HIV and the Brain: Update 2010 David B. Clifford, MD Melba and Forest Seay Professor  Washington University  in St. Louis
 
 
HIV-1 Associated Neurologic Problems <ul><li>Primary HIV-associated conditions </li></ul><ul><ul><li>HIV-associated  neuro...
Selected Secondary Problems <ul><li>Toxoplasma encephalitis </li></ul><ul><li>PML </li></ul><ul><li>Syphilis </li></ul>
HIV-Associated Dementia (HAD) <ul><li>Formerly AIDS Dementia Complex </li></ul><ul><li>Occurs with low CD4 </li></ul><ul><...
Approved Antiretroviral Agents 1987 - 2010 87  88  89  90  91  92  93  94  95  96  97  98  99  00  01  02  03  04  05  06 ...
Neurocognitive Impairment in the Pre-ARV, Pre-HAART and HAART Eras
Frascati Classification of  H IV- A ssociated  N eurocognitive  D isorders (HAND) <ul><li>ANI = Asymptomatic neurocognitiv...
Neurocognitive Impairment in the Pre-HAART and Post-HAART Eras Modified from Ellis et al, Nat Rev Neurosci 2007 and Grant ...
Cognitive Dysfunction in HIV <ul><li>HAND in HAART Era </li></ul><ul><li>Occurs at higher CD4 counts </li></ul><ul><li>Cou...
Cognitive Dysfunction in HIV <ul><li>AIDS Dementia (now HAD) </li></ul><ul><li>Pre-HAART </li></ul><ul><li>HAND (ANI/MND) ...
Diagnosis CHARTER Neurocognitive Test Battery <ul><li>Verbal Fluency </li></ul><ul><ul><li>Letter Fluency </li></ul></ul><...
International HIV Dementia Scale   <ul><li>International HIV Dementia Scale  </li></ul><ul><ul><ul><li>Naming four objects...
CogState http://library.cogstate.com/public/Brochures/12_Minute%20Brochure%20REV6_LowRes.pdf CROI 2010, Winston, et al Exe...
Diagnosis NPZ -4 used in ACTG <ul><li>Trail making A and B </li></ul><ul><li>Symbol digit test </li></ul><ul><li>Hopkins V...
Cognitive Screening Montreal Cognitive Assessment (MoCA) <ul><li>Broad balanced test </li></ul><ul><li>Online and free </l...
What causes HAND now? <ul><li>Co-morbidities </li></ul><ul><li>Virus </li></ul><ul><li>Inflammation </li></ul><ul><li>Perf...
Is this all due to non-HIV- associated co-morbidities? <ul><li>Contribution of other factors to cognitive performance </li...
Neurocognitive Impairment by Co-Morbidity Status % impairment
Damaged brain may heal poorly CD4 Nadir  <ul><li>Legacy of prior damage </li></ul><ul><li>Nadir CD4 count </li></ul><ul><u...
Correlates of CSF Viral Loads in 1,221 Volunteers of the CHARTER Cohort Scott Letendre, Chelsea FitzSimons, Ronald J. Elli...
Distribution of CSF Viral Loads Off ART On ART
Correlates of Detectable CSF Viral Loads 842 Volunteers Taking ART Direction Uni Multi Plasma Viral Load Higher < 0.001 < ...
CNS Penetration-Effectiveness Ranks 2010   4 3 2 1 NRTIs Zidovudine Abacavir Lamivudine Didanosine Emtricitabine Stavudine...
CNS Penetration-Effectiveness Ranks CPE 2008 Ranks CPE 2010 Ranks Cross-Sectional Analysis p = 0.008 n = 467 Letendre S, e...
Associations Between CSF Viral Loads and Global NP Performance <ul><li>Higher CSF viral loads alone were not associated wi...
Conclusions <ul><li>Plasma viral load was the strongest correlate of CSF viral load, emphasizing the importance of systemi...
Does CPE have a downside? <ul><li>A5170 found stopping ARV resulted in cognitive improvement </li></ul><ul><li>ACTG 736 re...
~60% still have elevated neopterin and IgG Index after 4 yrs HIV rx
Brain Perfusion
<ul><li>Multicenter AIDS Cohort </li></ul><ul><li>After accounting for education, depression and race </li></ul><ul><li>Ca...
Cardiovascular Risks Associated with Poor Cognitive Performance in SMART Study <ul><li>Traditional HIV associated risk fac...
HIV Indirectly Contributes to  Cognitive Impairment? Cognitive Normal Cognitive Impaired Carotid Intima Thickening HIV Age...
Arterial spin labeling (ASL) measures cerebral blood flow (CBF) Control - Tag    CBF (mL/100mL/min) Ances, Abst 157 CROI2...
Effects of HIV and Aging on rCBF Ances et al. ,  JID, Feb  2010 Age (years old)
Cross sectional: Global and Regional rCBF Are Affected by HAART HIV+ Naive HIV+ Meds HIV- Controls ( n=26 ) ( n=26 ) ( n=1...
Longitudinal: HAART Affects HIV Viral Load and Global rCBF
HIV Causes Synaptodendritic Injury Leading to Reduction in rCBF Normal Synapto-  dendritic  Density HIV Normal Cerebral  B...
