Jacqueline Hoare - US grants

? DESCRIPTION (provided by applicant): Oral antiretroviral (ARV) pre-exposure prophylaxis (PrEP) holds enormous potential for expanding prevention strategies for adolescents, who account for 39% of all new global infections. We urgently need to engage in exploratory research of PrEP as an adolescent prevention strategy given growing evidence on safety and partial efficacy of adult PrEP accompanied by the recent launch of initial adolescent safety trials We propose an exploratory R21 study to investigate adolescents' and clinicians' understandings of PrEP in South Africa, the country with the largest number of people living with HIV. This research can advance HIV prevention science by improving our understanding of the behavioral and social processes that may potentiate future implementation of adolescent PrEP trials, and to optimize the translation of clinical findings into public health practice through effective messaging about PrEP safety and efficacy. Adolescents undergo unique developmental milestones which are likely to influence PrEP acceptability, willingness to use or to support others' use of PrEP, understandings of messages about PrEP effectiveness, and behavioral decisions in different ways than adults. We focus on endemic settings to leverage lessons from adolescents navigating serodiscordant relationships and to capture PrEP relevant experiences of perinatally infected children who confront challenges relating to ARV adherence, balancing risk for infection of serodiscordant partners with decisions to initiate sex, and fertility desires We compare HIV-positive and HIV-negative adolescents' understandings of PrEP since acceptability, willingness to use or to support partner's use, and predicted behavioral impacts of PrEP may vary by HIV status. We explore how adolescents interpret messages of PrEP partial efficacy as derived from adult trials, and how expectations of PrEP efficacy might affect uptake, adherence, and risk compensation. We triangulate adolescent and clinician perspectives, and explore clinician's views on potential barriers and facilitators in PrEP implementation in resource-constrained endemic settings. Our immediate goals are to understand adolescent-specific factors that affect the design of safety, feasibility, and efficacy of PrEP trials for adolescents (d18 years) and to develop an initial empirical conceptual model to guide adolescent-tailored PrEP messaging to prevent behavioral disinhibition. We propose three aims: 1) to use focus groups (k = 6-10) with HIV-positive and HIV-negative adolescents to explore knowledge, acceptability, willingness to use PrEP or to support partner use, and how about PrEP education based on adult efficacy trials may influence uptake, adherence, and risk compensation; 2) to use in-depth interviews (n = 24- 32) with adolescents to explore Aim 1 topics in more depth and to probe for sensitive issues such as how stigma and disclosure might affect acceptability of PrEP; and 3) to use individual interviews (n = 20-30) with clinicians to understand opinions of PrEP, willingness to prescribe, barriers and facilitators for implementing PrEP, and how to support adherence and protective behaviors during future rollout of adolescent PrEP.

PROJECT SUMMARY/ABSTRACT Adherence to antiretroviral therapy (ART) continues to present major challenges to HIV treatment and prevention. Adherence is a particularly challenging issue for adolescents, as seen by dramatically lower rates of adherence among adolescents compared to adults. Yet, adherence is especially vital for adolescents given that adherence can improve quality of life, delay progression towards AIDS, reduce risk for horizontal or vertical transmission, and limit proliferation of drug resistant HIV. The unique developmental transitions that occur during adolescence can pose both challenges and opportunities for adherence, suggesting the need for adolescent-centered interventions. Few behavioral interventions are specifically tailored by and for adolescents on ART. Adolescent-patient-centered conditional economic incentives (CEIs) have not yet been explored as an approach towards improving adherence behaviors among adolescents. The theoretical premise of this patient- centered and behavioral economic approach is that individual decision making often favors self-actualization but needs to contend with immediate gratification and discounted future outcomes. Patient-centered CEIs contingent on a behavior or outcome can alter this calculus by allowing recipients to experience immediate benefits of a positive health behavior rather than the weaker reward of improved health in the distant future. Adolescence is an ideal developmental timepoint to utilize CEIs since behavioral patterns are being developed. As such, short-term delivery of CEIs during a critical phase might be enough to start habituation of behaviors over the long term. Adherence is an ideal behavior for habituation. The adherence literature demonstrates that early-adolescent adherence to ART predicts long-term adherence. We propose a qualitative exploratory R21 study to investigate the acceptability of CEIs as an adolescent-centered approach for improving adherence in South Africa ? the country with the largest epidemic, and the largest number of HIV-positive adolescents. We propose the following specific aims: (1) to explore with HIV-positive adolescents acceptability and willingness to use CEIs using in-depth individual interviews including how to tailor CEIs to capitalize on adolescent developmental transitions including increased independence and responsibility; how the amount, format and frequency of CEIs may influence adherence; and how to enhance durability of adherence behavior with CEIs used as a stand-alone intervention or in combination with other interventions; (2) to explore perspectives from parents and HIV clinical providers on how family and clinic environments can enhance effects and durability of CEIs on adolescent adherence; and (3) to refine design for a future CEI intervention and optimize CEIs in combination with other promising interventions through user-centered intervention design development. We incorporate qualitatively identified preferences for CEIs (from Aims 1 and 2) into a computerized quantitative survey with conjoint analysis (Aim 3). Findings will advance HIV intervention science and clinical practice for HIV-positive young people who will have the potential to live longer and healthier lives.

? DESCRIPTION (provided by applicant): DNA methylation (DNAm), an epigenetic process, is critical for neurodevelopment and for neurologic functioning throughout the lifespan. Aberrations in DNAm result in developmental, neurodegenerative, and psychiatric disorders. We have discovered that HIV+ adults have altered DNAm in both brain and peripheral blood mononuclear cells, resulting in accelerated biological aging. Perinatally HIV-infected (PHIV+) children are at increased risk of neurodevelopmental delay and lasting neurocognitive dysfunction. In this study, we examine the role of DNAm in the neurocognitive development of PHIV+ adolescents, while also considering important psychosocial, medical, virologic, and other factors. The immediate goal of this study is to delineate the complex relationship between these various factors in the pathogenesis of neurocognitive deficits in PHIV+ adolescents. The intermediate goal is to utilize the information gained to develop intervention strategies aimed at improving the lives of PHIV+ children as they progress into adulthood. The long term aim of this study is to develop a biomarker of currently concealed neuropathological processes that result from HIV, so that appropriate interventions can be provided to at-risk youths. This study will consider a host of environmental factors known to impact neurodevelopment, including stress, antiretroviral (ARV) medication use, economic adversity, medical comorbidities, and home/family environment. It will leverage the extant resource of the Cape Town Adolescent Antiretroviral Cohort (CTAAC), thereby maximizing efficiency and cost effectiveness, while minimizing human subjects' burden. The combination of cross sectional and longitudinal aims will allow fast translation of the findings and true characterization of neurodevelopmental and cognitive divergences resulting from epigenetic dysregulation due to HIV. In addition, the genome-wide methylation data generated can be used to enhance other research arms of the CTAAC, maximizing the potential return of investment. We also include a capacity building element by funding a postdoctoral fellow from UCT to be trained in biostatistics by UCLA researchers. This study is possible through the collaboration of two teams: The University of Cape Town team, which is currently carrying out the CTAAC neuro sub-study involving 200 HIV+ and 50 HIV- adolescents with diffusor tensor imaging, comprehensive neuropsychological testing, and assessment of childhood psychosocial factors, will provide all data and biological samples, as well as expertise in neuroimaging and pediatric neuroHIV. The University of California - Los Angeles team, which has extensive expertise in epigenetic biostatistical methods and genomic investigations of neuroHIV will process DNA samples and conduct the statistical analyses.

Project Summary Currently, over 30% of all new HIV infections globally are estimated to occur among youth ages 15 to 25 years. Adolescent girls are at very high risk of getting infected. This pattern is especially clear in sub-Saharan Africa, the region most severely affected by HIV/AIDS. Also, increasingly, children infected at birth grow into adolescents who have to deal with their HIV positive status. Combining the two, there are 5 million youth living with HIV(WHO). There is a global call to focus on the particular needs of youth. Youth living with HIV comprise two different sub-populations: those who are infected through sexual exposure (behaviourally infected yBHIV) and those infected through parent-to-child transmission (perinatally infected yPHIV), now surviving into young adults. Adolescence represents a critical period of brain maturation, with ongoing myelination, cortical growth and synaptic pruning. Gradual and differential maturation of the limbic system and prefrontal cortex modulates reward and affective behavior, and executive control. Substance use and HIV infection present further challenges to neurodevelopment and resilience in this vulnerable stage of development. Few studies have investigated substance use outcomes in yBHIV, or made direct comparisons by mode of infection. Studies which conflate yHIV by mode of infection may blur the substance use experiences of these two different sub-populations. The proposed study will elucidate mechanisms of substance induced neuroimmune dysfunction in youth living with HIV-1 (yHIV), who are on anti-retroviral therapy (ART), and will include youth between the ages of 15 and 21 yrs, including 200 yPHIV + 100 yBHIV + 100 healthy controls in Cape Town, South Africa. The proposed study will to follow an existing cohort of yHIV from Cape Town Adolescent Antiretroviral Cohort (CTAAC), into early adulthood in order to understand the individual and combined effects of substance use (SU) and HIV infection on brain structure and function, neurocognitive functioning and mental health. The long-term goal is to understand the drivers (structural/mental health/cognitive) of SU in youth living with HIV (yHIV) and the impact of SU on chronic HIV infection and general health including immune dysregulation, viral reservoir and other health outcomes measured in the CTAAC parent award, such as the stool microbiome, respiratory and cardiac function. The Cape Universities Body Imaging Centre (CUBIC) houses a state-of-the-art research-dedicated Siemens 3 T Skyra MRI scanner optimized for brain imaging, and unique in sub-Saharan Africa. We have developed the capability for advanced brain morphometry, spectroscopy, diffusion tensor and functional imaging. This project builds on existing successful collaborations.