HIV and Aging: The Importance of a Nuanced Approach Amy C. Justice, MD, PhD Professor, Yale University School of Medicine Section Chief, General Internal Medicine, VA Connecticut November 15, 2010 OHTN 2010, Toronto Ontario

Epidemiology Clinical Issues A New Approach to Care

2010 Success In United States: Everywhere cART available: Once daily pill (FTC/TDF/EFV) is well tolerated and achieves viral suppression in 84%* 85% of patients start on this and remain on it for extended periods** Everywhere cART available: Median CD4 counts increasing Viral load are declining AIDS defining events are rare *Gallent JE. et al. Tenofavir DF, Emtricitabine, and Efavirenz vs. Zidovudine, Lamivudine, and Efavirenz for HIV. NEJM 2006 354:251-60.**McKinnell JA. et al ARV Prescribing Patterns in Treatment-Naïve Patients in the United States. AIDS Patient Care and STDs 2010 24:79-85

Life Expectancy on HAART At HAART Initiation CD4 Cell Count (mm3) <100 100-199 >200 A 20 yr old will live to (years) 52 62 70 A 35 yr old will live to (years) 65 72 % Remaining Life Lost (all ages) 46% 27% 14% Adapted from ART-CC, Lancet 2008;372:293-99

Projected For years 2001-2003, data is based on 33 states and U.S. dependent areas with confidential name-based HIV infection reporting, Centers for Disease Control: HIV/AIDS Surveillance Report, 2005. For years 2004-2007, data is based on 34 states and 5 U.S. dependent areas with confidential name-based HIV infection reporting, Centers for Disease Control: HIV/AIDS Surveillance Report, 2007 *Data from 2008, onward projected based on 2001-2007 trends (calculated by author), 2001-2007 data from CDC Surveillance Reports 2007. New York and San Francisco data from their Departments of Public Health

Also an Issue in Sub-Saharan Africa 14% of those living with HIV are estimated to be 50+ years of age (3 million people) AIDS is the leading cause of death among those 50+ years (17%) 4% of those 50+ years old are infected with HIV (5% among <50 years) Negin J. Cumming RG. HIV Infection in Older Adults in sub-Saharan Africa: Extrapolating Prevalence from Existing Data Bull World Health Organ 2010; 88:847-853

Sex is Not Only for the Young Proportion reporting sex in last 12 months Based on ACRIA brochure, HIV and Older Adults (first three bullets) The first three bullets seem to be conflicting, but I rechecked the book from which the stats came (HIV/AIDS in Older Adults) and they were listed as such Lindau ST. et al. …Sexuality and Health among Older Adults in the US NEJM 2007 357(8):762-774

Sexual Risks Specific to Older Adults Everywhere Newly single (widowed/divorced) status Ratio of men to women increasingly skewed Less likely to use condoms Post menopausal women pregnancy no longer possible Men may have erectile dysfunction complicating condom use Lower estrogen lead to vaginal dryness and increased risk of virus entering blood stream

New HIV Diagnoses Over Age 50 Years Diagnoses of HIV Infection and AIDS in the US and Dependent Areas, 2008. HIV surveillance Report, Volume 20, CDC (2010).

Epidemiology Clinical Issues A New Approach to Care

Delayed Presentation By Age (NA ACCORD) Althoff KN. et al. under review, AIDS Research Therapy, presented HIV and Aging Meeting, Baltimore Oct 5 2010

12 Months after HIV Diagnosis by Age, 2007 (US Data: 37 states with confidential name-based HIV infection reporting) HIV surveillance Report, Volume 20, CDC (2010)

Immunity in HIV and Aging Synergistic effects of HIV and Aging lead to: Reduced naïve T cell numbers Increased levels of “senescent” T cells Reduced naïve CD4 diversity These changes accompanied by: Low level immune activation and inflammation In gut , loss of mucosal integrity/microbial translocation, contributes to inflammation

CD4 Response to cART by Age Age (yrs) Adjusted Hazard OR 18-<30 ref 30-<40 0.92 (0.85, 1.00) 40-<50 0.85 (0.78, 0.92) 50-<60 0.74 (0.65, 0.85) Althoff KN et al. AIDS 2010 24:2469-2479

Veterans Aging Cohort Study (VACS) Uses electronic medical record data pulled from the US VA national system Supplemented with patient surveys, chart reviews, registries, blood and tissue samples Two studies of HIV infected and age/race-ethnicity/site matched uninfected Virtual Cohort: 40K HIV+, 80K HIV- VAC 8: 3500 HIV+, 3500 HIV-

HANA Events Among HIV Infected and Demographically Matched Uninfected* 300 Events/10,000 Person Years *For references see end of talk

Likely To Increase with Aging Effects of chronic “inflammation” Liver disease, lung disease, bone marrow suppression Vascular disease, renal disease Cancer Multimorbidity Adverse events from poly pharmacy Organ system injury from multiple causes (frailty) Increased demand for supportive care services Need to prioritize care based on individual risk, patient preferences, and likely effectiveness

Epidemiology Clinical Issues A New Approach to Care

Multimorbidity and Aging Multimorbidity is the rule and increases with age Guidelines rarely consider other conditions Primary care providers Do not have time to attend to existing guidelines May make (somewhat arbitrary) priority decisions HIV providers have little guidance regarding management of age associated conditions Associated with HIV infection (HANA) Not associated with HIV

In Aging One Size Does Not Fit All As much variation in response and outcome within age strata as across them Need to differentiate priorities at: cART initiation (HIV primary focus) cART maintenance (Multimorbidity) End of life (Symptom management) We need to provide more nuanced care—tailored to risks/priorities of patient at that time

What Use is an Index? Intermediate outcome to compare effectiveness across interventions Individualized integration of benefit and harm from treatment Motivate behavior change A measure to study cumulative effects of multimorbidity and polypharmacy

Veterans Aging Cohort Study Risk Index (VACS Index) Composed of age and laboratory tests currently recommended for clinical management HIV Biomarkers: HIV-1 RNA and CD4 Count “non HIV Biomarkers”: Hemoglobin, hepatitis C, composite markers for liver and renal injury Developed in US veterans, validated in Europe and North America

Composite Biomarkers AGE * AST FIB 4 = PLT * sqrt(ALT ) eGFR = 186.3 * CREAT -1.154 * AGE -0.203 * FEM_VAL * BLACK_VAL FEM_VAL = 0.742 if female, 1 if male BLACK_VAL = 1.21 if black, 1 otherwise Sterling RK et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV Coinfection. Hepatology 2006 43:1317-1325 Stevens LA et al. Assessing Kidney Function-Measured and Estimated Glomerular Filtration Rate. NEJM 2006; 354:2473-2483

For more information: www.vacohort.org Tate J. et al. IDSA 2010 Vancouver, BC October 21-24th. Poster 1136

VACS Index in OPTIMA Brown S.T. et al. Poster Presentation, Abstract #16436 International AIDS Conference 2010

1 point on the VACS Index (up or down) converts to 4-5% change in relative risk of death --only a 3% difference with restricted index.

Subtle Abnormalities Are Important Age (yrs) CD4 (cells/mm3) HIV-1 RNA (copies/ml) Hemoglobin (g/dL) FIB 4 eGFR (ml/min) VACS Index Points* <50 500+ <500 <1.45 60+ na 200-499 500-105 1.45-3.25 45-59.9 6-7 50-64 100-199 >105 12-13.9 30-44.9 8-12 64+ <100 10-11.9 >3.25 <30 22-29 <10 38 *HCV infection is worth 5 points. Rule of Thumb: 5 point difference in score corresponds to a 25% increased risk of mortality.

FIB 4 Values by Age, ALT, and AST (Platelets 100k) PLT ALT AST 20 30 40 50 60 70 100 35 1.18 1.77 2.37 2.96 3.55 4.14   44 1.49 2.23 2.97 3.72 4.46 5.21 53 1.79 2.69 3.58 4.48 5.38 6.27 1.06 1.58 2.11 2.64 3.17 3.69 1.33 1.99 2.65 3.32 3.98 4.64 1.60 2.40 3.20 4.00 4.79 5.59 0.96 1.44 1.92 2.88 3.37 1.21 1.81 2.42 3.02 3.63 4.23 1.46 2.18 2.91 3.64 4.37 5.10 FIB 4 >3.25 is worth 25 points, 1.45-3.25 is worth 6 points

Advice to Providers HIV, age, and substance use increase risk of ‘non AIDS’ conditions What is common for those aging with HIV is not identical to uninfected individuals Guidelines for aging-related non-AIDS condition require adaptation for those with HIV HANA may justify earlier or more aggressive HAART HAART may cause some conditions, but effects are often less than those of HIV itself Some primary care guidelines may be contra-indicated due to reduced life expectancy and polypharmacy Pay attention to smaller lab abnormalities

Advice to Policy Makers Universal HIV screening and early treatment Encourage surveillance organizations to better describe those over 50 yrs. Study joint effects of aging, HIV, substance use Train those who work with: The aging on special issues surrounding HIV With HIV on special issues surrounding aging

