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The reasons for black/white disparities in HIV epidemics among men who have sex with men have puzzled researchers for decades. Understanding reasons for these disparities requires looking beyond individual-level behavioral risk to a more comprehensive framework. From July 2010-December 2012, 803 men (454 black, 349 white) were recruited through venue-based and online sampling; consenting men were provided HIV and STI testing, completed a behavioral survey and a sex partner inventory, and provided place of residence for geocoding. HIV prevalence was higher among black (43%) versus white (13% MSM (prevalence ratio (PR) 3.3, 95% confidence interval (CI): 2.5-4.4). Among HIV-positive men, the median CD4 count was significantly lower for black (490 cells/µL) than white (577 cells/µL) MSM; there was no difference in the HIV RNA viral load by race. Black men were younger, more likely to be bisexual and unemployed, had less educational attainment, and reported fewer male sex partners, fewer unprotected anal sex partners, and less non-injection drug use. Black MSM were significantly more likely than white MSM to have rectal chlamydia and gonorrhea, were more likely to have racially concordant partnerships, more likely to have casual (one-time) partners, and less likely to discuss serostatus with partners. The census tracts where black MSM lived had higher rates of poverty and unemployment, and lower median income. They also had lower proportions of male-male households, lower male to female sex ratios, and lower HIV diagnosis rates. Among black and white MSM in Atlanta, disparities in HIV and STI prevalence by race are comparable to those observed nationally. We identified differences between black and white MSM at the individual, dyadic/sexual network, and community levels. The reasons for black/white disparities in HIV prevalence in Atlanta are complex, and will likely require a multilevel framework to understand comprehensively.

Background.Although antiretroviral therapy has the ability to fully restore a normal CD4+ cell count (>500 cells/mm3) in most patients, it is not yet clear whether all patients can achieve normalization of their CD4+ cell count, in part because no study has followed up patients for >7 years. Methods.Three hundred sixty-six patients from 5 clinical cohorts who maintained a plasma human immunodeficiency virus (HIV) RNA level <1000 copies/mL for at least 4 years after initiation of antiretroviral therapy were included. Changes in CD4+ cell count were evaluated using mixed-effects modeling, spline-smoothing regression, and Kaplan-Meier techniques. Results.The majority (83%) of the patients were men. The median CD4+ cell count at the time of therapy initiation was 201 cells/mm3 (interquartile range, 72–344 cells/mm3), and the median age was 47 years. The median follow-up period was 7.5 years (interquartile range, 5.5–9.7 years). CD4+ cell counts continued to increase throughout the follow-up period, albeit slowly after year 4. Although almost all patients (95%) who started therapy with a CD4+ cell count ⩾300 cells/mm3 were able to attain a CD4+ cell count ⩾500 cells/mm3, 44% of patients who started therapy with a CD4+ cell count <100 cells/mm3 and 25% of patients who started therapy with a CD4+ cell count of 100–200 cells/mm3 were unable to achieve a CD4+ cell count >500 cells/mm3 over a mean duration of follow-up of 7.5 years; many did not reach this threshold by year 10. Twenty-four percent of individuals with a CD4+ cell count <500 cells/mm3 at year 4 had evidence of a CD4+ cell count plateau after year 4. The frequency of detectable viremia (“blips”) after year 4 was not associated with the magnitude of the CD4+ cell count change. Conclusions.A substantial proportion of patients who delay therapy until their CD4+ cell count decreases to <200 cells/mm3 do not achieve a normal CD4+ cell count, even after a decade of otherwise effective antiretroviral therapy. Although the majority of patients have evidence of slow increases in their CD4+ cell count over time, many do not. These individuals may have an elevated risk of non–AIDS-related morbidity and mortality.

Mucosal injury is common during consensual intercourse and induces an inflammatory response that could contribute to pathogen transmission including HIV. Here, we compared mucosal immune and microbiome responses to experimentally induced mucosal injury between men who have sex with men engaging in receptive anal intercourse (MSM-RAI) and men who do not engage in RAI (controls), all without HIV. Rectal mucosal secretions were collected from adult MSM-RAI ( n  = 19) and controls ( n  = 6) via anoscopy before and up to eight days after experimentally induced injury. Mucosal healing was evaluated by repeated injury surface area measurements with digital imaging. MSM-RAI demonstrated overall significantly higher concentrations of pro-inflammatory cytokines and a distinct rectal microbiome compared with controls. Wound healing was numerically faster in MSM-RAI but did not meet statistical significance ( p  = 0.09). Different cytokine injury response patterns were observed between MSM-RAI and controls; however, IL-6 and IP-10 were important mediators in both groups. Microbial guilds, particularly from the Lachnospiraceae and Prevotellaceae families, were associated with rectal mucosal inflammation. This work is the first experimental study of rectal mucosal injury and the immune environment in healthy humans and provides a more nuanced understanding of rectal mucosal inflammation after injury, which can inform our understanding of HIV transmission.

