Long-Term Consequences of Immune Activation and ART

William G Powderly, MD, ModeratorSally L. Hodder, MDJens Lundgren, MD

Long-Term Consequences of Immune Activation and ARTWilliam G. Powderly, MD

Dean of Medicine

Head, University College Dublin

School of Medicine and Medical Science

Dublin, Ireland

Immune Activation in HIV

• Chronic untreated HIV infection is associated with immune activation In established infection, ≤50% of peripheral CD8+ T cells appear

to be activated, compared with <10% in HIV-uninfected persons Similar trends in the CD4+ T-cell population Frequency of activated T cells predicts disease progression,

independent of HIV-1 RNA Antiretroviral therapy reduces HIV-associated T-cell activation,

although often incompletely

• Markers of inflammation elevated in untreated HIV infection Only partially reversed with effective ART

Mechanism of Immune Activation

• Partially a direct effect of HIV Decrease in markers of inflammation and immune activation

during ART

• Likely to be indirect effects also Most activated T cells are not HIV specific Markers of inflammation do not return to normal with sustained

effective ART suppression

• Other putative mechanisms of persistent immune activation have been postulated Microbial translocation Irreversible damage to lymphoid infrastructure, Irreversible thymic dysfunction Increased prevalence of coinfections (eg, CMV) Persistent low-level HIV replication

Significance of Immune Activation

• Constant T-cell proliferation and death in uncontrolled HIV may result in eventual immunologic exhaustion

• Even with treatment, persistent immune activation may lead to immune senescence and premature aging of the immune system

• Full immune recovery (with reversal of activation) may not be seen with effective ART, especially in patients with low CD4+ T-cell count nadir (<200 cells/mm³) prior to treatment

• Is there a relationship between persistent immune activation, immune senescence and diseases associated with aging?

Discussion Questions Related to CVD

What is the evidence that HIV infection is associated with an increased risk of cardiovascular disease?

What are the possible causes of this increased risk?

Is immune activation a possible cause?

Principal factors affecting risk of CVD in HIV

TraditionalTraditionalriskrisk

factorsfactors

HIVHIV

ARTART

++

++

++

0

1

2

3

4

5

0 0.5 1 1.5 2 2.5 3 3.5 4

% W

ith a

Maj

or C

VD

Eve

nt

Years from randomization

DC 2752 1306 713 379 10

VS 2720 1292 696 377 10

VS

DC

No. at risk

Relative hazard:1.57 (1.00 – 2.46)

p = 0.05

SMART/CVD: Phillips et al, AVT 2008

* Death from CVD, silent or clinical MI, stroke CAD requiring invasive procedure* Death from CVD, silent or clinical MI, stroke CAD requiring invasive procedure

Risk of Major CVD Events* by Treatment Arm

DC = Drug ConservationVS = Viral Suppression

Change in Log IL-6 (pg/mL) and HDL Cholesterol Concentration (μmol/L) from Baseline to 1 Month*

≤ 400 401-10,000 10,000-50,000 >50,000

Month 1 HIV RNA Level (copies/mL)

∆ IL

-6 (

pg

/mL

)

P<0.0001 for trend

∆ H

DL

(μ

mo

l/L)

* DC patients on ART at baseline with HIV RNA ≤ 400 copies/mL

∆ IL-6

∆ HDL P=0.0003 for trend

SMART/INSIGHT: Duprez et al, CROI, 2009

-0.4

-0.3

-0.2

-0.1

0

0.1

0.2

0.3

0.4

-0.4

-0.3

-0.2

-0.1

0

0.1

0.2

0.3

0.4

Time-Course for Association Between ARV Drug Exposure and Risk of MI

Start ABC

MIrisk

Some PI: progressive riskwith cumulative exposure

Stop ABC

* Recent = still using or stopped within last 6 months

35

30

25

20

15

10

5

0

Overall Low Moderate High Not known

Rat

e (p

er

100

0 P

Y)

Predicted 10-year CHD risk

No recent abacavir

D:A:D study: Sabin et al, Lancet, 2008

Rates of MI For Recent* Use of Abacavir by Predicted 10-Year CHD Risk

Recent abacavir

Discussion Questions

Are HIV-infected patients at a greater risk for bone disease?

Is HIV- associated bone disease related to virus or to treatment?

Bone Mineral Density in HIV-Infected Persons

• Multiple studies have found increased prevalence of osteoporosis and osteopenia in HIV-infected persons compared with uninfected persons

• Meta-analytical review of studies – 67% HIV infected persons had reduced BMD (OR 6.4)– 15% HIV+ had osteoporosis (OR 3.7)

Brown et al AIDS 2006;20:2165-2174

Triant VA et al. J Clin Endocrinaol Metab. 2008;93(9):3502.

