HIVASSOCIATED DEMENTIA

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HIV-ASSOCIATED DEMENTIA

• IN THE HAART ERA

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CLASSIC HIV-D

• ACCOMPANIES LATE-STAGE IMMUNE SUPPRESSION
• CD4 lt200/CU.ML IN MOST

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CLASSIC HIV-D

• A CLINICALLY UNIQUE SYNDROME
• GENERALLY COMBINES COGNITIVE AND MOTOR
  DYSFUNCTION
• FREQUENTLY ACCOMPANIED BY NEUROPATHY/MYELOPATHY

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CLASSIC HIV-D

• EARLY CONCENTRATION/ MEMORY DIFFICULTY
• LOSE TRACK OF CONVERSATION
• PROGRESS TO DIFFICULTY WITH WRITTEN MATERIAL
• APATHETIC APPEARANCE, INDIFFERENCE
• GENERALLY NOT DEPRESSED OCCASIONALLY MANIC,
  PSYCHOTIC
• OFTEN MARKED RESPONSE SLOWING

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CLASSIC HIV-D

• GENERALLY PROGRESSIVE MOTOR DYSFUNCTION WITH
  SLOWING
• GAIT ATAXIA, DIFFICULTY TURNING
• PROGRESS TO CANE-W/CHAIR
• BLADDER/BOWEL INCONTINENCE
• HYPERREFLEXIA, INCREASED JAW JERK AND SNOUT,
  ABNORMAL SACCADES

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CLASSIC HIV-D

• GENERALLY PREDICTED DEATH IN WEEKS/MONTHS

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MCMD MINOR COGNITIVE/MOTOR DISORDER

• PRESENT IN 30 OF SYMPTOMATIC ADULTS
• INDICATES WORSE AIDS PROGNOSIS
• PREDICTOR OF DEMENTIA
• ASSOCIATED WITH FUNCTIONAL DISABILITY
• MEDICATION ADHERENCE, DRIVING

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HIV-D DIAGNOSIS

• CHARACTERISTIC CLINICAL PICTURE
• RULE OUT VIRAL/BACTERIAL/FUNGAL OPPORTUNISTIC
  INFECTIONS OF THE CNS
• CSF AND RADIOLOGICAL EVALUATION VERY HELPFUL
• EASY TO MISS HIV-D IN THE SETTING OF LATE STAGE
  SYSTEMIC ILLNESS

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HIV NEUROPATHOLOGY

• EVEN IN NON-DEMENTED
• WHITE MATTER PALLOR EARLY
• REACTIVE ASTROCYTOSIS
• MICROGLIAL NODULES
• WITH HIV-D
• 25 MULTINUCLEATED GIANT CELLS
• NEURONAL LOSS MAY BE PROGRESSIVE FROM EARLY
  STAGES

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MICROGLIAL NODULES
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MULTINUCLEATED GIANT CELLS
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HIV-D PATHOGENESIS

• VIRUS KNOWN TO ENTER THE BRAIN EARLY AND REMAIN
  SEQUESTERED, AT LEAST IN MICROGLIA, FROM THEN ON
• HUMAN CSF STUDIES
• SIV STUDIES
• FIV STUDIES

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HIV-D PATHOGENESIS

• NO PRODUCTIVE NEURONAL INFECTION
• NEURONS DO NOT HAVE CD4 RECEPTORS
• NEURONAL LOSS LIKELY IMMUNE-MEDIATED
• INFECTED MACROPHAGE-ASTROCYTE-NEURON INTERACTION

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HIV-D PRE-HAART

• MOST STUDIES PRIOR TO HAART SHOWED SOME
  CORRELATION BETWEEN DEMENTIA AND-
• CD4 LEVEL
• PLASMA VIRAL LOAD
• CSF VIRAL LOAD
• VIRAL LOAD MAY ALSO HAVE PREDICTIVE VALUE

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HIV-D PRE-HAART

• IMMUNE MARKERS ELEVATED IN CSF
• QUINOLINIC ACID
• NEOPTERIN
• B2 MICROGLOBULIN
• EICOSANOIDS
• MCP-I
• TNF
• MMP 2,7,9
• M-CSF
• ETC.
• SOME CORRELATE WITH DEMENTIA SEVERITY

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HAART TREATMENT

• DRAMATIC BENEFIT IN SYSTEMIC DISEASE
• PLASMA VIRAL LOAD AND CD4 COUNT ARE SURROGATE
  MARKERS OF IMPROVEMENT
• PICTURE LESS CLEAR FOR CNS DISEASE

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HAART TREATMENT

• GENERALLY RAPID REDUCTION IN CSF HIV RNA
• Particularly in naïve
• BUT CSF VIROLOGICAL FAILURES FAIRLY COMMON

