Data from the Collaborative HIV Paediatric Study (CHIPS) Reports up to June 2015* * Numbers are based on reports received rather than children seen to the end of June /15 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 – the National Study of HIV in Pregnancy and Childhood (NSHPC), and – the MRC Clinical Trials Unit at UCL

Follow-up status of 1934 children enrolled in CHIPS * 94 deaths prior to 2008, 6 in 2008, 6 in 2009, 2 in 2010, 2 in 2011

Age group by year first presented to medical services in the UK/Ireland (1926*) * 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 172 (10%) 5 (8%) 4 (13%) 0 (0%) 3 (14%) 184 (10%) <1 yr 302 (17%) 2 (3%) 2 (6%) 0 (0%) 1 (5%) 307 (16%) 1-4 yrs 523 (29%) 7 (11%) 2 (6%) 6 (30%) 4 (18%) 542 (28%) 5-9 yrs 473 (26%) 10 (16%) 10 (31%) 4 (20%) 6 (27%) 503 (26%) yrs 287 (16%) 28 (44%) 14 (44%) 6 (30%) 8 (36%) 343 (18%) >=15 yrs 31 (2%) 12 (19%) 0 (0%) 4 (20%) 0 (0%) 47 (2%) Total 1788 (100%) 64 (100%) 32 (100%) 20 (100%) 22 (100%) 1936 (100%)

Year No. Median (IQR) Age group age < 1 yr 1-4 yrs 5-9 yrs yrs yrs ≥20 yrs ( ) 33(10%) 146(44%) 124(37%) 30(9%) 0(0%) 0(0%) ( ) 47(12%) 141(37%) 148(39%) 45(12%) 1(0%) 0(0%) ( ) 38(8%) 171(38%) 178(39%) 64(14%) 5(1%) 0(0%) ( ) 32(6%) 180(34%) 209(40%) 95(18%) 12(2%) 0(0%) ( ) 35(6%) 193(31%) 240(39%) 129(21%) 26(4%) 0(0%) ( ) 34(5%) 194(27%) 276(39%) 168(24%) 40(6%) 0(0%) ( ) 37(5%) 191(23%) 320(39%) 206(25%) 60(7%) 1(0%) ( ) 35(4%) 179(19%) 389(41%) 265(28%) 81(8%) 5(1%) ( ) 32(3%) 188(17%) 408(38%) 321(30%) 114(11%) 13(1%) ( ) 33(3%) 169(14%) 437(37%) 362(31%) 158(13%) 26(2%) ( ) 30(2%) 160(13%) 434(34%) 404(32%) 208(16%) 38(3%) ( ) 25(2%) 138(10%) 414(30%) 475(35%) 251(18%) 58(4%) ( ) 18(1%) 132(9%) 365(25%) 536(37%) 304(21%) 84(6%) ( ) 17(1%) 118(8%) 338(22%) 541(36%) 370(25%) 124(8%) ( ) 10(1%) 94(6%) 293(19%) 570(37%) 409(26%) 176(11%) ( ) 10(1%) 73(5%) 250(16%) 572(36%) 462(29%) 239(15%) ( ) 7(0%) 48(3%) 218(13%) 523(32%) 533(33%) 300(18%) ( ) 3(0%) 38(2%) 188(11%) 437(27%) 596(36%) 382(23%) ( ) 2(0%) 29(2%) 155(9%) 390(24%) 593(36%) 487(29%) Age of UK/Irish cohort of patients with HIV acquired in childhood, 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 ~50% were born abroad. Data for 2014 are incomplete as subject to reporting delay.

Age of UK/Irish cohort of patients with HIV acquired in childhood, N=

Year No. Median (IQR) Age group age < 1 yr 1-4 yrs 5-9 yrs yrs yrs ≥20 yrs (2-7) 1(3%) 16(46%) 13(37%) 5(14%) 0(0%) 0(0%) (1-6.5) 6(19%) 12(38%) 11(34%) 2(6%) 1(3%) 0(0%) (1-8) 3(6%) 23(44%) 17(33%) 8(15%) 1(2%) 0(0%) (3-9) 11(5%) 66(32%) 88(43%) 35(17%) 4(2%) 0(0%) (3-10) 6(2%) 112(40%) 87(31%) 61(22%) 13(5%) 0(0%) (3-8) 3(1%) 126(49%) 78(30%) 41(16%) 11(4%) 0(0%) (3-7) 7(3%) 119(46%) 103(39%) 26(10%) 6(2%) 0(0%) (3-7) 11(3%) 122(35%) 169(48%) 42(12%) 8(2%) 0(0%) (4-8) 11(2%) 143(32%) 230(51%) 57(13%) 10(2%) 1(0%) (4-9) 10(2%) 134(23%) 321(56%) 90(16%) 16(3%) 1(0%) (5-9) 10(2%) 122(20%) 361(59%) 98(16%) 16(3%) 1(0%) (6-10) 4(1%) 109(17%) 335(52%) 180(28%) 15(2%) 1(0%) (6-11) 10(1%) 106(14%) 325(44%) 270(37%) 22(3%) 0(0%) (7-12) 1(0%) 91(12%) 299(39%) 340(44%) 44(6%) 0(0%) (8-13) 1(0%) 77(9%) 245(29%) 448(54%) 57(7%) 4(0%) (8-13) 5(1%) 57(7%) 216(25%) 481(55%) 106(12%) 5(1%) (9-14) 1(0%) 37(4%) 192(21%) 449(50%) 206(23%) 9(1%) (10-15) 0(0%) 26(3%) 167(18%) 408(44%) 307(33%) 16(2%) (11-16) 2(0%) 22(2%) 129(14%) 357(37%) 410(43%) 35(4%) 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 or transferred to adult care are excluded from the year of death or loss to follow-up or transfer. 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 ~50% were born abroad. Data for 2014 are incomplete as subject to reporting delay. Age of UK/Irish cohort of patients with HIV acquired in childhood & seen in paediatric care,

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 or transferred to adult care are excluded from the year of death or loss to follow-up or transfer. 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 ~50% were born abroad. Data for 2014 are incomplete as subject to reporting delay. N=

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 are incomplete as subject to reporting delay 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/ /101 (26%) 2000/ /338 (39%) 2005/ /417 (62%) /238 (75%) Total 597/1094 (55%) * Response is based on the viral load value nearest 12 months (+/-3 months) after cART initiation ** Newly defined as: first line therapy is 3 or more drugs across two classes or 3NRTIs including ABC ***46/597 (8%) 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=1094 with measurements available

Year Viral load (copies/ml) ≤50 or ≤lower assay limit*** 1997/ /93 (24%) 2000/ /305 (39%) 2005/ /326 (60%) /133 (74%) Total 435/857 (51%) * Response is based on the viral load value nearest 12 months (+/-3 months) after cART initiation ** Newly defined as: first line therapy is 3 or more drugs across two classes or 3NRTIs including ABC *** 36/435 (8%) 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=857 with measurements available

Year Viral load (copies/ml) ≤50 or ≤lower assay limit*** 1997/1999 4/8 (50%) 2000/ /33 (42%) 2005/ /91 (70%) /105 (76%) Total 162/237 (68%) * Response is based on the viral load value nearest 12 months (+/-3 months) after cART initiation ** Newly defined as: first line therapy is 3 or more drugs across two classes or 3NRTIs including ABC *** 10/162 (6%) 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=237 with measurements available

Time to viral rebound (>1000c/ml) for children suppressing viral load ≤400c/ml within 12 months of starting cART naïve,

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 across drug class or change/addition of PI drug or addition of new drug class. 3 98/434 had missing viral load after 12 months on 1st line, and a further 88/434 had missing viral load after 12 months on 2nd line (5%) 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 1997/20003/13 (23%)4/11 (36%) 2001/200314/50 (28%)29/46 (63%) 2004/200624/67 (36%)47/77 (61%) 2007/200946/81 (57%)60/89 (67%) /125 (58%)100/133 (75%) Total 160/336 (48%)240/356 (67%) Viral load 12 months 1 after starting 1st and 2nd line cART for those switching 2 to 2nd line ( N=434 children switched to 2 nd line after at least 12 months on 1 st line 3 )

Data on 979 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=979) (Data provided by NSHPC) 516 (53%) are female 471 (48%) born UK/Ireland, 485 (50%) born abroad (not known for 21 children) Ethnicity: Diagnosis of maternal infection (N=906 vertically infected): White 56(6%) Black African 760(78%) Black other 8(1%) Indian 13(1%) Mixed 98(10%) Other 12(1%) Not known 32(3%) Known after delivery743(82%) Known before delivery131(14%) Not known32(4%)

462 (48%) London 41 (4%) Scotland 404 (41%) Rest of England 52 (5%) Ireland 12 (1%) Wales Regional distribution of main follow-up clinic for 979 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 5 (<1%) Northern Ireland

Year of last follow-up (N=956)

Clinical stage by age at last follow-up (N=956) No. of children< 2 years2-4 years5-9 years10-14 years≥15 yearsTotal(%) Stage N/A 5(83%)22(73%)94(59%)211(51%)149(43%) 481(50%) Stage B 1(17%)4(13%)27(17%)105(26%)117(33%) 254(27%) Stage C 0(0%)4(13%)39(24%)94(23%)84(24%) 221(23%) Total 6(100%)30(100%)160(100%)410(100%)350(100%)956(100%)

Antiretroviral drug experience N=905 children with follow-up since January 2013 No. of children < 2 years2-4 years5-9 years10-14 years≥15 yearsTotal(%) Naive 0(0%)3(12%)17(11%)42(11%)15(4%) 77(9%) 1-4 drugs 4(80%)13(50%)69(45%)143(37%)82(24%) 311(34%) 5-7 drugs 1(20%)10(38%)56(37%)123(32%)119(35%) 309(34%) 8+ drugs 0(0%)0 10(7%)74(19%)124(36%) 208(23%) Total 5(100%)26(100%)152(100%)382(100%)340(100%)905(100%)

ART at last follow-up N=828 children with follow-up since Jan 2013 were on treatment 28 on mono, 44 on dual, 700 on 3-drug, 52 on 4-drug and 4 on 5(+)-drug therapy

Most recent CD4% (N=832) Children followed up since January 2013 No. of children 0-10%11-20%21-30%>30%Total Naïve 0(0%)18(25%)26(36%)28(39%)72(100%) On mono 0(0%)3(14%)11(50%)8(36%)22(100%) On dual 1(2%)7(16%)12(28%)23(53%)43(100%) On initial cART 0(0%)17(6%)84(32%)163(62%)264(100%) On subseq cART 5(1%)32(8%)107(27%)251(64%)395(100%) Off ART 2(6%)7(19%)17(47%)10(28%)36(100%) Note: Row percentages now provided. Initial cART newly defined as first line therapy is 3 or more drugs across two classes or 3NRTIs including Abacavir. Subsequent cART defined as any switch across drug class or change/addition of PI drug or addition of new drug class.

Most recent CD4 count (N=828) Children ≥ 5 years old followed up since Jan 2013 No. of children >1000Total Naïve 0(0%)5(7%)15(21%)39(56%)11(16%)70(100%) On mono 1(4%)5(21%)4(17%)10(42%)4(17%)24(100%) On dual 2(5%)5(12%)3(7%)17(41%)14(34%)41(100%) On initial cART 0(0%)10(4%)35(13%)177(67%)43(16%)265(100%) On subseq cART 10(3%)23(6%)51(13%)205(52%)102(26%)391(100%) Off ART 3(8%)8(22%)8 15(41%)3(8%)37(100%) Note: Row percentages now provided. Initial cART newly defined as first line therapy is 3 or more drugs across two classes or 3NRTIs including Abacavir. Subsequent cART defined as any switch across drug class or change/addition of PI drug or addition of new drug class.

No. of chcaildren ≤50c/ml (or ≤lower assay limit**) >50c/ml (or>lower assay limit) – 100,000c/ml >100,000c/mlTotal Naïve 2(3%)71(95%)2(3%)75(100%) On mono 14(61%)9(39%)0(0%)23(100%) On dual 30(75%)10(25%)0(0%)40(100%) On initial cART 241(87%)35(13%)0(0%)276(100%) On subseq cART 326(82%)69(17%)1(1%)396(100%) Off ART 7(17%)28(68%)6(17%)41(100%) Most recent viral load (N=851) Children followed up since January 2013 Note: Row percentages now provided. Initial cART newly defined as first line therapy is 3 or more drugs across two classes or 3NRTIs including Abacavir. Subsequent cART defined as any switch across drug class or change/addition of PI drug or addition of new drug class. **6/620 ( 50 but ≤400c/ml and are included here.

Outcome 1: Retention in care Percentage of newly diagnosed children in 2012 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 2011 who were still on ART in 2012 Notes: The y axis shows percentages, and at the top of each bar shows the number of children

Outcome 3A: Immune status in children <5 yrs Percentage of children aged <5 years with ≥1 CD4 measure ≥25% in 2012, by ART status 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 2012, by ART status Notes: The y axis shows percentages, and at the top of each bar shows the number of children

Outcome 4A: Virological response on ART Percentage of children on ART with ≥2 VL measures <50c/ml and <400c/ml, in 2012 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: Virological 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 2012 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 previously 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. One paediatric death in 2011 has since been reported to CHIPS: The patient died whilst in paediatric care in the North London network with causes of death given as “CMV pneumonitis". This child presented aged 1 year and 6 months with a CD4% of 1% and CD4 count of 68c/ml. This child died aged 1 year and 7 months and had been in follow up for a month, and had been seen once. This patient is not known to have taken any ART drugs.

Outcome 5: Description of deaths in 2012 No paediatric deaths in 2012 have been reported to CHIPS.

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 Evelina – 3 St George’s – 4 GOSH - 7 Leicester – 2Nottingham – 1 Birmingham – 4Bristol – 1 Dublin – 3 Recent PENTA publications/presentations: Harrison L., Melvin A., Fiscus S., Saidi Y., Nastouli E., Harper L., Compagnucci A., Babiker A., McKinney R., Gibb D., Tudor-Williams G., HIV-1 Drug Resistance and Second-line Treatment in Children Randomized to Switch at Low versus Higher RNA Thresholds, JAIDS 2015 Sep 1;70(1). Once- versus twice-daily lopinavir/ritonavir in HIV-1 infected children: a randomised controlled trial (KONCERT/PENTA18/ANRS150). Accepted for publication in AIDS ART with weekends off is non-inferior to continuous ART in young people on EFV+2NRTI; Karina Butler on behalf of the PENTA 16 (BREATHER) trial team, Conference on Retroviruses and Opportunistic Infections, Seattle Feb th 2015, Abstract 38LB Freguja R, De Rossi A, Poulson H, Klein N, Del Bianco P,, Compagnucci, A, Saidi Y, Giaquinto C, Harper L, Gibb D on behalf of the PENTA Steering Committee: Long-term consequences of planned treatment interruption in HIV-1-infected children. CROI 2015, Seattle, USA, Feb Poster presentation abstract 919. Seeley J on behalf of the Bernays S, Paparini S, Namukwaya Kihika S, Rhodes T and the BREATHER Trial Team. “But it’s my story”: exploring the experience and effect of telling children how they have acquired HIV; 3 rd International ASSHH Conference, Stellenbosch, South Africa, 6-9 July Paparini S on behalf of Bernays S, Seeley S, Rhodes T, Namukwaya Kihika S, Kawuma-Kigawa R, Nakyambadde H, Kabajaasi O and the BREATHER Trial Team. Young people, clinical trials and ‘the HIV experience’: What can similarities across time and place tell us about growing up with HIV? 3 rd International ASSHH Conference, Stellenbosch, South Africa, 6-9 July Bernays S, Seeley J, Paparini S, Rhodes T and the ARROW and BREATHER trial teams ‘I am scared of getting caught up in my lie’: challenges to self-reported adherence for young people living with HIV; accepted for presentation at AIDS Impact, Amsterdam July, 2015 (abstract 3435) Bernays S, Seeley J, Paparini S, Rhodes T and the BREATHER trial teams ‘I was like, oh my God, what happens if it doesn’t work’?: young people living with HIV, clinical trial participation, and the truth economy accepted for presentation at BSA Medical Sociology Conference, York, 9-11 September 2015 (Paper ID No: W ).

Recent CHIPS-related publications / presentations (based either wholly or partly on CHIPS data) Childs T, Shingadia D, Goodall R, Doerholt K, Lyall H, Duong T, Judd A, Gibb DM, Collins IJ. Outcomes after viral load rebound on first-line antiretroviral therapy in HIV-infected children in the UK/ Ireland: an observational cohort study. Lancet HIV, Vol 2 No 4, e151-e158, April Payne H, Judd A¸ Donegan K, Okike IO, Ladhani S, Doerholt K, Heath PT. Incidence of pneumococcal and varicella disease in HIV-infected children and adolescents in the UK and Ireland, : two potentially vaccine- preventable infections. Pediatric Infectious Disease Journal 2015; 34(2): Duong T, Judd A, Collins J, Doerholt K, Lyall H, Foster C, Butler K, Tookey P, Shingadia D, Menson E, Dunn DT, Gibb DM. Long-term virological outcome in children on antiretroviral therapy in the UK and Ireland. AIDS 2014; 28(16): Hussain N, Lewis J, Childs T, Judd A, Klein N, Fidler K. To investigate the number of UK paediatric HIV patients with persistently low CD4 counts despite antiretroviral therapy. 21 st Annual Conference of the British HIV Association, Brighton 2015 (poster presentation). Patel A, Judd A, Foster C, Welch S, Menson E, Lim E, Klein N, Fidler K. To determine the prevalence of HIV seroreversion across 6 collaborating paediatric HIV centres in the UK. 21 st Annual Conference of the British HIV Association, Brighton 2015 (oral presentation). Herbert S, Barbour A, Judd A, Jungmann E, Foster C on behalf of the HIV Young People’s Network (HYPNET). Malignancy in HIV positive young people. 21 st Annual Conference of the British HIV Association, Brighton 2015 (poster presentation).

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: