Long  Term  Management  of  HIV  Infec2on  in  Aging  Adults:      

Current  Challenges,  Future  Strategies  

Andrew  Zolopa,  MD  Stanford  University  

Aging  of  HIV  Popula2on:  San  Francisco  

•  Popula:on-­‐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  popula:on,  up  from  41%  in  2006  -­‐-­‐fastest  

growing  subset  of  pa:ents  

Adapted from Scheer S, et al. 6th IAS; Rome, Italy; July 17-20, 2011. Abst. TUPE131.

Age Trends of Persons Living with HIV/AIDS in San Francisco

Late  HAART  Era  Pa2ents  S2ll  Have  a  10y  Shorter  Life  Expectancy  than  HIV-­‐  Controls  

Adapted  from  Lohse  N,  et  al.    Ann  Intern  Med  2007;146:87–95    

Prob

ability  of  S

urvival  

Pre-­‐HAART    (1995–1996)  

Early  HAART    (1997–1999)  

Survival  from  Age  25  Years  N=  3,990  

1  

0.75  

0.5  

0.25  

0  

25   30   35   40   45   50   55   60   65   70  

Age,  years  

Late  HAART    (2000–2005)  

Popula2on    controls  

(See  Also:  ART-­‐CC,  Lancet,  2008;  Lewden,  JAIDS,  2007)  

Changing  PaXerns  of  the  Causes  of  Death  in  a  Swiss  Cohort  (SHCS)  

•  SHCS  is  a  prospec2ve  observa2onal  cohort  •  Characteris2cs  of  par2cipants  that  died  from  2005-­‐2009  •  459  deaths/9,053  par2cipants  (5.1%)  

Adapted  from  Ruppik  M,  et  al.  18th  CROI;  Boston,  MA;  February  27-­‐March  2,  2011.  Abst.  789.  

Causes  of  Death  in  Par2cipants  in  the  Swiss  HIV  Cohort  Study    in  3  Different  Time  Periods,  and  in  the  Swiss  Popula2on  in  2007  

Years  of  Death  of  HIV+  Persons  Versus  Swiss  Popula2on    

Accelerated  or  Premature  Aging  in  HIV?  

•  Increased  Frailty  •  CVD  Increased  •  Cancer  •  Neurocogni2ve  

Impairment    •  Osteoporosis  •  End  Organ  Dz  •  Poten2al  Causes  

–  Drug  Toxici2es  –  Residual  HIV  –  Co-­‐infec2ons  –  Inflamma2on  

Many  morbidi2es  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]  

•  Cogni2ve  decline  [9]  

•  Frailty  [10]    •  Non-­‐AIDS  infec2ons  [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. McCutchan 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  morbidi2es  are  more  common  in  HIV,  even  ager  adjustment  for  age,  HAART  

exposure  and  tradi2onal  risk  factors  

Lifestyle  

HAART  Toxicity  

Persistent  Inflamma2on  

Premature  Aging  

Adapted  from  Deeks  and  Phillips,  BMJ,  2009  

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   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  

F1.2   1.4   0.45   0.8   0.56  

Adapted  from  Kuller  LH,  et  al.  PLoS  Med.  2008  ;5:  e203.  doi:10.1371/journal.pmed.0050203.  

Microbial  Transloca2on    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-­‐sec:onal  study  of  HIV  pa:ents  at  Australian  clinic,  comparing  1998  to  2010  −  Defini:on  of  lipodystrophy  (LD)  from  original  case  defini:on  

•  Results:  −  Par:cipants  older,  healthier  from  HIV  and  CV  risk  factor  perspec:ve  −  Prevalence  of  study-­‐defined  LD  has  declined  from  69  to  58%  −  In  mul:variate  analysis,  use  of  tenofovir  or  abacavir  associated  with  

significantly  lower  risk  •  Conclusion:    Although  prevalence  of  LD  has  declined,  it  remains  rela:vely  common  

–  especially  in  long-­‐term  survivors  

Adapted  from  Price  J,  et  al.  6th  IAS;  Rome,  Italy;  July  17-­‐20,  2011.  Abst.  MOPE264.  

Characteris2c   1998  (n=144)*   2010  (n=100)*   p-­‐value  

Age  (years)   42.1  ±  0.74   51.8  ±  0.87   <0.0001  

Smoking:  n  (%)   73  (51)   36  (36)   <0.0001  

HIV  Dura2on  (mos.)   86.2  ±  4.6   165.0  ±  10.4   <0.0001  

ART  Dura2on  (mos.)   36  (21-­‐72)   129  (51-­‐169)   <0.0001  

CD4  Count  (cells/mm3)   320  (178-­‐560)   585  (403-­‐754)   <0.0001  

HIV  VL  (copies/mL)   250  (250-­‐9800)   250  (250-­‐250)   <0.0001  

Undetectable  VL:  n  (%)   78  (57)   90  (90)   <0.0001  

Prevalence  of  LD:  %   69   58   0.02  

Adapted  from  PROGRESS  96  Week  Results  April  9,  2011                                      

PROGRESS  study  Week  96  (TLOVR)  

Adapted  from  PROGRESS  Bone  Mineral  Density  July  14,  2011                                      

Mean  Percent  Changes  in  Bone  Mineral  Density  Analyzed  Using  DXA  through  96  Weeks  of  Treatment  

Strategies  For  Long-­‐term  ART  

• Preferred  ART  regimens  currently  focus  on:    – effec:veness  of  viral  suppression    – rela:vely  short-­‐term  safety  

Are  preferred  ART  regimens  the  same  for  long-­‐term  treatment  (i.e.  decades)?  

• Long-­‐term  ART  goal:  reducing  toxicity  – Fewer  drugs  – Use  ART  with  “high  gene:c  barrier  to  resistance”  – Compartment  penetra:on?  

Efficacy  of  a  nucleoside-­‐sparing  regimen  of  darunavir/ritonavir  plus  raltegravir  

Adapted  from  ACTG  A5262  Team.  Efficacy  of  a  nucleoside-­‐sparing  regimen  of  darunavir/ritonavir  plus  raltegravir  in  treatment-­‐naive  HIV-­‐1-­‐infected  pa:ents  (ACTG  A5262).  AIDS.  2011  Nov  13;25(17):2113-­‐22.