For COVAIL recipients of a coronavirus disease 2019 (COVID-19) Sanofi booster vaccine, neutralizing antibody titers were assessed as a correlate of risk (CoR) of COVID-19. Peak and exposure-proximal titers were inverse CoRs with covariate-adjusted hazard ratios (95% confidence intervals) 0.30 (0.11, 0.78) and 0.25 (0.07, 0.85) per 10-fold increase in weighted average titer.

The robustness and statistical efficiency of phylodynamic models have been tested by many investigators. However, little attention has been given to model specification and inductive bias that can occur if the model is misspecified or provides an overly simplistic representation of the evolutionary process. Here, we carried out a study involving the simulation of HIV epidemics using a complex model and calibrated to men who have sex with men from San Diego, USA. We then used this epidemic trajectory to simulate genealogies, sequence alignments equivalent to HIV partial pol gene and the complete genome. We proceeded to estimate migration rates using a simplistic representation of the epidemiological model by testing model-based phylodynamics and phylogeographic methods. We observed that even though there were some biases on the estimates using a simplistic representation of the epidemiological model, we were still able to estimate the migration rates depending on the method and sample size used in the analyses.

BACKGROUND:Effective antiretroviral therapy to maintain durable viral suppression is key to ending the HIV epidemic in the United States. We evaluated the ability of machine learning algorithms to predict people with HIV (PWH) at risk of unsuppressed viral load. SETTING:Retrospective study among PWH from San Diego County (n = 18,916). The study used reported public health HIV data (2017-2022) to predict the outcome of HIV viral load >200 copies/mL during a year-long prediction window. METHODS:The data was partitioned by calendar date into two training and one validation datasets to accurately assess performance for predicting future observations. A random forest model was used to generate outcome predictions for the overall population and stratified by race. Mediation analysis was undertaken to assess underlying causality. RESULTS:The model had an area under the receiver operating characteristic curve of 82.2 (95% CI: 79.3 to 85.0), a sensitivity of 33.8% (95% CI: 28.6 to 39.0), and specificity of 96.9% (95% CI: 95.7 to 97.2) corresponding to a positive predictive value of 55.7% (95% CI: 48.7 to 62.8) and negative predictive value of 91.7% (95% CI: 90.6 to 92.8). The area under the receiver operating characteristic was similar across races. Prior viral load characteristics were identified as the most important variables; however, they partially acted as mediators of underlying demographic (eg, race) and HIV infection risk (eg, injection drug use). CONCLUSIONS:Machine learning algorithms using mandatory reported public health HIV data can predict which PWH will have future unsuppressed viral load. Future work will assess its clinical utility compared to existing data-to-care initiatives.

Abstract Neutralizing antibody titer has been a surrogate endpoint for guiding COVID-19 vaccine approval and use, although the pandemic’s evolution and the introduction of variant-adapted vaccine boosters raise questions as to this surrogate’s contemporary performance. For 985 recipients of an mRNA second bivalent or monovalent booster containing various Spike inserts [Prototype (Ancestral), Beta, Delta, and/or Omicron BA.1 or BA.4/5] in the COVAIL trial (NCT05289037), titers against 5 strains were assessed as correlates of risk of symptomatic COVID-19 (“COVID-19”) and as correlates of relative (Pfizer-BioNTech Omicron vs. Prototype) booster protection against COVID-19 over 6 months of follow-up during the BA.2-BA.5 Omicron-dominant period. Consistently across the Moderna and Pfizer-BioNTech vaccine platforms and across all variant Spike inserts assessed, both peak and exposure-proximal (“predicted-at-exposure”) titers correlated with lower Omicron COVID-19 risk in individuals previously infected with SARS-CoV-2, albeit significantly less so in naïve individuals [e.g., exposure-proximal hazard ratio per 10-fold increase in BA.1 titer 0.74 (95% CI 0.59, 0.94) for naïve vs. 0.41 (95% CI 0.23, 0.64) for non-naïve; interaction p = 0.013]. Neutralizing antibody titer was a strong inverse correlate of Omicron COVID-19 in non-naïve individuals and a weaker correlate in naïve individuals, posing questions about how prior infection alters the neutralization correlate.

