The Lancet and Cell Meeting
What Will it Take to Achieve an AIDS-free World?
Session 4: Long term consequences of living with HIV: comorbidities & ageing
San Francisco, 3-5 November 2013
Risk of serious disease and
death in people with HIV viral
suppression on ART: an
epidemiologic perspective
Trend in median CD4 count in clinic populations
CD4 count (/mm3)
700
600
500
400
300
200
100
0
1995
2000
Calendar year
2005
2010
Smith C, Lampe F, Johnson M, et al
Prevalence of viral load > 50c/mL in people on ART*
Proportion
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
2000
*Of those receiving ART>24 weeks
2005
Calendar year
2010
Smith C, Lampe F, Johnson M, et al
Trends in death rate in people with HIV: UK
Rate per 100 people
12
10
8
Number of deaths in year
Number seen for care in year
6
4
2
0
Year
Source: Public Health England
Trend in cause-specific death rate in people with
HIV: D:A:D
Rate of death per 1000 person-years
7
AIDS
6
5
4
Other - known
Liver
3
CVD
2
Non-AIDS cancer
1
0
Unknown
1999/2000 2001/2002 2003/2004 2005/2006 2007/2008 2009-2011
Calendar Year
D:A:D unpublished
Projected life expectancy of UK man infected age 30
100%
Dead from non-AIDS
Cumulative percentage
90%
Dead from AIDS
80%
Alive & diagnosed (on ART)
70%
Alive & diagnosed (off ART)
60%
Alive & undiagnosed
50%
40%
30%
20%
10%
0%
30
35
40
45
50
55
60
65
70
75
80
85
90
95 100
Age (years)
Nakagawa et al, AIDS 2012
What are the residual excess disease risks due
to HIV in people with viral suppression ?
Cause-specific death rate in SMART/ESPRIT control
arms: baseline viral load < 500 cps/mL
1
Rate
0.9
per
100
0.8
person0.7
yrs
0.6
0.5
0.4
0.3
0.2
0.1
0
All
causes
AIDS
CVD
Liver
Cancer Other/
unknown
What are the residual excess disease risks due
to HIV in people with viral suppression ?
Insufficient CD4 count recovery
Inflammation
Adverse effects of antiretroviral drugs
Note: looking at risks due to HIV and not correlates of HIV
such as lifestyle factors (smoking, alcohol, recreational
drug use) and mental health and hepatitis.
What are the residual excess disease risks due
to HIV in people with viral suppression ?
Insufficient CD4 count recovery
Inflammation
Adverse effects of antiretroviral drugs
CD4 count recovery on ART if fully virally suppressed
UK CHIC Study; Hughes et al, HIV Medicine 2010; see also Mocroft et al Lancet 2007
Attainment of CD4 count above key thresholds
in people starting ART with CD4 count < 100/mm3
with sustained virologic suppression
n=400
100
150
200
350
500
median CD4
count at start of
ART 38 /mm3
O’Connor et al; in revision
CD4 count and risk of death in people on ART with
viral suppression: COHERE
Most recent CD4
cell count (/mm3)
< 50
50 - 200
200 - 350
350 - 500
> 500
Death rate (/1000 person years)
Death from
any cause
Death from causes
unrelated to HIV
64.8
20.0
6.9
3.8
2.4
25.6
14.1
5.2
2.9
1.9
COHERE PLoS Med 2012; also Weber et al D:A:D Arch Intern Med 2006
CD4 count and risk of non-AIDS disease events
in people on ART with viral suppression: D:A:D
Rate 16
ratio
Liver
Non-AIDS Cancer
8
Renal
Stroke
MI
4
2
1
< 200
0.5
200-349
350-499
>500
CD4 count
Trend highly statistically significant in all cases except for MI
Source: D:A:D (unpublished)
Natural history of HIV: CD4 count distribution
according to time from infection
Lodi et al; JID 2011
What are the residual excess disease risks due
to HIV in people with viral suppression ?
