A network analysis of positive psychosocial factors and indication of suboptimal HIV care outcomes among Black women living with HIV.

Black women living with HIV (BWLWH) face barriers that impact health outcomes. However, positive psychosocial indicators may influence HIV care outcomes. Among this cross-sectional study of 119 BWLWH, a network analysis was utilized to examine relationships between positive psychosocial factors and HIV-related health outcomes. A preliminary polychoric analysis was conducted to examine correlations between the variables, and the network analyzed connections between resilience, self-efficacy, self-esteem, perceived social support, religious coping, post-traumatic growth, and an indicator variable for suboptimal HIV care outcomes (low medication adherence, detectable viral load, and missed HIV-related health visits) and determined the centrality measures within the network. Seven significant associations were found among the factors: self-efficacy and self-esteem, post-traumatic growth and resilience, post-traumatic growth and self-efficacy, post-traumatic growth and religious coping, perceived social support and resilience, self-esteem and resilience, self-esteem and perceived social support (bootstrapped 95% CI did not contain zero). Self-efficacy was the strongest indicator associated with the other factors. Although not statistically significant, the indicator for suboptimal HIV care outcomes was negatively associated with perceived social support and religious coping. Future interventions incorporating self-efficacy may be beneficial to the overall well-being of Black women.

Point-of-care urine tenofovir test predicts future HIV pre-exposure prophylaxis discontinuation among young users.

BACKGROUND: Young men who have sex with men and transgender women (YMSM/TGW) have disproportionately high HIV incidence and lower PrEP adherence. Point-of-care (POC) urine tenofovir (TFV) rapid assay (UTRA) testing permits real-time monitoring for nonadherence within clinical settings. We performed UTRA testing among PrEP users to examine the relationship between low PrEP adherence and future PrEP discontinuation, and the accuracy of POC testing compared to gold-standard liquid chromatography tandem mass spectrometry (LC/MS/MS). METHODS: YMSM/TGW participants (n = 100) were recruited during a daily PrEP visit. Logistic regression models analyzed the relationship between the primary predictor of urine POC assay results (cutoff 1,500 ng/mL) and the primary outcome of PrEP discontinuation, defined as no PrEP follow-up or prescription within 120 days. RESULTS: Overall, 19% of participants had low urine TFV and 21% discontinued PrEP, while 11% of participants self-reported low PrEP adherence (< 4 pills per week), which was only 43% sensitive/84% specific in predicting low TFV levels and was not associated with PrEP discontinuation. Low urine TFV level predicted PrEP discontinuation (AOR 6.1; 95% CI: 1.4-11; p = 0.005) and was 71% sensitive/90% specific for discontinuation after 120 days. Compared to LC/MS/MS, UTRA testing had a 98% positive and 100% negative predictive value. CONCLUSIONS: In a sample of YMSM/TGW on daily PrEP, POC UTRA testing predicted PrEP discontinuation more accurately than self-reported adherence, with high predictive values compared to LC/MS/MS. UTRA testing may be a clinical tool for directing preventive interventions towards those likelier to discontinue PrEP despite ongoing HIV vulnerability.

Structural Determinants of Health and Markers of Immune Activation and Systemic Inflammation in Sexual Minority Men With and Without HIV.

