HIV Testing and Preexposure Prophylaxis Prescriptions Among U.S. Commercially Insured Transgender Men and Women, 2014 to 2021.

BACKGROUND: Transgender persons are disproportionately affected by HIV, but preexposure prophylaxis (PrEP) use has been low in this population. Clinical encounters for gender-affirming hormone therapy (GAHT) provide opportunities for HIV prevention. OBJECTIVE: To estimate the number of commercially insured transgender women (TGW) and transgender men (TGM) in the United States and their use of HIV prevention services. DESIGN: Retrospective analysis of secondary data. SETTING: Merative MarketScan commercial databases from 2014 to 2021. PARTICIPANTS: TGW and TGM, defined as those with transgender-related diagnoses and prescriptions for feminizing or masculinizing GAHT. MEASUREMENTS: HIV testing and PrEP use. RESULTS: A substantially increasing trend was observed in the prevalence of transgender-related diagnosis codes from 2014 to 2021 and in the proportion of persons who used GAHT. The increases were driven by persons aged 18 to 34 years. In 2021, among 10 613 TGW with a test for or a diagnosis of a sexually transmitted infection (STI) in the previous 12 months, 61.1% had an HIV test; among those, 20.2% were prescribed PrEP. Among 4184 TGM with STI risk, 48.3% had an HIV test; among those, 10.2% were prescribed PrEP. The prevalence of TGW and TGM who had a test for or a diagnosis of an STI, had an HIV test, and were prescribed PrEP increased substantially from 2014 to 2021. LIMITATION: The findings represent only persons with commercial health insurance who sought health care services for GAHT. CONCLUSION: It is important to identify transgender persons to monitor their receipt of HIV prevention services. Encounters for GAHT provide opportunities to offer HIV prevention and other prevention services. Many HIV prevention opportunities were likely missed at clinical encounters for GAHT. PRIMARY FUNDING SOURCE: None.

Factors Associated with Use of HIV Prevention and Health Care Among Transgender Women - Seven Urban Areas, 2019-2020.

Transgender women* are disproportionately affected by HIV. Among 1,608 transgender women who participated in CDC's National HIV Behavioral Surveillance (NHBS) during 2019-2020, 42% received a positive HIV test result (1). This report provides results from seven U.S. urban areas where the 2019-2020 NHBS questionnaire was administered. Thirty-eight percent of participants reported having previously received a positive test result for HIV. Detrimental socioeconomic factors, including low income (44%), homelessness (39%), and severe food insecurity in the past 12 months (40%), were common and associated with lower receipt of HIV prevention and treatment services. Having a usual health care source or a provider with whom the participant was comfortable discussing gender-related health issues was associated with improved HIV prevention and treatment outcomes, including HIV testing, preexposure prophylaxis (PrEP) use, and viral suppression. These findings illustrate the benefit of gender-affirming approaches used by health care providers (2), and highlight the challenging socioeconomic conditions faced by many transgender women. Ensuring access to gender-affirming health care approaches and addressing the socioeconomic challenges of many transgender women could improve access to and use of HIV prevention and care in this population and will help achieve the goals of the Ending the HIV Epidemic in the United States initiative (3).

Epidemiologic and Clinical Features of Mpox in Transgender and Gender-Diverse Adults - United States, May-November 2022.

As of November 9, 2022, a total of 28,730 cases of monkeypox (mpox) had been reported in the United States,* primarily among adult cisgender men reporting recent male-to-male sexual contact (1). Transgender and gender-diverse persons, who constitute an estimated 0.5% of the U.S. adult population,† face unique health disparities and barriers to care (2-4). However, data on the epidemiologic and clinical features of Monkeypox virus infections in this population are limited (5). CDC analyzed U.S. case surveillance data on mpox cases in transgender and gender-diverse adults reported during May 17-November 4, 2022. During this period, 466 mpox cases in transgender and gender-diverse adults were reported, accounting for 1.7% of reported cases among adults. Most were in transgender women (43.1%) or gender-diverse persons (42.1%); 14.8% were in transgender men. Among 374 (80.3%) mpox cases in transgender and gender-diverse adults with information available on sexual or close intimate contact, 276 (73.8%) reported sexual or close intimate contact with a cisgender male partner during the 3 weeks preceding symptom onset. During the ongoing outbreak, transgender and gender-diverse persons have been disproportionately affected by mpox. Members of this population frequently reported recent sexual or close intimate contact with cisgender men, who might be in sexual networks experiencing the highest incidence of mpox. These findings highlight the importance of tailoring public health prevention and outreach efforts to transgender and gender-diverse communities and could guide strategies to reduce mpox transmission.

