The "3 Ps" of EmPowerment, Partnership and Protection - Stakeholder Perceptions of Beneficial Outcomes of Engagement in HIV Prevention Trials.

Background: Stakeholder engagement is increasingly recognized as a key component of ethical research in leading ethics guidelines. Ethics commentators have also argued that engagement has several beneficial outcomes for the field. Aim: This paper reports on the beneficial outcomes of stakeholder engagement in HIV prevention trials as perceived by stakeholders in the field. Method: We conducted 28 interviews between 2019 and 2021 with interviewees from various stakeholder groups in 12 countries and used thematic analysis to analyze the transcripts. Findings: We found three major themes - namely emPowerment where engagement is perceived to empower stakeholders, Partnerships where engagement is perceived to build equitable relationships and Protections where engagement is perceived to strengthen protections for participants and community stakeholders and to improve science. Conclusions: These findings map closely onto beneficial outcomes envisaged by ethics guidelines, however, the relationship between outcomes seen as beneficial deserves further exploration.

The impact of low input DNA on the reliability of DNA methylation as measured by the Illumina Infinium MethylationEPIC BeadChip.

DNA methylation (DNAm) is commonly assayed using the Illumina Infinium MethylationEPIC BeadChip, but there is currently little published evidence to define the lower limits of the amount of DNA that can be used whilst preserving data quality. Such evidence is valuable for analyses utilizing precious or limited DNA sources. We used a single pooled sample of DNA in quadruplicate at three dilutions to define replicability and noise, and an independent population dataset of 328 individuals (from a community-based study including US-born non-Hispanic Black and white persons) to assess the impact of total DNA input on the quality of data generated using the Illumina Infinium MethylationEPIC BeadChip. We found that data are less reliable and more noisy as DNA input decreases to 40ng, with clear reductions in data quality; and that low DNA input is associated with a reduction in power to detect EWAS associations, requiring larger sample sizes. We conclude that DNA input as low as 40ng can be used with the Illumina Infinium MethylationEPIC BeadChip, provided quality checks and sensitivity analyses are undertaken.

"It's Almost as if Stakeholder Engagement is the Annoying 'Have-to-do' ": Can Ethics Review Help Address the "3 Ts" of Tokenism, Toxicity, and Tailoring in Stakeholder Engagement?

Ethics guidance recommends that researchers engage stakeholders and that RECs review research for such engagement. The ethics review process may present a unique opportunity to support stakeholder engagement practices for HIV prevention studies. We conducted 28 interviews with experts from 12 countries to explore this issue, and analyzed the data using Thematic Analysis. We found that the value of engagement and review processes was strongly endorsed. However, we identified 3 major thematic complexities, namely: "Tokenism" where processes risk being "tick-box"; "Toxicity", where practices may inadvertently have negative consequences; and "Tailoring", where processes need careful variation in intensity. We make recommendations for how these "Ts" can be addressed during the review process to help contribute to thoughtful review of meaningful stakeholder engagement in research.

Where are the pregnant and breastfeeding women in new pre-exposure prophylaxis trials? The imperative to overcome the evidence gap.

Pregnant and breastfeeding populations are at substantial risk of acquiring HIV in some settings, yet are underrepresented in clinical trials of new pre-exposure prophylaxis (PrEP) agents. Several PrEP formulations are in development (eg, vaginal rings, long-acting injectables, and other modalities). Pregnant and breastfeeding populations are typically excluded from initial clinical trials. We identified 14 PrEP trials of novel agents in non-pregnant or non-breastfeeding populations, and six phase 1-3 trials and open label extensions among pregnant and breastfeeding populations, that are currently ongoing or complete. A framework shift is needed to consider the ethical costs of excluding pregnant and breastfeeding populations at risk for HIV in PrEP clinical trials and promote inclusion to maximise the benefits from PrEP tools in the pipeline. Research on new PrEP agents should include pregnant and breastfeeding populations to avoid delays in reaching those who could benefit from PrEP after efficacy is established.

Shifts in UNAIDS ethics guidance and implications for ethics review of preventive HIV vaccine trials.

