Background

1. Changes over time in the risk of death following HIV seroconversion compared with mortality in the general populationKholoud Porter, Krishnan Bhaskaran, Osamah Hamouda, Mette Sannes, Faroudy Boufassa, Anne Johnson, A Sarah Walker on behalf of CASCADE Collaboration

2. Background • Estimates of expected HIV mortality are important for clinical care and healthcare planning • As mortality rates fall, comparison to that of general population increasingly important • Mortality in HIV infected individuals will increasingly be influenced by non-HIV related causes of deaths • Details of cause of death missing or unreliable and often uncertainty over what may or may not be “HIV-related”

3. Objectives • To assess changes over calendar time in risk of excess mortality compared to general population and associated prognostic factors • To estimate excess probability of death at various durations of HIV infection

4. Methods (1) • CASCADE: 23 cohorts from Europe, Canada and Australia of persons with well-estimated dates of HIV seroconversion • Aged >15 years, sexual (MSM and MSW) or IDU exposure • Follow-up from SC to death/ censoring • Derived expected number of deaths from general population matched to study population stratified by: age, sex, calendar year at risk, country

5. Methods (2) • Observed deaths in study population modelled using Poisson process, subtracting expected deaths • time since SC divided into 1-year intervals • examined changes in risk of excess mortality over calendar time, adjusting for: age at SC, sex and risk group • investigated effects of these factors on excess mortality • Calculated life-table estimates of cumulative and relative survival, by infection duration in each calendar period. Hence, cumulative mortality and cumulative excess mortality

6. Study population 15 779 individuals, 108 329 person-years Male: 12363 (78%) Female: 3416 (22%) MSM: 8996 (57%) MSW: 3829 (24%) IDU: 2954 (19%) Median age at SC 29 years (IQR 24-36)

7. Excess deaths over calendar time

8. Factors associated with risk of excess mortality adjusted excess HR (95% CI) Calendar year Pre-1996 1.00 1996-97 0.52 (0.47- 0.59) 1998-99 0.16 (0.14- 0.19) 2000-01 0.12 (0.10- 0.14) 2002-03 0.10 (0.08- 0.12) 2004-06 0.06 (0.05- 0.08) Age group (yrs) 15-24 1 25-34 1.34 (1.21- 1.49) 35-44 1.90 (1.66- 2.18) 45+ 2.35 (1.93- 2.85) Sex Male 1.00 Female 0.79 (0.7- 0.91

9. Changes over time in effect of risk group on excess mortality * variation within calendar period

10. Cumulative excess mortality (sexual exposure only) 100 Age at SC 90 <45 years 80 45+ years 70 60 Cumulative % excess mortality 50 40 30 20 10 0 -10 15 < 1996 10 1996- 97 5 1998- 99 Years since seroconversion 15 2000- 01 10 2002- 03 5 2004- 06

11. All-cause mortality pre-1996 and 2004-06 (sexual exposure only) Pre-1996 (HIV infected) 2004- 2006 (HIV infected) 2004- 2006 (general uninfected) <45 years at seroconversion 45+ years at seroconversion 1.0 0.8 0.6 Estimated cumulative mortality 0.4 0.2 0.0 0 5 10 15 0 5 10 15 Time since seroconversion (years)

12. Conclusions • HIV patients are surviving longer: important to consider natural background mortality • The gap in mortality rates between HIV infected individuals in our study and the general population has narrowed considerably • A significantly elevated risk of death remains for all ages • IDUs remain at higher risk of death throughout HAART era • Ongoing monitoring is crucial as therapies and management change

13. CASCADE Collaborators Steering Committee: Julia Del Amo (Chair), Laurence Meyer (Vice Chair), Heiner Bucher, Geneviève Chêne, Deenan Pillay, Maria Prins, Magda Rosinska, Caroline Sabin, Giota Touloumi. Co-ordinating Centre: Kholoud Porter (Project Leader), Sara Lodi, Sarah Walker, Abdel Babiker, Janet Darbyshire. Clinical Advisory Board: Heiner Bucher, Andrea de Luca, Martin Fisher, Roberto Muga. Collaborators: Australia Sydney AIDS Prospective Study and Sydney Primary HIV Infection cohort (John Kaldor, Tony Kelleher, Linda Gelgor, Tim Ramacciotti, David Cooper, Don Smith); Canada South Alberta clinic (John Gill); Denmark Copenhagen HIV Seroconverter Cohort (Louise Bruun Jørgensen, Claus Nielsen, Court Pedersen); Estonia Tartu Ülikool (Irja Lutsar); France Aquitaine cohort (Geneviève Chêne, Francois Dabis, Rodolphe Thiebaut, Bernard Masquelier), French Hospital Database (Dominique Costagliola, Marguerite Guiguet),Lyon Primary Infection cohort (Philippe Vanhems),SEROCO cohort (Laurence Meyer, Faroudy Boufassa); Germany German cohort(Osamah Hamouda, Claudia Kücherer); Greece Greek Haemophilia cohort(Giota Touloumi, Nikos Pantazis, Angelos Hatzakis, Dimitrios Paraskevis, Anastasia Karafoulidou); Italy Italian Seroconversion Study (Giovanni Rezza, Maria Dorrucci, Benedetta Longo, Claudia Balotta); Netherlands Amsterdam Cohort Studies among homosexual men and drug users (Maria Prins, Liselotte van Asten, Akke van der Bij, Ronald Geskus, Roel Coutinho); Norway Oslo and Ulleval Hospital cohorts (Mette Sannes, Oddbjorn Brubakk, Anne Eskild, Johan N Bruun); Poland National Institute of Hygiene (Magdalena Rosinska); Portugal Universidade Nova de Lisboa (Ricardo Camacho); Russia Pasteur Institute (Tatyana Smolskaya); Spain Badalona IDU hospital cohort (Roberto Muga), Barcelona IDU Cohort (Patricia Garcia de Olalla),Madrid cohort (Julia Del Amo, Jorge del Romero),Valencia IDU cohort (Santiago Pérez-Hoyos, Ildefonso Hernandez Aguado); Switzerland Swiss HIV cohort (Heiner Bucher, Martin Rickenbach, Patrick Francioli); Ukraine Perinatal Prevention of AIDS Initiative (Ruslan Malyuta); UK Edinburgh Hospital cohort (Ray Brettle), Health Protection Agency (Valerie Delpech, Sam Lattimore, Gary Murphy, John Parry, Noel Gill), Royal Free Haemophilia cohort (Caroline Sabin, Christine Lee),UK Register of HIV Seroconverters (Kholoud Porter,Anne Johnson, Andrew Phillips, Abdel Babiker, Janet Darbyshire, Valerie Delpech),University College London (Deenan Pillay), University of Oxford (Harold Jaffe).