Ultrasound Blood-Brain Barrier Opening and Aducanumab in Alzheimer's Disease.

Antiamyloid antibodies have been used to reduce cerebral amyloid-beta (Aß) load in patients with Alzheimer's disease. We applied focused ultrasound with each of six monthly aducanumab infusions to temporarily open the blood-brain barrier with the goal of enhancing amyloid removal in selected brain regions in three participants over a period of 6 months. The reduction in the level of Aß was numerically greater in regions treated with focused ultrasound than in the homologous regions in the contralateral hemisphere that were not treated with focused ultrasound, as measured by fluorine-18 florbetaben positron-emission tomography. Cognitive tests and safety evaluations were conducted over a period of 30 to 180 days after treatment. (Funded by the Harry T. Mangurian, Jr. Foundation and the West Virginia University Rockefeller Neuroscience Institute.).

Noninvasive hippocampal blood-brain barrier opening in Alzheimer's disease with focused ultrasound.

The blood-brain barrier (BBB) presents a significant challenge for treating brain disorders. The hippocampus is a key target for novel therapeutics, playing an important role in Alzheimer's disease (AD), epilepsy, and depression. Preclinical studies have shown that magnetic resonance (MR)-guided low-intensity focused ultrasound (FUS) can reversibly open the BBB and facilitate delivery of targeted brain therapeutics. We report initial clinical trial results evaluating the safety, feasibility, and reversibility of BBB opening with FUS treatment of the hippocampus and entorhinal cortex (EC) in patients with early AD. Six subjects tolerated a total of 17 FUS treatments with no adverse events and neither cognitive nor neurological worsening. Post-FUS contrast MRI revealed immediate and sizable hippocampal parenchymal enhancement indicating BBB opening, followed by BBB closure within 24 h. The average opening was 95% of the targeted FUS volume, which corresponds to 29% of the overall hippocampus volume. We demonstrate that FUS can safely, noninvasively, transiently, reproducibly, and focally mediate BBB opening in the hippocampus/EC in humans. This provides a unique translational opportunity to investigate therapeutic delivery in AD and other conditions.

The opioid crisis and HIV in the USA: deadly synergies.

The opioid epidemic is one of the greatest public health problems that the USA faces. Opioid overdose death rates have increased steadily for more than a decade and doubled in 2013-17, as the highly potent synthetic opioid fentanyl entered the drug supply. Demographics of new HIV diagnoses among people who inject drugs are also changing, with more new HIV diagnoses occurring among White people, young people (aged 13-34 years), and people who reside outside large central metropolitan areas. Racial differences also exist in syringe sharing, which decreased among Black people and Hispanic people but remained unchanged among White people in 2005-15. Recent HIV outbreaks have occurred in rural areas of the USA, as well as among marginalised people in urban areas with robust HIV prevention and treatment services (eg, Seattle, WA). Multiple evidence-based interventions can effectively treat opioid use disorder and prevent HIV acquisition. However, considerable barriers exist precluding delivery of these solutions to many people who inject drugs. If the USA is serious about HIV prevention among this group, stigma must be eliminated, discriminatory policies must change, and comprehensive health care must be accessible to all. Finally, root causes of the opioid epidemic such as hopelessness need to be identified and addressed.

Call to action: how can the US Ending the HIV Epidemic initiative succeed?

