Data from the Collaborative HIV Paediatric Study (CHIPS) Reports up to March 2014* * Numbers are based on reports received rather than children seen to the end of March /14 data are subject to reporting delay and may therefore be incomplete.

Background to CHIPS The Collaborative HIV Paediatric Study (CHIPS) was established in April 2000 and is a multi-centre cohort study of HIV-1 infected children in the UK and Ireland. The collaboration is between – 67 clinics in the UK and Ireland that care for HIV-infected children, some of whom are enrolled in PENTA trials (PENTA 16 BREATHER and PENTA 18 KONCERT) – the National Study of HIV in Pregnancy and Childhood (NSHPC), and – the MRC Clinical Trials Unit at UCL

Follow-up status of 1873 children enrolled in CHIPS * 93 deaths prior to 2008, 6 in 2008, 6 in 2009, 2 in 2010, 1 in 2011

Age group by year first presented to medical services in the UK/Ireland (N=1873*) * Includes all children (those still in follow-up and those who have died, lost to follow-up, left the UK & Ireland or transferred to adult care) Up to Total At birth 168 (10%) 3 (5%) 5 (10%) 3 (13%) 0 (0%) 179 (10%) <1 yr 349 (20%) 4 (7%) 3 (6%) 0 (0%) 1 (14%) 357 (19%) 1-4 yrs 513 (30%) 8 (13%) 8 (15%) 1 (4%) 1 (14%) 531 (28%) 5-9 yrs 430 (25%) 12 (20%) 6 (12%) 7 (30%) 1 (14%) 456 (24%) yrs 253 (15%) 27 (45%) 21 (40%) 12 (52%) 2 (29%) 315 (17%) >=15 yrs 18 (1%) 6 (10%) 9 (17%) 0 (0%) 2 (29%) 35 (2%) Total 1731 (100%) 60 (100%) 52 (100%) 23 (100%) 7 (100%) 1873 (100%)

Year No. Median (IQR) Age group age < 1 yr 1-4 yrs 5-9 yrs yrs yrs ≥20 yrs ( ) 33(8%) 153(39%) 153(39%) 46(12%) 4(1%) 0(0%) ( ) 33(8%) 154(36%) 179(41%) 60(14%) 7(2%) 0(0%) ( ) 26(5%) 175(34%) 217(42%) 83(16%) 12(2%) 1(0%) ( ) 26(5%) 175(30%) 234(41%) 121(21%) 19(3%) 2(0%) (4-10.7) 24(4%) 195(29%) 258(38%) 150(22%) 42(6%) 2(0%) ( ) 23(3%) 206(26%) 292(37%) 203(26%) 54(7%) 1(0%) ( ) 22(2%) 194(22%) 346(39%) 244(27%) 81(9%) 4(0%) ( ) 23(2%) 189(18%) 394(38%) 306(30%) 104(10%) 11(1%) (6.1-13) 22(2%) 188(16%) 425(37%) 352(31%) 143(12%) 20(2%) ( ) 21(2%) 156(12%) 452(36%) 397(32%) 187(15%) 38(3%) ( ) 21(2%) 158(12%) 441(32%) 441(32%) 248(18%) 48(4%) (7.8-15) 14(1%) 149(10%) 398(28%) 518(36%) 290(20%) 75(5%) ( ) 17(1%) 130(9%) 369(24%) 536(36%) 354(23%) 103(7%) ( ) 9(1%) 111(7%) 336(21%) 559(36%) 401(26%) 153(10%) ( ) 9(1%) 85(5%) 281(17%) 582(36%) 438(27%) 212(13%) ( ) 8(0%) 63(4%) 241(15%) 557(34%) 497(30%) 280(17%) ( ) 7(0%) 45(3%) 207(13%) 484(29%) 554(34%) 348(21%) ( ) 4(0%) 38(2%) 172(11%) 401(26%) 488(32%) 438(28%) Age of UK/Irish paediatric cohort by year of follow-up, Note: Data are for all children and young people alive who were ever in follow-up from 1996 onwards, including children who have since transferred to adult care; those who subsequently died or were lost to follow-up are excluded from the year of death or loss to follow-up. All paediatric infections are included, regardless of mode of acquisition (94% perinatal). CHIPS includes all diagnosed HIV-infected children known to be living in the UK/Ireland, of whom ~55% were born abroad. Data for 2013 are incomplete as subject to reporting delay.

