1. The global epidemiology of perinatally HIV-infected adolescents:
a Collaborative Initiative for Paediatric HIV Education & Research (CIPHER)
Global Cohort Collaboration analysis
Amy Slogrove, Ali Judd, Valeriane Leroy for the
CIPHER Global Cohort Collaboration Adolescent Project Team
Good afternoon ladies & gentlemen. I am very pleased to share this analysis of the epidemiology of perinatally HIV-infected adolescents on behalf of the CIPHER global cohort collaboration adolescent project team
AIDS 2016, Durban, South Africa

2. Background Global access to antiretroviral therapy (ART) is expanding
Emerging population of perinatally HIV-infected adolescents (PHA) across all regions
HIV-infected adolescents face barriers compared to adults
Access to ART
Remaining in care
Access to ART is expanding across the globe, resulting in an emerging population of perinatally HIV-infected adolescents across all regions of the world.
HIV-infected adolescents face major barriers compared to HIV-infected adults, specifically in access to ART and remaining in care

3. Objective & Definitions
Primary Objective
Describe the global epidemiology and geographic trends of characteristics and outcomes (mortality, transfer out, loss to follow-up) of PHA surviving beyond age 10 years
Definitions
PHA – entered care before age 10 years, with no known non-vertical route of HIV-infection and were followed beyond age 10 years
Lost to follow-up (LTFU) – last visit >365 days prior to database closure; censored 365 days after last visit
The primary objective of this study is to describe the global epidemiology and geographic trends of characteristics and outcomes, specifically mortality, transfer and loss to follow-up, of perinatally HIV-infected adolescents surviving beyond age 10 years.
PHA were defined as HIV-infected children who entered care before age 10 years, as a proxy for perinatal HIV-infection, in addition had no known non-vertical route of HIV-infection and had at least one visit beyond age 10 years.
Adolescents were considered as lost to follow-up if their last visit was more than 365 days prior to database closure, and were censored at 365 days after last visit.

4. Methods CIPHER Global Cohort Collaboration
Individual retrospective data from 12 cohort networks were pooled, representing 50 countries
South America & Caribbean: CCASAnet
North America: IMPAACT & PHACS
Europe & Central Asia: EPPICC
South & Southeast Asia: EPPICC, IeDEA - Asia-Pacific, MSF
Sub-Saharan Africa: BIPAI, IeDEA - Central Africa, IeDEA - East Africa, IeDEA - Southern Africa, IeDEA - West Africa, MSF, Optimal Models (ICAP)
Through the CIPHER Global Cohort Collaboration, individual retrospective data from 12 cohort networks across 5 regions of the world and representing 50 countries were pooled.

5. Methods
Describe characteristics at first visit, ART start, age 10 years and last visit compared by region
Cumulative incidence for outcomes calculated by competing risks analysis (mortality, transfer out, loss to follow-up)
Mortality hazard ratios - Cox proportional hazards regression
This introductory analysis describes characteristics at first visit, ART start, age 10 years and last visit by region.
Outcomes were compared as cumulative incidence functions calculated by competing risks analysis to be able to estimate mortality in the presence of high rates of transfer and loss to follow up.
Mortality was compared across regions by hazard ratios from Cox proportional hazards regression. Adjusted hazards ratios were calculated using only complete cases without missing data as well as using all cases following multiple imputation for missing CD4 and height measurements.

6. South America & Caribbean
Perinatally HIV-infected
Adolescents
Total
N =
Female 50.6%
North America
1 032 (3%)
Female 50.1%
Europe & Central Asia
3 054 (8%)
Female 51.7%
South & SE Asia
2 902 (8%)
Female 50.1%
In total adolescents were included, 79% from sub-Saharan Africa, 8% each from Europe & Central Asia and South & SE Asia, with smaller contributions from North America and South America & Caribbean.
Just over half of the adolescents in each region were female
South America & Caribbean
903 (2%)
Female 53.8%
Sub-Saharan Africa
(79%)
Female 50.5%

7. South America & Caribbean
Median (IQR) year of birth
Total
Year 2000
(1998; 2002)
North America
Year 1994
(1992; 1996)
Europe & Central Asia
Year 1995
(1991; 1999)
South & SE Asia
Year 2001
(1999; 2002)
The median year of birth for this adolescent cohort was the year 2000, ranging from a median year of 1994 in North America to 2001 in South & Southeast Asia
South America & Caribbean
Year 1998
(1995; 2000)
Sub-Saharan Africa
Year 2000
(1999; 2002)

