Morbidity and Mortality in the HAART era Andrew Phillips Royal Free & University College Medical...

Morbidity and Mortality in the HAART era

Andrew PhillipsRoyal Free & University College Medical SchoolLondon

Death in the HAART era: rates and reasons

Trends in death rate: HOPS

Trends in death rate over calendar time in UK

Source: HPA

0

2

4

6

8

10

Number of deaths in year Number seen for care in year

1481 749 514 472 484 477 520 572 495 539 497Deaths

Seen for care(thousands,rounded)

15 16 18 20 22 26 32 36 41 46 52

96 97 98 99 00 01 02 03 04 05 06

Year

Rate per100 people

Breakdown of causes of death: France 2005

Lewden et al, CROI 2007

0 5 10 15 20 25 30 35 40

AIDS Cancer Hepatitis C CVD Suicide Non-AIDS infection Accident Hepatitis B Liver disease OD / drug abuse neurologic renal pulmonary digestive iatrogenic metabolic psychiatric other unknown

Percent

N = 937 deaths

ANRS EN19 Mortalité 2005

Audit of 397 deaths in UK 2005: Scenario leading to AIDS-related deaths

BHIVA Audit – Johnson et al 2006

Scenario % of AIDS deaths

Diagnosed too late for effective treatment 40%

Under care, but with untreatable complication 29%

Treatment ineffective due to poor adherence 12%

Chose not to receive treatment 8%

Known HIV, not under regular care, 6%re-presented too late

MDR HIV, ran out of options 5%

Incidence of non-AIDS death 1994-2004

0

1

2

3

4

5

6

7

8

9

10Rate per 100 personyears

Year

Test for trend: p < 0.0001

(excluding death from unknown causes)

95 96 97 98 99 00 01 02 03 04

EuroSIDA; Mocroft, Lundgren et al, personal communication

Might HIV increase the risk of serious non-AIDS conditions and non-AIDS death ?


Incidence of, and death from:

- Non-AIDS malignancies

- End stage renal disease

- Cardiovascular events

- Liver cirrhosis

- Deaths from other non-AIDS causes

- Not focussing on adverse effects of ART

Possible mechanisms: General

- Very early loss of CD4 T cells in gastrointestinal tract

- Loss of immunological and epithelial integrity of the mucosal barrier – leading to microbial translocation

- Generalized immune activation

- Fibrosis of lymphatic tissue

Veazey et al, Science 1998 Brenchley et al, Nature Med 2006Brenchley, J Exp Med 2004 Schacker et al, Clin Vacc Immunol 2006

Possible mechanisms: Non-AIDS malignancies

Immunodeficiency, leading to:

- reduced control of oncogenic pathogens

- damage due to infections and resulting chronic inflammation

- loss of ability to identify transformed cells

Littman et al. Cancer Epidemiol Biomarkers Prev 2005

Possible mechanisms:Kidney disease- HIV associated nephropathy (HIVAN) (viral nephritis reversed by ART)

- Link with other kidney pathologies (e.g. immune complex glomerulonephritis)

- High prevalence of proteinuria, associated with HIV RNA level and CD4 count

- HIV RNA and CD4 count predict raised creatinine levels

- proteinurea & elevated creatinine associated with all cause mortality in HIV patients

Szczech et al, Kidney International 2002 Lucas et al, AIDS 2004Szczech et al, Kidney International 2004 Kimmel et al, Ann Intern Med 2003

Possible mechanisms:Cardiovascular diseaseAssociation of HIV-infection with adverse changes in known or potential biomarkers forCVD.

- HDL-cholesterol depletion

- Inflammation (raised IL-6, C-reactive protein)

- Endothelial activation/dysfunction (VCAM, ICAM)

- Activation of coagulation (D-dimer)

Several of the changes appear to be at least partially reversed by ART

Riddler JAMA 2003 de Larranaga et al, Blood Coag. & Fibrinolys 2003Lau et al, Arch Intern Med 2006 Wolf et al, J Infect Dis 2002

Possible mechanisms:Liver disease

- immunodeficiency linked to more rapid progression of liver fibrosis in HBV and HCV infected people - affect CD4+ and CD8+ response to HBV / HCV

- alter HBV / HCV quasi-species

- increased hepatocyte apoptosis

Tan et al, Current HIV research 2006 Thio et al, Lancet 2002Eyster et al, JAIDS 1993 Soto et al, J Hepatol 1997


Types of evidence

comparison of risk of serious non-AIDS events between HIV-infected and HIV-uninfected people

studies of the association between CD4 count

(and HIV RNA) and risk of serious non-AIDS events

randomized trials of the impact on serious non- AIDS events of reduction in HIV RNA level and increase in CD4 count with ART

Comparison of risk of events between HIV-infected and HIV-uninfected people: limitations

- HIV -ve comparison group will differ from HIV-infected group in more ways than just the HIV infection (eg smoking)

Adjustment for such confounding bias may not be possible.