Modifiable Risk Factors <ul><li>Smoking </li></ul><ul><li>Diet </li></ul><ul><ul><li>Glucose </li></ul></ul><ul><ul><li>Li...
Modifiable Risk Factors <ul><li>Smoking </li></ul><ul><li>Diet </li></ul><ul><ul><li>Glucose </li></ul></ul><ul><ul><li>Li...
Conclusions <ul><li>Cognitive functions remain impaired in many optimally treated HIV patients </li></ul><ul><li>Optimal t...
History <ul><li>34 yo woman from Liberia </li></ul><ul><li>AIDS, off Rx, CD4 <50 </li></ul><ul><li>Extrapulmonary tubercul...
Extrapulmonary TBC – 2008 Clavicle Aspiration of lesion yields AFB
CT Brain – October 2009
History 2 <ul><li>Workup non-diagnostic </li></ul><ul><ul><li>CSF benign </li></ul></ul><ul><ul><li>CSF PCR negative for E...
 
 
Lab Eval 2010 <ul><li>CSF </li></ul><ul><ul><li>15 cells (lyms) </li></ul></ul><ul><ul><li>Glucose 70 mg/dl, protein 56 mg...
Toxoplasma Encephalitis
Toxoplasma Strains Type II Most commonly cause toxoplasmosis Type I  : Rarer but pathologic Type III Rarely assoc with dx
Signs/Sx of Toxoplasmosis <ul><li>Headache </li></ul><ul><li>Fever </li></ul><ul><li>Confusion </li></ul><ul><li>Hemipares...
 
Therapy for Toxoplasma encephalitis <ul><li>Initiation of HAART at appropriate time </li></ul><ul><li>Primary prevention <...
TE Therapy <ul><li>Sulfadiazine/Pyrimethamine/Folinic Acid </li></ul><ul><ul><li>Pyrimethamine 200 mg po loading dose, the...
TE Therapy <ul><li>Alternative for sulfadiazine: Clindamycin 150-300  mg q6h IV/PO </li></ul><ul><ul><li>Allergies </li></...
Co-trimoxizole as therapy <ul><li>Anecdotal experience and case reports </li></ul><ul><li>Pilot study: Torre et al (Italia...
Mortality  of  AIDS Defining Complications CROI 2007, Abstract 80, Mocroft et al Data derived from 15 HIV cohort studies i...
Progressive Multifocal Leukoencephalopathy <ul><li>Acquired demyelinating CNS disease  </li></ul><ul><li>JC virus is etiol...
Clinical Aspects of PML <ul><li>Signs and symptoms dependent on lesion location </li></ul><ul><ul><li>Motor sx  </li></ul>...
PML Survival in HAART Era
PML IRIS Vendrely, et al Acta Neuropathol (2005) 109:449-455 <ul><li>HIV associated PML with cognitive presentation </li><...
CSF PCR Performance Marzocchetti et al, J. Clin Microbiol, 2005
Therapeutic Approaches <ul><ul><li>Immune reconstitution </li></ul></ul><ul><ul><li>Adjunctive therapy </li></ul></ul><ul>...
Mefloquine (Larium) <ul><li>Antimalarial drug </li></ul><ul><ul><li>11 million people have taken since 1984 </li></ul></ul...
Case History <ul><li>67 yo married WM </li></ul><ul><li>3 wks increasing severe leg and back pain </li></ul><ul><li>HIV di...
Exam <ul><li>Articulate lawyer complaining of radicular pain to legs </li></ul><ul><li>Reflexes increased </li></ul><ul><l...
Localization <ul><li>Peripheral nerve? </li></ul><ul><ul><li>Wrong history </li></ul></ul><ul><ul><li>Wrong exam </li></ul...
Syphilis <ul><li>++RPR 1:128 </li></ul><ul><li>+FTA </li></ul><ul><li>CSF inflammatory with +VDRL </li></ul><ul><li>PCN tr...
Neurosyphilis and HIV <ul><li>Concurrent syphilis and HIV exposure not rare </li></ul><ul><li>Course to neurosyphilis may ...
Neurologic Complications in HIV <ul><li>Primary  </li></ul><ul><ul><li>Cognitive </li></ul></ul><ul><ul><li>Peripheral ner...
<ul><li>CHARTER investigators </li></ul><ul><ul><li>Igor Grant </li></ul></ul><ul><ul><li>Ann Collier </li></ul></ul><ul><...
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C3 Neurological Complications and Treatment of HIV Clifford

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  • So we have seen significant changes in the demographics of HIV neurocognitive dementia since HA, Before there were a larger number of subjects with HIV associated dementia (HAD).This has now changed with less having HAD but more having more milder forms of impairment such as mild neurocognitive disorders or asymptomatic neurocognitive disorders. Overall, the Incidence of HIV-associated neurocognitive disorders (HAND) has declined with HAART, but prevalence has not due either to longer survival of individuals with milder disorders or incomplete efficacy of HAART in the brain.
