1. Switch to second-line therapy in the CHIPS cohort Dr Kate Lee MRC Clinical Trials Unit On behalf of the Collaborative HIV Paediatric Study (CHIPS) Steering Committee

2. Aims Describe characteristics of switch to second- line therapy –Investigate predictors of switch –Explore CD4 and viral load at switch –Assess timing of switch with respect to viral load thresholds

3. Methods Children starting HAART naïve Switch defined as: –Switching 3+ drugs –Switching 2+ drugs with reason recorded as failure –with VL>50

4. Methods (cont’d) Median time to switch in children initiating HAART naive – Kaplan-Meier Predictors of switch – Cox model –Sex –Characteristics at HAART initiation –Ever achieved suppression <400 copies/ml Comparison of timing of switch with reaching viral load thresholds

5. 012345678 Ever suppressed <400c/ml Never suppressed <400c/ml Time (years) 0.00 0.25 0.50 0.75 1.00 Population (595 children) Children switching = 132 Median (range) follow-up = 3.1 yrs (0-8.2 yrs) Median age at HAART initiation = 5.6 (0-18) Overall median time to switch 7.2 years

6. Independent predictors of earlier switch Failure to ever achieve suppression <400 copies/ml HR = 7.5 [5.0-11.3] vs achieving suppression p<0.0001 Older at HAART initiation HR = 1.1 [1.0-1.1] p=0.03 per year older Later calendar year at HAART initiation HR = 2.1 [1.1-4.0] for 2002-05 vs 1997-99 p=0.03 No independent effects of sex or age, CD4%, HIV-1 RNA or prior CDC B/C events at HAART initiation

7. At switch (median, range) Age8.3 years (0.6-19.6) CD4485 cells/mm 3 (3-3592) 20%(0-47) Viral load27,835 c/ml (50-1348000)

8. CD4 and Viral load at switch 0 10 20 30 40 50 CD4% at switch 501001000300001000003000001000000 Viral load at switch Ever suppressed <400Never suppressed <400

9. Compared to viral load thresholds 1 st confirmed viral load >1000 c/ml 1 st confirmed viral load >30,000 c/ml Switch before reaching threshold 14%18% Switch within 6months of reaching threshold 3%1% Remain on first-line for >6months after threshold 15%3% Median time to switch after thresholds 3.3 years1.0 years By 3 years after HAART initiation (% of all children initiating HAART) Switching somewhere between 1000 and 30,000c/ml but no clear level

10. Conclusions Low rate of switching to second-line –Children never achieving virological suppression switch faster than those who had achieved suppression –Older children switch faster than younger children –Children starting HAART more recently also switch faster Little consistency in CD4 and viral load thresholds at switch –Children achieving virological suppression tend to switch at lower viral loads and higher CD4s –…but wide variation in both No clear viral threshold being used to trigger switch.

11. Acknowledgements We thank: –staff and families from the hospitals collaborating in CHIPS, and Gill Wait, CHIPS Data Manager –all paediatricians and other health professionals reporting to the NSHPC, and the British Paediatric Surveillance Unit of the Royal College of Paediatrics and Child Health –UK Department of Health, HPA, Bristol-Myers Squibb, Boehringer-Ingelheim, GlaxoSmithKline, Roche, Abbott and Gilead for financial support www.chipscohort.ac.uk

12. Acknowledgements Thanks to everyone providing data to the NSHPC and CHIPS !! Republic of Ireland: Our Lady's Children’s Hospital Crumlin, Dublin: K Butler, A Walsh. UK: Birmingham Heartlands Hospital, Birmingham: Y Heath, J Sills; Blackpool Victoria Hospital, Blackpool: N Laycock; Bristol Royal Hospital for Children, Bristol: A Finn, A Foot, L Hutchison; Central Middlesex Hospital, London: M Le Provost, A Williams; Chase Farm Hospital, Middlesex; Chelsea and Westminster Hospital, London: D Hamadache, EGH Lyall, P Seery; Ealing Hospital, Middlesex: V Shah, K Sloper; Glasgow Royal Hospital for Sick Children, Glasgow: C Doherty, R Hague; Great Ormond St Hospital for Children, London: M Clapson, S Fasolo, J Flynn, DM Gibb, N Klein, K Moshal, V Novelli, D Shingadia; Hillingdon Hospital, London; Homerton University Hospital, London: D Gurtin; John Radcliffe Hospital, Oxford: A Pollard, S Segal; King's College Hospital, London: C Ball, S Hawkins, D Nayagam; Leeds General Infirmary, Leeds: P Chetcuti; Leicester Royal Infirmary, Leicester: M Green, J Houghton; Luton and Dunstable Hospital, Luton: M Connan, M Eisenhut; Mayday University Hospital, Croydon: J Baverstock, J Handforth; Milton Keynes General Hospital, Milton Keynes: PK Roy; Newcastle General Hospital, Newcastle: J Clarke, K Doerholt, C Waruiru; Newham General Hospital, London: C Donoghue, E Cooper, S Liebeschuetz, S Wong; Ninewells Hospital and Medical School, Dundee: T Lornie; North Manchester General Hospital, Manchester: C Murphy, T Tan; North Middlesex Hospital, London: J Daniels, EGH Lyall, B Sampson-Davis; Northampton General Hospital, Northampton: F Thompson; Northwick Park Hospital, Middlesex; M Le Provost, A Williams; Nottingham City Hospital, Nottingham: D Curnock, A Smyth, M Yanney; Queen Elizabeth Hospital, Woolwich: W Faulknall, S Mitchell; Royal Belfast Hospital for Sick Children, Belfast: S Christie; Royal Edinburgh Hospital for Sick Children, Edinburgh: J Mok; Royal Free Hospital, London: S McKenna, V Van Someren; Royal Liverpool Children’s Hospital, Liverpool: C Benson, A Riordan; Royal London Hospital, London: B Ramaboea, A Riddell; Royal Preston Hospital, Preston: AN Campbell; Sheffield Children's Hospital, Sheffield: J Hobbs, F Shackley; St George's Hospital, London: R Chakraborty, S Donaghy, R Fluke, M Sharland, S Storey, C Wells; St Mary's Hospital, London: D Hamadache, C Hanley, EGH Lyall, G Tudor-Williams, C Walsh, S Walters; St Thomas' Hospital, London: R Cross, G Du Mont, E Menson; University Hospital Lewisham, London: D Scott, J Stroobant; University Hospital of North Staffordshire, Stoke On Trent: P McMaster; University Hospital of Wales, Cardiff: B O' Hare; Wexham Park, Slough: R Jones; Whipps Cross Hospital, London: K Gardiner; Whittington Hospital, London. Funding: NSHPC is funded by the Health Protection Agency, and has also received support from the UK Department of Health and the Medical Research Council. CHIPS is funded by the Department of Health and in the past received additional support from Bristol-Myers Squibb, Boehringer Ingelheim, GlaxoSmithKline, Roche, Abbott, and Gilead. Committees and participants (in alphabetical order): CHIPS Steering Committee: K Butler, K Doerholt, S Donaghy, DT Dunn, T Duong, DM Gibb, A Judd, EGH Lyall, J Masters, E Menson, V Novelli, C Peckham, A Riordan, M Sharland, D Shingadia, PA Tookey, G Tudor-Williams, G Wait MRC Clinical Trials Unit: DT Dunn, T Duong, L Farrelly, DM Gibb, D Johnson, A Judd, G Wait, AS Walker National Study of HIV in Pregnancy & Childhood, Institute of Child Health: J Masters, C Peckham, PA Tookey