Post-Congress Activity Expert Review on the EACS, HIV & Aging and the AASLD Meetings With Dr. Mark Wainberg (moderator) and Dr. Fred Crouzat, Dr. Alice Tseng, and Dr. Stephen Shafran

2nd International Workshop on HIV and Aging October 27-28, 2011 Baltimore, Maryland

Conceptual Model for Aging with HIV Infection Viral Hepatitis Alcohol and Other Substance Abuse AGING Presenting Conditions VACS Risk Index Interacting Pathophysiologic Processes Immune Dysfunction and Senescence. Microbial Translocation “Leaky Gut” Chronic Inflammation and Platelet Hypercoagulability HIV and Non-HIV Treatment Toxicity Oxidative Stress. Associated Comorbid Disease Organ System Injury Incremental Depletion in Organ System Reserve Health Care Outcomes Advanced Clinical Disease Functional Decline Organ System Failure Repeated Hospitalization/ Nursing Home Placement Death Adapted from Justice A et al. Alcohol Res Health 2010;33:258-66.

Guaraldi G, et al. Clin Infect Dis. 2011;53(11):1120-6 Guaraldi G, et al. Clin Infect Dis. 2011;53(11):1120-6. Epub 2011 Oct 13.

Untreated Cerebrovascular Disease May Have Implications for Cognitive Impairment (CI) in HIV MACS cohort: n = 207 HIV- & 428 HIV+ men, median ~50 yo, CD4 535, no history of CVD  carotid intima media thickness (IMT) and fasting glucose were predictors of poor psychomotor speed performance (p=0.04 & 0.037) AIDS, detectable VL and CD4 were not significant predictors SMART study: n=292, median CD4 536, 88% VL<400, 92% on cART Risk of cognitive impairment higher in pts with pre-existing CVD (OR 6.2, CI 1.4–26.4); use of HTN agents,  cholesterol & HBV also risk factors Current/nadir CD4, CPE scores not associated with impairment Results suggest that risk of CI more strongly related to CV & metabolic disease profiles than HIV serostatus or disease Neurology. 2009 Oct 20;73(16):1292-9. Vascular risk factors, HIV serostatus, and cognitive dysfunction in gay and bisexual men. Becker JT, Kingsley L, Mullen J, Cohen B, Martin E, Miller EN, Ragin A, Sacktor N, Selnes OA, Visscher BR; Multicenter AIDS Cohort Study. COLLABORATORS (63) Margolick JB, Armenian H, Crain B, Dobs A, Farzadegan H, Gallant J, Hylton J, Johnson L, Lai S, Sacktor N, Selnes O, Shepard J, Thio C, Phair JP, Chmiel JS, Badri S, Cohen B, Conover C, O'Gorman M, Ostrow D, Palella F, Variakojis D, Wolinsky SM, Detels R, Visscher BR, Aronow A, Bolan R, Breen E, Butch A, Coates T, Effros R, Fahey J, Jamieson B, Martínez-Maza O, Miller EN, Oishi J, Satz P, Vinters H, Wiley D, Witt M, Yang O, Young S, Zhang ZF, Rinaldo CR, Kingsley L, Becker JT, Evans RW, Mellors J, Riddler S, Silvestre A, Jacobson LP, Munoz A, Cole SR, Cox C, D'Souza G, Gange SJ, Schollenberger J, Seaberg EC, Su S, Huebner RE, Dominguez G, McDonald C, Brouwers P. Source University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. beckerjt@upmc.edu Abstract BACKGROUND: The purpose of this study was to evaluate the relationship between cognitive performance, risk factors for cardiovascular and cerebrovascular disease (CVD), and HIV infection in the era of highly active antiretroviral therapy. METHODS: We evaluated the cognitive functions of men enrolled in the cardiovascular disease substudy of the Multicenter AIDS Cohort Study who were aged > or =40 years, with no self-reported history of heart disease or cerebrovascular disease. Results from comprehensive neuropsychological evaluations were used to construct composite scores of psychomotor speed and memory performance. Subclinical CVD was assessed by measuring coronary artery calcium and carotid artery intima-media thickness (IMT), as well as laboratory measures, including total cholesterol, fasting