Botswana-Baylor Children's Clinical Center of Excellence

We investigated intra-host genetic evolution using two SARS-CoV-2 isolates from a fully vaccinated (primary schedule x2 doses of AstraZeneca plus a booster of Pfizer), >70-year-old woman with a history of lymphoma and hypertension who presented a SARS-CoV-2 infection for 3 weeks prior to death due to COVID-19. Two full genome sequences were determined from samples taken 13 days apart with both belonging to Pango lineage FL.2: the first detection of this Omicron sub-variant in Botswana. FL.2 is a sub-lineage of XBB.1.9.1. The repertoire of mutations and minority variants in the Spike protein differed between the two time points. Notably, we also observed deletions within the ORF1a and Membrane proteins; both regions are associated with high T-cell epitope density. The internal milieu of immune-suppressed individuals may accelerate SARS-CoV-2 evolution; hence, close monitoring is warranted.

BackgroundDue to antiretroviral therapy, many people with perinatally acquired HIV are surviving into young adulthood which is a critical period of human development. Research conducted in various settings globally has shown that young adults living with perinatally acquired HIV (YALPH) face multiple challenges related to HIV infection while also confronting the same challenges of young adulthood faced by other HIV-negative youth. However, there is a paucity of information on YALPH in Botswana and what needs to be done to improve their health and wellbeing. Therefore, this study explores the challenges and coping strategies of YALPH in order to inform health policies and programming in Botswana.MethodsIn-depth interviews were conducted with 45 YALPH (ages 18–27 years) who were enrolled on antiretroviral therapy at the Botswana-Baylor Children’s Clinical Centre of Excellence (Botswana-Baylor Clinic). The Botswana-Baylor Clinic is the largest centre for pediatric, adolescent, and young adult HIV treatment and care in Botswana. The maximum variation sampling method was used to select information-rich participants. The questions focused on the challenges YALPH faced and how they coped with HIV. The data was analyzed using content analysis.ResultsThe results showed that the majority of YALPH had suppressed HIV viral load and perceived themselves to be in good physical health and functioning. They did, however, face numerous challenges, including occasional or longstanding poor antiretroviral therapy adherence, disabilities and impairments, poor school performance and attainment, unemployment, financial stressors, fear of stigma, disclosure worries and concerns, and limited social support. The most vulnerable YALPH included those with disabilities and impairments, those transitioning out of residential care, young parents, the unemployed, and those with maladaptive coping strategies. The YALPH mainly used adaptive coping strategies. The most commonly used maladaptive coping strategies were self-distraction and venting.ConclusionInterventions to prevent, screen for, assess, and manage the challenges identified by this study are critical to improving the health and well-being of YALPH. In addition, diverse interventions that can contribute to the development of adaptive coping mechanisms and reduce the likelihood of maladaptive coping in YALPH should be sought.

IntroductionWhile pregnant people have been an important focus for HIV research, critical evidence gaps remain regarding prevention, co‐infection, and safety and efficacy of new antiretroviral therapies in pregnancy. Such gaps can result in harm: without safety data, drugs used may carry unacceptable risks to the foetus or pregnant person; without pregnancy‐specific dosing data, pregnant people face risks of both toxicity and undertreatment; and delays in gathering evidence can limit access to beneficial next‐generation drugs. Despite recognition of the need, numerous barriers and ethical complexities have limited progress. We describe the process, ethical foundations, recommendations and applications of guidance for advancing responsible inclusion of pregnant people in HIV/co‐infections research.DiscussionThe 26‐member international and interdisciplinary Pregnancy and HIV/AIDS: Seeking Equitable Study (PHASES) Working Group was convened to develop ethics‐centred guidance for advancing timely, responsible HIV/co‐infections research with pregnant people. Deliberations over 3 years drew on extensive qualitative research, stakeholder engagement, expert consultation and a series of workshops. The guidance, initially issued in July 2020, highlights conceptual shifts needed in framing research with pregnant people, and articulates three ethical foundations to ground recommendations: equitable protection from drug‐related risks, timely access to biomedical advances and equitable respect for pregnant people's health interests. The guidance advances 12 specific recommendations, actionable within the current regulatory environment, addressing multiple stakeholders across drug development and post‐approval research, and organized around four themes: building capacity, supporting inclusion, achieving priority research and ensuring respect. The recommendations describe strategies towards ethically redressing the evidence gap for pregnant people around HIV and co‐infections. The guidance has informed key efforts of leading organizations working to advance needed research, and identifies further opportunities for impact by a range of stakeholder groups.ConclusionsThere are clear pathways towards ethical inclusion of pregnant people in the biomedical research agenda, and strong agreement across the HIV research community about the need for – and the promise of – advancing them. Those who fund, conduct, oversee and advocate for research can use the PHASES guidance to facilitate more, better and earlier evidence to optimize the health and wellbeing of pregnant people and their children.

