Ethical Considerations for Engaging Children and Adolescents Living with HIV in Research in African Countries: A Systematic Review

Abstract

Research engaging children and adolescents living with HIV (CALWH) is critical for youth-friendly services and HIV care, and researchers need to ensure that such engagement is ethical. We conducted a systematic review to identify key ethical considerations for the engagement of CALWH in research. The review focused on primary research articles conducted in African countries that examined ethical issues in CALWH engaged in research. Ten studies met the inclusion criteria; the following seven key domains were extracted: 1) justifications for engaging CALWH in research; 2) community involvement; 3) informed consent/assent; 4) caregiver involvement; 5) perceptions of benefits; 6) perception of the risks of involvement; and 7) confidentiality. These domains can inform the ethical engagement of CALWH in research.

Introduction

Approximately 2.8 million children and adolescents are living with HIV globally, more than 90% of whom live in African countries(UNICEF, 2020). In recent years, advances in HIV treatment have shifted an HIV diagnosis from a terminal illness to a manageable, chronic disease, but physical, mental and social impacts remain, (Avert, 2020; Davies et al., 2016; Frigati et al., 2020; UNICEF, 2021a) and not enough HIV research or treatment options focus on children and adolescents. (Dahourou et al., 2017) In African countries, children and adolescents living with HIV (CALWH) have less access to antiretroviral treatment (ART) than adults, and adolescents have higher HIV-related mortality and worse rates of viral suppression compared to younger children and adults. (Evans et al., 2013; Mwau et al., 2018; Zanoni et al., 2016) CALWH face significant challenges with the need for lifelong medication for HIV, navigating the transitions of adolescence, and growing up in contexts where they are more likely to experience trauma, limited socioeconomic resources, and orphanhood. Despite these multiple vulnerabilities, there is a paucity of guidelines or research on how to ethically engage this population in research to address their HIV-related needs. (Afolabi et al., 2018; Bracken-Roche et al., 2017; Colom & Rohloff, 2018; Kalabuanga et al., 2016; Kongsholm et al., 2018; Lange et al., 2013; MacLeod et al., 2015; Rennie et al., 2017)

Engaging CALWH in research poses complex legal and ethical considerations related to their multiple vulnerabilities, especially in the context of a highly stigmatized infectious disease such as HIV. HIV-related stigma affects the timing and ways in which children and adolescents learn about their HIV status, how they interact with their families and communities, and how they seek and engage in HIV-related care. (McHenry et al., 2016; Parker & Aggleton, 2003; Yebei et al., 2008) In addition, the high rate of orphanhood among CALWH in African countries means that many CALWH are in the care of non-parent family members or institutions, which presents additional ethical challenges, particularly around issues of informed consent for research. (Mamukeyani, 2021; UNICEF, 2021b) Moreover, the history and current manifestations of systemic racism, neocolonialism (particularly in African countries), the disproportionate flow of financial resources for research coming from high-income settings, and the legacy of unethical research conduct and medical experimentation have all led to mistrust in research – and too often created substantial harm. (Crane, 2013; Newman et al., 2011; Saethre & Stadler, 2013) For example, human research practices in African countries have too often neglected adequate consent, (Afolabi et al., 2014; Krosin et al., 2006) withheld information on potential risks and benefits, (Appiah-Poku et al., 2011; Rennie et al., 2017; Vreeman et al., 2012), and disproportionately put the burdens of research on populations that are prevented from benefiting from its’ findings. (Strüver et al., 2022; Taylor-Robinson et al., 2021) All of these concerns mandate a very close examination of the strategies to maximize the ethical conduct of research involving vulnerable populations in these settings.

The ethical considerations of engaging adult vulnerable populations in research, including confidentiality, adequacy of informed consent, and post-trial access to treatment, are better understood. (Brewster, 2011; Dubé et al., 2017; Essack et al., 2010; Goldenberg et al., 2016; Haire et al., 2014; Hlongwa, 2016; Nalubega & Evans, 2015; Raciti et al., 2021) Very few studies, however, have explored the ethical considerations for engaging CALWH in research, particularly in African countries. The objective of this systematic review is to identify and critically analyze studies exploring the ethical considerations for engaging CALWH in research in African countries. With this review, we aim to scope out the key considerations for global researchers and ethics boards to consider when involving CALWH in research in African countries. Such findings may also help to identify critical gaps in procedures or guidelines to support the ethical conduct of research to benefit this vulnerable population of CALWH.

Methods

Search Strategy and Selection Criteria

We searched for articles using the PubMed database on April 19, 2021; the search was re-run in March 2022 and did not return additional articles. The search strategy combined search terms with Boolean operators as follows: (bioethic* OR ethic* OR research ethics OR ethics committee OR bioethics committee) AND (consent OR assent OR understanding OR research subjects OR risks benefits) AND (children OR adolescen* OR young people living with HIV OR YPLWH OR young people OR youth OR people living with HIV OR PLWH OR youth living with HIV OR YLWH OR vulnerable OR marginalized OR caregiver OR guardian OR parent) AND (policy OR guidelines OR framework) AND (Kenya OR east Africa OR KEMRI OR global health OR low-income country OR middle-income country OR low- and middle-income country OR LMIC OR resource-limited setting OR resource limited setting OR RLS OR sub-Saharan Africa OR SSA OR African Region OR global South OR transnational).