Background:As the US human immunodeficiency virus (HIV) epidemic is disproportionately affecting underserved communities, it is critically important to investigate how social determinants of health affect diagnosis, treatment, and prevention of HIV infection and access to care. This article presents an investigation of the HIV epidemic in Clark County, Nevada, to identify local predictors of progression along the HIV care continuum. Methods:Deidentified HIV surveillance data from 2011 to 2022 were analyzed. We investigated associations between stages of care and individual-level demographics and zip code-level characteristics using (1) generalized linear mixed-effects models for univariate analysis, (2) penalized generalized linear mixed-effects models to simultaneously conduct variable selection and estimation for multivariate analysis, and (3) geospatial analysis. Results:Individual-level factors (diagnosis year, age at diagnosis, being Hispanic, being a man who has sex with men, sex at birth, and individual-level membership in a genetic cluster) and zip code-level factors (genetic clustering and social determinants of health, including level of poverty, proportion Hispanic, proportion with high school education, proportion white, and employment status) were associated with progression through the care continuum. A key result from our multivariate analysis is higher-poverty areas are associated with lower rates of persons with HIV in care (estimate [SE], -0.42 [0.17]; P = .02) and viral suppression (-0.48 [0.15]; P = .001). Conclusions:Our findings highlight the need for linking and engaging individuals in higher-poverty neighborhoods to medical providers. Furthermore, our results support the need for additional treatment adherence services in those same neighborhoods to increase viral suppression rates.

ABSTRACTThe challenges of recruiting participants for end-of-life (EOL) research are multifaceted. The Last Gift study at the University of California San Diego, an observational study for people with HIV (PWH) with terminal illness, appeals to the altruism of potential participants and community of allied health providers. Involvement of the latter group highlights a potential ethical conundrum of a "dual role", as primary care providers (PCPs) navigate between clinical responsibilities to their patients, along with opportunities to discuss clinical research. To explore this conundrum and better understand study recruitment dynamics of the Last Gift study, we analyzed screening and enrollment data for a 12-month period (2022-2023). We found that PCPs can play an important role in the recruitment of PWH into EOL research, as having PCPs discuss the study with potential participants yielded more successful enrollments than contact by the study team alone. Our manuscript proposes considerations to mitigate dual role conflicts, including ensuring ethical awareness, prioritizing clinical care and offering strategies to involve PCPs in recruitment without causing unnecessary burden or coercion. These insights aim to guide similar EOL research efforts, emphasizing the need for balanced, ethical recruitment processes in the sensitive context of terminal illness.

There has been significant controversy surrounding the use of HIV sequence data to identify outbreaks of HIV transmission since the initiation of molecular HIV surveillance (MHS) in the US. The current approach to MHS is comprehensive cluster detection and response (CDR), in which clusters of related infections are identified and used as the basis for cluster-based or population-based interventions. With CDR, there are ethical and stigma concerns around the impingement of individual privacy, as well as legal concerns around the inference of transmission in regions where HIV criminalization laws and statutes exist. Here we propose an alternative approach to the analysis of HIV sequence and public health data that focuses on regions and populations rather than clusters, and still provides useful data for public health agencies.

BACKGROUND:To date, human immunodeficiency virus (HIV) molecular epidemiology has been primarily used to identify clusters of related infections (cluster detection and response) and then address interventions to these clusters. Community groups have raised concern regarding cluster detection and response related to privacy and ethical concerns. Here we demonstrate how an alternative approach to HIV molecular epidemiology can provide public health benefit. METHODS:A limited data set for Miami-Dade County provided by the Florida Department of Health was curated and annotated by neighborhood health district (NBHD) and genetic linkage (using a genetic distance threshold of ≤0.5%) and phylodynamic analyses were performed. Phylodynamic analyses were used to infer viral transmissions into Miami-Dade County and between NBHDs within the county. RESULTS:A total of 7274 HIV sequences from unique persons collected between 1 January 2015 and 31 December 2021 were analyzed, including 50% of the 7894 new diagnoses during this period. The proportion of sequences in local clusters increased over time. Higher ratios of local introductions, compared to viral egress (ie, source of local clusters in other NBHDs) were observed in 3 NBHDs in North Miami (range, 1.9-2.5), suggesting earlier diagnosis, but high numbers of susceptible persons not receiving preexposure prophylaxis. South Dade/Homestead had a low ratio (0.3) of local introductions compared with egress, suggesting later diagnosis and less durable suppression. CONCLUSIONS:Phylodynamic and genetic linkage analyses can highlight populations and geographic regions that might benefit more from particular types of HIV prevention interventions. These findings will need to be explored by evaluating the impact of scaling up interventions informed by these analyses.

