1. To overdose or underdose? The question for Kaletra in children in the UK/Irish CHIPS cohort AS Walker 1, KL Boyd 1, Menson E 2, K Butler 3, P Tookey 4, A Judd 1, A Riordan 5, D Shingadia 6, G Tudor-Williams 7, DM Gibb 1 on behalf of the CHIPS Steering Committee 1 MRC Clinical Trials Unit, London, UK; 2 St Thomas’s Hospital, London, UK; 3 Our Lady's Children’s Hospital Crumlin, Dublin, Ireland; 4 National Study of HIV in Pregnancy & Childhood, Institute of Child Health, London, UK; 5 Royal Liverpool Children’s Hospital, Liverpool, UK 6 Great Ormond St Hospital for Children, London, UK; 7 St Mary's Hospital, London, UK For children, the total daily licensed lopinavir dose is 460 mg/m 2 (600 mg/m 2 if used concurrently with NNRTI) This was chosen from the first Phase II trial of lopinavir in children ▪100 children were randomised to 460 mg/m 2 versus 600 mg/m 2 syrup ▪ART-naive subjects had a 3TC+d4T backbone; ART-experienced patients received NVP+NRTI(s) ▪ALL children were escalated to 600 mg/m 2 at a planned interim review 12- 20 weeks after randomisation, based on lopinavir pharmacokinetics (NOT adjusted for receipt of NVP/not) ▪48 week VL response excellent (79% <400 copies/ml) on the higher dose After the trial finished, a post-hoc analysis demonstrated the significant interaction between NNRTI and lopinavir PK By dose and NNRTI: mean AUC C min ▪460 mg/m 2, NNRTI:521.8(n=14) ▪460 mg/m 2, no NNRTI:733.4(n=12) ▪600 mg/m 2, NNRTI:863.6(n=12) ▪600 mg/m 2, no NNRTI:1166.5(n=15) The lower dose (460mg/m 2 ) was therefore licensed, even though the VL suppression data were from the higher dose (600mg/m 2 ) in all children Some paediatricians therefore prefer to target the higher dose, regardless of concomitant therapy BACKGROUND: how to choose a dose for kids? 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/m 2 Lower doses in children taking syrups or once daily lopinavir likely reflect greater precision to target a specific daily dose There was no effect of sex, calendar year, prior use of a PI, or most recent prior CD4% on current dose Dosing varied widely by centre with some centres generally following lower doses and others higher doses (Figure 2) PREDICTORS OF DOSE RECEIVED We thank the staff, families & children from all the hospitals who participate in CHIPS. 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, 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; 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. In children taking lopinavir WITHOUT NNRTI  What doses of lopinavir are paediatricians in CHIPS using?  What factors affect which dosing scheme is followed?  Is there any relationship between dose and viral load suppression? OBJECTIVES CHIPS collects details of all ART doses prescribed, as well as height and weight We calculated lopinavir dose in mg/m 2 every time height/weight was measured, as the fact that measurements were made meant that there had been an opportunity to change dose. We used CHIPS data to December 2007. We excluded doses/measurements when children were taking lopinavir with NNRTIs We investigated predictors of current dose in mg/m 2, including sex and other factors that would be known at the current clinic visit —VL and CD4% at the previous visit (  14 &  183 days previously) —current age, CDC stage, height/weight-for-age, calendar year, formulation (syrup versus capsules/tablets), frequency (once versus twice daily) —previous use of a protease inhibitor using mixed models with random effects for child and hospital, and autoregressive errors (based on date) for multiple measurements per child. We then considered two models relating dose and VL suppression —first lopinavir dose and VL suppression 6 months after first lopinavir initiation, using logistic regression —current lopinavir dose (>6 months after initiation) and next VL suppression using binomial mixed models METHODS 333 (25%) of 1336 children in CHIPS since January 2000 had ever taken lopinavir, 22 (2%) having only taken it with NNRTIs 238 of the 311 children who had taken lopinavir without NNRTIs were still on it at last follow-up, totalling 654 child-years on lopinavir without NNRTIs −Median age at lopinavir initiation was 9.0 years (IQR 5.1-12.1), at which point 124/311 (40%) children had a prior AIDS diagnosis −67 (22%) started lopinavir in their first 3/4-drug ART regimen, 37 (12%) as a substitution in first-line 3/4-drug ART, 129 (41%) as second- line/salvage, and 78 (25%) received lopinavir after prior mono/dual NRTI therapy 684 different doses were recorded in 299/311 children −355 (52%) were syrup, 260 (38%) capsules and 69 (10%) tablets −only 22 (3%) taken as once rather than twice daily doses Figure 1In total, dose/m 2 could be estimated 2748 times in 278 of these 299 children (Figure 1) (the others did not have height/weight recorded) −few (147, 6%) of these doses were >10% below the 460mg/m 2 target (<410 mg/m 2 ) −few (228, 9%) were >10% above the 600mg/m 2 target (>660 mg/m 2 ) −most were >410- 530-<660mg/m2 (958, 39%) Figure 1Two clear patterns of dosing following the different dosing schemes can be seen (Figure 1) RESULTS: who takes lopinavir? Figure 1 Doses received by body surface area 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 0 200 400 600 800 1000 1200 Absolute daily dose (mg) 0.511.52 Body Surface Area (m 2 ) 460mg/m 2 600 mg/m 2 Syrup Tablet/ Capsule 90-110% 460mg/m 2 90-110% 600 mg/m 2  We found no clear evidence that higher doses were associated with improved VL suppression overall  Higher doses may be associated with poorer viral load suppression in children who are prescribed them because of concerns about adherence or who have a lot of prior ART experience  More sophisticated modelling will be required to answer the question about dosing and VL suppression (or a trial!) SUMMARY Table 1 Independent predictors of doses received Factor (lower dose, higher dose) Independent effect on dose received (mg/m 2 ) 95% CIp Per year older under 10 Per year older over 10 -1 -9 [-5,+3] [-14,-5] <0.001 Prior CDC C+17[0,+34]0.05 Per unit higher weight-for-age-19[-24,-15]0.001 Per unit higher height-for-age-10[-14,-6]<0.001 Syrups versus caps/tabs-48[-58,-38]<0.001 Once versus twice daily-22[-40,-4]0.02 Per log 10 higher viral load*+2[0,+3]0.02 * High viral load an independent predictor of higher dose in the 2297 doses with prior VL available 160 (58%) of the 278 children with dose/m 2 estimated on lopinavir without NNRTI had (i) VL >1000 c/ml in the 6 months before initiating lopinavir for the first time, and (ii) lopinavir dose calculable in the first 3 months of taking lopinavir, and (iii) a 6 month VL response recorded 28% <50 c/ml, 68% <400 c/ml, 73% <1000 c/ml We found no evidence that initial lopinavir dose was associated with improved VL suppression 6 months after lopinavir initiation (adjusting for baseline viral load and age at initiation) −<400 c/ml: OR = 1.03 per 50 mg/m 2 greater (95% CI 0.86-1.23) p=0.73 −<50 c/ml : OR = 0.83 per 50 mg/m 2 greater (95% CI 0.68-1.02) p=0.10 this effect was predominantly observed with high doses over 600 mg/m 2 (OR=0.96 per 50 mg/m 2 greater below and 0.60 per 50 mg/m 2 greater above 600mg/m 2 ) this may reflect specific reasons for poorer response in children prescribed very high doses (??salvage) which our model was underpowered to detect VIRAL LOAD SUPPRESSION after initiation 0 1 2 3 4 5 Frequency -60-50-40-30-20-10010203040506070 Hospital dose (mg/m 2 ) compared to overall mean tend to follow higher dose (centres 41, 86, 139, 228, 37, 92) tend to follow lower dose (centres 7, 34, 71, 14, 18 72) Looking more generally, there were 1844 viral loads where dose in mg/m 2 was calculable in the preceding [14,183] days We found no strong evidence that dose was associated with improved VL suppression, adjusting for age at the viral load measurement and including hospital and child level random effects (no autocorrelation) −<400 c/ml: OR = 1.10 per 50 mg/m 2 greater (95% CI 0.96-1.25) p=0.16 −<50 c/ml: OR = 0.82 per 50 mg/m 2 greater (95% CI 0.73-0.91) p<0.001 again, this effect was predominantly observed with high doses over 600 mg/m 2 (OR=0.92 per 50 mg/m 2 below and 0.63 per 50 mg/m 2 above 600 mg/m 2, probably for similar reasons to the model for initial response A simple multinomial logit model (clustering on child) suggested that increasing dose was associated with VL 50- 1000 c/ml −IRR=0.91 per 50 mg/m 2 greater (95% CI 0.80-1.04) for 1000 c/ml −IRR=1.10 per 50 mg/m2 greater (95% CI 0.97-1.26) for 50- 1000 c/ml −IRR=0.90 per 50 mg/m2 greater (95% CI 0.75-1.08) for 400- 1000 c/ml VIRAL LOAD SUPPRESSION on lopinavir  Opinion appears to be split as to the most appropriate Lopinavir dose in children, with older or less stunted/wasted children or those without prior AIDS or with lower VLs more likely to receive lower doses, as well as those on once daily dosing  Doses were also higher with capsules/tablets, likely reflecting a preference for over- rather than under-dosing with solid formulations when exact doses cannot be achieved