  • ASL image of blood flow in brain, comparing HIV neg vs HIV positive (not impaired formally), key is Z score between groups, areas in yellow is where HIV negative have higher blood flow than HIV negative.. NO areas are blue, HIV doesn’t have higher flow…
  • Example fro CROI, Winston et al reporting small controlled trial, ALTAIR study that also looked at metabolic effects of regimens with MRS. Turned out that the quad nuc had optimal effect on cognitive function, while EFV based regimen improved status of neuronal damage on MRS better than others… Clearly an open story yet. The finding is an executive function result indicating that over 48 week there was decline in the number of errors in the testing on the quad nuc regimen
  • The distribution of CSF viral loads for the entire group was highly skewed. Skewing was largely due to only 16% of treated people having detectable viral loads. For this reason, the analysis was stratified by ART use.
  • † The final model includes an interaction between ethnicity (white vs. non-white) and CD4 count (≤ 200 vs. &gt; 200): non-white ethnicity is only associated with detectable CSF viral loads in those who have CD4 counts &gt; 200. On review of this slide last week, Ian Abramson (our lead statistician) suggested leaving the adherence covariate in the final model even though the p value for its parameter estimate was between 0.05 and 0.10 CPE 2010 performed better than CPE 2008 in these analyses
  • In Slideshow mode, the graph on right will change to reveal the graph restricted to regimens with 3 antiretrovirals. The first one on the right includes all 842 people taking ART regardless of the number of antiretrovirals in their regimen.
  • The table on the upper left shows the sample sizes and effect size estimates (Cohen’s d) for the 3 comparisons shown in the figure. The analysis compares Global Deficit Score in those who had CSF viral loads ≥ plasma viral loads to those who did not. The 3 groups are: all baseline visits with CSF and plasma viral loads, all baseline visits from people not taking ART (because they are much more likely to have detectable CSF viral loads), and all baseline visits from people not taking ART with minimal comorbidities (because they are less likely to have a cause of neurocognitive impairment other than HIV. The data show that the effect size increases as the sample size decreases. In the multivariable analysis summarized in the table in the lower right, having CSF VLs ≥ plasma VLs was still associated with worse Global Deficit Scores after including other independent variables associated with GDS. The multivariable analysis was limited to those who were not taking ART because we’re interested in whether CSF viral loads are associated with NP performance. In the analysis of people who were taking ART, the 16% of people who had detectable CSF viral loads did not have worse NP performance. The association between those with CSF VLs ≥ plasma VLs and global NP performance was present whether using GDS, Global Rating, or Global impairment status. In the group who was not taking ART and had minimal comorbidities, those who had CSF VLs ≥ plasma VLs had 2.3 increased odds of having global impairment (45% vs. 26%, p = 0.047).
  • Microtubule associate protein -2 (MAP-2) staining, rat fetal neuronal cultures Concentration dependent damage Concentrations relevant to clinical treatment
  • Edwina Wright and associates reported presentation 415 at CROI2010 in San Francisco All CD4&gt;350 5 test cog at baseline and month 6 Adjusted for age, sex, race, education and location of enrollment 292 participants Median age 40 yo CPE looked at Mean QPEZ5 -0.7 (so overall impaired) 14% impaired with -2 Z score Prior AIDS, baseline CD4, nadir CD4, HIV RNA, CPE included in model but not statistically significant associated No association with change of QNPZ which improved at 6 months with CVD
  • So the next two slides detail the different neuroimaging techniques used. I promise there are no equations here. So one of the techniques were used was called arterial spin labeling. This allows us to non-invasively measure the cerebral blood flow to the brain. In this technique tag arterial blood cells in the neck and then wait for them to get to the a slab in the brain and take a picture. In the second part we apply no tag and again take a picture of the same slab of brain. The difference between the control and tag images provides us a measure of how much blood flow was delivered to that part of the brain. It allows to non-invasively assess areas of the brain. Similar results have been seen between this technique and more invasive measures of cerebral blood flow in the brain. What is nice is no injection is required and this takes only minutes to acquire.
  • Visual cortex is selected area for this study. Overall many organ systems have been studied. In particular there has been a decrease in bone density in older HIV subjects. Hepatic and endocrine functions are effected by HIV and aging. Cardiac output and stroke volume are decreased in older HIV+ patients. Renal function is also reduced. A frailty phenotype has been created with frailty defined as enhanced vulnerability to stressors due to immunologic and inflammatory dysregulation. Overall a 55 year old HIV+ with 0-4 years of infection was equal to 65 year old uninfected subject. HIV led to about a 10 year aging. However, one area has not well investigated and that is the brain. Most studies that have been performed have looked at neuropsyhcological measures and seen the degree of dementia. What we wanted to do is use other biomarkers of brain function- in particular functional magnetic resonance imaging to look at the effects of HIV and aging. Talk about interaction
  • CROI 2010 talk – Now on a plot on left see the global CBF values for the three groups. What you can see is that there is a significant effect of HIV as the naïve subjects have lower CBF even though they have CD4s that are on average in the 350’s. In our HIV medicated patients there is an increase in CBF but they do not reach the baseline seen for controls. On the right we looked at the CBF not only in the brain overall but also within both cortical ( like the posterior cingulate and subcortical areas like the thalamus). What you can see is that the same trends hold here as they do for the global CBF. Even after introduction of meds the HIV patient never make it back all the way Incomplete recovery in patients with HAART suggests continued disturbances in the dynamic balance between synaptodendritic injury and repair.
