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The Lancet and Cell Meeting What Will it Take to Achieve an AIDS-free World ? Session 4: Long term consequences of living with HIV: c omorbidities & ageing San Francisco, 3-5 November 2013.

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The lancet and cell meeting what will it take to achieve an aids free world

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

Trend in median CD4 count in clinic populations

CD4 count (/mm3)

Smith C, Lampe F, Johnson M, et al


Prevalence of viral load 50c ml in people on art

Prevalence of viral load > 50c/mL in people on ART*

Proportion

2000 2005 2010

*Of those receiving ART>24 weeks

Smith C, Lampe F, Johnson M, et al


The lancet and cell meeting what will it take to achieve an aids free world

Trends in death rate in people with HIV: UK

Rate per 100 people

Number of deaths in year

Number seen for care in year

Year

Source: Public Health England


The lancet and cell meeting what will it take to achieve an aids free world

Trend in cause-specific death rate in people with

HIV: D:A:D

AIDS

Other - known

Liver

CVD

Non-AIDS cancer

Unknown

D:A:D unpublished


The lancet and cell meeting what will it take to achieve an aids free world

Projected life expectancy of UK man infected age 30

Nakagawa et al, AIDS 2012


The lancet and cell meeting what will it take to achieve an aids free world

What are the residual excess disease risks due to HIV in people with viral suppression ?


The lancet and cell meeting what will it take to achieve an aids free world

Cause-specific death rate in SMART/ESPRIT control arms: baseline viral load < 500 cps/mL

Rate

per

100

person-

yrs

All

causes

Cancer

Other/

unknown

Liver

CVD

AIDS


The lancet and cell meeting what will it take to achieve an aids free world

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.


The lancet and cell meeting what will it take to achieve an aids free world

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


The lancet and cell meeting what will it take to achieve an aids free world

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


The lancet and cell meeting what will it take to achieve an aids free world

Attainment of CD4 count above key thresholds

in people starting ART with CD4 count < 100/mm3

with sustained virologic suppression

n=400

median CD4

count at start of

ART 38 /mm3

100

150

200

350

500

O’Connor et al; in revision


The lancet and cell meeting what will it take to achieve an aids free world

CD4 count and risk of death in people on ART with viral suppression: COHERE

Most recent CD4Death rate (/1000 person years)

cell count (/mm3)

Death fromDeath from causes

any causeunrelated to HIV

< 5064.825.6

50 - 20020.014.1

200 - 350 6.9 5.2

350 - 500 3.8 2.9

> 500 2.4 1.9

COHERE PLoS Med 2012; also Weber et al D:A:D Arch Intern Med 2006


The lancet and cell meeting what will it take to achieve an aids free world

CD4 count and risk of non-AIDS disease events

in people on ART with viral suppression: D:A:D

Rate

ratio

Liver

Non-AIDS Cancer

Renal

Stroke

MI

< 200200-349350-499>500

CD4 count

Trend highly statistically significant in all cases except for MI

Source: D:A:D (unpublished)


The lancet and cell meeting what will it take to achieve an aids free world

Natural history of HIV: CD4 count distribution

according to time from infection

Lodi et al; JID 2011


The lancet and cell meeting what will it take to achieve an aids free world

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


The lancet and cell meeting what will it take to achieve an aids free world

Biomarker levels in SMART participants with viral load

< 400 cps/mL compared with HIV negative people in

CARDIA and MESA studies

  • People age 33-44People age 45-75

  • nfold-difference nfold-difference

  • IL-61391.39 (p < 0.001)2911.60 (p < 0.001)

  • D-dimer------------------------------2931.49 (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


The lancet and cell meeting what will it take to achieve an aids free world

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-61.04 (0.79 - 1.36)

  • D-dimer0.71 (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


The lancet and cell meeting what will it take to achieve an aids free world

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

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

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


The lancet and cell meeting what will it take to achieve an aids free world

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


The lancet and cell meeting what will it take to achieve an aids free world

Antiretroviral drugs and risk of myocardial infarction

D:A:D N Engl J Med 2003


The lancet and cell meeting what will it take to achieve an aids free world

Unanticipated association between abacavir use

and raised risk of myocardial infarction

D:A:D Lancet 2008


The lancet and cell meeting what will it take to achieve an aids free world

Antiretroviral drugs and renal impairment

People with initial eGFR > 90 mL/min

Progression to

eGFR < 60

Progression to

eGFR < 70

Rate ratio (95% CI)

Rate ratio (95% CI)

per extra year of exposure

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


A djusted rate ratios for associations between art exposure and aids and non aids defining cancer

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

1.1

1.0

1.0

aRR and 95% CI

aRR and 95% CI

0.8

0.8

Any cART

PI

NNRTI

Any cART

PI

NNRTI

ART exposure (/year)

ART exposure (/year)

Adjusted for age, sex, cohort, HIV mode of acquisition, ethnic group, calendaryear, body mass index, anyprior 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


The lancet and cell meeting what will it take to achieve an aids free world

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


The lancet and cell meeting what will it take to achieve an aids free world

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


The lancet and cell meeting what will it take to achieve an aids free world

Myocardial Infarction rates compared with general population: Kaiser-Permanante database

HIV +ve: 90,961

HIV –ve: 1,133,444

Relative rate95% CIp-value

(compared with

HIV negative)

MI overall1.4 1.3 - 1.7 <0.001

CHD overall 1.2 1.1 - 1.4 <0.001

CD4 > 500, on ART0.9 0.8 - 1.10.38

CD4 > 500, not on ART1.3 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.

Klein et al; CROI 2011


The lancet and cell meeting what will it take to achieve an aids free world

Comparison of MI risk with HIV uninfected: VACS study

Hazard ratio* (95% CI)

Uninfected1.00

Infected viral load > 5001.75 (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


The lancet and cell meeting what will it take to achieve an aids free world

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

Lewden et al, IJE 2012

See also Zwahlen et at

IJE, 2009

18-39 40-59 >60

Age

SMR


The lancet and cell meeting what will it take to achieve an aids free world

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 population0.88(0.86 - 0.90)

HIV infected without0.86(0.77 - 0.92)

HIV risk factors,

comorbidities or

substance abuse

Obel et al, PLoS One 2011


The lancet and cell meeting what will it take to achieve an aids free world

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

CD4 350-499CD4 > 500

SMR (95% CI) 1.771.00(1.17-2.55)(0.69-1.40)

Rodger et al, AIDS 2013


The lancet and cell meeting what will it take to achieve an aids free world

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 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.


The lancet and cell meeting what will it take to achieve an aids free world

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.


The lancet and cell meeting what will it take to achieve an aids free world

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


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