1. HIV 2012: You are only as YOUNG as your Immune System..
Daniel Nixon DO, PhD
Associate Professor of Medicine
Director – VCU HIV/AIDS Center (
Office

2. HIV…we now know where it came from and when (slide from Paul Sharp’s 2006 CROI lecture)
When? Between ~ 1884 and 1924
Nature. Oct 2, 2008

3. “Rumble in the Jungle”

4. Natural History of HIV: Focus on Advanced HIV and Opportunistic Diseases

5. Shifting recommendations for “When to start ART” – IAS USA panel, 1996-2010
> 500
VL>5K
VL>10K
<200
CD4
1996
1998
2000
2002
2004
2006
2008
2010

6. Guidelines 2012: When to Start ART
HIV with symptoms or Hep B/C
Asymptomatic/No Hepatitis – CD4
<200
DHHSMar2012
Yes
Yes (mod Rec)
IAS-USA
BHIVAFeb2012
Defer
EACSOct2011
Concider
WHO
Yes1 No
Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents -
1initiate at any CD4 if Hep B or active TB

7. Conflicting Evidence from Observational Studies for Initiating ART with CD4 > 350
Comparison CD4+ count strata HR for death
NA ACCORD <350 vs ( )
vs > (1.4 – 2.8)
ART CC vs ( )
vs ( )
HIV-Causal 350 vs ( )
Kitahata MM et al, N Engl J Med 2009
When to Start Consortium, Lancet 2009
HIV Causal Collaboration, Annals Int Med, 2011

8. CD4 at Initiation of ARV Therapy Predicts Extent of CD4 Recovery
1,378 Patients at 10 US Clinics followed From
Median Peak CD4 was progressively higher for specific CD4 strata (p<0.001)
Multivariate analysis: Increased mortality with CD4 < 50 (HR=4.6) and CD (HR=2.6) compared to 350 cells/mm3
Lower baseline CD4 at initiation also associated with increased risk of death from non-AIDS-related causes
Median CD4+ cell count
Palella F, et al. 17th CROI, 2010

9. Evidence from Randomized Trials for Initiating Treatment at CD4 200-350
CIPRA-HT001 – a single center trial in Haiti
2/3 of patients were clinical stage 2 or 3 and the median CD4+ count at initiation in the deferred ART group was 166 cells/mm3 (IQR: 130, 190).
SMART study - post-hoc analysis
Only involved 477 patients and of these only 249 were ART-naïve.
HPTN 052
Deferral strategy was cells; significant difference in extrapulmonary TB; not powered to address survival (10 versus 13 deaths).

10. Continuous ART at CD4> 350 associated with decreased serious non-AIDS Events in Subset of “relatively” Naïve to ART in SMART
HR (DC/VS)
Deferred vs. Early
DC Group
VS Group
N Rate
N Rate
95% CI
P-value
OD or death [1.5, 13.2] 0.009
OD fatal or non-fatal [1.2, 15.8] 0.02
Serious non-AIDS [1.6, 31.5] 0.01
Composite * [1.9, 13.5] 0.001
Emery et al, JID, April 2008

11. HPTN 052: ART prevents HIV transmission
1763 discordant couples (one HIV-infected partner)
Botswana, Brazil, India, Kenya, Malawi, South Africa, Thailand, Zimbabwe (+ single US couple)
CD4 count at entry: – 550 cells/mm䔡
Index case randomized to IMMEDIATE ART vs DEFERRED ART
Deferral until CD4 count drops to < 250 cells/mm䔡or disease
RESULTS:
1 new HIV infection in partners of those on ART
27 new HIV infections in partners of those deferring ART
96% efficacy of ART to prevent transmission in this population!!

12. START Study Early ART Group Deferred ART Group
HIV-infected individuals who are ART-naïve with CD4+ count > 500 cells/mm3
Early ART Group
Initiate ART immediately
following randomization
N=2,000
Deferred ART Group
Defer ART until the CD4+ count declines to < 350 cells/mm3 or
AIDS develops
N=2,000

13. What to Start 2012: DHHS Initial ART Recs
NNRTI based
Efavirenz1 + Tenofovir/Emtricitibine (TDF/FTC) daily
Protease-Inhibitor based
Atazanvir or Darunavir with low dose Ritonavir “boosting agent”+ TDF/FTC daily
Integrase Inhibitor based
Raltegravir bid + TDF/FTC daily
Pregnant Women
Lopinavir/Ritonavir bid + AZT and Lamiviudine bid
1. EFV NOT to be used during the 1st trimester of pregnancy or in women who are not using effective and consistent contraception.