Women Men

Fracture Prevalence Higher in HIV Patients

Fra

ctu

re P

reva

len

ce/1

00 P

erso

ns

0.5

1.0

1.5

2.0

2.5

3.0

0

HIVNon-HIV

P=0.002

P=0.01

P=0.53

P=0.01

Any Vertebral Hip Wrist

Fra

ctu

re P

reva

len

ce/1

00 P

erso

ns

0.5

1.0

1.5

2.0

2.5

3.0

0

HIVNon-HIV

P<0.0001

P<0.0001P=0.001

P=0.001

Any Vertebral Hip Wrist

• Population: 8,525 HIV+ and 2,208792 HIV-• Patients with fracture: 245 HIV+ and 39,073 HIV-• Overall fracture prevalence (per 100 persons): 2.87 HIV+ and 1.77 HIV-

Changes in Hip Bone Mineral Density with Antiretroviral Therapy

Intermittent (Fracture 0.03/100 PY)Continuous (Fracture 0.13/100 PY)

n = 109 86 51 9 n = 95 75 47 15

Est. diff.: 1.3 1.7 1.0 2.5P values: .002 .005 .27 .21

Gallant et al. JAMA 2004, 292:191. Grund B et al. ICAAC/IDSA 2008. Abstract 2312a.

d4T + 3TC + EFVTDF + 3TC + EFV

n=301 267 246 226 205 185 181 n=299 261 234 221 209 193 185

-4

-3

-2

-1

0

1

0 1 3 4Years

Ch

ang

e F

rom

B

asel

ine

(%)

2

Gilead 903 Study SMART Study

-8

-6

-2

0

4

8

2

6

Baseline 24 48 72 96 120 144

Weeks

P=0.06

Association of Osteoporosis with Antiretroviral Therapy

Brown TT et al. AIDS. 2006, 22:2168.

Antiretroviral Therapy Overall Protease Inhibitor Therapy

Odds ratio0.01 100

Study

Amiel (2004)

Bruera (2003)

Garcia (2001)

Knobel (2001)

Knishi (2005)

Mededdu (2004)

Vescini (2003)

Overall (95%CI)

Odds ratio (95%CI)

2.41 (0.77, 7.58)

4.81 (0.60, 38.74)

1.60 (0.13, 19.84)

2.68 (0.70, 10.33)

0.84 (0.03, 22.43)

11.00 (0.65, 187.76)

0.54 (0.05, 5.68)

2.38 (1.20, 4.75)

Odds ratio0.01 100

Odds ratio (95%CI)

0.61 (0.21, 1.72)

11.09 (0.57, 217.66)

1.18 (0.37, 3.78)

0.71 (0.11, 4.51)

1.57 (0.05, 43.79)

1.97 (0.47, 8.27)

2.63 (1.13, 7.03)

1.89 (0.23, 15.81)

3.25 (2.08, 9.83)

1.83 (0.35, 9.62)

1.24 (0.34, 4.52)

0.77 (0.15, 2.34)

1.57 (1.05, 2.34)

Study

Amiel (2004)

Brown (2004)

Bruera (2003)

Dolan (2004)

Huang (2002)

Knobel (2001)

Mededdu (2004)

Mondy (2003)

Nolan (2001)

Tebas (2000)

Vescini (2003)

Yiu (2005)

Overall (95%CI)

Caveat: Few studies adjusted for age or duration of infection

Effects of HIV on Bone Metabolism

• HIV-1 p55 gag and gp120– Significantly decrease calcium deposition in vitro1

– Reduce RUNX-2 activity in vitro1

• gp120 increases PPARγ activity1

• gp120 (100 ng/ml) induces RANKL2

1. Cotter EJ et al. AIDS Res Hum Retroviruses. 2007;23(12):1521-1529.2. Fakruddin JM et al. J Biol Chem. 2003;278:48251-48258.

RUNX-2 (Runt-related transcription factor-s) promotes osteoblast differentiation.PPARγ (Peroxisome proliferator-activated receptor gamma) promotes adipogenesis.RANKL (Receptor Activator for Nuclear Factor κ B Ligand), activates osteoclasts.

25-OH Vitamin D Deficiency Prevalent in HIV-Infection

1. Rodriguez M et al. AIDS Res Hum Retroviruses. 2009;25(1):9-14.2. Seminari E et al. HIV Med. 2005;6:145-150.3. Garcia Aparicio AM et al. Clin Rheumatol. 2006;25(4):537-539.

• 47% Boston outpatient HIV clinic (n=57)1

– Low Vitamin D intake in 31% < 50 years and 76% 51-70 years

– Low calcium intake in in 37% < 50 years and 71% 51-70 years

• 81% Italian HIV treatment-experienced patients (n=48)2

• 86% in Spanish cohort of men (n=30)3

– Mean 25,OH Vitamin D level 14.3 ng/ml in healthy controls vs.11.4 ng/ml (p=0.044)

All

Inflammatory marker Q1 Q2 Q3 Q4

CRP 13.5 13.7 16.5 17.4

IL-6 14.2 15.6 13.0 17.5

TNF 12.5 15.1 14.6 20.8†

IL-2sR 10.9 13.8 15.9 25.4§

IL-6sR 12.0 13.6 17.6 22.3‡§

TNF sRI 14.0 10.5 14.8 26.7‡§

TNF sRII 8.6 15.9 17.9 22.3

Cauley JA et al. J Bone Miner Res. 2007;22:1091.

