1. Long term trends in mortality and AIDS-defining events among perinatally HIV-infected children across Europe and Thailand
Ali Judd, Elizabeth Chappell, Katja Doerholt, Luisa Galli, Carlo Giaquinto, Di M. Gibb, Tessa Goetghebuer, Sophie Le Coeur, Antoni Noguera Julian, Anna Turkova and Ruth Goodall on behalf of the European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC)

2. I have no conflict of interest

3. Background
Studies have reported declining mortality after the start of cART in children across the world
Little is known about longer-term risk of death in those on ART for several years
Judd et al, CID 2007;45:918-24

4. Objectives
Among children with perinatal HIV followed in 19 cohorts across 16 European countries and Thailand:
How many deaths occurred and what were the causes?
Deaths within 6 months of cART start
Deaths after 6 months of cART
What was the mortality rate?
What were the risk factors for dying?
What new AIDS events occurred in those AIDS-free at cART start?

5. Methods
Children <18 years starting ART with ≥3 drugs, ≥2 classes (not unboosted PIs), or ≥3 NRTI-only (inc. ABC)
Followed from ART start to death, loss-to-follow-up (LTFU), transfer to adult care, or 21st birthday
Data up to 31st December 2013
Risk factors for mortality:
start of ART: sex, year of birth, born abroad, ethnicity, region, age, AIDS diagnosis, year of ART initiation, initial regimen, low CD4, viral load, BMI-for-age z-score
time-updated: age, low CD4, viral load, % of time suppressed since cART start, BMI-for-age z-score
Inverse-probability-of-censoring weighted Cox models:
Children lost-to-follow-up (LTFU) (12%) may be at greater risk of death or AIDS diagnosis
Models give larger weights to children who do not drop out but who are similar to those who are LTFU, to remove bias

6. Patient characteristics at ART initiation
n (%) or median [IQR]
Region
UK/Ireland
1124 (32%)
Thailand
700 (20%)
Russia/Ukraine
640 (18%)
Rest of Europe
1062 (30%)
Female
1856 (53%)
Age, years
5.2 [1.4, 9.3]
Low CD4-for-age*
1491 (55%)
CD4%
16 [9, 25]
Viral load, log10 copies/ml
5.0 [4.4, 5.7]
Previous AIDS diagnosis
663 (19%)
BMI-for-age z-score
-0.2 [-1.1, 0.8]
Initial regimen
NNRTI-based
2227 (63%)
PI-based
1140 (32%)
Other
159 (4%)
Calendar year
1997-<2004
973 (28%)
2004-<2008
1264 (36%)
≥2008
1289 (37%)
Median duration of follow up after ART initiation 5.6 [IQR 2.9, 8.7] years
*Low CD4-for-age defined as:
<25% for age <1 yr <20% for age 1-3 yrs <15% for age 3-5 yrs
<200 cells/mm3 or <15% for age ≥5 yrs

7. Number and causes of death
HIV-related infections
including 17 bacterial/sepsis, 9 pneumonia, 6 cryptococcosis, 6 Pneumocystis jirovecii pneumonia±CMV
58 (62%)
31 (72%)
27 (53%)
Overall (N=94)
>6m
(N=51)
≤6m
(N=43)
Other HIV-related
including 8 wasting syndrome, 6 heart failure/cardiomyopathy
22 (23%)
9 (21%)
13 (25%)
Not directly HIV-related
including 3 haemorrhages, 2 diabetes,
2 suicide 10
(11%)
1 (2%)
9 (18%)
Unknown
4 (4%)
2 (5%)
2 (4%)

