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 of

dea

th p

er 1

000

pers

on-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D:A:D unpublished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

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

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

100150

200

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 25.650 - 200 20.0 14.1200 - 350 6.9 5.2350 - 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 >500CD4 count

Rate ratio Liver

MI Stroke Renal Non-AIDS Cancer

Trend highly statistically significant in all cases except for MI

Lodi et al; JID 2011

Natural history of HIV: CD4 count distributionaccording to time from infection

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 N Engl J Med 2003

Antiretroviral drugs and risk of myocardial infarction

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 - 2We 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.

AcknowledgementsHelpful comments, advice and extra analyses from:Jim Neaton Colette SmithJason BakerFiona LampeAlison RodgerCaroline Sabin, Steve DeeksAmanda MocroftDavid KamaraJemma O’ConnorJacquie NeuhausDebby WentworthAlessandro Cozzi LepriJens Lundgren