Nothing about us without us: Advocacy and engagement in genetic medicine.

The development of new genetic medicines to treat sickle cell disease highlights the need for greater collaboration between researchers and people with lived experiences. Drawing on the adage "Nothing about us, without us," we call for increased investments in community advocacy and engagement.

Immune targeting of HIV-1 reservoir cells: a path to elimination strategies and cure.

Successful approaches for eradication or cure of HIV-1 infection are likely to include immunological mechanisms, but remarkably little is known about how human immune responses can recognize and interact with the few HIV-1-infected cells that harbour genome-intact viral DNA, persist long term despite antiretroviral therapy and represent the main barrier to a cure. For a long time regarded as being completely shielded from host immune responses due to viral latency, these cells do, on closer examination with single-cell analytic techniques, display discrete footprints of immune selection, implying that human immune responses may be able to effectively engage and target at least some of these cells. The failure to eliminate rebound-competent virally infected cells in the majority of persons likely reflects the evolution of a highly selected pool of reservoir cells that are effectively camouflaged from immune recognition or rely on sophisticated approaches for resisting immune-mediated killing. Understanding the fine-tuned interplay between host immune responses and viral reservoir cells will help to design improved interventions that exploit the immunological vulnerabilities of HIV-1 reservoir cells.

Towards access for all: 1st Working Group Report for the Global Gene Therapy Initiative (GGTI).

The gene and cell therapy field saw its first approved treatments in Europe in 2012 and the United States in 2017 and is projected to be at least a $10B USD industry by 2025. Despite this success, a massive gap exists between the companies, clinics, and researchers developing these therapeutic approaches, and their availability to the patients who need them. The unacceptable reality is a geographic exclusion of low-and middle-income countries (LMIC) in gene therapy development and ultimately the provision of gene therapies to patients in LMIC. This is particularly relevant for gene therapies to treat human immunodeficiency virus infection and hemoglobinopathies, global health crises impacting tens of millions of people primarily located in LMIC. Bridging this divide will require research, clinical and regulatory infrastructural development, capacity-building, training, an approval pathway and community adoption for success and sustainable affordability. In 2020, the Global Gene Therapy Initiative was formed to tackle the barriers to LMIC inclusion in gene therapy development. This working group includes diverse stakeholders from all sectors and has set a goal of introducing two gene therapy Phase I clinical trials in two LMIC, Uganda and India, by 2024. Here we report on progress to date for this initiative.

Community HIV clinicians' perceptions about HIV cure-related research in the Northwestern United States.

Background: Research on stakeholder perspectives of HIV cure research has involved people with HIV (PWH), who generally cite the importance of HIV clinician advice in making decisions about trial participation. However, there has been little exploration of non-researcher community HIV clinician perspectives, which are clearly critical to the success of HIV cure-related research.Objective: We aimed to learn how community HIV clinicians perceive HIV cure research and identify factors that would lead them to support or discourage HIV cure trial participation by their patients.Methods: We recruited a purposive sample of 12 community HIV clinicians in metro-Seattle, WA to participate in structured interviews. We completed 11 interviews via teleconference and received one written response. We used conventional content analysis to analyze the data.Results: Overall, community HIV clinicians were supportive of patient participation in HIV cure trials. Factors affecting support included knowledge of local trials, ease of referral, patient immune function and health stability, study risks and benefits, burden of study requirements, patient characteristics, patient life stability, potential impact on engagement in care, study communication plans, and beliefs that patients should have the autonomy to decide to participate. Participants had concerns about trials requiring treatment delays or interruptions and HIV transmission risk. While their knowledge of the field was limited, they were interested in learning more about open HIV cure trials.Conclusions: It would benefit the HIV cure research community if those leading HIV cure trials make stronger efforts to engage community clinicians who care for PWH, but are not active researchers, early in the trial design process. Such engagement prior to launching HIV cure trials will improve trial designs, leading to better enrollment and retention within these important studies.

Ethical and practical considerations for cell and gene therapy toward an HIV cure: findings from a qualitative in-depth interview study in the United States.

BACKGROUND: HIV cure research involving cell and gene therapy has intensified in recent years. There is a growing need to identify ethical standards and safeguards to ensure cell and gene therapy (CGT) HIV cure research remains valued and acceptable to as many stakeholders as possible as it advances on a global scale. METHODS: To elicit preliminary ethical and practical considerations to guide CGT HIV cure research, we implemented a qualitative, in-depth interview study with three key stakeholder groups in the United States: (1) biomedical HIV cure researchers, (2) bioethicists, and (3) community stakeholders. Interviews permitted evaluation of informants' perspectives on how CGT HIV cure research should ethically occur, and were transcribed verbatim. We applied conventional content analysis focused on inductive reasoning to analyze the rich qualitative data and derive key ethical and practical considerations related to CGT towards an HIV cure. RESULTS: We interviewed 13 biomedical researchers, 5 community members, and 1 bioethicist. Informants generated considerations related to: perceived benefits of CGT towards an HIV cure, perceived risks, considerations necessary to ensure an acceptable benefit/risk balance, CGT strategies considered unacceptable, additional ethical considerations, and considerations for first-in-human CGT HIV cure trials. Informants also proposed important safeguards to developing CGT approaches towards an HIV cure, such as the importance of mitigating off-target effects, mitigating risks associated with long-term duration of CGT interventions, and mitigating risks of immune overreactions. CONCLUSION: Our study identified preliminary considerations for CGT-based HIV cure across three key stakeholder groups. Respondents identified an ideal cure strategy as one which would durably control HIV infection, protect the individual from re-acquisition, and eliminate transmission to others. Known and unknown risks should be anticipated and perceived as learning opportunities to preserve and honor the altruism of participants. Preclinical studies should support these considerations and be transparently reviewed by regulatory experts and peers prior to first-in-human studies. To protect the public trust in CGT HIV cure research, ethical and practical considerations should be periodically revisited and updated as the science continues to evolve. Additional ethics studies are required to expand stakeholder participation to include traditionally marginalized groups and clinical care providers.

