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Historically, pregnant and lactating populations (PLP) have been excluded or disenrolled from biomedical HIV prevention trials, despite being more likely to acquire HIV during pregnancy and the post-partum period. We conducted a meta-analysis of pregnancy events in biomedical HIV prevention trials in sub-Saharan Africa to support trialists moving toward more inclusive clinical and implementation studies. We searched peer-reviewed literature reporting pregnancy events and contraceptive requirements in HIV prevention trials between 2001 and 2022. We hypothesized four variables to explain variation: contraceptive requirements, study start year, study product, and sub-region. We fit a meta-analytic model to estimate individual effect sizes and sampling variances, then conducted sub-group analyses to assess moderating effects. We identified 38 references for inclusion, across which the proportion of pregnancy events was 8% (95% confidence interval [CI]: 6–10%) with high heterogeneity (I2 = 99%). Studies not requiring contraceptives (21%, 95%CI: 7–48%) reported a significantly higher proportion of pregnancy events than studies requiring two methods (5%, 95%CI: 2–10%). Studies launched between 2001 and 2007 (11%, 95%CI: 8–16%), microbicide gel trials (12%, 95%CI: 8–18%), and studies conducted in Western Africa (28%, 95%CI: 13–51%) reported higher proportions of pregnancy events than reference groups. Together, these variables have a moderating effect on pregnancy events (p < 0.0001), explaining 63% of heterogeneity in trials. Results describe how, over time, more stringent contraceptive requirements reduced pregnancy events, which ensured necessary statistical power but limited reproductive choice by participants. With the move toward continuing PLP on experimental products, trialists can utilize estimated pregnancy events reported here to inform strategies that accommodate participants' changing fertility preferences. [ABSTRACT FROM AUTHOR]

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[R] 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[R] (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[R] (n = 45), injection (n = 45) or COC (n = 40). Significantly more Nuvaring[R] 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[R], 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[R] (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. Keywords: HIV prevention; youth; South Africa; preference; adolescent girls; adherence, 1 | INTRODUCTION South Africa has the highest burden of HIV in the world with a national prevalence of 18.9% [1-3]. Adolescent girls and young women account for 29% of [...]

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. [ABSTRACT FROM AUTHOR]

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. Keywords: Stakeholder engagement; community engagement; ethics review; Research Ethics Committee; Institutional Review Boards; HIV prevention trials, 1 | INTRODUCTION HIV prevention trials are complex endeavours. Ethics guidelines recognize several background complexities with such trials that trigger the need for stakeholder engagement. UNAIDS [1] notes the pragmatic [...]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract Background South Africa is likely to be the first country in the world to host an adolescent HIV vaccine trial. Adolescents may be enrolled in late 2007. In the development and review of adolescent HIV vaccine trial protocols there are many complexities to consider, and much work to be done if these important trials are to become a reality. Discussion This article sets out essential requirements for the lawful conduct of adolescent research in South Africa including compliance with consent requirements, child protection laws, and processes for the ethical and regulatory approval of research. Summary This article outlines likely complexities for researchers and research ethics committees, including determining that trial interventions meet current risk standards for child research. Explicit recommendations are made for role-players in other jurisdictions who may also be planning such trials. This article concludes with concrete steps for implementing these important trials in South Africa and other jurisdictions, including planning for consent processes; delineating privacy rights; compiling information necessary for ethics committees to assess risks to child participants; training trial site staff to recognize when disclosures trig mandatory reporting response; networking among relevant ethics commitees; and lobbying the National Regulatory Authority for guidance.