8. Age: Median (IQR) Age in Years First Visit ART Start Last Visit 15 6.75 10 15
Age in Years
6.7
(4.4; 8.4)
7.5
(5.2; 9.2)
12.4
(11.1; 14.4)
This slide shows the age of adolescents at the 3 key time points, first visit, ART start and last visit.
To orientate you to the graphics, the bar to the extreme left of each group represents the total cohort, with each region then represented individually to the right, and the horizontal red line indicates age 10 years.
The median age at first visit for the total cohort was 6.7 years, ranging from a median of 8 months in North America to 7 years in sub-Saharan Africa.
At ART start the median age for the total cohort was 7.5 years ranging from a median of 1 year in North America to 8 years in sub-Saharan Africa.
Adolescents were followed to a median age of 12.4 years ranging from just over 12 years in Africa to 16.5 years in Europe. This indicates that for most regions we are only describing very early adolescence.
First Visit
ART Start
Last Visit

9. CD4 Percent: Median (IQR)10 20 30 40
CD4 percent (%)
Corresponding with the variation in age at first visit and ART start is also wide variation in CD4% at these 2 time points, ranging from a median CD4 of 10% in S&SE Asia to 30% in North America.
By age 10 years and last visit there was far less heterogeneity across regions with median CD4% in all regions greater than 25%.
16%
(9; 25)
28%
(20; 34)
14%
(8; 20)
(21; 35)
First Visit
ART Start
Age 10 Years
Last Visit

10. CD4 Percent: Median (IQR)10 20 30 40
On ART
29% (21; 35)
CD4 percent (%)
Not on ART
25% (19; 32)
Focussing on the far right panel, this now shows CD4% at last visit by adolescents on ART or not at their last visit, and as expected CD4% is somewhat lower at a medina of 25% in those not on ART compared to median 29% in those on ART at their last visit.
First Visit
ART Start
Age 10 Years
Last Visit

11. Proportion on ART % on ART First Visit Age 10 Years Last Visit
88% (33 514)
Ever received ART 50 10 30 20 40 60 70 80 90
80%
(30 072)
67%
(26 953)
% on ART
This slide represents the proportion of children on ART at the 3 time points. 88% of children received ART at some stage. At age 10 years 2/3 of adolescents were on ART and 80% were on ART at their last visit. Of those not on ART at their last visit, 62% were ART naïve and 38% were ART experienced, but no longer on ART at last visit.
12% (4037) of those ever receiving ART started > 10 years of age. 8%
(3 091)
First Visit
Age 10 Years
Last Visit

12. Virologic Suppression
HIV viral load available in 39% of adolescents on ART
75%
(6 627/8 825)
72%
(9 388/13 114) 50 10 30 20 40 60 70 80
% Suppressed
Only 39% of adolescents that received ART had an HIV viral load measurement. Within this sub-group 75% at age 10 years and 72% at their last visit had an HIV viral load below 400 copies/ml or below the threshold of detection for the test at the time.
Age 10 Years
Last Visit

13. WHO Height-for-Age Z-score (HAZ)1 -1 -2 -3
Median (IQR) HAZ
Growth, measured by WHO height-for-age Z-score was severely impaired and in all regions HAZ at first visit and ART start fell well below the WHO Z-score of zero, indicated by the red horizontal line. By age 10 years and last visit some recovery was seen in North America and Europe, but substantial impairment remained particularly in S&SE Asia and SSA.
-1.92
(-2.91; -0.97)
-1.95
(-2.91; -1.02)
-1.53
(-2.35; -0.72)
-1.59
(-2.45; -0.72)
First Visit
ART Start
Age 10 years
Last Visit

14. WHO Height-for-Age Z-score (HAZ)1 -1 -2 -3
On ART
-1.58
(-2.43; -0.72)
Median (IQR) HAZ
Not on ART
-1.62
(-2.50; -0.72)
Focussing again on the far right panel, this now shows height-for-age Z-score by those on ART or not at their last visit, with very little difference between these two groups; median z-score of in those on ART compared to in those not on ART at last visit.
-1.59
(-2.45; -0.72)
First Visit
ART Start
Age 10 years
Last Visit

