1. CHVI Team Grant in HIV Vaccine Discovery and Social Research: Barriers to engaging young people in HIV vaccine trials in a priority setting “ Developing a multi-disciplinary strategy to examine HIV risk and clinical outcomes in South African adolescents” Mark A. Brockman (Simon Fraser University, Canada) Glenda Gray (Perinatal HIV Research Unit, Soweto, South Africa) Thumbi Ndung’u (Univ of KwaZulu-Natal, South Africa) Angela Kaida (Simon Fraser University, Canada) Jeremy Snyder (Simon Fraser University, Canada)

2. South Africa remains at the center of the HIV/AIDS epidemic ~5.6 million individuals are currently living with HIV HIV prevalence rate in adults (15-49 yrs) is 17.3% (national) Sentinel surveys of pregnant women in Gauteng (Soweto) and KwaZulu-Natal (Durban) indicate prevalence rates >40% HIV prevalence in adolescents aged 15-19 yrs (>15%) is among the highest in the world (UNAIDS, 2011) HIV in South Africa

3. ~50% of new HIV infections in South Africa occurs among individuals aged 15-24 yrs Young women are at particular risk: ~30% give birth before the age of 20 yrs Often in relationships with older male partners ~15% of South African females aged 15-24 yrs are living with HIV Adolescents and young adults (AYA) (aged 15-24) are therefore a key target population for HIV vaccine and prevention efforts Implementing effective approaches for this age group is likely to require detailed sociological and biomedical understanding of local epidemics, as well as novel engagement and retention strategies Adolescents and Young Adults (AYA)

4. Risk of HIV acquisition, and clinical outcome, in AYA is likely to be influenced by a complex array of social, behavioural, and biological determinants. However, a lack of high quality, population-based, linked social/behavioural, clinical, and biomedical datasets for high-risk AYA populations have hampered efforts to identify these factors in detail. Such data is likely to be critical to the future success of HIV vaccine studies that target this important population. Problem Statement

5. Goal: To implement cohort-based strategies to examine barriers and knowledge gaps that hinder engagement of AYA in HIV vaccine research and prevention trials. Our multi-disciplinary team of social, ethical, clinical, and biomedical researchers will address the following four objectives: A.Infrastructure and capacity: Develop prospective cohorts of high-risk South African adolescents to support multi-disciplinary HIV prevention research. B.Ethics and community: Develop culturally appropriate strategies to obtain youth consent and understand community attitudes towards youth participation in HIV prevention research trials. C.Social science: Understand social/behavioural determinants of HIV risk in AYA and identify unique barriers to participation in HIV vaccine trials. D.Biomedical science: Identify biological factors associated with HIV risk in AYA and examine the influence of host and viral genetics, biology, and immunology on the natural infection course in youth. Goal and Objectives

6. Leads: Glenda Gray (PHRU) and Thumbi Ndung’u (UKZN) Members: Mammekwa Mokgoro and Manjeetha Jaggernath (UKZN); Fatima Laher, Erica Lazarus, and Sakhile Mhlongo (PHRU) Programme Aim #1 To develop prospective cohorts of high-risk South African AYA with enhanced capacity to undertake multi-disciplinary research. Target enrolment (400 AYA, ages 16-24) 300 HIV-negative sexually active AYA (150 Soweto, 150 Durban) 100 HIV-positive sexually active AYA (50 Soweto, 50 Durban) Intended follow-up: 2 years Referrals for male circumcision, family planning, special counselling Baseline and bi-annual HIV/STI testing, surveys, and counselling More frequent follow-up of HIV+ and HIV incident cases Nested short-term biomedical research studies (~30 days) Collect linked social/behavioural, clinical, and biomedical data for participants Our Team: Cohorts and Infrastructure

7. Leads: Jeremy Snyder (SFU) and Cathy Slack (UKZN) Members: Busiswe Nkala (PHRU); Maud Mthembu (UKZN); Anita Ho (UBC) Programme Aims #2 and #3 To develop culturally and ethically appropriate strategies for obtaining informed consent of adolescents and young adults. To assess stakeholder concerns associated with enrolling youth in HIV research and barriers to delivering future HIV vaccines to adolescents. Stakeholder meetings in the community (parents, schools, etc) Informed consent, parental notification, confidentiality Mucosal sampling; host genetics/genomics Regulatory issues, REBs Our Team: Ethics and Community