Among sexual minority men (SMM), HIV and use of stimulants such as methamphetamine are linked with immune activation and systemic inflammation. Throughout the COVID-19 pandemic, SMM encountered financial challenges and structural obstacles that might have uniquely contributed to immune dysregulation and systemic inflammation, beyond the impacts of HIV and stimulant use. Between August 2020 and February 2022, 72 SMM with and without HIV residing in South Florida enrolled in a COVID-19 prospective cohort study. Multiple linear regression analyses examined unemployment, homelessness, and history of arrest as structural correlates of soluble markers of immune activation (i.e., sCD14 and sCD163) and inflammation (i.e., sTNF-α receptors I and II) at baseline after adjusting for HIV status, stimulant use, and recent SARS-CoV-2 infection. Enrolled participants were predominantly Latino (59%), gay-identified (85%), and with a mean age of 38 (SD, 12) years with approximately one-third (38%) of participants living with HIV. After adjusting for HIV status, SARS-CoV-2 infection, and recent stimulant use, unemployment independently predicted higher levels of sCD163 (ß = 0.24, p = 0.04) and sTNF-α receptor I (ß = 0.26, p = 0.02). Homelessness (ß = 0.25, p = 0.02) and history of arrest (ß = 0.24, p = 0.04) independently predicted higher levels of sCD14 after adjusting for HIV status, SARS-CoV-2 infection, and recent stimulant use. Independent associations exist between structural barriers and immune activation and systemic inflammation in SMM with and without HIV. Future longitudinal research should further elucidate complex bio-behavioral mechanisms linking structural factors with immune activation and inflammation.

Factors associated with PrEP-era HIV seroconversion in a 4-year U.S. national cohort of n = 6059 sexual and gender minority individuals who have sex with men, 2017-2022.

INTRODUCTION: Community-based cohort studies of HIV seroconversion can identify important avenues for enhancing HIV prevention efforts in the era of pre-exposure prophylaxis (PrEP). Within individuals, one can assess exposure and outcome variables repeatedly and with increased certainty regarding temporal ordering. This cohort study examined the association of several risk factors with subsequent HIV seroconversion. METHODS: We report data from a 4-year study (2017-2022) of 6059 HIV seronegative sexual and gender minority individuals who have sex with men who had indications for-, but were not using-, PrEP at enrolment. Participants completed repeat exposure assessments and self-collection of biospecimens for HIV testing. We examined the roles of race and ethnicity, socio-economic status, methamphetamine use and PrEP uptake over the course of follow-up in relation to HIV seroconversion. RESULTS: Over 4 years, 303 of the participants seroconverted across 18,421 person-years (incidence rate = 1.64 [95% CI: 1.59-1.70] per 100 person-years). In multivariable discrete-time survival analysis, factors independently associated with elevated HIV seroconversion risk included being Black/African American (adjusted risk ratio [aRR]: 2.44, 1.79-3.28), Hispanic/Latinx (1.53, 1.19-1.96), housing instability (1.58, 1.22-2.05) and past year methamphetamine use (3.82, 2.74-5.33). Conversely, time since study enrolment (24 vs. 12 months, 0.67, 0.51-0.87; 36 months, 0.60, 0.45-0.80; 48 months, 0.48, 0.35-0.66) and higher education (master's degree or higher vs. less than or equal to high school, 0.36, 0.17-0.66) were associated with reduced seroconversion risk. Compared to non-PrEP users in the past 2 years without a current clinical indication, those who started PrEP but then discontinued had higher seroconversion risk, irrespective of clinical indication (3.23, 1.74-6.46) or lack thereof (4.30, 1.85-9.88). However, those who initiated PrEP in the past year (0.14, 0.04-0.39) or persistently used PrEP in the past 2 years (0.33, 0.14-0.74) had a lower risk of seroconversion. Of all HIV seroconversions observed during follow-up assessments (12, 24, 36 and 48 months), methamphetamine was reported in the 12 months prior 128 (42.2%) times (overall). CONCLUSIONS: Interventions that acknowledge race and ethnicity, economic variables such as education and housing instability, and methamphetamine use are critically needed. Not only are interventions to engage individuals in PrEP care needed, but those that retain them, and re-engage those who may fall out of care are essential, given the exceptionally high risk of seroconversion in these groups.

Narratives of Disconnection: A Life Course Perspective of Methamphetamine Use Among Sexual Minority Men Living with HIV.

