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To overdose or underdose
To overdose or underdose? The question of Kaletra in children in the UK/Irish Collaborative HIV Paediatric Study (CHIPS) EN Menson, AS Walker, T Duong, K Doerholt, C Wells, M Sharland DM Gibb MRC Clinical Trials Unit, London, UK AS Walker, KL Boyd, K Doerholt, H Lyall, E Menson, K Butler, P Tookey, A Riordan, D Shingadia, A Judd, G Tudor-Williams, DM Gibb on behalf of the CHIPS Steering Committee
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Lopinavir in children The licensed lopinavir paediatric total daily dose is 460 mg/m2 without, and 600 mg/m2 with, concurrent NNRTIs Chosen from the first lopinavir/r Phase II trial randomising 100 children to 460 vs 600 mg/m2 syrup [Saez-Llorens 2003] backbone: ART-naive 3TC+d4T ART-experienced NVP+NRTI(s) based on overall lopinavir PK (NOT adjusted for receipt of NVP), ALL children were escalated to 600 mg/m2 at a planned interim review weeks after randomisation 48 week VL response on the higher 600 mg/m2 dose was excellent (79% <400 copies/ml) High HIV RNA viral load, especially in infants 2
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The problem After the trial finished, a post-hoc analysis showed the significant PK interaction between NNRTI and lopinavir mean AUC mean Cmin 460 mg/m2, NNRTI: (n=14) 460 mg/m2, no NNRTI: (n=12) 600 mg/m2, NNRTI: (n=12) 600 mg/m2, no NNRTI: (n=15) The lower dose (460 mg/m2) was therefore licensed for lopinavir/r without NNRTI, even though VL suppression data were from the higher dose Some paediatricians therefore prefer the higher dose, regardless of concomitant therapy licensed 3
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The questions In children taking lopinavir/r WITHOUT NNRTI
What doses of lopinavir/r are paediatricians using? What factors affect which dosing scheme is followed? Is there any relationship between dose and viral load suppression? 4
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Methods We calculated lopinavir doses (mg/m2) prescribed without NNRTIs in the UK/Irish CHIPS cohort from , every time height/weight was measured We investigated predictors of current lopinavir/r dose sex; VL and CD4% at the previous visit; current age, CDC stage, height/weight-for-age, calendar year, formulation, frequency and previous use of other PIs using mixed models allowing child and hospital level effects We explored the impact of lopinavir/r dose on initial VL suppression at 6 months using logistic models VL suppression during follow-up on lopinavir/r using binomial mixed models mixed models with random effects for child and hospital, and autoregressive errors for multiple measurements per child 5
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Who gets lopinavir? 333 (25%) of 1336 children in CHIPS since January 2000 had ever taken lopinavir 311 without NNRTIs, of whom 238 (77%) were still on lopinavir/r at last follow-up 654 child-years on lopinavir without NNRTIs at lopinavir initiation, median age 9 years (IQR 5-12) 40% had had a prior AIDS diagnosis 50% 40% 30% Percentage 20% 10% 0% 1st line cART 1st line subs 2nd line cART after mono /dual 6
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What doses are given? 684 different doses were recorded in 299/311 children 52% were syrup, 38% capsules and 10% tablets 662 (97%) taken as twice rather than once daily doses In total, dose/m2 could be estimated 2748 times in 278/299 children (the others did not have height/weight recorded) few (7%) of these doses were >10% below the 460 mg/m2 target few (9%) were >10% above the 600 mg/m2 target Two clear patterns of dosing following the different schemes 7
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Lopinavir doses (mg/m2)