Young men who have sex with men (YMSM) are disproportionately affected by HIV and bacterial sexually transmitted infections (STI) including gonorrhea, chlamydia, and syphilis; yet research into the immunologic effects of these infections is typically pursued in siloes. Here, we employed a syndemic approach to understand potential interactions of these infections on the rectal mucosal immune environment among YMSM. We enrolled YMSM aged 18–29 years with and without HIV and/or asymptomatic bacterial STI and collected blood, rectal secretions, and rectal tissue biopsies. YMSM with HIV were on suppressive antiretroviral therapy (ART) with preserved blood CD4 cell counts. We defined 7 innate and 19 adaptive immune cell subsets by flow cytometry, the rectal mucosal transcriptome by RNAseq, and the rectal mucosal microbiome by 16S rRNA sequencing and examined the effects of HIV and STI and their interactions. We measured tissue HIV RNA viral loads among YMSM with HIV and HIV replication in rectal explant challenge experiments among YMSM without HIV. HIV, but not asymptomatic STI, was associated with profound alterations in the cellular composition of the rectal mucosa. We did not detect a difference in the microbiome composition associated with HIV, but asymptomatic bacterial STI was associated with a higher probability of presence of potentially pathogenic taxa. When examining the rectal mucosal transcriptome, there was evidence of statistical interaction; asymptomatic bacterial STI was associated with upregulation of numerous inflammatory genes and enrichment for immune response pathways among YMSM with HIV, but not YMSM without HIV. Asymptomatic bacterial STI was not associated with differences in tissue HIV RNA viral loads or in HIV replication in explant challenge experiments. Our results suggest that asymptomatic bacterial STI may contribute to inflammation particularly among YMSM with HIV, and that future research should examine potential harms and interventions to reduce the health impact of these syndemic infections.

During January-August 2021, the Community Prevalence of SARS-CoV-2 Study used time/location sampling to recruit a cross-sectional, population-based cohort to estimate SARS-CoV-2 seroprevalence and nasal swab sample PCR positivity across 15 US communities. Survey-weighted estimates of SARS-CoV-2 infection and vaccine willingness among participants at each site were compared within demographic groups by using linear regression models with inverse variance weighting. Among 22,284 persons >2 months of age and older, median prevalence of infection (prior, active, or both) was 12.9% across sites and similar across age groups. Within each site, average prevalence of infection was 3 percentage points higher for Black than White persons and average vaccine willingness was 10 percentage points lower for Black than White persons and 7 percentage points lower for Black persons than for persons in other racial groups. The higher prevalence of SARS-CoV-2 infection among groups with lower vaccine willingness highlights the disparate effect of COVID-19 and its complications.

Young men who have sex with men (YMSM) represent a particularly high-risk group for HIV acquisition in the US, despite similarly reported rates of sexual activity as older, adult MSM (AMSM). Increased rates of HIV infection among YMSM compared to AMSM could be partially attributable to differences within the rectal mucosal (RM) immune environment associated with earlier sexual debut and less lifetime exposure to receptive anal intercourse. Using an ex vivo explant HIV challenge model, we found that rectal tissues from YMSM supported higher levels of p24 at peak viral replication timepoints compared to AMSM. Among YMSM, the RM was characterized by increased CD4+ T cell proliferation, as well as lower frequencies of tissue resident CD8+ T cells and pro-inflammatory cytokine producing CD4+ and CD8+ T cells. In addition, the microbiome composition of YMSM was enriched for anaerobic taxa that have previously been associated with HIV acquisition risk, including Prevotella, Peptostreptococcus , and Peptoniphilus . These distinct immunologic and microbiome characteristics were found to be associated with higher HIV replication following ex vivo challenge of rectal explants, suggesting the RM microenvironment of YMSM may be uniquely conducive to HIV infection.

Various metrics for HIV burden and treatment success [e.g. HIV prevalence, community viral load (CVL), population viral load (PVL), percent of HIV-positive persons with undetectable viral load] have important public health limitations for understanding disparities. Using data from an ongoing HIV incidence cohort of black and white men who have sex with men (MSM), we propose a new metric to measure the prevalence of those at risk of transmitting HIV and illustrate its value. MSM with plasma VL>400 copies/mL were defined as having 'transmission risk'. We calculated HIV prevalence, CVL, PVL, percent of HIV-positive with undetectable viral loads, and prevalence of plasma VL>400 copies/ml (%VL400) for black and white MSM. We used Monte Carlo simulation incorporating data on sexual mixing by race to estimate exposure of black and white HIV-negative MSM to a partner with transmission risk via unprotected anal intercourse (UAI). Of 709 MSM recruited, 42% (168/399) black and 14% (44/310) white MSM tested HIV-positive (p<.0001). No significant differences were seen in CVL, PVL, or percent of HIV positive with undetectable viral loads. The %VL400 was 25% (98/393) for black vs. 8% (25/310) for white MSM (p<.0001). Black MSM with 2 UAI partners were estimated to have 40% probability (95% CI: 35%, 45%) of having ≥1 UAI partner with transmission risk vs. 20% for white MSM (CI: 15%, 24%). Despite similarities in other metrics, black MSM in our cohort are three times as likely as white MSM to have HIV transmission risk. With comparable risk behaviors, HIV-negative black MSM have a substantially higher likelihood of encountering a UAI partner at risk of transmitting HIV. Our results support increasing HIV testing, linkage to care, and antiretroviral treatment of HIV-positive MSM to reduce prevalence of those with transmission risk, particularly for black MSM.

