The effect of short-course ART in PHI

1. The effect of short-course ART in PHI Final results from an international randomised controlled trial SPARTAC Sarah Fidler for SPARTAC Trial Investigators Imperial College, London, UK www.imperial.ac.uk/medicine/spartac

2. Background • HIV-induced immunological destruction begins early and despite later ART, is never completely reversed • Observational studies: encouraging data suggest potential immunological benefit of early ART • David Ho ‘HIT HIV HARD HIT EARLY’ [1995] • Hypothesis: ART initiated as near to HIV transmission as possible may protect against HIV-induced immune damage Currently no evidence from randomised trial to inform best clinical management of PHI

3. Primary Objective • To determine the effect of two short course ART schedules of different durations compared with no immediate ART in Primary HIV infection on time to CD4 <350 or initiation of long-term ART

4. Trial Design • Definition of PHI • laboratory evidence of infection within 6 months of a previous negative test, <3 bands WB, RITA incident, antibody negative PCR+ • Randomisation to one of three arms: • 48-week short course ART (ART-48) • 12-week short course ART (ART-12) • No therapy (Standard of Care SOC) • Primary end point • time to CD4 <350 cells/mm3 or long-term ART initiation • Sample size • 360 providing 90% power to detect relative reduction in risk of time to CD4 <350 cells/mm3 of 50% and 25% in ART-48 and ART-12 compared to SOC respectively over an average follow-up of 4 years

5. Secondary objectives • Development of an AIDS defining illness or death • HIV-specific CD4+ and CD8+ T-cell responses at week 60 • Slope of CD4 decline after intervention • Development of new drug resistance by week 120 • Differences in blood pressure from randomisation at weeks 12 and 48 • Time to virological failure of first long-term ART regimen

6. Enrolment & Exclusions SCREENED 429 58 EXCLUDED 15 not PHI 19 protocol exclusions 24 other reasons RANDOMISED 371 SOC 124 ART-12 123 ART-48 124 5 EXCLUDED • 2 not equivocal • 1 HIV-neg>8 months • 1 remained HIV-neg • 1 randomisation error SOC 124 ART-12 120 ART-48 123

7. International Sites Sites Participants • Australia 10 36 (10%) • Brazil 1 17 (5%) • Ireland 1 2 (1%) • Italy 2 23 (6%) • South Africa 9 118 (32%) • Spain 1 2 (1%) • Uganda 1 19 (5%) • United Kingdom 11 149 (40%) Total 35 366

8. Baseline demographics

9. Time to primary endpoint 1.00 ART48 HR 0.63 (0.45,0.90), p=0.01 0.75 SOC 0.50 Probability of not reaching primary endpoint ART12 HR 0.93 (0.67,1.29), p=0.67 0.25 0.00 0 .5 1 1.5 2 2.5 3 3.5 4 4.5 Time (years) SOC 123 109 93 82 75 66 59 46 30 18 ART-12 120 110 95 84 79 71 63 49 32 21 ART-48 123 121 117 109 100 88 80 63 41 19

10. Time to primary endpoint

11. 1.00 0.75 0.50 0.25 0.00 0 .5 1 1.5 2 2.5 3 3.5 4 4.5 Duration of infection and time to Primary Endpoint ART-48 ≤12 wks ART-48 >12 wks Probability of not reaching primary endpoint SOC >12 wks SOC ≤12 wks ART48 vs SOC < 12 w HR = 0.48 [0.30, 0.78] p=0.003 Time (years) SOC >12 wks 53 47 42 41 36 32 29 24 14 8 SOC ≤12 wks 70 62 51 41 39 34 30 22 16 10 ART-48 >12 wks 64 63 60 55 50 42 38 32 20 11 ART-48 ≤12 wks 59 58 57 54 50 46 42 31 21 8

12. HIV RNA changes following ART interruption* * Adjusted for baseline .2 SOC 0 ART-12 .2 Change in log10 HIV RNA from baseline ART-48 .4 .6 .8 12 12 24 24 36 36 48 48 60 60 Weeks from ART interruption (ART-48 and ART-12) or randomisation (SOC) Number measurements censored due to long-term ART initiation SOC 1 6 7 9 14 ART-12 3 4 10 17 18 ART-48 0 2 5 9 9

