Launch of the HAND Toolkit, Alzhemier’s Victoria
Understanding HAND
Dr Edwina Wright MD PhD
The Burnet Institute
World AIDS Conference,
Melbourne July 2014
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
HAND occurs in ≈ 20% of untreated HIV+ people with CD4+
cells < 200/mm3
1.
Updated Research Nosology for HIV-associated Neurocognitive Disorders, Antinori et al, Neurology 2007
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
Clinical
Pathogenesis
Caudate, Globus pallidus, Putamen
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
.
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
HAND: Synopsis
Clinical
Cognitive impairment
Forgetfulness, loss of concentration,
confusion and slowing
ofGlobus
thought
Caudate,
pallidus, Putamen
Clinical
Diagnosis of
Motor symptoms
Loss of Exclusion
balance, clumsiness, change in
handwriting, tremor, unsteady gait
Behavioural changes
Treatment
Apathy, social withdrawal, loss of
CART vs no cART or mono/dual
interest
in hobbies, world events and
therapy improves cognitive
function
their own well-being
cART with 3 or more drugs with
Some patients
effective CSF penetration
appears
superior in patients with HAND
.
present with mania
Navia et al, Ann Neurol 1986. www.goasiapacific.com.
al, Nat Rev
Immunol
http://www.med.harvard.edu/AANLIB/
medcine,
Navia et al, AnnGonzalez-Scarano
Neurol 1986 .etTross
et al,
AIDS2005.
1988.
Mijch et al, J Neuropsychiatry
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.
Neurosci
1999.2009.
Brew,
Oxford
Press
Letendre et al, Arch Neurol 2008.Clin
Cysique
et al, Neurology
Cysique,
Waters,
Brew.2001
BMC Neurol 2011. Bell, Anthony, Simmons. Current HIV Research, 2006
www.emedicine.com/NEURO/topic447.htm ; www.pulitzer.org/.../ works/africa1.html
HAND: Synopsis
Pathogenesis
• Lentivirus
3
Pathogenesis
Clinical
Caudate, Globus pallidus, Putamen
• Early CNS infection occurs
• PermissiveDiagnosis
infectionofmicroglia and
Exclusion
perivascular macrophages
• Non-productive infection astrocytes
Treatment • Histopathology: hallmark
CART vs no cART or mono/dual
encephalitis MNG cells
Caudate, Globus pallidus, Putamen
therapy improves cognitive function
• Topography: deep white matter and
cART with 3 or more
drugs
with
basal
ganglia
effective CSF penetration appears
superior in patients with HAND
.
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
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,
2004.
11.
Letendre
et Pathogens
al, Arch Neurol
12.etCysique
et al, 2009;
Neurology 2009. 13. Cysique, Waters, Brew. BMC Neurol 2011. 14. Bell, Anthony, Simmons. Current HIV
2011; Schnell Plos
2011; 2008.
Churchill
al, Ann Neurol
Research, 2006 www.emedicine.com/NEURO/topic447.htm ; www.pulitzer.org/.../ works/africa1.html
HAND: Synopsis
Clinical/Host/Viral
Factors
Clinical
Pathogenesis3
Caudate, Globus pallidus, Putamen
• Degree of immunodeficiency, CD4 nadir,
current CD4
Diagnosis of
cell count
Exclusion
• Older age at time of seroconversion
• Diabetes: OR 5.34 (1.66-17.7, p<0.01)
• Host genotype
•
•
•
•
•
Treatment RH 4.5 (1.36-16.28, p 0.0015)
MCP-1-2578G
CART low
vs-CCR5
no cART
or 3.1(1.33-7.6,
mono/dual p 0.009)
det RH
CCL3L1
therapy improves
cognitive
DARC-46
C/C :  time
to HADfunction
ApoE e4/e4: variable findings
cART with
or more
with
TNF308
A 3allele:
OR drugs
5.5 (1.8-17.0)
effective CSF penetration appears
• Others:
injecting drug use, female gender
superior in patients with HAND
• *HIV-1
Clades
.
Navia et al, Ann Neurol 1986. www.goasiapacific.com. Gonzalez-Scarano et al, Nat Rev Immunol 2005. http://www.med.harvard.edu/AANLIB/ medcine,
Cysique, 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
plosjournals.org. Ferrando
al, AIDS
1998.
et al,
AIDS
1999.
Cohen
RA, AIDS
2001.
et Pomara
al, ArchetNeurol
2004.Valcour
Letendre
al, 2008.
Annals
Neurol
2004.
HostetMicrobe
2008.
KorderPrice
Nat Med
1998.
Valcour
et al,
J Neurovirol
2004. Burt
et al,Cysique
PNAS 2008.
al PNAS 2008.
et al,et
PNAS
Quasney
et al,
Neurology
Letendre et al, Arch Neurol
2008.
Cysique
et2010.
al, Neurology
Cysique,
Waters,
Brew.
BMC
Neurol
2011. Bell,
Anthony, Simmons. Current HIV Research, 2006
2001.
