Situación actual de los

pacientes VIH+

Esteban Martínez

Hospital Clínic

Barcelona

0

10

20

30

40

50

60

70

80

84 86 88 90 92 94 96 98 00 02 04

0

500

1000

1500

2000

2500

3000ACTIVE PATIENTS

New patients

Deaths

Data from Hospital Clinic, Barcelona

This means long-term exposure to ART

Mo

rtality

per

100 p

ati

en

t-years

Nu

mb

er o

f pa

tien

ts

06

HIV infection has changed from a fatal

disease into a chronic condition

Lampe FC, et al. Conference on Retroviruses and Opportunistic Infections, 2005

0

15

30

45

60

75

90

105

120

135

150

Med

ian

CD

4+

incre

ase

97

119 120 121127 125

150Median CD4+ increase

24.8 23.0

17.312.4

10.0 8.0 8.4

0

10

20

30

40

50

1996 1997 1998 1999 2000 2001 2002

% with >500 copies/mL*

60

70

80

90

100

Pati

en

ts w

ith

VL

>5

00 c

op

ies/m

L o

n A

RV

4143 subjects from 5 clinic cohorts in Europe and Canada

*Data from 3111 patients on any ARV therapy at viral load measurement

Better immunological and virological

responses to ART

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

Pro

bab

ilit

y o

f su

rviv

al

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)

Population

controls

At least a 10-year shorter expected survival

than age- and gender-matched controls

CASCADE: age at seroconversion by year

Slide courtesy of Krishran Bharakan

n= 22 383 943 945 783 31115

20

25

30

35

40

Med

ian

, IQ

R

1980 1985 1990 1995 2000 2005

Year of SC

Adults with HIV diagnosed at increasing age

Changing spectrum of causes of death in

HIV-infected patients

Mortality 2005 1st quarter (n=405)

0 20 40 60

39

15

12

9

6

4

2

2

1

1

1

1

1

0

0

2

2

AIDS

Cancer

HCV

Cardiovascular

Suicide

Non-AIDS related infection

Accident

HBV

Neurological disorder

Overdose

Bronchopulmonary disease

Renal failure

Liver disease

Psychiatric illness

Antiretroviral treatment

Other

Unknown

Proportion (%)

Mortality 2000 (n=964)

Lewden C, et al. Int J Epidemiol. 2005;34:121–130. Lewden C et al. J Acquir Immune Defic Syndr 2008; 48: 590-8

0 20 40 60

47

11

9

7

6

4

2

2

2

2

2

1

1

3

AIDS

Cancer

HCV

Cardiovascular

Bacterial infection

Suicide

Liver disease

Accident

Overdose

Iatrogenic

HBV

Metabolic

Other infection

Proportion (%)

10 30 50

Unknown

France

Kaplan RC et al. Clin Infect Dis 2007; 5:1074-1081

Some risk factors

are higher in HIV-

infected adults,

many of which may

be causally related

to HIV and hence

not a true

confounder (lipids,

DM)

Closed circles, HIV+men; closed triangles, HIV+women.

Open circles, HIV- men; open triangles, HIV- women

Traditional health related risk factors more

prevalent among HIV-infected patients

MACS/WIHS cohorts

Markers of inflammation may persist at

elevated levels despite ART

* P<0.001 vs HIV uninfected

** P<0.001 vs HIV infected, untreatedAdapted from Kristoffersen US, et al. 15th CROI 2008; Poster 953.

N=115 HIV-infected patients

N=30 HIV-uninfected matched controls40,000

35,000

30,000

25,000

20,000

15,000

10,000

5,000

0Pla

sm

a c

on

cen

trati

on

of

hsC

RP

(n

g/m

L)

HIV uninfected HIV infected,

untreated

HIV infected,

3 months of

ART

HIV infected,

12 months of

ART

**

*

ART decreases immune activation, but

levels remain high vs HIV-negative subjects

Adapted from Hunt PW et al. J Infect Dis 2003; 187: 1534–1543

0

10

20

30

HIV infected

untreated

(N=13)

HIV infected

treated

(N=99)

HIV

uninfected

(N=6)

Perc

en

tag

e o

f acti

va

ted

CD

4+

T c

ells

P<0.001

P<0.001

0

10

20

30

HIV infected

untreated

(N=13)

HIV infected

treated

(N=99)

HIV

uninfected

(N=6)

Perc

en

tag

e o

f acti

va

ted

CD

8+

T c

ells

P<0.001

P<0.001

CD4+ CD8+

Endothelin-1

Monocyte

Tat

1. Eugenin EA et al. Am J Pathol 2008; 2 Liu K et al. Am J Physiol Lung Cell Mol Physiol 2005;

3. Park IW et al. Blood 2001; 4. Kanmogne GD et al. Biochem Biophys Res Commun 2005

CD4+ T

Vasoconstriction

Endothelial dysfunction

MCP-1, VCAM-1, ICAM-1Inflammation

Endothelial dysfunction

HIV infects artery walls and Tat promotes

endothelial dysfunction, and inflammation

AR

TE

RIA

L W

AL

L

AR

TE

RIA

L W

AL

L

VIH

Nef

Tat

LDL

LDL-ox

HDL (PON-1)

HDL-inf

MCP-1, SDF-1, CXC3L1,

RANTES.