Each non-AIDS condition has its own set of risk factors which could act differently in HIV-infected people.

- HIV infected subjects often mixture of those on ART and ART-naïve, so not possible in all studies to distinguish effect of HIV from effect of ART.

For 20 / 28 cancers examined there was significantly increased incidencein both groups – strongly suggesting a link with immunodeficiency

Standardized Incidence Ratio

HIV/AIDS Transplant

Lung 2.7 2.2Leukaemia 3.2 2.4Kidney 1.5 6.8Oesophagus 1.6 3.1Stomach 1.9 2.0

Meta-analysis: 444,172 people with HIV, 31,977 transplant patients

Grulich et al, Lancet 2007

HIV and risk of non-AIDS malignancies

CID 2007

AIDS 2007

HIV and risk of lung cancer, independent of smoking

Hazard ratio for End Stage Renal Disease

# people # ESRD Hazard ratio*

White HIV -ve 1,201,870 3991 1.0 HIV +ve 6,139 13 0.8 (0.5 – 1.3)

Black HIV -ve 206,636 1425 2.0 (1.9 – 2.2) HIV +ve 6,816 129 4.6 (3.4 – 6.1)

*Adjusted for age, sex, baseline eGFR category, CAD, HTN, heart failure, COPD, PVD, HCV infection, cerebrovascular disease, and SES.

Little effect of HIV in diabetics

Choi et al J Am Soc Nephr 2007

U.S. Veterans without diabetes

HIV and risk of End Stage Renal disease

HIV and Cardiovascular Disease

Subject source N CVD Risk in HIV +cases in vs. HIV –ve HIV +

Klein Administrative & 72 Increasedclinical managementdatabase

Mary-Krause HIV cohort / 60 Increased in thosegeneral population with > 18 m PI use

Currier Adminstrative 1360 Increased atdatabase younger ages

Triant Patient Data 189 IncreasedRegistry

Klein et al, JAIDS 2002 Mary-Krause et al, AIDS 2003Currier et al, JAIDS 2003 Triant et al, J Clin Endocrin Metab 2007

HIV (and haemophilia) status 25 year cumulative risk

of liver death

Severe haemophilia, not HIV 1.4 (0.7 – 3.0)

Moderate / mild haemophilia, not HIV 1.2 (0.5 – 2.6)

HIV-infected (all haemophilia severities) 6.5 (4.5 – 9.5)

HIV and Liver disease

4865 men and boys with haemophilia (and probable HCV infection),of whom 1218 HIV-infected

Darby et al, Lancet 1997Similarly for HBV in MACS – Thio et al, Lancet 2002

All cause death rates in ART-naïve patients with CD4 count > 350 /mm3, compared with the general population

Abstract N-264 Wednesday 10.30 - Lodwick et al


Types of evidence

comparison of risk of serious non-AIDS events between HIV-infected and HIV-uninfected

people




CD4 count and risk of death: DAD and CASCADE

200 – 350 – > 500 349 499

CD4 count (/mm3)

DAD

Rate

/ 100 personyears

95% CI

Non-AIDS causes All causes

CASCADE(ART-naïve)

Weber at al Marin et al

0.0

0.4

0.8

1.2

1.6

0.0

0.4

0.8

1.2

1.6

200 – 350 – > 500 349 499

Bonnet et al, HIV Medicine 2007

Number of hospitalizations Number (mean per patient) during 2000-2004

CD4 count of patients

> 500 2442 16 (0.01) 335 (0.14) 351 (0.14)

200-499 2922 60 (0.02) 581 (0.20) 641 (0.22)

< 200 1229 260 (0.21) 439 (0.36) 699 (0.57)

Hospitalization events according to cause and CD4 count: Aquitaine cohort, 2000-2004