Ethics of HIV cure research: an unfinished agenda.

BACKGROUND: The pursuit of a cure for HIV is a high priority for researchers, funding agencies, governments and people living with HIV (PLWH). To date, over 250 biomedical studies worldwide are or have been related to discovering a safe, effective, and scalable HIV cure, most of which are early translational research and experimental medicine. As HIV cure research increases, it is critical to identify and address the ethical challenges posed by this research. METHODS: We conducted a scoping review of the growing HIV cure research ethics literature, focusing on articles published in English peer-reviewed journals from 2013 to 2021. We extracted and summarized key developments in the ethics of HIV cure research. Twelve community advocates actively engaged in HIV cure research provided input on this summary and suggested areas warranting further ethical inquiry and foresight via email exchange and video conferencing. DISCUSSION: Despite substantial scholarship related to the ethics of HIV cure research, additional attention should focus on emerging issues in six categories of ethical issues: (1) social value (ongoing and emerging biomedical research and scalability considerations); (2) scientific validity (study design issues, such as the use of analytical treatment interruptions and placebos); (3) fair selection of participants (equity and justice considerations); (4) favorable benefit/risk balance (early phase research, benefit-risk balance, risk perception, psychological risks, and pediatric research); (5) informed consent (attention to language, decision-making, informed consent processes and scientific uncertainty); and (6) respect for enrolled participants and community (perspectives of people living with HIV and affected communities and representation). CONCLUSION: HIV cure research ethics has an unfinished agenda. Scientific research and bioethics should work in tandem to advance ethical HIV cure research. Because the science of HIV cure research will continue to rapidly advance, ethical considerations of the major themes we identified will need to be revisited and refined over time.

Acceptability of Cell and Gene Therapy for Curing HIV Infection Among People Living with HIV in the Northwestern United States: A Qualitative Study.

Multiple strategies to cure HIV infection are under investigation, including cell and gene therapy (C>) approaches. Research, and ultimately treatment, with these novel strategies will require patients' willingness to participate. To elicit the perspectives of people living with HIV specific to these novel approaches, we conducted 4 focus group discussions with a diverse group of 19 English-speaking men and women living with HIV in care at a large academic HIV clinic in the northwestern United States. Thematic analysis indicated participants expressed initial fear about C> research. They articulated specific concerns about risks, including analytical treatment interruptions, and thought only a person in desperate straits would participate. They voiced significant mistrust of research in general and believed there was already a cure from HIV that was being withheld from the poor. Overall, they were satisfied with their health and quality of life on antiretroviral therapy. These findings suggest the importance of community engagement and educational efforts about C> for HIV cure to ensure optimal collaborative partnerships.

ru2hot?: A public health education campaign for men who have sex with men to increase awareness of symptoms of acute HIV infection.

OBJECTIVES: Teach HIV-negative men who have sex with men (MSM) symptoms of acute HIV infection (AHI) and direct them to nucleic acid amplification testing (NAAT) though Public Health--Seattle & King County (PHSKC). DESIGN: Cross-sectional surveys, retrospective database analysis and chart review. METHODS: Beginning in June 2009, the ru2hot? campaign described AHI symptoms and NAAT. Two preintervention and two postintervention surveys assessed campaign visibility, symptom knowledge, and healthcare-seeking behaviour. Regression analyses evaluated secular trends in case-finding. RESULTS: 366 MSM completed surveys. In survey 4, 23% of 100 men reported seeing the campaign, and 25% knew 'ru2hot?' referred to AHI. From survey 1 to survey 4, the proportion of subjects who knew ≥2 symptoms or that AHI was a 'flu-like' illness was unchanged (61% vs 57%, p=0.6). However, in survey 4, 13 (72%) of 18 subjects who saw the campaign named fever as a symptom of AHI compared with 19 (35%) of 55 subjects who had not seen the campaign (p=0.005). From 9/2003 to 12/2010, 622 (2.2%) of 27 661 MSM tested HIV-positive, and 111 (18%) were identified by the Public Health--Seattle & King County NAAT programme. In terms of the impact of the campaign on case-finding, diagnosis of EIA-negative/NAAT-positive and OraQuick-negative/EIA-positive cases increased from six in 2004 to 20 in 2010 (p=0.01), but postcampaign numbers were unchanged. 23 (51%) of 45 cases identified before and 8 (44%) of 18 cases identified after the campaign reported symptoms at initial testing (p=0.6). CONCLUSIONS: Although a quarter of MSM surveyed saw the campaign and knowledge of fever (the symptom of emphasis) was high, case-finding was unchanged. Increasing campaign visibility could have had greater impact.