Reimagining Preexposure Prophylaxis Provision for Women in the United States.

Structural determinants of health drive inequities in the acquisition of human immunodeficiency virus (HIV) and the use of preexposure prophylaxis (PrEP) for HIV prevention among cisgender women in the United States. However, current PrEP clinical guidance and implementation paradigms largely focus on individual behaviors and characteristics, resulting in missed opportunities to improve PrEP access, and the implicit transferring of prevention work from health systems to individuals. In this viewpoint article, we outline ways to apply a structural lens to clinical guidance and PrEP implementation for women and propose areas for future work.

The Role of R-Ras Proteins in Normal and Pathologic Migration and Morphologic Change.

The contributions that the R-Ras subfamily [R-Ras, R-Ras2/teratocarcinoma 21 (TC21), and M-Ras] of small GTP-binding proteins make to normal and aberrant cellular functions have historically been poorly understood. However, this has begun to change with the realization that all three R-Ras subfamily members are occasionally mutated in Noonan syndrome (NS), a RASopathy characterized by the development of hematopoietic neoplasms and abnormalities affecting the immune, cardiovascular, and nervous systems. Consistent with the abnormalities seen in NS, a host of new studies have implicated R-Ras proteins in physiological and pathologic changes in cellular morphology, adhesion, and migration in the cardiovascular, immune, and nervous systems. These changes include regulating the migration and homing of mature and immature immune cells, vascular stabilization, clotting, and axonal and dendritic outgrowth during nervous system development. Dysregulated R-Ras signaling has also been linked to the pathogenesis of cardiovascular disease, intellectual disabilities, and human cancers. This review discusses the structure and regulation of R-Ras proteins and our current understanding of the signaling pathways that they regulate. It explores the phenotype of NS patients and their implications for the R-Ras subfamily functions. Next, it covers recent discoveries regarding physiological and pathologic R-Ras functions in key organ systems. Finally, it discusses how R-Ras signaling is dysregulated in cancers and mechanisms by which this may promote neoplasia.

R-Ras subfamily proteins elicit distinct physiologic effects and phosphoproteome alterations in neurofibromin-null MPNST cells.

BACKGROUND: Loss of the Ras GTPase-activating protein neurofibromin promotes nervous system tumor pathogenesis in patients with neurofibromatosis type 1 (NF1). Neurofibromin loss potentially hyperactivates classic Ras (H-Ras, N-Ras, K-Ras), M-Ras, and R-Ras (R-Ras, R-Ras2/TC21) subfamily proteins. We have shown that classic Ras proteins promote proliferation and survival, but not migration, in malignant peripheral nerve sheath tumor (MPNST) cells. However, it is unclear whether R-Ras, R-Ras2 and M-Ras are expressed and hyperactivated in MPNSTs and, if so, whether they contribute to MPNST pathogenesis. We assessed the expression and activation of these proteins in MPNST cells and inhibited them to determine the effect this had on proliferation, migration, invasion, survival and the phosphoproteome. METHODS: NF1-associated (ST88-14, 90-8, NMS2, NMS-PC, S462, T265-2c) and sporadic (STS-26T, YST-1) MPNST lines were used. Cells were transfected with doxycycline-inducible vectors expressing either a pan-inhibitor of the R-Ras subfamily [dominant negative (DN) R-Ras] or enhanced green fluorescent protein (eGFP). Methodologies used included immunoblotting, immunocytochemistry, PCR, Transwell migration, 3H-thymidine incorporation, calcein cleavage assays and shRNA knockdowns. Proteins in cells with or without DN R-Ras expression were differentially labeled with SILAC and mass spectrometry was used to identify phosphoproteins and determine their relative quantities in the presence and absence of DN R-Ras. Validation of R-Ras and R-Ras2 action and R-Ras regulated networks was performed using genetic and/or pharmacologic approaches. RESULTS: R-Ras2 was uniformly expressed in MPNST cells, with R-Ras present in a major subset. Both proteins were activated in neurofibromin-null MPNST cells. Consistent with classical Ras inhibition, DN R-Ras and R-Ras2 knockdown inhibited proliferation. However, DN R-Ras inhibition impaired migration and invasion but not survival. Mass spectrometry-based phosphoproteomics identified thirteen protein networks distinctly regulated by DN R-Ras, including multiple networks regulating cellular movement and morphology. ROCK1 was a prominent mediator in these networks. DN R-Ras expression and RRAS and RRAS2 knockdown inhibited migration and ROCK1 phosphorylation; ROCK1 inhibition similarly impaired migration and invasion, altered cellular morphology and triggered the accumulation of large intracellular vesicles. CONCLUSIONS: R-Ras proteins function distinctly from classic Ras proteins by regulating distinct signaling pathways that promote MPNST tumorigenesis by mediating migration and invasion. Mutations of the NF1 gene potentially results in the activation of multiple Ras proteins, which are key regulators of many biologic effects. The protein encoded by the NF1 gene, neurofibromin, acts as an inhibitor of both classic Ras and R-Ras proteins; loss of neurofibromin could cause these Ras proteins to become persistently active, leading to the development of cancer. We have previously shown that three related Ras proteins (the classic Ras proteins) are highly activated in malignant peripheral nerve sheath tumor (MPNST) cells with neurofibromin loss and that they drive cancer cell proliferation and survival by activating multiple cellular signaling pathways. Here, we examined the expression, activation and action of R-Ras proteins in MPNST cells that have lost neurofibromin. Both R-Ras and R-Ras2 are expressed in MPNST cells and activated. Inhibition of R-Ras action inhibited proliferation, migration and invasion but not survival. We examined the activation of cytoplasmic signaling pathways in the presence and absence of R-Ras signaling and found that R-Ras proteins regulated 13 signaling pathways distinct from those regulated by classic Ras proteins. Closer study of an R-Ras regulated pathway containing the signaling protein ROCK1 showed that inhibition of either R-Ras, R-Ras2 or ROCK1 similarly impaired cellular migration and invasion and altered cellular morphology. Inhibition of R-Ras/R-Ras2 and ROCK1 signaling also triggered the accumulation of abnormal intracellular vesicles, indicating that these signaling molecules regulate the movement of proteins and other molecules in the cellular interior. Video Abstract.