  • Here are our results of 11 subjects that we followed longitudinally. After starting on meds we see a significant decrease in plasma VL . Overall more than 70 % of our subjects had undetectable VL. On the right we see the global CBF for these patients. In 10/11 subjects there was a rise in the CBF. Thus an inverse relationship existed between VL load decrease and an increase in CBF
  • How do we tie these results all together. Here we see antibodies to staining to presynaptic synaptophysin (SYP) and postsynaptic microtubule associated protein 2 (MAP2). So normally there is a tight coupling between neurons at the synapse and there is normal CBF providing the necessary nutrients to meet these metabolic demands. After HIV there is a disruption at the synapse and blebbing present. This lead to impairment or loss of synaptodendritric communication. This will lead to corresponding changes in cerebral blood flow and a decrease in CBF. With the introduction of HAART we can see some normalization of both the synapse and cerebral blood flow. But these changes are not complete These results nicely complement cardiovascular studies that have looked at lfow mediated dilation and seen similar results. Some of these changes though can be reversed after the administration of HAART and can have restoration of function Elevated CSF neurofilament protein (NFL) concentrations, for example, are thought to reflect injury to myelinated axons. CSF NFL levels are increased both in the context of HIV dementia40,41 and also after the interruption of cART, which results in a marked rebound of HIV replication.
  • Au: Duplicate slide. Which slide do you want to keep?
  • Au: Can you get through 41 slides in 30 minutes?
  • Miro et al, HIV THERAPY
  • C3 Neurological Complications and Treatment of HIV Clifford

    1. 1. HIV and the Brain: Update 2010 David B. Clifford, MD Melba and Forest Seay Professor Washington University in St. Louis
    2. 4. HIV-1 Associated Neurologic Problems <ul><li>Primary HIV-associated conditions </li></ul><ul><ul><li>HIV-associated neurocognitive disorder and dementia </li></ul></ul><ul><ul><li>Myelopathy </li></ul></ul><ul><ul><li>Peripheral neuropathy </li></ul></ul><ul><ul><li>Myopathy </li></ul></ul>
    3. 5. Selected Secondary Problems <ul><li>Toxoplasma encephalitis </li></ul><ul><li>PML </li></ul><ul><li>Syphilis </li></ul>
    4. 6. HIV-Associated Dementia (HAD) <ul><li>Formerly AIDS Dementia Complex </li></ul><ul><li>Occurs with low CD4 </li></ul><ul><li>Progressive – untreated death in 6 months </li></ul><ul><li>Correlates at least moderately to active viral replication (in CNS) </li></ul><ul><ul><li>CSF VL high </li></ul></ul><ul><li>Correlates to immune activation markers </li></ul><ul><li>Pathology: Multinucleated giant cells </li></ul>
    5. 7. Approved Antiretroviral Agents 1987 - 2010 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 Nucleoside RTI Non-Nucleoside RTI Protease Inhibitor Fusion Inhibitor CCR Inhibitor Integrase Inhibitor RTG MVC T-20 SQV NFV LPV/r SQV.sgc APV RTV IDV ATV RFV TPV DRV NVP EFV DLV ZDV DDI DDC d4T 3TC 3TC/ZDV ABC ABC/3TC/ZDV TDF 3TC/ABC FTC/TDF TDF/FTC/EFV ETR
    6. 8. Neurocognitive Impairment in the Pre-ARV, Pre-HAART and HAART Eras
    7. 9. Frascati Classification of H IV- A ssociated N eurocognitive D isorders (HAND) <ul><li>ANI = Asymptomatic neurocognitive impairment </li></ul><ul><li>MND = Mild neurocognitive disorder </li></ul><ul><li>HAD = HIV-1 associated dementia </li></ul>
    8. 10. Neurocognitive Impairment in the Pre-HAART and Post-HAART Eras Modified from Ellis et al, Nat Rev Neurosci 2007 and Grant et al., CROI 2009 Incidence but not prevalence of HIV-associated neurocognitive disorders (HAND) has declined with HAART
    9. 11. Cognitive Dysfunction in HIV <ul><li>HAND in HAART Era </li></ul><ul><li>Occurs at higher CD4 counts </li></ul><ul><li>Course stable or oscillating, still under investigation </li></ul><ul><li>Occurs with undetectable plasma VL, generally CSF VL also controlled (?almost) </li></ul><ul><li>Poorer correlation to immune activation markers </li></ul><ul><li>Pathology: minimal changes in brain </li></ul>Letendre et al, 16 th CROI 2009 , Abstract 484b
    10. 12. Cognitive Dysfunction in HIV <ul><li>AIDS Dementia (now HAD) </li></ul><ul><li>Pre-HAART </li></ul><ul><li>HAND (ANI/MND) </li></ul><ul><li>Post=HAART </li></ul>