BACKGROUND:A key research priority for developing an HIV cure strategy is to define the viral dynamics and biomarkers associated with sustained post-treatment control. The ability to predict the likelihood of sustained post-treatment control or non-control could minimize the time off antiretroviral therapy (ART) for those destined to not control and anticipate longer periods off ART for those destined to control. METHODS:Mathematical modeling and machine learning were used to characterize virologic predictors of long-term virologic control using viral kinetics data from several studies in which participants interrupted ART. Predictors of post-ART outcomes were characterized using data accumulated from the time of treatment interruption, replicating real-time data collection in a clinical study, and classifying outcomes as either post-treatment control (plasma viremia ≤400 copies/mL at 2 of 3 time points for ≥24 weeks) or non-control. RESULTS:Potential predictors of virologic control were the time to rebound, the rate of initial rebound, and the peak plasma viremia. We found that people destined to be non-controllers could be identified within 3 weeks of rebound (prediction scores: accuracy, 80%; sensitivity, 82%; specificity, 71%). CONCLUSIONS:Given the widespread use of analytic treatment interruption in cure-related trials, these predictors may be useful to increase the safety of analytic treatment interruption through the early identification of people who are unlikely to become post-treatment controllers.

Abstract Background HIV molecular epidemiology (HIV ME) can support the early detection of emerging clusters of new HIV infections by combining HIV sequence data routinely obtained during the clinical treatment of people living with HIV with behavioral, geographic, and sociodemographic information. While information about emerging clusters promises to facilitate HIV prevention and treatment efforts, the use of this data also raises several ethical concerns. We sought to assess how those working on the frontlines of HIV ME, specifically public health practitioners (PHPs) and researchers, prioritized these issues. Methods Ethical issues were identified through literature review, qualitative in-depth interviews, and stakeholder engagement. PHPs and researchers using HIV ME prioritized the issues using best–worst scaling (BWS). A balanced incomplete block design was used to generate 11 choice tasks each consisting of a sub-set of 5 ethical concerns. In each task, respondents were asked to assess the most and least concerning issue. Data were analyzed using conditional logit, with a Swait-Louviere test of poolability. Latent class analysis was then used to explore preference heterogeneity. Results In total, 57 respondents completed the BWS experiment May–June 2023 with the Swait-Louviere test indicating that researchers and PHPs could be pooled (p = 0.512). Latent class analysis identified two classes, those highlighting “Harms” (n = 29) (prioritizing concerns about potential risk of legal prosecution, individual harm, and group stigma) and those highlighting “Utility” (n = 28) (prioritizing concerns about limited evidence, resource allocation, non-disclosure of data use for HIV ME, and the potential to infer the directionality of HIV transmission). There were no differences in the characteristics of members across classes. Conclusions The ethical issues of HIV ME vary in importance among stakeholders, reflecting different perspectives on the potential impact and usefulness of the data. Knowing these differences exist can directly inform the focus of future deliberations about the policies and practices of HIV ME in the United States.

