 2005. 4. http://www.med.harvard.edu/AANLIB/ 5.medcine, plosjournals.org. 6. Ferrando et al, AIDS 1998. 7. Price et al, AIDS 1999. 8. Cohen RA, AIDS 2001. 9. Cysique et al, Arch Neurol 2004. 10. Letendre et al, Annals Neurol 2004. 11. Letendre et al, Arch Neurol 2008. 12. Cysique et al, Neurology 2009. 13. Cysique, Waters, Brew. BMC Neurol 2011. 14. Bell, Anthony, Simmons. Current HIV Research, 2006 www.emedicine.com/NEURO/topic447.htm ; www.pulitzer.org/.../ works/africa1.html



HAND: Synopsis

Pathogenesis3Clinical



Pathogenesis• Lentivirus• Early CNS infection occurs• Permissive infection microglia and

perivascular macrophages• Non-productive infection astrocytes• Histopathology: hallmark

encephalitis MNG cells• Topography: deep white matter and

basal ganglia

Peluso et al, Virology 1985. Fischer-Smith et al, Am J Pathol 2004;Wiley et al PNAS 1986;Takahashi K, Ann Neurol 1996; McCrossan, Brain 2006. Spudich et al JID, 2011; Schnell Plos Pathogens 2011; Churchill et al, Ann Neurol 2009;





HAND: Synopsis

Clinical


Pathogenesis3

• Degree of immunodeficiency, CD4 nadir, current CD4 cell count

• Older age at time of seroconversion• Diabetes: OR 5.34 (1.66-17.7, p<0.01)• Host genotype

• MCP-1-2578G RH 4.5 (1.36-16.28, p 0.0015)• CCL3L1low-CCR5det RH 3.1(1.33-7.6, p 0.009) • DARC-46 C/C : time to HAD• ApoE e4/e4: variable findings• TNF308 A allele: OR 5.5 (1.8-17.0)

• Others: injecting drug use, female gender• *HIV-1 CladesCysique, Maruff, Brew, Neurology, 2006. Bhaskaran, Annals Neurology, 2008. Valcour et al, JAIDS 2005. Gonzalez et al, PNAS 2002. Gonzalez et al, Science 2005. He et al , Cell Host Microbe 2008. Korder Nat Med 1998. Valcour et al, J Neurovirol 2004. Burt et al, PNAS 2008. Pomara et al PNAS 2008. Valcour et al, PNAS 2008. Quasney et al, Neurology 2001. Spector et al, AIDS 2010. Simioni et al AIDS 2010. Robertson et al, AIDS 2007. Heaton et al, Neurology 2010.

Clinical/Host/Viral Factors


HAND: Synopsis

Pathogenesis


cART with 3 or more drugs with effective CSF penetration appears superior in patients with HAND

Clinical



Heaton et al, Neurology 2010. Sacktor et al, Journal of Magnetic Resonance Imaging 2005

HAD is a Diagnosis of Exclusion

Exclude important confounds-Depression, medical illnesses (diabetes, myocardial infarction, hep C), head trauma, seizures, CVAsNeuropsychological testing

MRI scan, +/- MRS (not yet routinely performed)

Lumbar puncture: HIV viral load and HIV genotype

There is no single or composite biomarker/radiological marker for diagnosis of HAND

NAA: n-acetyl aspartateReflects neuronal metabolismChemical associated with myelin sheaths HAD

CholineReflects membrane turnover- microglial cellsor astrocytes HAD

MyoinositolReflects inflammation and glial cell proliferation HAD

CreatineChemical involved in energy metabolism

Heaton et al, Neurology 2011

Neuropsychological Testing low incomesettings

• Mini Mental State Exam– Insensitive to MND and HAD

• HIV Dementia scale– Limited sensitivity for mild disease (J Neurol Sci. 2007)

but reasonable sensitivity and specificity for HAD

– Takes 10-15 minutes to administer– Maximum score is 12: a patient with a score ≤

10 should be evaluated for HAD


HAD: Synopsis

Pathogenesis



Clinical



1. Cysique et al 2004. 2. Letendre et al, 2008. 3. Cysique et al, 2009.

Treatment of HAND• Treat with cART

• >50% patients improve over at least 18 months• Evidence that use of regimens with good CNS penetration is necessary

in patients with HAND

Theory: Regimens with high CNS penetration => lower CSF viral load => improved neurocognition

Metric: CNS penetration effectiveness (CPE) score

Evidence: largely observational studies

Recent meta-analysis of 16 observationalstudies designed to determine benefit of high CPE score regimens-6 met analysis criteria-6/6 => high CPE score regimens were associated with cognition or CSF viral load BUT only 2/6 studies were adequately powered

Results one recent RCT- no benefit high CPE score but study was underpowered

Practice: Currently common practice to use high CPE scoring regimens to treat patients with HANDTozzi et al, JAIDS 2001. Cysique et al, Arch Neurol 2004. Letendre et al, Ann Neurol 2004. Letendre et al, Arch

Neurol 2008. Cysique et al, Neurology 2009. Cysique, Waters, Brew, BMC Neurol 2011. Ellis et al, CID 2014

HAD: Synopsis

Pathogenesis


cART with 3 or more drugs with effective CSF penetration appears superior in patients with HAND


ClinicalCognitive impairmentPsychomotor slowingBehavioural changes

Diagnosis of ExclusionOOn

HAD is one of the leading causes of dementia in young

adults globally

It is one of the few treatable dementias


What proportion of HIV+ patients who are fully virologically suppressed may have HAND?

≈30%

AANI> MND>> HAD

HAND• Legacy effect?• Poor CNS HIV control?• Ongoing CNS parenchymal infection +/or inflammation?HAND plus or HAND x• Cardiovascular risk factors?• Neurodegeneration?• Ageing?• cART toxicity?

Mothobi and Brew, Curr Opin ID 2012

Why is HAND so prevalent in virologically suppressed populations?

• HAND occurs in approximately 20% of untreated HIV+ people with < 200 CD4+ cells/mm3

• HAND is the leading cause of dementia in young adults globally

• HAND is treatable with HIV antiretroviral agents and the majority of patients make a good recovery

• HAND may occur in individuals who are taking antiretroviral therapy and requires appropriate referral and investigation

• Other factors including aging and cardiovascular risk factors may influence the neurocognitive health of HIV+ people over time

Summary

Picture Credits• www.genomicseducation.ca/. ../health/HIV.asp• www.emedicine.com/NEURO/topic447.html• www.pulitzer.org/.../ works/africa1.html • www.goasiapacific.com• Gonzalez-Scarano et al, Nat Rev Immunol 2005.

http://www.med.harvard.edu/AANLIB/ medicine, plosjournals.org• http://www.vectors4all.net/

Thank you

Understanding HAND

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