13. 0 12 24 36 48 60 72 84 96 108 144 120 132 156 264 168 180 192 204 216 228 240 252 276 288 Changes in CD4 values for ART-48 and SOC groups over entire study Average CD4 count over 4.5 years for ART-48 was 138 [90,185] cells/mm3 higher than SOC 200 100 ART-48 Mean (pointwise 95% CI) 0 -100 SOC -200 Weeks from randomisation

14. Secondary end points • No significant difference between the groups for AIDS, death or serious adverse events • No difference in CD4 decline after ART interruption in treatment groups compared to decline from randomisation in SOC (p=0.92). • In contrast to SMART there was no rebound in IL-6 and a drop in d-dimer compared with baseline levels 4 weeks after stopping ART. • Virological failure on long-term ART was similar across groups • Drug resistance by week 120: 6 had Stanford scores 4-5; 5 NNRTI-associated mutations and one PI-associated • CD8+ & CD4+ HIV-specific responses: Analyses ongoing

15. Conclusions • Spartac is the largest ever RCT in PHI enrolling men and women in both developed and developing world settings • ART-48 associated with a significant delay in time to CD4 <350 or long-term ART initiation, although the actual delay may not have been any longer than the time spent on treatment • Overall this effect was greater when ART-48 was started closer to the time of HIV infection. (p=0.09) • Compared to standard of Care • ART-48 associated with significant reduction in viral set point of HIV RNA of 0.44 (0.25,0.64) log10 copies/ml sustained to 60 weeks after stopping therapy • ART-48 conferred a higher average CD4 count of 138 cells over 4.5 years • Interruption of ART in PHI had no evidence of harm; development of drug resistance, or CD4 recovery after starting long-term ART • No evidence of a benefit of ART-12

