1. Can early antiretroviral therapy fully restore health? Workshop on Pathogeneses and Management of Long-Term Complications of ART IAS Conference, Rome July 18, 2011

2. Trends in death rate in people with HIV: UK Source: Health Protection Agency 99 00 01 02 03 04 05 06 07 08 09 Year Rate per 100 people Number of deaths in year Number seen for care in year

3. People on ART > 6 months: proportion with viral load > 50 copies/mL Royal Free clinic cohort. Smith C, Lampe F, Johnson M, unpublished 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

4. HIV and risk of non-AIDS diseases and death - HIV leads to increased risk of a variety of serious non-AIDS conditions - Such risk is generally associated with lower CD4 count - So what is the extent of ongoing increased risk of serious events associated with HIV if the CD4 count is high ? - Impossible to answer definitively, due to likely selection and confounding effects in studies comparing with HIV uninfected people.

5. Comparison of death rate in HIV positive and HIV negative people: FRAM 469 HIV infected, 280 sero-negative controls Hazard ratio* Overall 3.4 (95% CI: 1.35, 8.5); p = 0.009 Current CD4 > 350 2.3 (95% CI: 0.78 - 6.9); p = 0.13 *adjusted for cardiovascular risk factors Cockerham et al; JAIDS 2011

6. 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 95% CIp-value rate MI overall1.4 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

7. Death rates in ART naïve MSM with CD4 count above 350 cells/mm 3 compared with the general population Deaths Person- Death rateSMR (95% CI) years / 1000 pyrs 100 38,7642.58 1.30 (1.06 – 1.58) Lodwick et al; Lancet 2010 CD4 count > 500/mm 3 : SMR 1.03 (0.76 – 1.37) Focus on MSM due to lesser potential for confounding

8. Lewden et al, COHERE, EACS Cologne, 2009 See also Zwahlen et at IJE, 2009 Death rate in ART-experienced MSM with CD4 count > 500, compared with the general population n ~ 28,000 MSM 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

9. SMRs for non-AIDS deaths in non-IDU in SMART and ESPRIT control groups compared with the general United States population - Viral load 350 in past 6 months Person-yrs 15,324 Observed deaths 62 Expected deaths 62.45 SMR (95% CI) 0.99 (0.76-1.27) Rodger et al, SMART and ESPRIT, unpublished

10. Conclusions The extent of any increased risk of of death due to HIV in those with current CD4 count > 500 remains unclear, but appears to be modest, particularly if: - viral load is suppressed - no history of AIDS / low CD4 count

11. Acknowledgements Investigators in the following studies: SMART ESPRIT Royal Free clinic cohort D:A:D CASCADE COHERE Health Protection Agency (HPA), UK