INTRODUCTION: A major change in the ethics framework for preventive HIV vaccine trials worldwide is the release of the UNAIDS 2021 ethical considerations in HIV prevention trials. This new guidance comes at an exciting time when there are multiple HIV vaccine efficacy trials in the field. Research Ethics Committees (RECs) or Institutional Review Boards are a most likely audience for these guidelines. Our objective is to highlight shifts in ethics recommendations from the earlier 2012 UNAIDS guidance. DISCUSSION: We review recommendations related to four key issues, namely standard of prevention, post-trial access to safe and effective vaccines, enrolment of adolescents and enrolment of pregnant women. We outline implications and make recommendations for the ethics review process, including suggested lines of inquiry by RECs and responses by applicants. CONCLUSIONS: There have been several shifts in the UNAIDS ethics guidance with implications for HIV vaccine researchers submitting applications for initial ethics review or re-certification, and for RECs conducting such reviews. This review may assist RECs in a more efficient and consistent application of ethics recommendations. However, additional tools and training may further help stakeholders comply with new UNAIDS ethics recommendations during protocol development and ethics review.

Adolescent participation in HIV research: consortium experience in low and middle-income countries and scoping review.

Adolescents in low and middle-income countries (LMICs) have a high prevalence of HIV, therefore, it is important that they are included in HIV research. However, ethical challenges regarding consent can hinder adolescent research participation. We examined examples from the Prevention and Treatment Through a Comprehensive Care Continuum for HIV-affected Adolescents in Resource Constrained Settings (PATC3H) research consortium, which investigates adolescent HIV prevention and treatment in seven LMICs: Brazil, Kenya, Mozambique, Nigeria, South Africa, Uganda, and Zambia. PATC3H researchers were asked to identify ethical and practical challenges of adolescent consent to research participation in these countries. We also did a scoping review of strategies that could improve adolescent participation in LMIC HIV studies. Examples from PATC3H research highlighted many ethical challenges that affect adolescent participation, including inconsistent or absent consent guidance, guidelines that fail to account for the full array of adolescents' lives, and variation in how ethical review committees assess adolescent studies. Our scoping review identified three consent-related strategies to expand adolescent inclusion: waiving parental consent requirements, allowing adolescents to independently consent, and implementing surrogate decision making. Our analyses suggest that these strategies should be further explored and incorporated into ethical and legal research guidance to increase adolescent inclusion in LMIC HIV research.

Be legally wise: When is parental consent required for adolescents' access to pre-exposure prophylaxis (PrEP)?

BACKGROUND: South African adolescents (12-17 years) need an array of prevention tools to address their risk of acquiring the life-long, stigmatized condition that is HIV. Prevention tools include pre-exposure prophylaxis (PrEP). However, service providers may not be clear on the instances where self-consent is permissible or when parental consent should be secured. AIM: To consider the legal norms for minor consent to PrEP using the rules of statutory interpretation. SETTING: Legal and policy framework. RESULTS: We find that PrEP should be interpreted as a form of 'medical treatment'; understood broadly so that it falls within the ambit of one of consent norms in the Children's Act. When PrEP is interpreted as 'medical treatment', then self-consent to PrEP is permissible for persons over 12 years, if they have the mental capacity and maturity to understand the benefits, risks, social and other implications of the proposed treatment. Currently, PrEP is only licensed for persons over 35 kg. Reaching the age of 12 years is a necessary but not sufficient criteria for self-consent and service-providers must ensure capacity requirements are met before implementing a self-consent approach. Decisional support and adherence support are critical. CONCLUSIONS: We recommend that service-providers should take steps to ensure that those persons who meet an age requirement for self-consent, also meet the capacity requirement, and that best practices in this regard be shared. We also recommend that policy makers should ensure that PrEP guidelines are updated to reflect the adolescent consent approach articulated above. It is envisaged that these efforts will enable at-risk adolescents to access much needed interventions to reduce their HIV risk.

Acceptability, safety, and patterns of use of oral tenofovir disoproxil fumarate and emtricitabine for HIV pre-exposure prophylaxis in South African adolescents: an open-label single-arm phase 2 trial.

