Download Older and wiser: continued improvements in clinical outcome and

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 secondline 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
3
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%)
1.00
Overall median
time to switch
7.2 years
Population still on first-line
Ever suppressed <400c/ml
0.75
Never suppressed <400c/ml
0.50
0.25
0.00
0
1
2
3
4
5
6
Years since HAART initiation
7
8
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Independent predictors of earlier
switch
• Failure to ever achieve suppression <400 copies/ml
HR = 7.0 [4.7-9.8] vs achieving suppression p<0.001
• Older at HAART initiation
HR = 1.1 [1.0-1.2] per year older p=0.006
• Lower CD4% at HAART initiation
HR = 0.87 [0.78-0.97] per 5% higher p<0.001
• Later calendar year at HAART initiation
HR = 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
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or prior CDC B/C events at HAART initiation
At switch to second-line
(132 children)
Never suppressed
<400 c/ml
on first-line
Ever suppressed
<400 c/ml
on first-line
69 (52%)
63 (48%)
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)
910 (541-1779)
223 (100-840)
1043 (650-1564)
380 (246-610)
18 (9-26)
20 (14-26)
N (%)
Age (years)
CD4 (cells/mm3)
age < 5 years
age  5 years
CD4%
Results presented are medians (IQRs)
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CD4 and Viral load at switch
50
CD4% at switch
40
30
20
10
0
50 100
1000
30000 100000 300000 1000000
Viral load at switch
Ever suppressed <400
Never suppressed <400
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Compared to viral load thresholds
By 3 years after HAART initiation (% of all children
initiating HAART)
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%
3.3 years
1.0 years
Median time to switch
after threshold
• Switching somewhere between 1000 and 30,000c/ml
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but no clear level
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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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
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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