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Ethics review of psychological and sociobehavioural research is increasingly required by leading South African research institutions and universities, following international trends, and national statutory developments. Local and international scholarly journals are also more routinely requesting proof of ethics approval before accepting empirical work for publication. In some instances, psychological researchers may regard ethics review as a process that imposes delays and adds little value to proposed studies, and they may experience the process as frustrating and unrewarding. This article aims to briefly review the issue of ethics review for such research and to focus on pragmatic recommendations for psychological researchers navigating ethical review, including how they could engage their research ethics committee more effectively to strengthen this critical relationship. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background South Africa is a major hub of HIV prevention trials, with plans for a licensure trial to start in 2015. The appropriate standards of care and of prevention in HIV vaccine trials are complex and debated issues and ethical guidelines offer some direction. However, there has been limited empirical exploration of South African stakeholders' perspectives on ethical guidance related to prevention and care in HIV vaccine trials. Methods Site staff, Community Advisory Board members and Research Ethics Committee members involved with current HIV vaccine trials in South Africa were invited to participate in an exploration of their views. A questionnaire listed 10 care and 10 prevention recommendations drawn from two widely available sets of ethical guidelines for biomedical HIV prevention trials. Respondents (n = 98) rated each recommendation on five dimensions: "Familiarity with", "Ease of Understanding", "Ease of Implementing", "Perceived Protection", and "Agreement with" each ethical recommendation. The ratings were used to describe stakeholder perspectives on dimensions for each recommendation. Dimension ratings were averaged across the five dimensions and used as an indication of overall merit for each recommendation. Differences were explored across dimensions, between care-oriented and prevention-oriented recommendations, and between stakeholder groups. Results Both care and prevention recommendations were rated highly overall, with median ratings well above the scale midpoint. In general, informed consent recommendations were most positively rated. Care-related recommendations were rated significantly more positively than prevention-related recommendations, with the five lowest-rated recommendations being prevention-related. The most problematic dimension across all recommendations was "Ease of Implementing," and the least problematic was "Agreement with," suggesting the most pressing stakeholder concerns are practical rather than theoretical; that is, respondents agree with but see barriers to the attainment of these recommendations. Conclusions We propose that prevention recommendations be prioritized for refinement, especially those assigned bottom-ranking scores for "Ease of Implementing", and/ or "Ease of Understanding" in order to assist vaccine stakeholders to better comprehend and implement these recommendations. Further qualitative research could also assist to better understand nuances in stakeholder reservations about implementing such recommendations. [ABSTRACT FROM AUTHOR]

Globally, there are 5 million young people aged 15-24 years living with HIV, and many more millions are at risk for HIV acquisition. Compelling research questions exist that require the involvement of young people and other vulnerable populations in HIV-related research in diverse settings around the world. Despite this, there remains a reluctance to involve adolescent participants, including young women, in clinical research. Complex and, at times, contradictory legal and ethical requirements can be a challenge. Ethical benchmarks can be applied to ensure that research meets high-level standards and is planned for appropriately. [ABSTRACT FROM AUTHOR]

Community engagement is crucial to ongoing development and testing of sorely needed new biomedical HIV prevention technologies. Yet, negative trial results raise significant challenges for community engagement in HIV prevention trials, including the early termination of the Cellulose Sulfate microbicide trial and two Phase IIb HIV vaccine trials (STEP and Phambili). The present study aimed to explore the perspectives and experiences of civil society organization (CSO) representatives regarding negative HIV prevention trial results and perceived implications for future trials. We conducted in-depth interviews with 14 respondents from a broad range of South African and international CSOs, and analyzed data using thematic analysis. CSO representatives reported disappointment in response to negative trial results, but acknowledged such outcomes as inherent to clinical research. Respondents indicated that in theory negative trial results seem likely to impact on willingness to participate in future trials, but that in practice people in South Africa have continued to volunteer. Negative trial results were described as having contributed to improving ethical standards, and to a re-evaluation of the scientific agenda. Such negative results were identified as potentially impacting on funding for trials and engagement activities. Our findings indicate that trial closures may be used constructively to support opportunities for reflection and renewed vigilance in strategies for stakeholder engagement, communicating trial outcomes, and building research literacy among communities; however, these strategies require sustained resources for community engagement and capacity-building. [ABSTRACT FROM AUTHOR]

Some participants will get HIV-infected in HIV prevention trials, despite risk reduction measures. The subsequent treatment responsibilities of sponsor-investigators have been widely debated, especially where access to antiretroviral therapy (ART) is not available. In this paper, we explore two accounts of beneficence to establish whether they can shed light on sponsor-investigator responsibilities. We find the notion of general beneficence helpful insofar as it clarifies that some beneficent actions will be obligatory where they can be dispensed without scuppering the trial. We find the notion of specific beneficence helpful insofar as it directs investigators to attend to the needs of trial participants; however the range of interventions that could be provided remains unhelpfully broad. We then examine accounts of the investigator-participant relationship to narrow the range of interventions that investigators should provide, concluding that health-care, and HIV infection, are appropriate foci. We conclude that when investigators are able to meet the ART needs of their participants (e.g. referral, assisted referral or direct provision) without sacrificing trial quality, they must do so. However, there is little of this explicit direction to be found in the account of specific beneficence itself, but rather it is found in accounts of the relationship that are compatible with beneficence. [ABSTRACT FROM AUTHOR]