What Sexual and Gender Minority People Want Researchers to Know About Sexual Orientation and Gender Identity Questions: A Qualitative Study.

Sexual and gender minority (SGM) people-including members of the lesbian, gay, bisexual, transgender, and queer communities-are understudied and underrepresented in research. Current sexual orientation and gender identity (SOGI) questions do not sufficiently engage SGM people, and there is a critical gap in understanding how SOGI questions reduce inclusion and accurate empirical representation. We conducted a qualitative study to answer the question, "For SGM people, what are the major limitations with current SOGI questions?" Focus groups probed reactions to SOGI questions adapted from prior national surveys and clinical best practice guidelines. Questions were refined and presented in semi-structured cognitive interviews. Template analysis using a priori themes guided analysis. There were 74 participants: 55 in nine focus groups and 19 in cognitive interviews. Participants were diverse: 51.3% identified as gender minorities, 87.8% as sexual minorities, 8.1% as Hispanic/Latinx, 13.5% as Black or African-American, and 43.2% as Non-white. Two major themes emerged: (1) SOGI questions did not allow for identity fluidity and complexity, reducing inclusion and representation, and (2) SOGI question stems and answer choices were often not clear as to which SOGI dimension was being assessed. To our knowledge, this represents the largest body of qualitative data studying SGM perspectives when responding to SOGI questions. We present recommendations for future development and use of SOGI measures. Attention to these topics may improve meaningful participation of SGM people in research and implementation of such research within and for SGM communities.

Identifying the Role of Complement in Triggering Neuroinflammation after Traumatic Brain Injury.

The complement system is implicated in promoting acute secondary injury after traumatic brain injury (TBI), but its role in chronic post-traumatic neuropathology remains unclear. Using various injury-site targeted complement inhibitors that block different complement pathways and activation products, we investigated how complement is involved in neurodegeneration and chronic neuroinflammation after TBI in a clinically relevant setting of complement inhibition. The current paradigm is that complement propagates post-TBI neuropathology predominantly through the terminal membrane attack complex (MAC), but the focus has been on acute outcomes. Following controlled cortical impact in adult male mice, we demonstrate that although inhibition of the MAC (with CR2-CD59) reduces acute deficits, inhibition of C3 activation is required to prevent chronic inflammation and ongoing neuronal loss. Activation of C3 triggered a sustained degenerative mechanism of microglial and astrocyte activation, reduced dendritic and synaptic density, and inhibited neuroblast migration several weeks after TBI. Moreover, inhibiting all complement pathways (with CR2-Crry), or only the alternative complement pathway (with CR2-fH), provided similar and significant improvements in chronic histological, cognitive, and functional recovery, indicating a key role for the alternative pathway in propagating chronic post-TBI pathology. Although we confirm a role for the MAC in acute neuronal loss after TBI, this study shows that upstream products of complement activation generated predominantly via the alternative pathway propagate chronic neuroinflammation, thus challenging the current concept that the MAC represents a therapeutic target for treating TBI. A humanized version of CR2fH has been shown to be safe and non-immunogenic in clinical trials.SIGNIFICANCE STATEMENT Complement, and specifically the terminal membrane attack complex, has been implicated in secondary injury and neuronal loss after TBI. However, we demonstrate here that upstream complement activation products, generated predominantly via the alternative pathway, are responsible for propagating chronic inflammation and injury following CCI. Chronic inflammatory microgliosis is triggered by sustained complement activation after CCI, and is associated with chronic loss of neurons, dendrites and synapses, a process that continues to occur even 30 d after initial impact. Acute and injury-site targeted inhibition of the alternative pathway significantly improves chronic outcomes, and together these findings modify the conceptual paradigm for targeting the complement system to treat TBI.