VCAM, ICAM,

proteoglycans.

CD36

CD4+ T

Monocyte

Foam cell

Nef

HIV promotes lipid accumulation in arterial

walls leading to atherosclerosis

AR

TE

RIA

L W

AL

L

AR

TE

RIA

L W

AL

L

Apoptosis of endothelial cells 2

1. Lopez-Herrera A et al. Biochim Biophys Acta 2005;

2. Yano M et al. AIDS 2007;

Induction of metaloproteases 1

HIV favours plaque rupture and thrombus

development leading to ischemic disease

HIV Negative Untreated HAART0

1

2

3

4

5

6

7 P = 0.03

Hig

h s

en

sit

ivit

y

CR

P (

mg

/L)

HIV Negative Untreated HAART0

2

4

6

8

10

12

14

160.01

En

do

theli

um

-

dep

en

den

t F

MD

(%

)

0 5 10 15 20 25 300

2

4

6

8

10

12

HAART

Untreated

CRP

En

do

theli

um

-

dep

en

den

t F

MD

(%

)

Hsue P, et al. CROI 2010

ART decreases inflammation, but cannot

restore endothelial integrity

HIV is an important independent risk

factor for atherosclerosis

*p<0.01, **p<0.001, ***p<0.0001; †There was a significant gender interaction

Grünfeld C et al. AIDS 2009

Estimated effect (mm)

Characteristic Internal

carotid

Common

carotid

HIV infection 0.15** 0.033*

Male† 0.13*** 0.054***

Current smoker 0.17*** 0.020**

Past smoker 0.09*** 0.020***

Diabetes 0.12*** 0.026***

Age (per 10 years) 0.16*** 0.073***

Systolic BP (per 10 mmHg) 0.05*** 0.025***

Diastolic BP (per 10 mmHg) -0.07*** -0.026***

Total cholesterol (per 10 mg/dL) 0.009*** 0.004***

HDL (per 10 mg/dL) -0.020*** -0.011***

CV disease

Patient

Antiretroviral

drugsHIV

(and other infections)

Drug

consumptionTobacco

Alcohol

Cocaine

Other?

The risk of CV disease is increased in HIV-

infected patientsMetabolic

abnormalitiesDyslipidemia

Insulin resistance / DM

Body fat

changesLipoatrophy

Lipoaccumulation

Degree of

immunedeficiency

PIsDyslipidemia

Insulin resistance ?

Body fat changes?

Other?

NRTIsDyslipidemia?

Insulin resistance?

Body fat changes?

Other?

HIV, HCV, HBV?, other?Dyslipidemia

Systemic inflammation

Inmune activation

Vascular infection

Aging

Other?

The following co-morbidities were analysed: Hypertension, Type 2 Diabetes, Cardiovascular Disease and Osteoporosis.Poly-pathology prevalence was higher in cases than controls in all age strata (all p-values <0.001). Poly-pathology prevalence in cases aged 41-50 was similar to that in controls aged >60 (p=0.282).

Poly-pathology is more common with increasing age and HIV

Poly-pathology prevalence in cases and controls, stratified by age categories.

Guaraldi G et al. Poster 727 - CROI 2010

HIV infection leads to premature ageing

Adapted from Deeks SG, Phillips AN. Br Med J 2009; 338:a3172

Normal

ageing

(average age

in many

clinics now

around 50)

Lifestyle risk

factors

(smoking, drug

and alcohol

misuse)

Drug

toxicity

(for example

tenofovir and

renal

disease)

Persistent

immune

dysfunction

and

inflammation

Premature

ageing

Reduced bone

mineral densityIncreased prevalence

of osteoporosis or

osteopenia in spine,

hip or forearm:

63% of HIV+ patients2

Renal

dysfunction

30% of HIV+ patients

have abnormal kidney

function1

Emerging co-morbidities in HIV+:

HIV+ ~10-15 years older than HIV-

1. Gupta SK et al. Clin Infect Dis 2005;40:1559–85.

2. Brown TT et al. J Clin Endocrinol Metab 2004;89(3):1200–06.

3. Clifford DB. Top HIV Med 2008;16(2):94–98.

4. Triant VA et al. J Clin Endocrinol Metab 2007;92:2506–12.

5. Patel P et al. Ann Intern Med 2008;148:728–36.

Cardiovascular

disease

Neurocognitive

dysfunction

Neurological impairment present in ≥50% HIV+ patients3

CancerIncreased risk of non-

AIDS-defining cancers

e.g. anal, vaginal, liver,

lung, melanoma,

leukemia, colorectal

and renal5

75% increase in risk

of acute MI4

FrailtyIncreased frailty phenotype if HIV infected

3-14x; Associated with CD4 count

A

RR 1.75p <0.0001*

0

2

4

6

8

10

12

HIV+ HIV-

Eve

nts

Pe

r 1

00

0 P

Ys

B

0

20

40

60

80

100

18-34 35-44 45-54 55-64 65-74

Age Group (Years)

Triant V et al., JCEM, 2007

* Adjusted for age, gender, race, hypertension, diabetes and dyslipidaemia.

Proportion of patients with hypertension, diabetes and dyslipidaemia

significantly higher in HIV-positive vs HIV-negative cohort

n = 1,044,589

n = 3,851

# of MI 189 26,142E

ve

nts

Pe

r 1

00

0 P

Ys

HIV-infected patients have a higher

incidence of myocardial infarction

Reduced Bone Mineral Density in HIV+

Patients

Brown TT & Qaqish RB. AIDS. 2006; 20:2165-2174. Overton T et al. CROI 2007. Abstract 836

risk with age, duration HIV infection and CD4 count

0

0.5

1

1.5

2

2.5

3

3.5

All Vertebral Hip Wrist

Fra

ctu

re p

reva

len

ce

/10

0 p

ers

on

s

Adapted from Triant VA et al. J Clin Endocrinol Metab 2008;93:3499–3504

Population-based study

8,525 HIV-infected patients

2,208,792 non HIV-infected patients

HIV+

HIV-

p<0.0001

P<0.0001

p<0.0001

p=0.001

Greater rate of fractures in HIV-infected

versus uninfected individuals

Liver and kidney comorbidities more

common in HIV+ patients

Liver Disease Renal Disease*

Goulet J. Clin Infect Dis 2007; 45: 1593-1601

Non-AIDS–defining cancer rates higher in

HIV+ patients vs general population

Patel P et al. Ann Intern Med 2008; 148: 728-736

Cancer Type, Observed Rate per 100,000 Person-Years (95% CI)

ASD/HOPS(157,819

Person-Years)

SEER(334,802,121

Person-Years)

SRR* (95% CI)

Anal 51.4 (40.8-63.9) 1.5 (1.4-1.5) 42.9 (34.1-53.3)

Vaginal 33.9 (18.0-57.9) 3.2 (3.2-3.3) 21.0 (11.2-35.9)

Hodgkin’s lymphoma 51.4 (40.9-63.9) 3.3 (3.3-3.4) 14.7 (11.6-18.2)

Liver 31.7 (23.5-41.8) 5.3 (5.2-5.4) 7.7 (5.7-10.1)

Lung 88.8 (74.7-104.8) 67.5 (67.2-67.7) 3.3 (2.8-3.9)

Melanoma 24.7 (17.6-33.8) 18.4 (18.3-18.6) 2.6 (1.9-3.6)

Oropharyngeal 33.0 (24.6-43.3) 16.1 (16.0-16.2) 2.6 (1.9-3.4)

Leukemia 15.2 (9.8-22.7) 12.2 (12.1-12.3) 2.5 (1.6-3.8)

Colorectal 47.0 (36.9-59.0) 52.0 (51.7-52.2) 2.3 (1.8-2.9)

Renal 14.0 (8.8-21.1) 13.0 (12.8-13.1) 1.8 (1.1-2.7)

Prostate 32.7 (23.3-44.7) 173.5 (172.9-174.1) 0.6 (0.4-08)

ASD, Adult and Adolescent Spectrum of Disease Project; HOPS, HIV Outpatient Study; SEER, Surveillance,

Epidemiology, and End Results, 1992–2003;

*SRR, standardized rate ratio calculated as ASD/HOPS to SEER populations.

http://www.europeanaidsclinicalsociety.org/guidelinespdf/2_Non_Infectious_Co_Morbidities_in_HIV.pdf

Summary

• The HIV infected population is ageing

• HIV may affect the natural ageing process

• Co-morbidities are increasingly apparent

• ART needs to be chosen not only for providing long-term efficacy but also for having the lowest impact on ageing co-morbidities