Behavioral Efficacy of a Sexual Health Mobile App for Men Who Have Sex With Men: Randomized Controlled Trial of Mobile Messaging for Men.

BACKGROUND: Gay, bisexual, and other men who have sex with men (GBMSM) face the highest burden of HIV in the United States, and there is a paucity of efficacious mobile health (mHealth) HIV prevention and care interventions tailored specifically for GBMSM. We tested a mobile app combining prevention messages and access to core prevention services for GBMSM. OBJECTIVE: This study aims to measure the efficacy of the Mobile Messaging for Men (M-cubed) app and related services to increase HIV prevention and care behaviors in diverse US GBMSM. METHODS: We conducted a randomized open-label study with a waitlist control group among GBMSM in 3 groups (low-risk HIV-negative group, high-risk HIV-negative group, and living-with-HIV [LWH] group) recruited online and in venues in Atlanta, Detroit, and New York City. Participants were randomly assigned to receive access to the app immediately or at 9 months after randomization. The app provided prevention messages in 6 domains of sexual health and offered ordering of at-home HIV and sexually transmitted infection test kits, receiving preexposure prophylaxis (PrEP) evaluations and navigation, and service locators. Serostatus- and risk-specific prevention outcomes were evaluated at baseline, at the end of the intervention period, and at 3, 6, and 9 months after the intervention period. RESULTS: In total, 1226 GBMSM were enrolled and randomized; of these 611 (49.84%) were assigned to the intervention group and 608 (99.51%) were analyzed, while 615 (50.16%) were assigned to the control group and 612 (99.51%) were analyzed. For high-risk GBMSM, allocation to the intervention arm was associated with higher odds of HIV testing during the intervention period (adjusted odds ratio [aOR] 2.02, 95% CI 1.11-3.66) and with higher odds of using PrEP in the 3 months after the intervention period (aOR 2.41, 95% CI 1.00-5.76, P<.05). No changes in HIV prevention or care were associated with allocation to the intervention arm for the low-risk HIV-negative and LWH groups. CONCLUSIONS: Access to the M-cubed app was associated with increased HIV testing and PrEP use among high-risk HIV-negative GBMSM in 3 US cities. The app could be made available through funded HIV prevention providers; additional efforts are needed to understand optimal strategies to implement the app outside of the research setting. TRIAL REGISTRATION: ClinicalTrials.gov NCT03666247; https://clinicaltrials.gov/ct2/show/NCT03666247. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/16439.

Nonprescription Hormone Use Among Transgender Women - National HIV Behavioral Surveillance Among Transgender Women, Seven Urban Areas, United States, 2019-2020.

Certain transgender women who seek gender-affirming hormone treatment (GAHT) face economic and social barriers that limit or prevent access to medically supervised GAHT. Transgender women facing such barriers might acquire GAHT without prescription, potentially without proper dosage, administration, and health monitoring in the absence of medical supervision. For this report, survey data were analyzed from 1,165 transgender women in seven urban areas in the United States to examine associations between self-reported use of nonprescription GAHT and known correlates of nonprescription GAHT, including cost, insurance coverage for GAHT, homelessness, receiving money or drugs in exchange for sex during the past 12 months (exchange sex), lack of comfort discussing gender with provider, and lack of health care use. After controlling for complex sampling design, transgender women who reported recent health care use or insurance coverage for GAHT were less likely to report nonprescription GAHT, and those reporting recent exchange sex or recent homelessness were more likely to report nonprescription GAHT. Findings suggest that transgender women were more likely to use GAHT without a prescription in situations of economic and social marginalization (e.g., disengagement from health care, lack of insurance or trans-specific health care, homelessness, or engagement in sex work). Public health professionals can use these results to design effective interventions to facilitate prescribed hormone use among transgender women in the United States, although access to housing, trans-affirming health care, and insurance coverage might be needed to prevent nonprescription use.

