Graham P Taylor Professor of Human Retrovirology/Honorary Consultant

1. Perinatal, Paediatric and
Adolescence: What are the HIV
priorities?
Graham P Taylor
Professor of Human Retrovirology/Honorary Consultant

2. PERINATAL
Abigail 18 years.
Known HIV positive 6 years.
Attending sixth-form college.
On a fixed dose combination, one tablet, once per day
Books at 22 weeks
CD4 count 220 cells/µL
HIV viral load 132,453 HIV RNA copies/ml
Non-adherentWhat is your
diagnosis?

3. PERINATAL
You offer Abigail:
CNS/ Psychology adherence support
New therapy: Tenofovir/FTC/Darunavir/ritonavir
Reviewed 26/40
HIV viral load 96,432 HIV RNA copies/ml
Non-adherent
What is your
diagnosis?

4. PERINATAL
Abigail
Eight weeks later: presents in labour
Treatment: sd Nevirapine,
double dose Tenofovir,
sd Raltegravir
Delivers vaginally
Baby treatment zidovudine/lamivudine/nevirapine
What do you want to know?
Is the baby already
infected?

5. 5
Final Results From the 6-Year Randomized CHER
(Children with HIV Early antiRetroviral) Trial in South Africa
Mark Cotton, Avy Violari, Diana Gibb, Kennedy Otwombe, Deirdre
Josipovic, Ravindre Panchia, Patrick Jean-Phillipe, Edward
Handelsman, James McIntyre and Abdel Babiker
CROI 2012

6. 6
CHER Trial
Part A n=375
HIV infection diagnosed before 12 weeks and CD4% ≥25%
ART-Deferred
Defer ART until clinical
progression or CD4%
drop
N=125
ART-40W
Early ART to 40
weeks; then STOP,
until progression
N=125
ART-96W
Early ART to 96
weeks; then STOP,
until progression
N=125
Follow: up to 6 years
Primary endpoint: time to failure of first line ART
ART (start or re-start) when CD4% <20% or clinical event
1st
-line ART: Kaletra® + ZDV+3TC
Design

7. Proportion of children on ART
7
Overall proportion of time spent on ART
ART-Def 81%
ART-40W 70%
ART-96W 69%
Week on study
ART-DefART-Def
ART-40W
ART-96W
ProportiononART

8. 0.000.250.500.751.00
Proportionreachingprimaryendpoint
126 116 111 107 106 83ART-96W
125 114 106 99 97 74ART-40W
125 97 94 91 89 72ART-Def
Number at risk
0 48 96 144 192 240
Weeks since randomisation
ART-Def ART-40W ART-96W
HR (95% CI) relative to ART-Deferred
ART-40W: 0.73 (0.46 – 1.17, p=0.19)
ART-96W: 0.58 (0.35 – 0.96, p=0.03)
ART-40/96W: 0.65 (0.43 - 0.98, p=0.04)
Time to Primary Outcome
ART-Deferred vs ART-40W vs ART-96W
Death or failure of 1st
line ART

9. Progression to severe CDC B or CDC C or death
9
0.000.250.500.751.00
Proportionwithclinicalfailure
126 105 96 89 88 68ART-96W
126 106 85 83 82 67ART-40W
125 79 72 71 70 57ART-Def
Number at risk
0 48 96 144 192 240
Weeks since randomisation
ART-Def ART-40W ART-96W
HR (95% CI) relative to ART-Deferred
ART-40W: 0.5 (0.3 – 0.8, p=0.005)
ART-96W: 0.4 (0.3 – 0.7, p=0.0003)
Proportion

10. Priority 1. Early diagnosis of infant infection
HIV infected children should be
started on ART straight away as
this prevents AIDS, death,
severe neurological sequelae
and preserves immune
function.
Paediatric European Network for Treatment of AIDS Treatment
Guideline 2016 update: antiretroviral therapy
recommended for all children living with HIV

11. What test do you want in the baby?
1. HIV Ab
2. HIV DNA
3. HIV RNA
1. HIV Ab - is a test of maternal status
2. HIV DNA – not affected by maternal or neonatal therapy
3. HIV RNA - Sensitive and increasingly available
– maternal infection detected by this method
False negative if early HIV infection has been treated
transplacentally

12. More results - outcome 1
At delivery maternal HIV viral load 4,377 HIV RNA copies/ml
Further history indicates that Abigail took Atripla intermittently
Baby: Day 1 sample HIV DNA detected
What are your treatment options?

