Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 260
Filtrar
1.
AIDS ; 2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34586085

RESUMO

OBJECTIVE: To examine whether administering both vorinostat and disulfiram to people with HIV (PWH) on antiretroviral therapy (ART) is safe and can enhance HIV latency reversal. DESIGN: Vorinostat and disulfiram, can increase HIV transcription in people with HIV (PWH) on antiretroviral therapy (ART). Together these agents may lead to significant HIV latency reversal. METHODS: Virologically suppressed PWH on ART received disulfiram 2000 mg daily for 28 days and vorinostat 400 mg daily on days 8-10 and 22-24. The primary endpoint was plasma HIV RNA on day 11 relative to baseline using a single copy assay. Assessments included cell-associated (CA) unspliced (US) RNA as a marker of latency reversal, HIV DNA in CD4+ T-cells, plasma HIV RNA and plasma concentrations of ART, vorinostat and disulfiram. RESULTS: The first two participants (P1 and P2) experienced grade 3 neurotoxicity leading to trial suspension. After 24 days, P1 presented with confusion, lethargy, and ataxia having stopped disulfiram and ART. Symptoms resolved by day 29. After 11 days, P2 presented with paranoia, emotional lability, lethargy, ataxia and study drugs were ceased. Symptoms resolved by day 23. CA-US RNA increased by 1.4- and 1.3-fold for P1 and P2 respectively. Plasma HIV RNA was detectable from day 8-37 (peak 81 copies/mL) for P2 but was not increased in P1 Antiretroviral levels were therapeutic and neuronal injury markers were elevated in P1. CONCLUSIONS: The combination of prolonged high dose disulfiram and vorinostat was not safe in PWH on ART and should not be pursued despite evidence of latency reversal.

2.
Lancet HIV ; 8(10): e623-e632, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34508660

RESUMO

BACKGROUND: Most studies assessing the HIV care cascade have typically been cross-sectional analyses, which do not capture the transition time to subsequent stages. We aimed to assess the longitudinal HIV cascade of care in Australia, and changes over time in transition times and associated factors. METHODS: In this longitudinal cohort study, we included linked data for gay and bisexual men (GBM) with a new HIV diagnosis who attended clinics participating in the Australian Collaboration for Coordinated Enhanced Sentinel Surveillance in New South Wales and Victoria between Jan 1, 2012, and Dec 31, 2019. We assessed three cascade transition periods: diagnosis to linkage to care (stage 1 transition); linkage to care to antiretroviral therapy (ART) initiation (stage 2 transition); and ART initiation to virological suppression (viral load ≤200 copies per mL; stage 3 transition). We also calculated the probability of remaining virologically suppressed after the first recorded viral load of less than 200 copies per mL. We used the Kaplan-Meier method to estimate transition times and cumulative probability of stage transition. FINDINGS: We included 2196 GBM newly diagnosed with HIV between 2012 and 2019 contributing 6747 person-years of follow-up in our analysis. Median time from HIV diagnosis to linkage to care (stage 1 transition) was 2 days (IQR 1-3). Median time from linkage to care to ART initiation (stage 2 transition) was 33 days (30-35). Median time from ART initiation to first recorded virological suppression (stage 3 transition) was 49 days (47-52). The cumulative probability of ART initiation within 90 days of linkage to care increased from 36·9% (95% CI 32·9-40·6) in the 2012-13 calendar period to 94·1% (91·2-96·0) in the 2018-19 calendar period and cumulative probability of virological suppression within 90 days of ART initiation increased from 54·3% (48·8-59·3) in the 2012-13 calendar period to 82·9% (78·4-86·4) in the 2018-19 calendar period. 91·6% (90·1-93·1) of GBM remained virologically supressed up to 2 years after their first recorded virological suppression event. INTERPRETATION: In countries with high cross-sectional cascade estimates such as Australia, the impact of treatment as prevention is better estimated using longitudinal cascade analyses. FUNDING: National Health and Medical Research Council Australia.