N Note: Data are for all children and young people alive who were ever in follow-up from 1996 onwards, including children who have since transferred to adult care; those who subsequently died or were lost to follow-up are excluded from the year of death or loss to follow-up. All paediatric infections are included, regardless of mode of acquisition (94% perinatal). CHIPS includes all diagnosed HIV-infected children known to be living in the UK/Ireland, of whom ~55% were born abroad. Data for 2013 are incomplete as subject to reporting delay. Age of UK/Irish paediatric cohort by year of follow-up,

All hospital admissions during * Retrospective data on admissions not collected for children from clinics joining since Aug These children are counted from when they begin prospective follow-up in CHIPS. Admissions may be underreported for children in shared care where only information from the main CHIPS follow-up clinic is reported. Data for 2013/14 are incomplete and are not presented Year Number Number Proportion Total Rate (# children children admitted number admissions seen* admitted (%) admissions per 100 pyr)

Year Viral load (copies/ml) ≤50 or ≤lower assay limit** 1997/ /222 (47%) 2001/ /228 (59%) 2004/ /258 (72%) 2007/ /233 (73%) /145 (74%) Total 704/1086 (65%) * Response is based on the viral load value nearest 12 months (+/-3 months) after cART initiation **160/704 (23%) of undetectable results had a lower limit of detection >50 but ≤400c/ml and are included here. Viral load suppression 12 months * after starting cART naïve, all ages N=1086 with measurements available (273 missing)

Year Viral load (copies/ml) ≤50 or ≤lower assay limit** 1997/ /213 (46%) 2001/ /215 (59%) 2004/ /219 (72%) 2007/ /191 (72%) /94 (71%) Total 587/932 (63%) * Response is based on the viral load value nearest 12 months (+/-3 months) after cART initiation **145/587 (25%) of undetectable results had a lower limit of detection >50 but ≤400c/ml and are included here. Viral load suppression 12 months * after starting cART naïve at age ≤12 years N=932 with measurements available (232 missing)

Year Viral load (copies/ml) ≤50 or ≤lower assay limit** 1997/2000 6/9 (67%) 2001/2003 8/13 (62%) 2004/ /39 (74%) 2007/ /42 (79%) /51 (80%) Total 117/154 (76%) * Response is based on the viral load value nearest 12 months (+/-3 months) after cART initiation **15/117 (13%) of undetectable results had a lower limit of detection >50 but ≤400c/ml and are included here. Viral load suppression 12 months * after starting cART naïve at age ≥13 years N=154 with measurements available (41 missing)

Age at cART <2 years 2-4 years 5-9 years 10+ years Time to viral rebound (>1000c/ml) for children suppressing viral load ≤400c/ml within 12 months of starting cART naïve,

Age at cART <2 years 2-4 years 5-9 years 10+ years Time to viral rebound (>1000c/ml) for children suppressing viral load ≤400c/ml within 12 months of starting cART naïve,

1 Response is based on viral load value closest to 12 months (+/-3 months) after starting 1st/ 2nd line, for those starting cART naive and remaining on 1st line for at least 12 months and 2nd line for at least 12 months. 2 Defined as any switch of ≥3 ART drugs (regardless of reason for switch) or a switch of 2 ART drugs with reported reasons being ‘failure’ (immunological/virological/clinical failure or resistance), with viral load >50 copies/ml. 3 69/338 had missing viral load after 12 months on 1st line, and a further 64/338 had missing viral load after 12 months on 2nd line (17%) undetectable results had a lower limit of detection >50 but ≤400c/ml and are included. Year starting 2 nd - line cART Number (%) ≤50c/ml or ≤lower assay limit 4 12 months after starting st line cART2 nd line cART 1997/20002/16 (13%)6/16 (38%) 2001/200311/55 (20%)26/49 (53%) 2004/200618/59 (31%)39/67 (58%) 2007/200939/71 (55%)47/81 (58%) /68 (50%)45/66 (68%) Total 104/269 (39%)163/279 (58%) Viral load 12 months 1 after starting 1st and 2nd line cART for those switching 2 to 2nd line ( N=318 children switched to 2 nd line after at least 12 months on 1 st line 3 )

Data on 1,037 children who are in active follow-up Those who have died, lost to follow-up, left the UK & Ireland or transferred to adult care are excluded.

Demographics (N=1037) (Data provided by NSHPC) 534 (51%) are female 495 (48%) born UK/Ireland, 525 (51%) born abroad (not known for 17 children) Ethnicity: Diagnosis of maternal infection (N=999 vertically infected): White 57(5%) Black African 824(79%) Black other 10(1%) Indian 12(1%) Mixed 104(10%) Other 12(1%) Not known 18(2%) Known after delivery826(83%) Known before delivery 129(13%) Not known44(4%)

523 (50%) London 38 (4%) Scotland 404 (39%) Rest of England 60 (6%) Ireland 12 (1%) Wales Regional distribution of main follow-up clinic for 1037 children alive and followed up in CHIPS Children who have died, lost to follow-up, left the UK & Ireland or transferred to adult care are excluded

Year of last follow-up (N=1037)

Clinical stage by age at last follow-up (N=1037) No. of children< 2 years2-4 years5-9 years10-14 years≥15 yearsTotal(%) Stage N/A 10(100%)26(74%)114(62%)266(58%)163(47%) 579(56%) Stage B 0(0%)4(11%)19(10%)82(18%)96(28%) 201(19%) Stage C 0(0%)5(14%)52(28%)111(24%)89(26%) 257(25%) Total 10(100%)35(100%)185(100%)459(100%)348(100%)1037(100%)

Antiretroviral drug experience N=999 children with follow-up since January 2012 No. of children < 2 years2-4 years5-9 years10-14 years≥15 yearsTotal(%) Naive 2(25%)2(6%)26(14%)56(13%)19(6%) 105(11%) 1-4 drugs 6(75%)17(55%)80(44%)175(40%)92(27%) 370(37%) 5-7 drugs 0(0%)12(39%)63(35%)132(30%)108(31%) 315(32%) 8+ drugs 0(0%)0 11(6%)74(17%)124(36%) 209(21%) Total 8(100%)31(100%)180(100%)437(100%)343(100%)999(100%)

ART at last follow-up N=848 children with follow-up since Jan 2012 were on treatment 25 on mono, 43 on dual, 711 on 3-drug, 65 on 4-drug and 6 on 5(+)-drug therapy

Most recent CD4% (N=978) Children followed up since January 2012 (missing for 21 children) No. of children 0-10%11-20%21-30%>30% Naïve 0(0%)26(25%)46(15%)31(6%) On mono 2(12%)4(4%)11(4%)8(1%) On dual 2(12%)6(6%)16(5%)18(3%) On initial cART 0(0%)26(25%)123(39%)242(45%) On subseq cART 11(65%)34(32%)95(30%)229(42%) Off ART 2(12%)10(9%)22(7%)12(2%) Total 17(100%)106(100%)313(100%)540(100%)

Most recent CD4 count (N=938) Children ≥ 5 years old followed up since Jan 2012 (missing for 20 children) No. of children >1000 Naïve 0(0%)6(10%)34(22%)53(11%)7(3%) On mono 2(10%)3(5%)5(3%)11(2%)4 On dual 2(10%)3(5%)4(3%)23(5%)9(4%) On initial cART 2(10%)18(29%)44(29%)198(40%)101(49%) On subseq cART 8(38%)31(50%)50(33%)192(39%)82(40%) Off ART 7(33%)1(2%)16(10%)16(3%)4(2%) Total 21(100%)62(100%)153(100%)493(100%)207(100%)

No. of children ≤50c/ml (or ≤lower assay limit**) >50c/ml (or>lower assay limit) – 100,000c/ml >100,000c/ml Naïve 5(1%)92(30%)4(27%) On mono 13(2%)12(2%)0(0%) On dual 28(4%)14(3%)1(7%) On initial cART 333(49%)57(22%)0(3%) On subseq cART 290(43%)75(30%)3(20%) Off ART 4(1%)35(13%)7(47%) Total 673(100%)285(100%)15(100%) Most recent viral load (N=975) Children followed up since January 2012 (missing for 24 children) **5/673 ( 50 but ≤400c/ml and are included here.

Outcome 1: Retention in care Percentage of newly diagnosed children in 2011 who had ≥2 CD4 and ≥2 VL measurements within 12 months of diagnosis Notes: The y axis shows percentages, and at the top of each bar shows the number of children

Outcome 2: Retention on ART Percentage of patients newly starting ART in 2010 who were still on ART in 2011 Notes: The y axis shows percentages, and at the top of each bar shows the number of children Percentage (%)

Outcome 3A: Immune status in children <5 yrs Percentage of children aged <5 years with ≥1 CD4 measure ≥25% in 2011, by ART status Percentage (%) Notes: The y axis shows percentages, and at the top of each bar shows the number of children

Outcome 3B: Immune status in children ≥5 years Percentage of children aged ≥5 years with ≥1 CD4 measure ≥350 cells/mm 3 in 2011, by ART status Notes: The y axis shows percentages, and at the top of each bar shows the number of children Percentage (%)

