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HIV-ASSOCIATED NEUROCOGNITIVE DISORDER (HAND)

HIV-ASSOCIATED NEUROCOGNITIVE DISORDER (HAND) . Dr. Patrick Li Queen Elizabeth Hospital Hong Kong. Background. Chiodi F, et al. Brain Pathology 1991;1:185–91 Gray F, et al. Brain Pathol 1996;6:1–15. HIV is neurotropic and invades the nervous system from the time of primary infection

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HIV-ASSOCIATED NEUROCOGNITIVE DISORDER (HAND)

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  1. HIV-ASSOCIATED NEUROCOGNITIVEDISORDER (HAND) Dr. Patrick Li Queen Elizabeth HospitalHong Kong

  2. Background Chiodi F, et al. Brain Pathology 1991;1:185–91 Gray F, et al. Brain Pathol1996;6:1–15 HIV is neurotropic and invades the nervous system from the time of primary infection HIV-associated dementia is an AIDS-defining illness Recognition of minor and asymptomatic neurocognitive impairment in HIV-infected persons Overall prevalence of HIV-associated neurocognitive disorders (HAND) has not decreased with cART HAND is associated with increased mortality and morbidity 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

  3. Typical features of HIV-associated dementia Navia BA, et al. Ann Neurol1986;19:517–24 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

  4. Spectrum of HAND Antinori A, et al. Neurology 2007;69:1789–99 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

  5. Neuropsychological impairment in the era of cART HIV infection without cognitive impairment Mild Neurocognitive Disorder Asymptomatic Neurocognitive Impairment HIV-Associated Dementia CHARTER Study (n=1,555 HIV-infected adults) 52% had NP impairment: HAD 2%, MND 12%, ANI 33% Heaton RK, et al. Neurology 2010;75:2087–96 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

  6. Prevalence of HAND in cART era 1. Wright E, et al. Neurology 2008;71:50–6; 2. SimioniS, et al. AIDS 2010;24:1243–50; 3. Lawler K, et al. J Int AIDS Soc2010;13:15; 4. Patel VN, et al. J Int J STD AIDS 2010; 21:356–8; 5. JoskaJA, et al. AIDS Behav 2010; 14:371–8; 6. PumpraditW, et al. J Neurovirol2010;16:76–82; 7. Chan LG, et al. BMJ Open 2012;2:e000662 Asia-Pacific (2008)1: 12% (0-23% in 10 sites; 63% on cART) Switzerland (2010)2: 69% (aviremic for median of 48 months) Botswana (2010)3: 38% (98% on cART) Malawi (2010)4: 14% (75% on cART) South Africa (2010)5: 23.5% (48% on cART) Thailand (2010)6: 37.5% (2NN Cohort) Singapore (2012)7: 22.7% (91% on cART) 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

  7. Prevalence of HAND and CDC stage Grant I, et al. Ann Intern Med 1987;107:828–36 Heaton RK, et al. J IntNeuropsycholSoc 1995;1:231–51 Heaton RK, et al. Neurology 2010;75:2087–96 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

  8. Risk of HAND is increasedwith lower CD4 nadir 0.7 2 0.6 1.5 0.5 1 All subjects Probability of impairment Odds of impairment 0.75 0.4 HAND eligible 0.5 0.3 0.2 0 200 400 600 800 1000 CD4 nadir (cells/µL) Ellis RJ, et al. AIDS 2011;25:1747–51 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

  9. Impact/consequences of HAND 1. Sevigny JJ, et al. Arch Neurol 2007;64:97–102; 2. Vivithanaporn P, et al. Neurology 2010;75:1150–8; 3. Heaton RK, et al. J IntNeuropsycholSoc 2004;10:317–31; 4. Heaton RK, et al. Psychosom Med 1994;56:8–17; 5. Woods SP, et al. Arch ClinNeuropsychol 2008;23:257–70; 6. Hinkin CH, et al. Neurology 2002;59:1944–50; 7. Marcotte TD, et al. J ClinExpNeuropsychol 2006;28:13–28 Poorer survival1,2 Diminished self-care ability and quality of life3 Deterioration in work performance, higher unemployment rate4 Suboptimal drug adherence5,6 Impaired driving, increased accident risk7 Significant personal, economic and societal burden 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

