1. Launch of the HAND Toolkit, Alzhemier’s Victoria
Understanding HAND
Dr Edwina Wright MD PhD
The Burnet Institute
World AIDS Conference,
Melbourne July 2014

2. HIV-1 Associated Neurocognitive Disorders: HAND
Asymptomatic Neurocognitive Impairment (ANI)
Asymptomatic
Impairment ≥ 2 domains, ≥ 1SD below the mean for matched controls
Mild Neurocognitive Disorder (MND)
Mild symptoms but still working and active
Impairment: same as ANI
HIV-Associated Dementia (HAD)
Significant impairment ADLs
Impairment ≥ two domains, ≥2SD below the mean for
matched controls
CONFOUNDS AND HAND CAN CO-EXIST
HAND occurs in ≈ 20% of untreated HIV+ people with CD4+ cells < 200/mm3
Updated Research Nosology for HIV-associated Neurocognitive Disorders, Antinori et al, Neurology 2007

3. 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
IRONY OF INCREASED COMPLEXITY OF MEDICATION REGIMENS e.g. medications for hypertension, high lipids, vitamin D etc
../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)

4. HAND: Synopsis Pathogenesis Clinical Diagnosis of Exclusion Treatment
Caudate, Globus pallidus, Putamen
Pathogenesis
Clinical
Diagnosis of Exclusion
Navia et al, Ann Neurol Gonzalez-Scarano et al, Nat Rev Immunol medcine, plosjournals.org. Ferrando et al, AIDS Price et al, AIDS Cohen RA, AIDS Cysique et al, Arch Neurol Letendre et al, Annals Neurol Letendre et al, Arch Neurol Cysique et al, Neurology Cysique, Waters, Brew. BMC Neurol Bell, Anthony, Simmons. Current HIV Research, ; works/africa1.html
Treatment
CART 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 .
Quinolinic acid, TNF, nitric oxide, neopterin, gp120, Tat, nef, glutamate
Cytokines, viral toxin mediated damage
Neurons damaged and astrocytes unable to mitigate damage
Examine impaired patients in each group (16 vs 21 patients) the neuroHAART group performed significantly better verbal memory performance, independent plasma VL (Cysique L, Arch Neurol 2004)
PUT IN SCOTT LETENDRES article

5. HAND: Synopsis Clinical Cognitive impairment Motor symptoms
Caudate, Globus pallidus, Putamen
Clinical
Clinical
Cognitive impairment
Forgetfulness, loss of concentration, confusion and slowing of thought
Motor symptoms
Loss of balance, clumsiness, change in handwriting, tremor, unsteady gait
Behavioural changes
Apathy, social withdrawal, loss of interest in hobbies, world events and their own well-being
Some patients present with mania
Diagnosis of Exclusion
Treatment
CART 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 .
Quinolinic acid, TNF, nitric oxide, neopterin, gp120, Tat, nef, glutamate
Cytokines, viral toxin mediated damage
Neurons damaged and astrocytes unable to mitigate damage
Examine impaired patients in each group (16 vs 21 patients) the neuroHAART group performed significantly better verbal memory performance, independent plasma VL (Cysique L, Arch Neurol 2004)
PUT IN SCOTT LETENDRES article
Navia et al, Ann Neurol Gonzalez-Scarano et al, Nat Rev Immunol medcine, plosjournals.org. Ferrando et al, AIDS Price et al, AIDS Cohen RA, AIDS Cysique et al, Arch Neurol Letendre et al, Annals Neurol Letendre et al, Arch Neurol Cysique et al, Neurology Cysique, Waters, Brew. BMC Neurol Bell, Anthony, Simmons. Current HIV Research, ; works/africa1.html
Navia et al, Ann Neurol Tross et al, AIDS Mijch et al, J Neuropsychiatry Clin Neurosci Brew, Oxford Press 2001