Articles were included in this review if they met the following criteria: (1) had a primary objective of examining ethical issues involving research with CALWH 10–23 years, (2) a primary research article, review of primary research, or case study, and (3) pertained to research conducted in African countries. Primary research articles included quantitative, qualitative and mixed method studies. Commentaries and editorials were excluded. Articles that had a multinational focus and included African countries in their analysis were retained. There were no limitations related to publication date or language.

Screening Process

One author (EG) conducted the database search, exported articles to a review management tool, Covidence, (Innovation) and removed duplicates. Two authors (EG and NC) independently screened article titles, abstracts and full text articles and discussed conflicts with a third reviewer (AC) to reach consensus. One author (EG) searched the references of each included article, and screened them for potentially relevant additional articles to include in this review.

Data Extraction and Analysis

Two authors (EG and NC) extracted data from the included studies in a Google Sheets database. A data extraction guide was created to record the following: author, publication year, study type, study site, publication journal, objective, outcome measures, legal, policy or ethical framework used for analysis (if applicable), findings and recommendations. One author (EG) synthesized the data using inductive analysis to identify and organize the ethical considerations and topics discussed across the studies into themes, which were discussed and refined in consultation with other authors (NC, DL, AC, MS). Major findings from each theme were summarized and compared across articles.

Results

The database search yielded 10,404 articles; after removing 82 duplicate results, 10,322 peer-reviewed articles were screened for title and abstract (Figure 1). A large number of articles did not meet inclusion criteria at the title and abstract phase and were subsequently excluded. Two authors (EG and NC) conducted full text review of 49 articles; 36 were from the initial search results and 13 from the references of screened articles. The majority of articles were excluded because they only included adult populations (n = 29); other articles were excluded for not focusing on youth living with HIV (n = 1), not meeting study type criteria (n = 2), and not explicitly discussing ethical issues relevant to CALWH (n = 1). Ten articles met the inclusion criteria and were included for review. One article, Vreeman et al. [2012], was included despite not involving CALWH in research, because HIV and its implications for the ethical inclusion of CALWH in research were an important part of the study’s context and findings. Figure 1 summarizes our screening and inclusion process.

Figure 1.

PRISMA Diagram.

Of the ten studies, five were conducted in Kenya, two in South Africa, one in Zimbabwe, one in Zambia and one from the PAT3CH consortium, which involves Brazil, Kenya, Mozambique, Nigeria, South Africa, Uganda, Zambia. Four studies utilized qualitative research, three were case studies, two used mixed methods, and one was a scenario analysis supplemented by a scoping review. One study included only children, six studies focused on adolescents, one study included both children and adolescents, and two studies included subject matter experts and community members discussing CALWH. The majority (N=6) of studies focused primarily on broad ethical challenges; others focused on issues surrounding informed consent (N =2), caregiver involvement in CALWH research (N=1), and recruitment of CALWH for research (N=1). All articles included researchers from the countries in which the research was based, and three articles had first authors reporting primary affiliations with institutes in African countries.

We describe the aims, inclusion criteria and methods of the included articles in Table 1. In analysis of these articles, the following 7 domains emerged as areas for consideration to conduct ethical research with CALWH: 1) justifications for including CALWH in research; 2) community involvement in CALWH participation; 3) informed consent and assent; 4) caregiver involvement in the research process; 5) perceptions of benefits of research; 6) perception of the risks of involvement in research; and 7) confidentiality (Figure 2). The key findings from each of these domains are summarized in Table 2, with a column for each major domain emerging from the data, and then explored in greater detail in the following paragraphs.

Table 1.

Characteristics of Included Studies.

Article	Study Site	Article Type	Study Population/Inclusion Criteria	Objective
Bwakura-Dangarembizi etal. (2012) *	Zimbabwe	Case study of HIV trial	Previously untreated CALWH aged 3 months to 17 years eligible for ART (n = 400).	Report on researchers’ experiences in obtaining informed consent to enroll orphaned children into an HIV trial in Zimbabwe.
Day et al. (2020)	PAT3CH1 Consortium (Brazil, Kenya, Mozambique, Nigeria, South Africa, Uganda, Zambia)	Scenario analysis and scoping review	Two scenarios from the international research consortium, and full-length articles or reports describing enhancing adolescent HIV research participation through modified consent processes in LMIC contexts.**	Identify ethical and practical challenges to adolescent consent for research in these countries and conduct a scoping review of strategies to improve their participation in HIV studies in LMICs.
Groves et al. (2018)	Kenya	Qualitative study using focus group discussions with youth advisory boards	Adolescents 15–19 years old in youth-based institutions (i.e., schools, youth centers and compassion homes) (n = 40; n = 8 self-identified as living with HIV).	Understand adolescents’ perspectives on parental involvement in research studies on HIV, particularly during consent and disclosure of testing results.
Mackworth-Young et al. (2019)	Zambia	Qualitative study using ethnographic methods	Middle-income adolescent women living with HIV, 17–19 years old, receiving care at one of 2 health facilities in Lusaka (n = 7).	Explore ‘ethics in practice’ involved with studying middle-income young women living with HIV through an ethnographic study.
Rennie et al. (2017)	Kenya	Qualitative study using focus group discussions with community and youth advisory boards	Adolescents and stakeholders involved in institutions working with any youth population (i.e., government offices, churches, non-governmental organizations, HIV comprehensive care centers, compassion homes, schools) (n = 68).	Solicit opinions about conducting HIV adolescent research appropriately; focusing on community perceptions of benefit in such studies.
Simons-Rudolph et al. (2020)	Kenya	Mixed methods study using baseline survey, rapid HIV testing, and 2-month follow-up interviews	Adolescents aged 15–19, had never tested positive for HIV and had not been tested in the past 6 months (n = 4096); interviews conducted with all those with positive or inconclusive HIV tests (n = 35) and every 30th adolescent with a negative test (n = 47).	Better understand effective strategies for recruiting youth for HIV studies, motivations for participation, perceptions of HIV testing in a research context, and participants’ understanding of the risks of participation.
Singh et al. (2006) *	South Africa	Case study of HIV vaccine trial	Adolescents older than 18 from a prenatal and family planning clinic.**	Present ethico-legal challenges of the study and explore the scientific and social grounds for excluding adolescents in HIV observational studies.
Vreeman et al. (2009)	Kenya	Case study of pharmacokinetics trial	CLWH aged 3–13 who were initiating antiretroviral therapy with nevirapine.**	Explore issues that arise when conducting pediatric research in resource-limited settings.
Vreeman et al. (2012)	Kenya	Qualitative study using Mabaraza (traditional community assemblies)	Provincial administration (chief, assistant chief, village elders), caregivers of orphaned and separated children, and members of the general public. (n = 108)	Inform ethical research practices involving vulnerable children in resource-limited settings with a focus on the involvement of orphans and street children in research, using dialogic engagement with community members about pediatric research and informed consent.
Woollett et al. (2017) *	South Africa	Mixed methods study using standard mental health assessments	ALWH aged 13–19 enrolled in care at one of five clinics in Johannesburg (n = 343).	Explore legal and ethical issues related to conducting mental health research for ALWH in South Africa.

