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HIV-ASSOCIATED NEUROCOGNITIVE DISORDER (HAND) Dr. Patrick Li Queen Elizabeth Hospital Hong Kong.

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Presentation on theme: "HIV-ASSOCIATED NEUROCOGNITIVE DISORDER (HAND) Dr. Patrick Li Queen Elizabeth Hospital Hong Kong."— Presentation transcript:

1 HIV-ASSOCIATED NEUROCOGNITIVE DISORDER (HAND) Dr. Patrick Li Queen Elizabeth Hospital Hong Kong

2 HAND in the cART Era (HIV Associated Neurocognitive Disorders) Dr. Patrick Li, Queen Elizabeth Hospital, Hong Kong Satellite Session SUSA01, 30 th June th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

3 Declarations Served on Advisory Board or received conference grant from: – AbbVie – ViiV Healthcare – Merck Sharp & Dohme – Janssen Pharmaceutica – Boehringer Ingelheim – Bristol-Myers Squibb 7 th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

4 Background 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 Chiodi F, et al. Brain Pathology 1991;1:185–91 Gray F, et al. Brain Pathol 1996;6:1–15 7 th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

5 Typical features of HIV-associated dementia Cognitive impairment o Mental slowness or loss of mental stamina o Memory problems o Poor concentration and comprehension Behavioural abnormalities o Apathy o Lethargy o Diminished emotional response o Reduced gregariousness o Depression o Agitation/increased irritability Motor dysfunction o Unsteady gait o Poor balance o Incoordination o Abnormal tone o Tremors Navia BA, et al. Ann Neurol 1986;19:517–24 7 th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

6 No alternative cause Delirium absent Acquired impairment in ≥ 2 cognitive abilities Interferes with daily functioning Asymptomatic Neurocognitive Impairment (ANI) ✔✔✔ No Mild Neurocognitive Disorder (MND) ✔✔✔ Mild HIV-Associated Dementia (HAD) ✔✔ Marked Antinori A, et al. Neurology 2007;69:1789–99 Spectrum of HAND 7 th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

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

8 Prevalence of HAND in cART era 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) 1. Wright E, et al. Neurology 2008;71:50–6; 2. Simioni S, et al. AIDS 2010;24:1243–50; 3. Lawler K, et al. J Int AIDS Soc 2010;13:15; 4. Patel VN, et al. J Int J STD AIDS 2010; 21:356–8; 5. Joska JA, et al. AIDS Behav 2010; 14:371–8; 6. Pumpradit W, et al. J Neurovirol 2010;16:76–82; 7. Chan LG, et al. BMJ Open 2012;2:e th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

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

10 Risk of HAND is increased with lower CD4 nadir Ellis RJ, et al. AIDS 2011;25:1747– CD4 nadir (cells/µL) Probability of impairment Odds of impairment HAND eligible All subjects 7 th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

11 Impact/consequences of HAND Poorer survival 1,2 Diminished self-care ability and quality of life 3 Deterioration in work performance, higher unemployment rate 4 Suboptimal drug adherence 5,6 Impaired driving, increased accident risk 7 Significant personal, economic and societal burden 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 Int Neuropsychol Soc 2004;10:317–31; 4. Heaton RK, et al. Psychosom Med 1994;56:8–17; 5. Woods SP, et al. Arch Clin Neuropsychol 2008;23:257–70; 6. Hinkin CH, et al. Neurology 2002;59:1944–50; 7. Marcotte TD, et al. J Clin Exp Neuropsychol 2006;28:13–28 7 th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

12 HAND predicts an increased risk of death Vivithanaporn P, et al. Neurology 2010;75:1150– Years since HIV diagnosis Survival (%) Without HAND (n=1549) HAND (n=102) 7 th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

13 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 7 th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

14 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 7 th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