3.
Curr Opin HIV AIDS ; 16(5): 249-256, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34334614

RESUMO

PURPOSE OF REVIEW: To provide an overview of studies to date that have identified posttreatment controllers (PTCs) and to explore current evidence around clinical characteristics, immune effector function, and inflammatory and viral reservoir characteristics that may underlie the control mechanism. RECENT FINDINGS: PTCs are broadly defined as individuals capable of maintaining control of HIV replication after cessation of antiretroviral therapy (ART). While starting ART early after HIV infection is associated with PTC, genetic disposition or CD8+ T-cell function do not appear to explain this phenomenon, but these features have not been exhaustively analyzed in PTCs. A lower frequency of latently infected cells prior to stopping ART has been associated with achieving PTC, including a lower level of intact HIV DNA, but more studies are needed to map the genetic location, epigenetic characteristics, and tissue distribution of the intact HIV reservoir in PTCs. SUMMARY: Current studies are small and heterogeneous and there is a significant need to agree on a uniform definition of PTC. Many aspects of PTC are still unexplored including whether specific features of genetic disposition, immune effector functions, and/or viral reservoir characteristics play a role in PTC. A large multisite international cohort study could aide in providing the important insights needed to fully understand PTC.


Assuntos
Infecções por HIV , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Estudos de Coortes , Infecções por HIV/tratamento farmacológico , Humanos , Carga Viral , Replicação Viral
4.
Health Res Policy Syst ; 19(1): 110, 2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34348732

RESUMO

BACKGROUND: Public health emergencies-such as the 2020 COVID-19 pandemic-accelerate the need for both evidence generation and rapid dissemination and implementation (D&I) of evidence where it is most needed. In this paper, we reflect on how D&I frameworks and methods can be pragmatic (i.e., relevant to real-world context) tools for rapid and iterative planning, implementation, evaluation, and dissemination of evidence to address public health emergencies. THE PRAGMATIC, RAPID, AND ITERATIVE D&I (PRIDI) CYCLE: The PRIDI cycle is based on a "double-loop" learning process that recognizes the need for responsiveness and iterative adaptation of implementation cycle (inner loop) to the moving landscapes, presented by the outer loops of emerging goals and desired outcomes, emerging interventions and D&I strategies, evolving evidence, and emerging characteristics and needs of individuals and contexts. Stakeholders iteratively evaluate these surrounding landscapes of implementation, and reconsider implementation plans and activities. CONCLUSION: Even when the health system priority is provision of the best care to the individuals in need, and scientists are focused on development of effective diagnostic and therapeutic technologies, planning for D&I is critical. Without a flexible and adaptive process of D&I, which is responsive to emerging evidence generation cycles, and closely connected to the needs and priorities of stakeholders and target users through engagement and feedback, the interventions to mitigate public health emergencies (e.g., COVID-19 pandemic), and other emerging issues, will have limited reach and impact on populations that would most benefit. The PRIDI cycle is intended to provide a pragmatic approach to support planning for D&I throughout the evidence generation and usage processes.


Assuntos
COVID-19 , Saúde Pública , Emergências , Humanos , Pandemias , SARS-CoV-2
7.
medRxiv ; 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34230936

RESUMO

Current tests for SARS-CoV-2 antibodies (IgG, IgM, IgA) cannot differentiate recent and past infections. We describe a point of care, lateral flow assay for SARS-CoV-2 dIgA based on the highly selective binding of dIgA to a chimeric form of secretory component (CSC), that distinguishes dIgA from monomeric IgA. Detection of specific dIgA uses a complex of biotinylated SARS-CoV-2 receptor binding domain and streptavidin-colloidal gold. SARS-CoV-2-specific dIgA was measured both in 112 cross-sectional samples and a longitudinal panel of 362 plasma samples from 45 patients with PCR-confirmed SARS-CoV-2 infection, and 193 discrete pre-COVID-19 or PCR-negative patient samples. The assay demonstrated 100% sensitivity from 11 days post-symptom onset, and a specificity of 98.2%. With an estimated half-life of 6.3 days, dIgA provides a unique biomarker for the detection of recent SARS-CoV-2 infections with potential to enhance diagnosis and management of COVID-19 at point-of-care.

