The Central Nervous System and Antiretroviral Therapy

1
New Approaches to Diagnosis and Management
of Neurological Complications in the HAART Era
Scott Letendre, MD Associate Professor of
Medicine HIV Neurobehavioral Research Center and
Antiviral Research Center University of
California, San Diego 25 July 2007 4th IAS
Conference on HIV Pathogenesis, Treatment
Prevention Sydney, Australia
2
Acknowledgements

• Study Volunteers
• University of California, San Diego
• Allen McCutchan
• Ronald Ellis
• Igor Grant
• Chip Schooley
• Connie Benson
• Doug Richman
• Davey Smith
• Steven Paul Woods
• Robert Heaton
• Beau Ances

• National Institutes of Health
• NIMH, NINDS, NIDA
• CHARTER Group
• David Clifford
• Ann Collier
• Benjamin Gelman
• Christina Marra
• Justin McArthur
• Susan Morgello
• David Simpson

3
Overview Main Points

• NeuroAIDS continues to be an important problem
  for people living with HIV
• In both less and more resource limited settings
• NeuroAIDS can be recognized easily
• Additional tests can improve confidence in the
  diagnosis and exclude NOIs
• NeuroAIDS can be treated
• Antiretroviral therapy that better distributes
  into the CNS leads to better outcomes

4
Persistently High PrevalenceRumors of its death
are greatly exaggerated
Hopkins Moores HIV Clinic Adapted from McArthur,
et al, J NeuroVirol, 2003
Sevigny et al, Neurology 2004, 63 2084-90
5
Persistently High PrevalenceResource Limited
Settings
56
47
37
Proportion Impaired
31
12
Yepthomi, J International Neuropsychological
Society, 2006 Unpublished Data, NARI-UCSD
Collaboration, 2006 Unpublished Data, China
CDC-UCSD Collaboration, 2007 Wong et al,
Neurology, 2007 Wright et al, XVI International
AIDS Conference, 2006
6
Overview Main Points

• NeuroAIDS continues to be an important problem
  for people living with HIV
• In both less and more resource limited settings
• NeuroAIDS can be recognized easily
• Additional tests can improve confidence in the
  diagnosis and exclude NOIs
• NeuroAIDS can be treated
• Antiretroviral therapy that better distributes
  into the CNS leads to better outcomes

7
Recognizing NeuroAIDS

• Suspect it
• Assess it
• Verify it
• Exclude Other
• Conditions

8
Suspect ItKnow the Risk Factors

• Host
• AIDS, Anemia
• Age, Gender
• Insulin Resistance
• Stimulants
• Methamphetamine
• Cocaine
• Genetics
• Chemokines

• Viral
• Genetics
• Clade Differences
• Neuroadaptation
• Co-pathogens
• Hepatitis C

9
Suspect ItKnow the Risk Factors

• Host
• AIDS, Anemia
• Age, Gender
• Insulin Resistance
• Stimulants
• Methamphetamine
• Cocaine
• Genetics
• Chemokines

• Viral
• Genetics
• Clade-Subtype
• Neuroadaptation
• Co-pathogens
• Hepatitis C

Valcour et al, Neurology, 2004, 63 822-7 Valcour
et al, JAIDS, 2006, 43 405-10 Cherner et al,
Neurology, 2005, 64 1343-7 Gonzalez et al, PNAS,
2002, 99 13795-800 Ranga et al, J Virol, 2004,
78 2586-90 Letendre et al, J Infect Dis, 2007,
196 361-70
10
Ellis, et al, Nat Rev Neurosci 2007, 8 33-44
Modified by D. Smith
11
Clinical FeaturesHCV Infection of Astrocytes and
Macrophages
HCV mRNA in the brains of HIV HCV by nested PCR
HCV antigens in brains by heparin columns by WB
HCV antigens in astrocytes of HIV HCV cases
GFAP HCV
HCV- HCV HCV
Slide Courtesy E. Masliah
12
Assess ItInternational HIV Dementia Scale

• Memory-Registration Word Recall
• Motor Speed Finger tapping
• Psychomotor Speed Alternating hand movements

• IHDS Score
• Maximum score is 12 points
• Score of 10 Possible dementia

Sacktor N, et al. AIDS. 2005 19 1367-74
13
Assess ItBrief NeuroCognitive Screen (BNCS)