14. HIV drugs and especially protease inhibitors have many Interactions..
Statins
Interacting Protease Inhibitor
Prescribing recommendation
Atorvastatin
Tipranavir/r
Lopinavir/r
Darunavir/r
Fosamprenavir
Fosamprenavir/r
Saquinavir/r
Nelfinavir
Avoid concurrent administration
Use with caution and lowest dose
Do not exceed 20 mg atorvastatin
Do not exceed 40 mg atorvastatin
Fluvastatin
No data available
Lovastatin/Simvastatin
Contraindicated
Pitavastatin
Atazanavir/r
No dose limitations
Pravastatin
No dose limitions
Rosuvastatin
Do not exceed 10mg
Statins
Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. March 29,
FDA drug safety communication, March 1, 2012,

15. Survival From Age 25 Years Probability of Survival
Survival Trends in HIV-infected Patients Have Changed Since the Adoption of HAART
Survival From Age 25 Years 1
0.75
Population Controls
Probability of Survival
0.5
Late HAART ( )
0.25
Early HAART ( )
Pre-HAART ( ) 25 30 35 40 45 50 55 60 65 70
Age (years)
Cumulative survival curve for HIV-infected persons (without hepatitis C coinfection) and persons from the general population N=383,862 (HIV-infected patients, n=3990; General population controls, n=379,872)
Lohse N, et al. Ann Int Med. 2007

16. HIV - the Good News & the Bad
Antiretroviral drugs have tripled average life expectancy over the last decade, by reducing opportunistic infections, however:
In ART era only ~10% deaths in HIV infected clinical trials subjects were due to AIDS defining illnesses.
Non-AIDS malig ~ 21%
CVD ~ 9%
Liver Disease ~ 9%
Non-AIDS Infection ~8%

17. No. of Patients with Events The SMART Study Group. N Engl J Med 2006
In addition to reducing AIDS/Death, ART reduces serious Non-AIDS Outcomes
No. of Patients with Events
Hazard Ratio (95% CI)
Rate
Endpoints DC VS
Major CVD, hepatic
or renal disease
1.7
CVD
1.6
Hepatic (Cirrhosis)
1.4
Renal (ESRD)
4.5
Non-AIDS Malig
1.4
Other non-AIDS death
1.8
Any of the above
1.6
+ MI (clinical or silent), stroke, surgery for CAD
++ Except non-melanoma skin
Favors DC
Favors VS
The SMART Study Group. N Engl J Med 2006

18. INFLAMMATION?? Inflammatory Biomakers are Elevated with HIV (SMART) compared to non-HIV (MESA)
Neuhaus J et al. JID 2010

19. SMART Nested Case Control Biomarker Study (85 cases/170con)
Conditional logistic used to estimate ORs for mortality (lowest quartile as reference)
Adjusted OR consider covariates corresponding to: age, race, ART, HIV RNA, CD4+ count, BMI, total/HDL cholesterol, smoking, diabetes, Hep B/C co-infection, use of lipid and BP lowering medication

20. Baseline Biomarkers and All Cause Mortality
Un-adjusted
Adjusted
Marker
OR (4th/1st)
P-value
hs-CRP
2.0
0.05
3.1
0.02
Amyloid A
2.2
0.07
Amyloid P
0.7
0.39
1.1
0.78
IL-6
8.3
<0.0001
12.4
D-dimer
41.2
F1.2
1.0
0.92
1.3
0.64
Kuller L et al, PLoS Med 2008

21. D-dimer: Effect of ART Interruption (DC) for Participants on ART and with an HIV-RNA ≤ 400 copies/mL
DC Group
VS Group
P<0.001 (27% increase in DC)
Median (IQR) D-dimer (µg/mL)
Baseline
Month 1
Kuller L et al, PLoS Med 2008