With more than 1·2 million people living with HIV in the USA, a complex epidemic across the large and diverse country, and a fragmented health-care system marked by widening health disparities, the US HIV epidemic requires sustained scientific and public health attention. The epidemic has been stubbornly persistent; high incidence densities have been sustained over decades and the epidemic is increasingly concentrated among racial, ethnic, and sexual and gender minority communities. This fact remains true despite extraordinary scientific advances in prevention, treatment, and care-advances that have been led, to a substantial degree, by US-supported science and researchers. In this watershed year of 2021 and in the face of the COVID-19 pandemic, it is clear that the USA will not meet the stated goals of the National HIV/AIDS Strategy, particularly those goals relating to reductions in new infections, decreases in morbidity, and reductions in HIV stigma. The six papers in the Lancet Series on HIV in the USA have each examined the underlying causes of these challenges and laid out paths forward for an invigorated, sustained, and more equitable response to the US HIV epidemic than has been seen to date. The sciences of HIV surveillance, prevention, treatment, and implementation all suggest that the visionary goals of the Ending the HIV Epidemic initiative in the USA might be achievable. However, fundamental barriers and challenges need to be addressed and the research effort sustained if we are to succeed.

Novel Strategies to Increase COVID-19 Testing Among Underserved and Vulnerable Populations in West Virginia.

This project addressed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing barriers in rural West Virginia by providing testing enhancements that included (1) a flexible testing staff, (2) mobile testing, (3) essential supplies, and (4) specialized testing in communities of color. A total of 142 775 polymerase chain reaction tests were performed from December 2021 through February 2022; positivity rates were 21% and 17% in clinics and mobile testing venues, respectively. The project results showed that, within a statewide network of health care clinics, administrators quickly identified and distributed enhancements and thus reduced testing barriers. (Am J Public Health. 2022;112(S9):S892-S895. https://doi.org/10.2105/AJPH.2022.307004).

Strategies for increasing impact, engagement, and accessibility in HIV prevention programs: suggestions from women in urban high HIV burden counties in the Eastern United States (HPTN 064).

BACKGROUND: Merely having the tools to end HIV is insufficient. Effectively ending the epidemic necessitates addressing barriers that impede engagement in biomedical and behavioral prevention and wide scale implementation and utilization of existing interventions. This qualitative study identifies suggestions for increasing access to, engagement in, and impact of HIV prevention among women living in cities in high HIV burden counties in the eastern US. METHODS: Data analyzed for the current study were collected via a qualitative sub-study within the HIV Prevention Trials Network Study 064 (HPTN 064), a multisite observational cohort study designed to estimate HIV incidence among women residing in communities with elevated HIV prevalence who also reported personal or partner characteristics associated with increased risk of HIV acquisition. Focus group and interview participants in the qualitative sub-study (N = 288) were from four cities in the eastern US. RESULTS: Thematic analyses revealed four themes describing women's most frequently stated ideas for improving prevention efforts: 1) Promote Multilevel Empowerment, 2) Create Engaging Program Content, 3) Build "Market Demand", and 4) Ensure Accessibility. We conducted additional analyses to identify contradictory patterns in the data, which revealed an additional three themes: 1) Address Structural Risk Factors, 2) Increase Engagement via Pleasure Promotion, 3) Expand Awareness of and Access to Prevention Resources. CONCLUSIONS: Findings may be useful for enhancing women's engagement in and uptake of behavioral and biomedical HIV prevention resources, improving policy, and addressing multilevel risk factors. TRIAL REGISTRATION: Clinicaltrials.gov: NCT00995176 , prospectively registered.

Safety and Tolerability of Maraviroc-Containing Regimens to Prevent HIV Infection in Women: A Phase 2 Randomized Trial.