15 HAND screening instruments BenefitsLimitations MMSE – Familiar to most clinicians – Quick to perform (10 minutes) – Not sensitive to HIV-related cognitive impairment HDS – Validated for HAND – Quick to perform (10 minutes) – Validated in Caucasian population – Needs training for testing anti- saccadic eye movements – Less sensitive for milder forms of HAND IHDS – Validated for HAND – Quick to perform (5 minutes) – Validated in different cultures – Requires less training – Less sensitive for milder forms of HAND MoCA – Quick to perform (10 minutes) – Translated into 35 languages – Freely available online – One recent study showed 63% sensitivity and 71% specificity for HAND MOS- HIV – Easy to perform, can be done by patients in waiting room – Translated into many languages – Evaluates functional status and quality of life – Only identifies symptomatic disease – Subjective reporting of symptoms Valcour V, et al. Clin Infect Dis 2011;53:836–42 Overton ET, et al. J Neurovirol 2013:19:109–16

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20 Grooved Pegboard (GP) 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 Klove H. Med Clin N America 1963;47:1647–58 Lafayette Instrument Grooved Pegboard Test User’s Manual; Lafayette, USA 7 th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

21 Trail Making Test B (TMT-B) 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) AverageDeficientRule of Thumb 75 seconds> 273 secondsMost in 3 minutes Lezak MD. Neuropsychological Assessment. 4th ed. New York: Oxford University Press (2004) Reitan RM. Percept Mot Skills 1958;8:271–6 7 th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

22 Digit Symbol Substitution Test (DSST) Tests – Visual acuity & attention – Psychomotor speed – Information processing Also incorporates an element of memory testing Score is based on number of symbols correctly coded in 90 seconds Score usually ranges between 0–76: lower scores = greater impairment Lezak MD. Neuropsychological Assessment. 4th ed. New York: Oxford University Press (2004) DW. WAIS-R manual 1981, New York: Psychological Corporation 7 th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

23 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 7 th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

24 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 7 th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

25 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 7 th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

26 Screening questions for HAND Patients: Are you slower in your thinking than you used to be? Are you more forgetful than you used to be? Is it harder to organise things? Are you less able to find pleasure in the thing that you used to enjoy? (to exclude depression) Significant others: Is the patient more forgetful? Has the patient’s personality changed? Is the patient finding it harder to organise his life? 7 th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013 Asia-Pacific and Middle East Regions Advisory Board

27 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 7 th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

28 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 7 th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

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30 EACS guidelines: Diagnosis of HAND Patients with cognitive symptoms, evaluate with – Neurological examination – Neuropsychological testing – CSF examination – Brain MRI Patients without symptoms, screen with 3 questions and IADL questionnaire: – Frequent memory loss – Slower reasoning, planning, problem solving – Difficulty with attention – Exclude confounding conditions (psychiatric condition, psychotropic drugs, alcohol abuse, other CNS disease) EACS Guidelines Nov 2012 [www.europeanaidsclinicalsociety.org] 7 th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

31 EACS guidelines for HAND diagnosis EACS Guidelines Nov 2012 [www.europeanaidsclinicalsociety.org] Abnormal Screening for NCI: 3 questions Neurological examination Brain MRI CSF examination HAND diagnosis (HAD, MND) IADL questionnaire Abnormal NP Examination Abnormal Additional causes of NCI other than HIV excluded Normal Repeat 3 questions after 2 yrs All patients without highly confounding conditions Clear symptoms and/or signs of NCI and no highly confounding conditions 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)?

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

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

34 EACS guidelines: Treatment of HAND If patient is not on cART: – Start cART as guided by resistance test (plasma and CSF) – Consider inclusion of potentially CNS-active drugs If patient is on cART: – Optimise ART regimen as guided by resistance test (plasma and CSF) to achieve full virologic suppression – Consider inclusion of potentially CNS-active drugs – Reconsider other causes of cognitive impairment if full virologic suppression in plasma and CSF EACS Guidelines Nov 2012 [www.europeanaidsclinicalsociety.org] 7 th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

