SBS Department Overview:

The Social and Behavioral Sciences department (SBS) at Rakai Health Sciences Program (RHSP) focuses on gathering and analyzing qualitative research data (non-numerical data) to understand human behavior, attitudes, beliefs, and motivations. Overall, it enriches the understanding of human behavior, informing strategic decisions, and advancing knowledge in the field of HIV through rigorous inquiry.

Aims of the department:

Long-term impact of universal treatment and dolutegravir on population HIV virologic and incidence outcomes in Africa

Background

HIV treatment in Africa has evolved dramatically in recent years with the rollout of Universal Test-and-Treat (UTT). However, despite universal test and treat rollout, HIV incidence has declined only modestly, with no African country on track to meet UNAIDS 2030 targets for epidemic control. Control efforts are challenged by substantial numbers of “hard-to-engage” HIV-positive persons who remain viremic2 . Relatedly, there have been significant increases in HIV drug resistance (HIVDR) with expanded antiretroviral therapy (ART). The growing threat of HIIV drug resistance propelled the recent roll-out of Dolutegravir (DTG), an integrase inhibitor with a high barrier to resistance. While Universal test and treat and Dolutegravir may result in lower rates of viremia and HIVDR, there is considerable uncertainty about the magnitude and durability of their population-level impact, especially in the context of the coronavirus disease 19 (COVID-19) global pandemic, which was disrupting African HIV prevention and treatment programs supported by the United States President’s Emergency Plan for AIDS Relief (PEFAR).

To address these issues, we are conducting the Longitudinal Viral Load and Epidemiological Watch (LONGVIEW) Study, a population-level, prospective assessment of durable viral load (VL) suppression (i.e., sustained suppression over the life course), HIVDR, and incidence before and after COVID-19 emergence in southcentral Uganda. This study is nested within the Rakai Community Cohort Study (RCCS), a prospective, population-based study of ~20,000 persons, aged 15-49 years, in 40 communities with HIV prevalence ranging from ~9 to 40% and ~20% transmitted HIVDR. We measure Viral loads and perform deep sequence viral phylogenetics on all HIV-seropositive participants over 7 surveys (n~3800 per survey) conducted between 2013 and 2025, spanning roll-out of Universal test and treat in 2017, Dolutegravir in 2019, and emergence of COVID-19 in 2020.

Objectives

Aim 1 – This study will quantify population and individual trends in viremia and HIV drug resistance.

Aim 2 - assess the impact COVID-19 on HIV treatment seeking, utilization, and provision of care

Aim 3 - measure population HIV incidence trends as well as transmission risk across the infection and care continuum

Our overarching hypothesis is that despite UTT and DTG rollout, the COVID-19 pandemic will disrupt HIV services resulting in significant declines in durable population VL suppression, increases in HIV-DR, including emergence of DTG resistance, and rising HIV incidence.

The Longview study follows individuals who are in the Rakai community cohort study who are HIV positive and virally unsuppressed according to the Ugandan national guidelines. These individuals are categorized into those who are newly diagnosed (group 2), with previous diagnosis however never been on ART (group 3) and then those who are currently or have ever been on ART but are virally unsuppressed. These participants are followed up and an interview is conducted to establish if these clients are in care plus the facility of HIV/AIDs care and treatment and if not yet in care, then reasons for this are cited. There after clinical data about the identified participants at their respective clinics is extracted using a questionnaire identifying if they are active in care or defaulting, past & current ART regimens, CD4, current Viral loads, differentiated service delivery models and time spent on ART at the facility. We also provide counselling basing on their viral load.

International Epidemiology Databases to Evaluate AIDS (IeDEA) Consortium

Introduction

IeDEA collects observational data representing over 2.2 million people living with and at risk for HIV, contributed by clinical centers and research groups in 44 countries. IeDEA data are organized into 7 geographic regions (regional cohorts) and coordinated by centers for the Asia-Pacific, the Caribbean, Central and South America region, Central, East, Southern, and West Africa, and North America IeDEA conducts both regional and global research.

Research Team Composition

The IeDEA community is composed of investigators, study coordinators, and data teams representing multiple countries, languages, and backgrounds. Consortium members meet regularly through interest-based Working Groups to guide the collaborative research projects. Rakai Health Sciences Program (RHSP) in the East Africa region is a clinical site and research group contributing data to IeDEA. For more information, please check, IeDEA International Epidemiology Databases to Evaluate AIDS

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Rakai Orphans in Communities (ROC)

Introduction

The loss of one or both parents can have devastating consequences for children, adolescents, extended families, communities, and nations. Recently, improvements in HIV treatment and prevention have led to dramatic declines in orphanhood. This appears to be the result of combination HIV prevention (CHP), particularly expanded access to highly effective antiretroviral therapy (ART) and declining HIV-related mortality among adults – adults who are often parents. The declines in HIV-related orphanhood proffer substantial benefits to children and youth, families, and their communities. Little is known about how declines in orphanhood among youth may have impacted social and economic factors that influence HIV risk as orphans move into the adolescent and young adult (AYA) years.