BACKGROUND: Maraviroc (MVC) is a candidate drug for HIV preexposure prophylaxis (PrEP). OBJECTIVE: To assess the safety and tolerability of MVC-containing PrEP over 48 weeks in U.S. women at risk for HIV infection. DESIGN: Phase 2 randomized, controlled, double-blinded study of 4 antiretroviral regimens used as PrEP. (ClinicalTrials.gov: NCT01505114). SETTING: 12 clinical research sites of the HIV Prevention Trials Network and AIDS Clinical Trials Group. PARTICIPANTS: HIV-uninfected women reporting condomless vaginal or anal intercourse with at least 1 man with HIV infection or unknown serostatus within 90 days. INTERVENTION: MVC only, MVC-emtricitabine (FTC), MVC-tenofovir disoproxil fumarate (TDF), and TDF-FTC (control). MEASUREMENTS: At each visit, clinical and laboratory (including HIV) assessments were done. Primary outcomes were grade 3 and 4 adverse events and time to permanent discontinuation of the study regimen. All randomly assigned participants were analyzed according to their original assignment. RESULTS: Among 188 participants, 85% completed follow-up, 11% withdrew early, and 4% were lost to follow-up; 19% discontinued their regimen prematurely. The number discontinuing and the time to discontinuation did not differ among regimens. Grade 3 or 4 adverse events occurred in 5 (MVC), 13 (MVC-FTC), 9 (MVC-TDF), and 8 (TDF-FTC) participants; rates did not differ among regimens. One death (by suicide) occurred in the MVC-TDF group but was judged not to be related to study drugs. Of available plasma samples at week 48 (n = 126), 60% showed detectable drug concentrations. No new HIV infections occurred. LIMITATIONS: Participants were not necessarily at high risk for HIV infection. The regimen comprised 3 pills taken daily. The study was not powered for efficacy. CONCLUSION: Maraviroc-containing PrEP regimens were safe and well-tolerated compared with TDF-FTC in U.S. women. No new HIV infections occurred, although whether this was due to study drugs or low risk in the population is uncertain. Maraviroc-containing PrEP for women may warrant further study. PRIMARY FUNDING SOURCE: National Institutes of Health.

Socioecological factors influencing women's HIV risk in the United States: qualitative findings from the women's HIV SeroIncidence study (HPTN 064).

BACKGROUND: We sought to understand the multilevel syndemic factors that are concurrently contributing to the HIV epidemic among women living in the US. We specifically examined community, network, dyadic, and individual factors to explain HIV vulnerability within a socioecological framework. METHODS: We gathered qualitative data (120 interviews and 31 focus groups) from a subset of women ages 18-44 years (N = 2,099) enrolled in the HPTN 064 HIV seroincidence estimation study across 10 US communities. We analyzed data from 4 diverse locations: Atlanta, New York City (the Bronx), Raleigh, and Washington, DC. Data were thematically coded using grounded theory methodology. Intercoder reliability was assessed to evaluate consistency of team-based coding practices. RESULTS: The following themes were identified at 4 levels including 1) exosystem (community): poverty prevalence, discrimination, gender imbalances, community violence, and housing challenges; 2) mesosystem (network): organizational social support and sexual concurrency; 3) microsystem (dyadic): sex exchange, interpersonal social support, intimate partner violence; and 4) individual: HIV/STI awareness, risk taking, and substance use. A strong theme emerged with over 80 % of responses linked to the fundamental role of financial insecurity underlying risk-taking behavioral pathways. CONCLUSIONS: Multilevel syndemic factors contribute to women's vulnerability to HIV in the US. Financial insecurity is a predominant theme, suggesting the need for tailored programming for women to reduce HIV risk. TRIAL REGISTRATION: Clinicaltrials.gov, NCT00995176.

HIV Salvage Therapy Does Not Require Nucleoside Reverse Transcriptase Inhibitors: A Randomized, Controlled Trial.

