World AIDS Conference 2014

1. 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

2. Background 1917 U Alabama cohort • 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 Tate 2012; Hasse 2014; Herrin (CROI 2013)

3. 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)

4. Analysis time Methods (1) • Inclusion criteria and analysis time: • Exposure of interest: Absolute change in BMI (kg/m2) at 1 year post ART initiation

5. 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 www.chip.dk

6. 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

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

8. Patient characteristics at ART initiation

9. CVD • Overall, 97 CVD events in 43982 person-years= 2.21 events/1000 person-years (95% CI: 1.76-2.68) • 46 MIs, 33 strokes, 18 invasive procedures • The rates (/1000 person-years) (95% CI) by pre-ART BMI:

10. Adjusted IRR for CVD per unit gain in BMI Over-weight 25-30 Obese >30 Underweight <18.5 Normal 18.5-25 Pre-ART BMI P for effect modification in adjusted models: 0.041.

11. Adjusted for demographics All time-updated variables Adjusted IRR for CVD per unit gain in BMI Q3 23.0-25.5 Q4 >25 Q2 20.9-23.0 Pre-ART BMI Quartiles P for effect modification in adjusted models: 0.011

12. Diabetes mellitus • 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 :

13. Adjusted for demographics All time-updated variables Adjusted IRR for DM per unit gain in BMI Obese >30 Overweight 25-30 Normal 18.5-25 All patients* Underweight <18.5 Pre-ART BMI *P for effect modification in adjusted models:> 0.05.

14. 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

15. 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

16. 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

17. Acknowledgements SteeringCommittee:Membersindicatedw/*;¢chair; CohortPIs:WEl-Sadr*(CPCRA),GCalvo*(BASS),FDabis*(Aquitaine),OKirk*(EuroSIDA),MLaw*(AHOD),Ad’ArminioMonforte*(ICONA),LMorfeldt*(HivBIVUS),CPradier*(Nice),PReiss*(ATHENA),RWeber*(SHCS),SDeWit*(Brussels) Cohortcoordinatorsanddatamanagers:MHillebreght,SZaheri,LGras,(ATHENA),MBruyand,SGeffard,(Aquitaine),HMcManus,SWright(AHOD),SMateu,FTorres(BASS),MDelforge(Brussels),GBartsch,GThompsen(CPCRA),JKjær(EuroSIDA),IuriFanti(ICONA),EFontas,CCaissotti(Nice),ASundström,GThulin(HivBIVUS),MRickenbach(SHCS) Statisticians:CASabin*,ANPhillips*,DAKamara,CJSmith,AMocroft D:A:Dcoordinatingoffice:LRyom,RBrandt,JTverland,DRaben,ABojesen,JNielsen,JDLundgren*¢ MemberoftheD:A:DOversightCommittee:BPowderly*,NShortman*,CMoecklinghoff*,GReilly*,XFranquet* D:A:Dworkinggroupexperts:Kidney:LRyom,AMocroft,OKirk*,PReiss*,MRoss,CAFux,PMorlat,OMoranne,AMKesselring,DAKamara,CJSmith,JDLundgren*¢MortalityCJSmith,LRyom,ANPhillips*,RWeber*,PMorlat,CPradier*,PReiss*,NFriis-Møller,JKowalska,JDLundgren*¢CancerCASabin*,LRyom,MLaw*,Ad'ArminioMonforte*,FDabis*,MBruyand,PReiss*,CJSmith,DAKamara,MBower,GFätkenheuer,ADonald,AGrulich,JDLundgren*¢ Externalendpointreviewer:ASjøl(CVD),PMeidahl(oncology),JSIversen(nephrology) Funding:‘OversightCommitteeforTheEvaluationofMetabolicComplicationsofHAART’withrepresentativesfromacademia,patientcommunity,FDA,EMAandaconsortiumofAbbVie,BoehringerIngelheim, Bristol-Myers Squibb, Gilead Sciences, ViiV Healthcare, Merck, Pfizer, F. Hoffmann-La Roche and Janssen Pharmaceuticals