¹Prevention and Treatment through a Comprehensive Care Continuum for HIV-affected Adolescents in Resource Constrained Settings

^*First author reporting affiliation with an institute in African country

^**Sample size not disclosed in article

Figure 2.

Key Domains of Ethical Engagement of CALWH.

Table 2.

Study Findings Organized by Domains for the Ethical Conduct of Research with CALWH.

	Domains
Article	Justification for CALWH Inclusion	Community Involvement	Informed Consent/Assent	Caregiver Involvement	Benefits	Risks	Confidentiality
Bwakura-Dangarembizi etal. (2012)	Not discussed	Ethics committees should consult community to ensure study aims and procedures align with local cultural context	Not discussed	Legal guardian consent is required for CALWH under 18, despite the fact that many caregivers are not legal guardians	Not discussed	Not discussed	Not discussed
Day et al. (2020)	Biological differences between youth and adults living with HIV; access to potential benefits, HIV burden is large in LMICs; youth can adequately understand study risks	Communities could act as surrogates for informed consent for CALWH	Obtaining youth consent is a roadblock to participation: ethical guidelines are inconsistent or absent on this subject, regulations fail to recognize variety in adolescents’ lived experiences. In South Africa, the National Health Act requires guardian consent and child consent if they have understanding for the participation of individuals younger than 18 years. However, the DOH include provisions for waiving guardian permission for individuals younger than 18 years in various circumstances.	Caregiver consent is required for minors, and may be waived for mature or emancipated minors	ALWH should be involved in research to access potential direct benefits	Discrepancies in local practices could exclude adolescents from participation in some South African HIV studies.	Not discussed
Groves et al. (2018)	Youth perspectives have been missing in discourse about HIV research	Not discussed	The concept of the adolescent as an “autonomous individual” did not resonate widely with adolescents in the study	Research guidance in Kenya has provisions to allow for adolescent participation without caregiver consent by invoking the value of personal autonomy	Adolescent participants felt benefits of parental involvement include support and helping HIV-negative youth remain HIV-negative	Adolescent participants felt parental involvement may help protect CALWH from exploitation and community gossip; acknowledged risk of parental retribution upon discovering an HIV diagnosis	Benefits of parental support during the HIV testing and research process may outweigh the potential loss of confidentiality
Mackworth-Young et al. (2019)	SSA has high youth HIV burden and is understudied	Forming youth advisory boards could make research more participatory	ALWH consent was required regardless of age	Caregivers and ALWH were consulted for consent despite participants being over 18 years	Perceived benefits may include non-material benefits such as psycho-emotional support from research staff	Youth participants demonstrated ability to weigh risks of HIV status disclosure against perceived benefits when faced with a decision regarding keeping study materials for themselves	The practicality of maintaining participants’ confidentiality was ethically challenging as the investigator at times had to lie to hide participants’ HIV status from others; participants decided whether to keep study-related materials and determined their own risk of breached confidentiality
Rennie et al. (2017)	Biological differences between youth and adults with HIV, high burden of HIV in youth in SSA	Community engagement should inform protocols and improve trust and understanding about research	Ensuring participants have adequately understood the contents of informed consent is a fundamental requirement	Not discussed	Most participants reported receiving individual benefits such as social support and information from participation; socioeconomic status likely affects perceptions of benefits	Reported risks included negative reactions to discovering HIV positive status; risks were outweighed by perceived benefits	Not discussed
Simons-Rudolph et al. (2020)	Not discussed	Community involvement is important for recruitment and offsetting power differentials and mistrust	Kenyan guidelines stipulate that the legal age of majority (18) is the required age of consent for research	Caregiver consent is not required for youth over 18 years	The expectation of HIV testing and the false hope of financial assistance motivated participation	More than half of respondents did not demonstrate an understanding of study risks	CALWH cited confidentiality as being important when deciding to participate in a study
Singh et al. (2006) 1	WHO guidelines give no justification for excluding CALWH; there is an ethical duty of beneficence	Research ethics committees should be informed by communities, especially regarding CALWH consent	South African guidelines list 14 as the autonomous age of consent for therapeutic research only.	Caregiver consent can be logistically impossible due to requirements for legal guardians, necessitate breaching participant confidentiality and increase participant’s risk	Not discussed	Study risks may involve requiring caregiver consent and associated loss of confidentiality	Confidentiality for CALWH participants is at risk when caregiver consent is required
Vreeman et al. (2009)	Biological differences in HIV treatment by age	Community engagement should involve consulting local institutional research ethics committees	US IRB recommends assent from children 7 years and older; Kenyan ethical committees recommend assent for ages 14 years and older	Adults are typically given the decision-making role in Western Kenya; guidelines stipulate that children’s objections should be respected regardless of caregiver’s consent	Potential research subjects may be swayed by misconceptions that research will directly benefit them	Not discussed	Not discussed
Vreeman et al. (2012)	CALWH should be included in research so that their own communities can benefit	Communities may provide proxy consent for CALWH participation; community involvement is an important protective measure in research	Age of consent is generally regarded as 18 years; consent requirements should consider the maturity and capability of youths	Caregiver consent is required for minors (below 18 years), participants without caregivers may get consent from community chief or government representatives	Participants expect both individual and community benefits such as protection, knowledge, health care, and financial assistance	Participants primarily cited risks as missing out on presumed benefits of research; some participants reported concerns that their child would not be allowed to return home	Not discussed
Woollett et al. (2017)	CALWH have unique HIV-related risks and there is a gap in research in this population	Communities should advise on all aspects of the research project in order to manage the power dynamics with researchers and establish trust	Youths 14 years and older are capable of making competent decisions about research participation; questions should be added to informed consent to ensure understanding	Requirements for caregivers to be legal guardians may inhibit CALWH research participation since many CALWH are orphans	CALWH anticipate direct benefits from participation; youth participants may put more emphasis on benefits than risks	Risks include CALWH losing confidentiality to their parents where caregiver consent is required	The requirement of caregiver consent may violate confidentiality; confidentiality may need to be compromised by reporting mandates in extreme situations (such as abuse or neglect)