BACKGROUND: Nucleoside reverse transcriptase inhibitors (NRTIs) are often included in antiretroviral regimens in treatment-experienced patients in the absence of data from randomized trials. OBJECTIVE: To compare treatment success between participants who omit versus those who add NRTIs to an optimized antiretroviral regimen of 3 or more agents. DESIGN: Multicenter, randomized, controlled trial. (ClinicalTrials.gov: NCT00537394). SETTING: Outpatient HIV clinics. PARTICIPANTS: Treatment-experienced patients with HIV infection and viral resistance. INTERVENTION: Open-label optimized regimens (not including NRTIs) were selected on the basis of treatment history and susceptibility testing. Participants were randomly assigned to omit or add NRTIs. MEASUREMENTS: The primary efficacy outcome was regimen failure through 48 weeks using a noninferiority margin of 15%. The primary safety outcome was time to initial episode of a severe sign, symptom, or laboratory abnormality before discontinuation of NRTI assignment. RESULTS: 360 participants were randomly assigned, and 93% completed a 48-week visit. The cumulative probability of regimen failure was 29.8% in the omit-NRTIs group versus 25.9% in the add-NRTIs group (difference, 3.2 percentage points [95% CI, -6.1 to 12.5 percentage points]). No significant between-group differences were found in the primary safety end points or the proportion of participants with HIV RNA level less than 50 copies/mL. No deaths occurred in the omit-NRTIs group compared with 7 deaths in the add-NRTIs group. LIMITATION: Unblinded study design, and the study may not be applicable to resource-poor settings. CONCLUSION: Treatment-experienced patients with HIV infection starting a new optimized regimen can safely omit NRTIs without compromising virologic efficacy. Omitting NRTIs will reduce pill burden, cost, and toxicity in this patient population. PRIMARY FUNDING SOURCES: National Institute of Allergy and Infectious Diseases, Boehringer Ingelheim, Janssen, Merck, ViiV Healthcare, Roche, and Monogram Biosciences (LabCorp).

Violence Against Women in Selected Areas of the United States.

OBJECTIVES: We determined the prevalence of recent emotional, physical, and sexual violence against women and their associations with HIV-related risk factors in women living in the United States. METHODS: We performed an assessment of women ages 18 to 44 years with a history of unprotected sex and 1 or more personal or partner HIV risk factors in the past 6 months from 2009 to 2010. We used multivariable logistic regression to examine the association of experiencing violence. RESULTS: Among 2099 women, the prevalence of emotional abuse, physical violence, and sexual violence in the previous 6 months was 31%, 19%, and 7%, respectively. Nonmarried status, food insecurity, childhood abuse, depression symptomology, and posttraumatic stress disorder were significantly associated with multiple types of violence. All types of violence were associated with at least 3 different partner or personal HIV risk behaviors, including unprotected anal sex, previous sexually transmitted infection diagnosis, sex work, or partner substance abuse. CONCLUSIONS: Our data suggested that personal and partner HIV risk behaviors, mental illness, and specific forms of violence frequently co-occurred in the lives of impoverished women. We shed light on factors purported to contribute to a syndemic in this population. HIV prevention programs in similar populations should address these co-occurring issues in a comprehensive manner.

Prevalence and correlates of knowledge of male partner HIV testing and serostatus among African-American women living in high poverty, high HIV prevalence communities (HPTN 064).

Knowledge of sexual partners' HIV infection can reduce risky sexual behaviors. Yet, there are no published studies to-date examining prevalence and characteristics associated with knowledge among African-American women living in high poverty communities disproportionately affected by HIV. Using the HIV Prevention Trial Network's (HPTN) 064 Study data, multivariable logistic regression was used to examine individual, partner, and partnership-level determinants of women's knowledge (n = 1,768 women). Results showed that women's demographic characteristics alone did not account for the variation in serostatus awareness. Rather, lower knowledge of partner serostatus was associated with having two or more sex partners (OR = 0.49, 95 % CI 0.37-0.65), food insecurity (OR = 0.68, 95 % CI 0.49-0.94), partner age >35 years (OR = 0.68, 95 % CI 0.49-0.94), and partner concurrency (OR = 0.63, 95 % CI 0.49-0.83). Access to financial support (OR = 1.42, 95 % CI 1.05-1.92) and coresidence (OR = 1.43, 95 % CI 1.05-1.95) were associated with higher knowledge of partner serostatus. HIV prevention efforts addressing African-American women's vulnerabilities should employ integrated behavioral, economic, and empowerment approaches.

Modeling the impact of interventions along the HIV continuum of care in Newark, New Jersey.