22. D-dimer: Effect of ART Initiation (VS) for Participants Not on ART at Entry Stored plasma for 254 subjects (126 DC arm, 128 VS arm), naïve to ART or off ART >6 mo analyzed for IL-6, hs-CRP, & D-dimer (baseline, mo 2 & 6)
DC Group
VS Group
P=0.002
P<0.001
(22% lower for VS)
Baseline
Month 2
Month 6
Baker JV et al. JAIDS 2010

23. Inflammatory or Coagulopathy Biomarkers Associated with Mortality in RCTs of HIV-infected Individuals
Biomarker
Odds ratios*: 1st vs 4th Quartile
Effect of HAART
Other HIV disease Associations
D-dimer
12.4 (SMART), 2.4 (FIRST) 2.6 (Phidisa)
Decreases
CVD
hs-CRP
2.0 (SMART), 2.1 (FIRST), 3.6 (Phidisa)
No decrease
CVD, OD
IL-6
8.3 (SMART), 1.8 (FIRST), 3.8 (Phidisa), 1.5** (ACTG 384 and 5015 )
May decrease
sCD14
6.0 (SMART)
Unknown
Microbial translocation
While HAART partially reduces some biomarker levels, they still remain elevated compared with healthy non-HIV infected individuals

24. But where would the inflammation be coming from
But where would the inflammation be coming from?? Infection destroys gut-associated lymphoid tissue within 4 weeks of infection -> Recovery is impaired, even with ART..
Brenchley JM et al J Exp Med. 2004

25. HIV-induced gut CD4+ T-cell depletion leads to LPS/microbial translocation into the circulation -> CHRONIC IMMUNE ACTIVATION
Brenchley, JM et al. Nature Medicine 2006

26. Excessive CD8+T-cell stimulation and activation predicts CD4+ depletion and AIDS
CD8+ T-cell activation is predictive of HIV disease progression, independent of HIV viral load (Giorgi JV et al. JID Calbone J et al. AIDS 2000)
Patients with HIV viremia fully suppressed by ART that have blunted CD4 recovery show continued CD8+ T-cell activation (Anthony KB et al. JAIDS. 2003, Hunt PW et al. JID 2003)
Elite controllers not on ART with undetectable HIV RNA & CD4 depletion have CD8+ T-cell activation (Hunt PW et al. JID 2008)
Note: that CD8 “activation” refers to expression of cell surface markers (e.g. CD38 and HLA-DR)..in REALITY, the CD4/CD8 cells are hypoactive/anergic functionally in setting of HIV infection

27. “Inflamm-aging” - Francesch C. et al. Ann NY Acad Sc 2000
De Martinis M et al. Exp and Mol Path 2006

28. HIV and “Inflamm-aging”
HIV infection shares numerous clinical similarities w/ aging
increased incidence of CVD, malignancy, infection, and chronic viral reactivation, sarco/osteopenia, neurocognitive decline, & frailty

29. HIV and “Inflamm-aging”
HIV infection shares numerous clinical similarities w/ aging
increased incidence of CVD, malignancy, infection, and chronic viral reactivation, sarco/osteopenia, neurocognitive decline, & frailty
HIV infection results in T-cell activation and Immunosenescence
In both aging and HIV infection, this leads to an elevated proportion of CD28(-), CD57(+), memory CD8+ T cells characterized by reduced capacity to produce IL-2, Incr IL-6, apoptosis resistance, & shortened telomers
Up to half of peripheral CD8+ T-cells are activated in HIV+ individuals, compared with < 10% in healthy HIV - people

30. HIV and “Inflamm-aging”
HIV infection shares numerous clinical similarities w/ aging
increased incidence of CVD, malignancy, infection, and chronic viral reactivation, sarco/osteopenia, neurocognitive decline, & frailty
HIV infection results in T-cell activation and Immunosenescence
In both aging and HIV infection, this leads to an elevated proportion of CD28(-), CD57(+), memory CD8+ T cells characterized by reduced capacity to produce IL-2, Incr IL-6, apoptosis resistance, & shortened telomers
Up to half of peripheral CD8+ T-cells are activated in HIV+ individuals, compared with < 10% in healthy HIV - people
HIV+ individuals (median age, 56 years) with good immune reconstitution and viral suppression had T-cell similarities to older (median age, 88 years) HIV- individuals (Desai SR et al. CROI 2009)