8.
BMJ Open ; 11(7): e048993, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34210734

RESUMO

INTRODUCTION: HIV transmission within serodifferent heterosexual couples plays a key role in sustaining the global HIV pandemic. In the USA, transmission within established mixed-status couples accounts for up to half of all new HIV infections among heterosexuals. Oral HIV pre-exposure prophylaxis (PrEP) is a highly effective prevention method, although underutilised among serodifferent couples. Moreover, there is a dearth of research on US HIV-serodifferent couples' perspectives and use of PrEP, alone or in combination with other prevention methods. In this paper, we describe the study protocol for the Magnetic Couples Study, designed to fill critical knowledge gaps regarding HIV-serodifferent heterosexual couples' perspectives, experiences and utilisation of PrEP. METHODS AND ANALYSIS: The Magnetic Couples Study is a mixed methods prospective cohort study designed to describe temporal patterns and identify determinants at multiple levels (individual, couple, HCF) of PrEP outcomes along the care continuum (PrEP awareness, linkage, uptake, retention and medication adherence) among HIV-serodifferent heterosexual couples residing in New York City. The study will also examine clinical management of PrEP, side effects and changes in sexual-related and substance use-related behaviour. A prospective cohort of 230 mixed-status couples already on oral PrEP was recruited, with quarterly assessments over 18 months; in addition, a cross-sectional sample of 150 mixed-status couples not currently on PrEP was recruited. In-depth semistructured qualitative interviews were conducted with a subsample of 25 couples. Actor-partner interdependence modelling using multilevel analysis will be employed for the analysis of longitudinal dyadic data. Framework analysis will be used to analyse qualitative data. A parallel convergent design will be used for mixed methods integration. ETHICS AND DISSEMINATION: The study was approved by the University of Rochester Institutional Review Board (RSRB00052766). Study findings will be disseminated to community members and providers and to researchers and policy makers.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , Profilaxia Pré-Exposição , Fármacos Anti-HIV/uso terapêutico , Estudos Transversais , Características da Família , Infecções por HIV/tratamento farmacológico , Infecções por HIV/prevenção & controle , Heterossexualidade , Humanos , Fenômenos Magnéticos , Cidade de Nova Iorque , Estudos Prospectivos , Parceiros Sexuais
9.
Front Genet ; 12: 680725, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34194479

RESUMO

HIV-1 Tat protein is essential for virus production. RNA-binding proteins that facilitate Tat production may be absent or downregulated in resting CD4+ T-cells, the main reservoir of latent HIV in people with HIV (PWH) on antiretroviral therapy (ART). In this study, we examined the role of Tat RNA-binding proteins on the expression of Tat and control of latent and productive infection. Affinity purification coupled with mass spectrometry analysis was used to detect binding partners of MS2-tagged tat mRNA in a T cell-line model of HIV latency. The effect of knockdown and overexpression of the proteins of interest on Tat transactivation and translation was assessed by luciferase-based reporter assays and infections with a dual color HIV reporter virus. Out of the 243 interactions identified, knockdown of SRP14 (Signal Recognition Particle 14) negatively affected tat mRNA processing and translation as well as Tat-mediated transactivation, which led to an increase in latent infection. On the other hand, knockdown of HMGB3 (High Mobility Group Box 3) resulted in an increase in Tat transactivation and translation as well as an increase in productive infection. Footprinting experiments revealed that SRP14 and HMGB3 proteins bind to TIM-TAM, a conserved RNA sequence-structure in tat mRNA that functions as a Tat IRES modulator of tat mRNA. Overexpression of SRP14 in resting CD4+ T-cells from patients on ART was sufficient to reverse HIV-1 latency and induce virus production. The role of SRP14 and HMGB3 proteins in controlling HIV Tat expression during latency will be further assessed as potential drug targets.

11.
Cell ; 184(8): 2167-2182.e22, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33811809

RESUMO

Cardiac injury and dysfunction occur in COVID-19 patients and increase the risk of mortality. Causes are ill defined but could be through direct cardiac infection and/or inflammation-induced dysfunction. To identify mechanisms and cardio-protective drugs, we use a state-of-the-art pipeline combining human cardiac organoids with phosphoproteomics and single nuclei RNA sequencing. We identify an inflammatory "cytokine-storm", a cocktail of interferon gamma, interleukin 1ß, and poly(I:C), induced diastolic dysfunction. Bromodomain-containing protein 4 is activated along with a viral response that is consistent in both human cardiac organoids (hCOs) and hearts of SARS-CoV-2-infected K18-hACE2 mice. Bromodomain and extraterminal family inhibitors (BETi) recover dysfunction in hCOs and completely prevent cardiac dysfunction and death in a mouse cytokine-storm model. Additionally, BETi decreases transcription of genes in the viral response, decreases ACE2 expression, and reduces SARS-CoV-2 infection of cardiomyocytes. Together, BETi, including the Food and Drug Administration (FDA) breakthrough designated drug, apabetalone, are promising candidates to prevent COVID-19 mediated cardiac damage.