BACKGROUND: HIV incidence among adolescents in southern Africa remains unacceptably high. Pre-exposure prophylaxis (PrEP) is an effective HIV prevention intervention but there are few data on its implementation among adolescents. We aimed to investigate the safety, feasibility, and acceptability of PrEP with oral tenofovir disoproxil fumarate and emtricitabine as part of a comprehensive HIV prevention package in an adolescent population in South Africa. METHODS: This open-label single-arm phase 2 study (PlusPills) was done in two research clinics in Cape Town and Johannesburg, South Africa. Adolescents aged 15-19 years were recruited into the study through recruitment events and outreach in the community. Potential participants were eligible for enrolment if they reported being sexually active. Exclusion criteria were a positive test for HIV or pregnancy at enrolment, breastfeeding, or any relevant co-morbidities. Participants were given oral tenofovir disoproxil fumarate and emtricitabine for PrEP to take daily for the first 12 weeks and were then given the choice to opt in or out of PrEP use at three monthly intervals during scheduled clinic visits. Participants were invited to monthly visits for adherence counselling and HIV testing during the study period. The primary outcomes were acceptability, use, and safety of PrEP. Acceptability was measured by the proportion of participants who reported willingness to take up PrEP and remain on PrEP at each study timepoint. Use was defined as the number of participants who continued to use PrEP after the initial 12-week period until the end of the study (week 48). Safety was measured by grade 2, 3, and 4 laboratory and clinical adverse events using the Division of AIDS table for grading the severity of adult and paediatric adverse events, version 1.0. Dried blood spot samples were collected at each study time-point to measure tenofovir diphosphate concentrations. This trial is registered with ClinicalTrials.gov, NCT02213328. FINDINGS: Between April 28, 2015, and Nov 11, 2016, 244 participants were screened, and 148 participants were enrolled (median age was 18 years; 99 participants [67%] were female) and initiated PrEP. PrEP was stopped by 26 of the 148 (18%) participants at 12 weeks. Cumulative PrEP opt-out, from the total cohort, was 41% (60 of 148 participants) at week 24 and 43% (63 of 148 participants) at week 36. PrEP was well tolerated with only minor adverse events (grade 2) thought to be related to study drug, which included headache (n=4, 3%), gastrointestinal upset (n=8, 5%), and skin rash (n=2, 1%). Two participants (1%) experienced grade 3 weight loss, which was deemed related to the study drug and resolved fully when PrEP was discontinued. Tenofovir diphosphate concentrations were detectable (>16 fmol/punch) in dried blood spot samples in 108 (92%) of 118 participants who reported PrEP use at week 12, in 74 (74%) of 100 participants at week 24, and in 22 (59%) of 37 participants by the study end at week 48. INTERPRETATION: In this cohort of self-selected South African adolescents at risk of HIV acquisition, PrEP appears safe and tolerable in those who continued use. PrEP use decreased throughout the course of the study as the number of planned study visits declined. Adolescents in southern Africa needs access to PrEP with tailored adherence support and possibly the option for more frequent and flexible visit schedules. FUNDING: National Institute of Allergy and Infectious Diseases of the US National Institutes of Health.

An open-label, randomized crossover study to evaluate the acceptability and preference for contraceptive options in female adolescents, 15 to 19 years of age in Cape Town, as a proxy for HIV prevention methods (UChoose).