Inflammatory Biomarkers Associated With Bone Fracture

† P<.05 from trend test.‡ P<.01 from trend test.§ P<.001 from trend test.

Incidence Rate (per 1000 Person-Years) of Fracture by Quartiles of Inflammatory

Cauley JA et al. J Bone Miner Res. 2007;22:1092.

Cumulative Nonspine Fracture by Highest Quartile Inflammatory Markers*

Years

0

4

8

12

16

20

% W

ith

No

n-s

pin

e F

ract

ure

0 81 2 3 4 65 7

2

6

10

14

18

2+

0 or 1

P = 0.0093 (log rank test)

*CRP, IL-6, TNFα

Discussion Questions

Are there important long-term CNS consequences of HIV in adequately treated patients?

Is CNS penetration of antiviral drugs important?

HIV-1 Infection and the CNS

21.1

17.8

10.5

0

5

10

15

20

25

1990-1992 1993-1995 1996-1998

Mean Incidence HIV DementiaMACS Cohort 1990-1998

Nu

mb

er/1

000

per

son

yea

rs

Antinori A et al. Neurology. 2007;69:1789-1799Sacktor N et al. Neurology. 2001;56:257-260

• HIV-Associated Neurocognitive Disorder– Asymptomatic

neurocognitive impairment

– Minor neurocognitive disorder

– Dementia

Mean Incidence HIV DementiaMACS Cohort 1990-1998

Does CNS Antiretroviral Agent Penetration Matter?

Letendre S et al. Arch Neurol. 2008;65(1):65-70.

Pro

po

rtio

n o

f S

ub

ject

s W

ith

D

etec

tab

le C

SF

Vir

al L

oad

CPE Score

Pro

po

rtio

n o

f S

ub

ject

s W

ith

Det

ecta

ble

C

SF

Vir

al L

oa

d

0

0.1

0.2

0.3

0.4

0.5

≥3.5(n=25)

≤0.5(n=38)

1(n=128)

1.5(n=100)

2(n=100)

3(n=13)

2.5(n=63)

CPE Score

N=31 (24 ART naïve)CSF penetrating drugs: d4T,AZT, ABC, EFV, NVP IDV

Does CSF HIV RNA Affect Neurocognitive Function?

Letendre S et al. Ann Neurol. 2004;56:419.

Red

uct

ion

in G

DS

at

Fo

llow

-up

CSF HIV RNA Suppression at Follow-up

Not Suppressed Suppressed

1.0

0.5

0.0

-0.5

N=14 N=17

2=6.25 P=.01

Sinclair E et al. JAIDS. 2008;47:548.

ART Affects CNS Immune Activation

% C

SF

CD

8 C

D38

+D

R+

Blood CD8 Activation

Off Failure Success HIV–

% B

ld C

D8

CD

38+

DR

+

100

40

80

60

20

0

CSF CD8 Activation

Off Failure Success HIV–

100

40

80

60

20

0

Off

Failure

Success

HIV–

Discussion Question Related to Cancers

Will we see more cancers in HIV infected patients in the next 10 years?

AIDS and Non-AIDS Defining Cancers in Baltimore Cohort

Long et al, AIDS 2008

Incidence of non-AIDS defining cancers in HIV-infected and uninfected persons in VA

Bedimo et al, JAIDS 2009.

Why Will Incidence of Cancers Increase in the Next 10 Years

• Risk of AIDS-related cancers decreased due to benefit of ART Except HPV-induced genital cancers

• HIV-infected population is aging Risk of fatal non-AIDS-defining cancers increases 47% per 5

year older age (i.e. >2-fold increase over a 10 year period Secondary cancers - may further increase the 47% estimate1

• Immunodeficiency• Chronic pro-oncogenic viral infections

e.g. HPV, EBV, viral hepatitis

• Other cancers (and associated therapy hereof) e.g. bladder cancer after prostate cancer2; leukemia after NHL3

• ART ?

1 D:A:D study group, AIDS 20082 Shirodkar et al, Curr Opin Urol 20093 Mudie et al, J Clin Oncol 2006

For 20 / 28 cancers examined there was significantly increased incidencein both groups – strongly suggesting a link with immunodeficiency

Standardized Incidence Ratio

HIV/AIDS Transplant

Lung 2.7 2.2Leukaemia 3.2 2.4Kidney 1.5 6.8Oesophagus 1.6 3.1Stomach 1.9 2.0

Meta-analysis: 444,172 people with HIV, 31,977 transplant patients

Grulich et al, Lancet 2007.

HIV and Risk of Non-AIDS Malignancies

HPV Cancers and HIV Transmission

• Temporal trends in US cohort - incidence of anal cancer (/100,000 PYs) 19 (1992-95), 48.3 (1996-99), 78.2 (2000-2003)

• Impact of ART on risk of malignant transformation ART was not associated with altered risk of

cytological progression or regression

• Oral HPV infection in HIV may enhance smoking induced risk of oropharyngeal cancer

• Anal HPV infection may increase risk of HIV transmission

Patel et al, Ann Intern Med 2008; Paramsothy et al, Obstet and Gynecol 2009; Chin-Hong et al, AIDS 2009;Gillison, Curr Opin Oncol 2009.