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

2. Death in the HAART era: rates and reasons

3. Trends in death rate: HOPS

4. Trends in death rate over calendar time in UK Source: HPA 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 per 100 people

5. Breakdown of causes of death: France 2005 Lewden et al, CROI 2007 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

6. 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%

7. Incidence of non-AIDS death 1994-2004 Rate per 100 person years 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

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

9. 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

10. 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 1998Brenchley et al, Nature Med 2006 Brenchley, J Exp Med 2004Schacker et al, Clin Vacc Immunol 2006

11. 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

12. 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 2004 Szczech et al, Kidney International 2004Kimmel et al, Ann Intern Med 2003

13. 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 2003de Larranaga et al, Blood Coag. & Fibrinolys 2003 Lau et al, Arch Intern Med 2006Wolf et al, J Infect Dis 2002

14. 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 2006Thio et al, Lancet 2002 Eyster et al, JAIDS 1993Soto et al, J Hepatol 1997

15. 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

16. 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.

17. For 20 / 28 cancers examined there was significantly increased incidence in both groups – strongly suggesting a link with immunodeficiency Standardized Incidence Ratio HIV/AIDS Transplant Lung 2.72.2 Leukaemia 3.22.4 Kidney 1.56.8 Oesophagus 1.63.1 Stomach 1.92.0 Meta-analysis: 444,172 people with HIV, 31,977 transplant patients Grulich et al, Lancet 2007 HIV and risk of non-AIDS malignancies

18. CID 2007 AIDS 2007 HIV and risk of lung cancer, independent of smoking

19. Hazard ratio for End Stage Renal Disease # people# ESRDHazard ratio* White HIV -ve1,201,87039911.0 HIV +ve 6,139 130.8 (0.5 – 1.3) Black HIV -ve 206,63614252.0 (1.9 – 2.2) HIV +ve 6,816 1294.6 (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

20. HIV and Cardiovascular Disease Subject sourceN CVDRisk in HIV + cases invs. HIV –ve HIV + KleinAdministrative & 72Increased clinical management database Mary-Krause HIV cohort /60Increased in those general populationwith > 18 m PI use CurrierAdminstrative 1360Increased at databaseyounger ages TriantPatient Data 189Increased Registry Klein et al, JAIDS 2002Mary-Krause et al, AIDS 2003 Currier et al, JAIDS 2003Triant et al, J Clin Endocrin Metab 2007

21. HIV (and haemophilia) status 25 year cumulative risk of liver death Severe haemophilia, not HIV1.4 (0.7 – 3.0) Moderate / mild haemophilia, not HIV1.2 (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 1997 Similarly for HBV in MACS – Thio et al, Lancet 2002

22. 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

23. 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

24. CD4 count and risk of death: DAD and CASCADE 200 – 350 – > 500 349 499 CD4 count (/mm 3 ) DAD Rate / 100 person years 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

25. Bonnet et al, HIV Medicine 2007 Number of hospitalizations Number (mean per patient) during 2000-2004 CD4 count of patients > 500244216 (0.01)335 (0.14)351 (0.14) 200-499292260 (0.02)581 (0.20)641 (0.22) < 2001229260 (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 ANRS C03 Aquitaine Cohort

26. 1.01.5 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 0.5 0.2 SMART, unpublished Adjusted hazard ratio 400 copies/mL

27. 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

28. Intermittent ART Stop or defer ART when CD4 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 ART 96% CD4 > 200 Follow-up 84% on ART, 16% off ART SMART Study

29. 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 3510 113 73 Of the 85 deaths that occurred in SMART, only 7 (8%) were from AIDS diseases

30. Number of eventsHazard ratio Deferred vs. Deferred Immediate Immediate ART ART 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)

31. 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

32. 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.

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

34. 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)

35. 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.

36. 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)