INTRODUCTION: Young women in Southern Africa have extremely high HIV incidence rates necessitating the availability of female-controlled prevention methods. Understanding adolescent preference for seeking contraception would improve our understanding of acceptability, feasibility and adherence to similar modes of delivery for HIV prevention. METHODS: UChoose was an open-label randomized crossover study over 32 weeks which aimed to evaluate the acceptability and preference for contraceptive options in healthy, HIV-uninfected, female adolescents aged 15 to 19 years, as a proxy for similar HIV prevention methods. Participants were assigned to a contraceptive method for a period of 16 weeks in the form of a bi-monthly injectable contraceptive, monthly vaginal Nuvaring® or daily combined oral contraceptive (COC) and then asked to state their preference. At 16 weeks, participants crossed over to another contraceptive method, to ensure that all participants tried the Nuvaring® (least familiar modality) and additionally, either the injection or COC. Primary outcomes were contraceptive acceptability and preference. At the end of the 32 weeks they were also asked to imagine their preference for an HIV prevention modality. Secondary endpoints included changes in sexual behaviour, contraceptive adherence and preference for biomedical and behavioural HIV prevention methods. RESULTS: Of the 180 participants screened, 130 were enrolled and randomized to the Nuvaring® (n = 45), injection (n = 45) or COC (n = 40). Significantly more Nuvaring® users (24/116; 20.7%) requested to change to another contraceptive option compared to injection (1/73; 1.4% p = 0.0002) and COC users (4/49; 8% p = 0.074). Of those that remained on the Nuvaring® , adherence was significantly higher than to COC (p < 0.0001). Significantly more injection users (77/80; 96.3%) thought this delivery mode was convenient to use compared to Nuvaring® (74/89; 83.1%; p = 0.0409) or COC (38/50; 76.0%; p = 0.0034). Overall, the preferred contraceptive choice was injection, followed by the ring and lastly the pill. CONCLUSIONS: Adherence to daily COC was difficult for adolescents in this cohort and the least favoured potential HIV prevention option. While some preferred vaginal ring use, these data suggest that long-acting injectables would be the preferred prevention method for adolescent girls and young women. This study highlights the need for additional options for HIV prevention in youth.

Adolescent Barriers to HIV Prevention Research: Are Parental Consent Requirements the Biggest Obstacle?

PURPOSE: One third of people newly living with HIV/AIDS are adolescents. Research on adolescent HIV prevention is critical owing to differences between adolescents and adults. Parental permission requirements are often considered a barrier to adolescent enrollment in research, but whether adolescents view this barrier as the most important one is unclear. METHODS: Adolescents were approached in schools in KwaZulu-Natal, South Africa, and at a sexually transmitted infection clinic at the Children's Hospital of Aurora, Colorado. Surveys with a hypothetical vignette about participation in a pre-exposure prophylaxis trial were conducted on smartphones or tablets with 75 adolescents at each site. We calculated descriptive statistics for all variables, using 2-sample tests for equality of proportions with continuity correction. Statistical significance was calculated at p < 0.05. Multivariate analyses were also conducted. RESULTS: Most adolescents thought side effects (77%) and parental consent requirements (69%) were very important barriers to research participation. When asked to rank barriers, adolescents did not agree on a single barrier as most important, but the largest group of adolescents ranked parental consent requirements as most important (29.5%). Parental consent was seen as more of a barrier for adolescents in South Africa than in the United States. Concerns about being experimented on or researchers' mandatory reporting to authorities were ranked much lower. Finally, most (71%, n = 106) adolescents said they would want to extra support from another adult if parental permission was not required. CONCLUSION: Adolescents consider both parental permission requirements and side effects important barriers to their enrollment in HIV prevention research. Legal reform and better communication strategies may help address these barriers.

"Why Don't You Go Into Suburbs? Why Are You Targeting Us?": Trust and Mistrust in HIV Vaccine Trials in South Africa.

Trust is a key element of high-quality stakeholder relations, which are themselves essential for the success of HIV vaccine trials. Where trust is absent, community stakeholders might not volunteer to become involved in key trial activities, and potential participants might not volunteer for enrollment. We explored site staff and Community Advisory Board (CAB) members' experiences of trust/mistrust among community members and potential participants. We analyzed 10 focus group discussions with site staff and CAB members at two active South African HIV vaccine trial sites. We report on key characteristics perceived to contribute to the trustworthiness of communicators, as well as factors associated with mistrust. Attributes associated with trustworthy communicators included shared racial identity, competence, and independence (not being "captured"). Key foci for mistrust included explanations about site selection, stored samples, vaccination, and Vaccine Induced Sero-Positivity (VISP). Our findings suggest that community members' trust is not necessarily global, in which trials are trusted or not; rather, it appears fairly nuanced and is impacted by various perceived attributes of communicators and the information they provide. We make recommendations for clinical trial site stakeholders invested in building trust and for future research into trust at these sites.

Strengthening stakeholder engagement through ethics review in biomedical HIV prevention trials: opportunities and complexities.