¹The Child Care Act of 1983, (Act) which designated 14 years as the age of consent, has now been repealed. Under the 2003 National Health Act, (Hassim et al., 2008) the age of consent in South Africa for health-related research is 18 years. Under the 2005 Children’s Act, (Proudlock & Jamieson, 2008) the age of consent for medical treatment is 12 years if the child is determined to have sufficient maturity and capacity.

Justification for Including Children and Adolescents in Research

Eight papers included in this review addressed the ethical justifications for including CALWH in HIV research, all noting that researchers have an ethical duty based on beneficence and justice to conduct research with this group. (Day et al., 2020; Groves et al., 2018; Mackworth-Young et al., 2019; Rennie et al., 2017; Singh et al., 2006; Vreeman et al., 2012; Vreeman et al., 2009; Woollett et al., 2017) Authors noted that research conducted with CALWH in high-income settings may not translate to other settings, especially in African countries that have a large burden of HIV among children and adolescents. (Day et al., 2020; Mackworth-Young et al., 2019; Rennie et al., 2017; Singh et al., 2006) Authors highlighted that CALWH perspectives are missing from and necessary to inform ethical research studies, and that CALWH should have access to the benefits associated with research, including basic health services. (Woollett et al., 2017) (Day et al., 2020; Groves et al., 2018; Rennie et al., 2017; Vreeman et al., 2012) Others highlighted the biological differences between adult and pediatric groups as a reason for engaging CALWH in research, noting unique ART dosing considerations (Day et al., 2020; Rennie et al., 2017; Vreeman et al., 2009), HIV-related morbidity and mortality risks, and mental health risks associated with long-term treatment. (Woollett et al., 2017)

Community Involvement

Most articles (N = 9) highlighted the role of community involvement in research; “community” was used to describe the people, groups and structures surrounding CALWH, including key stakeholders such as local leaders and school and health administrators. Community engagement was recommended as a strategy to manage participant-researcher dynamics, ensure participant safety, (Bwakura-Dangarembizi et al., 2012; Day et al., 2020; Mackworth-Young et al., 2019; Rennie et al., 2017; Simons-Rudolph et al., 2020; Singh et al., 2006; Vreeman et al., 2012; Vreeman et al., 2009; Woollett et al., 2017) inform the cultural and age-appropriate participation of CALWH in research(Bwakura-Dangarembizi et al., 2012; Singh et al., 2006; Vreeman et al., 2009) (Vreeman et al., 2012; Woollett et al., 2017) and provide sociocultural context in international research collaborations. (Mackworth-Young et al., 2019; Simons-Rudolph et al., 2020; Woollett et al., 2017) For adolescents, who may require additional support in decision-making, and particularly those living in LMIC where communities play a larger role in the raising of children and adolescents, community engagement in research participation is critical. Additionally, as orphanhood is high among adolescents in African countries, where the burden of HIV is highest, community participation may fill the consenting gap typically filled by biological parents. (Strode & Essack, 2022) Deeper community engagement throughout the research process may be important for off-setting power differentials in the participant-researcher relationship(Rennie et al., 2017; Simons-Rudolph et al., 2020; Woollett et al., 2017) and support informed consent decision-making when caregivers are not available or where caregivers may not have the best interests of the youth in mind. (Day et al., 2020; Vreeman et al., 2012) The formation of youth advisory boards to advise on research design, analysis and interpretation has frequently been suggested to make research more participatory. (Groves et al., 2018; Rennie et al., 2017) Lastly, community involvement was seen as an important component to ensure that study recruitment efforts are fair, respect individuals’ privacy and confidentiality, and ensure participants’ safety. (Mackworth-Young et al., 2019; Simons-Rudolph et al., 2020)

