1. Deferred antiretroviral therapy is associated with lower eGFR in HIV- positive individuals with high CD4 counts A Mocroft 1, AC Achhra 2, M Ross 3, L Ryom 4, A Avihingsanon 5, E Bakowska 6, WH Belloso 7, A Clarke 8, H Furrer 9, G Lucas 10, M Ristola 11, M Rassool 12, J Ross 13, C Somboonwit 14, C Wyatt 3 for the INSIGHT study group 1 University College London, London, UK. 2 Kirby Institute, UNSW Australia, Australia. 3 Icahn School of Medicine at Mount Sinai, New York, USA. 4 Dept. of Infectious diseases, CHIP, University of Copenhagen, Denmark. 5 HIV Netherlands Australia Thailand (HIV-NAT) Research Collaboration, Chulalongkorn University, Bangkok, Thailand. 6 Wojewodzki Szpital Zakazny, Warsaw, Poland. 7 CICAL and Hospital Italiano de Buenos Aires, Buenos Aires, Argentina. 8 Royal Sussex County Hospital, Brighton, United Kingdom. 9 Department of Infectious Disease, Bern University Hospital, University of Bern, Bern, Switzerland. 10 Department of Medicine, Johns Hopkins Medicine, Baltimore. 11 Helsinki University Central Hospital, Helsinki, Finland. 12 Department of Medicine, University of Witwatersrand and Helen Joseph Hospital, Johannesburg South Africa. 13 Queen Elizabeth Hospital Birmingham, Birmingham, UK. 14 Department of Medicine, University of South Florida, USA.

2. METHODS Overall mean change from baseline in CKD-EPI eGFR between the immediate and deferred arms was compared using random effects linear regression models STUDY AIM : To evaluate changes in estimated glomerular filtration rate (eGFR) among participants randomised to immediate or deferred ART within the INSIGHT START trial P=0.049 Mean difference in eGFR immediate vs. deferred Model 1.0.56 (0.003 – 1.11); p=0.049 20.55 (0.03 – 1.07); p=0.037 31.72 (1.11 – 2.34); p<0.0001 Imm: 2294 2191 1846 1078 Def: 2335 2167 1822 1071 *Model 1: adjusted for baseline eGFR and years since randomization **Model 2: Model 1 + additionally adjusted for age, gender, race, region of enrolment, time since HIV diagnosis, use of injecting drugs, CD4, viral load, proteinuria, body mass index, hepatitis B/C, diabetes, hypertension, dyslipidemia, cardiovascular disease, smoking status, ACE inhibitors or NSAIDS, all measured at randomisation. Not adjusted for TDF or boosted PI use ***Model 3: Model 2 + additionally adjusted for current receipt of TDF and boosted PI.

3. CONCLUSIONS Immediate initiation of ART in those with CD4 count >500 cells/mm 3 associated with a higher overall eGFR over median FU of 2.1 years Both host genetics (race) and the use of renal toxic antiretrovirals have an impact on renal function in HIV+ persons starting ART with a high CD4 count Immediate ART was also associated with a lower risk of incident ≥1+ proteinuria with a trend towards lower risk of several other secondary CKD outcomes Follow-up eGFR in the immediate vs. deferred ART arm in the START trial differed by race P<0.0001, test for interaction OutcomeMean difference Immediate arm vs. deferred arm (95% CI), P value Black raceNon-Black race eGFR-CKD-EPI mL/min/1.73m 2 2.43 (1.43 – 3.42); p<0.001-0.23 (-0.87 – 0.42); p=0.49 Adjusting for current use of TDF and/or PI 3.90 (2.48 – 4.97); p<0.0011.05 (0.33 – 1.77); p=0.004

4. The authors wish to acknowledge all START participants and members of the START study group for their contribution. The START study is primarily funded by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Numbers UM1-AI068641 and UM1AI120197 A list of the INSIGHT START study team is available at http://www.nejm.org.libproxy.ucl.ac.uk/doi/suppl/10.1056/ NEJMoa1506816/suppl_file/nejmoa1506816_appendix.p df Acknowledgements