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

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Presentation on theme: "Dr Edwina Wright MD PhD The Burnet Institute World AIDS Conference, Melbourne July 2014 Understanding HAND Launch of the HAND Toolkit, Alzhemier’s Victoria."— Presentation transcript:

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

2 HIV-1 Associated Neurocognitive Disorders: HAND 1. 1.Updated Research Nosology for HIV-associated Neurocognitive Disorders, Antinori et al, Neurology 2007 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 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/mm 3

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 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 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. Clinical Diagnosis of Exclusion Caudate, Globus pallidus, Putamen

5 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 Caudate, Globus pallidus, Putamen 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. HAND: Synopsis Clinical Diagnosis of Exclusion 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 Navia et al, Ann Neurol 1986. Tross et al, AIDS 1988. Mijch et al, J Neuropsychiatry Clin Neurosci 1999. Brew, Oxford Press 2001

6 Caudate, Globus pallidus, Putamen 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 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. HAND: Synopsis Pathogenesis 3 Clinical Diagnosis of Exclusion 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 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 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 Caudate, Globus pallidus, Putamen 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. HAND: Synopsis Clinical Diagnosis of Exclusion Pathogenesis 3 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) CCL3L1 low -CCR5 det 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. Clinical/Host/Viral Factors

8 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 Pathogenesis 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 Clinical Diagnosis of Exclusion Caudate, Globus pallidus, Putamen 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, 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 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 10-15 minutes to administer –Maximum score is 12: a patient with a score ≤ 10 should be evaluated for HAD

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

13 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?

14 HAND occurs in approximately 20% of untreated HIV+ people with < 200 CD4+ cells/mm 3 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

15 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


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