BACKGROUND: Sexual minority men (SMM) are exposed to societal and structural stressors that translate into poor health outcomes. One such outcome is substance use, which research has long documented as a prominent disparity among SMM. Methamphetamine is a particularly deleterious substance for SMM because its use is often framed as a coping response to social and structural stressors. METHOD: Guided by stress and coping theory and a life course perspective, the purpose of this qualitative study is to assess the development of coping strategies in the context of prominent social and structural determinants among SMM living with HIV who use methamphetamine. RESULTS: Data were collected from 2016 to 2018 via in-depth interviews with 24 SMM living with HIV who use methamphetamine in San Francisco, CA. Mean age of participants was 47 and over half self-identified as ethnoracial minorities. Narrative analysis surfaced a sequential pattern of disconnection at foundational, relational, and recovery levels. This analysis revealed that multi-level stressors were present across the life course that amplified engagement in methamphetamine use. CONCLUSION: Findings highlight the benefits of holistic, integrated, and trauma-informed approaches to address the function of methamphetamine use as a response to societal, cultural, and institutional processes of stigmatization and discrimination. Peer-based approaches may also be beneficial to reframe the ways in which SMM living with HIV who use methamphetamine form and sustain relationships.

A positive affect intervention alters leukocyte DNA methylation in sexual minority men with HIV who use methamphetamine.

OBJECTIVE: This epigenomics sub-study embedded within a randomized controlled trial examined whether an evidenced-based behavioral intervention model that decreased stimulant use altered leukocyte DNA methylation (DNAm). METHODS: Sexual minority men with HIV who use methamphetamine were randomized to a five-session positive affect intervention (n = 32) or an attention-control condition (n = 21), both delivered during three months of contingency management for stimulant abstinence. All participants exhibited sustained HIV virologic control - an HIV viral load less than 40 copies/mL at baseline and six months post-randomization. The Illumina EPIC BeadChip measured leukocyte methylation of cytosine-phosphate-guanosine (CpG) sites mapping onto five a priori candidate genes of interest (i.e., ADRB2, BDNF, FKBP5, NR3C1, OXTR). Functional DNAm pathways and soluble markers of immune dysfunction were secondary outcomes. RESULTS: Compared to the attention-control condition, the positive affect intervention significantly decreased methylation of CpG sites on genes that regulate ß2 adrenergic and oxytocin receptors. There was an inconsistent pattern for the direction of the intervention effects on methylation of CpG sites on genes for glucocorticoid receptors and brain-derived neurotrophic factor. Pathway analyses adjusting for the false discovery rate (padj < 0.05) revealed significant intervention-related alterations in DNAm of Reactome pathways corresponding to neural function as well as dopamine, glutamate, and serotonin release. Positive affect intervention effects on DNAm were accompanied by significant reductions in the self-reported frequency of stimulant use. CONCLUSIONS: There is an epigenetic signature of an evidence-based behavioral intervention model that reduced stimulant use, which will guide the identification of biomarkers for treatment responses.

I was like sh*t this is gonna hurt': Implementing Self-Sampling of Dried Blood Spots to Measure HIV Viral Load.

Background: Sexual minority men (SMM) with HIV who use stimulants may experience greater difficulties with antiretroviral therapy adherence which amplifies risk for unsuppressed HIV viral load (VL). Remote monitoring of VL could support efforts to rapidly respond to sub-optimal adherence. Methods: This qualitative study enrolled 24 SMM with HIV who use stimulants to examine experiences with two different dried blood spots (DBS) self-sampling devices (i.e., Tasso-M20 vs. HemaSpot HD) to measure VL. Participants were asked to complete self-sampling of DBS using both devices, and then participated in a 45-minute semi-structured interview. Interviews focused on ease of use, device preference, experiences with receiving and mailing kits, and barriers to participating in research. A thematic analysis was conducted to analyze interviews transcripts. Results: Twenty-two participants (92%) returned the Tasso-M20 and 21 (88%) returned the Hemaspot HD devices. Among the 22 participants that completed qualitative interviews, twenty-three codes were identified and collapsed within seven themes. Preferences for devices were based on convenience, pain and prior experiences with finger-pricking technology. Participants emphasized that clearer instructions with contingency plans for self-sampling of DBS would improve the user experience with self-sampling of DBS. Intersectional stigma (e.g., HIV, sexual minority status, and substance use) was noted as an important consideration in implementing self-sampling of DBS. Promoting decision making, or the option to choose sampling method based on personal preferences, may improve engagement and likelihood of DBS completion. Conclusions: Findings will guide the broader implementation of self-sampling of DBS to optimize VL monitoring in SMM with HIV who use stimulants.