BACKGROUND:Long-acting treatment for HIV has potential to improve adherence, provide durable viral suppression, and have long-term individual and public health benefits. We evaluated treatment with two antibodies that broadly and potently neutralise HIV (broadly neutralising antibodies; bNAbs), combined with lenacapavir, a long-acting capsid inhibitor, as a long-acting regimen. METHODS:This ongoing, randomised, blind, phase 1b proof-of-concept study conducted at 11 HIV treatment centres in the USA included adults with a plasma HIV-1 RNA concentration below 50 copies per mL who had at least 18 months on oral antiretroviral therapy (ART), CD4 counts of at least 500 cells per μL, and protocol-defined susceptibility to bNAbs teropavimab (3BNC117-LS) and zinlirvimab (10-1074-LS). Participants stopped oral ART and were randomly assigned (1:1) to one dose of 927 mg subcutaneous lenacapavir plus an oral loading dose, 30 mg/kg intravenous teropavimab, and 10 mg/kg or 30 mg/kg intravenous zinlirvimab on day 1. Investigational site personnel and participants were masked to treatment assignment throughout the randomised period. The primary endpoint was incidence of serious adverse events until week 26 in all randomly assigned participants who received one dose or more of any study drug. This study is registered with ClinicalTrials.gov, NCT04811040. FINDINGS:Between June 29 and Dec 8, 2021, 21 participants were randomly assigned, ten in each group received the complete study regimen and one withdrew before completing the regimen on day 1. 18 (86%) of 21 participants were male; participants ranged in age from 25 years to 61 years and had a median CD4 cell count of 909 (IQR 687-1270) cells per μL at study entry. No serious adverse events occurred. Two grade 3 adverse events occurred (lenacapavir injection-site erythaema and injection-site cellulitis), which had both resolved. The most common adverse events were symptoms of injection-site reactions, reported in 17 (85%) of 20 participants who received subcutaneous lenacapavir; 12 (60%) of 20 were grade 1. One (10%; 95% CI 0-45) participant had viral rebound (confirmed HIV-1 RNA concentration of ≥50 copies per mL) in the zinlirvimab 10 mg/kg group, which was resuppressed on ART, and one participant in the zinlirvimab 30 mg/kg group withdrew at week 12 with HIV RNA <50 copies per mL. INTERPRETATION:Lenacapavir with teropavimab and zinlirvimab 10 mg/kg or 30 mg/kg was generally well tolerated with no serious adverse events. HIV-1 suppression for at least 26 weeks is feasible with this regimen at either zinlirvimab dose in selected people with HIV-1. FUNDING:Gilead Sciences.

Background Standard-of-care nucleic acid amplification tests (routine NAATs) for Neisseria gonorrhoeae (GC) and Chlamydia trachomatis (CT) can take several days to result and therefore delay treatment. Rapid point-of-care GC/CT NAAT (rapid NAAT) could reduce the time to treatment and therefore onward transmission. This study evaluated the incremental cost per infectious day averted and overall cost of implementation associated with rapid compared with routine NAAT. Methods Prospective sexually transmitted infection (STI) treatment data from men who have sex with men and transgender women in San Diego who received rapid NAAT between November 2018 and February 2021 were evaluated. Historical time from testing to treatment for routine NAAT was abstracted from the literature. Costs per test for rapid and routine NAAT were calculated using a micro-costing approach. The incremental cost per infectious day averted comparing rapid to routine NAAT and the costs of rapid GC/CT NAAT implementation in San Diego Public Health STI clinics were calculated. Results Overall, 2333 individuals underwent rapid NAAT with a median time from sample collection to treatment of 2 days compared with 7 to 14 days for routine NAAT equating to a reduction of 5 to 12 days. The cost of rapid and routine GC/CT NAAT was $57.86 and $18.38 per test, respectively, with a cost-effectiveness of between $2.43 and $5.82 per infectious day averted. The incremental cost of rapid NAAT improved when at least 2000 tests were performed annually. Conclusions Although rapid GC/CT NAAT is more expensive than routine testing, the reduction of infectious days between testing and treatment may reduce transmission and provide improved STI treatment services to patients.

Background A key research priority for developing a human immunodeficiency virus (HIV) cure strategy is to define the viral dynamics and biomarkers associated with sustained posttreatment control. The ability to predict the likelihood of sustained posttreatment control or noncontrol could minimize the time off antiretroviral therapy (ART) for those destined to be controllers and anticipate longer periods off ART for those destined to be controllers.Methods Mathematical modeling and machine learning were used to characterize virologic predictors of long-term virologic control, using viral kinetics data from several studies in which participants interrupted ART. Predictors of post-ART outcomes were characterized using data accumulated from the time of treatment interruption, replicating real-time data collection in a clinical study, and classifying outcomes as either posttreatment control (plasma viremia, <= 400 copies/mL at 2 of 3 time points for >= 24 weeks) or noncontrol.Results Potential predictors of virologic control were the time to rebound, the rate of initial rebound, and the peak plasma viremia. We found that people destined to be noncontrollers could be identified within 3 weeks of rebound (prediction scores: accuracy, 80%; sensitivity, 82%; specificity, 71%).Conclusions Given the widespread use of analytic treatment interruption in cure-related trials, these predictors may be useful to increase the safety of analytic treatment interruption through early identification of people who are unlikely to become posttreatment controllers.

INTRODUCTION:The Last Gift study at the University of California San Diego (UCSD), United States enrolls terminally ill people with HIV (PWH) in HIV cure research. METHODS:From 2017 to 2022, we conducted surveys with Last Gift participants and their next-of-kin/loved ones to evaluate willingness to participate in different types of HIV cure research at the end of life (EOL). We analyzed willingness data descriptively. RESULTS:We surveyed 17 Last Gift participants and 17 next-of-kin/loved ones. More than half of Last Gift participants ( n  = 10; 58.8%) expressed willingness to participate in studies involving totally new treatments or approaches ('first-in-human' studies), a combination of different approaches, the use of unique antibodies, proteins or molecules, or therapeutic vaccines. Under one-quarter of Last Gift participants ( n  = 4; 23.5%) expressed willingness to participate in research involving interventions that may shorten their life expectancy to benefit medical research. Most Last Gift participants and their next-of-kin/loved ones also expressed high acceptance for various types of donations and biopsies at the EOL (e.g. hair donations and skin, lymph node or gut biopsies). DISCUSSION:Knowing whether people would be willing to participate in different types of EOL HIV cure research can help inform the design of future innovative studies. As a research community, we have a duty to design studies with adequate safeguards to preserve the public trust in research and honor PWH's important gift to humanity.

Objective:We sought to determine if standard influenza and pneumococcal vaccines can be used to stimulate HIV reservoirs during antiretroviral therapy (ART).Design:A prospective, randomized, double-blinded, placebo-controlled, crossover trial of two clinically recommended vaccines (influenza and pneumococcal).Methods:Persons with HIV on ART (N = 54) were enrolled in the clinical trial. Blood was collected at baseline and days 2,4,7,14, and 30 postimmunizations. Levels of cellular HIV RNA and HIV DNA were measured by ddPCR. Expression of immunological markers on T cell subsets was measured by flow cytometry. Changes in unspliced cellular HIV RNA from baseline to day 7 postinjection between each vaccine and placebo was the primary outcome.Results:Forty-seven participants completed at least one cycle and there were no serious adverse events related to the intervention. We observed no significant differences in the change in cellular HIV RNA after either vaccine compared with placebo at any timepoint. In secondary analyses, we observed a transient increase in total HIV DNA levels after influenza vaccine, as well as increased T cell activation and exhaustion on CD4+ T cells after pneumococcal vaccine.Conclusion:Clinically recommended vaccines were well tolerated but did not appear to stimulate the immune system strongly enough to elicit significantly noticeable HIV RNA transcription during ART.Clinicaltrials.gov identifier: NCT02707692.Conclusion:Clinically recommended vaccines were well tolerated but did not appear to stimulate the immune system strongly enough to elicit significantly noticeable HIV RNA transcription during ART.Clinicaltrials.gov identifier: NCT02707692.

Expanding HIV cluster detection using molecular HIV surveillance (MHS) raises ethical and social concerns, which may impede HIV outbreak detection and response as well as deter people living with HIV from seeking care. This underscores the need for effective communication strategies. We examined two methods for explaining MHS among men who have sex with men (MSM) living with HIV and at-risk without HIV in the United States. Participants recruited during the 2021 American Men’s Internet Survey (AMIS) were randomized to view a brief video (N = 822) or text (N = 1701) explaining MHS. Respondents with high video engagement were less likely to be concerned about MHS. In the text group, discomfort with MHS decreased as awareness of different public health activities increased. Overall, information about MHS and increased awareness of it improved its acceptability. Effective communication is an essential prerequisite for meaningfully engaging stakeholders regarding MHS implementation in HIV prevention and control efforts.