Characteristics Associated with Pre-Exposure Prophylaxis Discussion and Use Among Transgender Women Without HIV Infection - National HIV Behavioral Surveillance Among Transgender Women, Seven Urban Areas, United States, 2019-2020.

CDC recommends pre-exposure prophylaxis (PrEP) for transgender women who have sex with men and who report sexual behaviors that place them at substantial ongoing risk for HIV exposure, including those who engage in nonsterile syringe sharing. Providing transgender women with access to PrEP is a critical strategy for reducing HIV acquisition and ending the HIV epidemic. Survey results from the National HIV Behavioral Surveillance Among Transgender Women were used to assess characteristics associated with past-year discussions of PrEP with a health care provider and PrEP use. Bivariate analyses were conducted to assess the association between covariates (sociodemographic, HIV-associated characteristics, and gender-affirming care) and each outcome, accounting for sampling design. All covariates that were statistically significant at p<0.05 in the bivariate analyses were included in multivariate models, and manual backward elimination was used to obtain final models that retained statistically significant covariates. Among 902 transgender women from seven urban areas in the United States without HIV infection in the analyses, 57% had recently discussed PrEP with a health care provider, and 32% recently had used PrEP. In the final multivariate model, the following subgroups of transgender women were more likely to report recent PrEP use: those who identified as Black or African American or Hispanic or Latina, had two or more sex partners in the past 12 months, had condomless sex in the past 12 months, reported their last sex partner was infected with HIV, had condomless sex with their last sex partner whose HIV status was positive or unknown, ever had transgender-specific health care, and currently had transgender-specific health insurance coverage. Participants who were less likely to have recently used PrEP were those who wanted to but were not currently taking hormones and those aged <40 years. Providing increased access to gender-affirming care and training health care providers who serve transgender women to incorporate PrEP into existing services might increase PrEP use among transgender women.

Social Support and the Association Between Certain Forms of Violence and Harassment and Suicidal Ideation Among Transgender Women - National HIV Behavioral Surveillance Among Transgender Women, Seven Urban Areas, United States, 2019-2020.

Violence and harassment toward transgender women are associated with suicidal thoughts and behaviors, and social support might moderate such association. This analysis explored the association between certain forms of violence and harassment and suicidal ideation and moderation by social support. Better understanding of these associations could guide mental health services and structural interventions appropriate to lived experiences of transgender women. This cross-sectional analysis used data from CDC's National HIV Behavioral Surveillance Among Transgender Women. During 2019-2020, transgender women were recruited via respondent-driven sampling from seven urban areas in the United States for an HIV biobehavioral survey. The association between experiencing certain forms of violence and harassment (i.e., gender-based verbal and physical abuse or harassment, physical intimate partner abuse or harassment, and sexual violence) and suicidal ideation was measured using adjusted prevalence ratios and 95% CIs generated from log-linked Poisson regression models controlling for respondent-driven sampling design and confounders. To examine moderation, the extents of social support from family, friends, and significant others were assessed for interaction with certain forms of violence and harassment; if p interaction was <0.05, stratified adjusted prevalence ratios were presented. Among 1,608 transgender women, 59.7% experienced certain forms of violence and harassment and 17.7% reported suicidal ideation during the past 12 months; 75.2% reported high social support from significant others, 69.4% from friends, and 46.8% from family. Experiencing certain forms of violence and harassment and having low-moderate social support from any source was associated with higher prevalence of suicidal ideation. Social support from family moderated the association between experiencing certain forms of violence and harassment and suicidal ideation (p interaction = 0.01); however, even in the presence of high family social support, experiencing certain forms of violence and harassment was associated with higher prevalence of suicidal ideation. Social support did not completely moderate the positive association between experiencing violence and harassment and suicidal ideation. Further understanding of the social support dynamics of transgender women might improve the quality and use of social support. Policymakers and health care workers should work closely with transgender women communities to reduce the prevalence of violence, harassment, and suicide by implementing integrated, holistic, and transinclusive approaches.