1200 2 caps 2 tabs/3 caps 4 caps 3 tabs 5 caps 4 tabs/6 caps: adult recommended dose 7 caps 8 caps 6 tabs/9 caps Syrup Tablet/ Capsule 1000 800 Absolute daily dose (mg) 600 400 200 .5 1 1.5 2 Body Surface Area (m2) 8
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Lopinavir doses (mg/m2)
1200 2 caps 2 tabs/3 caps 4 caps 3 tabs 5 caps 4 tabs/6 caps: adult recommended dose 7 caps 8 caps 6 tabs/9 caps Syrup Tablet/ Capsule 1000 800 460mg/m2 Absolute daily dose (mg) 90-110% 460mg/m2 600 37% doses 400 600 mg/m2 200 90-110% 600 mg/m2 35% doses .5 1 1.5 2 Body Surface Area (m2) 9
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Independent predictors of dose
Factor Independent effect on dose received (mg/m2) 95% CI p Associated with lower doses Per year older under 10 Per year older over 10 -1 -9 [-5,+3] [-14,-5] <0.001 Syrups versus caps/tabs -48 [-58,-38] Once versus twice daily -22 [-40,-4] 0.02 Associated with higher doses Prior CDC C event +17 [0,+34] 0.05 Per unit lower weight-for-age +19 [+15,+24] 0.001 Per unit lower height-for-age +10 [+6,+14] Per log10 higher viral load +2 [0,+3] 10
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Predictors of dose (ctd)
The mean dose for a 10 year old, without prior CDC C event, average weight- and height-for-age, on capsules/tablets twice daily was 546 mg/m2 No effect of sex, calendar year, prior use of a PI, or most recent prior CD4% Dosing varied widely by centre with some hospitals generally following lower doses and others higher doses 5 tend to follow lower dose 4 tend to follow higher dose 3 Frequency 2 1 -60 -40 -20 +20 +40 +60 Hospital dose (mg/m2) compared to overall mean 11
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Viral load suppression after lopinavir/r initiation
160/278 (58%) children had (i) pre-lopinavir/r VL >1000 copies/ml (ii) lopinavir dose calculable in the first 3 months after initiation (iii) a 6 month VL measurement at 6 months, 28% <50 copies/ml, 68% <400 copies/ml, 73% <1000 copies/ml median (IQR) lopinavir dose 524 mg/m2 ( ) only 7% >10% below the 460 mg/m2 target only 11% >10% above the 600 mg/m2 target 12
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Viral load suppression after lopinavir/r initiation
No evidence that initial lopinavir dose was associated with significantly improved VL suppression at 6 months 13
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Viral load suppression after lopinavir/r initiation
No evidence that initial lopinavir dose was associated with significantly improved VL suppression at 6 months <400 c/ml: aOR = 1.06 per 50 mg/m2 (95% CI ) p=0.58 <50 c/ml: aOR = 0.81 per 50 mg/m2 (95% CI ) p=0.06 NB: vast majority of doses >414 mg/m2 (10% below 460 mg/m2 target) 14
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Viral load suppression after lopinavir/r initiation
No evidence that initial lopinavir dose was associated with significantly improved VL suppression at 6 months <400 c/ml: aOR = 1.06 per 50 mg/m2 (95% CI ) p=0.58 <50 c/ml: aOR = 0.81 per 50 mg/m2 (95% CI ) p=0.06 NB: vast majority of doses >414 mg/m2 (10% below 460 mg/m2 target) Major influence of high doses over 600 mg/m2 <50 c/ml: aOR = 0.97 below 600 mg/m2 aOR = 0.58 above 600 mg/m2 “being prescribed a very high dose” may reflect specific reasons for poorer response in specific children (?salvage ?adherence) 15
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Viral load suppression after lopinavir/r initiation
No evidence that initial lopinavir dose was associated with significantly improved VL suppression at 6 months <400 c/ml: aOR = 1.06 per 50 mg/m2 (95% CI ) p=0.58 <50 c/ml: aOR = 0.81 per 50 mg/m2 (95% CI ) p=0.06 NB: vast majority of doses >414 mg/m2 (10% below 460 mg/m2 target) Major influence of high doses over 600 mg/m2 <50 c/ml: aOR = 0.97 below 600 mg/m2 aOR = 0.58 above 600 mg/m2 “being prescribed a very high dose” may reflect specific reasons for poorer response in specific children (?salvage ?adherence) Similar results looking at VLs over follow-up 16