8. Leads: Angela Kaida (SFU) and Glenda Gray (PHRU) Members: Janan Dietrich (PHRU); Mammekwa Mokgoro and Maud Mthembu (UKZN); David Bangsberg (MGH); Robert Hogg and Cari Miller (SFU) Programme Aims #4 and #5 To understand complex social, behavioural, and cultural factors associated with risk of HIV acquisition among AYA in South Africa. To assess social and cultural barriers preventing participation by South African AYA in HIV prevention research and vaccine trials. Bi-annual surveys and interviews for mixed-methods data collection Determine predictors of retention success Identify preferred communication methods Validate measures of HIV prevention knowledge and counselling Our Team: Social and Behavioural Science

9. Leads: Mark Brockman (SFU) and Thumbi Ndung’u (UKZN) Members: Glenda Gray, Fatima Laher (PHRU); Lynn Morris, Caroline Tiemessen (NICD); Tom Hope (NU); Jo-Anne Passmore (UCT); David Knipe (HMS); Richard Harrigan, Art Poon (BC CfE); Zabrina Brumme, Masa Niikura, Ralph Pantophlet (SFU) Programme Aims #6, #7, and #8 To examine the prevalence of non-HIV pathogens and consequence on mucosal immune activity in HIV-negative South African AYA. To identify host and viral genetic factors associated with risk of HIV acquisition and early disease course. To evaluate the contribution of innate and adaptive host immune factors on HIV acquisition and early disease course. Our Team: Biomedical Science

10. Progress and Current Activities: Team meeting held in Durban (June, 2012) Discussed and prioritized research aims Sub-contracts/funding agreements have been signed with all sites Completing Ethics protocol for submission at PHRU (due: Feb 1 st ) Anticipated first enrollment date June 1 st, 2013 Preparing Ethics application materials at UKZN (Spring submission) Challenges “Economy”: closure of prior cohorts (funded through other programs) required us to start from scratch Delays due to administration of invoicing and “indirect” costs to South African sites Activities and Challenges

11. Better stakeholder knowledge and community interactions Improved understanding of how HIV risk behaviours may change over time among South African AYAs Potential social/behavioural differences between sites Strategies to improve recruitment and retention of AYA in trials Baseline data for mucosal and peripheral inflammation in AYA Potential genetic, co-infection, and/or behavioural factors Impact on HIV risk Identification of linkages between behaviour and biology Anticipated Outcomes

12. Thank you! Angela Kaida, Jeremy Snyder, Zabrina Brumme, Robert Hogg, Masahiro Niikura, Ralph Pantophlet, Laura Cotton Thumbi Ndung’u, Manjeetha Jaggarnath, Mammekwa Mokgoro Glenda Gray, Fatima Laher, Janan Dietrich, Sakhile Mhlongo, Busiswe Nkala Lynn Morris, Caroline Tiemessen

13. HIV negative at entry (n=300): Counseling X (X) X (X) X (X) X SurveyX X X X Blood Panel X HIV Rapid Test X (X) X (X) X (X) X PBMC/PlasmaX X STI testingX X X X REFERRALS FOR: Male circumcision Special counseling/family planning NESTED RESEARCH PROJECTS: Baseline STI prevalence Mucosal inflammation Immune response to other infections/vaccines HIV Rapid Test Positive HIV Early Cohort (12m)(6m)(18m) ++ (Entry)

14. HIV + at entry (Chronic cohort) (n=100): (12m)(6m)(18m) ++ Counseling X X X X X X X Survey X X X X Blood Panel X PBMC/Plasma X X X X X X CD4/pVL X X X X STI serology X (X) REFERRALS FOR: ARVs and co-infections Special counseling/family planning NESTED RESEARCH PROJECTS: Baseline STI prevalence in HIV+ vs Negative Inflammation (CVL) Estimated date of infection (viral diversity) Tissue biology/immunology HIV diversity; plasma vs. semen (men) or CVL (women) Mucosal antibodies Molecular epidemiology of subtype C Viral fitness (Entry)

15. HIV Rapid Test + (Incident cases; n=5/yr?): (12m)(6m)(18m) ++ HIV Rapid Test X Counseling X X X X X X X X X Survey X X X X X X X PBMC/Plasma X X X X X X X X STI (?) X X X X REFERRALS FOR: ARVs and co-infections Special counseling/family planning NESTED RESEARCH PROJECTS: Estimated date of infection (viral diversity) Genetics/fitness of transmitted virus (vs. partner?) Impact of existing inflammation/STIs Host genetics/genomics (HLA, KIR, etc) Early viral evolution and host immunity (1-2-3m) (+)