Participant Informed Consent and Assent

Most (N = 9) articles discussed the age of consent and requirement of youth’s assent for research. (Day et al., 2020; Groves et al., 2018; Mackworth-Young et al., 2019; Rennie et al., 2017; Simons-Rudolph et al., 2020; Singh et al., 2006; Vreeman et al., 2012; Vreeman et al., 2009; Woollett et al., 2017) Age of consent varied by country. In Kenya, Uganda, Zambia and Brazil, caregiver consent is required for participants under 18; adolescents in Mozambique are considered minors until the age of 21; there was no clear legislation on the matter in Nigeria. (Day et al., 2020; Simons-Rudolph et al., 2020; Singh et al., 2006) Singh and colleagues reported on the Child Care Act of 1983, (Singh et al., 2006) which designated the age of consent for therapeutic research in South Africa at 14 years. This age was used as a justification for enrolling children into therapeutic studies with self-consent at 14 as therapeutic research was equated with medical treatment and the age of self-consent to medical treatment was set at 14. The law was subsequently changed and the argument fell away as the National Health Act set the age of consent to all forms of research at 18 years. (Hassim et al., 2008) While not reported in the included articles, it is important to note that South Africa has subsequently made two important legal changes to consent processes: The National Health Act established the National Health Research Ethics Council, which provided additional guidelines in 2015 that no-longer separates research into therapeutic or non-therapeutic approaches, and allows for parental waivers in key circumstances. Additionally, under the Child Care Act of 1984, the age of consent to medical treatment under specific circumstances was changed from 14 years to 12.

One article viewed the age requirement to provide informed consent as a barrier to participation in research, noting that it does not accommodate for a variety of living situations and experiences of adolescents, and eliminates participants under the age of 18 who wished to participate but were not able to without caregiver consent. (Day et al., 2020) Participants in Kenya thought that certain groups, such as orphans, street children and others living independently, should be able to consent for themselves even if they are minors because they are living independently. (Vreeman et al., 2012) Guidelines varied for the age of assent, which can present ethical challenges for multinational research teams; in one study, an Institutional Review Board in the United States recommended mandating assent from children aged 7 years or older, whereas the Kenya Institutional Research and Ethics Committee implemented assent procedures for adolescents 14 years and older. (Vreeman et al., 2009) In this situation with conflicting recommendations, the final consensus was to follow the more conservative recommendation, and assent was required of children ages 7 years and older.

The capacity to assent was viewed as more dependent on maturity than age, noting that school-age children may be capable of meaningful assent, and adolescents 14 years and older were as capable as adults in making competent decisions. (Singh et al., 2006; Vreeman et al., 2012; Vreeman et al., 2009; Woollett et al., 2017) One study, however, suggested that the concept of the adolescent as an “autonomous young individual” did not resonate with Kenyan adolescents. (Groves et al., 2018) Studies highlight the need for practical mechanisms to ensure participant understanding during the consent process, such as thorough questions about study risks and benefits in the informed consent process. (Rennie et al., 2017; Woollett et al., 2017)

Caregiver Consent

Most (N = 9) articles addressed caregiver consent in adolescent research (Bwakura-Dangarembizi et al., 2012; Day et al., 2020; Groves et al., 2018; Mackworth-Young et al., 2019; Simons-Rudolph et al., 2020; Singh et al., 2006; Vreeman et al., 2012; Vreeman et al., 2009; Woollett et al., 2017) and cited requirements for such consent for minors involved in research. (Bwakura-Dangarembizi et al., 2012; Day et al., 2020; Groves et al., 2018; Simons-Rudolph et al., 2020; Singh et al., 2006; Vreeman et al., 2012; Vreeman et al., 2009; Woollett et al., 2017) All seven countries in the PAT3CH consortium (Brazil, Kenya, Mozambique, Nigeria, South Africa, Uganda, Zambia) required parent or legal guardian consent for adolescents under the age of majority, but waived the requirement for emancipated and mature minors, the definitions of which vary by country. (Day et al., 2020) Adolescent participants had varying perspectives on caregiver consent—some did not want to participate in research where caregiver consent was required due to fear of disclosure of their HIV status; (Singh et al., 2006) others thought the caregiver should be involved to protect adolescents from deception while involved in a research study or provide support when receiving HIV test results. (Groves et al., 2018) Caregivers and community members in Kenya believed that caregiver consent should be required up to 18 years of age, and when no caregiver can provide consent, researchers should work with the village chief or government arm responsible for children to obtain consent. (Vreeman et al., 2012)