BACKGROUND: The human immunodeficiency virus (HIV) epidemic in Newark, New Jersey, is among the most severe in the United States. Prevalence ranges up to 3.3% in some groups. The aim of this study is to use a mathematical model of the epidemic in Newark to assess the impact of interventions along the continuum of care, leading to virologic suppression. METHODS: A model was constructed of HIV infection including specific care-continuum steps. The model was calibrated to HIV/AIDS cases in Newark among different populations over a 10-year period. Interventions applied to model fits were increasing proportions tested, linked and retained in care, linked and adherent to treatment, and increasing testing frequency, high-risk-group testing, and adherence. Impacts were assessed by measuring incidence and death reductions 10 years postintervention. RESULTS: The most effective interventions for reducing incidence were improving treatment adherence and increasing testing frequency and coverage. No single intervention reduced incidence in 2023 by >5%, and the most effective combination of interventions reduced incidence by approximately 16% (2%-24%). The most efficacious interventions for reducing deaths were increasing retention, linkage to care, testing coverage, and adherence. Increasing retention reduced deaths by approximately 27% (24%-29%); the most efficacious combination of interventions reduced deaths in 2023 by approximately 52% (46%-57%). CONCLUSIONS: Reducing HIV deaths in Newark over a 10-year period may be a realizable goal, but reducing incidence is less likely. Our results highlight the importance of addressing leaks across the entire continuum of care and reinforcing efforts to prevention new HIV infections with additional interventions.

HIV diversity as a biomarker for HIV incidence estimation: including a high-resolution melting diversity assay in a multiassay algorithm.

Multiassay algorithms (MAAs) can be used to estimate cross-sectional HIV incidence. We previously identified a robust MAA that includes the BED capture enzyme immunoassay (BED-CEIA), the Bio-Rad Avidity assay, viral load, and CD4 cell count. In this report, we evaluated MAAs that include a high-resolution melting (HRM) diversity assay that does not require sequencing. HRM scores were determined for eight regions of the HIV genome (2 in gag, 1 in pol, and 5 in env). The MAAs that were evaluated included the BED-CEIA, the Bio-Rad Avidity assay, viral load, and the HRM diversity assay, using HRM scores from different regions and a range of region-specific HRM diversity assay cutoffs. The performance characteristics based on the proportion of samples that were classified as MAA positive by duration of infection were determined for each MAA, including the mean window period. The cross-sectional incidence estimates obtained using optimized MAAs were compared to longitudinal incidence estimates for three cohorts in the United States. The performance of the HRM-based MAA was nearly identical to that of the MAA that included CD4 cell count. The HRM-based MAA had a mean window period of 154 days and provided cross-sectional incidence estimates that were similar to those based on cohort follow-up. HIV diversity is a useful biomarker for estimating HIV incidence. MAAs that include the HRM diversity assay can provide accurate HIV incidence estimates using stored blood plasma or serum samples without a requirement for CD4 cell count data.

HIV acquisition among women from selected areas of the United States: a cohort study.

BACKGROUND: Women account for 23% of newly diagnosed HIV infections in the United States, but there are few recent, well-characterized cohorts of U.S. women in whom behavior characteristics and HIV acquisition have been well-described. OBJECTIVE: To evaluate HIV incidence and describe behaviors among U.S. women residing in areas of high HIV prevalence. DESIGN: Multisite, longitudinal cohort of women who had HIV rapid testing and audio computer-assisted self-interviews at baseline and every 6 months for up to 12 months. (ClinicalTrials.gov: NCT00995176) SETTING: 10 urban and periurban communities with high HIV prevalence and poverty rates, located in the northeastern and southeastern United States. PATIENTS: Venue-based sampling was used to recruit women aged 18 to 44 years who recently had unprotected sex and had 1 or more additional personal or partner risk factors and no self-reported previous HIV diagnosis. MEASUREMENTS: HIV prevalence and incidence, frequency of HIV risk behaviors, and health status perceptions. RESULTS: Among 2099 high-risk women (85.9% black and 11.7% of Hispanic ethnicity), 32 (1.5%) were diagnosed with HIV infection at enrollment. Annual HIV incidence was 0.32% (95% CI, 0.14% to 0.74%). Older age, substance use, and knowing a partner had HIV were associated with HIV prevalence. Ten women died during the study (0.61% per year). LIMITATIONS: Longitudinal assessment of risk behaviors was limited to a maximum of 12 months. There were few incident HIV infections, precluding identification of characteristics predictive of HIV acquisition. CONCLUSION: This study enrolled a cohort of women with HIV incidence substantially higher than the Centers for Disease Control and Prevention national estimate in the general population of U.S. black women. Concerted efforts to improve preventive health care strategies for HIV and overall health status are needed for similar populations. PRIMARY FUNDING SOURCE: National Institutes of Health.