The Association Between Sexual Violence and Suicidal Ideation Among Transgender Women and the Role of Gender-Affirming Healthcare Providers in Seven Urban Areas in the United States, 2019 to 2020.

Transgender women are disproportionately affected by sexual violence and corresponding mental health sequelae; however, many do not access healthcare due to experiences with transphobia. This analysis evaluated the association between sexual violence and suicidal ideation and the moderating effect of having a healthcare provider (HCP) with whom transgender women were comfortable discussing gender-related issues ("gender-affirming HCP"). We analyzed cross-sectional data from the Centers for Disease Control and Prevention's National HIV Behavioral Surveillance among Transgender Women (NHBS-Trans). Transgender women were recruited using respondent-driven sampling from seven urban areas from 2019 to 2020 and participated in an HIV biobehavioral survey. This analysis was restricted to transgender women who visited a HCP in the past 12 months ("healthcare-seeking transgender women" [HSTW]) (N = 1,489). Log-linked Poisson regression models provided adjusted prevalence ratios (aPRs) and 95% confidence intervals (CIs) to estimate the association between sexual violence and suicidal ideation in the past 12 months. The interaction between sexual violence and having a gender-affirming HCP was statistically significant (p-value = .034). Among 1,489 HSTW, 225 (15.1%) experienced sexual violence and 261 (17.5%) reported suicidal ideation; 1,203 (80.8%) reported having a gender-affirming HCP. Sexual violence was associated with suicidal ideation (aPR = 2.65, 95% CI [2.08, 3.38]); the association was notably higher among those who did not have a gender-affirming HCP (aPR = 3.61, [2.17, 6.02]) than among those who did (aPR = 1.87, [1.48, 2.37]). Eliminating transphobia and promoting trauma- and violence-informed approaches in healthcare are necessary for sexual violence and suicide prevention among HSTW.

Structural and Psychosocial Syndemic Conditions and Condomless Anal Intercourse Among Transgender Women - National HIV Behavioral Surveillance Among Transgender Women, Seven Urban Areas, United States, 2019-2020.

Psychosocial and structural syndemic conditions, including polydrug use and experiencing homelessness, frequently co-occur and might jointly increase HIV risk. Limited studies have assessed racial and ethnic differences in exposure to syndemic conditions and behaviors associated with HIV transmission among transgender women. This report examines the relation between syndemic conditions and condomless anal intercourse (CAI) among transgender women in seven urban areas in the United States to develop HIV prevention interventions for transgender women. During 2019-2020, transgender women in seven urban areas were recruited using respondent-driven sampling for a biobehavioral survey. Reported syndemic conditions (psychosocial: polydrug use, sexual violence, and psychological distress; structural: homelessness, incarceration, and exchange sex) were summed to create a syndemic score. Using modified Poisson regression to account for RDS, the study assessed whether the strength of the association between syndemic score and CAI differed by race and ethnicity. To assess additive interaction, the relative excess prevalence owing to interaction (REPI) and 95% CIs for selected pairs of syndemic conditions on CAI prevalence stratified by race and ethnicity were estimated. Of 1,348 transgender women (Black = 546, White = 176, and Hispanic = 626), 55% reported CAI; and 24% reported ≥3 syndemic conditions. Reporting additional syndemic conditions was associated with CAI for White, Hispanic, and Black participants. The association was significantly stronger for White than Black and Hispanic participants. Limited significant superadditive interactions were found, although the majority were between structural syndemic conditions. Racial and ethnic differences in REPI estimates were observed. Reporting more syndemic conditions was associated with increased CAI across racial and ethnic groups, demonstrating that HIV prevention efforts for transgender women should address structural and psychosocial syndemic conditions. Results differed by race and ethnicity, indicating that syndemic-focused interventions for transgender women should be tailored to racial and ethnic groups.

