Peter Reiss

1
Complications of HIV and HIV TreatmentImplicatio
ns for Cardiovascular Risk

• Peter Reiss
• Academic Medical Center
• Amsterdam, The Netherlands

2
Tolerability and Safety of HIV Treatment Has
Improved With Time
Patients First Initiating cART ATHENA Cohort
L.Gras et al. CROI 2007, Los Angelesabs 799
3
Tolerability and Safety of HIV Treatment Has
Improved With Time

• How? some examples

• Ever expanding treatment armamentarium
• Protease inhibitors associated with less effect
  on
• lipid glucose metabolism, potentially
  associated with less CVD risk
• Nucleoside/nucleotide analogues not associated
  with lipoatrophy
• Improved knowledge of underlying mechanisms
• The role of mitochondrial toxicity
• Improved knowledge of toxicity determinants
• Hypersensitivity to certain NNRTIs in relation
  to CD4 count viral load
• Hypersensitivity to abacavir and genetic
  susceptibilty

4
Antiretroviral Drug Approval1987 - 2006
TDF FTC EFV
AZT 3TC ABC
LPV/r tabs
ENF ATV FTC FPV
SQV sgc
TPV
DRV
TDF
EFV ABC
LPV/r
APV
RTV IDV NVP
NFV DLV
3TC SQV
d4T
ddC
ddI
AZT
5
(No Transcript)
6
Incidence of Myocardial Infarction according to
cART Exposure
Relative rate per additional year of exposure to
cART 1.16 (95 CI 1.09-1.23)
Total 345 94469
Events
16 17 20 41
61 62 51 47 30

11815 7105 9027 12098
14892 14394 11351 7935 5853
PYFU
Adjusted for conventional risk factors not
influenced by cART
Friss-Møller et al NEJM 2007
7
Effect of Exposure to PI and NNRTI before and
after Adjusting for Lipids
PI exposure (per additional year) NNRTI
exposure (per additional year)
RR 1.16 RR 1.10 RR 1.05 RR 1.00

• Adjusted for sex, age, cohort, calendar year,
  prior CVD, family history of CVD, smoking,
  body-mass index, the other drug class

Friss-Møller et al NEJM 2007
8
DAD Recent and/or Cumulative Antiretroviral
Exposure and Risk of MI
RR of cumulative exposure/year95CI
NRTI
RR of recent exposureyes/no95CI
1.9
1.9
1.5
1.5
1.2
1.2
1.0
1.0
0.8
0.8
0.6
0.6
ZDV
ddI
ddC
d4T
3TC
ABC
TDF
PYFU 138,109 74,407
29,676 95,320 152,009
53,300 39,157 MI 523 331 148 40
554 221
139
RR of cumulative exposure/year95CI
NNRTI
PI
1.2
1.13
1.1
1.0
0.9
IDV
NFV
LPV/RTV
SQV
NVP
EFV
PYFU 68,469 56,529
37,136 44,657
61,855 58,946 MI 298 197
150 221
228 221
Current or within last 6 months. Approximate
test for heterogeneity P 0.02
Lundgren JD, et al. CROI 2009. Abstract 44LB.
Graphics reproduced with permission.
9
Carotid IMT differs dependent on PI or NNRTI
Exposure
IMT (mean SD)
1
plt0.001 NNRTI vs PI plt0.01 EFV or NVP vs PI
0.9
0.8
IMT (mm)


0.7

0.6
0.5
PI n62
NNRTI n68
EFV n30
NVP n38
Treatment group

• Multivariate analysis higher Framingham risk
  score,higher BMI, use of PI duration of cART
  use independently associated with increased C-IMT

Sankatsing R et al. modified from Atherosclerosis
2009202589-595
10
Metabolic effects of PIs
11
Avoiding Dyslipidaemia Study 934Mean Change
Fasting Total Cholesterol
plt0.001
TDFFTCEFV
50
CBVEFV
45
38 (0.98 mmol/L)
40
35
30
25 (0.65 mmol/L)
Mean Change from Baseline (mg/dl)
25

20
15
10
5
0

0
4
16
24
32
48
60
72
84
96
Study Week
At Baseline (in mg/dL) TDF FTC 165, CBV 161
Data on File. Gilead Sciences.
12
HIV and ART-associated complications which
contribute to CVD risk
NRTI PI
HIV infection related factors
Host factors
Altered Fat Distribution
Insulin Resistance
Dyslipidemia
Arterial wall inflammation function
HIV
Risk of Atherosclerosis?
-
ART
13
Insulin resistance and lipoatrophy with ZDV/3TC
Limb fat mass