8. Time to death 2.4% Deaths Rate per 100,000 PY (95% CI) ≤6m 43
2502 (1856, 3374)
>6m 51
270 (206, 356)

9. Rate of death by calendar year

10. Risk factors for death >6 months of cART
# deaths PY
aHR
95% CI p
AT START OF ART
Cohort
Thai/Russia/Ukraine 33
6215
1.00 -
0.040
Other 18
12641
0.49
0.25, 0.97
Year of ART initiation
1997-<2004 30
8494
2004-<2008 16
7502
0.44
0.23, 0.84
≥2008 5
2860
0.16, 1.52
TIME-UPDATED
Age (years)
<2 6
807
3.74
1.27, 11.00
0.005
2-<5 1
2957
0.20
0.02, 1.60
5-<14 23
11465
≥14 21
3628
1.79
0.89, 3.64
Low CD4-for-age
Yes
1146
<0.001 No 9
13504
0.06
0.03, 0.16
Viral load (copies/ml)
≤400 12
11806
0.36
0.15, 0.85
0.045
>400 25
2610
BMI-for-age
z-score
>0 8
6141
1.12
0.43, 2.87
-3 to 0 14
6085
<-3
133
18.53
6.76, 50.80

11. Predictors of deaths <6 months and AIDS
Predictors of death ≤6 months of cART
Similar to those for death >6m
AIDS-defining events
Overall 217 events in 176 children, rate of first event 1,123 (95% CI 969, 1,302) per 100,000 PY
Most common events were encephalopathy (n=38, 18%), TB (n=34, 16%) and wasting syndrome (n=31, 14%)
Similar risk factors as death >6m, except BMI-for-age z-score and year at ART initiation which were not significant

12. Conclusions
Strengths of our analysis were the large number of patients, long duration of follow-up and varied age at ART initiation
Almost half of deaths occurred within 6 months of ART initiation
After 6 months, low CD4-for-age, low BMI-for-age z-score, and age <2 or ≥14 were the strongest predictors for mortality
Indication of raised mortality risk in those currently aged ≥14 is similar to other studies suggesting worsening health in adolescents with perinatal HIV
WHO reported that HIV was the 2nd leading cause of death for adolescents worldwide by 2012

13. Acknowledgements
This project has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under EuroCoord grant agreement n˚ and the PENTA Foundation.
Participating cohorts:
Belgium: Hospital St Pierre Cohort, Brussels (Dr Tessa Goetghebuer)
France: French Perinatal Cohort Study/Enquête Périnatale Français (Dr Josiane Warszawski)
Germany: German Paediatric & Adolescent HIV Cohort (GEPIC) (Dr Chris Königs)
Greece: Greek cohort (Dr Vana Spoulou)
Italy: Italian Register for HIV infection in children (Prof Maurizio de Martino, Prof Luisa Galli)
Netherlands: ATHENA paediatric cohort (Dr Colette Smit)
Poland: Polish paediatric cohort (Dr Magda Marczynska)
Portugal: Centro Hospitalar do Porto (Dr Laura Marques)
Portugal: Hospital de Santa Maria/CHLN (Dr Filipa Prata)
Romania: "Victor Babes" Hospital Cohort, Bucharest (Dr Luminita Ene)
Russia: Republican Hospital of Infectious Diseases, St Petersburg (Prof Evgeny Voronin, Dr Liubov Okhonskaia)
Spain: CoRISPE-cat, Catalonia (Dr Antoni Noguera Julian)
Spain: CoRISPE-1, rest of Spain (Dr Pablo Rojo Conejo, Dr José Tomás Ramos Amador)
Sweden: Karolinska University Hospital, Stockholm (Dr Lars Naver)
Switzerland: Swiss Mother and Child HIV Cohort Study (Dr Christoph Rudin)
Thailand: Program for HIV Prevention & Treatment (Dr Gonzague Jourdain, Dr Nicole Ngo-Giang-Huong)
Ukraine: Paediatric HIV Cohort (Dr Ruslan Malyuta, Dr Galena Kiseleva)
UK & Ireland: National Study of HIV in Pregnancy and Childhood (Dr Claire Thorne)
UK & Ireland: Collaborative HIV Paediatric Study (Dr Ali Judd, Prof Di Gibb)
Europe-wide: European Collaborative Study (Dr Claire Thorne)
We thank the children and their families who participated in these cohort studies.