Recent Advances in the Diagnosis and Pathogenesis of Neurofibromatosis Type 1 (NF1)-associated Peripheral Nervous System Neoplasms.

The diagnosis of a neurofibroma or a malignant peripheral nerve sheath tumor (MPNST) often raises the question of whether the patient has the genetic disorder neurofibromatosis type 1 (NF1) as well as how this will impact the patient's outcome, what their risk is for developing additional neoplasms and whether treatment options differ for NF1-associated and sporadic peripheral nerve sheath tumors. Establishing a diagnosis of NF1 is challenging as this disorder has numerous neoplastic and non-neoplastic manifestations which are variably present in individual patients. Further, other genetic diseases affecting the Ras signaling cascade (RASopathies) mimic many of the clinical features of NF1. Here, we review the clinical manifestations of NF1 and compare and contrast them with those of the RASopathies. We also consider current approaches to genetic testing for germline NF1 mutations. We then focus on NF1-associated neurofibromas, considering first the complicated clinical behavior and pathology of these neoplasms and then discussing our current understanding of the genomic abnormalities that drive their pathogenesis, including the mutations encountered in atypical neurofibromas. As several neurofibroma subtypes are capable of undergoing malignant transformation to become MPNSTs, we compare and contrast patient outcomes in sporadic, NF1-associated and radiation-induced MPNSTs, and review the challenging pathology of these lesions. The mutations involved in neurofibroma-MPNST progression, including the recent identification of mutations affecting epigenetic regulators, are then considered. Finally, we explore how our current understanding of neurofibroma and MPNST pathogenesis is informing the design of new therapies for these neoplasms.

Consensus statement: Supporting Safer Conception and Pregnancy For Men And Women Living with and Affected by HIV.

Safer conception interventions reduce HIV incidence while supporting the reproductive goals of people living with or affected by HIV. We developed a consensus statement to address demand, summarize science, identify information gaps, outline research and policy priorities, and advocate for safer conception services. This statement emerged from a process incorporating consultation from meetings, literature, and key stakeholders. Three co-authors developed an outline which was discussed and modified with co-authors, working group members, and additional clinical, policy, and community experts in safer conception, HIV, and fertility. Co-authors and working group members developed and approved the final manuscript. Consensus across themes of demand, safer conception strategies, and implementation were identified. There is demand for safer conception services. Access is limited by stigma towards PLWH having children and limits to provider knowledge. Efficacy, effectiveness, safety, and acceptability data support a range of safer conception strategies including ART, PrEP, limiting condomless sex to peak fertility, home insemination, male circumcision, STI treatment, couples-based HIV testing, semen processing, and fertility care. Lack of guidelines and training limit implementation. Key outstanding questions within each theme are identified. Consumer demand, scientific data, and global goals to reduce HIV incidence support safer conception service implementation. We recommend that providers offer services to HIV-affected men and women, and program administrators integrate safer conception care into HIV and reproductive health programs. Answers to outstanding questions will refine services but should not hinder steps to empower people to adopt safer conception strategies to meet reproductive goals.

Use of HIV pre-exposure prophylaxis during the preconception, antepartum and postpartum periods at two United States medical centers.