15. Outcomes: Total Cohort
Transferred out
15.6%
(95% CI 15.1; 16.0)
Cumulative Incidence Function
LTFU
11.3%
(95% CI 10.9; 11.8)
For the total cohort, between 10 and 15 years of age, cumulative incidence for observed mortality (in blue) was 2.6%, LTFU (in green) was 11.3% and transfer out (red) was 15.6%
Mortality
2.6%
(95% CI 2.4; 2.8%)
Time in years from age 10

16. South America & Caribbean
Outcomes: by Region
All PHA
North America
South America & Caribbean
Transferred Out
Cumulative Incidence Function
LTFU
Mortality
Europe
South & Southeast Asia
Sub-Saharan Africa
This slide shows the cumulative incidence curve for each region with the curve for all adolescents in the upper left panel for comparison, the red dashed horizontal line indicating 5%.
Mortality between 10 and 15 years of age was below 5% in all regions, with LTFU and transfers out close to 5% in most regions except SSA, in the bottom far right panel, where transfers (in red) reached almost 20% by age 15 years and LTFU (in green) approximately 13%.
Time in years from age 10

17. Mortality Hazard Ratios
Unadjusted HR
(95% CI)
Adjusted HR*
Total N
38 187
Europe & Central Asia
1.00
North America
1.70 (0.87; 3.31)
2.18 (1.11; 4.31)
South & Southeast Asia
3.21 (2.03; 5.07)
1.75 (1.06; 2.89)
South America & Caribbean
6.07 (3.88; 9.50)
4.52 (2.85; 7.18)
Sub-Saharan Africa
4.35 (3.02; 6.28)
2.53 (1.65; 3.88)
The unadjusted hazards for mortality was significantly elevated in South & Southeast Asia, South America & Caribbean & Sub-Saharan Africa relative to Europe

18. Mortality Hazard Ratios
Unadjusted HR
(95% CI)
Adjusted HR*
Total N
38 187
Europe & Central Asia
1.00
North America
1.70 (0.87; 3.31)
2.18 (1.11; 4.31)
South & Southeast Asia
3.21 (2.03; 5.07)
1.75 (1.06; 2.89)
South America & Caribbean
6.07 (3.88; 9.50)
4.52 (2.85; 7.18)
Sub-Saharan Africa
4.35 (3.02; 6.28)
2.53 (1.65; 3.88)
The adjusted model, presented in the last column, takes into consideration the marked differences by region in age, CD4 and height at the first visit, as well as differences in calendar period of birth across regions, all factors determining mortality. I would like to preface the presentation of this adjusted model with the fact that this is still a preliminary analysis and there are a number of regional differences, particularly related to changes over time that we are still finding solutions to dealing with in the analysis.
That said, in this adjusted model there is an increase in the HR for North America, but for the remaining 3 regions there are reductions in the mortality hazards after adjusting for baseline differences. Nevertheless, adolescents in South & Southeast Asia, South America & the Caribbean and Sub-Saharan Africa remain at a substantially elevated hazard of mortality compared to European adolescents, despite surviving to 10 years of age.
* Preliminary multivariable model: adjusted for gender, calendar period of birth, age at first visit, CD4% at first visit, HAZ at first visit

19. Discussion Survivor cohort that beat the odds
Limited to PHA that presented before 10 years of age
At first visit and ART start, age & CD4% differed substantially by region
By 10 years and at last visit, CD4% , proportion on ART and proportion virologically suppressed were similar across regions
Height growth remained severely impaired in most regions even in those receiving ART
Observed mortality < 3% during adolescence in PHA surviving to 10 years of age should be considered as a conservative estimate
Mortality during adolescence is substantially elevated for perinatally HIV-infected adolescents in South America & Africa relative to Europe
In interpreting these findings it needs to be born in mind that this is a survivor cohort, and that in most regions these are children that beat the odds for their generation and made it to adolescence. Also important to note is that this analysis was limited to adolescents that did present before age 10 years and excludes the important group of perinatally HIV-infected adolescents that are still only being identified and diagnosed after age 10 years.
In this context we see that there was substantial variation by region in age and CD4% at first visit and ART start. However by age 10 years and last visit, CD4%, proportion on ART and proportion virologically suppressed were similar across regions.
Height growth remained severely impaired even in adolescents receiving ART.
Loss to follow-up was high in SSA, and observed mortality of less than 3% during adolescence should be considered as a conservative estimate in light of probable under-ascertainment of mortality as well as the relatively short duration of follow-up only capturing early adolescence for most PHA.
Despite probable under-ascertainment of mortality in Africa, perinatally HIV-infected adolescents in Africa remain at a substantially elevated hazard of mortality during adolescence relative to their European peers as do adolescents in South America & the Caribbean.