Transgender Women Experiencing Homelessness - National HIV Behavioral Surveillance Among Transgender Women, Seven Urban Areas, United States, 2019-2020.

Transgender women experience high prevalence of homelessness, which can affect their likelihood of acquiring HIV infection and can lead to poor medical outcomes. CDC analyzed data from the National HIV Behavioral Surveillance Among Transgender Women to identify whether personal characteristics and social factors affecting transgender women were associated with duration of homelessness during the past 12 months. Longer duration and chronic homelessness might indicate greater unmet needs, which increases their likelihood for acquiring HIV infection. Ordinal logistic regression was conducted to calculate adjusted prevalence odds ratios and 95% CIs for transgender women from seven urban areas in the United States experiencing homelessness 30-365 nights, 1-29 nights, and zero nights during the past 12 months. Among 1,566 transgender women, 9% reported 1-29 nights homeless and 31% reported 30-365 nights homeless during the past 12 months. Among participants who reported physical intimate partner violence or forced sex, 50% and 47%, respectively, reported experiencing 30-365 nights homeless. Furthermore, 55% who had been evicted or denied housing because of their gender identity and 58% who had been incarcerated during the past year experienced 30-365 nights homeless. The odds of transgender women experiencing longer duration of homelessness was associated with being younger and having a disability; higher psychological distress scores were associated with longer duration of homelessness. Analysis of social determinants of health found transgender women experiencing longer homelessness to be less educated, living below the Federal poverty level, and having lower social support. Therefore, focusing on HIV prevention and interventions addressing housing instability to reduce the duration of homelessness among transgender women is important. Further, integrating housing services with behavioral health services and clinical care, specifically designed for transgender women, could reduce HIV acquisition risk and improve HIV infection outcomes.

Overview and Methodology of the National HIV Behavioral Surveillance Among Transgender Women - Seven Urban Areas, United States, 2019-2020.

Transgender women, especially transgender women of color, are disproportionately affected by HIV. However, no surveillance system collects data on HIV risk factors among this population. To address this gap, CDC developed a surveillance system entitled National HIV Behavioral Surveillance Among Transgender Women (NHBS-Trans) to assess behavioral and contextual data through systematic biobehavioral surveillance to monitor behavioral risk factors, prevention usage, and HIV prevalence among transgender women. NHBS-Trans used respondent-driven sampling in seven urban areas in the United States. Trained interviewers used a standardized, anonymous questionnaire to collect information on HIV-related behavioral risk factors, HIV testing, and use of prevention services. Each of the seven participating project areas recruited approximately 200 eligible transgender women and offered anonymous HIV testing. Overall, in the seven project areas, 1,757 participants completed the eligibility screener for NHBS-Trans during 2019-2020; of these, 6.6% were seeds (i.e., a limited number of initial participants who were chosen by referrals from persons and community-based organizations who knew or were part of the local population of transgender women). A total of 1,637 (93.2%) participants were eligible, consented, and completed the interview. Of these, 1,624 (99.2%) agreed to HIV testing. Of the total 1,637 participants, 29 participants did not report identity of woman or transgender woman, resulting in a final sample of 1,608 transgender women. NHBS-Trans project area staff members (n = 14) reported that the survey was timely and addressed a critical need for HIV surveillance in a population that is often overlooked. The MMWR supplement includes this overview report on NHBS-Trans, which describes the methods (history, participant eligibility criteria, questionnaire, data collection, and HIV testing) as well as evaluation of project implementation and the performance of the questionnaire content, specifically the acceptability for transgender women. The other NHBS-Trans reports in the supplement include information on pre-exposure prophylaxis use, psychosocial syndemic conditions and condomless anal intercourse, nonprescription hormone use, homelessness, discrimination and the association between employment discrimination and health care access and use, and social support and the association between certain types of violence and harassment (gender-based verbal and physical abuse or harassment, physical intimate partner abuse or harassment, and sexual violence) and suicidal ideation. NHBS-Trans provides important data related to the goals of the Ending the HIV Epidemic in the U.S. initiative. Findings from NHBS-Trans can help guide community leaders, clinicians, and public health officials in improving access to and use of HIV prevention and treatment services by transgender women.

