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Risk of serious disease and death in people with HIV viral suppression on ART: an epidemiologic perspective
The Lancet and Cell MeetingWhat Will it Take to Achieve an AIDS-free World? Session 4: Long term consequences of living with HIV: comorbidities & ageingSan Francisco, 3-5 November 2013
Trend in median CD4 count in clinic populations
0
100
200
300
400
500
600
700
Calendar year 1995 2000 2005 2010
CD4 count (/mm3)
Smith C, Lampe F, Johnson M, et al
Prevalence of viral load > 50c/mL in people on ART*
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
Calendar year 2000 2005 2010
Smith C, Lampe F, Johnson M, et al
Proportion
*Of those receiving ART>24 weeks
Trends in death rate in people with HIV: UK
Source: Public Health England
Number of deaths in year Number seen for care in year
Year
Rate per 100 people
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
0
2
4
6
8
10
12
1999/2000 2001/2002 2003/2004 2005/2006 2007/2008 2009-20110
1
2
3
4
5
6
7
Calendar Year
Rat
e o
f d
eath
per
100
0 p
erso
n-y
ears
Trend in cause-specific death rate in people with HIV: D:A:D
AIDS
Other - known
Liver
CVD
Unknown
Non-AIDS cancer
D:A:D unpublished
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
30 35 40 45 50 55 60 65 70 75 80 85 90 95 100
Age (years)
Cum
ulat
ive
perc
enta
ge
Dead from non-AIDS
Dead from AIDS
Alive & diagnosed (on ART)
Alive & diagnosed (off ART)
Alive & undiagnosed
Projected life expectancy of UK man infected age 30
Nakagawa et al, AIDS 2012
Cause-specific death rate in SMART/ESPRIT control arms: baseline viral load < 500 cps/mL
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1Rate per100 person-yrs
Liver CVD AIDS Other/unknown
Cancer All causes
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 thresholdsin people starting ART with CD4 count < 100/mm3
with sustained virologic suppression
100
150200
350500
n=400
median CD4count at start ofART 38 /mm3
O’Connor et al; in revision
CD4 count and risk of death in people on ART with viral suppression: COHERE
COHERE PLoS Med 2012; also Weber et al D:A:D Arch Intern Med 2006
Most recent CD4 Death rate (/1000 person years)cell count (/mm3)
Death from Death from causesany cause unrelated to HIV
< 50 64.8 25.6
50 - 200 20.0 14.1
200 - 350 6.9 5.2
350 - 500 3.8 2.9
> 500 2.4 1.9
CD4 count and risk of non-AIDS disease events in people on ART with viral suppression: D:A:D
Source: D:A:D (unpublished)
0.1
1
10
100
< 200 200-349 350-499 >500
CD4 count
Rate ratio
Liver
MI Stroke
Renal
Non-AIDS Cancer
Trend highly statistically significant in all cases except for MI
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
Neuhaus et al, JID 2010
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
Odds ratio for elevated* IL-6 and D-dimer levels in HIV positive people on ART with viral load < 500 cps/mLcompared with HIV negative people: VACS study
Armah et al, CID 2012
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.
INSIGHT, unpublishedGrund et al, CROI 2013
n=3766adjusted for age and sex
Baseline IL-6 / D-dimer levels and risk of serious non-AIDS and mortality in people in SMART, ESPRIT and SILCAAT control arms with viral load < 500 cps/mL
IL-6 and D-dimer and risk of serious non-AIDS events and death
adjusted for age and sex
Grund et al, CROI 2013
n=3766
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
D:A:D Lancet 2008
Unanticipated association between abacavir useand raised risk of myocardial infarction
Antiretroviral drugs and renal impairment
Ryom L et al; D:A:D CID 2013
People with initial eGFR > 90 mL/min
Rate ratio (95% CI)Rate ratio (95% CI)per extra year of exposure
Rate ratio (95% CI)per extra year of exposure
Progression toeGFR < 60
Progression toeGFR < 70
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.
Adjusted rate ratios for associations between ART exposure and AIDS- and non-AIDS-defining cancer
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
AIDS-defining cancer (n = 1,151) Non-AIDS-defining cancer (n = 1,091)
aRR
and
95%
CI
0.8
1.1
1.0
Any cART PI NNRTI0.8
ART exposure (/year)
1.1
1.0
Any cART PI NNRTI0.8
aRR
and
95%
CI
ART exposure (/year)
Bruyand et al D:A:D CROI 2013 Also Chao et al, AIDS 2012, Piketty et al J Clin Oncol 2012
Comparisons of people with high CD4 count with HIV negative populations
What are the residual excess disease risks due to HIV in people with viral suppression ?
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
Comparisons of people with high CD4 count with HIV negative populations - issues with interpretation
Myocardial Infarction rates compared with general population: Kaiser-Permanante database
Klein et al; CROI 2011
HIV +ve: 90,961 HIV –ve: 1,133,444
Relative rate 95% CI p-value (compared with HIV negative)
MI overall 1.4 1.3 - 1.7 <0.001 CHD overall 1.2 1.1 - 1.4 <0.001 CD4 > 500, on ART 0.9 0.8 - 1.1 0.38 CD4 > 500, not on ART 1.3 0.9 - 1.9 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.
Comparison of MI risk with HIV uninfected: VACS study
Freiberg et al; JAMA Intern Med 2013
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-CoAreductase-inhibitor use, hepatitis C virus infection, renal disease, body massindex, and cocaine and alcohol abuse and dependence.
Lewden et al, IJE 2012
See also Zwahlen et at IJE, 2009
Death rate in ART-experienced MSM with CD4 count > 500, compared with the general population: COHERE
n ~ 28,000MSM
Previous AIDS
No previous AIDS
18-39 40-59 >60 Age
5 yrs
4 yrs
3 yrs
2 yrs
1 yr
SMR
Time with CD4 > 500
Current
Survival in people on ART without risk factorscompared with the general population in Denmark
Obel et al, PLoS One 2011
Estimated probability of survival from age 25 to65 years (95% CI)
General population 0.88 (0.86 - 0.90)
HIV infected without 0.86 (0.77 - 0.92)HIV risk factors, comorbidities orsubstance abuse
SMR in non-IDU in SMART and ESPRIT controlgroups compared with the general population
- Viral load < 400 and CD4 count > 350 in past 6 months
CD4 350-499 CD4 > 500
SMR (95% CI) 1.77 1.00(1.17-2.55) (0.69-1.40)
Rodger et al, AIDS 2013
Summary and Conclusions - 1The main causes or potential causes of excess risk of serious disease due to HIV in people with viral suppression are on-going 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.