20. Adolescent Project Team
Co-chairs: Ali Judd (EPPICC) and Valeriane Leroy (IeDEA-West-Africa)
Data center: Mary-Ann Davies, Michael Schomaker, Amy Slogrove
Data managers: Sebastian Wanless, Charlotte Duff
Members:
BIPAI (Baylor): Nancy Calles
CCASAnet: Jorge Pinto
EPPICC: Josiane Warszawski
IeDEA Asia-Pacific: Kulkanya Chokephaibulkit
IeDEA Central Africa: Marcel Yotebieng
IeDEA East Africa: Kara Wools-Kaloustian
IeDEA Southern Africa: Nicky Maxwell
IeDEA West-Africa: François Eboua
IMPAACT: Paige Williams
MSF: Jihane Ben-Farhat
Optimal Models (ICAP): Chloe Teasdale
PHACS: George Seage

21. Acknowledgements International AIDS Society CIPHER Steering Committee
CIPHER Global Cohort Collaboration Oversight Group
Marissa Vicari – Manager, CIPHER
UCT CIDER Data Centre
Mary-Ann Davies, Michael Schomaker, Dolphina Cogill, Nicky Maxwell
Networks
BIPAI, CCASAnet, EPPICC, IeDEA-Asia-Pacific, IeDEA-Central Africa, IeDEA-East Africa, IeDEA-Southern Africa, IeDEA-West Africa, IMPAACT, MSF, PHACS, Optimal Models

23. LTFU-Mortality Scenarios
Reference = Europe
Original HR estimate A
100% of all LTFU is mortality B
50% of all LTFU is mortality C
20% of all LTFU is mortality D 1 5 10

24. LTFU-Mortality Scenarios
Reference = Europe
Original HR estimate A
50% of LTFU in Africa & 5% of LTFU rest B
20% of LTFU in Africa & 5% of LTFU rest C
5% of LTFU in Africa & 20% of LTFU rest D 1 5 10

25. Mortality Hazard Ratios
Unadjusted HR
(95% CI)
Complete Cases Only
Adjusted HR*
Multiple Imputation
Total N
38 187
10 302
Europe & Central Asia
1.00
North America
1.70 (0.87; 3.31)
2.63 (0.67; 10.41)
2.18 (1.11; 4.31)
S&SE Asia
3.21 (2.03; 5.07)
1.77 (0.57; 5.47)
1.75 (1.06; 2.89)
South America & Carib
6.07 (3.88; 9.50)
3.75 (1.14; 12.36)
4.52 (2.85; 7.18)
Sub-Saharan Africa
4.35 (3.02; 6.28)
4.10 (1.51; 11.13)
2.53 (1.65; 3.88)
* Adjusted for gender, calendar period of birth, age at first visit, CD4% at first visit, HAZ at first visit

26. Mortality Hazard Ratios
Unadjusted HR
(95% CI)
Complete Cases Only
Adjusted HR*
Multiple Imputation
Total N
38 187
10 302
Sub-Saharan Africa
1.00
Europe & Central Asia
0.23 (0.16; 0.33)
0.24 (0.09; 0.66)
0.40 (0.26; 0.61)
North America
0.39 (0.22; 0.69)
0.64 (0.18; 2.33)
0.86 (0.44; 1.68)
S&SE Asia
0.74 (0.55; 1.00)
0.43 (0.23; 0.81)
0.69 (0.51; 0.94)
South America & Carib
1.39 (1.03; 1.88)
0.92 (0.36; 2.34)
1.79 (1.28; 2.50)
HR with Africa as reference – models the same as in main presentation
* Adjusted for gender, calendar period of birth, age at first visit, CD4% at first visit, HAZ at first visit