Outcome 4A: Virologic response on ART Percentage of children on ART with ≥2 VL measures <50c/ml and <400c/ml, in 2011 Percentage (%) Notes: The y axis shows percentages, and at the top of each bar shows the number of children Dotted bar: VL <400c/ml Plain bar: VL <50 c/ml

Outcome 4B: Virologic response on ART, age≥13yrs Percentage of young people aged ≥13 years on ART with ≥2 VL measures <50c/ml, and <400 c/ml, in 2011 Percentage (%) Notes: The y axis shows percentages, and at the top of each bar shows the number of children Dotted bar: VL <400c/ml Plain bar: VL <50 c/ml

Outcome 5: Description of deaths in 2011 One paediatric death was reported to CHIPS in 2011: The patient died whilst in paediatric care in the South London network with causes of death given as "acute liver failure" and "septic shock". This child presented aged 2 years with a CD4% of 21% and CD4 count of 323c/ml. This child died aged 2 years and had been in follow up for less than a year, and had been seen twice in the 12 months prior to their death. This patient is not known to have taken any ART drugs.

Involvement in PENTA trials Some patients from CHIPS are currently involved in BREATHER (PENTA 16). For further details about BREATHER please contact Centres with patients in BREATHER London – 14 Leicester – 2 Birmingham – 2Bristol – 2 Ireland – 3 Nottingham – 2 Recent PENTA publications/presentations: D Bastiaans, S Forcat, H Lyall et al. Pharmacokinetics of paediatric lopinavir/ritonavir tablets in children when dosed twice daily according to FDA weight bands. The Pediatric Infectious Disease Journal, March 2014, 33 (3). Klein N., Sefe D., Mosconi I et al. on Behalf of the Paediatric European Network for Treatment of AIDS (PENTA) 11 Trial Team. The Immunological and Virological Consequences of Planned Treatment Interruptions in Children with HIV Infection. Plos One, Oct 2013;8(10). Lyall H, on behalf of the KONCERT Trial Team. Final Results of KONCERT: A randomized noninferiority trial of QD vs BD LPV/r dosing in children. CROI 2014, Boston. Harrison L, Ananworanich J, Hamadache D, Compagnucci A, Penazzato M, et al. on behalf of the Paediatric European Network for Treatment of AIDS (PENTA) 11 Trial Team. Adherence to Antiretroviral Therapy and Acceptability of Planned Treatment Interruptions in HIV-Infected Children. AIDS Behav January; 17(1): 193–202.

Recent CHIPS-related publications / presentations (based either wholly or partly on CHIPS data) Gkentzi D, Tebruegge M, Tudor-Williams G, et al. Incidence, Spectrum and Outcome of Immune Reconstitution Syndrome in HIV-Infected Children Following Initiation of Antiretroviral Therapy. Pediatric Infectious Disease Journal, March Fish R, Judd A, Jungmann E, et al. Mortality in perinatally HIV-infected young people in England following transition to adult care: an HIV Young Persons Network (HYPNet) audit. HIV Med 2014 (4): Engsig FN, Zangerle R, Katsarou O, et al. for the Antiretroviral Therapy Cohort Collaboration (ART-CC) and the Collaboration of Observational HIV Epidemiological Research Europe (COHERE) in EuroCoord. Long-term Mortality in HIV-Positive Individuals Virally Suppressed for >3 Years With Incomplete CD4 Recovery. Clin Infect Dis Feb 25.Long-term Mortality in HIV-Positive Individuals Virally Suppressed for >3 Years With Incomplete CD4 Recovery. Judd A, Duong T, Galli L et al. Post-licensing safety of fosamprenavir in HIV-infected children in Europe. Pharmacoepidemiology and Drug Safety 2014; 23(3): Judd A, Collins IJ, Lodi S, et al. Moving on up: Tracking young people with perinatal HIV as they transition to adult care in Europe. 18th International Workshop on HIV Observational Databases, Stiges, Collins IJ, Turkova A, Judd A, et al. Tuberculosis (TB) co-infection in HIV-infected children in the UK Ireland. 18th International Workshop on HIV Observational Databases, Stiges, Collins IJ, Judd A, Tookey P, et al. Improving clinical status of perinatally HIV-infected patients at transfer to adult care over time. 18th International Workshop on HIV Observational Databases, Stiges, 2014.

Acknowledgements We thank the families and staff at hospitals which participate in CHIPS. CHIPS is funded by the NHS (London Specialised Commissioning Group), and has received additional support from Bristol-Myers Squibb, Boehringer Ingelheim, GlaxoSmithKline, Roche, Abbott, and Gilead. For further information on CHIPS, please visit: