Data from theCollaborative HIV Paediatric Study

(CHIPS) Reports up to March 2014*

* Numbers are based on reports received rather than children seen to the end of March 2014. 2013/14 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

Still in CHIPS fol-

low-up

Transferred to non-CHIPS

clinics

Left country Lost to fol-low-up

Transferred to adult care

Died*0

200

400

600

800

1000

1200

1018

1997 36

595

108Num

ber

of c

hild

ren

* 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 2009 2010 2011 2012 2013+ 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%) 10-14 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 10-14 yrs 15-19 yrs ≥20 yrs 1996 389 5.2 (2.8-7.7) 33(8%) 153(39%) 153(39%) 46(12%) 4(1%) 0(0%) 1997 433 5.6 (3.1-8.4) 33(8%) 154(36%) 179(41%) 60(14%) 7(2%) 0(0%) 1998 514 6.1 (3.3-9.1) 26(5%) 175(34%) 217(42%) 83(16%) 12(2%) 1(0%) 1999 577 6.7 (3.7-9.9) 26(5%) 175(30%) 234(41%) 121(21%) 19(3%) 2(0%) 2000 671 7.2 (4-10.7) 24(4%) 195(29%) 258(38%) 150(22%) 42(6%) 2(0%) 2001 779 7.7 (4.5-11.1) 23(3%) 206(26%) 292(37%) 203(26%) 54(7%) 1(0%) 2002 891 8.2 (5.1-11.9) 22(2%) 194(22%) 346(39%) 244(27%) 81(9%) 4(0%) 2003 1027 8.7 (5.7-12.4) 23(2%) 189(18%) 394(38%) 306(30%) 104(10%) 11(1%) 2004 1150 9.3 (6.1-13) 22(2%) 188(16%) 425(37%) 352(31%) 143(12%) 20(2%) 2005 1251 9.9 (6.7-13.7) 21(2%) 156(12%) 452(36%) 397(32%) 187(15%) 38(3%) 2006 1357 10.5 (7.1-14.3) 21(2%) 158(12%) 441(32%) 441(32%) 248(18%) 48(4%) 2007 1444 11.3 (7.8-15) 14(1%) 149(10%) 398(28%) 518(36%) 290(20%) 75(5%) 2008 1509 12.1 (8.6-15.8) 17(1%) 130(9%) 369(24%) 536(36%) 354(23%) 103(7%) 2009 1569 12.9 (9.4-16.5) 9(1%) 111(7%) 336(21%) 559(36%) 401(26%) 153(10%) 2010 1607 13.7 (10.2-17.4) 9(1%) 85(5%) 281(17%) 582(36%) 438(27%) 212(13%) 2011 1646 14.6 (11.1-18.3) 8(0%) 63(4%) 241(15%) 557(34%) 497(30%) 280(17%) 2012 1645 15.5 (12-19.3) 7(0%) 45(3%) 207(13%) 484(29%) 554(34%) 348(21%) 2013 1541 16.3 (12.6-20.4) 4(0%) 38(2%) 172(11%) 401(26%) 488(32%) 438(28%)

Age of UK/Irish paediatric cohortby year of follow-up, 1996-2013

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 389 514 671 891 1150 1357 1509 1607 1645 433 577 779 1027 1251 1444 1569 1646 1541

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 cohortby year of follow-up, 1996-2013

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 20130%

20%

40%

60%

80%

100%

20+15-1910-145-91-4<1

Year

Percen

t

All hospital admissions during 2000-2012

* Retrospective data on admissions not collected for children from clinics joining since Aug 2003. 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.

2000 601 165 27 327 59.1 2001 665 179 27 315 51.4 2002 727 158 22 247 36.6 2003 830 187 23 320 42.3 2004 953 182 19 287 33.9 2005 1083 177 16 289 29.3 2006 1139 164 14 244 22.9 2007 1171 146 12 216 19.6 2008 1201 147 12 217 19.2 2009 1203 122 10 155 13.9 2010 1175 94 8 137 12.3 2011 1163 108 9 145 13.4 2012 1069 68 6 82 8.2

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** 1997/2000 104/222 (47%) 2001/2003 135/228 (59%) 2004/2006 186/258 (72%)

2007/2009 171/233 (73%) 2010- 108/145 (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** 1997/2000 98/213 (46%) 2001/2003 127/215 (59%) 2004/2006 157/219 (72%) 2007/2009 138/191 (72%)

2010- 67/94 (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 yearsN=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%) 2004/2006 29/39 (74%) 2007/2009 33/42 (79%)

2010- 41/51 (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 yearsN=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, 2000-2003

0.0

00

.25

0.5

00

.75

1.0

0

Pro

port

ion

su

ppre

sse

d

48 28 20 17 11Age = 10+ yrs88 70 62 49 45Age = 5-9 yrs61 48 46 41 36Age = 2-4 yrs65 51 43 42 41Age = < 2 yrs

Number at risk

0 1 2 3 4

Time (years) suppressed on cART

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, 2004-2012

0.0

00

.25

0.5

00

.75

1.0

0

Pro

port

ion

su

ppre

sse

d

293 209 134 87 53Age = 10+ yrs170 144 124 101 76Age = 5-9 yrs73 60 53 45 37Age = 2-4 yrs108 81 61 54 47Age = < 2 yrs

Number at risk

0 1 2 3 4

Time (years) suppressed on cART

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. 4 57 (17%) undetectable results had a lower limit of detection >50 but ≤400c/ml and are included.

Year starting 2nd-line cART

Number (%) ≤50c/ml or ≤lower assay limit4 12 months after starting....

1st line cART 2nd line cART

1997/2000 2/16 (13%) 6/16 (38%)

2001/2003 11/55 (20%) 26/49 (53%)

2004/2006 18/59 (31%) 39/67 (58%)

2007/2009 39/71 (55%) 47/81 (58%)

2010- 34/68 (50%) 45/66 (68%)

Total 104/269 (39%) 163/279 (58%)

Viral load 12 months1 after starting 1st and 2nd line cART for those switching2 to 2nd line

(N=318 children switched to 2nd line after at least 12 months on 1st line3)

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 delivery 826 (83%)

Known before delivery 129 (13%)

Not known 44 (4%)

523 (50%)London

38 (4%) Scotland

404 (39%)Rest of England

60 (6%)Ireland

12 (1%)Wales

Regional distribution ofmain 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)

Up to 2011 2012 Jan-Jun 2013 Since July 20130

100

200

300

400

500

600

38

95

539

365

Num

ber

of c

hild

ren

Clinical stage by age at last follow-up (N=1037)

No. of children < 2 years 2-4 years 5-9 years 10-14 years ≥15 years Total (%)

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%)

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

% o

f ch

ildr

en

Antiretroviral drug experience N=999 children with follow-up since January 2012

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

% o

f ch

ildr

en

No. of children < 2 years 2-4 years 5-9 years 10-14 years ≥15 years Total (%)

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 (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-upN=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

PI+

NR

TI

NN

RT

I+N

RT

I

PI+

NN

RT

I

3 N

RT

I

2 N

RT

I

1 P

I

2PI

Oth

er

0

100

200

300

400

500

600

393 398

10 2 8 261

10

Num

ber

of c

hild

ren

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%)

0

50

100

150

200

250

300

Num

ber

of c

hild

ren

Most recent CD4 count (N=938)Children ≥ 5 years old followed up since Jan 2012 (missing for 20 children)

No. of children 0-200 201-350 351-500 501-1000 >1000

Naïve 0 (0%) 6 (10%) 34 (22%) 53 (11%) 7 (3%)

On mono 2 (10%) 3 (5%) 5 (3%) 11 (2%) 4 (2%)

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%)

0

50

100

150

200

250

Nu

mb

er o

f ch

ild

ren

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%)

0

50

100

150

200

250

300

350

400

Nu

mb

er o

f ch

ild

ren

Most recent viral load (N=975)Children followed up since January 2012 (missing for 24 children)

**5/673 (<1%) of undetectable results had a lower limit of detection >50 but ≤400c/ml and are included here.

Outcome 1: Retention in carePercentage 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

London

(n=31)

Rest of E

ngland

(n=17)

Scot/W

ales/NI/I

reland

(

n=4)

Total UK/Ir

eland

(n=53)0

20

40

60

80

10029 16

449

Perc

enta

ge (%

)

Outcome 2: Retention on ARTPercentage 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

Perc

enta

ge (

%)

London

(n=32)

Rest of E

ngland

(n=25)

Scot/W

ales/NI/I

reland

(

n=5)

Total UK/Ir

eland

(n=62)0

20

40

60

80

10031 25 5 61

Outcome 3A: Immune status in children <5 yrs Percentage of children aged <5 years with ≥1 CD4 measure ≥25%

in 2011, by ART status

Perc

enta

ge (

%)

Notes: The y axis shows percentages, and at the top of each bar shows the number of children

On ART (n=52)

Not on ART (n=15)

Unknown ART status (n=3)

0

20

40

60

80

10024

5

1

22

5

1

6 1 152

112

London Rest of England Scotland/Wales/N.Ireland/Ireland Total UK/Ireland

Outcome 3B: Immune status in children ≥5 years Percentage of children aged ≥5 years with ≥1 CD4 measure

≥350 cells/mm3 in 2011, by ART status

Notes: The y axis shows percentages, and at the top of each bar shows the number of children

Perc

enta

ge (

%)

On ART (n=700)

Not on ART (n=207)

Unknown ART status (n=40)

0

20

40

60

80

100

325 109 26268

60 870

24 1663 193 36

London Rest of England Scotland/Wales/N.Ireland/Ireland Total UK/Ireland

0

20

40

60

80

100

340 28183

704

295 241

79

615

Outcome 4A: Virologic response on ART Percentage of children on ART with ≥2 VL measures <50c/ml

and <400c/ml, in 2011

Perc

enta

ge (

%)

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

0

20

40

60

80

100

141 92

35

268

116 75

33

224

Outcome 4B: Virologic response on ART, age≥13yrsPercentage of young people aged ≥13 years on ART with ≥2 VL

measures <50c/ml, and <400 c/ml, in 2011

Perc

enta

ge (

%)

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 trialsSome patients from CHIPS are currently involved in BREATHER (PENTA 16). For further details about BREATHERplease contact penta@ctu.mrc.ac.uk.

Centres with patients in BREATHER

London – 14 Leicester – 2Birmingham – 2 Bristol – 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. 2013 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 2014.

• 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): 239-44.

• 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. 2014 Feb 25.

• 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): 321-325.

• 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, 2014.

• 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, 2014.

• 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:www.chipscohort.ac.uk