1. 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

2. Epidemiology Clinical Issues A New Approach to Care

3. 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 : **McKinnell JA. et al ARV Prescribing Patterns in Treatment-Naïve Patients in the United States. AIDS Patient Care and STDs :79-85

4. Life Expectancy on HAART
At HAART
Initiation
CD4 Cell Count (mm3)
<100
>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

5. Projected
For years , 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 , 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 trends (calculated by author), data from CDC Surveillance Reports New York and San Francisco data from their Departments of Public Health

6. 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:

7. 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 (8):

8. 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

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

10. Epidemiology Clinical Issues A New Approach to Care

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

12. 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)

13. 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

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

15. 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-

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

17. 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

18. Epidemiology Clinical Issues A New Approach to Care

19. 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

20. 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

22. 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

23. 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

24. 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 :
Stevens LA et al. Assessing Kidney Function-Measured and Estimated Glomerular Filtration Rate. NEJM 2006; 354:

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

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

27. 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.

28. 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
6-7
50-64
>105
8-12
64+
<100
>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.

29. 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, is worth 6 points

30. 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

31. 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

32. National VACS Project Team 2010

33. 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-A ), NIMH (P30-MH062294), and the Veterans Health Administration Office of Research and Development (VA REA ) and Office of Academic Affiliations (Medical Informatics Fellowship).

34. 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
(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 AIDS. 2007;21:
(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:
(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:
(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 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) 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:
(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].