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Conclusions and further work
Opinion appears to be split as to the most appropriate lopinavir/r dose in children We found no clear evidence that higher doses were associated with improved VL suppression the vast majority were receiving at least licensed dose other potential confounders: total ART exposure and proxies for adherence (eg ever <400 copies/ml on ART, ?TDM) Investigation of impact on toxicity, particularly lipid levels, planned 17
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Underdosing of HIV drugs in children
An unintended consequence of uncertainty as to the best lopinavir/r dose is that only a small minority of children have been below minimum recommended dose - in contrast to most other ARVs 18 Menson et al, BMJ 2006, 332:
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Acknowledgements We thank the staff, families & children from all the hospitals who participate in CHIPS CHIPS Steering Committee: K Boyd, K Butler, K Doerholt, S Donaghy, DT Dunn, DM Gibb, A Judd, EGH Lyall, J Masters, E Menson, B Murphy, V Novelli, C Peckham, A Riordan, M Sharland, D Shingadia, PA Tookey, G Tudor-Williams. MRC Clinical Trials Unit: K Boyd, DT Dunn, L Farrelly, DM Gibb, D Johnson, A Judd, B Murphy, AS Walker; National Study of HIV in Pregnancy & Childhood, UCL Institute of Child Health: J Masters, C Peckham, PA Tookey. 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. 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; Bolton Royal Hospital, Bolton: P Ainley-Walker; Bristol Royal Hospital for Children, Bristol: A Finn, A Foot, L Hutchison; Calderdale Royal Hospital, Halifax: G Sharpe;Central Middlesex Hospital, London: M Le Provost, A Williams; Chase Farm Hospital, Middlesex; Chelsea and Westminster Hospital, London: D Hamadache, EGH Lyall, P Seery; Derbyshire Children's Hospital, Derby: Ruggins; Ealing Hospital, Middlesex: V Shah, K Sloper; Eastbourne District General Hospital, Eastbourne: G Gopal; 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; Harrogate District Hospital, Harrogate: P Tovey; Hillingdon Hospital, London; Hinchingbrooke Hospital: H Dixon; Homerton University Hospital, London: D Gurtin; Huddersfield Royal Infirmary, Huddersfield: JP Garside; James Cook Hospital, Middlesbrough: A Fall; James Paget Hospital, Great Yarmouth: J Chapman; 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; Norfolk and Norwich Hospital, Norwich: C Kavanagh; Nottingham City Hospital, Nottingham: D Curnock, A Smyth, M Yanney; Queen Elizabeth Hospital, Woolwich: W Faulknall, S Mitchell; Raigmore Hospital, Inverness: T Reddy; Royal Belfast Hospital for Sick Children, Belfast: S Christie; Royal Berkshire Hospital, Reading: A Gordon; Royal Children’s Hospital, Aberdeen: D Rogahn; Royal Cornwall Hospital, Truro: S Harris; Royal Devon and Exeter Hospital, Exeter: A Collinson; 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; Salisbury District General Hospital, Salisbury: N Brown; Sheffield Children's Hospital, Sheffield: J Hobbs, F Shackley; Southampton General Hospital, Southampton: S N Faust; St George's Hospital, London: R Chakraborty, S Donaghy, R Fluke, M Sharland, S Storey, C Wells; St Luke's Hospital, Bradford: S Gorman; 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; Torbay Hospital, Torquay: J Broomhall; 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; West Cumberland Hospital, Whitehaven: D Lee; Wexham Park, Slough: R Jones; Whipps Cross Hospital, London: K Gardiner; Whittington Hospital, London; Wythenshawe Hospital, Manchester: D Denning. 19
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