Spector
et al, AIDS
Simioni et al2009.
AIDS 2010.
Robertson
et al, AIDS
2007.
Heaton
et al, Neurology
2010.
www.emedicine.com/NEURO/topic447.htm ; www.pulitzer.org/.../ works/africa1.html
HAND: Synopsis
HAD is a Diagnosis of Exclusion
Exclude important confounds
Pathogenesis
-Depression, medical illnesses
Clinical
(diabetes, myocardial infarction,
hep C), head trauma, seizures,
CVAs
Neuropsychological testing
Caudate, Globus pallidus, Putamen
Diagnosis of
Exclusion
MRI scan, +/- MRSTreatment
(not yet
CART vs no cART or mono/dual
routinely performed)
therapy improves cognitive function
Lumbar puncture: HIV viral load
and HIV genotype cART with 3 or more drugs with
effective CSF penetration appears
superior
in patients with HAND
There is no single or
composite
biomarker/radiological marker
Navia et al, Ann Neurol 1986. www.goasiapacific.com. Gonzalez-Scarano et al, Nat Rev Immunol 2005. http://www.med.harvard.edu/AANLIB/ medcine,
for diagnosis
HAND
plosjournals.org.
Ferrando et al,of
AIDS
1998. Price et al, AIDS 1999. Cohen RA, AIDS 2001. Cysique et al, Arch Neurol 2004. Letendre et al, Annals Neurol 2004.
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
Letendre etet
al, al,
ArchNeurology
Neurol 2008. Cysique
al, Neurology
2009.
Cysique,of
Waters,
Brew. BMC
Neurol 2011.Imaging
Simmons. Current HIV Research, 2006
Heaton
2010.etSacktor
et al,
Journal
Magnetic
Resonance
2005
HeatonBell,
etAnthony,
al, Neurology
2011
www.emedicine.com/NEURO/topic447.htm ; www.pulitzer.org/.../ works/africa1.html
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 10-15 minutes to administer
– Maximum score is 12: a patient with a score ≤
10 should be evaluated for HAD
HAD: Synopsis
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
Clinical
Theory: Pathogenesis
Regimens with high CNS penetration => lower CSF viral load =>
Caudate, Globus pallidus, Putamen
improved neurocognition
4
of
Metric: CNS penetration effectivenessDiagnosis
(CPE)
Zidovudine
score
Nevirapine
Exclusion
Evidence: largely observational studies
Indinavir-r
3
2
Abacavir
Emtricitabine
Lamivudine
Stavudine
Didanosine
Etravirine
Didanosine
Tenofovir
Zalcitabine
Atazanavir
Atazanavir-r
Nelfinavir
Ritonavir
Saquinavir
Saquinavir-r
Tipranavir-r
Enfuvirtide
Delavirdine
Efavirenz
Darunavir-r
Indinavir
Lopinavir-r
Fosamprenavir-r
1. Cysique et al 2004. 2. Letendre et al, 2008. 3. Cysique et al, 2009.
1
Recent meta-analysis of 16 observational
Raltegravir
Maraviroc
Treatment
studies designed to determine benefit
vs score
no cART
or mono/dual
ofCART
high CPE
regimens
-6therapy
met analysis
criteria cognitive function
improves
-6/6 => high CPE score regimens were associated with cognition or  CSF viral
load BUT only 2/6 studies were adequately powered
cART with 3 or more drugs with
effective
appears
Results
one CSF
recentpenetration
RCT- no benefit
high CPE score but study was underpowered
superior in patients with HAND
Practice:
Currently common practice to use high CPE scoring regimens to treat
.
patients with HAND
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.
Tozzi et
etal,
al,Neurology
JAIDS 2001.
al, Arch
Neurol
2004.2011.
Letendre
et al, Ann
NeurolCurrent
2004.HIV
Letendre
et 2006
al, Arch
Letendre et al, Arch Neurol 2008. Cysique
2009.Cysique
Cysique,et
Waters,
Brew.
BMC Neurol
Bell, Anthony,
Simmons.
Research,
www.emedicine.com/NEURO/topic447.htmNeurol
; www.pulitzer.org/.../
works/africa1.html
2008. Cysique
et al, Neurology
2009. Cysique, Waters, Brew, BMC Neurol 2011. Ellis et al, CID 2014
HAD: Synopsis
Clinical
Cognitive impairment
Psychomotor slowing
Behavioural changes
Caudate, Globus pallidus, Putamen
HAD is one of the leading
causes of dementia in young
Diagnosis of
adultsOOn
globally
Exclusion
Pathogenesis
It is one of the few treatable
Treatment
CART vs no cART ordementias
mono/dual
therapy improves cognitive function
cART with 3 or more drugs with
effective CSF penetration appears
superior in patients with HAND
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
What proportion of HIV+ patients who are fully
virologically suppressed may have HAND?
≈30%
ANI> MND>>
HAD
A
Why is HAND so prevalent in virologically suppressed
populations?
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
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
Thank you
Picture Credits
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•
•
•
•
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/