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HAART TREATMENT

• RECENT AUTOPSY STUDY SHOWED SIGNIFICANT DROP IN
  BRAIN TISSUE VIRAL LOAD IN PATIENTS TREATED WITH
  HAART IN PRIOR 3 MONTHS

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HIV-D EPIDEMIOLOGYPRE-HAART

• ANNUAL INCIDENCE AFTER AIDS 7
• CUMULATIVE RISK 5-20

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HAART TREATMENT

• MULTIPLE STUDIES SHOW IMPROVEMENT IN
  NEUROPSYCHOLOGICAL FUNCTION POST-HAART IN ADULTS
  AND CHILDREN
• IMPROVEMENT CONTINUES FOR AT LEAST 3 MTH
• SOME STUDIES SHOW IMPROVEMENT MAINTAINED UP TO 2
  YEARS AFTER ON MEDICATIONS

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HAART TREATMENT

• CLASSIC HIV-D ONLY SEEN IN ANTIRETROVIRAL-NAÏVE
  OR PROTRACTED NON-COMPLIANCE
• REVERSAL OF COGNITIVE DEFECTS MAY BE DRAMATIC,
  PARTICULARLY IN PREVIOUSLY UNTREATED CASES

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HAART TREATMENT

• HOWEVER
• STILL SIGNIFICANT DEFICITS IN TREATED POPULATIONS
• PROGRESSIVE DEFICITS REPORTED IN SOME TREATED
  SUBJECTS

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HIV-D EPIDEMIOLOGYPOST-HAART

• MACS 50 REDUCTION IN INCIDENCE
• 1990-92 21.3/1000 PERSON YEARS
• 1996-98 10.0/1000 PERSON YEARS
• NEAD AND ALLRT NO REDUCTION IN PREVALENCE
• EACH SHOW 30 CURRENT PREVALENCE
• PROBABLY VIA INCREASED SURVIVAL
• SAN FRANCISCO COHORT
• 1992 3.7/100 LIVING WITH AIDS
• 2002 0.34/100
• 2004 0.24

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HIV-D EPIDEMIOLOGYPOST-HAART

• ALLRT, 1498 SUBJECTS
• PROSPECTIVE LONGITUDINAL ALL ON HAART
• DIGIT SYMBOL, TRAILS A B
• 43 IMPAIRED AT BASELINE
• IMPAIRMENT CORRELATED WITH NADIR CD4 lt200
• 26 IMPAIRED BECAME UNIMPAIRED
• MEDIAN 52 WEEKS
• 19 UNIMPAIRED BECAME IMPAIRED
• MEDIAN 93 WEEKS

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HIV-D EPIDEMIOLOGYPOST-HAART

• ACTG 362, 643 SUBJECTS
• PROSPECTIVE LONGITUDINAL ALL ON HAART
• DIGIT SYMBOL, TRAILS A B
• AT 48 WEEKS, OF 57 SUBJECTS WITH NEUROPSYCH.
  IMPAIRMENT AT ENTRY, 47 REMAINED IMPAIRED AND
  53 CONVERTED TO UNIMPAIRED
• OF 117 UNIMPAIRED, 6 BECAME IMPAIRED

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PROGRESSION

• MOVEMENT IN BOTH DIRECTIONS
• NEAD COHORT AT JHU
• 44 OF DEMENTED HAD PROGRESSED FROM NON-DEMENTED
  TO DEMENTED IN 6MTH
• 37.5 OF DEMENTED IMPROVED TO NON-DEMENTED IN 6
  MTH
• WHILE CONCORDANCE IS GOOD, THIS RAISES CONCERNS
  ABOUT SPECIFICITY OF TESTING

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MCMD

• NO REDUCTION IN PREVALENCE POST-HAART
• 30 OVERALL
• 37 WITH ADVANCED HIV (CD4,200)

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HAART TREATMENT

• IN HAART TREATED PATIENTS
• PLASMA VIRAL LOAD
• CSF VIRAL LOAD
• CSF IMMUNE MARKERS
• REPORTED CORRELATION WITH CSF PENETRANCE
• BUT NOT CORRELATED WITH OR PREDICTIVE OF DEMENTIA

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HAART EFFECTS ON COGNITION

• SOME STUDIES CROSS-SECTIONAL
• RAISES QUESTION OF RESIDUAL RATHER THAN
  PROGRESSIVE DEFICITS
• SOME SHOW COGNITION CORRELATES WITH IMMUNOLOGICAL
  SUCCESS
• OTHER STUDIES DO NOT EVALUATE FOR IMMUNOLOGICAL
  SUCCESS OF TREATMENT
• RAISES QUESTION OF HOW COGNITIVE DECLINE RELATES
  TO TREATMENT FAILURE OR ONLY PARTIAL SUCCESS

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WHY HAART MAY NOT STOP CNS PROGRESSION

