Morbidity and Mortality in the HAART era

Andrew Phillips Royal Free & University College Medical School London

Death in the HAART era: rates and reasons

Trends in death rate: HOPS

Trends in death rate over calendar time in UK Rate per 100 people 10 8 Number of deaths in year Number seen for care in year 6 4 2 0 96 97 98 99 00 01 02 03 04 05 06 Year Deaths 1481 749 514 472 484 477 520 572 495 539 497 Seen for care 15 16 18 20 22 26 32 36 41 46 52 (thousands,rounded)

Source: HPA

Breakdown of causes of death: France 2005 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 N = 937 deaths 0

ANRS EN19 Mortalité 2005

5 10 15 20 Percent 25 30 35 40

Lewden et al, CROI 2007

Audit of 397 deaths in UK 2005: Scenario leading to AIDS-related deaths Scenario % of AIDS deaths Diagnosed too late for effective treatment Under care, but with untreatable complication Treatment ineffective due to poor adherence Chose not to receive treatment Known HIV, not under regular care, re-presented too late MDR HIV, ran out of options 40% 29% 12% 8% 6% 5%

BHIVA Audit – Johnson et al 2006

Incidence of non-AIDS death 1994-2004 (excluding death from unknown causes) 10 Rate per 100 person years 9 8 7 Test for trend: p < 0.0001 6 5 4 3 2 1 0 95 96 97 98 99 00 01 02 03 04 Year

EuroSIDA; Mocroft, Lundgren et al, personal communication

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

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, J Exp Med 2004 Brenchley et al, Nature Med 2006 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 Szczech et al, Kidney International 2004 Lucas et al, AIDS 2004 Kimmel et al, Ann Intern Med 2003

Possible mechanisms: Cardiovascular disease Association of HIV-infection with adverse changes in known or potential biomarkers for CVD. - 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 Lau et al, Arch Intern Med 2006 de Larranaga et al, Blood Coag. & Fibrinolys 2003 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 Eyster et al, JAIDS 1993 Thio et al, Lancet 2002 Soto et al, J Hepatol 1997

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

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.

HIV and risk of non-AIDS malignancies Meta-analysis: 444,172 people with HIV, 31,977 transplant patients For 20 / 28 cancers examined there was significantly increased incidence in both groups – strongly suggesting a link with immunodeficiency Lung Leukaemia Kidney Oesophagus Stomach Standardized Incidence Ratio HIV/AIDS Transplant 2.7

3.2

1.5

1.6

1.9

2.2

2.4

6.8

3.1

2.0

Grulich et al, Lancet 2007

HIV and risk of lung cancer, independent of smoking

CID 2007 AIDS 2007

HIV and risk of End Stage Renal disease U.S. Veterans without diabetes Hazard ratio for End Stage Renal Disease # people # ESRD White HIV -ve HIV +ve Black HIV -ve HIV +ve 1,201,870 6,139 206,636 6,816 3991 13 1425 129 Hazard ratio* 1.0

0.8 (0.5 – 1.3) 2.0 (1.9 – 2.2) 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

HIV and Cardiovascular Disease Subject source Klein Mary-Krause Currier Triant Administrative & clinical management database HIV cohort / general population Adminstrative database Patient Data Registry

Klein et al, JAIDS 2002 Currier et al, JAIDS 2003

N CVD cases in HIV + 72 60 1360 189 Risk in HIV + vs. HIV –ve Increased Increased in those with > 18 m PI use Increased at younger ages Increased

Mary-Krause et al, AIDS 2003 Triant et al, J Clin Endocrin Metab 2007

HIV and Liver disease 4865 men and boys with haemophilia (and probable HCV infection), of whom 1218 HIV-infected HIV (and haemophilia) status Severe haemophilia, not HIV Moderate / mild haemophilia, not HIV HIV-infected (all haemophilia severities) 25 year cumulative risk of liver death 1.4 (0.7 – 3.0) 1.2 (0.5 – 2.6) 6.5 (4.5 – 9.5)

Darby et al, Lancet 1997

Similarly for HBV in MACS

– Thio et al, Lancet 2002

All cause death rates in ART naïve patients with CD4 count > 350 /mm 3 , compared with the general population Abstract N-264 Wednesday 10.30 - Lodwick et al

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

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

CD4 count and risk of death: DAD and CASCADE 1.6

1.2

0.8

Rate 0.4

/ 100 person years 0.0

95% CI 1.6

1.2

0.8

0.4

0.0

Non-AIDS causes All causes 200 – 350 – > 500 349 499 200 – 350 – > 500 349 499 CD4 count (/mm 3 ) CASCADE (ART naïve) DAD

Weber at al Marin et al

Hospitalization events according to cause and CD4 count: Aquitaine cohort, 2000-2004 3863 patients CD4 count Number of patients Number of hospitalizations (mean per patient) during 2000-2004 AIDS non-AIDS All > 500 200-499 < 200 2442 2922 1229 16 (0.01) 60 (0.02) 260 (0.21) 335 (0.14) 581 (0.20) 439 (0.36) 351 (0.14) 641 (0.22) 699 (0.57)

ANRS C03 Aquitaine Cohort p < 0.001

p < 0.001

Bonnet et al, HIV Medicine 2007

HIV RNA and risk of serious non-AIDS events: SMART All serious non-AIDS Non-AIDS malignancy Renal CVD Liver Other non-AIDS death 0.2

0.5

1.0

1.5

Adjusted hazard ratio < 400 vs. > 400 copies/mL Adjusted for age, gender, prior AIDS, hep B/C, smoking, latest CD4 count

SMART, unpublished

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

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

SMART Study Participants with CD4 count > 350 84% on ART, 16% off ART Randomization n = 2720 n = 2752 Continuous ART Intermittent ART 94% on ART 99% CD4 > 200 Follow-up Stop or defer ART when CD4 count > 350, restart or start ART when CD4 count < 250 33% on ART 96% CD4 > 200

N Engl J Med 2006

Risk of serious non-AIDS events in SMART Number of events Intermittent Continuous ART ART All serious non-AIDS 113 73 Non-AIDS malignancy 27 24 Renal 9 2 CVD 48 31 Liver 10 7 Other non-AIDS death 30 16 0.5

1 2 3 5 10 Hazard ratio Intermittent ART vs. Continuous ART Of the 85 deaths that occurred in SMART, only 7 (8%) were from AIDS diseases

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

Risk of serious non-AIDS events in SMART: patients ART naïve or off ART for > 6 months N = 477 patients Number of events Deferred Immediate ART ART 12 2 Hazard ratio Deferred vs.

Immediate ART (95% CI)

p-value

7.02 (1.57 – 31.4)

0.01 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

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

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 /mm 3 - 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, UCL Caroline 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) EuroSIDA SMART FIRST CASCADE HOPS 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)