• Multicenter, randomized, open-label trial in
  ARV-naïve men
• LPV/r (400/100 BID) ZDV/3TC (n11)
• LPV/r (533/133 BID) NVP (n9)
• Conclusions
• ZDV/3TC contributes to early(3-month) reduction
  in peripheral glucose uptake, prior to a
  demonstrable loss of limb fat and/or gain in VAT
• No evidence of insulin resistance or lipoatrophy
  with NRTI-sparing regimen

Limb fat mass (mg)
Insulin-stimulated peripheral glucose disposal
Glucose disposal (mol/kg/min)
van Vonderen M, et al. 4th IAS, Sydney 2007,
TUPEB077
14
Avoiding Lipoatrophy Study 934 Median (Q1,
Q3) Total Limb Fat for Patients with Week 48
Data
p 0.034 between arms
p lt 0.001 between arms
p 0.001 within CBV arm
p 0.01 within TDF arm
15
10 years into the era of combination
antiretroviral therapy...

• Remarkable potential for sustained control of HIV
  infection
• Remarkable improvement in survival as a result of
  markedly reduced incidence of infections and
  tumours traditionally associated with
  HIV-related immunodeficiency
• Antiretroviral regimens have become safer and
  better tolerated
• but...

16
Growing Old with HIVAthena Cohort 1986-2007
Slide courtesy of Luuk Gras, HIV Monitoring
Foundation
17
Many HAART treated patients do not reach a normal
life span, particularly if HAART is started late
CD4 Nadir

100-200
gt200
lt 100




42
50
32
Life expectancy, years (at age 20)
Depending on when HAART is started, life
expectancy during the current HAART era is 10 to
30 years less than that in uninfected patients
ART-Cohort Collaboration Lancet 2008
18
What then do patients get sick and die from?

• Diseases each of which in the general population
  is known to be more prevalent in the elderly
• But in the setting of HIV infection these
  diseases seem to be more common even after
  controlling for age
• Could the aging process be accelerated in HIV?

19
Of the studies that have compared HIV negatives
with HAART-treated patients, most show a
difference

• Cardiovascular disease (Klein 02 Hsue 03
  Mary-Krause 03 Briant 08, others)
• Bone fractures/osteoporosis (Briant 08 Arnsten
  07)
• Left ventricular dysfunction (Deeks, personal
  communication)
• Pulmonary hypertension (Barnett 08 Hsue 08,
  others)
• Liver failure and kidney failure (Odden 07)
• Cognitive decline (controversial) (reviewed
  McCutchan 07)
• Frailty (Desquibet 07)
• Cancers other than KS or NHL (mostly
  infection-related)

20
Risk of MI in Patients Presenting at Least Twice
to Either of Two Hospitals in Boston (1996-2004)
According to HIV Status
A
B
RR 1.75
n 3,851
12
p lt0.0001
100
10
80
n 1,044,589
8
60
Events Per 1000 PYs
Events Per 1000 PYs
6
40
4
20
2
0
18-34
35-44
45-54
55-64
65-74
0
HIV
Non-HIV
Age Group (Years)
of MI 189 26,142
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
Triant et al., JCEM, 2007
21
HIV Infection is an independent risk factor for
atherosclerosis similar in magnitude to
traditional cardiovascular disease risk factors
plt0.01, plt0.001, plt0.0001 There was a
significant gender interaction
Grünfeld C et al. AIDS 2009 Epub ahead of print
22
(Chronic) kidney disease is increasing as a
complication of chronic HIV infection
Where are my kidneys?
Exposure time to certain antiretrovirals Exposure
time to other associated co-morbidities (e.g
hypertension, diabetes, HCV etc) Ageing Exposure
time to HIV infection
23
HIV and ART-associated complications which
contribute to CVD risk
NRTI PI
HIV infection related factors
Host factors
Altered Fat Distribution
Insulin Resistance
Dyslipidemia
Arterial wall inflammation function
HIV
Risk of Atherosclerosis?
-
ART
24
Osteoporosis (T-score -2.5) inHIV-infected
patients and uninfected controlsa meta-analysis
Brown, TT Qaqish, RB AIDS 2006 20 2165-2174
25
Greater rate of fractures in HIV-infected versus
uninfected individuals
Population-based study 8,525 HIV-infected
patients 2,208,792 non HIV-infected patients
3.5
plt0.0001
HIV
3
HIV-
2.5
Fracture prevalence/100 persons
2
plt0.0001
Plt0.0001
1.5
p0.01
1
0.5
0
All
Vertebral
Hip
Wrist
From Triant et al, JCEM 2008 epub
26
Neurocognitive Impairment in the Pre-ARV,
Pre-HAART and HAART Eras
27
Frailty