Prevalence of Discrimination and the Association Between Employment Discrimination and Health Care Access and Use - National HIV Behavioral Surveillance Among Transgender Women, Seven Urban Areas, United States, 2019-2020.

Transgender women experience discrimination in many settings, including in employment. Because employment and health insurance are intertwined in the United States, employment discrimination might be related to lower health insurance coverage and health care use, including gender-affirming care. This analysis used data from transgender women (N = 1,608) in seven urban areas in the United States collected during 2019-2020 to present the prevalence of six discrimination types (employment, housing, bathroom, businesses, health care, and abuse) and to measure the association between employment discrimination (defined as trouble getting a job or fired due to being transgender) and sociodemographic characteristics, health care access, and health care use. Log-linked Poisson regression models were conducted to estimate adjusted prevalence ratios and 95% CIs. Seven in 10 transgender women experienced at least one type of discrimination during the past 12 months. During the same period, 9.9% of transgender women were fired and 32.4% had trouble getting a job because of being transgender. Employment discrimination was associated with younger age and lower socioeconomic status. Having trouble getting a job was associated with health care access and health care use factors, including having no health insurance or having Medicaid only, having an unmet medical need because of cost, never having transgender-specific care, and having an unmet need for gender-affirming procedures. These findings suggest that employment discrimination contributes to transgender women's economic marginalization and their ability to obtain adequate health insurance coverage and achieve their transition goals. These findings might help guide efforts that protect transgender women's right to pursue their work, health, and life goals without discrimination.

Video selection and assessment for an app-based HIV prevention messaging intervention: formative research.

Background: Gay, bisexual, and other men who have sex with men (GBMSM) continue to be overrepresented in human immunodeficiency virus (HIV) infection in the United States. HIV prevention and care interventions that are tailored to an individual's serostatus have the potential to lower the rate of new infections among GBMSM. Mobile technology is a critical tool for disseminating targeted messaging and increasing uptake of basic prevention services including HIV testing, sexually transmitted infection (STI) testing, and pre-exposure prophylaxis (PrEP). Mobile Messaging for Men (M-Cubed) is a mobile health HIV prevention intervention designed to deliver video- and text-based prevention messages, provide STI and HIV information, and link GBMSM to prevention and healthcare resources. The current report describes an iterative process of identifying and selecting publicly available videos to be used as part of the M-Cubed intervention. We also conducted interviews with GBMSM to assess the acceptability, comprehension, and potential audience reach of the selected video messages. Methods: The selection of videos included balancing of specific criteria [e.g., accuracy of scientific information, video length, prevention domains: HIV/STI testing, antiretroviral therapy (ART), PrEP, engagement in care, and condom use] to ensure that they were intended for our GBMSM audiences: HIV-negative men who engage in condomless anal sex, HIV-negative men who do not engage in condomless anal sex, and men living with HIV. This formative study included in-person interviews with 26 GBMSM from three U.S. cities heavily impacted by the HIV epidemic-New York City, Detroit, and Atlanta. Results: Following a qualitative content analysis, the study team identified five themes across the interviews: participant reactions to the video messages, message comprehension, PrEP concerns, targeting of video messaging, and prompted action. Conclusions: Study results informed a final selection of 12 video messages for inclusion in a randomized controlled trial of M-Cubed. Findings may serve as a guide for researchers who plan to develop HIV prevention interventions that utilize publicly available videos to promote behavioral change. Further, the findings presented here suggest the importance of developing videos with broad age and gender diversity for use in interventions such as M-Cubed, and in other health promotion settings.