    11. 13. Diagnosis CHARTER Neurocognitive Test Battery <ul><li>Verbal Fluency </li></ul><ul><ul><li>Letter Fluency </li></ul></ul><ul><ul><li>Category Fluency </li></ul></ul><ul><li>Speed of Information Proc. </li></ul><ul><ul><li>WAIS-III Symbol Search </li></ul></ul><ul><ul><li>WAIS-III Digit Symbol </li></ul></ul><ul><ul><li>Trail Making Test Part A </li></ul></ul><ul><li>Attention/Working Memory </li></ul><ul><ul><li>Paced Auditory Serial Addition Test - 50 </li></ul></ul><ul><ul><li>WAIS-III Letter-Number Sequencing </li></ul></ul><ul><li>Motor </li></ul><ul><ul><li>Grooved Pegboard </li></ul></ul><ul><li>Abstraction/Executive </li></ul><ul><ul><li>Wisconsin Card Sorting Test 64 </li></ul></ul><ul><ul><li>Trail Making Test Part B </li></ul></ul><ul><li>Learning and Memory </li></ul><ul><ul><li>Hopkins Verbal Learning Test-R </li></ul></ul><ul><ul><li>Brief Visuospatial Memory Test-R </li></ul></ul><ul><ul><li>Story Memory Test </li></ul></ul><ul><ul><li>Figure Memory Test </li></ul></ul><ul><ul><li>Everyday Functioning: Patient’s Assessment of Own Functioning Inventory </li></ul></ul><ul><ul><li>Activities of Daily Living Scale </li></ul></ul>
    12. 14. International HIV Dementia Scale <ul><li>International HIV Dementia Scale </li></ul><ul><ul><ul><li>Naming four objects </li></ul></ul></ul><ul><ul><ul><li>Fingertapping </li></ul></ul></ul><ul><ul><ul><li>“ Luria” psychomotor learning task </li></ul></ul></ul><ul><ul><ul><li>Recall of names </li></ul></ul></ul>Sacktor et al. Neurology 2003 60;1:A186-187
    13. 15. CogState http://library.cogstate.com/public/Brochures/12_Minute%20Brochure%20REV6_LowRes.pdf CROI 2010, Winston, et al Executive Function
    14. 16. Diagnosis NPZ -4 used in ACTG <ul><li>Trail making A and B </li></ul><ul><li>Symbol digit test </li></ul><ul><li>Hopkins Verbal Learning test </li></ul>Robertson, et al, ALLRT
    15. 17. Cognitive Screening Montreal Cognitive Assessment (MoCA) <ul><li>Broad balanced test </li></ul><ul><li>Online and free </li></ul><ul><li>Bedside scoring </li></ul><ul><li>Being assessed in comparison with tools currently used that require licenses, and norming </li></ul>http://www.mocatest.org/
    16. 18. What causes HAND now? <ul><li>Co-morbidities </li></ul><ul><li>Virus </li></ul><ul><li>Inflammation </li></ul><ul><li>Perfusion/Vascular </li></ul>
    17. 19. Is this all due to non-HIV- associated co-morbidities? <ul><li>Contribution of other factors to cognitive performance </li></ul><ul><ul><li>?trauma </li></ul></ul><ul><ul><li>?drugs </li></ul></ul><ul><ul><li>?hepatitis </li></ul></ul><ul><ul><li>?psychiatric dx/rx </li></ul></ul>
    18. 20. Neurocognitive Impairment by Co-Morbidity Status % impairment
    19. 21. Damaged brain may heal poorly CD4 Nadir <ul><li>Legacy of prior damage </li></ul><ul><li>Nadir CD4 count </li></ul><ul><ul><li>CHARTER analysis suggest significant impact of nadir <350 </li></ul></ul><ul><ul><li>Data too limited to test higher nadirs </li></ul></ul><ul><li>Implies earlier rx could be helpful </li></ul>CROI 2010, Poster 429, Ellis, et al
    20. 22. Correlates of CSF Viral Loads in 1,221 Volunteers of the CHARTER Cohort Scott Letendre, Chelsea FitzSimons, Ronald J. Ellis, David Clifford, Ann C. Collier, Benjamin Gelman, Christina Marra, Justin McArthur, J. Allen McCutchan, Susan Morgello, David Simpson, Florin Vaida, Robert Heaton, and Igor Grant for the CHARTER Group CROI 2010, #172
    21. 23. Distribution of CSF Viral Loads Off ART On ART
    22. 24. Correlates of Detectable CSF Viral Loads 842 Volunteers Taking ART Direction Uni Multi Plasma Viral Load Higher < 0.001 < 0.001 CD4+ Cell Count < 200 < 0.001 0.03† No. Past Antiretrovirals Larger 0.003 - Duration Current Regimen Shorter < 0.001 - Ethnicity Non-White < 0.001 0.003 Adherence < 95% < 0.001 0.09 Age Older 0.03 - CPE Rank Lower 0.007 < 0.001
    23. 25. CNS Penetration-Effectiveness Ranks 2010   4 3 2 1 NRTIs Zidovudine Abacavir Lamivudine Didanosine Emtricitabine Stavudine Tenofovir       Zalcitabine NNRTIs Nevirapine Delavirdine Etravirine     Efavirenz     PIs Indinavir-r Darunavir-r Atazanavir Nelfinavir Fosamprenavir-r Atazanavir-r Ritonavir Indinavir Fosamprenavir Saquinavir Lopinavir-r Saquinavir-r Tipranavir-r Entry Inhs   Vicriviroc Maraviroc   Enfuvirtide Integrase Inhs   Raltegravir    
