Long Term Management of HIV Infection in Aging

Long Term Management of HIV Infection in Aging Adults: Current Challenges, Future Strategies Andrew Zolopa, MD Stanford University

Aging of HIV Population: San Francisco • Population-based HIV registry from 2006 -2010 • Registry increased from 9, 001 to 9, 673 mostly due to decline in deaths • Those older than 50 now 53% of population, up from 41% in 2006 --fastest growing subset of patients Age Trends of Persons Living with HIV/AIDS in San Francisco Adapted from Scheer S, et al. 6 th IAS; Rome, Italy; July 17 -20, 2011. Abst. TUPE 131.

Late HAART Era Patients Still Have a 10 y Shorter Life Expectancy than HIV- Controls Survival from Age 25 Years N= 3, 990 Probability of Survival 1 0. 75 Population controls 0. 5 Late HAART (2000– 2005) 0. 25 Early HAART (1997– 1999) Pre-HAART (1995– 1996) 0 25 30 35 40 45 50 55 Age, years Adapted from Lohse N, et al. Ann Intern Med 2007; 146: 87– 95 (See Also: ART-CC, Lancet, 2008; Lewden, JAIDS, 2007) 60 65 70

Changing Patterns of the Causes of Death in a Swiss Cohort (SHCS) • • • SHCS is a prospective observational cohort Characteristics of participants that died from 2005 -2009 459 deaths/9, 053 participants (5. 1%) Causes of Death in Participants in the Swiss HIV Cohort Study in 3 Different Time Periods, and in the Swiss Population in 2007 Years of Death of HIV+ Persons Versus Swiss Population Adapted from Ruppik M, et al. 18 th CROI; Boston, MA; February 27 -March 2, 2011. Abst. 789.

Accelerated or Premature Aging in HIV? • • Increased Frailty CVD Increased Cancer Neurocognitive Impairment • Osteoporosis • End Organ Dz • Potential Causes – – Drug Toxicities Residual HIV Co-infections Inflammation

Many morbidities associated with aging also appear to be increased in treated HIV disease • • Bone fractures / osteoporosis [5, 6] Cardiovascular disease [1 -3] Cancer (non-AIDS) [4] Liver disease [7] Renal disease [8] Cognitive decline [9] Frailty [10] Non-AIDS infections [11] 1. Klein D, et al. J Acquir Immune Defic Syndr. 2002; 30: 471 -477. 2; Hsue P, et al. Circulation. 2004; 109: 316 -319. 3. Grinspoon SK, et al. Circulation. 2008; 118: 198 -210. 4. Patel P, et al. Ann Int Med, 2008; 148: 728 -736. 5. Triant V, et al. J Clin Endocrinol Metab. 2008; 93: 3499 -3504. 6. Arnsten JH, et al. AIDS. 2007 ; 21: 617 -623. 7. Odden MC, et al. Arch Intern Med. 2007; 167: 2213 -2219. 8. Choi A, et al. AIDS, 2009; 23(16): 2143 -49. 9. Mc. Cutchan JA, et a. AIDS. 2007 ; 21: 1109 -1117. 10. Desquilbet L, et al. J Gerontol A Biol Sci Med Sci. 2007; 62: 1279 -1286; Sogaard OS, et al. , Clin Infect Dis, 2008; 47: 1345 -53.

Non-AIDS morbidities are more common in HIV, even after adjustment for age, HAART exposure and traditional risk factors HAART Toxicity Lifestyle Persistent Inflammation Adapted from Deeks and Phillips, BMJ, 2009 Premature Aging

SMART: Untreated HIV Disease Associated With Increased Risk of Non-AIDS Morbidity Adapted from El Sadr W, et al. N Engl J Med. 2006; 355: 2283 -2296.

SMART: Inflammatory Markers Strongly Associated With Mortality and CVD Events Biomarker All-Cause Mortality (N=85) Fatal or Non-fatal CVD (N=136) OR P-value hs-CRP 3. 5 0. 004 1. 6 0. 20 IL-6 12. 6 <0. 0001 2. 8 0. 003 Amyloid A 2. 3 0. 08 1. 6 0. 12 Amyloid P 1. 1 0. 90 2. 8 0. 002 D-dimer 13. 3 <0. 0001 2. 0 0. 06 F 1. 2 1. 4 0. 45 0. 8 0. 56 Adapted from Kuller LH, et al. PLo. S Med. 2008 ; 5: e 203. doi: 10. 1371/journal. pmed. 0050203.

Microbial Translocation Due to a “Leaky” Gut Cohen J. Science. 2008 319: 888

Early Immune Senescence: A Model for Premature Aging in HIV Desai S, Landay A. Curr HIV AIDS Rep 2010; 7: 4 -10.

• • • Prevalence of Lipodystrophy in Current ART Era Cross-sectional study of HIV patients at Australian clinic, comparing 1998 to 2010 − Definition of lipodystrophy (LD) from original case definition Results: − Participants older, healthier from HIV and CV risk factor perspective − Prevalence of study-defined LD has declined from 69 to 58% − In multivariate analysis, use of tenofovir or abacavir associated with significantly lower risk Conclusion: Although prevalence of LD has declined, it remains relatively common – especially in long-term survivors Characteristic 1998 (n=144)* 2010 (n=100)* p-value 42. 1 ± 0. 74 51. 8 ± 0. 87 <0. 0001 73 (51) 36 (36) <0. 0001 HIV Duration (mos. ) 86. 2 ± 4. 6 165. 0 ± 10. 4 <0. 0001 ART Duration (mos. ) 36 (21 -72) 129 (51 -169) <0. 0001 CD 4 Count (cells/mm 3) 320 (178 -560) 585 (403 -754) <0. 0001 HIV VL (copies/m. L) 250 (250 -9800) 250 (250 -250) <0. 0001 78 (57) 90 (90) <0. 0001 69 58 0. 02 Age (years) Smoking: n (%) Undetectable VL: n (%) Prevalence of LD: % Adapted from Price J, et al. 6 th IAS; Rome, Italy; July 17 -20, 2011. Abst. MOPE 264.

PROGRESS study Week 96 (TLOVR) Adapted from PROGRESS 96 Week Results April 9, 2011

Mean Percent Changes in Bone Mineral Density Analyzed Using DXA through 96 Weeks of Treatment Adapted from PROGRESS Bone Mineral Density July 14, 2011

Strategies For Long-term ART • Preferred ART regimens currently focus on: – effectiveness of viral suppression – relatively short-term safety Are preferred ART regimens the same for longterm treatment (i. e. decades)? • Long-term ART goal: reducing toxicity – Fewer drugs – Use ART with “high genetic barrier to resistance” – Compartment penetration?

Efficacy of a nucleoside-sparing regimen of darunavir/ritonavir plus raltegravir Adapted from ACTG A 5262 Team. Efficacy of a nucleoside-sparing regimen of darunavir/ritonavir plus raltegravir in treatment-naive HIV-1 -infected patients (ACTG A 5262). AIDS. 2011 Nov 13; 25(17): 2113 -22.