BACKGROUND: Pregnancy may increase a woman's susceptibility to HIV. Maternal HIV acquisition during pregnancy and lactation is associated with increased perinatal and lactational HIV transmission. There are no published reports of preexposure prophylaxis use after the first trimester of pregnancy or during lactation. OBJECTIVE: The purpose of this study was to report the use of preexposure prophylaxis and to identify gaps in HIV prevention services for women who were at substantial risk of HIV preconception and during pregnancy and lactation at 2 United States medical centers. STUDY DESIGN: Chart review was performed on women who were identified as "at significant risk" for HIV acquisition preconception (women desiring pregnancy) and during pregnancy and lactation at 2 medical centers in San Francisco and New York from 2010-2015. Women were referred to specialty clinics for women who were living with or were at substantial risk of HIV. RESULTS: Twenty-seven women who were identified had a median age of 27 years. One-half of the women had unstable housing, 22% of the women had ongoing intimate partner violence, and 22% of the women had active substance use. Twenty-six women had a male partner living with HIV, and 1 woman had a male partner who had sex with men. Of the partners who were living with HIV, 73% (19/26) were receiving antiretroviral therapy, and 42% (11/26) had documented viral suppression. Thirty-nine percent (10/26) of partners had known detectable virus, and 19% (5/26) had unknown viral loads. Women were identified by clinicians, health educators, and health departments. Approximately one-third of the women were identified preconception (8/27); the majority of the women were identified during pregnancy (18/27) with a median gestational age of 20 weeks (interquartile range, 11-23), and 1 woman was identified in the postpartum period. None of the pregnant referrals had received safer conception counseling to reduce HIV transmission. Twenty-six percent of all women (7/27) were eligible for postexposure prophylaxis at referral, of whom 57% (4/7) were offered postexposure prophylaxis. In 30% (8/27), the last HIV exposure was not assessed and postexposure prophylaxis was not offered. The median time from identification as "at substantial risk" to consultation was 30 days (interquartile range, 2-62). Two women were lost to follow up before consultation. One woman who was identified as "at significant risk" was not referred because of multiple pregnancy complications. She remained in obstetrics care and was HIV-negative at delivery but was lost to follow up until 10 months after delivery when she was diagnosed with HIV. No other seroconversions were identified. Of referrals who presented and were offered preexposure prophylaxis, 67% women (16/24) chose to take it, which was relatively consistent whether the women were preconception (5/8), pregnant (10/15), or after delivery (1/1). Median length of time on preexposure prophylaxis was 30 weeks (interquartile range, 20-53). One-half of women (10/20) who were in care at delivery did not attend a postpartum visit. CONCLUSION: Women at 2 United States centers frequently chose to use preexposure prophylaxis for HIV prevention when it was offered preconception and during pregnancy and lactation. Further research and education are needed to close critical gaps in screening for women who are at risk of HIV for pre- and postexposure prophylaxis eligibility and gaps in care linkage before and during pregnancy and lactation. Postpartum women are particularly vulnerable to loss-to-follow-up and miss opportunities for safe and effective HIV prevention.

PrEP as Peri-conception HIV Prevention for Women and Men.

Daily oral tenofovir (TDF)-based pre-exposure prophylaxis (PrEP) is an effective HIV prevention strategy and recommended for men and women with substantial risk of HIV acquisition. The peri-conception period, the stage prior to pregnancy when condom use is necessarily reduced, has elevated HIV risk that can be mitigated by PrEP use. Data from a randomized trial suggest that peri-conception PrEP use by HIV-seronegative women does not increase the risk of pregnancy loss, birth defects or congenital anomalies, preterm birth, or infant growth faltering. Women considering PrEP use throughout pregnancy must weigh the known increased risk of HIV acquisition with unknown risks of drug effects on infant growth. PrEP has been used safely by HIV-seronegative men with HIV-seropositive female partners who have become pregnant. As an effective user-controlled HIV prevention strategy, PrEP offers autonomy and empowerment for HIV prevention and can be recommended alongside antiretroviral therapy, fertility screening, vaginal self-insemination, intercourse timed to peak fertility, medically assisted reproduction, and other safer conception strategies to provide multiple options. The integration of PrEP into safer conception programs is warranted and will safely reduce HIV transmission to women, men, and children during the peri-conception period.

"Womanhood does not reside in documentation": Queer and feminist student activism for transgender women's inclusion at women's colleges.

This article considers queer-driven student activism at Smith College, as well as admissions policy shifts at a number of prominent U.S. women's colleges for transgender women's inclusion. The author illustrates how student attempts to dismantle the transmisogyny at Smith as a purportedly feminist "women's" space, as well as some women's colleges' shifts in admissions policy, challenge divisions between transgender and cisgender women. This paradigmatic shift reflects the campuses as comparative havens for gender and sexual exploration, the influence of postmodern gender theory in understanding identity, and the growth of "queer" as an all-encompassing signifier for sexual and gender transgression.