Access to treatment, in HIV vaccine trials (HVTs), remains ethically controversial. In most prevention trials, including in South Africa, participants who seroconvert are referred to publicly funded programmes for treatment. This strategy is problematic when there is inadequate and uneven access to public sector antiretroviral therapy (ART) and support resources. The responsibilities, if any, of researchers, sponsors and public health authorities involved in HVTs has been hotly debated among academics, scholars, representatives of international organizations and sponsors. However, there is little published on community perceptions. Recent guidance asserts that communities should make inputs into treatment and care decisions. This qualitative study explored a South African community's perceptions of who should provide what to HVT participants as well as how and why this should be done. Twenty-nine adults working at or attending five primary health care clinics in two rural areas in KwaZulu-Natal participated in in-depth interviews. Respondents expressed that researchers should ‘help participants to access’ treatment and care ‘because they are in a position to do so’ and ‘are in a relationship with’ trial participants. Respondents suggested that researchers could help by ‘facilitating referral’ until such time that participants can access care and treatment on their own. We highlight a series of implications for researchers in HVTs, including their need to be aware of prospective participants' considerable trust in and respect for researchers, the responsibility that this places on them, and the need for clear communication with communities so as not to erode community trust. [ABSTRACT FROM AUTHOR]

There is little published literature on the ethical concerns of stakeholders in HIV vaccine trials. This study explored the ethical challenges identified by various stakeholders, through an open-ended, in-depth approach. While the few previous studies have been largely quantitative, respondents in this study had the opportunity to spontaneously identify the issues that they perceived to be of priority concern in the South African context. Stakeholders spontaneously identified the following as ethical priorities: informed consent, social harms, collaborative relationships between research stakeholders, the participation of children and adolescents, access to treatment for participants who become infected with HIV, physical harms, fair participant and community selection, confidentiality, benefits, and payment. While there is some speculation that research in developing countries poses special ethical challenges, overall no issues were identified that have not been anticipated in international guidance, literature and popular frameworks. However, the South African context affords a distinctive gloss to these expected issues; for example, respondents were concerned that the predominant selection of black participants may perpetuate racist practices of apartheid. Stakeholders should be aware of contextual factors impacting on the implementation of ethical principles. We make a series of recommendations for South African trials, including amendments to the ethical-legal framework and research policies, and, for further research. [ABSTRACT FROM AUTHOR]

Background: South Africa is likely to be the first country in the world to host an adolescent HIV vaccine trial. Adolescents may be enrolled in late 2007. In the development and review of adolescent HIV vaccine trial protocols there are many complexities to consider, and much work to be done if these important trials are to become a reality. Discussion: This article sets out essential requirements for the lawful conduct of adolescent research in South Africa including compliance with consent requirements, child protection laws, and processes for the ethical and regulatory approval of research. Summary: This article outlines likely complexities for researchers and research ethics committees, including determining that trial interventions meet current risk standards for child research. Explicit recommendations are made for role-players in other jurisdictions who may also be planning such trials. This article concludes with concrete steps for implementing these important trials in South Africa and other jurisdictions, including planning for consent processes; delineating privacy rights; compiling information necessary for ethics committees to assess risks to child participants; training trial site staff to recognize when disclosures trig mandatory reporting response; networking among relevant ethics commitees; and lobbying the National Regulatory Authority for guidance. [ABSTRACT FROM AUTHOR]

An abstract of the article "Participants' Models of HIV Vaccine Trial-related Concepts: The Dilemma of Trust for the Informed Consent Process" by Clinton L. Rautenbach, Graham C. Lindegger and colleagues is presented.

An abstract of the article "Increasing the National Impact and Uptake of Good Participatory Practice Guidelines for Biomedical HIV Prevention (GPP): Three Country Case Studies" by Julius Ecuru, Udom Likhitwonnawut and colleagues is presented.

An abstract of the article "Assessment of Understanding for Informed Consent in HIV Vaccine Trials" by Graham C. Lindegger and colleagues is presented.

The article focuses on preventive therapeutics for the HIV infected adolescents in South Africa. There are over five million HIV-infected people living in South Africa, more than in any other country. According to the UNAIDS, more than a quarter of the world's 40 million HIV-1-infected people are between the ages of 15 and 24, and 700 000 of the new infections that arose in 2003 were recorded in children under 15 years of age. Preventive HIV vaccines have been in clinical trials internationally since 1988 and in South Africa since November 2003. Live-attenuated and whole-killed vaccines are considered too risky for human trials and vaccine development initially relied on the protein subunit approach used successfully for hepatitis B vaccination. The envelope proteins of HIV were tested in clinical trials for several years until it became clear that these vaccines did not elicit a protective antibody response. Efforts were then redirected towards vaccine technology that induces a cellular immune response to more conserved regions of the virus.