  10. HAND predicts an increasedrisk of death Without HAND (n=1549) 100 90 80 Survival (%) HAND (n=102) 70 60 0 5 10 15 20 Years since HIV diagnosis Vivithanaporn P, et al. Neurology 2010;75:1150–8 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

  11. Problem with recognition of HAND Vast majority of patients with HAND have mild or no symptoms Patients may not volunteer symptoms from lack of awareness or insight ID physicians caring for HIV/AIDS patients may not have relevant training for diagnosis and management of HAND Practical difficulties with routine screening for HAND in busy clinic settings Limited access to formal neuropsychological testing 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

  12. Screening instruments for HAND Mini-Mental State Examination HIV Dementia Scale International HIV Dementia Scale Montreal Cognitive Assessment (MoCA) Medical Outcomes Study HIV Health Survey (MOS-HIV) Other screening protocols 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

  13. HAND screening instruments Valcour V, et al. Clin Infect Dis 2011;53:836–42 Overton ET, et al. J Neurovirol2013:19:109–16

  14. Grooved Pegboard (GP) Klove H. Med Clin N America 1963;47:1647–58 Lafayette Instrument Grooved Pegboard Test User’s Manual; Lafayette, USA • Requires minimal operator training • Measures • Manipulative dexterity • Visual-motor coordination • Performance and speed in fine motor tasks • Administered to dominant and non-dominant hands • Trial time allowed: 5 minutes • Several scores may be recorded: • (1) Time (in seconds) to perform each trial from start to end • (2) No. of unintentional “drops” of peg from time of pick-up to correct placement in hole during each trial • (3) No. of pegs correctly placed in the holes in each trial 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

  15. Trail Making Test B (TMT-B) Lezak MD. Neuropsychological Assessment. 4th ed. New York: Oxford University Press (2004) Reitan RM. Percept Mot Skills 1958;8:271–6 • Measures • Visual attention • Information processing • Psychomotor speed • Executive functioning • Average completion time: 75 seconds • Results reported as time (in seconds) required to complete the task (higher score = greater impairment) 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

  16. Digit Symbol Substitution Test (DSST) Lezak MD. Neuropsychological Assessment. 4th ed. New York: Oxford University Press (2004) DW. WAIS-R manual 1981, New York: Psychological Corporation • Tests • Visual acuity & attention • Psychomotor speed • Information processing • Also incorporates an element of memory testing • Score is based on number of symbols correctly coded in90 seconds • Score usually ranges between 0–76: lower scores = greater impairment 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

  17. Patients with neurocognitive impairment Neurological examination for focal signs Referral for full neuropsychological assessment (IHDS or MoCA as alternative to facilitate diagnosis) Evaluation for confounding factors Investigation for other treatable causes Neuroimaging CSF examination: opportunistic infection; CSF HIV RNA level 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

  18. Co-morbidities/confounding factors • Co-infections • Hepatitis B/C, toxoplasma, CMV, cryptococcus, tuberculosis,malaria, meningitis • Medications • Drugs with CNS effects, psychotropic medications, adverse effects of cART • Aging • Substance use • Alcohol, opiates • Psychiatric disorders • Mood and anxiety disorders, depression, bipolar disorders, personality disorders, schizophrenia • Systemic/Metabolic disorders • Anaemia, diabetes, dyslipidaemias, B12 deficiency 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

  19. Targeted screening for HAND Higher awareness and index of suspicion Routinely asking about cognitive, behaviour or motor symptoms from patients, significant others, or observation during consultation “Red flags” such as older age, low nadir CD4, previous CNS opportunistic infection, not on cART, HCV co-infection Use of screening tool such as MoCA to identify patients requiring comprehensive neuropsychological testing 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