"I have it just like you do": voices of HIV-negative partners in serodifferent relationships receiving primary care at a public clinic in San Francisco.

HIV transmission among serodifferent couples has a significant impact on incidence of HIV worldwide. Antiretroviral interventions (i.e., preexposure prophylaxis, post-exposure prophylaxis, and treatment as prevention) are important aspects of comprehensive prevention and care for serodifferent couples. In this study, HIV-negative members of serodifferent couples were interviewed using open-ended questions to explore their health-care needs, perceptions of clinic-based prevention services, and experience of having an HIV-infected partner. Analysis of interviews with 10 HIV-negative partners revealed the following themes: (1) health needs during joint medical visits; (2) sexual risk reduction strategies; (3) relationship dynamics; and (4) strategies for coping. This study elucidated relationship, health and health care factors that might affect development and implementation of clinic-based prevention interventions for HIV serodifferent couples. The findings point to possible relationship-centered recommendations for health-care providers who serve HIV-affected couples in clinical settings.

Breastfeeding and HIV-infected women in the United States: harm reduction counseling strategies.

Social and cultural forces have led some human immunodeficiency virus (HIV)-infected women to question the recommendation in the United States not to breastfeed. Without an open dialogue, women may choose to breastfeed exclusively or intermittently and not disclose this to their provider. We review the evidence from global studies of the risks of breastfeeding among HIV-infected mothers and propose a harm reduction model for women considering breastfeeding.

Do Ask, Tell, and Show: Contextual Factors Affecting Sexual Orientation and Gender Identity Disclosure for Sexual and Gender Minority People.

Purpose: Sexual and gender minority (SGM) people-including members of lesbian, gay, bisexual, transgender, and queer communities-remain underrepresented in health research due to poor collection of sexual orientation and gender identity (SOGI) data. We sought to understand the contextual factors affecting how SGM research participants interact with SOGI questions to enhance participant experience and increase the accuracy and sensitivity of research findings. Methods: We recruited SGM adults for in-person semi-structured focus groups or online cognitive interviews from 2016 to 2018. During focus groups and cognitive interviews, we asked participants to respond to SOGI question sets. We employed template analysis to describe the contextual factors that affected SGM participants' responses to SOGI questions. Results: We had a total of 74 participants, including 55 participants organized into nine focus groups and 19 participants in cognitive interviews. Most self-identified as a sexual minority person (88%), and 51% identified as a gender minority person. Two main themes were: (1) the need to know the relevance (of why SOGI questions are asked) and (2) the importance of environmental and contextual cues (communicating physical safety and freedom from discrimination that influenced SOGI disclosure). Conclusions: Contextualizing the relevance of SOGI data sought could help improve the accuracy and sensitivity of data collection efforts. Environmental cues that communicate acceptance and safety for SGM individuals in research settings may support disclosure. Researchers should consider these contextual factors when designing future studies to improve research experiences for SGM individuals and increase the likelihood of future participation.

Implementation Strategies for Creating Inclusive, All-Women HIV Care Environments: Perspectives From Trans and Cis Women.

INTRODUCTION: Transgender (trans) women in the United States have disproportionately high rates of HIV acquisition, yet there remains a dearth of culturally appropriate and gender affirming HIV care services for them. Trans women often are aggregated with men who have sex with men based on biological essentialism and behaviorally defined characteristics, even though they have more in common with cisgender (cis) women, such as gender identity and psychosocial factors that influence HIV risk. As a result, trans women often are rendered invisible and underserved in the HIV response. We explore the feasibility of constructing inclusive, all-women HIV care environments as a way to redress the dearth of appropriate services for trans women living with HIV and to affirm their gender identity as women. METHODS: Thirty-eight women living with HIV and five providers participated in a qualitative focus group and interview study between April 2016 and January 2017, exploring the desirability and practicality of including trans women in HIV treatment and support services traditionally focused on cis women. Transcripts were coded and template analysis was employed to discern key themes. RESULTS: Participants identified concrete strategies for implementation of inclusive, all-women HIV care related to representation and visibility of trans women, community input, education and training, aspects of the clinic environment, and flexibility and creativity. The impact of trauma and the need for safety and gender affirmation were emphasized throughout. CONCLUSIONS: Trans and cis women found the idea of inclusive, all-women's HIV care environments attractive and feasible, notwithstanding cultural and structural challenges to creating them.