Insufficient CD4 count recovery
Inflammation
Adverse effects of antiretroviral drugs
Biomarker levels in SMART participants with viral load
< 400 cps/mL compared with HIV negative people in
CARDIA and MESA studies
People age 33-44
People age 45-75
n
fold-difference
n
fold-difference
IL-6
139
1.39 (p < 0.001)
291
1.60 (p < 0.001)
D-dimer
------------------------------
293
1.49 (p < 0.001)
adjusted for age, race, sex, body mass index, smoking, ratio of total
cholesterol:high-density lipoprotein cholesterol, diabetes, lipid-lowering
therapy, and blood pressure–lowering therapy
Neuhaus et al, JID 2010
Odds ratio for elevated* IL-6 and D-dimer levels in HIV
positive people on ART with viral load < 500 cps/mL
compared with HIV negative people: VACS study
Odds Ratio
(95% confidence interval)
IL-6
1.04 (0.79 - 1.36)
D-dimer
0.71 (0.53 - 0.97)
n ~ 1800; *elevated level is > 75th percentile
adjusted for age, race/ethnicity, prevalent CVD, hypertension,
diabetes, smoking, BMI, cholesterol lowering medication use, HDL,
LDL, triglycerides, cocaine use in the past year, alcohol use, HCV
infection, and renal disease.
Armah et al, CID 2012
Baseline IL-6 / D-dimer levels and risk of serious nonAIDS and mortality in people in SMART, ESPRIT and
SILCAAT control arms with viral load < 500 cps/mL
n=3766
adjusted for age and sex
Grund
et al,
CROI 2013
INSIGHT,
unpublished
IL-6 and D-dimer and risk of serious non-AIDS
events and death
adjusted for age and sex
n=3766
Grund et al, CROI 2013
What are the residual excess disease risks due
to HIV in people with viral suppression ?
Insufficient CD4 count recovery
Inflammation
Adverse effects of antiretroviral drugs
Antiretroviral drugs and risk of myocardial infarction
D:A:D N Engl J Med 2003
Unanticipated association between abacavir use
and raised risk of myocardial infarction
D:A:D Lancet 2008
Antiretroviral drugs and renal impairment
People with initial eGFR > 90 mL/min
Progression to
eGFR < 70
Rate ratio (95% CI)
per extra year of exposure
Progression to
eGFR < 60
Rate ratio (95% CI)
per extra year of exposure
adjusted for baseline eGFR, age, sex, ethnicity, risk group, sex, nadir CD4 count, cohort, prior
AIDS, baseline date, HBV, HCV, smoking, hypertension, diabetes, CVD, CD4 count, viral load,
cumulative exposure to specific drugs.
Ryom L et al; D:A:D CID 2013
Adjusted rate ratios for associations between ART
exposure and AIDS- and non-AIDS-defining cancer
AIDS-defining cancer (n = 1,151)
Non-AIDS-defining cancer (n = 1,091)
1.1
aRR and 95% CI
aRR and 95% CI
1.1
1.0
1.0
0.8
0.8
0.8
Any cART
PI
NNRTI
ART exposure (/year)
Any cART
PI
NNRTI
ART exposure (/year)
Adjusted for age, sex, cohort, HIV mode of acquisition, ethnic group, calendar year, body mass
index, any prior cancer, prior AIDS diagnosis, prior AIDS cancer, smoking status, HCV and HBV
status
Bruyand et al D:A:D CROI 2013
Also Chao et al, AIDS 2012, Piketty et al J Clin Oncol 2012
What are the residual excess disease risks due
to HIV in people with viral suppression ?