    24. 26. CNS Penetration-Effectiveness Ranks CPE 2008 Ranks CPE 2010 Ranks Cross-Sectional Analysis p = 0.008 n = 467 Letendre S, et al. Arch Neurol 2008; 65:65-70
    25. 27. Associations Between CSF Viral Loads and Global NP Performance <ul><li>Higher CSF viral loads alone were not associated with worse NP performance </li></ul><ul><li>Comparing CSF to plasma viral loads identified that those whose CSF viral loads were at least as high as their plasma viral loads had worse NP performance </li></ul><ul><ul><li>R 2 = 0.28, p < 0.0001 </li></ul></ul>CSF VL ≥ Plasma VL Sample Size Cohen’s d p Value All Subjects 1,221 0.12 0.03 Not Taking ART 379 0.38 0.01 Minimal Comorbidities 207 0.65 0.001 Volunteers Not Taking ART Risk Direction Uni Multi CSF VL ≥ Plasma VL Higher 0.03 0.0003 Ethnicity White < 0.001 0.0002 CD4+ Cell Count Lower 0.003 0.002 Comorbidity Group Worse < 0.0001 < 0.0001
    26. 28. Conclusions <ul><li>Plasma viral load was the strongest correlate of CSF viral load, emphasizing the importance of systemic HIV suppression for control of HIV in the nervous system </li></ul><ul><ul><li>Without ART, higher CSF VLs also correlated with older age and more advanced current and past immunosuppression </li></ul></ul><ul><ul><li>With ART, detectable CSF VLs were associated with worse adherence, worse estimated antiretroviral penetration, and non-white ethnicity </li></ul></ul><ul><ul><li>The mechanisms by which age and ethnicity influence CSF VL are unknown </li></ul></ul><ul><li>Among people not taking ART, worse global neurocognitive performance was associated with having CSF VLs that were at least as high as plasma VLs </li></ul>
    27. 29. Does CPE have a downside? <ul><li>A5170 found stopping ARV resulted in cognitive improvement </li></ul><ul><li>ACTG 736 results suggested poorer performance in better penetrating regimens </li></ul><ul><li>Elevated penetration could cause increased toxicity </li></ul>CROI 2010, Liner et al, Poster 435 A=Control, B=ATV, C=EFV (dendrites), D=EFV(neuron loss) MAP-2 A B C D
    28. 30. ~60% still have elevated neopterin and IgG Index after 4 yrs HIV rx
    29. 31. Brain Perfusion
    30. 32. <ul><li>Multicenter AIDS Cohort </li></ul><ul><li>After accounting for education, depression and race </li></ul><ul><li>Carotid intima-media thickness (IMT) and GFR associated with psychomotor speed </li></ul><ul><li>IMT associated with memory </li></ul><ul><li>HIV serostatus not associated with poorer cognitive performance overall </li></ul><ul><li>In HIV+, HIV detection in plasma associated with poorer memory </li></ul>
    31. 33. Cardiovascular Risks Associated with Poor Cognitive Performance in SMART Study <ul><li>Traditional HIV associated risk factors were not associated with baseline NP performance </li></ul><ul><li>CVD risk factors were associated with poorer baseline performance </li></ul>CROI 2010
    32. 34. HIV Indirectly Contributes to Cognitive Impairment? Cognitive Normal Cognitive Impaired Carotid Intima Thickening HIV Age HBP DM Lipids
    33. 35. Arterial spin labeling (ASL) measures cerebral blood flow (CBF) Control - Tag  CBF (mL/100mL/min) Ances, Abst 157 CROI2009 Tag by Magnetic Inversion Wait Acquire image 1: Control Wait Acquire image 2:
    34. 36. Effects of HIV and Aging on rCBF Ances et al. , JID, Feb 2010 Age (years old)
    35. 37. Cross sectional: Global and Regional rCBF Are Affected by HAART HIV+ Naive HIV+ Meds HIV- Controls ( n=26 ) ( n=26 ) ( n=13 ) P < 0.05 P < 0.01 P < 0.05 P < 0.05 P < 0.05 P < 0.05
    36. 38. Longitudinal: HAART Affects HIV Viral Load and Global rCBF
    37. 39. HIV Causes Synaptodendritic Injury Leading to Reduction in rCBF Normal Synapto- dendritic Density HIV Normal Cerebral Blood Flow Disruption or Loss of Synapto-dendritic communication Reduced Cerebral Blood Flow HAART Masliah et al, Ann Neurol 1997 Masliah et al, Ann Neurol 1997
    38. 40. Modifiable Risk Factors <ul><li>Smoking </li></ul><ul><li>Diet </li></ul><ul><ul><li>Glucose </li></ul></ul><ul><ul><li>Lipids </li></ul></ul><ul><li>Rest </li></ul><ul><li>Exercise </li></ul><ul><ul><li>Physical </li></ul></ul><ul><ul><li>Mental </li></ul></ul>