glucose, glycosylated hemoglobin, glomerular filtration rate (estimated), and standardized blood pressure and heart rate measures. RESULTS: After accounting for education, depression, and race, carotid IMT and glomerular filtration rate were significantly associated with psychomotor speed, whereas IMT was associated with memory test performance. HIV serostatus was not significantly associated with poorer cognitive test performance. However, among the HIV-infected individuals, the presence of detectable HIV RNA in plasma was linked to lower memory performance. CONCLUSIONS: These findings suggest that HIV infection may not be the most important predictor of cognitive performance among older gay and bisexual men in the post-highly active antiretroviral therapy era, at least among those with access to medical care and to appropriate medications. Medical factors associated with normal aging are significantly associated with performance on neuropsychological tests, and good clinical management of these factors both in HIV-infected individuals and those at risk for infection may have beneficial effects in the short term and could reduce the risk of subsequent cognitive decline. Neurology. 2010 Sep 7;75(10):864-73. Epub 2010 Aug 11. Cardiovascular risk factors associated with lower baseline cognitive performance in HIV-positive persons. Wright EJ, Grund B, Robertson K, Brew BJ, Roediger M, Bain MP, Drummond F, Vjecha MJ, Hoy J, Miller C, Penalva de Oliveira AC, Pumpradit W, Shlay JC, El-Sadr W, Price RW; INSIGHT SMART Study Group. Infectious Diseases Unit, Alfred Hospital, Commercial Road, Melbourne, Victoria 3004, Australia. e.wright@alfred.org.au OBJECTIVE: To determine factors associated with baseline neurocognitive performance in HIV-infected participants enrolled in the Strategies for Management of Antiretroviral Therapy (SMART) neurology substudy. Participants from Australia, North America, Brazil, and Thailand were administered a 5-test neurocognitive battery. Z scores and the neurocognitive performance outcome measure, the quantitative neurocognitive performance z score (QNPZ-5), were calculated using US norms. Neurocognitive impairment was defined as z scores <-2 in two or more cognitive domains. Associations of test scores, the QNPZ-5, and impairment with baseline factors including demographics and risk factors for HIV-associated dementia (HAD) and cardiovascular disease (CVD) were determined in multiple regression. The 292 participants had a median CD4 cell count of 536 cells/mm(3), 88% had an HIV viral load < or =400 copies/mL, and 92% were taking antiretrovirals. Demographics, HIV, and clinical factors differed between locations. The mean QNPZ-5 score was -0.72; 14% of participants had neurocognitive impairment. For most tests, scores and z scores differed significantly between locations, with and without adjustment for age, sex, education, and race. Prior CVD was associated with neurocognitive impairment. Prior CVD, hypercholesterolemia, and hypertension were associated with poorer neurocognitive performance but conventional HAD risk factors and the CNS penetration effectiveness rank of antiretroviral regimens were not. In this HIV-positive population with high CD4 cell counts, neurocognitive impairment was associated with prior CVD. Lower neurocognitive performance was associated with prior CVD, hypertension, and hypercholesterolemia, but not conventional HAD risk factors. The contribution of CVD and cardiovascular risk factors to the neurocognition of HIV-positive populations warrants further investigation. Becker JT, et al. Neurology 2009;73:1292-9. Wright EJ, et al. Neurology 2010 ;75:864-73.