INTRODUCTION: Clinical trials of biomedical HIV prevention modalities require the cooperation of multiple stakeholders. Key stakeholders, such as community members, may have stark vulnerabilities. Consequently, calls for HIV prevention researchers to implement "stakeholder engagement" are increasingly common. Such engagement is held to benefit inter-stakeholder relations, stakeholders themselves and the research itself. The ethics review process presents a unique opportunity to strengthen stakeholder engagement practices in HIV prevention trials. However, this is not necessarily straightforward. In this article, we consider several complexities. First, is stakeholder engagement a legitimate component of what Research Ethics Committees (RECs) should review for HIV prevention trials? Second, what are the core features of engagement that should be under ethics review? Third, what are the key practices that should be highlighted in ethics review? METHODS: To address these questions, we examined the international ethics guidelines specialized for such trials (UNAIDS 2012, UNAIDS-AVAC GPP 2011) and directly applicable to such trials (CIOMS 2016; WHO 2011). Thematic analysis was used to code and analyse these guidelines. RESULTS AND DISCUSSION: Ethics guidelines support REC review of engagement. Guidance recommends that engagement be broad and inclusive; early and sustained; and dynamic and responsive. Broad engagement practices include evaluating the context, planning in writing, and resourcing. RECs should assess engagement as part of a comprehensive review, and recommend revisions where necessary. Researchers should profile key elements of engagement valued in ethics guidance, when they draft ethics submissions. Importantly, the ethics review process should not undermine the 'dynamic responsiveness' required for excellent engagement in this field. CONCLUSIONS: As evidence-informed engagement strategies emerge, these should inform the ethics submission and review process. Both parties in the review process should strive to avoid a superficial, check-list type approach that caricatures what should be a thorough, nuanced ethics review of a rich, responsive engagement process.

Commentary on "A Framework for Community and Stakeholder Engagement: Experiences From a Multicenter Study in Southern Africa".

Community and stakeholder engagement (CSE) is increasingly acknowledged as foundational to global health research. This commentary builds on the multisite framework for CSE described in an eco-health study conducted in Southern Africa. We acknowledge the context-specific nature of some of the challenges for CSE and draw attention to significant issues and concerns that arose from our studies of CSE in the context of multisite HIV prevention trials in South Africa, India, and Canada: (a) Pretrial-historically based mistrust, identification of appropriate gatekeepers, and considering the breadth of community; (b) Trial implementation-impact of early trial cessations, appropriate community roles and responsibilities, and multifaceted stigma; and (c) Posttrial-supporting and sustaining CSE mechanisms independent of particular trials. Many of these challenges are exacerbated by widespread disparities in wealth and power between trial sponsors and participating communities, further supporting the central importance of sound CSE practices and infrastructures to advance ethical biomedical and public health research.

Defining and Negotiating the Social Value of Research in Public Health Facilities: Perceptions of Stakeholders in a Research-Active Province of South Africa.

This article reports on qualitative research conducted in KwaZulu-Natal, South Africa, among researchers and gate-keepers of health facilities in the province. Results suggest disparate but not irreconcilable perceptions of the social value of research in provincial health facilities. This study found that researchers tended to emphasize the contribution of research to the generation of knowledge and to the health of future patients while gate-keepers of health facilities tended to emphasize its contribution to the healthcare system and to current patients. Furthermore, relations between research stakeholders were perceived to be somewhat fragile, making it difficult for stakeholders to achieve consensus about the social value of research, as well as on ways to maximize value. Interventions to negotiate a shared perspective on the social value of research would appear to be warranted, and the findings of this study suggest some focus areas for such intervention.

". . . I've Gone Through This My Own Self, So I Practice What I Preach . . . ".

There has not been enough study of the processes by which site staff help participating community members and potential participants to understand complicated concepts for HIV vaccine trials. This article describes strategies reported in six focus group discussions with Community Advisory Board members, educators, and consent counselors at an active HIV vaccine trial site in South Africa. Thematic analysis identified a considerable range of strategies, and findings suggest that such staff do not only try to promote understanding of critical information but also try to build trust in communicated information, to respect cultural differences, and to promote voluntariness. Findings also suggest occasional tensions between these implicit goals. Actual engagement and consent encounters at HIV vaccine trial sites should be observed, recorded, and analyzed; and the relationship between practices and valued outcomes should be assessed. These efforts may help to make consent-related encounters as "potent" as possible given finite resources.