• ARVs HAVE POOR PENETRANCE ACROSS THE BLOOD BRAIN
  BARRIER
• POTENTIAL FOR VIRAL SEQUESTRATION IN THE BRAIN
• MAY CAUSE CONTINUING NEUROLOGICAL DECLINE
• MAY INCREASE POTENTIAL FOR RESISTANCE WITH
  RESEEDING OF SYSTEMIC COMPARTMENT

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CNS PENETRANCE OF ARVs

• GENERALLY POOR
• NRTI PENETRANCE MEDIATED BY ORGANIC ACID
  TRANSPORT SYSTEMS
• PROTEASE INHIBITORS ELIMINATED VIA
  P-GLYCOPROTEINS, WHICH ARE LOCATED AT THE BBB

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RELATIVELY BETTER CSF PENETRATION

• ZIDOVUDINE
• NEVARIPINE
• EFAVARENZ
• STAVUDINE
• LAMIVUDINE
• ABACAVIR
• INDINAVIR
• NOT CLEAR HOW THIS REFLECTS PARENCHYMAL LEVELS

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CSF PENETRANT ARVs

• SOME STUDIES SUGGESTED IMPROVEMENT IN SOME
  FEATURE OF NEUROPSYCHOLOGICAL TESTING
• OTHERS SHOWED NONE
• THEREFORE-
• MIXED RESULTS BUT INCREASING EVIDENCE PENETRANCE
  HAS A SIGNIFICANT EFFECT ON NEUROLOGICAL
  FUNCTIONING

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RECOMMENDED TREATMENT INITIATION- ASYMPTOMATIC

• U.S.A.
• CD4 lt350/mm3
• VIRAL LOAD gt55,000 COPIES/mL
• RESOURCE-LIMITED COUNTRIES
• CD4 lt200/mm3
• VIRAL LOAD gt100,000 COPIES/Ml
• NOT EVALUATED FOR NERVOUS SYSTEM DISEASE

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WOULD EARLY TX PROTECT THE CNS

• PRE- HAART INCIDENCE OF DEMENTIA
• 0.4 IN ASYMPTOMATIC STAGES
• 16 WITH SYMPTOMATIC DISEASE
• MORE DEMENTIA WITH ADVANCING AGE
• POSSIBLY DUE TO AGE-INDUCED LOSS OF NEURONAL
  RESERVE
• MCMD IS PREDICTIVE OF DEMENTIA

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WOULD EARLY TX PROTECT THE CNS

• MULTIPLE PRE-HAART LONGITUDINAL STUDIES INDICATED
  PROGRESSION ON A NUMBER OF PARAMETERS
• PROGRESSIVE DECLINE ON MOTOR COGNITIVE TASKS
• PROGRESSIVE PROLONGATION OF EPs-VISUAL, BAER, P3
• DECLINES IN BRAIN VOLUME, MRS,DTI, fMRI CORRELATE
  WITH COGNITIVE CHANGE
• CHANGES GENERALLY MILD BUT TROUBLING

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WOULD EARLY TX PROTECT THE CNS

• HIGH BASELINE PLASMA VIRAL LOAD PREDICTS DEMENTIA
• CSF NOT ADEQUATELY STUDIED
• STRUCTURED TREATMENT INTERRUPTION LEADS TO
  ELEVATED CSF LYMPHOCYTE COUNT AND VIRAL LOAD

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CONCLUSIONS

• HAART HAS COMPLETELY CHANGED THE CLINICAL PICTURE
  OF HIV-D
• CLASSICAL HIV-D NO LONGER SEEN EXCEPT IN
  UNTREATED OR UNCOMPLIANT
• DRAMATIC IMPROVEMENT LIKELY IN NAÏVE PATIENTS
• MAXIMAL IMPROVEMENT MAY TAKE SEVERAL MONTHS

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CONCLUSIONS

• COGNITIVE/MOTOR DYSFUNCTION COMMON BUT MUCH LESS
  MARKED
• NOT YET CLEAR HOW MUCH IS DUE TO PRIOR DAMAGE
  WITH INCOMPLETE RECOVERY
• EVIDENCE OF PROGRESSION IN SOME
• NOT YET CLEAR HOW MUCH IS RELATED TO INCOMPLETE
  CNS VIRAL SUPPRESSION

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CONCLUSIONS

• NO CLEAR SURROGATE MARKERS OF CNS DISEASE IN
  TREATED PATIENTS

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CONCLUSIONS

• INCOMPLETE EVIDENCE THAT CNS PENETRANT ARVs MAY
  BE BENEFICIAL
• PROBABLY REASONABLE TO ADD THESE IN
  NEUROLOGICALLY IMPAIRED PATIENTS

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CONCLUSIONS

• OPTIMAL TIME TO START HAART TO PROTECT CNS NOT
  ESTABLISHED
• SEVERAL LINES OF EVIDENCE SUGGEST THE EARLIER THE
  BETTER
• MUST BE WEIGHED AGAINST COST, LIKELIHOOD OF
  RESISTANCE