• Trailmaking (AB)
• WAIS-R Digit Symbol task
• Requires lt 15 min

Ellis R, et al. J Neurovirol. 2005 11 503-11
14
Assess ItRange of HIV Neurocognitive Disorders
NeuropsychologicalDeficitabnormality in ONE
COGNITIVE ability
15
Assess ItRevised Criteria for HAND
Excerpt from Expert Panel Consensus Guidelines,
Neurology, 2007, In Press
16
Assess ItPrevalence of Disorders by Disease Stage
Proportion with Disorder
17
Verify ItCSF Viral Loads Before HAART
5.5
McArthur 1997
5
Brew 1996
4.5
Ellis 1997
4
HIV RNA, CSF (log10 copies/mL)
3.5
3
2.5
2
1.5
Severe
MCMD
Mild
Mod
HIV Non-Demented
HIV Dementia
Slide Courtesy Justin McArthur
18
Verify ItCSF Viral Loads After HAART
n 67
Hightower GK et al, XVI International HIV Drug
Resistance Workshop 2007
19
Verify ItCSF Viral Loads After HAART
Currently Not Taking ART
n 49
Hightower GK et al, XVI International HIV Drug
Resistance Workshop 2007
20
Verify ItCSF Viral Loads After HAART
Drug Sensitive HIV
n 30
Hightower GK et al, XVI International HIV Drug
Resistance Workshop 2007
21
Verify ItOther Biomarkers

• Astrocyte Activation
• MCP-1 / CCL2
• S100?
• Macrophage Activation and Oxidative Stress
• ?2 Microglobulin
• Neopterin
• Interferon-related proteins

• Neurotoxins
• TNF-? and related proteins
• Glutamate, excitotoxins
• Neuronal Injury
• Neurofilament Light
• Apoptotic proteins
• Many others

22
Verify ItOther Biomarkers

• Astrocyte Activation
• MCP-1 / CCL2
• S100?
• Macrophage Activation and Oxidative Stress
• ?2 Microglobulin
• Neopterin
• Interferon-related proteins

• Neurotoxins
• TNF-? and related proteins
• Glutamate, excitotoxins
• Neuronal Injury
• Neurofilament Light
• Apoptotic proteins
• Many others

Gisslen et al, J Infect Dis, 2007, 195 1774-8
23
Verify ItNeuroimaging

• Structural Imaging
• White matter injury and grey matter atrophy
• Magnetic Resonance Spectroscopy
• Neuronal Loss (?NAA)
• Inflammation (?Cho)
• ?Lactate and Lipid
• BOLD-fMRI
• More Cerebral Blood Flow and Oxygen Consumption
  to Perform Tasks

Roc, et al, Arch Neurol, 2007, ePub
Ances, et al, 14th CROI, 2007, Abstract 377
24
Overview Main Points

• NeuroAIDS continues to be an important problem
  for people living with HIV
• In both less and more resource limited settings
• NeuroAIDS can be recognized easily
• Additional tests can improve confidence in the
  diagnosis and exclude NOIs
• NeuroAIDS can be treated
• Antiretroviral therapy that better distributes
  into the CNS leads to better outcomes

25
NeuroAIDS Can Be TreatedNot All Antiretrovirals
Are Effective in the CNS
Slide Courtesy W.M. Pardridge, UCLA
26
NeuroAIDS Can Be TreatedCNS Penetration-Effective
ness Score
Letendre et al, Archives of Neurology, In Press
27
NeuroAIDS Can Be TreatedHigher CPE Scores and
Lower Viral Loads in CSF
Letendre et al, Archives of Neurology, In Press
28
NeuroAIDS Can Be TreatedFailing Therapy Can
Reduce CSF VLs

• 139 HIV-infected subjects without neurologic
  disease
• CSF Viral Loads
• Successful 72 lt 2.5 c/mL
• Failed median 1.8 log c/mL
• No therapy 3.5 log c/mL
• Each treated group had lower neopterin levels in
  CSF than those on no therapy

Spudich et al, J Infect Dis, 2006, 194 1686-96
29
Future Issuesand miles to go before we sleep

• Develop more clinically relevant tools
• Cognitive Assessments
• Biomarkers
• Neuroimaging
• Optimize ART and Adjunctive Therapies
• Drug Distribution
• Drug Resistance
• Immune Reconstitution
• Roles of host and viral genetics
• Earlier recognition and better treatment of
  neurologic OIs