Perceptions of Benefits

Eight studies discussed perceptions of the benefits of adolescent participation in HIV research, including direct, individual and community benefits. (Bwakura-Dangarembizi et al., 2012; Day et al., 2020; Groves et al., 2018; Mackworth-Young et al., 2019; Rennie et al., 2017; Simons-Rudolph et al., 2020; Vreeman et al., 2012; Vreeman et al., 2009; Woollett et al., 2017) Access to potential benefits was cited as one of the ethical justifications for the inclusion of CALWH in research, (Day et al., 2020) despite reports that adolescents often do not fully understand said benefits or risks. (Rennie et al., 2017; Woollett et al., 2017) Despite research studies not offering tangible benefits, participants reported receiving other benefits in the form of psycho-emotional support from research team members and caregivers, participation in reflective activities, relationship-building with researchers, HIV testing, and counseling. (Bwakura-Dangarembizi et al., 2012; Groves et al., 2018; Mackworth-Young et al., 2019; Rennie et al., 2017; Simons-Rudolph et al., 2020) Additionally, in a study in Kenya, despite not receiving monetary benefits as part of a study, adolescent participants cited financial compensation as a major reason for participation. (Simons-Rudolph et al., 2020) Vreeman et al. [2009] reported concerns that financial reimbursements for participation may influence potential participant decision-making regarding consent, particularly among orphans or those in vulnerable socioeconomic positions, who may depend on financial assistance or other incentives associated with research. (Rennie et al., 2017; Vreeman et al., 2009) An informed consent process that confirms adequate understanding of the benefits, risks, and study procedures can help protect research participants. (Rennie et al., 2017; Vreeman et al., 2012)

Risks of Involvement

Eight articles addressed the typical risks– potential loss of confidentiality, discomfort with interview questions and physical discomfort from needle pricks during HIV testing —and perceptions of these risks associated with CALWH involvement in research. (Groves et al., 2018; Mackworth-Young et al., 2019; Rennie et al., 2017; Simons-Rudolph et al., 2020; Singh et al., 2006; Vreeman et al., 2012; Woollett et al., 2017) Adolescent and caregiver understanding and consideration of study risks was viewed as incomplete, and overshadowed by perception of expected benefits. (Rennie et al., 2017; Simons-Rudolph et al., 2020) Despite this, some authors report that young participants are capable of balancing the risks and benefits of research when given adequate information and autonomy. (Day et al., 2020; Mackworth-Young et al., 2019) Adolescent participants identified social stigma, pain from needle prick for HIV testing, and parental retribution upon learning about their child’s HIV status or sexual activity as risks of involvement in research. (Groves et al., 2018; Rennie et al., 2017; Simons-Rudolph et al., 2020; Singh et al., 2006; Woollett et al., 2017) Authors reported that some youth participants were willing to take these risks for altruistic reasons. (Rennie et al., 2017; Woollett et al., 2017) Caregiver-perceived risks included not receiving presumed benefits from the research, such as access to treatment, and the research leading youth to participate in dangerous behavior, such as “sexual immorality or theft” after learning more about HIV. (Vreeman et al., 2012) Perceptions of risks may be inaccurate when weighed against potential benefits, and a thorough understanding of related risks is important prior to CALWH participation in research.

Confidentiality

Half of the articles discussed the role of confidentiality in CALWH decision making, particularly in the context of stigmatization and discrimination associated with accidental disclosure of one’s HIV status(Groves et al., 2018; Mackworth-Young et al., 2019; Simons-Rudolph et al., 2020; Singh et al., 2006; Woollett et al., 2017) Adolescents report concerns regarding other people learning of their HIV status and considering who would have access to their HIV test results before deciding to participate (Simons-Rudolph et al., 2020); some researchers had to use cover-up stories about the purpose of their research in order to prevent unintentional disclosure to family and community members. (Mackworth-Young et al., 2019) These concerns are also held by caregivers who may delay disclosure to the child due to fears of others finding out. Authors also mentioned, however, that in the event of extreme circumstances such as suspected abuse, exceptions to maintaining confidentiality might be legally unavoidable. (Woollett et al., 2017) Articles described measures to improve participants’ autonomy in addressing confidentiality issues, including giving participants the choice to keep study-related diaries with sensitive information, and to improve discreet reporting of sensitive questions through technology such as tablets or computers. (Mackworth-Young et al., 2019; Woollett et al., 2017)

Discussion

This review identified 10 research articles that addressed the ethical considerations of engaging children and adolescent living with HIV in research in African countries, and seven domains for investigators to consider when formulating ethical research with CALWH in these settings (Figure 2). The included studies unanimously indicated that the inclusion of CALWH in HIV research is justified and ethically necessary, and most authors argued that community involvement can help mitigate potential ethical challenges. Views on informed consent and assent for youth participants and their caregivers varied, suggesting a need for more universal guidelines on age and capacity-specific requirements for consent. The role of caregivers in research is critical to consider in this population, and further guidelines on the involvement of caregivers in the context of emancipated minors and CALWH without parents or legal guardians, and in engaging youth in behaviorally sensitive research studies, would be beneficial. Privacy and confidentiality remains a significant concern when involving caregivers in the research process, particularly due to the fear of their caregiver learning of their HIV status. The age of consent in these circumstances has been raised extensively, and the South Africa National Research Ethics Guidelines allow for a waiver of parental consent be used in favor of adolescent self-consent in certain circumstances. (Slack & Strode, 2016; Strode & Essack, 2022; Strode et al., 2018; Worku et al., 2016) Adolescent self-consent may be granted for those over 16 years if the study is minimal risk, has received engaged the community on research questions, and investigates behaviorally sensitive information. (Strode & Essack, 2022)Interestingly, discussion of and research studies related to adolescent self-consent remains limited in African countries. Broader community involvement in studies with vulnerable children and adolescents may facilitate increased participation, but should be balanced with increasing options for adolescents to provide self-consent, especially in studies related to stigmatized issues.