Comparisons of people with high CD4 count
with HIV negative populations
Comparisons of people with high CD4 count with
HIV negative populations - issues with interpretation
Confounding due to differences between HIV positive and
HIV negative or general population comparator;
e.g. smoking, drug use, socio-economic status,
mental health, access to regular health care
Differential ascertainment of events
Selection bias within the HIV positive people;
e.g. achieved viral suppression, diagnosed earlier at higher CD4
count, better health seeking behaviour, entry into a clinical trial
Small relative risks correspond to large absolute risk
differences at older ages
Myocardial Infarction rates compared with general
population: Kaiser-Permanante database
HIV +ve:
90,961
HIV –ve: 1,133,444
Relative rate
(compared with
HIV negative)
MI overall
CHD overall
CD4 > 500, on ART
CD4 > 500, not on ART
1.4
1.2
0.9
1.3
95% CI
p-value
1.3 - 1.7
1.1 - 1.4
0.8 - 1.1
0.9 - 1.9
<0.001
<0.001
0.38
0.19
matched on age, sex, medical center, year of start of follow-up. Adjusted
for smoking, alcohol/drug use, obesity, diabetes, lipid lowering drugs,
antihypertensive drugs.
Klein et al; CROI 2011
Comparison of MI risk with HIV uninfected: VACS
study
Hazard ratio* (95% CI)
Uninfected
1.00
Infected viral load > 500
1.75 (1.40 - 2.18)
Infected viral load < 500
1.39 (1.17 - 1.66)
*adjusted for age, sex, race/ethnicity, hypertension, lipids, smoking, HMG-CoA
reductase-inhibitor use, hepatitis C virus infection, renal disease, body mass
index, and cocaine and alcohol abuse and dependence.
Freiberg et al; JAMA Intern Med 2013
Death rate in ART-experienced MSM with CD4 count >
500, compared with the general population: COHERE
n ~ 28,000
MSM
Time with CD4 > 500
Current
1 yr
Previous AIDS
2 yrs
3 yrs
4 yrs
5 yrs
No previous AIDS
SMR
18-39 40-59 >60
Age
Lewden et al, IJE 2012
See also Zwahlen et at
IJE, 2009
Survival in people on ART without risk factors
compared with the general population in Denmark
Estimated probability of
survival from age 25 to
65 years (95% CI)
General population
0.88
(0.86 - 0.90)
HIV infected without
HIV risk factors,
comorbidities or
substance abuse
0.86
(0.77 - 0.92)
Obel et al, PLoS One 2011
SMR in non-IDU in SMART and ESPRIT control
groups compared with the general population
- Viral load < 400 and CD4 count > 350 in past 6 months
SMR (95% CI)
CD4 350-499
CD4 > 500
1.77
1.00
(1.17-2.55)
(0.69-1.40)
Rodger et al, AIDS 2013
Summary and Conclusions - 1
The main causes or potential causes of excess risk of serious
disease due to HIV in people with viral suppression are ongoing CD4 cell immunodeficency, inflammation and related
factors, and adverse effects of ART.
CD4 cell immunodefiency is markedly improved with virally
suppressive ART but full re-normalisation can take several
years and may not always be achieveable.
Some excess inflammation appears to persist in people with
viral suppression.
Potential therapeutic approaches to enhance the rate of CD4
count restoration and/or reduce inflammation should be
investigated.
Summary and Conclusions - 2
We should remain vigilant over potential adverse effects of
antiretroviral drugs.
Comparisons of people with high CD4 count with HIV
negative people show some evidence, albeit inconsistent,
for modest residual raised risk of serious clinical events and
death.
Interpretation is difficult and significant biases in either
direction are highly possible.
Nonetheless, there is sufficient evidence for excess risks, and
concern that these will become more significant with ageing,
that this group must remain the focus of study.
Acknowledgements
Helpful comments, advice and extra analyses from:
Jim Neaton
Colette Smith
Jason Baker
Fiona Lampe
Alison Rodger
Caroline Sabin,
Steve Deeks
Amanda Mocroft
David Kamara
Jemma O’Connor
Jacquie Neuhaus
Debby Wentworth
Alessandro Cozzi Lepri
Jens Lundgren