Determinants of developing widened spatial QRS-T angle in HIV-infected individuals: results from the Strategies for Management of Antiretroviral Therapy [SMART] Study.

BACKGROUND: A widened electrocardiographic spatial QRS-T angle has been shown to be predictive of cardiovascular disease in HIV-infected individuals. However, determinants and risk factors of developing widened QRS-T angle over time in this population remain unknown. METHODS AND RESULTS: Spatial QRS-T angle was automatically measured from standard electrocardiogram of 1444 HIV-infected individuals without baseline widened spatial QRS-T angle from the Strategies for Management of Antiretroviral Therapy [SMART], a clinical trial comparing two antiretroviral treatment strategies [Drug Conservation (DC) vs. Viral Suppression (VS)]. Conditional logistic regression analysis was used to examine the association between baseline characteristics and incident widened spatial QRS-T angle (a new angle>93° in males and>74° in females). During 2544 person-years of follow-up, 199 participants developed widened angle at a rate of 7.8 per 100 person-years. In unadjusted models, female sex, black race (vs. white), DC treatment strategy, current and past smokers (vs. never), history of alcohol abuse, greater body mass index, history of diabetes and higher levels of hs-C-reactive protein were associated with incident widened spatial QRS-T angle. When these variables were entered together in the same model with adjustment for demographics and treatment strategy, DC treatment strategy [OR (95% CI): 1.50 (1.09, 2.07)], female gender [1.69 (1.17, 2.45)], current and past smoking (vs. never) [2.49 (1.63, 3.81) and 1.93 (1.21, 3.09), respectively], and diabetes [2.28 (1.33, 3.91)] predicted incident widened spatial QRS-T angle. CONCLUSIONS: Drug conservation treatment strategy, female gender, smoking, and diabetes are independently predictive of incident widened spatial QRS-T angle in HIV-infected individuals.

Use of a multifaceted approach to analyze HIV incidence in a cohort study of women in the United States: HIV Prevention Trials Network 064 Study.

BACKGROUND: Reliable methods for estimating the incidence of human immunodeficiency virus (HIV) infection are needed to monitor the epidemic, identify at-risk populations, and evaluate HIV prevention strategies. We used a multifaceted approach to estimate HIV incidence in the HIV Prevention Trials Network (HPTN) 064 study. METHODS: The HPTN 064 study enrolled 2067 HIV-seronegative women and 32 HIV-seropositive women with no prior HIV infection diagnosis. Women were followed for up to 12 months. HIV incidence estimates were based on (1) detection of acute HIV infection, (2) documentation of HIV seroconversion, and (3) detection of recent HIV infection, using a multiassay algorithm (MAA). RESULTS: Two women had acute HIV infection at enrollment, 4 seroconverted, and 2 were identified as recently infected at enrollment using the MAA. The annual HIV incidence estimate based on acute infection at enrollment (2.52% [95% confidence interval {CI}, .17%-9.33%], using a 14-day window period) was higher than the estimate based on seroconversion (0.24% [95% CI, .07%-.62%]; P = .027). Incidence estimates obtained using the MAA at enrollment and at the end of study were 0.25% (95% CI, .03%-.93%) and 0.13% (95% CI, .006%-.76%), respectively. CONCLUSIONS: We detected a high frequency of acute infection at enrollment. Cross-sectional HIV incidence estimates obtained using the MAA were similar to the longitudinal estimate based on HIV seroconversion. CLINICAL TRIALS REGISTRATION: NCT00995176.

