Sex, Age, Race and Intervention Type in Clinical Studies of HIV Cure: A Systematic Review

This systematic review was undertaken to determine the extent to which adult subjects representing sex (female), race (nonwhite), and age (>50 years) categories are included in clinical studies of HIV curative interventions and thus, by extension, the potential for data to be analyzed that may shed light on the influence of such demographic variables on safety and/or efficacy. English-language publications retrieved from PubMed and from references of retrieved papers describing clinical studies of curative interventions were read and demographic, recruitment year, and intervention-type details were noted. Variables of interest included participation by sex, age, and race; changes in participation rates by recruitment year; and differences in participation by intervention type. Of 151 publications, 23% reported full demographic data of study enrollees, and only 6% reported conducting efficacy analyses by demographic variables. Included studies recruited participants from 1991 to 2011. No study conducted safety analyses by demographic variables. The representation of women, older people, and nonwhites did not reflect national or international burdens of HIV infection. Participation of demographic subgroups differed by intervention type and study location. Rates of participation of demographic groups of interest did not vary with time. Limited data suggest efficacy, particularly of early therapy initiation followed by treatment interruption, may vary by demographic variables, in this case sex. More data are needed to determine associations between demographic characteristics and safety/efficacy of curative interventions. Studies should be powered to conduct such analyses and cure-relevant measures should be standardized.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140121/1/aid.2014.0205.pd

The Impact of the Reward Systems on employee motivation: The Case of a Department Store

The aim of this research is to study the impact of reward systems used within a city centre department store on employee motivation. At its core the research looks to discover whether intrinsic or extrinsic motivation is the strongest, uncover if pay is a motivator and how to enhance motivation through pay and reward management. According to the literature review previous studies suggest that organisations use reward systems and strategies to motivate their employees, increase individual performance and to improve business performance. The literature review analyses current practises used in the department store to analyse benefit and limitation factors. The research was undertaken via a single case study at a department store and adopted the use of quantitative data via a questionnaire and qualitative data via structured interviews. The research found that although extrinsic rewards were present, intrinsic remains the dominant motivating factor amongst individuals, and that even within this individuals had different intrinsic motivators

Estrogen receptor-1 is a key regulator of HIV-1 latency that imparts gender-specific restrictions on the latent reservoir.

Unbiased shRNA library screens revealed that the estrogen receptor-1 (ESR-1) is a key factor regulating HIV-1 latency. In both Jurkat T cells and a Th17 primary cell model for HIV-1 latency, selective estrogen receptor modulators (SERMs, i.e., fulvestrant, raloxifene, and tamoxifen) are weak proviral activators and sensitize cells to latency-reversing agents (LRAs) including low doses of TNF-α (an NF-κB inducer), the histone deacetylase inhibitor vorinostat (soruberoylanilide hydroxamic acid, SAHA), and IL-15. To probe the physiologic relevance of these observations, leukapheresis samples from a cohort of 12 well-matched reproductive-age women and men on fully suppressive antiretroviral therapy were evaluated by an assay measuring the production of spliced envelope (env) mRNA (the EDITS assay) by next-generation sequencing. The cells were activated by T cell receptor (TCR) stimulation, IL-15, or SAHA in the presence of either β-estradiol or an SERM. β-Estradiol potently inhibited TCR activation of HIV-1 transcription, while SERMs enhanced the activity of most LRAs. Although both sexes responded to SERMs and β-estradiol, females showed much higher levels of inhibition in response to the hormone and higher reactivity in response to ESR-1 modulators than males. Importantly, the total inducible RNA reservoir, as measured by the EDITS assay, was significantly smaller in the women than in the men. We conclude that concurrent exposure to estrogen is likely to limit the efficacy of viral emergence from latency and that ESR-1 is a pharmacologically attractive target that can be exploited in the design of therapeutic strategies for latency reversal

Characterizing Symptoms and Identifying Biomarkers of Long COVID in People With and Without HIV: Protocol for a Remotely Conducted Prospective Observational Cohort Study

