Whitman-Walker Health

Purpose: There is limited research on the use of community advisory boards (CABs) in health research with transgender and nonbinary communities. Transgender communities are navigating challenging histories of health researcher exploitation and research distrust alongside exponential research growth. We explored strategies for forming and managing CABs when conducting transgender community-informed health research. Methods: We used purposive and snowball sampling to identify key informants (KIs): research leaders, implementing staff, and community partners engaging in transgender health research. Between October 2018 and December 2020, we conducted 30 semi-structured in-depth interviews. We used coding followed byiterative thematic analysis and memoing to identify themes. Results: KIs emphasized the importance of involving CABs early in the research process and communicating transparently about their decision-making power and roles. They urged research teams to anticipate and address both multilevel (e.g., gender affirmation-related and socioeconomic) and historical (e.g., local research harms) barriers to CAB participation, and to intentionally engage groups that are historically underrepresented in research. KIs warned against tokenistic CAB models and called on researchers to show up for transgender communities beyond research goals. Research-related trainings and skills-building opportunities could equip CAB members to contribute meaningfully to research decisions, but KIs find that they are often under-planned and under-budgeted. Health Equity Implications: This study contributes to our understanding of how to engage and support CABs working on transgender health research, and how sociostructural factors shape their experiences. We offer a series of recommendations and questions researchers should consider when forming CABs for transgender health research and community-informed research broadly.

Abstract Neurofibromatosis type 1 (NF1) is a genetic disorder characterized by benign tumors, including plexiform neurofibromas, which can be difficult to treat. Currently, only two FDA-approved therapies exist: selumetinib, approved for pediatric patients with inoperable tumors, and mirdametinib, approved for patients aged two and older with symptomatic peripheral neuropathy where surgical resection is not possible. These limited options highlight the urgent need for novel therapeutic strategies, including combination therapies and therapies applicable to adult populations. In this study, we introduce the Composite Matrix Reduction Score (CMRS), a novel algorithm designed to evaluate the in vitro efficacy of drug combinations for NF1-related plexiform neurofibromas. Using a high-throughput 6×6 combinatorial matrix, we screened three cell lines: ipnNF95.11c (NF1+/-, non-tumor reference), and two NF1-/- tumor lines: ipNF05.5mc and ipNF95.6. Cell viability responses to drug combinations were normalized to vehicle controls, and combination effects were compared to single-agent responses. Tumor-to-non-tumor response ratios were aggregated to generate a composite ranking for each drug pair. Our results show that certain drug combinations outperformed single agents in reducing tumor cell viability, consistent with findings in other cancers. A focused analysis on selumetinib combinations supported the CMRS algorithm and identified potential synergistic partners that may surpass a single-agent therapy, highlighting candidates for continued investigation. CMRS provides a scalable, standardized framework for prioritizing drug combinations in NF1 and potentially other cancers. By integrating multi-cell line analysis, this approach enhances the identification of promising therapeutic candidates and mechanisms of action for further preclinical development.

Novel cellular therapies may enable HIV control or cure. HIV-specific T cells targeting conserved immunogenic protein regions of HIV Gag/Pol and the entirety of HIV Nef, termed HST-NEETs, eliminate HIV infected cells in vitro. Here we enroll seven participants in an open-label, single-arm phase 1 study (NCT03485963) to evaluate the safety (primary endpoint) of two autologous administrations of HST-NEET products without prescribed lymphodepletion. Adults with well-controlled HIV on anti-retroviral therapy are eligible. Six participants completed safety monitoring. No serious product-related toxicities are observed. Secondary endpoints are to assess expansion and persistence of HIV-reactive T cell clones, and changes to the HIV reservoir for each infused participant. HIV-specific T cell and HIV anti-Env antibody responses increase in two participants after infusion two. A trend towards decreasing levels of intact proviruses is observed in 2 participants. Three participants show persistence of HIV-reactive, product-associated T cell clones for ≥40 weeks post infusions. HST-NEETs infusions are well-tolerated. Future trials are needed to evaluate the efficacy of HST-NEETs in this population.

Abstract Persistent HIV reservoirs in CD4⁺ T-cells pose a barrier to curing HIV infection. We identified overexpression of enhancer of zeste homolog 2 (EZH2) in HIV-infected CD4⁺ T- cells that survive cytotoxic T lymphocyte (CTL) exposure, suggesting a mechanism of CTL resistance. Inhibition of EZH2 with the FDA-approved drug tazemetostat increased surface expression of major histocompatibility complex class I (MHC-I) on CD4⁺ T-cells, counterbalancing HIV Nef–mediated MHC-I downregulation. This improved CTL-mediated elimination of HIV-infected cells and suppressed viral replication in vitro. In a participant-derived xenograft mouse model, tazemetostat elevated MHC-I and the pro-apoptotic protein BIM in CD4⁺ T-cells, facilitating CD8⁺ T-cell–mediated reductions of HIV reservoir seeding. Additionally, tazemetostat promoted sustained skewing of CD8⁺ T-cells toward less differentiated and exhausted phenotypes. Our findings reveal EZH2 overexpression as a novel mechanism of CTL resistance and support the clinical evaluation of tazemetostat to enhance clearance of HIV reservoirs and improve CD8+ T-cell function.

Long-acting cabotegravir (CAB-LA) is highly effective for HIV prevention, but delayed HIV diagnoses and integrase strand transfer inhibitor (INSTI) resistance were observed in trials. We report the first case in routine clinical care of HIV infection on CAB-LA with INSTI resistance. The SeroPrEP study enrolls individuals in the United States who acquire HIV on pre-exposure prophylaxis modalities to assess diagnostics, antiretroviral (ARV) drug levels, resistance, and treatment outcomes. Resistance mutations in full-length HIV-1 integrase were identified by single-genome sequencing (SGS). Cabotegravir concentrations in plasma and hair segments were measured by liquid chromatography-tandem mass spectrometry. A 23-year-old gender-nonbinary person, male at birth, restarted CAB-LA 6 months after discontinuation due to losing insurance. Prior to restart, HIV-1 RNA was not detected, but 20 days elapsed before CAB-LA injection. After the second CAB-LA injection, HIV antigen/antibody returned reactive (HIV-1 RNA 451 copies/mL). SGS of plasma HIV-1 RNA identified INSTI mutation Q148R in 2/24 sequences 2 days postdiagnosis; commercial genotype failed amplification. Cabotegravir hair concentration was 0.190 ng/mg 2 weeks prediagnosis; plasma cabotegravir was high (3.37 μg/mL; ∼20× PA-IC90) 14 days postdiagnosis. Viral suppression was maintained for 6 months on darunavir/cobicistat/emtricitabine/tenofovir alafenamide, then switched to doravirine + emtricitabine/tenofovir alafenamide due to nausea. In this first case of HIV infection on CAB-LA with INSTI resistance in routine care, cabotegravir resistance was detected only with a sensitive research assay. Accelerated pathways to minimize time between HIV testing and CAB-LA initiation are needed to optimize acute HIV detection and mitigate resistance risk. Sustained product access regardless of insurance is imperative to reduce HIV infections on CAB-LA.

Pre-Exposure Prophylaxis (PrEP) related stigma is linked to inadequate PrEP uptake, yet there are no validated scales to test this association among Spanish-speaking LSMM. The current study examined if the Spanish-translated PrEP Stigma Scale (PSS) was psychometrically appropriate for implementing in Spanish language dominant Latino/e/x Sexual Minority Men (SMM). Recruitment was conducted using geosocial networking applications, social media sites, and e-mail blasts (N=3,049). First, we utilized Item Response Theory (IRT) modeling to evaluate the reliability of the PSS items and the latent construct across both language groups (nEnglish = 2844 and nSpanish = 205). Subsequently, we applied the PSS scale in a theoretical application by examining its association with key steps in the PrEP uptake cascade (i.e., perceived PrEP candidacy, PrEP willingness, PrEP intentions, and having spoken to provider about PrEP) stratified by language. Results of the IRT analyses provided evidence that the translated version of the PSS was appropriate for use among this sample. Further, among English respondents, PrEP stigma was negatively associated with perceived PrEP candidacy (B=-0.30, p=<.001), PrEP willingness (B=-0.46, p=<.001), and PrEP intentions (B=-0.23, p=.003). PrEP stigma, among Spanish respondents, was not significantly associated with any of the PrEP cascade steps. This study demonstrated that the PSS scale performs adequately for both English and Spanish-speaking Latino SMM. However, researchers and health professionals alike should pay close attention to the nuanced effects in U.S. based English and Spanish language samples as PrEP stigma may impact the PrEP cascade for one language sample and not the other.

Accurately measuring gender and sex is crucial in public health and epidemiology. Iteratively reexamining how variables—including gender and sex—are conceptualized and operationalized is necessary to achieve impactful research. Reexamining gender and sex advances epidemiology toward its goals of health promotion and disease elimination. While we cannot reduce the complexities of sex and gender to simply an issue of measurement, striving to capture these concepts and experiences accurately must be an ongoing dialogue and practice—to the benefit of the field and population health. We assert that epidemiology must counteract misconceptions and accurately measure gender and sex in epidemiology. We aim to summarize existing critiques and guiding principles in measuring gender and sex that can be applied in practice.

Background:Among communities with elevated HIV burden, increased uptake of PrEP, including long-acting injectable (LAI) PrEP, could lower HIV incidence. Lack of data on LAI PrEP interest among transgender women in the United States has limited scientific understanding of the potential impact of LAI PrEP on new infections within transgender communities. Our objective was to determine the percent of transgender women interested in LAI PrEP and identify correlates of interest.Methods:Transgender women enrolled in the LITE Cohort who completed 12-month surveys between March 2019 and September 2021 were asked about interest in using LAI PrEP. Prevalence ratios (PR) estimated with modified Poisson regression models were assessed for predictors of interest in LAI PrEP.Results:Among 867 participants, 15% were current users of oral PrEP and 11% were former oral PrEP users. In total, 47% reported interest in LAI PrEP. Interest in LAI PrEP was more common among participants who were Black (PR: 1.28; 95% CI: 1.05 to 1.55), college-educated (PR: 1.28; 95% CI: 1.04 to 1.57), food insecure (PR: 1.19; 95% CI: 1.00 to 1.41), and had PrEP indications (PR: 1.44; 95% CI: 1.21 to 1.71). LAI PrEP interest was also more common among adherent users of oral PrEP and those who had discontinued oral PrEP, compared with PrEP-naïve participants.Conclusions:Interest in LAI PrEP among transgender women varied by demographic and clinical characteristics. Increased interest in LAI PrEP among Black transgender women, those with PrEP indications, and those who had previously discontinued oral PrEP underscores the need to increase LAI PrEP access for transgender women who are interested.

Health equity is the state in which everyone has fair and just opportunities to attain their highest level of health. The field of human genomics has fallen short in increasing health equity, largely because the diversity of the human population has been inadequately reflected among participants of genomics research. This lack of diversity leads to disparities that can have scientific and clinical consequences. Achieving health equity related to genomics will require greater effort in addressing inequities within the field. As part of the commitment of the National Human Genome Research Institute (NHGRI) to advancing health equity, it convened experts in genomics and health equity research to make recommendations and performed a review of current literature to identify the landscape of gaps and opportunities at the interface between human genomics and health equity research. This Perspective describes these findings and examines health equity within the context of human genomics and genomic medicine.