HIV testing of children is not simple for health providers and researchers: Legal and policy frameworks guidance in South Africa.

Antiretroviral treatment coverage for children and adolescents is significantly lower than that for adults. A first step in improving this situation is ensuring increased access to HIV counselling and testing services. Current legal and policy frameworks outline four norms that should inform HIV testing of children in South Africa: limiting HIV testing to defined circumstances, and ensuring that consent is obtained, counselling is provided and confidentiality is maintained. Implementing these norms is not simple. We discuss the challenges and opportunities these norms present for children, their families, health providers and researchers working in this area. Better alignment between evolving public health approaches and the HIV counselling and testing legal/policy frameworks (and the internal coherence of domestic frameworks) would better serve children, their parents and those who work with them.

Child research in South Africa: How do the new regulations help?

Child research is governed by legal norms in the National Health Act (2003) and the Regulations. There is increasing harmony between the two on many issues, including the conditions under which children should be enrolled in research. The most striking disjuncture in the ethical-legal framework remains the allowable consent strategy for child research, where the law requires mandatory parental or legal guardian consent for all child research, while ethical guidelines afford research stakeholders the discretion to implement exceptions to this approach in specific justifiable circumstances.

Towards a Science of Community Stakeholder Engagement in Biomedical HIV Prevention Trials: An Embedded Four-Country Case Study.

OBJECTIVES: Broad international guidelines and studies in the context of individual clinical trials highlight the centrality of community stakeholder engagement in conducting ethically rigorous HIV prevention trials. We explored and identified challenges and facilitators for community stakeholder engagement in biomedical HIV prevention trials in diverse global settings. Our aim was to assess and deepen the empirical foundation for priorities included in the GPP guidelines and to highlight challenges in implementation that may merit further attention in subsequent GPP iterations. METHODS: From 2008-2012 we conducted an embedded, multiple case study centered in Thailand, India, South Africa and Canada. We conducted in-depth interviews and focus groups with respondents from different trial-related subsystems: civil society organization representatives, community advocates, service providers, clinical trialists/researchers, former trial participants, and key HIV risk populations. Interviews/focus groups were recorded, and coded using thematic content analysis. After intra-case analyses, we conducted cross-case analysis to contrast and synthesize themes and sub-themes across cases. Lastly, we applied the case study findings to explore and assess UNAIDS/AVAC GPP guidelines and the GPP Blueprint for Stakeholder Engagement. RESULTS: Across settings, we identified three cross-cutting themes as essential to community stakeholder engagement: trial literacy, including lexicon challenges and misconceptions that imperil sound communication; mistrust due to historical exploitation; and participatory processes: engaging early; considering the breadth of "community"; and, developing appropriate stakeholder roles. Site-specific challenges arose in resource-limited settings and settings where trials were halted. CONCLUSIONS: This multiple case study revealed common themes underlying community stakeholder engagement across four country settings that largely mirror GPP goals and the GPP Blueprint, as well as highlighting challenges in the implementation of important guidelines. GPP guidance documents could be strengthened through greater focus on: identifying and addressing the community-specific roots of mistrust and its impact on trial literacy activities; achieving and evaluating representativeness in community stakeholder groups; and addressing the impact of power and funding streams on meaningful engagement and independent decision-making.

I'm positive, but i'm negative: Competing Voices in Informed Consent and Implications for HIV vaccine trials.

HIV vaccine trials (HVTs) are ethically complex, and sound informed consent processes should facilitate optimal decision-making for participants. This study aimed to explore representations of critical HVT-related concepts to enhance the consent process. Four focus group discussions were conducted with participants from key constituencies at a South African HVT site. Thematic analysis was employed to identify representations of key HVT-related concepts. The findings suggest that (potential) participants may negotiate multiple, competing versions of HVT-related concepts in a somewhat unrecognized process, which may have significant implications for the consent process. Stakeholders involved in consent and engagement activities at sites should be assisted to elicit, engage, and resolve competing representations of HVT-related concepts. More empirical research is needed to explore how such stakeholders address competing representations in their interactions with potential participants.