The literature suggests it can be difficult for CALWH to accurately recall and weigh benefits against study risks. (Rennie et al., 2017; Simons-Rudolph et al., 2020) This is consistent with other reports on HIV research ethics with vulnerable populations, including a study that found pregnant women living with HIV also struggled to accurately weigh risks and benefits of research participation. (Raciti et al., 2021) These findings suggest the need for researchers to improve the cultural and age-appropriate adaptations of consent forms and processes used to help participants and their families understand the risks and benefits of participation. Confidentiality and the fear of accidental disclosure were common themes among the included articles, and many adolescents cited confidentiality as a major reason for wanting minimal engagement with caregivers throughout the research process. Alternatively, one study reported that CALWH did want their caregivers involved for support during the HIV testing and research processes. Some authors also suggested a more active role for the community to engage in the research process to ensure studies were appropriate and to prevent youth participants from being taken advantage of.

A common thread between these emerging themes was the concept of fear of accidental disclosure and HIV stigma. Adolescent research participants commonly cited accidental disclosure of HIV status as a risk of participation, and it is critical to consider that this may involve subsequent risks such as discrimination, violence, or being ousted from their home. (Mackworth-Young et al., 2019; Woollett et al., 2017) Some authors in this review mentioned strategies such as using technology to collect sensitive information to prevent accidental disclosure or keeping participants’ study-related journals so that they were not found by family or friends. (Mackworth-Young et al., 2019) Other literature suggests the use of protocols that include working with participants to identify research activities that could potentially compromise confidentiality or providing participants with a guide to protecting their privacy in daily life. (Mustanski et al., 2017) Evaluating and understanding the level of community-based HIV-related stigma in a given context could be critical for researchers to adequately protect their CALWH from the risks of stigma associated with study participation.

Best Practices

This review identified several key domains related to the ethical involvement of CALWH in HIV research in African countries, while also noting some potential areas requiring further inquiry. The inclusion of CALWH in HIV research is both ethically justified and necessary, considering their unique vulnerabilities in HIV treatment. These domains may be used by researchers, ethics committee members or other stakeholders in institutions conducting research to develop guidelines or processes for ethically engaging CALWH in research. The limited body of research reviewed in this article suggests that local communities should be involved in the research process in some capacity, that caregiver involvement and consent requirements must be considered with nuance, and that additional, age-appropriate strategies to ensure that adolescents understand and weigh benefits and risks are needed.

This review was limited to research conducted in African countries, which may limit its generalizability to other settings. This narrow scope allows for in-depth insight into the opinions of adolescents, caregivers, communities and researchers in African countries, which is critical considering the large burden of HIV in this population, and the number of global health research partnerships hosted by African researchers. Similarly, due to the paucity of literature among children and adolescents separately, we focused on the broader CALWH group, which may have limited the specific applicability of the findings. The literature search resulted in only 10 articles, which may have been the result of highly specific criteria that excluded ethical considerations for all research other than that involving CALWH. While this limits the applicability of these findings to other types of research, it provides important considerations for conducting research with individuals already living with HIV, and highlights the lack of research and need for future studies on this topic. Finally, this review searched only articles in the PubMed database, which may have missed relevant articles from other databases. We used PubMed because it is most likely to capture relevant articles; we searched the references of included articles to identify additional relevant literature. Further studies may be conducted using databases other than PubMed.

Research Agenda

Few articles considered the views of adolescents themselves; adolescents’ engagement is needed to better understand their concerns and needs related to participation in research. Although some authors suggested that community leaders may act as surrogates and provide informed consent for CALWH participants without legal guardians, there was no discussion of the potential ethical challenges of this strategy for participants who do not want their HIV status or participation in research known. Considering how frequently the fear of disclosure and stigma were mentioned in relation to research participation, and the proposed role of community members providing consent or knowing about youth’s participation in studies, there appears to be tension between the role of confidentiality and community involvement in the research process. This conflict also necessitates further investigation.

The research presented in this review also described power differentials between participants and researchers; however, none of the included studies discussed these power dynamics in terms of international research collaborations between high-income countries and LMICs. One study described a multinational collaboration between Kenya and the U.S. and the challenges and associated strategies to address differences in regulations surrounding the requirement of assent from minors. Other recent literature proposes establishing partnerships that are guided by clear frameworks developed by diverse stakeholders but designated by the LMIC of implementation; the foundation of multi-national research consortia may help facilitate these changes. (Jao et al., 2015; Munung et al., 2017; Pratt & Hyder, 2016) Ensuring that framework and guideline designation be conducted by LMIC partners may support better implementation of culturally relevant and age appropriate programs for CALWH, and should be viewed as an investment in scientific development and autonomy for partner sites. These efforts may help to counter-act the historical effects of colonialism and systemic racism, have the capacity to breed trust between researchers and shift existing power differentials within international research teams Continued research is necessary to evaluate power differentials between international research teams and funding sources for research with CALWH in LMICs, and should include considerations of the impacts of systemic racism and neo-colonialism in medicine.