• A syndrome that involves enhanced vulnerability
  to stressors and is thought to be due to
  dysregulation of multiple physiologic systems
• The biologic basis of frailty in the elderly
  population is unknown, although emerging
• evidence indicates underlying immunologic and
  inflammatory dysregulation in concert with
  alterations in multiple other physiologic systems
  including sarcopenia, anemia, and hormonal
  impairments

Desquilbet et al J Gerontology 2007
28
Frailty phenotype

• 3 of the following 5
• physical shrinking (unintentional weight loss)
• exhaustion (self-reported)
• low physical activity level
• slowness (time to walk 15 feet)
• weakness (grip strength)

Fried et al.J Gerontol Med Sci. 2001 Desquilbet
et al J Gerontology 2007
29
Frailty in HIV

• Compared to HIV-uninfected men of similar age,
  ethnicity and education, HIV-infected men were
  more likely to have the frailty phenotype
• Frailty prevalence increases with longer duration
  of infection (risk 3-14 fold ? in men infected
  with HIV for 4 to 12 years)
• The frailty prevalence for 55-year-old men
  infected with HIV for 4 years was similar to
  that of uninfected men 65 years old (3.4)

Aging accelerated in HIV?
Desquilbet et al J Gerontology 2007
30
What May Be Driving the Increased Risk of
non-AIDS Morbidity and Mortality?

• Likely a Multifactorial Process
• Traditional known risk factors (e.g. age,
  smoking, hypertension etc...)
• HIV viral factors per sé
• Persistent immunodeficiency
• Persistent Immune Activation and Inflammation
• Drug toxicities

31
Low CD4 on therapy predicts risk of AIDS and more
importantly the risk of non-AIDS events (DAD)
100
HIV/AIDS Cancer Heart Liver
10
Relative Risk
1.0
gt500
lt50
5099
100199
200349
350499
CD4 Cells/mm3

• See also Weber Arch Int Med 2006, CASCADE AIDS
  08,
• Baker AIDS 08, dArmino Monforte AIDS 08

32
Suboptimal CD4 T Cell Gains are Common Among
Patients who Initiate HAART Late (ATHENA)
Baseline CD4(cells/mm3)
1000
900
gt500 (n389)
800
350 500 (n694)
700
200 350 (n1,513)
600
50 200 (n1,773)
CD4 Cell Count (cells/mm3)
500
lt50 (n930)
400
300
50 of those with CD4 nadir lt200 fail to reach
500 after 7 years VL suppression.
200
100
0
0
48
96
144
192
240
288
366
Week
Gras L, et al. JAIDS. 200745183192.
33
T cell activation declines during long-term
HAART, but remains abnormal, even after many
years of viral suppression
Hunt JID 2003
34
Higher CD8 T cell activation is associated with
lower treatment-mediated CD4 T cell gains
Hunt et al, JID, 2003
35
CMV-specific inflammatory changes predicts
accelerated atherosclerosis
Hsue et al, AIDS, 2006
36
Increased atherosclerosis in HIV Elite
Controllers in the absence of antiretroviral
therapy, detectable viremia, or overt
immunodeficiency

• Chronic inflammation (higher in elite controllers
  than in HIV-uninfected persons) may account for
  early atherosclerosis even in these patients.

Hsue PY et al. AIDS 2009 231059-1067
37
Inflammation Participates In All Stages Of
Atherosclerosis
Libby P Nature 2002
38
Microbial translocation declines during long-term
HAART, but remains abnormal One possible
contributor to persistent inflammation
P



0
.
0
0
2
P



0
.
0
0
1
3
0
0
2
0
0
Plasma LPS (pg/mL)
1
0
0
0
HIV
H
A
A
R
T
V
L

lt

7
5
Jiang/Brenchley (in press)
39
Inflammatory markers are associated with
mortality during stable HAART in SMART study
Biomarker
All-Cause Mortality
OR
P-value
hs-CRP
2.7
0.08
Amyloid A
1.50
0.40
Amyloid P
0.7
0.46
D-dimer
7.1
0.08
F1.2
0.7
0.55
Kuller L et al. Plos Medicine 2008
40
Biology of liver injury, inflammation and
fibrogenesis
Acute phase proteins (?a2MG, ?Haptoglobin))
Rockey D and Bissel M Hepatology 2006
41
Inflammation in the Liver Promotes Fibrosis
Hyaluronic acid
Procollagen III
Type IV Collagen
MMP Matrix Metallo Proteinase TIMP Tissue
Inhibitor of Metallo Proteinase
Rockey D and Bissel M Hepatology 2006
42
HIV Neuropathogenesis Pre-HAART
Virus Driven dysfunction
G. Jones and C. Power Neurobiology of Disease
2006
43
HIV Neuropathogenesis-Post-HAART
Inflammatory factor driven neurotoxicity
Glial activation
G. Jones and C. Power Neurobiology of Disease
2006
44
60 still have elevated neopterin and IgG Index
after 4 yrs HIV rx
45
Inflammation promotes bone remodelling

