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Understanding HAND

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

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Understanding HAND

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  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 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 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)

  4. HAND: Synopsis Pathogenesis Clinical 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

  5. HAND: Synopsis • 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 Clinical 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 • Navia et al, Ann Neurol 1986 . Tross et al, AIDS 1988. Mijch et al, J Neuropsychiatry Clin Neurosci 1999. Brew, Oxford Press 2001

  6. HAND: Synopsis 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 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 . • 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 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;

  7. HAND: Synopsis Clinical/Host/Viral Factors Pathogenesis3 Clinical • 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 • TNF308 A allele: OR 5.5 (1.8-17.0) • Others: injecting drug use, female gender • *HIV-1 Clades • 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 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. 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

  8. HAND: Synopsis 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 Pathogenesis Clinical 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 • 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 • 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 Heaton et al, Neurology 2010. Sacktor et al, Journal of Magnetic Resonance Imaging 2005 Heaton et al, Neurology 2011

  9. 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

  10. HAD: Synopsis 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 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 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 Tozzi 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

  11. HAD: Synopsis Caudate, Globus pallidus, Putamen OOn Pathogenesis Clinical Cognitive impairment Psychomotor slowing Behavioural changes HAD is one of the leading causes of dementia in young adults globally It is one of the few treatable dementias 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

  12. What proportion of HIV+ patients who are fully virologically suppressed may have HAND? ≈30% A ANI> MND>> HAD

  13. 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

  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 • 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/

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