Treatment of Vascular Risk Factors Impacts Neurocognitive Function in HIV n=98 HIV+ adults mean 44 yo, 81% male, 70% AA, 62% prior AIDS 23 pts with CVS risk factors (DM, HTN) 13 treated, 10 untreated Pts with untreated CVS risk demonstrated  processing speed, learning/memory and executive functioning vs. those on medication (p=0.01, 0.04, 0.09) Clin Neuropsychol. 2010 Feb;24(2):265-85. Neurocognitive functioning in HIV-1 infection: effects of cerebrovascular risk factors and age. Foley J, Ettenhofer M, Wright MJ, Siddiqi I, Choi M, Thames AD, Mason K, Castellon S, Hinkin CH. Source UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA 90095-8353, USA. jmfoley@ucla.edu Abstract This study examined the interactive effects of cerebrovascular risks, advancing age, and HIV infection on neurocognition, and explored whether pharmacological treatment of cerebrovascular risk factors attenuated neurocognitive dysfunction. Participants included 98 HIV-seropositive adults (cerebrovascular risk: 23.5%; age > 50: 27.6%). Cerebrovascular risk was associated with slower processing speed even after controlling for age effects (b = -2.071; p =.04), and the interaction of age and cerebrovascular risk was associated with poorer verbal fluency (b = 1.276, p =.002). Participants with pharmacologically untreated cerebrovascular risk demonstrated reduced processing speed, learning/memory, and executive functioning relative to those on medication. Poor cerebrovascular health confers significant risk for HIV+ individuals, and this effect may be of greater consequence than advancing age. The cognitive impact of risk appears to be more pronounced in the absence of adequate pharmacological treatment. Foley J, et al. Clin Neuropsychol 2010;24:265-85.

Strategies to Improve Cognition Mindfulness-Based Cognitive Therapy (MBCT) 40 HIV+ subjects randomized to participate in MBCT (2-hr class/wk x 8) or continue with routine care mean 50 yo, 20 yrs since HIV Dx, 16 yrs on ART, current CD4 527, VL<25 in 39 subjects MBCT group reported significant  in quality of life vs. controls (energy, pain, emotional reactions, sleep, social isolation, mobility) Visualization/Mental Imagery 70 HIV+ pts assigned prospective memory (PM) medication task; randomized to visualization exercise vs. repeating instructions 83% male, mean 56 yo, 70% Caucasian, 91% cART, 93% CD4 >200, 85% VL undetectable visualization significantly improved ability to complete PM task (55% vs. 30%, p<0.05) Fumaz et al. [#O_09]. Presented at the 2nd International Workshop on HIV & Aging, October 27-28, 2011, Baltimore, USA. Woods et al. Ibid, #O_10.

Saturday, November 19th, 2011

Falls: A Geriatric Syndrome Falls common in people ≥ 65 yrs of age 30% rate per year, associated with significant morbidity (ER visits, nursing home placements, loss of independence) Risk factors: comorbidities (depression, HTN, arthritis, DM, pain, urinary incontinence) physical impairment (balance, strength, gait, cognition) polypharmacy (esp. psychoactive meds) Erlandson KM, et al. [#O_05] Presented at the 2nd International Workshop on HIV & Aging, October 27-28, 2011, Baltimore, USA.

Falls in HIV-Infected Persons: Prevalence and Risk Factors Cross-sectional study of 359 HIV+ pts 45-65 yo on cART for > 6 months with VL<48 copies/mL Verbally questioned about falls in past year 70% no falls 30% ≥ 1 fall 18% frequent falls (≥ 2 falls) Current CD4, nadir CD4, duration of ART similar b/w frequent & non-fallers Risk factors for frequent falls: female, smokers, comorbidities and polypharmacy (p<0.01) Frequent fallers: weaker grip strength, greater difficulty arising from a chair, greater difficulty with balance, slower gait speed over 400 m (all statistically significant) Frailty by Fried’s definition1 (OR 9.3, CI 3.6-24.3, p<0.001) Conclusions: fall risk for middle-aged HIV+ persons is consistent with rates in general population ≥ 65 yo  risk with comorbidities and meds Fried and colleagues [2] reported an operational definition of frailty based on the presence of three or more frailty indicators: unintentional weight loss, slow walking speed, subjective exhaustion, low grip strength and low levels of physical activity. Fried LP, Tangen CM, Walston J, et al. ; Cardiovascular Health Study Collaborative Research Group. Frailty in older adults: evidence for a phenotype. J Gerontol Med Sci 2001;56:M146-56. Erlandson KM, et al. [#O_05] Presented at the 2nd International Workshop on HIV & Aging, October 27-28, 2011, Baltimore, USA.