31. HIV and “Inflamm-aging”
HIV infection shares numerous clinical similarities w/ aging
increased incidence of CVD, malignancy, infection, and chronic viral reactivation, sarco/osteopenia, neurocognitive decline, & frailty
HIV infection results in T-cell activation and Immunosenescence
In both aging and HIV infection, this leads to an elevated proportion of CD28(-), CD57(+), memory CD8+ T cells characterized by reduced capacity to produce IL-2, Incr IL-6, apoptosis resistance, & shortened telomers
Up to half of peripheral CD8+ T-cells are activated in HIV+ individuals, compared with < 10% in healthy HIV - people
HIV+ individuals (median age, 56 years) with good immune reconstitution and viral suppression had T-cell similarities to older (median age, 88 years) HIV- individuals (Desai SR et al. CROI 2009)
As with increased CD8+ T-cell activation, increased senescence (reduced CD28 expression on CD8+ & CD4+ T cells) associated with more rapid HIV disease progression (Cao W et al. JAIDS 2009)

32. CMV and “Inflamm-aging”
CMV+ adults over ~ 65y/o have a much greater expansion of CD28- cells than age-matched CMV- controls
many of these cells reflect the oligoclonal expansion of CMV-specific T cells Hadrup SR et al. J Immuno 2006, Ouyang Q et al. J Clin Immuno 2003 Almanzar G et al. J Virol 2005

33. CMV and “Inflamm-aging”
CMV+ adults over ~ 65y/o have a much greater expansion of CD28- cells than age-matched CMV- controls
many of these cells reflect the oligoclonal expansion of CMV-specific T cells Hadrup SR et al. J Immuno 2006, Ouyang Q et al. J Clin Immuno 2003 Almanzar G et al. J Virol 2005
Clinical significance of these findings is not clear, however, it has already been shown that:
CMV+ older persons are less likely to respond to vaccines than age-matched, CMV- persons Trzonkowski P et al. Vaccine 2003
CMV-associated changes in the immune system are predictive of early mortality among older persons Hadrup SR et al. J Immuno 2006, Wikby A et al. J Gerontol 2005

34. CMV & the Swedish OCTO and NONA studies
231/240 individuals
mean age of ~ 90 years
followed longitudinally x 4+yrs
Grouped by Immune Risk Profile .
Pawelec G et al. Immuno Reviews 2005

35. T-cells are not the only problem… HIV infection Associated w/ BOTH Adaptive and Innate Immune System Activation
Excess CD4 and CD8 T-cell activation observed in patients with HIV
Increased CD8 HLA-DR/CD38 expression associated with rapid CD4 loss, impaired CD4 recovery, poor immunologic responder on ART, & accelerated immune senescence
Excess B-cell activation observed in patients w/ HIV
Hypergammaglobulinemia, Autoantibodies
Excess Platelet activation observed in patients w/ HIV
Increased expression of TF, P-selectin, sCD40
Excess Monocyte/Macrophage activation w/ HIV
Increased expression of TF, CD14/sCD14
NOTE: CMV infection of monocytes  differentiation to proinflammatory “M1” macrophages (Chan G et al. J Immun 2008)

36. Macrophage Activation and HIV-Associated Vascular Disease
Moore KJ
Cell 2011
HIV+ persons are at 2-fold  risk for CHD “risk equivalent”
Freiberg CROI 2011

37. CHD Risk Factors: Traditional and HIV-specific
Age
Gender
Family
History
HIV Infection
Smoking
Antiretroviral
Therapy
CHD Risk
Hypertension
If we take coronary heart disease as an example of potentially the most common non-AIDS condition, the pathogenesis is clearly multifactorial. In terms prevention, we can take advantage of this by selecting treatments, or combinations of treatments, that target multiple factors. Specifically, treatments that reduce risk arising from HIV-related factors as well as traditional risk factors will, presumably, have a larger impact on reducing clinical risk.
Lipids & Lipoproteins
Endothelial
Injury and
Inflammation
Metabolic Disease
(hyperglycemia, insulin
resistance, and obesity) 37