• Example Reumatoid Arthritis (a chronic
  inflammatory condition) promotes osteoclast
  activity and osteoporosis
• Activated T cells and various cytokines increase
  the expression of receptor activator of nuclear
  factor kappaB ligand (RANKL), thereby promoting
  osteoclastic activity
• The interaction between the immune system and
  bone may well also contribute to the pathogenesis
  of the osteopenia observed in HIV infection
  (osteoimmunology)

Rauner M Int Arch Allergy Immunol 2007
46
Premature aging clinical features of
physiological aging at an earlier age

• Hutchinson-Gilford progeria syndrome

• Lipoatrophy
• Insulin resistance
• Osteoporosis
• Skin and hair alterations
• Premature atherosclerosis and
  coronary artery disease
• Early death

11-old progeria child
Mutations in the gene encoding lamin A/C
47
Some ART can induce a premature aging phenotype
Thymidine analogues
mtDNA
ROS reactive oxygen species, AGE advanced
glycosylation end-products
48
In spite of sustained suppression of HIV by cART
Residual bacterial translocation
Residual viral activation (CMV)
Residual Replication?
Viral products
Residual systemic immune activation
Immune senescence
Chronic low-grade inflammation
Residual immunodeficiency
Premature Cellular Aging Organ
malfunction CVD Kidney disease Liver disease Bone
disease Cancers CNS disease Death
Accumulation of prolamin A (progerin)
Mitochondrial dysfunction
ROS ?
TA-NRTI (d4T, AZT) PI
Protease inhibitors
Reiss P. Clin Infect Dis in press
49
Use of Thymidine Analogue nRTI Use, and of
Stavudine (d4T) in Particular is Associated
with...

• Lipoatrophy (poorly reversible stigmatising)
• An atherogenic lipid profile
• Insulin resistance and diabetes mellitus
• And other important toxicities such as neuropathy
  and lactic acidosis....

50
Causes of toxicity-driven substitutions in
patients on stavudine in Khayelitsha Cohort
Lactic acidosis / symptomatic hyperlactataemia
Changed by 36mo
Reason for subst.
n
(, 95 CI)
1228
1074
484
118
20
11
6
8.7 (5.3-14.0)
Hyperlactataemia/LA
Peripheral Neuropathy
1228
1068
486
120
19
9
5
6.4 (4.0-10.2)
Other
1228
1073
495
123
21
11
6
1.7 (0.6-4.6)
Combined
1228
1065
471
113
18
9
5
16.5 (12.0-22.6)
A.Boule CROI 2006
51
Incidence of DM and exposure to stavudine
Rel rate per additional yr of exposure to
d4T 1.19 (95 CI 1.15-1.24)
Incidence DM (/1000 PYFU)
744 DM events in 130,151 PY 5.72/1,000
PYFU (95 CI 5.31-6.13)
2-3 yrs
gt6 yrs
lt1 yr
None
1-2 yrs
3-4 yrs
4-5 yrs
5-6 yrs
Exposure to stavudine
S. De Wit et al. 8th Int Congress on Drug Therapy
in HIV Infection Glasgow nov 2006
52
Estimates of diabetes prevalence, 2007 African
Region
10.4?18.7 million 2007?2025
Slide courtesy of A. Motala D.Gan
53
Antiretroviral Therapy in Africa( of those in
need)
In the majority of cases regimens continue to
include d4T, mainly because of cost considerations
54
CVD risk management in HIV
Smoking BP Weight Lipids Glucose Renal
Age Sex
INFLAMMATION
Plaque instability and rupture
Thrombosis
Atheroma formation and growth
Lipids Glucose Adipose tissue Renal
ART
55
Summary

• End-organ disease, including but not limited to
  CVD renal disease, likely to become an
  increasing complication in an ageing HIV
  population
• Patient management expected to increasingly
  reflect the above
• Need to carefully monitor these non-AIDS
  outcomes within observational HIV cohorts
• The immune dysregulation associated with HIV,
  potentially in spite of suppressive HAART, may be
  contributing more to end-organ disease than
  previously thought
• Further research in this area clearly needed

56
Insanity is repeating the same experiments and
expecting different results
Advocacy to shift the HIV treatment paradigm in
resource-limited settings needed now !
57
Acknowledgement

• Marit van Vonderen, Mariette Ackermans, Hans
  Sauerwein
• John Kastelein, Erik Stroes, Raaj Sankatsing,Marc
  van der Valk
• Jens Lundgren,Nina Friss-Møller the DAD Study
  Group
• Corine Isnard Bagnis Jacqueline Capeau, Andrew
  Phillips INSIGHT, Steve Deeks and numerous
  others...