6. HAND: Synopsis Pathogenesis Lentivirus Early CNS infection occurs
Caudate, Globus pallidus, Putamen
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
Pathogenesis3
Clinical
Diagnosis of Exclusion
1.Navia et al, Ann Neurol Gonzalez-Scarano et al,Nat Rev Immunol medcine, plosjournals.org. 6. Ferrando et al, AIDS Price et al, AIDS Cohen RA, AIDS Cysique et al, Arch Neurol Letendre et al, Annals Neurol Letendre et al, Arch Neurol Cysique et al, Neurology Cysique, Waters, Brew. BMC Neurol Bell, Anthony, Simmons. Current HIV Research, ; works/africa1.html
Treatment
CART 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 .
Quinolinic acid, TNF, nitric oxide, neopterin, gp120, Tat, nef, glutamate
Cytokines, viral toxin mediated damage
Neurons damaged and astrocytes unable to mitigate damage
Examine impaired patients in each group (16 vs 21 patients) the neuroHAART group performed significantly better verbal memory performance, independent plasma VL (Cysique L, Arch Neurol 2004)
PUT IN SCOTT LETENDRES article
Degree of immunodeficiency, CD4 nadir, current CD4 cell count1
Older age at time of seroconversion1
Diabetes: OR 5.34 ( , p<0.01)2
Host genotype
MCP G RH 4.5 ( , p )3
CCL3L1low-CCR5det RH 3.1( , p 0.009) 4
DARC-46 C/C 5:  time to HAD
ApoE e4/e4: 6,7,8,9,10, 12 variable findings
TNF308 A allele: OR 5.5 ( )11
Others- injecting drug use, female gender13
Caudate, Globus pallidus, Putamen
Peluso et al, Virology Fischer-Smith et al, Am J Pathol 2004;Wiley et al PNAS 1986;Takahashi K, Ann Neurol 1996; McCrossan, Brain Spudich et al JID, 2011; Schnell Plos Pathogens 2011; Churchill et al, Ann Neurol 2009;

7. HAND: Synopsis Clinical/Host/Viral Factors
Caudate, Globus pallidus, Putamen
Pathogenesis3
Degree of immunodeficiency, CD4 nadir, current CD4 cell count
Older age at time of seroconversion
Diabetes: OR 5.34 ( , p<0.01)
Host genotype
MCP G RH 4.5 ( , p )
CCL3L1low-CCR5det RH 3.1( , p 0.009)
DARC-46 C/C :  time to HAD
ApoE e4/e4: variable findings
TNF308 A allele: OR 5.5 ( )
Others: injecting drug use, female gender
*HIV-1 Clades
Cysique, Maruff, Brew, Neurology, Bhaskaran, Annals Neurology, Valcour et al, JAIDS Gonzalez et al, PNAS Gonzalez et al, Science He et al , Cell Host Microbe Korder Nat Med Valcour et al, J Neurovirol Burt et al, PNAS Pomara et al PNAS Valcour et al, PNAS Quasney et al, Neurology Spector et al, AIDS Simioni et al AIDS Robertson et al, AIDS Heaton et al, Neurology 2010.
Clinical/Host/Viral Factors
Clinical
Diagnosis of Exclusion
Treatment
CART 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 .
Quinolinic acid, TNF, nitric oxide, neopterin, gp120, Tat, nef, glutamate
Cytokines, viral toxin mediated damage
Neurons damaged and astrocytes unable to mitigate damage
Examine impaired patients in each group (16 vs 21 patients) the neuroHAART group performed significantly better verbal memory performance, independent plasma VL (Cysique L, Arch Neurol 2004)
PUT IN SCOTT LETENDRES article
Navia et al, Ann Neurol Gonzalez-Scarano et al, Nat Rev Immunol medcine, plosjournals.org. Ferrando et al, AIDS Price et al, AIDS Cohen RA, AIDS Cysique et al, Arch Neurol Letendre et al, Annals Neurol Letendre et al, Arch Neurol Cysique et al, Neurology Cysique, Waters, Brew. BMC Neurol Bell, Anthony, Simmons. Current HIV Research, ; works/africa1.html