38. Biomarkers and Cardiovascular Disease: SMART: HDL, D-dimer, IL-6, CRP, & NT-pro-B BNP associated with CVD
Baseline hsCRP (p<0.0001), IL-6 (p<0.0001), & D-dimer (p=0.0008) elevated in CVD cases
Total HDL (p<0.0001) was reduced in CVD cases
HDL negatively associated with D-dimer and IL-6 (R= -0.25)
N-terminal pro-B-type Natriuretic Peptide elevated in CVD (OR highest vs. lowest quartile – adjusted = 2.3, P =0.02)
Duprez D.A. et al. Atherosclerosis 2009
Duprez D.A. et al. 17th CROI 2010

39. Modulating Immune Activation: Aspirin
Population
ASA dose
Design
CRP
IL-6
TNF-α
Chronic stable angina
300mg
Placebo controlled  --
Metabolic syndrome
100mg NS
Post-myocardial infarction
160mg
vs. warfarin
Diabetes (Type 2)*
300/100mg
Dose comparison
NS*
Healthy volunteers
325mg
Cross-over
There are also a number of studies that studying the effect of aspirin on clinically relevant biomarkers of inflammation. A theme from these studies is the effect seems to vary by the target population, or baseline risk/pathogenesis, and potentially by dose (consistent with the COX-2 inhibition).
We were motivated by these and other data to study 325mg of aspirin for the effects on inflammation and T-cell activation
*Levels declined after starting aspirin but did not reach significance for either dose (n=20/arm)
Circulation 1999, Diab. Ob. Met 2008, JPP 2009, AJC 2003, AJC 2003 39

40. Relative Risk of MI by baseline CRP Stratified by Aspirin (325mg QOD) versus Placebo
The issue of the absolute risk benefits from treatments in the context of the baseline risk of the target population, are also very central to decisions about use of aspirin as primary prevention. These are data from the physicians health study that show the relative risk reduction for MI associated with aspirin treatment, was dependent on the degree of inflammation at baseline (as reflected in CRP levels). Thus, participants with greater inflammation benefited more from aspirin…. and this may have obvious implications for HIV-infected patients.
Ridker et. al. NEJM 1997
However, A 2009 Lancet Meta-analysis of RCTs found that:
Aspirin is of uncertain net value as primary prevention of vascular disease 40

41. Modulating Immune Activation: ACTG A5275 - Atorvastatin
Why look at statins in (non-hyperlipidemic) HIV+ patients?
Blocking HMG-CoA reductase with a statin reduces activation of GTP-binding proteins RAS and Rho - “molecular switches” that regulate transcription of inflammatory response genes
Statins inhibit expression of IL-6 (hs- CRP), TF (d-dimer), sCD14, and TNF-a
Statins decrease CD8+ T-cell activation
Statins reduce these biomarkers in numerous settings (e.g. sepsis, pneumonia, influenza, COPD, hepatocellular CA, CVD)
JUPITER Study
Rosuvastatin decreased mortality and venous thrombotic disease in subjects with hsCRP>2 mg/L and “normal” LDL (<130 mg/dl)
Individuals achieving hsCRP < 2 mg/L (entry criteria >2) had 62% decrease in events
Ridker et al. NEJM 2008, Ridker et al. Lancet 2009

42. MI Rates by SBP & HIV Status in VACS
These are data from VACS are courtesy of Kaku Armah and Matt Freiberg, and will be presented in more detail at this year’s CROI. This nicely demonstrates that for any given BP the absolute MI rates are greater among HIV-infected veterans versus controls. Similarly, there is some suggestion that the risk gradient for an elevated versus normal blood pressure is more extreme among. This is consistent with the notion that the absolute benefits from BP lowering therapy may be greater as well, and support aggressive traditional risk factor modification.
SBP Category (mmHg):
<120
<140 (on Rx)
≥140
aHR for HIV uninfected
ref
1.1
1.2
1.4
aHR for HIV infected
1.7
2.8
* Adjusted for age, race/ethnicity, diabetes cholesterol, smoking, HCV, BMI, renal disease, and cocain/EtOH
Armah & Freiberg CROI 2012 42