  20. Observed clues for HAND Decreased precision and clarity of history Circumstantiality Perseveration Word finding difficulty, paraphrasia Paucity of details and absence of imagery Emotional lability Decreased concern about limitations Decreased drug adherence 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

  21. Assessment of functional impairment Self-report or by informant Cognitively related instrumental ADLs Shopping, food preparation, laundry, housekeeping, transport, use of telephone Medication management, financial management, work performance or efficiency Increased need for assistance 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

  22. www.europeanaidsclinicalsociety.org 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

  23. EACS guidelines for HAND diagnosis All patients without highly confounding conditions Screening for NCI: 3 questions Normal Abnormal Repeat 3questions after 2 yrs IADL questionnaire Normal Abnormal Clear symptoms and/or signs of NCI and no highly confounding conditions NP Examination Normal Abnormal Neurological examination Brain MRI CSF examination 3 questions 1. Do you experience frequent memory loss (e.g. do you forget the occurrence of special events even the more recent ones, appointments, etc.)? 2. Do you feel that you are slower when reasoning, planning activities, or solving problems? 3. Do you have difficulties paying attention (e.g. to a conversation, a book, or a movie)? Additional causes of NCI other than HIV excluded HAND diagnosis (HAD, MND) EACS Guidelines Nov 2012[www.europeanaidsclinicalsociety.org]

  24. Possible reasons for HAND prevalence Confounding conditions Immune restoration CNS penetration of ARV Toxicity of ARV “Legacy” effect Ageing effect 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

  25. Management for HAND • Exclude and manage reversible causes • Optimisation of ART regimen: • Achieve full viral suppression in blood and CSF • Genotypic resistance testing • CPE score of ART regimen • Consider possibility of antiretroviral toxicity • Adjunctive therapy so far not proven effective • Medication adherence management • Cognitive rehabilitation • Support to activities of daily living 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

  26. EACS treatment guidelines for HAND HAND diagnosis (HAD, MND) EACS Guidelines Nov 2012 [www.europeanaidsclinicalsociety.org] Off ART On ART Plasma VL > 50 c/mL CSF VL > 50 c/mL Plasma VL < 50 c/mL CSF VL < 50 c/mL Plasma VL < 50 c/mL Start plasma and CSF GDR-guided ART Consider inclusion of potentially CNS-active drugs Optimise ART by plasma (CSF, if VL > 50c/mL) GDR testing Consider inclusion of potentially CNS-active drugs Optimise ART by CSF GDR testing Include potentially CNS-active drugs Continue ongoing ART Consider inclusion of potentially CNS-active drugs Reconsider other causes of NCI Repeat 3 questions after 6 months If CSF VL > 50 c/mL Consider repeating after 3–6 months Repeat 3 questions after 6 months If CSF VL > 50 c/mL Consider repeating after 3–6 months Repeat 3 questions after 6 months Repeat CSF after 3–6 months Repeat 3 questions after 6 months

  27. BHIVA recommendationson HAND BHIVA guidelines for the treatment of HIV-1 positive adults with antiretroviral therapy 2012 8.4.2 When to start ART • We recommend patients with symptomatic HIV-associated neurocognitive disorders start ART irrespective of CD4+ lymphocyte count (1C) 8.4.3 What to start • We recommend patients with HIV-associated NC disorders start standard combination ART regimens (1C) 8.4.4 Modification of antiretroviral therapy • In patients with ongoing or worsening NC impairment despite ART we recommend the following best practice management • Re-assessment for confounding conditions • Assessment of CSF HIV RNA, CSF HIV genotropism and genotyping of CSF HIV RNA • In subjects with detectable CSF HIV RNA, modifications to antiretroviral therapy should be based on plasma and CSF genotypic and genotropism results 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