Enhanced SARS-CoV-2 case prediction using public health data and machine learning models.

Objectives: The goal of this study is to propose and test a scalable framework for machine learning (ML) algorithms to predict near-term severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cases by incorporating and evaluating the impact of real-time dynamic public health data. Materials and Methods: Data used in this study include patient-level results, procurement, and location information of all SARS-CoV-2 tests reported in West Virginia as part of their mandatory reporting system from January 2021 to March 2022. We propose a method for incorporating and comparing widely available public health metrics inside of a ML framework, specifically a long-short-term memory network, to forecast SARS-CoV-2 cases across various feature sets. Results: Our approach provides better prediction of localized case counts and indicates the impact of the dynamic elements of the pandemic on predictions, such as the influence of the mixture of viral variants in the population and variable testing and vaccination rates during various eras of the pandemic. Discussion: Utilizing real-time public health metrics, including estimated Rt from multiple SARS-CoV-2 variants, vaccination rates, and testing information, provided a significant increase in the accuracy of the model during the Omicron and Delta period, thus providing more precise forecasting of daily case counts at the county level. This work provides insights on the influence of various features on predictive performance in rural and non-rural areas. Conclusion: Our proposed framework incorporates available public health metrics with operational data on the impact of testing, vaccination, and current viral variant mixtures in the population to provide a foundation for combining dynamic public health metrics and ML models to deliver forecasting and insights in healthcare domains. It also shows the importance of developing and deploying ML frameworks in rural settings.

Associations between COVID-19 therapies and outcomes in rural and urban America: A multisite, temporal analysis from the Alpha to Omicron SARS-CoV-2 variants.

PURPOSE: To investigate the enduring disparities in adverse COVID-19 events between urban and rural communities in the United States, focusing on the effects of SARS-CoV-2 vaccination and therapeutic advances on patient outcomes. METHODS: Using National COVID Cohort Collaborative (N3C) data from 2021 to 2023, this retrospective cohort study examined COVID-19 hospitalization, inpatient death, and other adverse events. Populations were categorized into urban, urban-adjacent rural (UAR), and nonurban-adjacent rural (NAR). Adjustments included demographics, variant-dominant waves, comorbidities, region, and SARS-CoV-2 treatment and vaccination. Statistical methods included Kaplan-Meier survival estimates, multivariable logistic, and Cox regression. FINDINGS: The study included 3,018,646 patients, with rural residents constituting 506,204. These rural dwellers were older, had more comorbidities, and were less vaccinated than their urban counterparts. Adjusted analyses revealed higher hospitalization odds in UAR and NAR (aOR 1.07 [1.05-1.08] and 1.06 [1.03-1.08]), greater inpatient death hazard (aHR 1.30 [1.26-1.35] UAR and 1.37 [1.30-1.45] NAR), and greater risk of other adverse events compared to urban dwellers. Delta increased, while Omicron decreased, inpatient adverse events relative to pre-Delta, with rural disparities persisting throughout. Treatment effectiveness and vaccination were similarly protective across all cohorts, but dexamethasone post-ventilation was effective only in urban areas. Nirmatrelvir/ritonavir and molnupiravir better protected rural residents against hospitalization. CONCLUSIONS: Despite advancements in treatment and vaccinations, disparities in adverse COVID-19 outcomes persist between urban and rural communities. The effectiveness of some therapeutic agents appears to vary based on rurality, suggesting a nuanced relationship between treatment and geographic location while highlighting the need for targeted rural health care strategies.