43. Brusselle et al. Lancet 2011

44. Macrophage Activation and HIV-Associated Pulmonary Disease
Alveolar Macrophage expression of Matrix MP from HIV+ smokers w/ early emphysema >> than in HIV- smokers w/ early emphysema
Kaner RJ et al. J. Leuk Bio 2009
HIV and Matrix MP co-localize to areas of empysema at autopsy
VA Cohort (n=100,000 matched)
Crothers K et al. Am J Resp Crit Care Med 2011
Yearsly MM et al. Diag Mol Path 2005

45. Macrophage Activation and HIV-Associated Bone Density Loss
HIV infection associated with an increased risk (~3X higher that HIV neg) of osteopenia, fracture, and avascular necrosis of bone
Bone is an immunologically rich tissue & activated macrophages, T-cells, osteoclasts, & inflammatory cytokines play a central role in accelerated bone loss
Mansky KC Clin Interventions in Aging 2010

46. HIV and Osteopenia – Some Issues
DXA Scanning if >50 y/o (McComskey et al. CID 2010)
Quit Smoking and Drinking (>3drinks/d)!
Treat Hypogonadism or Hypothyroidism
Weight Bearing Exercise
Safe Home
Vit D – treating low Vit D (<25 ng/dl) reasonable
Efavirenz is associated with reduction in 25-hydroxy vit D levels
Limited data on vitamin D supplementation in HIV-positive patients have shown transient, beneficial effects on PTH, but no effects on BMD.
Bisphosphonates effective (6 RCTs)
Treat with t-score ≤ 2.5 or with FRAX 10 year fracture prob score >20 (NOF 2008)
Protease Inhibitors and Tenofovir as Risks?
Avoid starting protease inhibitors if possible with t-score ≤ 2.5

47. Macrophage Activation and HIV-Associated Mortality
Only sCD14 levels* (a marker of monocyte/macrophage activation) are associated with mortality among microbial translocation biomarkers
*after adjustment for other risk factors/biomarkers 1st/4th OR = 4.1 (p=0.02)
Biomarker
DC-arm
VS-arm
p-value for
Interaction
OR (95% CI)a
p-value
OR (95% CI)
sCD14 (x106 pg/ml)
3.5 (1.5,8.3)
0.004
2.0 (0.8,5.4)
0.15
0.43
LPS (pg/ml)
1.0 (0.6,1.7)
0.96
0.7 (0.3,1.7)
0.40
0.63
I-FABP (pg/ml)
0.9 (0.4,2.1)
0.84
2.3 (0.6,8.8)
0.19
0.58
16S rDNA (copies/l)
0.9 (0.3,2.2)
0.90
0.5 (0.2,1.4)
0.21
0.26
EndoCAb (MMU/ml)
1.1 (0.8,1.6)
0.49
0.9 (0.5,1.4)
0.66
0.57
Sandler N. et al J. Infect Dis. 2011

48. Model of HIV induced “Aging”
Desai S and Landay A Curr HIV/AIDS Rep 2010

49. Model of VIRAL induced “Aging”
HCV
CMV
CMV
LPS
HIV
Bact 16sDNA
Activated Macrophages and T-cells produce IL-6, MMP, etc.
in brain, bone, lung, liver, vasculature ~ tissue level

50. Take Home Points
Chronic antigen (HIV, LPS, CMV, HCV, etc.) stimulation leads to excessive stimulation/activation of ALL arms of the immune system
Chronic immune activation leads to an immune system more likely to cause tissue inflammation & less likely to do its job! This has implications that extend well beyond HIV!
Premature aging – senescence and hypofunction of the immune system
Progression to AIDS
End organ damage
Inflammation correlates with many bad outcomes
Treating HIV helps & should be done but doesn’t entirely halt this problem
Numerous strategies to modulate immune activation/inflammation under study

51. Take Home Points Inflammation also increased by:
Smoking: e.g. a study found that HIV - women who stopped smoking showed decreased levels of CRP, IL-6, TNF-alpha within weeks after quitting
Diet / Obesity: adipocytes are “cytokine factories”
Other common disease processes like diabetes
Role of PCP: Managing these sources of inflammation, CVD risk reduction (e.g. BP, ASA, Statin), alcohol cessation, expanded cancer and bone density screening, helping with adherence, watch drug-drug interactions, & STD risk reduction
Don’t forget routine OPT-OUT HIV testing.. Inpatient, outpatient, ED

52. THANK YOU for your ATTENTION!