BACKGROUND:Many persons with HIV remain out of care (PWH-OOC). We evaluated InstaCare, a complex intervention integrating the brief behavioral intervention 60 minutes for Health with the rapid restart of antiretroviral therapy (rapid ART). SETTING:Prospective open-label randomized controlled trial among PWH-OOC in San Diego, USA. METHODS:PWH-OOC were randomized 1:1 to InstaCare or a time-and-attention control integrating a diet-and-nutrition behavioral intervention also with rapid ART initiation (restart ≤7 days from enrollment). All participants had access to support services (free transport, HIV peer navigation, adherence counseling, and linkage to care) and primary care services (mental health, case management, social work, medication-assisted treatment, and specialist pharmacy). The primary outcomes were viral suppression (<50 copies/mL) and re-engagement with care (≥2 HIV care visits >90 days apart) by 24 weeks. Outcomes were reported on an intention-to-treat basis. RESULTS:Between November 2020 and August 2022, 52 PWH-OOC were enrolled. Baseline substance use in the preceding month (49%), unstable housing (51%), moderate/severe depression (49%), and moderate/severe anxiety (41.7%) were prevalent. Rapid ART was provided for all participants. At week 24, the proportion with HIV viral load <50 copies/mL was 37.3% (19/51) (InstaCare 28.0%, control 46.2%, P = 0.25). Fourteen (27.5%) were engaged with care (InstaCare 7/25 [28.0%], control 7/26 [26.9%], P = 1.00). Most participants (94%) reported low or very low emotional distress associated with rapid ART. Study lost to follow-up by week 24 was high (23/51, 45%). CONCLUSIONS:The InstaCare complex intervention did not improve viral suppression or reengagement with care among PWH-OOC. Investigation of high-intensity, individually adapted interventions is needed among PWH-OOC.

Molecular HIV Surveillance (MHS) has been described as key to enabling rapid responses to HIV outbreaks. It operates by linking individuals with genetically similar viral sequences, which forms a network. A major limitation of MHS is that it depends on sequence collection, which very rarely covers the entire population of interest. Ignoring missing data by conducting complete case analysis–which assumes that the observed network is complete–has been shown to result in significantly biased estimates of network properties. We use MHS to investigate disease dynamics of the HIV epidemic in Miami-Dade County (MDC) among men who have sex with men (MSM)–only 30.1 do so, we present an approach for making Bayesian inferences on partially observed networks. Through a simulation study, we demonstrate a reduction in error of 43 increased mixing between MSM communities in MDC, defined by race and transmission risk compared to the results based on complete case analysis. Our approach makes use of a flexible network model–congruence class model–to overcome the high computational burden of previously reported Bayesian approaches to estimate network properties from partially observed networks.

Objective: To assess how antiretroviral therapy (ART) initiation during acute or early HIV infection (AEHI) affects the viral reservoir and host immune responses. Design: Single-arm trial of ART initiation during AEHI at 30 sites in the Americas, Africa, and Asia. Methods: HIV DNA was measured at week 48 of ART in 5 million CD4(+) T cells by sensitive qPCR assays targeting HIV gag and pol. Peripheral blood mononuclear cells were stimulated with potential HIV T cell epitope peptide pools consisting of env, gag, nef, and pol peptides and stained for expression of CD3, CD4, CD8, and intracellular cytokines/chemokines. Results: From 2017 to 2019, 188 participants initiated ART during Fiebig stages I (n = 6), II (n = 43), III (n = 56), IV (n = 23), and V (n = 60). Median age was 27 years (interquartile range 23-38), 27 (14%) participants were female, and 180 (97%) cisgender. Among 154 virally suppressed participants at week 48, 100% had detectable HIV gag or pol DNA. Participants treated during Fiebig I had the lowest HIV DNA levels (P < 0.001). Week 48 HIV DNA mostly did not correlate with concurrent CD4(+) or CD8(+) T cell HIV-specific immune responses (rho range -0.11 to +0.19, all P > 0.025). At week 48, the magnitude, but not polyfunctionality, of HIV-specific T cell responses was moderately reduced among participants who initiated ART earliest. Conclusion: Earlier ART initiation during AEHI reduced but did not eliminate the persistence of HIV-infected cells in blood. These findings explain the rapid viral rebound observed after ART cessation in early-treated individuals with undetectable HIV DNA by less sensitive methods.