8. HAND: Synopsis HAD is a Diagnosis of Exclusion
Caudate, Globus pallidus, Putamen
HAD is a Diagnosis of Exclusion
Exclude important confounds
-Depression, medical illnesses (diabetes, myocardial infarction, hep C), head trauma, seizures, CVAs
Neuropsychological 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 aspartate
Reflects neuronal metabolism
Chemical associated with myelin sheaths
 HAD
Choline
Reflects membrane turnover- microglial cells
or astrocytes
HAD
Myoinositol
Reflects inflammation and glial cell proliferation
 HAD
Creatine
Chemical involved in energy metabolism
Pathogenesis
Clinical
Diagnosis of Exclusion
Treatment
CART 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
Quinolinic acid, TNF, nitric oxide, neopterin, gp120, Tat, nef, glutamate
Cytokines, viral toxin mediated damage
Neurons damaged and astrocytes unable to mitigate damage
Examine impaired patients in each group (16 vs 21 patients) the neuroHAART group performed significantly better verbal memory performance, independent plasma VL (Cysique L, Arch Neurol 2004)
PUT IN SCOTT LETENDRES article
Navia et al, Ann Neurol Gonzalez-Scarano et al, Nat Rev Immunol medcine, plosjournals.org. Ferrando et al, AIDS Price et al, AIDS Cohen RA, AIDS Cysique et al, Arch Neurol Letendre et al, Annals Neurol Letendre et al, Arch Neurol Cysique et al, Neurology Cysique, Waters, Brew. BMC Neurol Bell, Anthony, Simmons. Current HIV Research, ; works/africa1.html
Heaton et al, Neurology Sacktor et al, Journal of Magnetic Resonance Imaging 2005
Heaton et al, Neurology 2011

9. Neuropsychological Testing low income settings
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 minutes to administer
Maximum score is 12: a patient with a score ≤ 10 should be evaluated for HAD

10. HAD: Synopsis
Caudate, Globus pallidus, Putamen
1. Cysique et al Letendre et al, 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 observational
studies 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 HAND
Pathogenesis
Clinical
Diagnosis of Exclusion
Treatment
CART 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 .
Quinolinic acid, TNF, nitric oxide, neopterin, gp120, Tat, nef, glutamate
Cytokines, viral toxin mediated damage
Neurons damaged and astrocytes unable to mitigate damage
Examine impaired patients in each group (16 vs 21 patients) the neuroHAART group performed significantly better verbal memory performance, independent plasma VL (Cysique L, Arch Neurol 2004)
PUT IN SCOTT LETENDRES article
Navia et al, Ann Neurol Gonzalez-Scarano et al, Nat Rev Immunol medcine, plosjournals.org. Ferrando et al, AIDS Price et al, AIDS Cohen RA, AIDS Cysique et al, Arch Neurol Letendre et al, Annals Neurol Letendre et al, Arch Neurol Cysique et al, Neurology Cysique, Waters, Brew. BMC Neurol Bell, Anthony, Simmons. Current HIV Research, ; works/africa1.html
Tozzi et al, JAIDS Cysique et al, Arch Neurol Letendre et al, Ann Neurol Letendre et al, Arch Neurol Cysique et al, Neurology Cysique, Waters, Brew, BMC Neurol Ellis et al, CID 2014

11. HAD: Synopsis
Caudate, Globus pallidus, Putamen
OOn
HAD is one of the leading causes of dementia in young adults globally
It is one of the few treatable dementias
Pathogenesis
Clinical
Cognitive impairment
Psychomotor slowing
Behavioural changes
Diagnosis of Exclusion
Treatment
CART 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
Quinolinic acid, TNF, nitric oxide, neopterin, gp120, Tat, nef, glutamate
Cytokines, viral toxin mediated damage
Neurons damaged and astrocytes unable to mitigate damage
Examine impaired patients in each group (16 vs 21 patients) the neuroHAART group performed significantly better verbal memory performance, independent plasma VL (Cysique L, Arch Neurol 2004)
PUT IN SCOTT LETENDRES article
Navia et al, Ann Neurol Gonzalez-Scarano et al, Nat Rev Immunol medcine, plosjournals.org. Ferrando et al, AIDS Price et al, AIDS Cohen RA, AIDS Cysique et al, Arch Neurol Letendre et al, Annals Neurol Letendre et al, Arch Neurol Cysique et al, Neurology Cysique, Waters, Brew. BMC Neurol Bell, Anthony, Simmons. Current HIV Research, ; works/africa1.html

12. ≈30% ANI> MND>> HAD
What proportion of HIV+ patients who are fully virologically suppressed may have HAND?
≈30% A
ANI> MND>> HAD
PUT A RED HIV RIBBON ON THIS PERSONS T SHIRT?

13. Why is HAND so prevalent in virologically suppressed populations?
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

14. Summary
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

15. Thank you Picture Credits www.genomicseducation.ca/. ../health/HIV.asp
works/africa1.html
Gonzalez-Scarano et al, Nat Rev Immunol medicine, plosjournals.org