Loneliness, Methamphetamine Use, and Cardiovascular Risk Factors Among Sexual Minority Men in the COVID-19 Era.

BACKGROUND: Important gaps exist in our understanding of loneliness and biobehavioral outcomes among sexual minority men (SMM), such as faster HIV disease progression. At the same time, SMM who use methamphetamine are approximately one-third more likely than non-users to develop cardiovascular disease. This study examined associations of loneliness, stimulant use, and cardiovascular risk in SMM with and without HIV. METHOD: Participants were enrolled from August 2020 to February 2022 in a 6-month prospective cohort study. The study leveraged self-report baseline data from 103 SMM, with a subset of 56 SMM that provided a blood sample to measure markers of cardiovascular risk. RESULTS: Loneliness showed negative bivariate associations with total cholesterol and LDL cholesterol in the cardiometabolic subsample (n = 56). SMM with methamphetamine use (t(101) = 2.03, p < .05; d = .42) and those that screened positive for a stimulant use disorder (t(101) = 2.07, p < .05; d = .46) had significantly higher mean loneliness scores. In linear regression analyses, negative associations of loneliness with LDL and total cholesterol were observed only among SMM who used methamphetamine. CONCLUSION: We observed lower cholesterol in SMM reporting loneliness and methamphetamine use. Thus, in addition to the observed associations of loneliness with cholesterol, there are important medical consequences of methamphetamine use including cardiovascular risk, higher HIV acquisition risk and progression, as well as stimulant overdose death. This cross-sectional study underscores the need for clinical research to develop and test interventions targeting loneliness among SMM with stimulant use disorders.

PrEP Discontinuation In A US National Cohort Of Sexual And Gender Minority Populations, 2017-22.

In the US, sexual and gender minority populations are disproportionately affected by HIV. Pre-exposure prophylaxis (PrEP) is a key prevention method, but its effectiveness relies on consistent usage. Our four-year national cohort study explored PrEP discontinuation among sexual and gender minority people who initiated PrEP. We found a high annual rate of discontinuation (35-40 percent) after PrEP initiation. Multivariable analysis with 6,410 person-years identified housing instability and prior history of PrEP discontinuation as predictors of discontinuation. Conversely, older age, clinical indication for PrEP, and having health insurance were associated with ongoing PrEP use. To promote sustained PrEP use, strategies should focus on supporting those at high risk for discontinuation, such as younger people, those without stable housing or health insurance, and prior PrEP discontinuers.

Leveraging qualitative approaches to guide sustainable international research collaborations.

Qualitative research approaches were used to launch an international research collaboration between the U. S. and Cambodia. Cambodian officials requested assistance in learning qualitative approaches to complement the research skills of Cambodian mental health providers. This article provides a description of how U. S. researchers responded to that request and engaged with Cambodian psychiatrists to explore mental health needs and interventions in both countries and initiate a sustainable relationship. The early focus on qualitative research methodologies may be an avenue that mitigates some of the challenges that can characterize international research. In this study, early communications involved developing a plan to teach qualitative methods while also collecting and analyzing data in both countries that would address the mental health concerns experienced by respective care providers. A case study exemplar was embedded with a scripted focus group guide to collect data from U. S. focus groups, then share with Cambodian psychiatrists. Components of hermeneutic phenomenological interviewing and descriptive content analysis were used to simultaneously teach and enact the research methods, gather data in both countries to analyze, and inspire participants to replicate the methods in their ongoing work. Cambodian psychiatrists were able to demonstrate competence in facilitating focus groups after being participant-observers. Researcher/practitioners from both U. S. and Cambodian teams gained new understandings about the mental health needs of their patients. The mutual engagement of a research focus is an effective way to establish cross-cultural relationships. The challenges of staying with stable teams over times remain, but the content shared and learned in a participatory structure yields understandings that cross cultural boundaries. Anticipated and unexpected challenges may be offset by an intention of reciprocity and mutual engagement. The use of qualitative methodologies, early and repeatedly, can facilitate relational understanding.