The specific aims for ROC study are to:

1.     Define, over time, the potentially changing consequences of orphanhood including the relationship between orphanhood and HIV infection and HIV risk behaviors among youth from RCCS Rounds 6-23 (1999-2027).

2.     Explore issues related to mechanism and measurement to better understand the population burden of orphanhood, heterogeneity among orphans, and the circular relationships between 1- HIV infection among adults and subsequent orphaning and 2- orphanhood and HIV risk among youth. A key issue of mechanism is the timing of orphaning (i.e., age they became an orphan) and how that affects the consequences of orphaning.

3.     Through life history interviews, explore the mechanisms by which orphanhood and age at orphaning may influence HIV risk and social outcomes and begin to assess and address how programs can be tailored to meet the needs of this vulnerable population.  Interviews will be conducted with youth and their adult caretakers during childhood and adolescence; each should be able to differentially report on events and circumstances of the orphaning period.

4.     Estimate the economic impact of declining HIV-related orphanhood on youth, families, and communities in Rakai and in Uganda, using data from RCCS. In a cost-benefit analysis, we will examine benefits of declining orphanhood (decreased adult mortality, decreased orphanhood, increased educational status, decreased HIV infection among youth) and costs (costs for ART, MMC). Addressing HIV-related orphanhood is an important PEPFAR priority but economic impacts have received little recent scientific attention, particularly, the impact of declining orphanhood on youth risk for HIV infection.

Improving understanding of Capacity to consent to biomedical HIV prevention Research among adolescents in Rakai Uganda (ICARE)

In our prior study of adolescent capacity to consent to observational research in Uganda (R01HD091003- 03S1), we used the MacArthur Competence Assessment Tool for Clinical Research (MacCAT-CR), a highly flexible tool that has accumulated the most adolescent data and described age-related capacity of adolescents to consent to lower-risk research. In this study, we will leverage The Rakai Community Cohort Study (RCCS) to test adolescent capacity to consent to biomedical research, identify differences in developmental decision-making, characterize eligibility for, beliefs about, and interest in oral and injectable pre-exposure prophylaxis (PrEP), and construct a digital toolkit for including adolescents in biomedical research. The RCCS presents a unique opportunity to compare cognitive capacity to consent for biomedical research among adolescents with and without prior research experience at three developmental stages – early (10-14 years), middle (15-17 years), and late (18-19 years) – with the cognitive capacity of their parents/guardians. Limited data are available on adolescents’ actual capacity to consent, particularly in low- and middle-income countries and low-resource, high-HIV prevalence settings.

Study-specific aims are:

1. Sampling from RCCS-experienced and RCCS-naïve households, and using the MacCAT-CR, examine adolescent capacity to consent to biomedical research and correlates of that capacity. 1.a: Compare capacity to consent among early, middle, and late adolescents and their guardians. 1.b: Assess correlates of capacity, including actionable factors such as health literacy and education, and biomedical-related factors such as PrEP eligibility, use, awareness, beliefs, peer norms, and stigma.

2. Using a systematic qualitative analysis – guided by our conceptual framework for mapping age differences – examine processes of decision-making around biomedical prevention and biomedical research (e.g., stigma, understanding of biomedical prevention and research risks and benefits and constructs like randomization, privacy, safety, and autonomy) among guardians and early, middle, and late adolescents.

3. In partnership with US and Uganda researchers, and IRB members, construct a digital toolkit to support decision-making regarding key aspects of minor consent in low-resource settings. ICARE will provide guidance for ethical boards seeking to harmonize consent for adolescent healthcare and research to address disparities in research by age, and facilitate studies that prioritize adolescents to end the HIV epidemic.

The PANGEA-HIV (Phylogenetics And Networks for Generalized Epidemics in Africa) consortium is a collaboration between scientists from the Rakai Health Sciences Program (Uganda), Africa Health Research Institute (South Africa), Johns Hopkins University (USA), Medical Research Council/Uganda Virus Research Institute (Uganda), Zambart Project (Zambia), London School of Hygiene and Tropical Medicine (UK), Imperial College London (UK), Partners in Prevention Project at the University of Washington (USA), Botswana Harvard AIDS Institute Partnership (Botswana/USA), University of Edinburgh (UK), and the University of Oxford (UK).