    39. 41. Modifiable Risk Factors <ul><li>Smoking </li></ul><ul><li>Diet </li></ul><ul><ul><li>Glucose </li></ul></ul><ul><ul><li>Lipids </li></ul></ul><ul><li>Rest </li></ul><ul><li>Exercise </li></ul><ul><ul><li>Physical </li></ul></ul><ul><ul><li>Mental </li></ul></ul>
    40. 42. Conclusions <ul><li>Cognitive functions remain impaired in many optimally treated HIV patients </li></ul><ul><li>Optimal therapy should avoid low nadir CD4, optimize HIV control, minimize chronic immune activation, and optimize cerebral perfusion </li></ul><ul><li>Healthy lifestyles as well as HIV control should contribute to better neurologic outcomes </li></ul>
    41. 43. History <ul><li>34 yo woman from Liberia </li></ul><ul><li>AIDS, off Rx, CD4 <50 </li></ul><ul><li>Extrapulmonary tuberculosis in elbow and leg for several years </li></ul><ul><li>Hepatitis B </li></ul><ul><li>Cardiomyopathy </li></ul><ul><li>Positive serum RPR </li></ul><ul><li>Presents with headache 10/09 </li></ul>
    42. 44. Extrapulmonary TBC – 2008 Clavicle Aspiration of lesion yields AFB
    43. 45. CT Brain – October 2009
    44. 46. History 2 <ul><li>Workup non-diagnostic </li></ul><ul><ul><li>CSF benign </li></ul></ul><ul><ul><li>CSF PCR negative for EBV, toxo, JC HSV </li></ul></ul><ul><ul><li>CSF cultures negative </li></ul></ul><ul><li>Neurosurgery unwilling to biopsy brain </li></ul><ul><li>Treated for TBC with four drugs, taken intermittently </li></ul><ul><li>Presents 01/2010 worsening </li></ul><ul><ul><li>Control right hand poor, decreased feeling in right hand </li></ul></ul>
    45. 49. Lab Eval 2010 <ul><li>CSF </li></ul><ul><ul><li>15 cells (lyms) </li></ul></ul><ul><ul><li>Glucose 70 mg/dl, protein 56 mg/dl </li></ul></ul><ul><ul><li>Toxo PCR positive, EBV negative </li></ul></ul><ul><li>Plasma </li></ul><ul><ul><li>Neg histoplasma, coccidio </li></ul></ul><ul><ul><li>RPR 1:4, FTA negative </li></ul></ul>
    46. 50. Toxoplasma Encephalitis
    47. 51. Toxoplasma Strains Type II Most commonly cause toxoplasmosis Type I : Rarer but pathologic Type III Rarely assoc with dx
    48. 52. Signs/Sx of Toxoplasmosis <ul><li>Headache </li></ul><ul><li>Fever </li></ul><ul><li>Confusion </li></ul><ul><li>Hemiparesis, other focal signs </li></ul><ul><li>Posterior fossa syndrome </li></ul><ul><li>Seizures </li></ul><ul><li>ICP elevation </li></ul>
    49. 54. Therapy for Toxoplasma encephalitis <ul><li>Initiation of HAART at appropriate time </li></ul><ul><li>Primary prevention </li></ul><ul><ul><li>If CD4 < 200 use primary prophylaxis </li></ul></ul><ul><ul><li>Same as for P. jerevicii </li></ul></ul>
    50. 55. TE Therapy <ul><li>Sulfadiazine/Pyrimethamine/Folinic Acid </li></ul><ul><ul><li>Pyrimethamine 200 mg po loading dose, then 75 mg PO qd </li></ul></ul><ul><ul><li>Sulfadiazine 1.5 grams q 6 h </li></ul></ul><ul><ul><li>Folinic acid 5-10 mg qd PO </li></ul></ul><ul><li>Problems </li></ul><ul><ul><li>Sulfa allergies </li></ul></ul><ul><ul><li>Crystalluria </li></ul></ul><ul><ul><li>Oral Pill burden </li></ul></ul>
    51. 56. TE Therapy <ul><li>Alternative for sulfadiazine: Clindamycin 150-300 mg q6h IV/PO </li></ul><ul><ul><li>Allergies </li></ul></ul><ul><ul><li>GI toxicity </li></ul></ul>
    52. 57. Co-trimoxizole as therapy <ul><li>Anecdotal experience and case reports </li></ul><ul><li>Pilot study: Torre et al (Italian Collaborative Study Group), Antimicrob Agents and Chemoth 1998; 1346-9. </li></ul><ul><li>Randomized pilot study </li></ul><ul><li>Suggests T-S may be reasonable alternative to P-S, but lacked power to demonstrate noninferiority </li></ul>
    53. 58. Mortality of AIDS Defining Complications CROI 2007, Abstract 80, Mocroft et al Data derived from 15 HIV cohort studies including >30K subjects Graber et al, CROI 07 Abstract 525, also identifies PML as one of the conditions in which HAART has had the least impact on mortality hazard ratio
    54. 59. Progressive Multifocal Leukoencephalopathy <ul><li>Acquired demyelinating CNS disease </li></ul><ul><li>JC virus is etiologic agent </li></ul><ul><li>~5% of untreated HIV deaths </li></ul><ul><li>Disease exclusively in immunocompromised </li></ul><ul><li>Remains problem in HAART era, and in other populations </li></ul><ul><li>Worldwide distribution </li></ul>