35 EACS treatment guidelines for HAND Start plasma and CSF GDR-guided ART Consider inclusion of potentially CNS-active drugs 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 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 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 Off ARTOn ART HAND diagnosis (HAD, MND) EACS Guidelines Nov 2012 [www.europeanaidsclinicalsociety.org]

36 BHIVA recommendations on HAND When to start ART We recommend patients with symptomatic HIV-associated neurocognitive disorders start ART irrespective of CD4+ lymphocyte count (1C) What to start We recommend patients with HIV-associated NC disorders start standard combination ART regimens (1C) 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 BHIVA guidelines for the treatment of HIV-1 positive adults with antiretroviral therapy th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

37 Asia-Pacific & Middle East Regions Advisory Board recommended algorithm for HAND management YesNo Does the patient have detectable VL in plasma? Initiate ART with neuroactive drugs with CPE score ≥7 irrespective of CD4 count Yes No Assess adherence If adherent, perform resistance testing Optimise the regimen according to resistance testing & CPE Consider lumbar puncture, if available, for assessment of CSF viral load If high, change ART to drugs with high CPE score ≥7 If low, consider discontinuing drugs with neurotoxic potential and referral to specialist services If HAND is suspected: Is the patient on ART?

38 ‘Potentially CNS-active drugs’ 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 EACS Guidelines Nov 2012 [www.europeanaidsclinicalsociety.org] 7 th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

39 ‘Potentially CNS-active drugs’ 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 EACS Guidelines Nov 2012 [www.europeanaidsclinicalsociety.org] 7 th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

40 CNS Penetration-Effectiveness (CPE) score ranking 2010 CPE Score Drug Class4321 NRTIsZidovudineAbacavir Emtricitabine Didanosine Lamivudine Stavudine Tenofovir Zalcitabine NNRTIsNevirapineDelavirdine Efavirenz Etravirine Protease Inhibitors Indinavir/rDarunavir/r Fosamprenavir/r Indinavir Lopinavir/r Atazanavir Atazanavir/r Fosamprenavir Nelfinavir Ritonavir Saquinavir Saquinavir/r Tipranavir/r Entry/Fusion Inhibitors MaravirocEnfuvirtide Integrase Inhibitors Raltegravir /r = ritonavir boosted 1. Letendre S. Top Antivir Med 2011;19:137–42 2. Tozzi V, et al. J Acquir Immune Defic Syndr 2009;52:56–63 7 th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

41 CPE score and CSF viral load control Letendre S. Top Antivir Med 2011;19:137– ≤345678≥9 Revised CPE rank Proportion detectable CSF viral load P< n=615 9% 11% 13% 18% 22% 39% 43% 7 th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

42 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 CNS penetration effectiveness ranking – Patients assessed for neurocognitive function (measured via global deficit score [GDS]) 16 weeks after starting regimen In patients with HAND, no neurocognitive benefit of CNS-targeted vs. standard ART 7 th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013 Ellis R, et al. CROI Abstract 20. Reproduced from the CCO website Outcome at week 16 CNS-T (n=26) Non-CNS-T (n=23) P value Mean change in adjusted GDS (SD) (0.54)-0.07 (0.43)0.76 HIV-1 RNA <50 c/mL, % Plasma CFS Screened (N=326) Randomized (n=59) Not eligible (n=196) Other exclusions (n=171) Non-CNS-T arm (n=30) Non-CNS-T arm (n=23) Reached endpoint (n=19) CNS-T arm (n=29) CNS-T arm (n=26) Reached endpoint (n=23) Lost to follow-up Protocol violation ITT

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44 Neurotoxicity of antiretroviral agents In vitro study of antiretroviral neurotoxicity using rat forebrain 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 Robertson K, et al. J Neurovirol 2012;18:388–99 7 th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

45 Low prevalence of neurocognitive impairment in early diagnosed and managed HIV-infected persons HIV+ patients categorized as earlier ( 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 Crum-Cianflone NF, et al. Neurology 2013;80:371–9 7 th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

46 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 7 th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

47 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 7 th IAS Conference on HIV Pathogenesis, Treatment and Prevention 2013

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