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Wide disparity in switch to second-line therapy in HIV infected children CHIPS

Kate Lee

MRC Clinical Trials Unit

On behalf of the Collaborative HIV Paediatric Study (CHIPS) Steering Committee

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Background

• There are guidelines on when to start therapy

• Few guidelines on when to switch– Timing of switch– Determinants of switch

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Aims

• Describe characteristics of switch to second-line therapy in children initiating HAART naïve– Investigate predictors of switch– Explore CD4 and viral load at switch– Assess timing of switch with respect to viral load

thresholds

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CHIPS and the NSHPC

• CHIPS (Collaborative HIV Paediatric Study) is a multicentre cohort study of HIV infected children under care in 39 hospitals in the UK & Ireland since 1996

– Surveillance of obstetric and paediatric HIV in the UK and Ireland is carried out through the National Study of HIV in Pregnancy and Childhood (NSHPC)

90% of HIV-infected children in the UK and Ireland are in CHIPS

• Data to December 2005

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Methods

• Children starting HAART naïve

• Switch defined as:– Switching 3 or more drugs– Switching 2 drugs with reason recorded as failure

(immunological / virological / clinical / resistance)

– with VL>50 copies/ml

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Methods (cont’d)

• Median time from HAART initiation to switch in children initiating HAART naive – Kaplan-Meier

• Predictors of switch – Cox model– Sex– Age, calendar year, CD4, viral load and CDC stage at

HAART initiation– Ever achieved suppression <400 copies/ml (time dependent

covariate)

• Comparison of timing of switch with reaching viral load thresholds – competing risks

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Population

• 595 children started HAART naive• Median (IQR):

age = 4.7 years (1.5-8.8) CD4% = 14% (8 -20.5)(CD4 = 366 cell/mm3 (159-700))viral load = 138,201 copies/ml (123,722-

154,373)• Median (range) follow-up = 3.1 years (0-8.2)• Number (%) ever suppressed <400 c/ml = 462 (78%)• 40 different first-line combinations used

– 61% received an NNRTI – 32% a PI– 1% both– 8% NRTIs only

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Time to switch to second-line

Children switching = 132 (22%)

Overall median time to switch

7.2 years

0 1 2 3 4 5 6 7 8

Ever suppressed <400c/ml

Never suppressed <400c/ml

Years since HAART initiation

0.00

0.25

0.50

0.75

1.00

Pop

ulat

ion

still

on

first

-line

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Independent predictors of earlier switch

• Failure to ever achieve suppression <400 copies/mlHR = 7.0 [4.7-9.8] vs achieving suppression p<0.001

• Older at HAART initiationHR = 1.1 [1.0-1.2] per year older p=0.006

• Lower CD4% at HAART initiationHR = 0.87 [0.78-0.97] per 5% higher p<0.001

• Later calendar year at HAART initiationHR = 1.5 [0.9-3.0] for 2002-05 vs 1997-99 p=0.15

• No independent effects of sex or current age, HIV-1 RNA or prior CDC B/C events at HAART initiation

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At switch to second-line (132 children)

Never suppressed <400 c/ml

on first-line

Ever suppressed <400 c/ml

on first-line

N (%) 69 (52%) 63 (48%)

Age (years) 5.8 (3.2-10.5) 9.7 (5.5-13.0)

Viral load (c/ml) 79569(62,127-101,907)

8206(5,382-12,512)

Previous VL (c/ml) 59000(17,000-206,099)

12383(5,290-97,500)

CD4 (cells/mm3) age < 5 years age 5 years

910 (541-1779)223 (100-840)

1043 (650-1564)380 (246-610)

CD4% 18 (9-26) 20 (14-26)

Results presented are medians (IQRs)

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CD4 and Viral load at switch

0

10

20

30

40

50C

D4%

at s

witc

h

50 100 1000 30000 100000 300000 1000000Viral load at switch

Ever suppressed <400 Never suppressed <400

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Compared to viral load thresholds

1st VL >1000 c/ml (subsequently

confirmed)

1st V >30,000 c/ml

(subsequently confirmed)

Switch before reaching threshold

14% 18%

Switch within 6months of reaching threshold

3% 1%

Remain on first-line for >6months after threshold

16% 3%

Median time to switch after threshold

3.3 years 1.0 years

By 3 years after HAART initiation (% of all childreninitiating HAART)

• Switching somewhere between 1000 and 30,000c/ml but no clear level

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Conclusions

• Low rate of switching to second-line– Children never achieving virological suppression switch sooner

than those who had achieved suppression as expected– Older children switch sooner than younger children– Children starting HAART more recently or with lower CD4%

also switch sooner

• 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.

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Limitations

• Cohort data– Missing data– Closest value may not be truly representative

• Definition of switch– How to define?– Reported reason may not be reliable

• Generalisability– Drug usage

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Summary

• Paediatricians seem to be fairly conservative about switching ART for all children.

• There is an urgent need for evidence on which to base switching to guide management for the future.

• PENPACT 1 results due 2009

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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

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AcknowledgementsThanks 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 WaitMRC Clinical Trials Unit: DT Dunn, T Duong, L Farrelly, DM Gibb, D Johnson, A Judd, G Wait, AS WalkerNational Study of HIV in Pregnancy & Childhood, Institute of Child Health: J Masters, C Peckham, PA Tookey