Multiple Comorbidities are Associated with Greater Fall Risk in HIV-1 Infected Persons OR (CI) 3.0 (1.4-6.8) 5.6 (2.6-12.1) 3.2 (1.8-5.6) 8.2 (2.0-33.9) 3.2 (1.5-5.5) 4.6 (2.6-8.2) 3.7 (1.9-6.9) Erlandson KM, et al. [#O_05] Presented at the 2nd International Workshop on HIV & Aging, October 27-28, 2011, Baltimore, USA.

Polypharmacy is Associated with Greater Odds of Falling in HIV-Infected Persons OR (CI) 3.6 (1.8-7.3) 4.5 (2.6-8.1) 3.9 (1.9-8.1) 4.6 (2.6-8.1) 2.8 (1.4-5.3) 5.5 (3.1-9.8) Erlandson KM, et al. [#O_05] Presented at the 2nd International Workshop on HIV & Aging, October 27-28, 2011, Baltimore, USA.

Frailty and Hospitalizations in IDUs Prospective cohort of subjects with current/past IDU n=1206, median 48 yo, 4652 person visits 28% HIV+ (n=345): median CD4 290, VL 3.1 log, CD4 nadir 138, 21.7% AIDS diagnosis, 51% on cART Overall prevalence of frailty 8.3%, pre-frailty 59% associated with age, female, socioeconomic class, depressive Sx, HIV status higher risk in advanced HIV with poor virologic control frailty was an independent predictor of hospitalization (adjusted HR 1.5, CI 1.01-2.17) Criteria: weight loss, low physical activity, exhaustion, weakness, slow gait Frailty phenotype: frail = 3 or more criteria prefrail = 1 or 2 criteria robust = 0 Piggott DA, et al. Frailty and Incident Hospitalization among HIV+ and At Risk Injection Drug Users (IDUs). [#O_06]. Presented at the 2nd International Workshop on HIV & Aging, October 27-28, 2011, Baltimore, USA.

Frailty and Hospitalizations in IDUs Frailty and HIV Clinical Status: Prefrail Adj OR* (95% CI) Frail Adj OR* (95% CI) HIV negative Ref HIV+, CD4350, VL UD 1.14 (0.81, 1.62) 1.13 (0.65, 1.97) HIV+, CD4<350, VL UD 1.37 (0.97, 1.95) 1.75 (1.02, 2.98) HIV+, CD4350, VL+ 1.14 (0.79, 1.63) 1.80 (1.00, 3.21) HIV+, CD4<350, VL+ 1.49 (1.17, 1.89) 2.26 (1.51, 3.39) Criteria: weight loss, low physical activity, exhaustion, weakness, slow gait Frailty phenotype: frail = 3 or more criteria prefrail = 1 or 2 criteria robust = 0 Piggott DA, et al. Frailty and Incident Hospitalization among HIV+ and At Risk Injection Drug Users (IDUs). [#O_06]. Presented at the 2nd International Workshop on HIV & Aging, October 27-28, 2011, Baltimore, USA.

Hospitalization by Frailty Status in ALIVE Piggott DA, et al. Frailty and Incident Hospitalization among HIV+ and At Risk Injection Drug Users (IDUs). [#O_06]. Presented at the 2nd International Workshop on HIV & Aging, October 27-28, 2011, Baltimore, USA.

Current Realities/Challenges of Aging Well with HIV Cure DNA repair oxidative stress telomere protection? HIV cure vs. Chronic Management medication adherence exercise risk modification management of comorbidities cognitive-based tx search for treatable factors Adapted from Valcour V. Presented at the 2nd International Workshop on HIV & Aging, October 27-28, 2011, Baltimore, USA.