Background: Living with HIV is a risk factor for severe acute COVID-19, but it is unknown whether it is a risk factor for long COVID./ Objective: This study aims to characterize symptoms, sequelae, and cognition formally and prospectively 12 months following SARS-CoV-2 infection in people living with HIV compared with people without HIV. People with no history of SARS-CoV-2 infection, both with and without HIV, are enrolled as controls. The study also aims to identify blood-based biomarkers or patterns of immune dysregulation associated with long COVID./ Methods: This prospective observational cohort study enrolled participants into 1 of the following 4 study arms: people living with HIV who had SARS-CoV-2 infection for the first time <4 weeks before enrollment (HIV+COVID+ arm), people without HIV who had SARS-CoV-2 infection for the first time within 4 weeks of enrollment (HIV−COVID+ arm), people living with HIV who believed they never had SARS-CoV-2 infection (HIV+COVID− arm), and people without HIV who believed they never had SARS-CoV-2 infection (HIV−COVID− arm). At enrollment, participants in the COVID+ arms recalled their symptoms, mental health status, and quality of life in the month before having SARS-CoV-2 infection via a comprehensive survey administered by telephone or on the web. All participants completed the same comprehensive survey 1, 2, 4, 6, and 12 months after post–acute COVID-19 symptom onset or diagnosis, if asymptomatic, (COVID+ arms) or after enrollment (COVID− arms) on the web or by telephone. In total, 11 cognitive assessments were administered by telephone at 1 and 4 months after symptom onset (COVID+ arms) or after enrollment (COVID− arms). A mobile phlebotomist met the participants at a location of their choice for height and weight measurements, orthostatic vital signs, and a blood draw. Participants in the COVID+ arms donated blood 1 and 4 months after COVID-19, and participants in the COVID− arms donated blood once or none. Blood was then shipped overnight to the receiving study laboratory, processed, and stored./ Results: This project was funded in early 2021, and recruitment began in June 2021. Data analyses will be completed by summer 2023. As of February 2023, a total of 387 participants were enrolled in this study, with 345 participants having completed enrollment or baseline surveys together with at least one other completed study event. The 345 participants includes 76 (22%) HIV+COVID+, 121 (35.1%) HIV−COVID+, 78 (22.6%) HIV+COVID−, and 70 (20.3%) HIV−COVID− participants./ Conclusions: This study will provide longitudinal data to characterize COVID-19 recovery over 12 months in people living with and without HIV. Additionally, this study will determine whether biomarkers or patterns of immune dsyregulation associate with decreased cognitive function or symptoms of long COVID

Controversies in HIV cure research

International audienceABSTRACT: BACKGROUND: Antiretroviral therapy significantly reduces HIV viral burden and prolongs life, but does not cure HIV infection. The major scientific barrier to a cure is thought to be the persistence of the virus in cellular and/or anatomical reservoirs. DISCUSSION: Most efforts to date, including pharmaco, immuno or gene therapy, have failed to cure patients, with the notable exception of a stem cell transplant recipient commonly known as the Berlin patient. This case has revived interest in the potential to cure HIV infection and has highlighted the need to resolve critical questions in the basic, pre-clinical and clinical research spheres as they pertain specifically to efforts to eradicate HIV from the body of an infected person (a sterilizing cure) or at least render the need for lifelong antiretroviral therapy obsolete (functional cure). This paper describes ongoing debates in each of these research spheres as they were presented and discussed at a satellite session that took place at the 6th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention in Rome in July 2011. SUMMARY: The resolution of these debates may have important implications for the search for a cure, the most efficient ways to identify and test promising interventions, and ultimately the availability of such a cure to diverse groups of HIV patients around the world

Comparative Analysis of Measures of Viral Reservoirs in HIV-1 Eradication Studies

HIV-1 reservoirs preclude virus eradication in patients receiving highly active antiretroviral therapy (HAART). The best characterized reservoir is a small, difficult-to-quantify pool of resting memory CD4+ T cells carrying latent but replication-competent viral genomes. Because strategies targeting this latent reservoir are now being tested in clinical trials, well-validated high-throughput assays that quantify this reservoir are urgently needed. Here we compare eleven different approaches for quantitating persistent HIV-1 in 30 patients on HAART, using the original viral outgrowth assay for resting CD4+ T cells carrying inducible, replication-competent viral genomes as a standard for comparison. PCR-based assays for cells containing HIV-1 DNA gave infected cell frequencies at least 2 logs higher than the viral outgrowth assay, even in subjects who started HAART during acute/early infection. This difference may reflect defective viral genomes. The ratio of infected cell frequencies determined by viral outgrowth and PCR-based assays varied dramatically between patients. Although strong correlations with the viral outgrowth assay could not be formally excluded for most assays, correlations achieved statistical significance only for integrated HIV-1 DNA in peripheral blood mononuclear cells and HIV-1 RNA/DNA ratio in rectal CD4+ T cells. Residual viremia was below the limit of detection in many subjects and did not correlate with the viral outgrowth assays. The dramatic differences in infected cell frequencies and the lack of a precise correlation between culture and PCR-based assays raise the possibility that the successful clearance of latently infected cells may be masked by a larger and variable pool of cells with defective proviruses. These defective proviruses are detected by PCR but may not be affected by reactivation strategies and may not require eradication to accomplish an effective cure. A molecular understanding of the discrepancy between infected cell frequencies measured by viral outgrowth versus PCR assays is an urgent priority in HIV-1 cure research