National VACS Project Team 2010

Veterans Aging Cohort Study PI and Co-PI: AC Justice, DA Fiellin Scientific Officer (NIAAA): K Bryant Participating VA Medical Centers: Atlanta (D. Rimland), Baltimore (KA Oursler, R Titanji), Bronx (S Brown, S Garrison), Houston (M Rodriguez-Barradas, N Masozera), Los Angeles (M Goetz, D Leaf), Manhattan-Brooklyn (M Simberkoff, D Blumenthal, H Leaf, J Leung), Pittsburgh (A Butt, E Hoffman), and Washington DC (C Gibert, R Peck) Core Faculty: K Akgun, S Braithwaite, C Brandt, K Bryant, R Cook, K Crothers, J Chang, S Crystal, N Day, R Dubrow, M Duggal, J Erdos, M Freiberg, M Gaziano, M Gerschenson, A Gordon, J Goulet, N Kim, M Kozal, K Kraemer, V LoRe, S Maisto, K Mattocks, P Miller, P O’Connor, C Parikh, C Rinaldo, J Samet Staff: H Bathulapalli, T Bohan, D Cohen, A Consorte, P Cunningham, A Dinh, C Frank, K Gordon, J Huston, F Kidwai, F Levin, K McGinnis, L Park, C Rogina, J Rogers, L Sacchetti, M Skanderson, J Tate, E Williams Major Collaborators: VA Public Health Strategic Healthcare Group, VA Pharmacy Benefits Management, Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), Yale Center for Interdisciplinary Research on AIDS (CIRA), Center for Health Equity Research and Promotion (CHERP), ART-CC, NA-ACCORD, HIV-Causal Major Funding by: National Institutes of Health: NIAAA (U10-AA13566), NIA (R01-AG029154), NHLBI (R01-HL095136; R01-HL090342; RCI-HL100347) , NIAID (U01-A1069918), NIMH (P30-MH062294), and the Veterans Health Administration Office of Research and Development (VA REA 08-266) and Office of Academic Affiliations (Medical Informatics Fellowship).

Reference List for bar graphs of HANA incidence rates (1) Bedimo RJ, McGinnis KA, Dunlap M, Rodriguez-Barradas MC, Justice AC. Incidence of Non-AIDS-Defining Malignancies in HIV-Infected Versus Noninfected Patients in the HAART Era: Impact of Immunosuppression. J Acquir Immune Defic Syndr. 2009. (3) Lucas GM, Mehta SH, Atta MG, Kirk GD, Galai N, Vlahov D et al. End-stage renal disease and chronic kidney disease in a cohort of African-American HIV-infected and at-risk HIV-seronegative participants followed between 1988 and 2004. AIDS. 2007;21:2435-43. (4) Fischer MJ, Wyatt CM, Gordon K, Gibert CL, Brown ST, Rimland D et al. Hepatitis C and the risk of kidney disease and mortality in veterans with HIV. J Acquir Immune Defic Syndr. 2010;53:222-26. (5) Justice AC, Zingmond DS, Gordon KS, Fultz SL, Goulet JL, King JT, Jr. et al. Drug toxicity, HIV progression, or comorbidity of aging: does tipranavir use increase the risk of intracranial hemorrhage? Clin Infect Dis. 2008;47:1226-30. (6) Sico, J., Chang, CC, Freiberg, M., Hylek, E, Butt, A., Gibert, C., Goetz, M. B., Rimland, D, Kuller, L., Justice AC, and for the VACS Project Team. HIV Infection and the Risk of Ischemic Stroke in the VACS VC. SGIM 2010 Poster . 4-28-2010. Ref Type: Abstract (7) Womack, J., Goulet, J., Gibert, C., Brandt, C., Mattocks, K., Rimland, D, Rodriquez-Barradas, M. C., Tate, J., Yin, M., Justice, A., and and VACS Project Team. HIV Infection and Fragility Fracture risk among Male Veterans. CROI 2010 Presentation (Abstract #129). 2-18-2010. Ref Type: Abstract (8)Thorpe J. et al.CROI 2010 absract # 683 (9) Thein HH. Et al. Natural history of Hepatitis C virus infection in HIV-infected individuals and the impact of HIV in te era of HAART: a meta-analysis. AIDS 2008;22:1979-91. (10) Crothers K, Huang L, Goulet J, Goetz MB, Brown S, Rodriguez-Barradas M et al. HIV Infection and Risk for Incident Pulmonary Diseases in the Combination Antiretroviral Therapy Era. AJRCCM. 2010; [In press].