The ethics of exclusion: why pregnant and lactating women must be front and centre of HIV research

Journal of the International AIDS SocietyVolume 25, Issue S2 e25926 ViewpointOpen Access The ethics of exclusion: why pregnant and lactating women must be front and centre of HIV research Jerome Amir Singh, Corresponding Author Jerome Amir Singh singhj9@ukzn.ac.za orcid.org/0000-0002-6275-6853 Howard College School of Law, University of KwaZulu-Natal, Durban, South Africa Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada Corresponding author: Jerome Amir Singh, Howard College School of Law, University of KwaZulu-Natal, King George V Ave, Durban 4041, South Africa. (singhj9@ukzn.ac.za)Search for more papers by this authorDhayendre Moodley, Dhayendre Moodley orcid.org/0000-0003-1849-9631 Department of Obstetrics and Gynaecology, School of Clinical Medicine, and Centre for the AIDS Programme of Research in South Africa, University of KwaZulu-Natal, Durban, South AfricaSearch for more papers by this authorMaggie Little, Maggie Little Kennedy Institute for Ethics and Department of Philosophy, Georgetown University, Washington, DC, USASearch for more papers by this authorFlorencia Luna, Florencia Luna CONICET (National Scientific and Technological Research Council), FLACSO, Buenos Aires, ArgentinaSearch for more papers by this authorKatherine Littler, Katherine Littler Global Health Ethics & Governance Unit, Research for Health Department, World Health Organization, Geneva, SwitzerlandSearch for more papers by this authorNagalingeswaran Kumarasamy, Nagalingeswaran Kumarasamy VHS Infectious Diseases Medical Centre, Voluntary Health Services, Chennai, IndiaSearch for more papers by this author Jerome Amir Singh, Corresponding Author Jerome Amir Singh singhj9@ukzn.ac.za orcid.org/0000-0002-6275-6853 Howard College School of Law, University of KwaZulu-Natal, Durban, South Africa Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada Corresponding author: Jerome Amir Singh, Howard College School of Law, University of KwaZulu-Natal, King George V Ave, Durban 4041, South Africa. (singhj9@ukzn.ac.za)Search for more papers by this authorDhayendre Moodley, Dhayendre Moodley orcid.org/0000-0003-1849-9631 Department of Obstetrics and Gynaecology, School of Clinical Medicine, and Centre for the AIDS Programme of Research in South Africa, University of KwaZulu-Natal, Durban, South AfricaSearch for more papers by this authorMaggie Little, Maggie Little Kennedy Institute for Ethics and Department of Philosophy, Georgetown University, Washington, DC, USASearch for more papers by this authorFlorencia Luna, Florencia Luna CONICET (National Scientific and Technological Research Council), FLACSO, Buenos Aires, ArgentinaSearch for more papers by this authorKatherine Littler, Katherine Littler Global Health Ethics & Governance Unit, Research for Health Department, World Health Organization, Geneva, SwitzerlandSearch for more papers by this authorNagalingeswaran Kumarasamy, Nagalingeswaran Kumarasamy VHS Infectious Diseases Medical Centre, Voluntary Health Services, Chennai, IndiaSearch for more papers by this author First published: 19 July 2022 https://doi.org/10.1002/jia2.25926Citations: 1 In any reproduction of this article there should not be any suggestion that WHO or the article endorse any specific organization or products. The use of the WHO logo is not permitted. This notice should be preserved along with the article's URL. AboutReferencesRelatedInformationPDFSections COMPETING INTERESTS AUTHORS' CONTRIBUTIONS ACKNOWLEDGEMENTS FUNDING DISCLAIMERREFERENCESCiting LiteraturePDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessClose modalShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Pregnant and breastfeeding women (PBW) need new antiretroviral (ARV) agents and drug delivery technologies that are safe and effective for treatment and prevention of HIV. Perhaps unsurprisingly, this group is underrepresented in studies investigating new preventive or therapeutic interventions, with foetal safety commonly cited as a reason to exclude pregnant women from research [1]. This exclusion has precipitated critical knowledge gaps, including in the field of HIV/AIDS, thereby delaying PBW's access to better ARV treatment or preventive agents and drug delivery technologies (e.g. administration through extended-release/long-acting injections, infusions or implants). In 2020, an international, interdisciplinary and intersectoral working group convened as part of the PHASES (Pregnancy and HIV/AIDS: Seeking Equitable Study) Project, funded by the U.S. National Institutes of Health, identified critical evidence gaps in optimal dosing during pregnancy, foetal safety and maternal outcomes associated with new ARV agents and provided ethical guidance to end these evidence gaps [2]. Further guidance on how and when pregnant women should be included in research investigating new ARVs and drug delivery technologies emerged from a workshop convened by the World Health Organization (WHO) and the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network [3]. Building on these landmark documents, this work briefly reiterates the marginalization of PBW in studies investigating new ARVs, and further argues that PBW should be considered distinct populations for inclusion in studies of novel ARV agents. Historic factors have contributed to PBW being excluded from studies investigating new ARV agents and drug delivery technologies [4], many of which still persist today. These include misunderstandings about regulatory mechanisms that govern research involving drugs in PBW, concerns about the legal liability of drug developers, sponsors and investigators, and a protectionist culture around such population participating in research [4]. This characterization has stereotyped PBW as a "vulnerable" population in need of protection [5]. For example, while research ethics guidance published by the Council for the International Organization of Medical Sciences (CIOMS) and the WHO (hereinafter the "CIOMS Guidelines") notes: "Pregnant women must not be considered vulnerable simply because they are pregnant" [6], until recently, the United States Code of Federal Regulations (CFR) characterized pregnant women as "vulnerable" [7]. However, vulnerability is contextual, multiple-layered and dynamic [8]. Some ethicists argue that using this designation for pregnant women is inappropriate and disrespectful [9].The CIOMS Guidelines notes: "A direct consequence of the routine exclusion of pregnant women from clinical trials is their use of medications (both prescription and non-prescription) lacking data from clinical trials about the potential individual benefits and harms to themselves, their foetuses and their future children" [6]. In 2017, the CFR revised its language, dropping pregnant women from the list of vulnerable research populations [10]. Despite such guidance at the international level, PBW are still routinely excluded from studies investigating new ARV agents. Ironically, such a blanket exclusion heightens vulnerability and is counter to the health interests of PBW—and their infants. PBW living with HIV, like non-pregnant women, need access to optimal HIV treatments, both to reduce vertical transmission of HIV and to safeguard their own health. In addition, PBW who are at high risk of HIV transmission and are having unprotected sex during pregnancy and postpartum, like their non-pregnant and non-breastfeeding counterparts, should have access to effective and safe options of pre-exposure prophylaxis (PrEP). Many women engage in sexual activity during pregnancy and resume sexual activity early after childbirth without the use of contraception [11, 12]. WHO recommends daily PrEP for women who are at high risk of HIV transmission and having unprotected sex during pregnancy [13]. Despite WHO noting that biological factors increase a woman's susceptibility, and social and behavioural factors may increase exposure, to HIV infection, and moreover, that PBW who acquire HIV during this period have a greater risk of transmitting HIV to their infant than women who acquired HIV before pregnancy [13], PBW have been excluded from PrEP clinical trials. Moreover, for both treatment and prevention trials, women of reproductive age who are not pregnant are usually required to use dual contraception to participate in registrational trials [14, 15], while participants who become pregnant during a trial are often required to discontinue study drugs [16]. While such exclusion criteria and trial enrolment conditions are supposedly aimed at protecting the interests of foetuses and infants, an ethics-centric approach dictates that HIV research should be responsive to the need to gather evidence on the full range of people who could benefit from the drug. The interests of PBW as a population are best served through their responsible enrolment in research, rather than their blanket exclusion. Epidemiological context also matters. For instance, the need to include PBW women in HIV clinical trials is arguably greater in settings with high HIV prevalence rates among women of reproductive age. The criteria of responsible enrolment are clearly important. The inclusion of any population in drug research, especially interventional drug research, requires the assessment of the potential risks of such inclusion, as weighed against potential benefits in comparison with the risk/benefit profile of existing options. It also requires ensuring valid consent. In the context of ARV research with PBW, these criteria—spelled out in

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