PrEP Uptake and Methamphetamine Use Patterns in a 4-Year U.S. National Prospective Cohort Study of Sexual and Gender Minority People, 2017-2022.

Methamphetamine use is on the rise among sexual and gender minority people who have sex with men (SGMSM), escalating their HIV risk. Despite pre-exposure prophylaxis (PrEP) being an effective biomedical HIV prevention tool, its uptake in relation to methamphetamine use patterns in SGMSM has not been studied. In a U.S. cohort study from 2017 to 2022, 6,253 HIV-negative SGMSM indicated for but not using PrEP were followed for four years. Methamphetamine use was categorized (i.e., newly initiated, persistently used, never used, used but quit), and PrEP uptake assessed using generalized estimating equation (GEE), adjusted for attrition. Participants had a median age of 29, with 51.9% White, 11.1% Black, 24.5% Latinx, and 12.5% other races/ethnicities. Over the four years, PrEP use increased from 16.3 to 27.2%. GEE models identified risk factors including housing instability and food insecurity. In contrast, older age, health insurance, clinical indications, and prior PrEP use increased uptake. Notably, Latinx participants were more likely to use PrEP than Whites. Regarding methamphetamine use, those who newly initiated it were more likely to use PrEP compared to non-users. However, those who quit methamphetamine and those who persistently used it had PrEP usage rates comparable to those of non-users. Though PrEP uptake increased, it remained low in SGMSM. Methamphetamine use was associated with PrEP uptake. Healthcare providers should assess methamphetamine use for harm reduction. Prioritizing younger, uninsured SGMSM and addressing basic needs can enhance PrEP uptake and reduce HIV vulnerabilities.

Sexual and Gender Minorities' Vaccine Uptake and Behavioral Change in Response to the Mpox Outbreak in the United States: August 2022 Through November 2022.

BACKGROUND: In the summer of 2022, the United States faced a nationwide outbreak of mpox, with cases concentrated in sexual and gender minorities who have sex with men. Understanding rates of mpox vaccine uptake and concomitant behavioral change is essential to guide the implementation of targeted public health responses to the potential reemergence of mpox. METHODS: Between August 2022 and November 2022, 8551 individuals recruited via geosocial networking apps completed a brief survey that assessed mpox vaccine uptake, intentions to get a mpox vaccine, and behavioral change. RESULTS: In August, 17.4% of participants reported having received at least 1 dose of the mpox vaccine. By November, this prevalence estimate was 35.0%. Black participants were significantly less likely to be vaccinated, and vaccine hesitancy increased among Black participants over time. Among those who had not yet received a vaccination, the intention to get vaccinated decreased over time. We observed trends that coincided with the evolving outbreak, such as decreased worry about mpox and less engagement in risk reduction behaviors over time. CONCLUSIONS: Despite a 2-fold increase in mpox vaccine uptake between August 2022 and November 2022 in sexual and gender minorities who have sex with men, disparities in vaccine uptake were observed among Black participants. Findings will guide the implementation of public health responses to the potential reemergence of mpox and other viral infectious diseases (eg, meningitis) with a specific focus on optimizing vaccine uptake in Black communities.

Problematic Cannabis Use Is Associated with Reduced Rectal Microbial Species Richness and Diversity Among a Pilot Sample of Young Sexual and Gender Minorities.