13. Limited! - What’s available?

14. What are your treatment options?
a) pre-term and nil by mouth – ZDV IV
b) Pre-term and enterally fed –
zidovudine/lamivudine/nevirapine/lopinavir
c) Term and enterally fed -
zidovudine/lamivudine/nevirapine/lopinavir

15. Priority 2. Paediatric formulations and parenteral
formulations
(1)safe and effective ART for children,
(2)palatable and easy-to-swallow medications,
(3)fixed-dose combinations to decrease pill burden,
(4)once-a-day formulations to lengthen dosing intervals,
(5)medications that are easy to transport and store,
(6)formulations that are simple for caregivers to
administer
AIDS Res Treat. 2016; 2016: 1654938. Published online 2016 Jun 16. doi: 10.1155/2016/1654938
The Need for Pediatric Formulations to Treat Children with HIV
Adrienne F. Schlatter, Andrew R. Deathe,and Rachel C. Vreeman

16. Alternative scenario – Abigail’s baby is not infected
At delivery maternal HIV viral load 4,377 HIV RNA
copies/ml
Further history indicates that she took Atripla
intermittently
Baby: Day 1 sample HIV DNA not detected
Abigail has been taking her medications correctly for
the last two weeks
and decides to breast feed her baby

17. WHO HIV and Infant Feeding Guidelines 2016
Mothers living with HIV should
breastfeed for at least 12 months and
may continue breastfeeding for up to
24 months or longer (similar to the
general population) while being fully
supported for ART adherence.

18. Breast-feeding related HIV Transmission during ARVs
Study Intervention (PP) Transmission Rate Reference
Vit A RCT n 103
156
288
Observational study
15 months FU
Exclusive BF 25%
Never BF 20%
Mixed feeding 35%
Coutsoudis et al
AIDS 2001;15:379-
387
DREAM n 341
Mozambique
Observational study
HAART + 6/12 Excl BF
Observed 2.8%
Expected 40%
Marazzi et al, PIDJ,
2009; 28:483-7
n 441
Tanzania
Observational study
HAART + 6/12 Excl BF
6/52 4.1%
6/12 5.1%
Kilewo et al, JAIDS,
2009; 52: 406-16
n 102
Uganda
Observational study
HAART + 6/12 Excl BF
No Transmissions
19% MR
Homsy et al, JAIDS,
2010;53:28-35
Maternal n 227
Choice n 305
Breast Fed
Formula-Fed
0.5%
0 %
Peltier et al, AIDS
2009;23:2415-2413
Mma Bana n 265
Rwanda 265
RCT 170
Trizivir
CBV/Kaletra
CBV/NVP
0.7%
0 %
0 %
Shapiro et al, NEJM,
2010;362:2282-2294
BAN n 851
Malawi 848
RCT 668
CBV/NVP or Kaletra
Infant NVP
Nutritional supplements
3.0%
1.8%
6.4%
Chesale et al, NEJM,
2010;362:2271-2281

19. Efficacy of WHO recommendation for continued
breastfeeding and maternal cART
Ngoma M et al JIAS 2015;18 19352
ExclBF
Complementary
BF
COB
ZDV/3TC/LPV/Rit from 14 –
26 GA weeks to beyond
Cessation of Breast feeding

20. Priority 3. Long-term outcome data on transmission
through breast-feeding whilst on cART – what is best?

21. Adolescent HIV

22. 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 cohort
by year of follow-up, 1996-2013
>60% 16+

23. HIV is the leading cause of death among adolescents in
Africa
• Adolescence is the only age group in which AIDS
deaths increased between 2005 and 2012
• 36.7 million people living with HIV - 1.8 million
between 10-19 years old – majority perinatally
infected
• 2.1 million new HIV infections: 250,000 in 10-19
year olds in 2015
• Young women aged 15–24 years are
disproportionately affected, accounting for 20%
of all new diagnoses, even though they represent
just 11% of the adult population

24.  11 deaths
 Transfer: median age 17 yrs, CD4 120. At death: 21 yrs, CD4 27
 Causes: suicide (2), end stage AIDS (3), respiratory infections (2)
PML, CNS lymphoma, ICH and Toxoplasmosis.
 9/11 mental health diagnosis
 All had treatable virus in year of death

 11 deaths
 Transfer: median age 17 yrs, CD4 120. At death: 21 yrs, CD4 27
 Causes: suicide (2), end stage AIDS (3), respiratory infections (2)
PML, CNS lymphoma, ICH and Toxoplasmosis.
 9/11 mental health diagnosis
 All had treatable virus in year of death


25. What happens in chronic disease?
Renal transplant: 35% lost graft within 36 months of transfer
Watson A 2000
Diabetes: 10-69% no medical f/up after paediatric care
Pacaud D 1996, Frank
M 1996

26. 19.8% were LTFU in the year after turning 22 years.
Independent associations with LTFU were:
1) Receiving care at an adult versus pediatric HIV
clinic (AOR, 2.91; 95% CI, 1.42-5.93),
2) having fewer than four primary HIV visits/year
(AOR, 2.72; 95% CI, 1.67-4.42),
3) Having antiretroviral therapy prescription
(AOR, 0.50; 95% CI, .41-.60)
LTFU was prevalent at each age transition,
19.8% were LTFU in the year after turning 22 years.
Independent associations with LTFU were:
1) Receiving care at an adult versus pediatric HIV
clinic (AOR, 2.91; 95% CI, 1.42-5.93),
2) having fewer than four primary HIV visits/year
(AOR, 2.72; 95% CI, 1.67-4.42),
3) Having antiretroviral therapy prescription
(AOR, 0.50; 95% CI, .41-.60)
LTFU was prevalent at each age transition,
Agwu et al.

27. • 237 PaHIV median age 20 yrs
• median age HIV diagnosis 6 yrs
• 22% psychiatric diagnosis:
depression > psychosis > anxiety
• 25% psychological diagnosis:
anxiety, depression, self harm, risk
behaviours
• association with lower CD4 count
(p<0.002)
Marthe Le Provost – AALPHI
cohort
UK risk factors for
Adolescent Mental Health
Black ethnicity
Migrant population
Parental unemployment
Looked after child
Poverty
UK risk factors for
Adolescent Mental Health
Black ethnicity
Migrant population
Parental unemployment
Looked after child
Poverty

28. current smoking 1.32 (1.13, 1.54)
illegal drugs 1.49 (1.15, 1.92)
early sexual debut 1.33 (1.03, 1.72)
eating disorder 1.44 (1.26, 1.74)
antisocial acts 1.48 (1.26, 1.74)
attempted suicide 2.24 (1.55, 3.24)
more likely to report 3 or > 4 simultaneous behaviours
JC Suris et al, 2007 J Begent CHIVA 2010
RISK BEHAVIOURS IN YOUTH
WITH CHRONIC CONDITIONS

29. HIV TRANSITION @ Imperial

30. • 1988 Born in Romania
• 1996 Dual therapy
• 1999 Triple therapy
• Never full virological suppression
• 2001 CD4 110 - gastrostomy tube
• 2005 CD4 470, VL <50 for 4 yrs - tube out
KATIE – Childhood years

31. • 2006 DNA’d. PID, miscarriage, supportive partner
• 2006 HIV – ve son: premature
• 2007 CD4 20 - PEG
• 2008 Adherence poor despite MDT, partner, peers
• 2009 CD4 0 - Directly Observed Therapy
• 2010 VL <50, CD4 220 - lipodystrophy
• 2012 CD4 20 PCP
KATIE - Adolescence