Genomic science is increasingly central to the provision of health care. Producing and applying robust genomics knowledge is a complex endeavour in which no single individual, profession, discipline or community holds all the answers. Engagement and involvement of diverse stakeholders can support alignment of societal and scientific interests, understandings and perspectives and promises better science and fairer outcomes. In this context we argue for F.A.I.R.E.R. data and data use that is Findable, Accessible, Interoperable, Reproducible, Equitable and Responsible. Yet there is a paucity of international guidance on how to engage publics, patients and participants in genomics. To support meaningful and effective engagement and involvement we developed an Engagement Framework for involving and engaging participants, patients and publics in genomics research and health implementation. The Engagement Framework is intended to support all those working in genomics research, medicine, and healthcare to deliberatively consider approaches to participant, patient and public engagement and involvement in their work. Through a series of questions, the Engagement Framework prompts new ways of thinking about the aims and purposes of engagement, and support reflection on the strengths, limitations, likely outcomes and impacts of choosing different approaches to engagement. To guide genomics activities, we describe four themes and associated questions for deliberative reflection: (i) fairness; (ii) context; (iii) heterogeneity, and (iv) recognising tensions and conflict. The four key components in the Engagement provide a framework to assist those involved in genomics to reflect on decisions they make for their initiatives, including the strategies selected, the participant, patient and public stakeholders engaged, and the anticipated goals. The Engagement Framework is one step in an actively evolving process of building genomics research and implementation cultures which foster responsible leadership and are attentive to objectives which increase equality, diversity and inclusion in participation and outcomes.

ABSTRACT HIV infection and in utero exposure, common in Sub-Saharan Africa, are associated with pediatric neurocognitive impairment. Cognitive screening can identify impairments, but it is rarely used in this setting. The Penn Computerized Neurocognitive Battery (PennCNB), an evidence-based cognitive screening tool, was adapted for use in Botswana. To facilitate future implementation, 20 semi-structured interviews were conducted to elicit key stakeholders’ perspectives on factors likely to be related to successful uptake of the PennCNB in clinical settings. An integrated analytic approach combining constructs from the Consolidated Framework for Implementation Research and modified grounded theory was used. Results underscore the need for cognitive screening in Botswana and the acceptability of the PennCNB. Implementation barriers include limited time and resources, whereas facilitators include standard procedures for introducing new tools into medical settings and for training implementers. Recommended implementation strategies include integrating screening into the existing workflow, implementing the tool in the medical and educational sectors, and targeting selection of children for assessment. This research addresses the research-to-practice gap by engaging in pre-implementation inquiry and designing for implementation. Results will inform the development of strategies to maximize the likelihood of successful implementation of the PennCNB to identify neurocognitive impairment in children in this high-need setting.

Human leucocyte antigen (HLA) class I molecules present endogenously processed antigens to T-cells and have been linked to differences in HIV-1 disease progression. HLA allelotypes show considerable geographical and inter-individual variation, as does the rate of progression of HIV-1 disease, with long-term non-progression (LTNP) of disease having most evidence of an underlying genetic contribution. However, most genetic analyses of LTNP have occurred in adults of European ancestry, limiting the potential transferability of observed associations to diverse populations who carry the burden of disease. This is particularly true of HIV-1 infected children. Here, using exome sequencing (ES) to infer HLA allelotypes, we determine associations with HIV-1 LTNP in two diverse African pediatric populations. We performed a case-control association study of 394 LTNPs and 420 rapid progressors retrospectively identified from electronic medical records of pediatric HIV-1 populations in Uganda and Botswana. We utilized high-depth ES to perform high-resolution HLA allelotyping and assessed evidence of association between HLA class I alleles and LTNP. Sixteen HLA alleles and haplotypes had significantly different frequencies between Uganda and Botswana, with allelic differences being more prominent in HLA-A compared to HLA-B and C allelotypes. Three HLA allelotypes showed association with LTNP, including a novel association in HLA-C (HLA-B∗57:03, aOR 3.21, Pc = 0.0259; B∗58:01, aOR 1.89, Pc = 0.033; C∗03:02, aOR 4.74, Pc = 0.033). Together, these alleles convey an estimated population attributable risk (PAR) of non-progression of 16.5%. We also observed novel haplotype associations with HLA-B∗57:03-C∗07:01 (aOR 5.40, Pc = 0.025) and HLA-B∗58:01-C∗03:02 (aOR 4.88, Pc = 0.011) with a PAR of 9.8%, as well as a previously unreported independent additive effect and heterozygote advantage of HLA-C∗03:02 with B∗58:01 (aOR 4.15, Pc = 0.005) that appears to limit disease progression, despite weak LD (r2 = 0.18) between these alleles. These associations remained irrespective of gender or country. In one of the largest studies of HIV in Africa, we find evidence of a protective effect of canonical HLA-B alleles and a novel HLA-C association that appears to augment existing HIV-1 control alleles in pediatric populations. Our findings outline the value of using multi-ethnic populations in genetic studies and offer a novel HIV-1 association of relevance to ongoing vaccine studies.