    55. 60. Clinical Aspects of PML <ul><li>Signs and symptoms dependent on lesion location </li></ul><ul><ul><li>Motor sx </li></ul></ul><ul><ul><li>Seizures (20%) </li></ul></ul><ul><ul><li>Behavioral signs </li></ul></ul><ul><li>Progressive over weeks to a few months </li></ul><ul><li>Generally have dominant clinical focus that progresses and is consistent with MR lesion visualized </li></ul>
    56. 61. PML Survival in HAART Era
    57. 62. PML IRIS Vendrely, et al Acta Neuropathol (2005) 109:449-455 <ul><li>HIV associated PML with cognitive presentation </li></ul><ul><li>Brisk increase of CD4 117 to 300 and drop in HIV VL </li></ul><ul><li>Clinical state continued to progress </li></ul><ul><li>Biopsy performed </li></ul>
    58. 63. CSF PCR Performance Marzocchetti et al, J. Clin Microbiol, 2005
    59. 64. Therapeutic Approaches <ul><ul><li>Immune reconstitution </li></ul></ul><ul><ul><li>Adjunctive therapy </li></ul></ul><ul><ul><ul><li>Cytosine arabinoside </li></ul></ul></ul><ul><ul><ul><li>Cidofovir </li></ul></ul></ul><ul><ul><ul><li>5HT2a inhibitors (mirtazepine) </li></ul></ul></ul><ul><ul><ul><li>Mefloquine </li></ul></ul></ul>
    60. 65. Mefloquine (Larium) <ul><li>Antimalarial drug </li></ul><ul><ul><li>11 million people have taken since 1984 </li></ul></ul><ul><li>Toxicity </li></ul><ul><ul><li>Psychiatric sx: anxiety, paranoia, depression, hallucinations, psychotic behavior </li></ul></ul><ul><ul><li>Increased risk of sz in epilpetics </li></ul></ul><ul><ul><li>Prolong QTc with quinine derivatives </li></ul></ul><ul><li>Clinical trial now in progress </li></ul>
    61. 66. Case History <ul><li>67 yo married WM </li></ul><ul><li>3 wks increasing severe leg and back pain </li></ul><ul><li>HIV discovered 3 mo previously </li></ul><ul><li>CD4 75 </li></ul><ul><li>Atripla started 2 mo ago </li></ul>
    62. 67. Exam <ul><li>Articulate lawyer complaining of radicular pain to legs </li></ul><ul><li>Reflexes increased </li></ul><ul><li>No distal sensory loss </li></ul>
    63. 68. Localization <ul><li>Peripheral nerve? </li></ul><ul><ul><li>Wrong history </li></ul></ul><ul><ul><li>Wrong exam </li></ul></ul><ul><ul><li>No other risks identified </li></ul></ul><ul><li>Spinal cord ?– radicular </li></ul><ul><ul><li>Brisk reflexes suggest UMN finding </li></ul></ul><ul><ul><li>Radicular suggests root </li></ul></ul><ul><ul><li>Babinski </li></ul></ul><ul><li>MR scan ordered to rule out compressive lesion </li></ul><ul><li>B12/folate </li></ul><ul><li>Copper </li></ul><ul><li>HTLV-1 </li></ul><ul><li>Records checked </li></ul><ul><ul><li>NO RPR </li></ul></ul>
    64. 69. Syphilis <ul><li>++RPR 1:128 </li></ul><ul><li>+FTA </li></ul><ul><li>CSF inflammatory with +VDRL </li></ul><ul><li>PCN treatment resulted in prompt improvement </li></ul>
    65. 70. Neurosyphilis and HIV <ul><li>Concurrent syphilis and HIV exposure not rare </li></ul><ul><li>Course to neurosyphilis may be accelerated in HIV </li></ul><ul><li>IRIS and syphilis may explain this presentation </li></ul><ul><li>Treatment may be more difficult </li></ul><ul><li>Care to consider syphilis, and treat aggressively with close followup important </li></ul>
    66. 71. Neurologic Complications in HIV <ul><li>Primary </li></ul><ul><ul><li>Cognitive </li></ul></ul><ul><ul><li>Peripheral nerve </li></ul></ul><ul><li>Secondary </li></ul><ul><ul><li>Toxoplasma </li></ul></ul><ul><ul><li>PML </li></ul></ul><ul><ul><li>Syphilis </li></ul></ul><ul><li>Diagnosis important </li></ul><ul><li>All are now treatable </li></ul><ul><li>Ongoing investigations promise better outcomes </li></ul>
    67. 72. <ul><li>CHARTER investigators </li></ul><ul><ul><li>Igor Grant </li></ul></ul><ul><ul><li>Ann Collier </li></ul></ul><ul><ul><li>Ben Gelman </li></ul></ul><ul><ul><li>Justin McArthur </li></ul></ul><ul><ul><li>David Simpson </li></ul></ul><ul><ul><li>Susan Morgello </li></ul></ul><ul><ul><li>Scott Letendre </li></ul></ul><ul><ul><li>Ron Ellis </li></ul></ul><ul><li>NARC investigators </li></ul><ul><li>ACTG investigators </li></ul><ul><li>Washington U – STL </li></ul><ul><ul><li>Turner Overton </li></ul></ul><ul><ul><li>Beau Ances </li></ul></ul><ul><ul><li>Mary Gould </li></ul></ul><ul><ul><li>Mengesha Teshome </li></ul></ul><ul><li>Patients and families </li></ul>Washington University AIDS Trials Group Thanks !
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