16. THANKSAll The study participants Trial Steering Committee (TSC): Independent TSC Members: A Breckenridge (Chair), P Clayden, C Conlon, F Conradie, J Kaldor*, F Maggiolo; F Ssali Country Principal Investigators: D A Cooper, P Kaleebu, G Ramjee, M Schechter, G Tambussi, J.Miro J Weber Trial Physician: Sarah Fidler Trial Statistician: Abdel Babiker Data and Safety Monitoring Committee (DSMC): T Peto (Chair) A McLaren (in memoriam), V Beral, G Chene, J Hakim Co-ordinating Trial Centre: MRC Clinical Trials Unit, London (A Babiker, K Porter, M Thomason, F Ewings, M Gabriel, D Johnson, K Thompson, A Cursley*, K Donegan*, E Fossey*, P Kelleher*, K Lee*, B Murphy*, D Nock*) Central Immunology Laboratories and Repositories: The Peter Medawar Building for Pathogen Research, University of Oxford, UK (R Phillips, J Frater, L Ohm Laursen*, N Robinson, P Goulder, H Brown) Central Virology Laboratories and Repositories: Jefferiss Trust Laboratories, Imperial College, London, UK (M McClure, D Bonsall*, O Erlwein*, A Helander*, S Kaye, M Robinson, Lisa Cook*, Gemma Adcock*) Clinical Endpoint Review Committee: N Paton, S Fidler Imperial College Trial Secretariat: S Keeling, A Becker Imperial College DSMC Secretariat: C Boocock * Left the study team before the trial ended Investigators and Staff at Participating Sites Australia: St Vincent’s Hospital, Sydney (A Kelleher), Northside Clinic, Melbourne (R Moore), East Sydney Doctors, Sydney, (R McFarlane), Prahran Market Clinic, Melbourne (N Roth), Taylor Square Private Clinic, Sydney (R Finlayson), The Centre Clinic, Melbourne (B Kiem Tee), Sexual Health Centre, Melbourne (T Read), AIDS Medical Unit, Brisbane (M Kelly), Burwood Rd Practice, Sydney (N.Doong) Holdsworth House Medical Practice, Sydney ( M. Bloch) Aids Research Initiative, Sydney ( C. Workman). Coordinating centre in Australia: Kirby Institute University of New South Wales, Sydney (P Grey, D A Cooper, A Kelleher, M Law). Brazil: Projeto Praça Onze, Hospital Escola São Francisco de Assis, Universidade federal do Rio de Janeiro, Rio de Janeiro (M Schechter, P Gama, M Mercon*, M Barbosa de Souza, C Beppu Yoshida, J R Grangeiro da Silva, A Sampaio Amaral, D Fernandes de Aguiar, M de Fátima Melo, R Quaresma Garrido Italy: Ospedale San Raffaele, Milan (G Tambussi, S Nozza, M Pogliaghi, S ChiappettaL Della Torre, Elisa Gasparotto,), Ospedale Lazzaro Spallanzani, Roma (G D’Offizi, C Vlassi, A Corpolongo) South Africa: Cape Town: Desmond Tutu HIV Centre, Institute of Infectious Diseases, Cape Town (R Wood, J Pitt, C Orrell, F Cilliers, R Croxford, K Middelkoop, L G Bekker, C Heiberg, J Aploon, N Killa, E Fielder, T Buhler)Johannesburg: The Wits Reproductive Health and HIV Institute, University of Witswatersrand, Hillbrow Health Precinct, Johannesburg. (H Rees, F Venter, T Palanee) Contract Laboratory Services, Johannesburg Hospital, Johannesburg (W Stevens, C Ingram, M Majam, M Papathanasopoulos) Kwazulu-Natal: HIV Prevention Unit, Medical Research Council, Durban (G Ramjee, S Gappoo, J Moodley, A Premrajh, L Zako) Uganda: MRC/Uganda Virus Research Institute, Entebbe (H Grosskurth, A Kamali, P Kaleebu, U Bahemuka, J Mugisha*, H F Njaj*) Spain: Hospital Clinic-IDIBAPS. University of Barcelona, Barcelona (JM Miro, M López-Dieguez*, C Manzardo, JA Arnaiz, T Pumarola, M Plana, M Tuset, MC Ligero, MT García, T Gallart, JM Gatell) UK and Ireland: Royal Sussex County Hospital, Brighton (M Fisher, K Hobbs, N Perry, D Pao, D Maitland, L Heald), St James’s Hospital, Dublin (F Mulcahy, G Courtney, S O’Dea, D Reidy), Regional Infectious Diseases Unit, Western General Hospital and Genitourinary Dept, Royal Infirmary of Edinburgh, Edinburgh (C Leen, G Scott, L Ellis, S Morris, P Simmonds), Chelsea and Westminster Hospital, London (B Gazzard, D Hawkins, C Higgs), Homerton Hospital, London (J Anderson, S Mguni), Mortimer Market Centre, London (I Williams, N De Esteban, P Pellegrino, A Arenas-Pinto, D Cornforth*, J Turner*) North Middlesex Hospital (J Ainsworth, A Waters), Royal Free Hospital (M Johnson, S Kinloch, A Carroll, P Byrne, Z Cuthbertson), Barts & the London NHS Trust, London (C Orkin, J Hand, C De Souza), St Mary’s Hospital, London (J Weber, S Fidler, E Hamlyn, E Thomson*, J Fox*, K Legg, S Mullaney*, A Winston, S Wilson, P Ambrose), Birmingham Heartlands Hospital (S Taylor, G Gilleran)

18. Next steps

19. Baseline resistance

20. International trial sites UK = 152 Spain = 2 Ireland = 2 Italy = 19 Uganda = 20 Brazil = 17 Australia = 37 South Africa = 118

21. IL-6 and d-dimer levels at baseline and change 4 weeks after stopping ART IL-6 0.00 (-0.07,0.06) IL-6 0.15 (-0.08,0.36) d-dimer -0.46 (-0.68,-0.29) .05 1 d-dimer -0.07 (-0.13,-0.01) .5 0 0 Mean change (95% CI) in log10 log10 value of biomarker -.05 -.5 -.1 -1 -1.5 -.15 Baseline (randomisation) 4 weeks after stopping ART (adjusted for baseline)

22. Enrolment by country