3863 patients

AIDS non-AIDS All

p < 0.001 p < 0.001

ANRS C03 Aquitaine Cohort

1.0 1.5

Renal

Liver

All serious non-AIDS

HIV RNA and risk of serious non-AIDS events: SMART

CVD

Non-AIDS malignancy

Other non-AIDS death

Adjusted for age, gender, prior AIDS, hep B/C, smoking, latest CD4 count

0.50.2

SMART, unpublished

Adjusted hazard ratio < 400 vs. > 400 copies/mL


Types of evidence

comparison of risk of serious non-AIDS events between HIV-infected and HIV-uninfected

people




Intermittent ART

Stop or defer ART whenCD4 count > 350, restart or start ART when CD4 count < 250

Continuous ART

Participants with CD4 count > 350

n = 2720 n = 2752

N Engl J Med 2006

Randomization

94% on ART 99% CD4 > 200

33% on ART96% CD4 > 200

Follow-up

84% on ART, 16% off ART

SMART Study

Risk of serious non-AIDS events in SMART

SMART Study Group, NEJM 2006 & Neaton et al, Current Opinion in HIV/AIDS 2008

1 2

Renal 9 2

Liver 10 7

All serious non-AIDS

CVD 48 31

Non-AIDS malignancy 27 24

Other non-AIDS death 30 16

0.5 Hazard ratio Intermittent ART vs. Continuous ART

Number of events

Intermittent Continuous ART ART

3 5 10

113 73

Of the 85 deaths that occurred in SMART, only 7 (8%) were from AIDS diseases

Number of events Hazard ratio Deferred vs.Deferred Immediate Immediate ARTART ART (95% CI) p-value

12 2 7.02 (1.57 – 31.4) 0.01

N = 477 patients

Risk of serious non-AIDS events in SMART: patients ART naïve or off ART for > 6 months

Emery et al, JID (in press)

Inflammatory and coagulation markers in SMART

Abstract D-60 Wednesday 10.00 – Kuller et al

- Illustrates value of biomarker studies based on stored samples from a randomized trial with clinical endpoints


Summary

- On balance, evidence suggests HIV may well play a role in several serious non-AIDS defining events.

- In the upper CD4 count range, while overall risk of any disease is relatively low, non-AIDS events are much more common than AIDS events. - Given the associations with latest level of CD4 count / HIV RNA and the results from SMART use of ART may well reduce risk of some serious non-AIDS events.

What steps can we take towards further reduction in morbidity and

mortality ?

What steps can we take towards further reduction in morbidity and mortality ?

- Continued efforts to diagnose HIV as early as possible

- Research into prediction of non-AIDS events in context of HIV

- ART-naïve and ART-treated - standardize diagnostic criteria and data collection methods

- Trial of ART initiation in people with CD4 count > 500 /mm3

- non-AIDS diseases relatively common at higher CD4 count - SMART suggests risk / benefits of ART favour benefit - durable virological benefit of current ART - cost-effectiveness / reduction in transmission risk - basis for identifying biomarkers that mediate raised risk, providing insights into mechanisms (also beyond HIV)

Conclusions

- The study of serious non-AIDS conditions is an important emerging area for HIV research

- Research is needed to provide a basis for defining models of care for people with HIV which take into account the risk of all serious conditions - Research into mechanisms by which HIV affects risk of non- AIDS conditions is needed, and it may help us understand more about the causes of such conditions outside HIV

- The possibility that ART should be initiated much earlier should be investigated in a randomized trial. Such a trial will form a key resource for this new research area.

Acknowledgements

Jens Lundgren, Jim Neaton

HIV Epidemiology & Biostatistics Group, Royal Free, UCLCaroline Sabin, Amanda Mocroft, Fiona Lampe, Alessandro Cozz-Lepri, Colette Smith, Zoe Fox, Wendy Bannister, Loveleen Bansi, Rebecca Lodwick, Joanne Reekie

DAD (Aquitaine, Nice, CPCRA, EuroSIDA, ICONA,SHCS, Brussels, BASS, AHOD, ATHENA, HivBivus)EuroSIDASMART FIRSTCASCADEHOPS

Extra analyses: Jacquie Neuhaus (SMART), Grace Peng, Jason Baker (FIRST), Benoit Marin, Genevieve Chene, Abdel Babiker (CASCADE), Colette Smith, Caroline Sabin (DAD), Amanda Mocroft (EuroSIDA)

Morbidity and Mortality in the HAART era Andrew Phillips Royal Free & University College Medical...

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