Monoclonal antibodies are commonly engineered with an introduction of Met428Leu and Asn434Ser, known as the LS mutation, in the fragment crystallizable region to improve pharmacokinetic profiles. The LS mutation delays antibody clearance by enhancing binding affinity to the neonatal fragment crystallizable receptor found on endothelial cells. To characterize the LS mutation for monoclonal antibodies targeting HIV, we compared pharmacokinetic parameters between parental versus LS variants for five pairs of anti-HIV immunoglobin G1 monoclonal antibodies (VRC01/LS/VRC07-523LS, 3BNC117/LS, PGDM1400/LS PGT121/LS, 10-1074/LS), analyzing data from 16 clinical trials of 583 participants without HIV. We described serum concentrations of these monoclonal antibodies following intravenous or subcutaneous administration by an open two-compartment disposition, with first-order elimination from the central compartment using non-linear mixed effects pharmacokinetic models. We compared estimated pharmacokinetic parameters using the targeted maximum likelihood estimation method, accounting for participant differences. We observed lower clearance rate, central volume, and peripheral volume of distribution for all LS variants compared to parental monoclonal antibodies. LS monoclonal antibodies showed several improvements in pharmacokinetic parameters, including increases in the elimination half-life by 2.7- to 4.1-fold, the dose-normalized area-under-the-curve by 4.1- to 9.5-fold, and the predicted concentration at 4 weeks post-administration by 3.4- to 7.6-fold. Results suggest a favorable pharmacokinetic profile of LS variants regardless of HIV epitope specificity. Insights support lower dosages and/or less frequent dosing of LS variants to achieve similar levels of antibody exposure in future clinical applications.

Reductions in human immunodeficiency virus (HIV) incidence with pre-exposure prophylaxis (PrEP) for men who have sex with men (MSM) will require significant coverage of those at risk. We propose a simplified framework, similar to the HIV care continuum, to achieve protection with PrEP as follows: 1. At-risk MSM; 2. Awareness of and willingness to take PrEP; 3. Access to healthcare; 4. Receiving a prescription; and 5. Adhering to effective PrEP. We evaluated the PrEP care continuum on an Atlanta cohort of MSM and projected how many MSM might achieve protection from HIV. Even with optimistic estimates, few Atlanta MSM (15%) are projected to achieve protection from HIV with PrEP given the significant barriers described. Each continuum step represents an important point for intervention that could substantially increase the overall effectiveness of PrEP. In addition, novel strategies for PrEP delivery are needed to achieve the necessary effectiveness for Atlanta MSM at risk of HIV.

Introduction HPTN 083 demonstrated the superiority of long‐acting cabotegravir (CAB‐LA) versus daily oral emtricitabine/tenofovir disoproxil fumarate (TDF/FTC) as pre‐exposure prophylaxis (PrEP) among cisgender men and transgender women who have sex with men (MSM/TGW). HPTN 083 provided the first opportunity to understand experiences with injectable PrEP in a clinical trial. Methods Participants from two US sites (Chicago, IL and Atlanta, GA) and one international site (Rio de Janeiro, Brazil) were purposively sampled for individual qualitative interviews (N = 40), between November 2019 and March 2020, to explore trial experiences, barriers to adherence and other factors that may have impacted study implementation or outcomes. The blinded phase ended early due to efficacy; this analysis includes interviews conducted prior to unblinding with three groups defined by adherence (i.e. injection visit attendance): adherent (n = 27), non‐adherent (n = 12) and early discontinuers (n = 1). Data were organized using NVivo software and analysed using content analysis. Results Participants (mean age: 27) were primarily cisgender MSM (90%) and Black/African American (60%). Reasons for trial enrolment and PrEP use included a preference for using HIV prevention medication versus treatment in the event of HIV acquisition; the ability to enhance health via study‐related education and services; access to a novel, convenient HIV prevention product at no cost; and contributing to MSM/TGW communities through research. Participants contrasted positive experiences with study staff with their routine clinical care, and emphasized increased scheduling flexibility, thorough communication, non‐judgemental counselling and open, affirming environments (e.g. compassion, less stigma) as adherence facilitators. Injection experiences were positive overall; some described early injection‐related anxiety, which abated with time and when given some measure of control (e.g. pre‐injection countdown), and minimal injection site discomfort. Some concerns and misperceptions about injectable PrEP were reported. Barriers to adherence, across all adherence categories, included structural factors (e.g. financial constraints, travel) and competing demands (e.g. work schedules). Conclusions Respondents viewed injectable PrEP trial participation as a positive experience and a means of enhancing wellbeing. Study site flexibility and affirming clinic environments, inclusive of non‐judgemental counselling, were key facilitators of adherence. To support injection persistence, interventions that address structural barriers and promote flexible means of injection delivery may be most effective.