1. Neurocognitive function in perinatally HIV- infected young people and HIV-negative siblings in England Kate Sturgeon, Ali Judd, Aimie Nunn, Diane Melvin, Caroline Foster, Alan Winston, Marthe Le Prevost, Di Gibb, Alejandro Arenas-Pinto On behalf of the Adolescents and Adults Living with Perinatal HIV (AALPHI) Steering Committee

2. Background Perinatally HIV-infected children perform less well than controls on general cognitive tests, processing speed and visual/spatial tasks Few neurocognitive studies in young people –most are in younger children as part of trials –many do not have appropriate control groups –most are not longitudinal and so cannot assess change Unclear of effect of background/ upbringing compared to HIV and ART exposure

3. AALPHI Aims 5 key domains: Neurocognitive Cardiac Metabolic Sexual and reproductive health Anthropometry and bone composition

4. AALPHI Inclusion criteria HIV-infected cases (PHIV+) n=300 13-21 years Able to give informed consent/assent Living in the UK for over 6 months Willing to give a blood sample Able to speak and understand English Willing to be followed up annually for duration of the study HIV negative controls (PHIV-) n=100 13-23 years Able to give informed consent/assent Awareness of HIV in the family Living in the same household as case or have an HIV positive parent, sibling, friend or partner Living in the UK for over six months Able to speak and understand English Willing to have an HIV test Willing to be followed up annually for duration of the study

5. Methods Participants: –295 PHIV+ aged 13-21 yrs, all had UK paediatric care –90 HIV- aged 13-23 yrs, half are siblings of PHIV+ Baseline: 12 tests across 6 neurocognitive domains –Executive function –Speed of info. processing –Attention/ working memory –Speed of Learning –Visual Memory –Fine motor skills

6. Neurocognitive Tests Interview 1 DomainNeurocognitive Test Executive functionCogstate groton maze Color Trails 2 Speed of information processingCogstate detection task Color Trails 1 Attention/working memory Cogstate Identification WAIS-IV coding Speed of learningCogstate One Card Learning International Shopping List Visual memoryCogstate International shopping list delayed One back test Fine motor skillsGrooved pegboard

7. Analysis z-scores calculated using normative manufacturer data for each test and averaged per cognitive domain –z-score > 0 = above average function compared to norms –z-score < 0 = below average function compared to norms NPZ-6 = mean z-score across all 6 domains Predictors of NPZ-6 using linear regression –A priori: age, sex, ethnic, born outside UK, AIDS (CDC-C) –Psychosocial: death of parents, fostered/adopted, current education/employ, who living with, whether parent in work –Alcohol, smoking and drugs, anxiety/depression (HADS) –PHIV+ only: year 1 st presented, nadir & current CD4, cumulative yrs VL<400c/ml, age starting ART, current ART status, current EFV use

8. Characteristics of PHIV+ and HIV- PHIV+ (n=295)HIV- (n=90) % or median [IQR] Male42%31% Age16 [15, 18]16 [14,18] Black African ethnicity85%72% Born outside UK78%60% Occupation School80%70% Employment14%26% Neither6%4% Live with parents91%88% Death of one/both biol. parents36%26% Fostered/adopted11%0%

9. Clinical parameters for PHIV+ No CDC C (n=218)CDC C (n=76) % or median [IQR] Year 1 st in UK services Pre-199616%21% 1997-200020%34% 2001 +64%45% Age at ART initiation8.0 [5.2, 12.0]3.8 [1.4, 6.2] Age at first CDC event-3.0 [0.5, 6.4] ART status at last visit Naïve12%0% On cART83%95% Off cART5% VL>50 at last visit (on cART)21%32% CD4 at last visit582 [408, 769]641 [422, 873]

10. Neurocognitive performance by domain/CDC Cognitive domainp-value Executive function 0.027 Speed of info. processing 0.019 Attention/working memory 0.534 Speed of learning 0.014 Visual memory <0.001 Fine motor skills 0.020 Summary NPZ-6 0.002 HIV- PHIV+ (no CDC C) PHIV+ (CDC C) better performance poorer performance Data are mean z-scores with 95% CIs

11. Multivariable factors associated with NPZ-6 p-value PHIV+ (no CDC C) v. HIV- 0.887 PHIV+ (CDC C) v. HIV- 0.001 Age at study entry (per year increase) 0.005 Female v. male 0.722 Black v. white ethnicity <0.001 Born outside v. in UK 0.472 Death of one parent v. parents alive 0.278 Death of both parents 0.012 Depression (per point increase in severity on HADS scale) 0.014 better performancepoorer performance Results are the same when patients with encephalopathy (n=11) are excluded Results are the same when model is restricted to PHIV+ only (no effect of CD4, age started ART, current EFV use)

12. DomainInterview 1Interview 2 Executive Function CogstateGroton mazeNIH ToolboxFlanker Inhibitory Control & Attention test Color TrailsColor Trails 2NIH ToolboxDimensional Change Card Sort Test Speed of info processing CogstateDetection taskNIH ToolboxPattern Comparison Processing Speed test Color TrailsColor Trails 1 Attention/concent ration CogstateIdentificationNIH ToolboxFlanker Inhibitory Control & Attention test WAIS-IVCoding Learning CogstateOne card learningHVLT-RTotal recall CogstateInternational shopping list Memory CogstateInt. shopping list delayedHVLT-RDelayed recall CogstateOne back task Working memory NIH ToolboxList Sorting Episodic Memory NIH ToolboxPicture Sequence Test Fine motor skillsPegboardGrooved Pegboard Language WIAT IIReading British Picture Vocabulary Test

13. Discussion PHIV+ & HIV- scored worse than population norms –CogState norms are largely Australian caucasian males PHIV+ CDC C had the poorest performance –many presented with AIDS and started ART after PHIV+ with no CDC C scored similarly to HIV- overall Other differences were due to non-HIV factors: –Most black African participants were born in Africa before cART was available and from many different countries; varying age at entry to UK & degree of cultural adjustment –Death of both parents, and depression, also associated with poorer scores Impact on day-to-day life needs further investigation

14. Anxiety and depression in AALPHI Measured using the Hospital Anxiety and Depression Scale (HADS) In a multivariable model adjusted for UK norms (YP aged 25-29)*: –No difference in scores between PHIV+ and HIV- or UK norms *Breeman - QualLifeRes 2015;24:39108 ) AnxietyDepression Increased anxiety (lower z scores) : -Death of both parents -Reported ever thinking life not worth living Increased depression: -Death of one or both parents Lower anxiety (higher z score): -Higher self-esteem (Rosenburg) -Higher quality of life (PedsQL) Lower depression: -Female sex -Higher self-esteem -Higher quality of life

15. We thank all young people, parents and staff from the clinics and voluntary services in AALPHI. UCL Project team: A. Judd, M. Le Prevost, A. Mudd, A. Nunn, K. Rowson, K. Sturgeon. Investigators: M. Conway, K. Doerholt, D. Dunn, C. Foster, D. Gibb, A. Judd (PI), S. Kinloch, N. Klein, H. Lyall, D. Melvin, D. Pillay, K. Prime, T. Rhodes, C. Sabin, M. Sharland, C. Thorne, P. Tookey. UCL Data Services: C. Diaz Montana, K. Fairbrother, M. Rauchenberger, N. Tappenden, S. Townsend. Neurocognitive subgroup: A. Arenas-Pinto, C. Foster, A. Judd, D. Melvin, A. Winston. Steering Committee chairs: D. Gibb, D. Mercey NHS clinics (named alphabetically): LONDON: Chelsea and Westminster NHS Foundation Trust, F. Boag, P. Seery; Great Ormond Street Hospital NHS Foundation Trust, M. Clapson, V. Noveli; Guys and St Thomas’ NHS Foundation Trust, A. Callahgan, E. Menson; Imperial College Healthcare NHS Trust, C. Foster, A. Walley; King’s College Hospital NHS Foundation Trust, E. Cheserem, E. Hamlyn; Mortimer Market Centre, Central and North West London NHS Foundation Trust, R. Gilson, T. Peake; Newham University Hospital, S. Liebeschuetz, R. O’Connell; North Middlesex University Hospital NHS Trust, J. Daniels, A. Waters; Royal Free London NHS Foundation Trust, T. Fernandez, S. Kinloch de Loes; St George’s University Hospitals NHS Foundation Trust, S. Donaghy, K. Prime. REST OF ENGLAND: Alder Hey Children’s NHS Foundation Trust, S. Paulus, A. Riordan; Birmingham Heartlands, Heart of England NHS Foundation Trust J. Daglish, C. Robertson; Bristol Royal Infirmary, University Hospitals Bristol NHS Foundation Trust, J. Bernatoniene, L. Hutchinson, University Hospitals Bristol NHS Foundation Trust, M. Gompel, L. Jennings; Leeds Teaching Hospitals NHS Trust, M. Dowie, S. O’Riordan; University Hospitals of Leicester NHS Trust, W. Ausalut, S. Bandi; North Manchester General Hospital, Pennine Acute Hospitals NHS Trust, P. McMaster, K. Rowson; Royal Liverpool and Broadgreen University Hospitals NHS Trust, M. Chaponda, S Paulus. Voluntary services (named alphabetically): Blue Sky Trust, C. Dufton, B. Oliver; Body and Soul, A. Ash, J. Marsh; Faith in People, I. Clowes, M. Overton; Positively UK, M. Kiwanuka, A. Namiba; Positive Parenting & Children, N. Bengtsson, B. Chipalo. Funding: Monument Trust and PENTA Foundation. a.judd@ucl.ac.uk