Although the literature identified in this review touched on the topics of disclosure, stigma, privacy and the roles of ethics committees through discussion of broader topics, none of these ideas were emphasized. Considering the importance of these topics, further investigation is warranted on the role of these concepts in research involving CALWH, and these domains may need to be added to the list for consideration (Figure 2).

Educational Implications

The list of key domains identified in this review may be used as a guide for investigators, ethics committee members and research staff for developing knowledge about the ethical engagement of CALWH in research. These domains should supplement broader ethical education including principles of beneficence, nonmaleficence, autonomy and justice. (Varkey, 2021)

Biographies

Emma Gillette Emma Gillette is a Clinical Research Coordinator at the Icahn School of Medicine at Mount Sinai, where her main research interests are global health, pediatric HIV, and the development of youth-friendly HIV services. She has experience coordinating research which engages children and adolescents living with HIV, and for this review she conducted the literature search, screened the articles, wrote the first draft of the manuscript, and incorporated co-authors’ insights.

Winstone Nyandiko Prof. Winstone Nyandiko is a professor at Moi University College of Health Sciences, and his primary research interests include pediatric and adolescent HIV in western Kenya. He contributed to the conception of the idea for this review and revised the manuscript.

Ashley Chory Ashley Chory is a Senior Program Manager for Adolescent Health Programs at the Arnhold Institute for Global Health at the Icahn School of Medicine at Mount Sinai. Her research experience and interests focus on adolescent health. For this study, she contributed to idea conceptualization, resolved conflicts in article screening between EG and NC and participated in the development and revisions of the manuscript.

Michael Scanlon Michael Scanlon is the Assistant Director of Research at Indiana University, and his primary research interests include pediatric and adolescent HIV, particularly through the use of qualitative methods. His contributions to this review included idea conceptualization and reviewing of manuscript drafts.

Josephine Aluoch Josephine Aluoch is a Research Program Manager at AMPATH. Her primary research interests include pediatric and adolescent HIV. In this study, she reviewed manuscript drafts and provided overall insight.

Nandini Choudhury Nandini Choudhury is a doctoral student in Population Health at the NYU Grossman School of Medicine, New York, NY, USA. Her research experience and interests lie at the intersection of health inequities and implementation research using mixed methods, especially in low and middle income countries. At the time of this study, she worked as a Data Analyst at the Icahn School of Medicine at Mount Sinai. For this study, she screened articles together with the first author, extracted and analyzed data, and reviewed the manuscript.

Daniel Lagat Daniel Lagat’s primary research interests include pediatric and adolescent HIV and bioethics. For this study, he helped develop the search criteria for the review, provided insight on analysis, and reviewed manuscript drafts.

Celestine Ashimosi Celestine Ashimosi is a Research Coordinator for AMPATH. Her research interests focus on pediatric and adolescent HIV in western Kenya, and she has experience facilitating research involving CALWH. For this study, she reviewed drafts of the manuscript.

Whitney Biegon Whitney Biegon is a Peer Navigator for AMPATH. Her research interests focus on pediatric and adolescent HIV in western Kenya, and she has experience facilitating research involving CALWH. For this study, she reviewed drafts of the manuscript.

Dennis Munyoro is a Peer Navigator for AMPATH. His research interests focus on pediatric and adolescent HIV in western Kenya, and he has experience facilitating research involving CALWH. For this study, he reviewed drafts of the manuscript.

Janet Lidweye is a Research Assistant for AMPATH. Her research interests focus on pediatric and adolescent HIV in western Kenya, and she has experience facilitating research involving CALWH. For this study, she reviewed drafts of the manuscript.

Jack Nyagaya Jack Nyagaya is a Research Assistant for AMPATH. His research interests focus on pediatric and adolescent HIV in western Kenya, and he has experience facilitating research involving CALWH. For this study, he reviewed drafts of the manuscript.

Ilene Wilets a bioethicist at the Icahn School of Medicine at Mount Sinai. Her research interests include medical and research ethics, human subjects protection regulation, decision making for research participation, and global health research. Her role in the current study included content oversight by providing ethical expertise, and review of all manuscript drafts.

Allison DeLong is a biostatistician and data scientist in the Center for Statistical Sciences at the School of Public Health at Brown University in Providence, RI, USA. She has contributed to numerous studies of CALWH based in Kenya and other settings. For this study, Allison reviewed the criteria for the literature search and provided comments on the methods and presentation of results.

Rami Kantor Rami Kantor is Professor of Medicine at the Division of Infectious Diseases at Brown University in Providence, RI, USA. He is a physician scientist and the co-principal investigator of the parent and supplement grants that originated and supported this study. He has multidisciplinary expertise in HIV research in diverse settings and populations, with a focus on transmission, monitoring, treatment failure and drug resistance.

Violet Naanyu Prof. Violet Naanyu is a Professor in the Department of Sociology, Psychology and Anthropology at the Moi University School of Arts and Social Sciences. Her research interests focus on medical sociology, medical anthropology, and global bioethics, particularly for vulnerable populations. For this project, she aided in the study design and provided review of final manuscript drafts.

Rachel Vreeman Dr. Rachel Vreeman is the Chair and Director of the Department of Health System Design and Global Health, and her research interests primarily include pediatric HIV, health systems strengthening, and adolescent health. She provided expertise for the conceptualization of the idea for this review, and careful review of all manuscript drafts.