Compared to young heterosexual men, young sexual and gender minorities (YSGM) have elevated systemic inflammation and unique intestinal microbial profiles, influenced by HIV infection and substance use. However, links between cannabis use and microbial dysbiosis in this population have not been well described. In this pilot study, we aimed to characterize the complex interrelationships between cannabis use and microbial community structure in YSGM in relationship to HIV status. Cannabis use was assessed by self-administered Cannabis Use Disorder Identification Test (CUDIT) questionnaires and rectal microbial community alpha-diversity metrics were assessed via 16S ribosomal ribonucleic acid (rRNA) sequencing in a subset of YSGM (n = 42) in the RADAR cohort (aged 16-29) in Chicago. Multivariable regression models were used to assess the relationship between cannabis use and microbiome alpha-diversity metrics, adjusting for HIV status and other risk characteristics, including inflammation, which was evaluated by plasma levels of C-reactive protein (CRP). Problematic cannabis use, but not general use, was significantly inversely associated with microbial community richness (Adj. Beta = -8.13; 95% confidence interval [CI]: -15.68 to -0.59) and Shannon diversity (Adj. Beta = -0.04; 95% CI: -0.07 to 0.009). No significant association was observed between CUDIT score and community evenness, nor was any significant moderation observed by HIV status. We observed that problematic cannabis use was associated with reduced microbial community richness and Shannon diversity, adjusting for within population differences in inflammation and HIV status. Future research should aim to assess how cannabis use contributes to microbiome-related health factors among YSGM and if decreasing cannabis use can restore gut microbial community structure.

In the Interest of Time: Assessing the Role of Resilience Across an Intergenerational Sample of People Living with HIV.

BACKGROUND: Biomedical advances have improved the quality of life of people living with HIV (PLWH); however, barriers to optimal well-being remain. A key feature in understanding the lived experiences of PLWH is resilience. The concept of resilience is quite complex in terms of its antecedents and expressions, suggesting the need for more nuanced understandings of how it could be harnessed to better support this population. METHOD: The concept of resilience was explored in a qualitative study involving 22 PLWH, selectively sampled by era of diagnosis. Through interviews focused on context and experiences of living with HIV, the sample highlighted resilience processes corresponding to Positive reappraisal of life events, Positive reappraisal of self, and Community as resilience. RESULTS: Participants who have lived with HIV longer more commonly described engaging in psychological processes of resilience, whereas those who were more recently diagnosed reported engaging in more social processes. However, these processes were not mutually exclusive and the ability to perform resilience through community seems to be key to optimizing outcomes, irrespective of era of diagnosis. CONCLUSION: PLWH are a heterogeneous population where engagement in distinct processes of resilience may have important implications for optimal social and health outcomes. Better understanding of the distinct and diverse pathways through which PLWH engage in resilience may inform interventions promoting optimal well-being.

Examining the Effect of SARS-CoV-2 Pandemic-Induced Stress and Anxiety on Humoral Immunity in Health Care Workers.

OBJECTIVE: The effect of stress on vaccine-induced humoral immunity and therapeutic interventions to mitigate pandemic-related stress remain underexplored. METHOD: Participants in a longitudinal cohort study ( n = 189) completed a validated measure, GAD-7, and 10-instrument stress measure to assess stress and anxiety after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. Serum was collected to obtain SARS-CoV-2 antibody titer levels. RESULTS: Participants experienced increased stress due to the SARS-CoV-2 pandemic with a positive correlation between GAD-7 scores and peak antibody titers overall; however, there was a negative association with scores commensurate with severe anxiety. Health care workers and younger participants were more significantly affected by anxiety. CONCLUSIONS: Mild anxiety levels may have immune-enhancing effects, whereas severe anxiety may cause antibody generation reduction. Mental health-focused interventions are imperative for younger adults and health care workers. Young adults may be more resilient to increased stress levels.

Brief Report: Substance Use Care Continuum in Women With and Without HIV in the Southern United States.

