World AIDS Conference 2014 Impact of short-term change in body mass index after antiretroviral therapy initiation on subsequent risk of cardiovascular disease and diabetes in HIV-positive individuals: the D:A:D study A.C. Achhra, A. Mocroft, P. Reiss, C. Sabin, L. Ryom, S. de Wit, C. Smith, A. d'Arminio Monforte, A. Phillips, R. Weber, J. Lundgren, M.G. Law, The D:A:D Study Group

Background  Excess weight is a growing concern in HIV-positive individuals on ART  ART initiation is often associated with weight gain Thought to be a good prognostic indicator Impact on cardiovascular health?  VA cohort: per 5lb. gain on ART initiation  ~10% more risk of incident diabetes  Better understanding this relationship could help manage risk of serious events in HIV-positive individuals 1917 U Alabama cohort Tate 2012; Hasse 2014; Herrin (CROI 2013)

Objective  To assess the relationship between short-term change in BMI after first ART initiation and the subsequent risk of: cardiovascular disease (CVD) diabetes mellitus (DM)

Methods (1) Enter D:A:D cohort: N=49717 ART naive, starting ART: N= Year post ART BMI available N=9438 No CVD before this time: N=9321 CVD event or censored (Feb 2013) Final N=9321 Analysis time  Inclusion criteria and analysis time:  Exposure of interest: Absolute change in BMI (kg/m 2 ) at 1 year post ART initiation

Methods (2): Endpoints CVD  Cardiovascular disease (CVD): composite of myocardial infarction (MI), sudden cardiac death, or invasive procedure (coronary artery bypass graft, carotid endarterectomy, or angioplasty) or confirmed stroke  Validated in real time by a defined protocol DM  DM verified in a DAD event form or by the use of anti- diabetic drugs, more details at

Statistical Methods  BMI change as a continuous variable Exploratory analysis of change in BMI  Incidence rate ratios (IRR) were determined using Poisson regression adjusted for relevant risk factors: Adjusted for key risk factors identified in previous D:A:D analyses for each of the outcome; also CD4 and BMI at ART start and cohort Models sequentially adjusted for key variables at different time points.  Assessed if pre-ART BMI (categorised) is an effect modifier for each of the outcomes Provide category specific IRRs ( per unit change in BMI) Friis-Møller 2010; Petoumenos 2012

BMI change post ART initiation Overall mean change at 1 year: 0.67

Patient characteristics at ART initiation

 Overall, 97 CVD events in person-years= 2.21 events/1000 person-years (95% CI: ) 46 MIs, 33 strokes, 18 invasive procedures  The rates (/1000 person-years) (95% CI) by pre-ART BMI: CVD Underweight (<18.5):1.73 ( ) Normal ( ):2.13 ( ) Over-weight (25-30):2.41 ( ) Obese (>30):2.78 ( )

Adjusted IRR for CVD per unit gain in BMI Pre-ART BMI P for effect modification in adjusted models: Underweight <18.5 Normal Over-weight Obese >30

Adjusted IRR for CVD per unit gain in BMI Pre-ART BMI Quartiles P for effect modification in adjusted models: Q Q Q4 >25 Adjusted for demographics All time-updated variables

 Similar inclusion criteria Those with DM before study entry excluded  125 DM events in 9193 eligible individuals (43278 person-years), at the rate of 2.89/1000 person-years  The rates (/1000 person-years) by pre-ART BMI : Diabetes mellitus Underweight:2.04 ( ) Normal:2.01 ( ) Over-weight:4.05 ( ) Obese:9.97 ( )

Adjusted IRR for DM per unit gain in BMI All patients*Underweight <18.5 Normal Overweight Obese >30 Pre-ART BMI *P for effect modification in adjusted models:> Adjusted for demographics All time-updated variables

Sensitivity analyses  Results robust to following sensitivity analyses:  exclude IDU (resulted in smaller P value for CVD outcome)  restrict to those with viral load <400 copies/mL at 1 year  model % change in BMI

Strengths and Limitations  Heterogeneous cohort with real-time outcome ascertainment  Many key potential confounders available  Modern cohort on contemporary regimens  Selected sample  BMI may not accurately reflect central obesity; waist- hip ratio unavailable  Life-style factors (e.g. diet/exercise) unavailable  Limited number of specific CVD events

Conclusion  Short-term gain in BMI post ART initiation could be associated with the increased risk of CVD, largely in those with normal/mid- levels of pre-ART BMI Need to be verified in different studies  Gain in BMI also associated with risk of diabetes in all groups  No appreciable change in risk of CVD with gain in BMI in those with high pre-ART BMI Low power? Bias? Limitation of BMI? Regression to mean? Interpret cautiously  Further research needed regarding weight management in this population

Acknowledgements Steering Committee: Members indicated w/ *; ¢ chair; Cohort PIs: W El-Sadr* (CPCRA), G Calvo* (BASS), F Dabis* (Aquitaine), O Kirk* (EuroSIDA), M Law* (AHOD), A d’Arminio Monforte* (ICONA), L Morfeldt* (HivBIVUS), C Pradier* (Nice), P Reiss* (ATHENA), R Weber* (SHCS), S De Wit* (Brussels) Cohort coordinators and data managers: M Hillebreght, S Zaheri, L Gras, (ATHENA), M Bruyand, S Geffard, (Aquitaine), H McManus, S Wright (AHOD), S Mateu, F Torres (BASS), M Delforge (Brussels), G Bartsch, G Thompsen (CPCRA), J Kjær (EuroSIDA), Iuri Fanti (ICONA), E Fontas, C Caissotti (Nice), A Sundström, G Thulin (HivBIVUS), M Rickenbach (SHCS) Statisticians: CA Sabin*, AN Phillips*, DA Kamara, CJ Smith, A Mocroft D:A:D coordinating office: L Ryom, R Brandt, J Tverland, D Raben, A Bojesen, J Nielsen, JD Lundgren*¢ Member of the D:A:D Oversight Committee: B Powderly*, N Shortman*, C Moecklinghoff *, G Reilly*, X Franquet* D:A:D working group experts: Kidney: L Ryom, A Mocroft, O Kirk *, P Reiss *, M Ross, CA Fux, P Morlat, O Moranne, AM Kesselring, DA Kamara, CJ Smith, JD Lundgren *¢ Mortality CJ Smith, L Ryom, AN Phillips *, R Weber*, P Morlat, C Pradier *, P Reiss *, N Friis- Møller, J Kowalska, JD Lundgren*¢ Cancer CA Sabin *, L Ryom, M Law *, A d'Arminio Monforte*, F Dabis*, M Bruyand, P Reiss *, CJ Smith, DA Kamara, M Bower, G Fätkenheuer, A Donald, A Grulich, JD Lundgren*¢ External endpoint reviewer: A Sjøl (CVD), P Meidahl (oncology), JS Iversen (nephrology) Funding: ‘Oversight Committee for The Evaluation of Metabolic Complications of HAART’ with representatives from academia, patient community, FDA, EMA and a consortium of AbbVie, BoehringerIngelheim, Bristol-Myers Squibb, Gilead Sciences, ViiV Healthcare, Merck, Pfizer, F. Hoffmann-La Roche and Janssen Pharmaceuticals