Social and clinical determinants of preferences and their achievement at the end of life: Prospective cohort study of older adults receiving palliative care in three countries

© 2017 The Author(s). Background: Achieving choice is proposed as a quality marker. But little is known about what influences preferences especially among older adults. We aimed to determine and compare, across three countries, factors associated with preferences for place of death and treatment, and actual site of death. Methods: We recruited adults aged ≥65-years from hospital-based multiprofessional palliative care services in London, Dublin, New York, and followed them for >17 months. All services offered consultation on hospital wards, support for existing clinical teams, outpatient services and received funding from their National Health Service and/or relevant Insurance reimbursements. The New York service additionally had 10 inpatient beds. All worked with and referred patients to local hospices. Face-to-face interviews recorded most and least preferred place of death, treatment goal priorities, demographic and clinical information using validated questionnaires. Multivariable and multilevel analyses assessed associated factors. Results: One hundred and thirty eight older adults (64 London, 59 Dublin, 15 New York) were recruited, 110 died during follow-up. Home was the most preferred place of death (77/138, 56%) followed by inpatient palliative care/hospice units (22%). Hospital was least preferred (35/138, 25%), followed by nursing home (20%) and home (16%); hospice/palliative care unit was rarely least preferred (4%). Most respondents prioritised improving quality of life, either alone (54%), or equal with life extension (39%); few (3%) chose only life extension. There were no significant differences between countries. Main associates with home preference were: cancer diagnosis (OR 3.72, 95% CI 1.40-9.90) and living with someone (OR 2.19, 1.33-3.62). Adults with non-cancer diagnoses were more likely to prefer palliative care units (OR 2.39, 1.14-5.03). Conversely, functional independence (OR 1.05, 1.04-1.06) and valuing quality of life (OR 3.11, 2.89-3.36) were associated with dying at home. There was a mismatch between preferences and achievements - of 85 people who preferred home or a palliative care unit, 19 (25%) achieved their first preference. Conclusion: Although home is the most common first preference, it is polarising and for 16% it is the least preferred. Inpatient palliative care unit emerges as the second most preferred place, is rarely least preferred, and yet was often not achieved for those who wanted to die there. Factors affecting stated preferences and met preferences differ. Available services, notably community support and palliative care units, require expansion. Contrasting actual place of death with capacity for meeting patient and family needs may be a better quality indicator than simply 'achieved preferences'

Using breath carbon monoxide to validate self-reported tobacco smoking in remote Australian Indigenous communities

Background: This paper examines the specificity and sensitivity of a breath carbon monoxide (BCO) test and\ud optimum BCO cutoff level for validating self-reported tobacco smoking in Indigenous Australians in Arnhem Land,\ud Northern Territory (NT).\ud \ud Methods: In a sample of 400 people (≥16 years) interviewed about tobacco use in three communities, both selfreported\ud smoking and BCO data were recorded for 309 study participants. Of these, 249 reported smoking tobacco\ud within the preceding 24 hours, and 60 reported they had never smoked or had not smoked tobacco for ≥6\ud months. The sample was opportunistically recruited using quotas to reflect age and gender balances in the\ud communities where the combined Indigenous populations comprised 1,104 males and 1,215 females (≥16 years).\ud Local Indigenous research workers assisted researchers in interviewing participants and facilitating BCO tests using\ud a portable hand-held analyzer.\ud \ud Results: A BCO cutoff of ≥7 parts per million (ppm) provided good agreement between self-report and BCO\ud (96.0% sensitivity, 93.3% specificity). An alternative cutoff of ≥5 ppm increased sensitivity from 96.0% to 99.6% with no change in specificity (93.3%). With data for two self-reported nonsmokers who also reported that they smoked\ud cannabis removed from the analysis, specificity increased to 96.6%.\ud \ud Conclusion: In these disadvantaged Indigenous populations, where data describing smoking are few, testing for\ud BCO provides a practical, noninvasive, and immediate method to validate self-reported smoking. In further studies\ud of tobacco smoking in these populations, cannabis use should be considered where self-reported nonsmokers\ud show high BCO