PrEP Awareness in the Context of HIV/AIDS Conspiracy Beliefs Among Black/African American and Hispanic/Latino MSM in Three Urban US Cities.

We examined HIV conspiracy beliefs and PrEP awareness in a convenience sample of minority MSM. Participants in three cities completed a behavioral self-assessment on sociodemographics, PrEP awareness, and HIV/AIDS conspiracy beliefs. HIV/AIDS conspiracy beliefs were more common among Black than Latino MSM (58% vs. 42%, p < .05), and among younger men than older men (age 18-29 (50%), 30-39 (22%), 40+ (28%); p < .05). PrEP awareness co-occurred with conspiracy belief less (37%) than with non-belief (63%, p < .05), persisting in multivariable regression (aOR = 0.52, 95% CI = 0.38-0.71). This relationship suggests that current HIV care and prevention messaging is either inaccessible or not credible to some minority subpopulations.

HIV Prevention Via Mobile Messaging for Men Who Have Sex With Men (M-Cubed): Protocol for a Randomized Controlled Trial.

BACKGROUND: Men who have sex with men (MSM) continue to be the predominately impacted risk group in the United States HIV epidemic and are a priority group for risk reduction in national strategic goals for HIV prevention. Modeling studies have demonstrated that a comprehensive package of status-tailored HIV prevention and care interventions have the potential to substantially reduce new infections among MSM. However, uptake of basic prevention services, including HIV testing, sexually transmitted infection (STI) testing, condom distribution, condom-compatible lubricant distribution, and preexposure prophylaxis (PrEP), is suboptimal. Further, stronger public health strategies are needed to promote engagement in HIV care and viral load suppression among MSM living with HIV. Mobile health (mHealth) tools can help inform and encourage MSM regarding HIV prevention, care, and treatment, especially among men who lack access to conventional medical services. This protocol details the design and procedures of a randomized controlled trial (RCT) of a novel mHealth intervention that comprises a comprehensive HIV prevention app and brief, tailored text- and video-based messages that are systematically presented to participants based on the participants' HIV status and level of HIV acquisition risk. OBJECTIVE: The objective of the RCT was to test the efficacy of the Mobile Messaging for Men (M-Cubed, or M3) app among at least 1200 MSM in Atlanta, Detroit, and New York. The goal was to determine its ability to increase HIV testing (HIV-negative men), STI testing (all men), condom use for anal sex (all men), evaluation for PrEP eligibility, uptake of PrEP (higher risk HIV-negative men), engagement in HIV care (men living with HIV), and uptake of and adherence to antiretroviral medications (men living with HIV). A unique benefit of this approach is the HIV serostatus-inclusiveness of the intervention, which includes both HIV-negative and HIV-positive MSM. METHODS: MSM were recruited through online and venue-based approaches in Atlanta, Detroit, and New York City. Men who were eligible and consented were randomized to the intervention (immediate access to the M3 app for a period of three months) or to the waitlist-control (delayed access) group. Outcomes were evaluated immediately postintervention or control period, and again three and six months after the intervention period. Main outcomes will be reported as period prevalence ratios or hazards, depending on the outcome. Where appropriate, serostatus/risk-specific outcomes will be evaluated in relevant subgroups. Men randomized to the control condition were offered the opportunity to use (and evaluate) the M3 app for a three-month period after the final RCT outcome assessment. RESULTS: M3 enrollment began in January 2018 and concluded in November 2018. A total of 1229 MSM were enrolled. Data collection was completed in September 2019. CONCLUSIONS: This RCT of the M3 mobile app seeks to determine the effects of an HIV serostatus-inclusive intervention on the use of multiple HIV prevention and care-related outcomes among MSM. A strength of the design is that it incorporates a large sample and broad range of MSM with differing prevention needs in three cities with high prevalence of HIV among MSM. TRIAL REGISTRATION: ClinicalTrials.gov NCT03666247; https://clinicaltrials.gov/ct2/show/NCT03666247. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/16439.