The overarching goal of the PANGEA consortium is to identify individual and population level factors that drive the epidemic using HIV-1 phylogenetic data, analyze the dynamics underlying the epidemic, and translate these findings into information that can be used to target HIV interventions more effectively. The RHSP is a major contributor to the PANGEA consortium through several samples collected within the ongoing, open, population-based Rakai Community Cohort study. To date, PANGEA has generated and analyzed over 40,000 deeply sequenced HIV genomes from eastern and southern Africa (Rakai, Uganda; MRC, Uganda; PopART, Zambia; BCPP, Botswana; and AHRI, South Africa), and revealed a lack of large HIV phylogenetic clusters suggesting that most new HIV diagnoses have occurred sporadically across several transmission chains within individual African communities. This suggests that HIV transmission in Africa remains broadly generalized, in contrast to European and American HIV epidemics which are concentrated in key populations and more work utilizing multiple population sampling strategies may reveal crucial targets for enhanced epidemic control amidst declining HIV incidence in sub-Saharan Africa.

REACH (Research Enterprise to advance a cure for HIV)

The REACH study is a NIH based Martin Delaney funded consortium that seeks to foster dynamic, multidisciplinary collaborations between basic, applied, and clinical researchers studying HIV persistence and developing potential curative strategies. The RHSP runs a HIV cure study cohort of 90 HIV positive individuals who are contributing to a greater understanding of HIV cure / viral persistence from an African perspective. Through this cohort (initially funded by NIAID), baseline estimations of reservoir size and differences have been described among Ugandan men and women compared to Americans. Interestingly, transient declines in replication competent viral reservoir size have been described following DTG rollout and further work is ongoing, including that based on onsite technology transfer of ddPCR platform technology (IPDA assay) to better understand underlying mechanisms of viral reservoir persistence, trends/evolution, and possible targeting towards eradication.  

The INSTEP (Integrated Female Sexually Transmitted Infection Testing for HIV Epidemic Control through PrEP) study

The INSTEP study is a new study being rolled out at the RHSP. INSTEP is a randomized trial assessing whether access to integrated curable STI (cSTI) testing will improve PrEP use among women in Africa and seeks to provide compelling evidence on critical effectiveness, implementation, and modeled data to influence policy and programmatic decisions that will inform strategic delivery of high impact HIV prevention. STIs are a risk factor for HIV acquisition and are used as a self-screening tool prior to PrEP enrollment in Uganda but unfortunately, over 85-90% of STI episodes may be symptomless. STI laboratory diagnosis is costly and not widely available in Africa, and this implies that a significant number of persons with symptomless STIs, especially vulnerable females may not perceive themselves to be at risk/PrEP eligible. Our preliminary observational data suggests a high burden of undiagnosed cSTIs among African women at high risk for HIV and that adding cSTI diagnostic testing to existing PrEP eligibility screening efforts would nearly double the number of PrEP eligible women. Preliminary data also show women with cSTI symptoms are more likely to perceive themselves as being at high HIV risk, and that women diagnosed with cSTIs are more likely to use PrEP. Thus, INSTEP aims to individually randomize enrolled females to the standard of care self-risk screening tools for PrEP eligibility (with syndromic STI management) versus self-risk screening plus cSTI diagnostic testing for chlamydia, gonorrhea, trichomonas, and syphilis to increase PrEP use among cis-gender African women aged 15 to 39 years in the RCCS cohort.

Specific AIMS

1. Conduct an individually randomized effectiveness implementation trial of self-risk screening alone versus self-risk screening plus cSTI testing to increase PrEP use among African women at high HIV risk. ~4,500 HIV-negative women will be randomized 1:1. Primary outcomes will be PrEP uptake after screening and adherence and persistence at 6 months assessed through survey, clinical records, and drug level testing.

2. To perform a mixed-methods, implementation science evaluation of female cSTI testing for improving PrEP use for HIV prevention. We will use qualitative and quantitative methods to assess mechanisms, barriers, and facilitators to improving PrEP outcomes through cSTI testing and how this varies by cSTI pathogen, SRST outcomes, and demographic profiles. 

3. To determine the most efficient, population-level female cSTI testing strategies to reduce HIV incidence in African settings. We will use data and results from Aims 1 and 2 to inform mathematical models which will evaluate different cSTI testing approaches to reduce HIV incidence at a population level by considering what cSTIs to screen for, in what health care settings, and at what cost thresholds.

Mental Health And Cognition in HIV Infection in Rakai Uganda extended Rakai Neurology Cohort Study (EXRNCS)

Background

Central nervous system (CNS) complications in HIV infection persist despite effective antiretroviral therapy (ART) and impact HIV care including ART adherence particularly in resource-limited settings. Two of the most common, often comorbid CNS complications in the current era are major depressive disorder (MDD) and neurocognitive impairment (NCI).

Study goal: This study set to evaluate the mechanisms of mental health disorders including MDD and NCI more broadly with detailed evaluations and a novel methodology. The study focuses on several key pathways with strong scientific premise for contributing to MDD and NCI that could result in novel peripheral biological signatures of MDD, NCI, or the combination of the two in the context of viral suppression: neuronal/axonal injury, inflammatory, and novel exosome markers. The study also evaluates the significance of viral compartmentalization on long-term MDD and  NCI. 

Study procedures: We proposed further follow up, new assessments for additional mental health disorders, and laboratory investigations among PLWH on long-term ART to improve our understanding of the causal mechanisms of mental health disorders and NCI in PLWH, with primary focus on MDD and NCI. Data on anxiety and stress which are often comorbid with MDD, will also be collected,

The study will examine the role of plasma markers of neuronal injury and inflammatory markers from exosomes derived from brain but obtained in the blood, and their association with MDD and NCI which have not previously been examined in PLWH in SSA.

Study Design for the extended Rakai Neurology Cohort Study (exRNCS)

Participants. The study has enrolled 350 people living with HIV (PLWH). These have had a baseline visit and a follow-up visit at 24 months after enrollment. Controls: From the Rakai Community Cohort Study (RCCS), we also recruited 250 HIV-negative (HIV-neg) controls who were age, sex, and community-matched to the PLWH. The goal of recruiting HIV-neg controls was to obtain normative mental health disorder data, neuropsychological testing and blood and CSF control data. Archived blood and CSF specimens are also available from 400 HIV-neg controls from the Rakai Neurological Cohort Study (RNCS) to serve as additional HIV-neg control data for the proposed markers.

 Exclusion Criteria: severe cognitive or psychiatric impairment precluding written consent, physical disability preventing travel to the RHSP clinic for study procedures, known CNS opportunistic infection (e.g., cryptococcal meningitis), or prior CNS disease (e.g., stroke).

Recruitment. During the Baseline and follow-up for PLWH and HIV-neg controls, individuals had first clinical assessment and optional lumbar puncture (LP). All participants will have a two-year follow-up 24 months after enrollment visit, with identical assessments including the optional LP.

Study procedures. The same battery of assessments are administered at both study visits for PLWH and HIV-neg controls. The complete testing visit required ~5 hours. Our battery was chosen to provide all of the necessary information to diagnose HAND with a NP test battery to determine NCI, functional status assessment to determine activities of daily living impairment, and neuromedical exams to evaluate for confounding conditions.

General Health. Participants are administered a structured questionnaire to record sociodemographic characteristics, health and health care utilization, ART adherence, alcohol use /abuse, smoking, sexual behaviors, HIV prevention behaviors, use of non-ART medications, and disability. Symptom reporting includes symptoms within the past month and past year to reduce recall bias.  A general medical exam is also completed.

Neurological Evaluations. Evaluations include: 1) Neurological symptoms questionnaire; 2) Neurological exam; and 3) Uganda Neuro psychological Test Battery

MDD and other mental health assessments. All participants complete the Structured Clinical Interview for DSM-V Axis I Disorders (SCID-V) to assess current and lifetime mental health disorders as well as mental health questionnaires including: the Childhood Trauma Questionnaire, Patient Health Questionnaire (PHQ)-9, Generalized Anxiety Disorder Screener (GAD)-7, Center for Epidemiological Studies-Depression Scale (CES-D), PTSD Checklist-Civilian version (PCL-C), Perceived Stress Scale-10 (PSS-10), Beck Anxiety Inventory (BAI), the World Health Organization (WHO) Violence Against Women Questionnaire, sexual coercion questions from the Rakai Project, and domestic violence questions from the community HIV epidemiological research (CHER) survey-2 (adapted from the Conflicts Tactics Scale). These assessments will allow us to examine anxiety, PTSD, and alcohol abuse in addition to MDD.

Behavioral & Self-Report RDoC Assessments. Behavioral and self-report measures to assess the RDoC domains of declarative memory, cognitive control, and NVS are also assessed.