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Semelhante a C3 Neurological Complications and Treatment of HIV Clifford
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C3 Neurological Complications and Treatment of HIV Clifford
- 1. HIV and the Brain: Update 2010 David B. Clifford, MD Melba and Forest Seay Professor Washington University in St. Louis
- 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
- 8. Neurocognitive Impairment in the Pre-ARV, Pre-HAART and HAART Eras
- 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
- 15. CogState http://library.cogstate.com/public/Brochures/12_Minute%20Brochure%20REV6_LowRes.pdf CROI 2010, Winston, et al Executive Function
- 20. Neurocognitive Impairment by Co-Morbidity Status % impairment
- 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
- 23. Distribution of CSF Viral Loads Off ART On ART
- 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
- 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
- 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
- 30. ~60% still have elevated neopterin and IgG Index after 4 yrs HIV rx
- 31. Brain Perfusion
- 34. HIV Indirectly Contributes to Cognitive Impairment? Cognitive Normal Cognitive Impaired Carotid Intima Thickening HIV Age HBP DM Lipids
- 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:
- 36. Effects of HIV and Aging on rCBF Ances et al. , JID, Feb 2010 Age (years old)
- 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
- 38. Longitudinal: HAART Affects HIV Viral Load and Global rCBF
- 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
- 44. Extrapulmonary TBC – 2008 Clavicle Aspiration of lesion yields AFB
- 45. CT Brain – October 2009
- 51. Toxoplasma Strains Type II Most commonly cause toxoplasmosis Type I : Rarer but pathologic Type III Rarely assoc with dx
- 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
- 61. PML Survival in HAART Era
- 63. CSF PCR Performance Marzocchetti et al, J. Clin Microbiol, 2005
Notas do Editor
- 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. > 200): non-white ethnicity is only associated with detectable CSF viral loads in those who have CD4 counts > 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>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