BACKGROUND: Substance use (SU) contributes to poor outcomes among persons living with HIV. Women living with HIV (WWH) in the United States are disproportionately affected in the South, and examining SU patterns, treatment, and HIV outcomes in this population is integral to addressing HIV and SU disparities. METHODS: WWH and comparable women without HIV (WWOH) who enrolled 2013-2015 in the Women's Interagency HIV Study Southern sites (Atlanta, Birmingham/Jackson, Chapel Hill, and Miami) and reported SU (self-reported nonmedical use of drugs) in the past year were included. SU and treatment were described annually from enrollment to the end of follow-up. HIV outcomes were compared by SU treatment engagement. RESULTS: At enrollment, among 840 women (608 WWH, 232 WWOH), 18% (n = 155) reported SU in the past year (16% WWH, 24% WWOH); 25% (n = 38) of whom reported SU treatment. Over time, 30%, 21%, and 18% reported SU treatment at 1, 2, and 3 years, respectively, which did not significantly differ by HIV status. Retention in HIV care did not differ by SU treatment. Viral suppression was significantly higher in women who reported SU treatment only at enrollment ( P = 0.03). CONCLUSIONS: We identified a substantial gap in SU treatment engagement, with only a quarter reporting treatment utilization, which persisted over time. SU treatment engagement was associated with viral suppression at enrollment but not at other time points or with retention in HIV care. These findings can identify gaps and guide future strategies for integrating HIV and SU care for WWH.

HIV Prevention and Care Among Black Cisgender Sexual Minority Men and Transgender Women: Protocol for an HIV Status-Neutral Cohort Study Using an Observational-Implementation Hybrid Approach.

BACKGROUND: Black cisgender gay, bisexual, and other sexual minority men (SMM) and transgender women (TW) continue to be heavily affected by HIV. Further research is needed to better understand HIV prevention and care outcomes in this population. In particular, there is a need for research examining the impact of substance use and sleep health on HIV prevention and treatment outcomes among Black SMM and TW. OBJECTIVE: This paper outlines the study methods being used in the recently launched follow-up study to the Neighborhoods and Networks (N2) study, which we refer to as N2 Part 2 (N2P2). N2P2 aims to address this gap in the literature, build off the findings of the original N2 study, and identify socioenvironmental determinants of health, including whether neighborhood and network factors mediate and moderate these relationships. METHODS: Building on the N2 cohort study in Chicago from 2018 to 2022, N2P2 used a prospective longitudinal cohort design and an observational-implementation hybrid approach. With sustained high levels of community engagement, we aim to recruit a new sample of 600 Black SMM and TW participants residing in the Chicago metropolitan statistical area. Participants are asked to participate in 3 study visits across an 18-month study period (1 visit every 9 months). Four different forms of data are collected per wave: (1) an in-person survey, (2) biological specimen collection, (3) a daily remote ecological momentary assessment for 14 days after each study visit, and (4) data from electronic health records. These forms of data collection continue to assess neighborhood and network factors and specifically explore substance use, sleep, immune function, obesity, and the implementation of potential interventions that address relevant constructs (eg, alcohol use and pre-exposure prophylaxis adherence). RESULTS: The N2P2 study was funded in August 2021 by the National Institute of Drug Abuse (R01DA054553 and R21DA053156) and National Heart, Lung, and Blood Institute (R01HL160325). This study was launched in November 2022. Recruitment and enrollment for the first wave of data collection are currently ongoing. CONCLUSIONS: The N2P2 study is applying innovative methods to comprehensively explore the impacts of substance use and sleep health on HIV-related outcomes among an HIV status-neutral cohort of Black SMM and TW in Chicago. This study is applying an observational-implementation hybrid design to help us achieve findings that support rapid translation, a critical priority among populations such as Black SMM and TW that experience long-standing inequities with regard to HIV and other health-related outcomes. N2P2 will directly build off the findings that have resulted from the original N2 study among Black SMM and TW in Chicago. These findings provide a better understanding of multilevel (eg, individual, network, and neighborhood) factors that contribute to HIV-related outcomes and viral suppression among Black SMM and TW. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/48548.