32. Afternoons, walk-in, MDT, sexual health,
Contraception, peer support, vaccination,
social care, finances

33. OPD REMINDER
ART ALARM
ART SWITCH PIC
ADHERENCE APP
MD2Me – Generic 2/12 Web-based & text-delivered disease management and
skill-based intervention with trends towards improved transition readiness
HUANG et al PEDIATRICS
Volume 133;6, June 2014

34. ATTENDANCE
Text reminders
Walk in any Wednesday – no questions asked
If DNA; calls, texts, letters, whats app, local service, past
paediatric healthcare team, community nursing, GP
Never “discharged” due to DNA
Re-engage at crisis points – admission, transfer in if local
hospital
5/157 (3%) not seen in 900 in last year: HMP (2), agrophobia
and alcoholism (1) – home visits and bloods, contactable
by phone only (1), LTFU (1); university- GP trying to chase
LTNP

35. • New partner
• CD4 20
• DRV/r mono
5/2016
• VL <20
• CD4 582
• Aged 28
Katie
2013 -16

36. Priority 5: Long-acting ART –ECLAIR and LATTE-2
92% had SE mostly pain
Murray M et al CROI 2016
Cabotegravir Integrase Inhibitor oral
T/2 40 hours,
IM nanosuspension T/2 20-40 days
Rilpivirine (RPV) T/2 oral 50h 300mg/ml
nanosuspension IM T/2 30-90d. CAB +
RPV oral was at least as effective as
Efavirenz based triple therapy (LATTE)
Margolis D et al CROI 2014
Margolis D et al CROI 2016

37. Bridging Worlds: Perinatally infected youth in
adult care
DR CAROLINE FOSTER
IMPERIAL COLLEGE HEALTHCARE NHS TRUST LONDON
September 2016
Massive thanks to Caroline
Foster our adolescent
doctor!

38. RIVER - Research into eradication of HIV reservoirs
Early HIV
infection
Quadruple
Therapy
HIV
Vaccination
Vorinostat
‘Kick’

39. Unmask latent infection
Anatomical hidden reservoirs – gut, genitalia, brain
poor HAART penetration
Functional reservoirs - long-lived latently infected
cells
HIV infected central memory cells (TCM)
HIV infected transitional memory cells (TTM)
HIV infected T memory stem cells (Tscm)
high proliferative potential
Buzon M et al CROI 2013
NEW

40. Unmask latent infection
Histone deactelylase inhibitors
Sodium valproate
Vorinostat
B-catenin inhibitors
Stops stem cells from differentiating into
memory cells
T-cell activation
IL-2
Interferon-α2b
IL-7 – not effective in ERAMUNE

41. Histone acetylation and deacetylation

42. What was reported?
Suppression of HIV viral load with quadruple
therapy
What was described?
HIV Cure

43. ‘Functional cure’
10
100
1,000
10,000
100,000
0 5 10 15 20 25 30
Viral load
ART/care
discontinued
Months
Persaud et al. CROI 2013. Abst. 48LB

44. Virological studies to detect residual HIV
in this very-early treated child
Proviral DNA
Copies/
10*6 cells
Cells tested /well
(No replicates pos)
PBMC
24/12
26/12
<2.7
4.2
122,000 (0/2)
133,000 (1/6)
Resting CD4 T-cells
24/12
26/12
<3.5
<2.5
96,500 (0/3)
134,000 (0/6)
Enriched for
activated T-cells
24/12
26/12
< 2.2
<2.6
154,000 (0/6)
130,000 (0/6)
Monocyte-derived
adherent cells
24/12
26/12
37.6
<11.5
14,300 (1/3)
29,000 (0/6)
HIV RNA
Plasma
24/12
26/12
1 copy/ml
<2 copies/ml
n/a
n/a
Infectious virus from
resting CD4+
24/12
Not
recovered
n/a
Persaud et al. CROI 2013. Abst. 48LB