"Far More than Just a Prescription": Focus Groups With U.S. Family Planning Providers and Staff About Integrating PrEP for HIV Prevention Into Their Work.

BACKGROUND: Cisgender women in the United States use pre-exposure prophylaxis (PrEP) for HIV prevention at lower rates relative to other groups. Advocacy groups and patients identify family planning clinics as the preferred sites to lead PrEP implementation for women in the United States. However, limited qualitative exploration exists of U.S. family planning practitioners' attitudes toward integrating PrEP into their work. METHODS: We conducted qualitative focus groups with a convenience sample of family planning clinicians, counselors, and clinic managers to explore barriers and facilitators to PrEP provision in U.S. family planning clinics. RESULTS: We conducted six focus groups (total participants = 37) with respondents who worked in family planning clinics in San Francisco, California; Kansas City, Missouri; and Philadelphia, Pennsylvania. Key themes emerged highlighting how PrEP at times runs contrary to other family planning agendas, including efficient clinic visits, condom promotion, and long-acting reversible contraception counseling. Throughout these discussions, participants expressed discomfort with HIV vulnerabilities rooted in social and structural determinants of health. CONCLUSIONS: Findings suggest that those seeking to implement PrEP for U.S. cisgender women may benefit from exploring 1) how to integrate patient/provider conversations about the structural determinants of health and their relationship to HIV and other sexual and reproductive health outcomes and 2) how to foster person-centered prevention conversations in the context of busy family planning visits.

Online Navigation for Pre-Exposure Prophylaxis via PleasePrEPMe Chat for HIV Prevention: Protocol for a Development and Use Study.

BACKGROUND: Pre-exposure prophylaxis is an HIV medication taken by an individual who is HIV-negative to prevent infection before exposure to the virus. Numerous clinical studies in various communities have shown high rates of effectiveness when pre-exposure prophylaxis is taken as prescribed. Since FDA (US Food and Drug Administration) approval of the first product for pre-exposure prophylaxis in 2012, uptake has been lower than the estimated 1.1 million US adults who could benefit from its use, with an estimated 70,394 individuals on pre-exposure prophylaxis in 2017. Of these, only 11% were Black and 13% were Hispanic despite Black and Hispanic individuals comprising two-thirds of individuals who could benefit, highlighting racial and ethnic disparities in pre-exposure prophylaxis uptake. Patient navigators have been shown to be effective in improving the linkage and retention in care outcomes of people living with HIV across the HIV treatment cascade and can be used throughout the pre-exposure prophylaxis care continuum to assist decision making and connect potential users to pre-exposure prophylaxis services. OBJECTIVE: PleasePrEPMe Chat was designed as a novel online strategy aimed at improving engagement in pre-exposure prophylaxis care services with pre-exposure prophylaxis-eligible populations in California via free HIV-prevention information and health care navigation services. METHODS: Visitors connected with navigators via online bilingual (English, Spanish) chat. During the chat, navigators helped locate pre-exposure prophylaxis services through the PleasePrEPMe provider directory, provided links to HIV-prevention resources, and supported uninsured, insured, and undocumented visitors with benefits navigation. Data such as date, time, type of encounter, visitor type, key demographics, discussion topics, insurance, and other relevant information were collected via a chat log and through the HealthEngage chat platform. RESULTS: From April 2017 to December 2019, PleasePrEPMe completed 2191 online chats. Mean interaction time was 16 minutes, with 68% of chats covering more than one topic. Conversation topics included health care navigation (1104/2191, 50.39%), provider identification (954/2191, 43.54%), pre-exposure prophylaxis information (773/2191, 35.28%), post-exposure prophylaxis information (318/2191, 14.91%), and the California Pre-Exposure Prophylaxis Assistance Program (232/2191, 10.59%). Referrals to pre-exposure prophylaxis- or non pre-exposure prophylaxis-related resources included directory updates, HIV testing and treatment, undetectable=untransmittable, reproductive health, sexually transmitted infections, and other prevention methods. A total of 368 chat visitors completed a voluntary satisfaction scale rating the quality and helpfulness of the service provided, producing a mean rating of 4.7 out of 5. CONCLUSIONS: Online chat is a method for reaching people not already engaged in HIV-prevention services, supporting HIV-prevention decision making, and linking people seeking information online with in-person services. Additional research to evaluate online sexual health information services and understand how social determinants of health influence online engagement is needed to better understand how to reach priority populations not well served by current HIV-prevention services. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/20187.