  28. ‘Potentially CNS-active drugs’ EACS Guidelines Nov 2012[www.europeanaidsclinicalsociety.org] ARV drugs with either demonstrated clear CSF penetration when studied in healthy HIV-infected populations (concentration above the IC90 in > 90% examined patients) or Proven short-term (3–6 months) efficacy on cognitive function or CSF viral load decay when evaluated as single agents or in controlled studies in peer-reviewed papers 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

  29. ‘Potentially CNS-active drugs’ EACS Guidelines Nov 2012[www.europeanaidsclinicalsociety.org] • Agents with demonstrated clear CSF penetration • NRTIs: ZDV, ABC • NNRTIs: EFV, NVP • Boosted PIs: IND/r, LPV/r, DRV/r • Other classes: MAR • Drugs with proven “efficacy” • NRTIs: ZDV, d4T, ABC • Boosted PIs: LPV/r 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

  30. CNS Penetration-Effectiveness (CPE)score ranking 2010 1. Letendre S. Top Antivir Med 2011;19:137–42 2. Tozzi V, et al. J Acquir Immune DeficSyndr 2009;52:56–63 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

  31. CPE score and CSF viral load control 0.6 43% P<0.0001 n=615 39% 0.5 0.4 Proportion detectable CSF viral load 0.3 22% 18% 0.2 13% 11% 9% 0.1 0.0 ≤3 4 5 6 7 8 ≥9 Revised CPE rank Letendre S. Top Antivir Med 2011;19:137–42 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

  32. In patients with HAND, no neurocognitive benefit of CNS-targeted vs. standard ART Screened (N=326) Not eligible (n=196) Other exclusions (n=171) Randomized (n=59) CNS-T arm (n=29) Non-CNS-T arm (n=30) Lost to follow-up ITT CNS-T arm (n=26) Non-CNS-T arm (n=23) Protocol violation Reached endpoint (n=23) Reached endpoint (n=19) Ellis R, et al. CROI 2013. Abstract 20. Reproduced from the CCO website 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013 • Does use of ART regimen with high CNS penetration enhance neurocognitive performance in patients with HAND who are initiating or changing ART? • Planning committee provided list of suitable ART regimens to primary physician based on viral susceptibility • Rated as CNS-targeted vs. non-CNS-targeted ART based on CNSpenetration effectiveness ranking • Patients assessed for neurocognitivefunction (measured via global deficitscore [GDS]) 16 weeks after startingregimen

  33. 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

  34. Neurotoxicity of antiretroviral agents Robertson K, et al. J Neurovirol2012;18:388–99 In vitro study of antiretroviral neurotoxicity using ratforebrain cultures Dendritic beading and dendritic tree simplification Some toxic concentrations overlapped concentrations currently seen in the CSF Level of toxicity was generally modest at clinically relevant concentrations Highest neurotoxicities associated with abacavir, efavirenz, etravirine, nevaripine and atazanavir; lowest with darunavir, emtricitabine, tenofovir and maraviroc 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

  35. Low prevalence of neurocognitiveimpairment in early diagnosed and managed HIV-infected persons Crum-CianfloneNF, et al. Neurology 2013;80:371–9 HIV+ patients categorized as earlier (<6 years of HIV, no AIDS-defining conditions, and CD4 nadir >200) or later stage patients (n = 100 in each group); both groups diagnosed early with access to care 50 matched HIV-ve control Neurocognitive impairment was diagnosed among 19% HIV+ patients: similar prevalence among earlier and later stage patients (18% vs. 20%, p = 0.72); similar to HIV- patients 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

  36. Caveats Long-term implications of ANI uncertain Natural course of different categories of HAND with and without cART uncertain The concept of CNS penetration by ART influencing the efficacy in treating HAND is yet to be validated in large scale prospective RCTs 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

  37. Summary HAND is common, important and under-recognised High index of suspicion and routine screening can facilitate early diagnosis Intervention available to manage HAND More research necessary to develop and validate simple screening tool, determine the natural history of HAND, and optimal treatment 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

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