Assuntos
COVID-19/complicações , Cardiotônicos/uso terapêutico , Proteínas de Ciclo Celular/antagonistas & inibidores , Cardiopatias/tratamento farmacológico , Quinazolinonas/uso terapêutico , Fatores de Transcrição/antagonistas & inibidores , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , COVID-19/tratamento farmacológico , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Citocinas/metabolismo , Feminino , Cardiopatias/etiologia , Células-Tronco Embrionárias Humanas , Humanos , Inflamação/complicações , Inflamação/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Transcrição/metabolismo
12.
AIDS ; 35(10): 1631-1636, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-33859108

RESUMO

OBJECTIVE: The aim of this study was to quantify HIV-specific immunological and virological changes in people with HIV (PWH) on antiretroviral therapy (ART) with malignancy who received immune checkpoint blockade (ICB). DESIGN: An observational cohort study. METHODS: Blood samples were collected before and after four cycles of ICB in HIV-positive adults on ART. Virological assessments performed on CD4+ T cells included cell-associated unspliced HIV RNA, cell-associated HIV DNA, Tat/rev-induced limiting dilution assay (TILDA) and plasma HIV RNA using a single copy assay (SCA). Flow cytometry was used to assess the frequency of precursor exhausted T cells (Tpex) and exhausted T cells (Tex), and Gag-specific CD4+ and CD8+ T cells positive for IFN-γ, TNF-α or CD107a by intracellular cytokine staining (ICS). RESULTS: Participant (P)1 received avelumab (anti-PD-L1) for Merkel cell carcinoma. P2 and P3 received ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) for metastatic melanoma. An increase in CA-US RNA following each infusion was noted in all three participants. There were no consistent changes in HIV DNA or the proportion of cells with inducible MS HIV RNA. P2 demonstrated a striking increase in the frequency of gag-specific central and effector memory CD8+ T cells producing IFN-γ, TNF-α and CD107a following anti-PD1 and anti-CTLA-4. The frequency of CD8+ Tpex cells pre-ICB was also highest in this participant. CONCLUSION: In three PWH with cancer on ART, we found that ICB activated latent HIV and enhanced HIV-specific T cell function but with considerable variation.


Assuntos
Infecções por HIV , HIV-1 , Neoplasias , Adulto , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Infecções por HIV/tratamento farmacológico , Humanos , Neoplasias/tratamento farmacológico , Latência Viral
13.
Arch Sex Behav ; 50(5): 2031-2047, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33903969

RESUMO

Threats to sexual health among U.S. Black men who have sex with men (MSM) may manifest in a context of social adverse experiences. Situational sex is one such context, which we characterize as sexual behaviors driven either by a desire to cultivate a specific sexual experience or attributable to social vulnerability. Two characterizations of situational sex explored in this study were drug use during sex and transactional sex. Guided by ecological and syndemic frameworks, we conducted a secondary data analysis of social conditions and sexual behaviors among a prospective cohort of Black MSM from the HIV Prevention Trial Network (HPTN) 061 study. Using structural equation modeling, this analysis examined the indirect effect of syndemic factors (substance use, depression, violence exposure) in the relationship between ecological constructs (anti-Black/homophobic stigma, childhood violence, and economic vulnerability) and situational sex (drug use during sex, transactional sex). Model fit indices, CFI (.870) and SRMR (.091), demonstrated reasonable fit. Significant indirect effects emerged via substance use for economic vulnerability (indirect effect = .181, 95% CI [.078, .294]) and anti-Black/homophobic violence and stigma (indirect effect = .061, 95% CI [.008, .121]) on drug use during sex; as well as on transactional sex (economic vulnerability indirect effect = .059, 95% CI [.018, .121] and anti-Black/homophobic stigma and violence indirect effect = .020, 95% CI [.003, .051]). Findings implicate the need for social and fiscal intervention to address upstream, ecological, and syndemic factors that influence inherent vulnerability of situational sex and overall threats to sexual health among Black MSM.


Assuntos
Minorias Sexuais e de Gênero , Transtornos Relacionados ao Uso de Substâncias , Afro-Americanos , Análise de Dados , Infecções por HIV , Homossexualidade Masculina , Humanos , Masculino , Preparações Farmacêuticas , Estudos Prospectivos , Comportamento Sexual , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Sindemia
14.
J Int Assoc Provid AIDS Care ; 20: 2325958220978113, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33733909

RESUMO

In Ghana, the HIV prevalence among MSM is more than 10 times greater than the general population of adults, and rates of engagement in HIV medical care are low among MSM diagnosed with HIV. Using structured surveys, we investigated the impact of HIV-related stigma, same-sex behavior stigma, and gender nonconformity stigma on linkage to HIV care (LTC) in MSM (N = 225) living with HIV in Ghana. Autonomy-supportive healthcare climate (OR = 1.63, p < .01), vicarious HIV stigma (OR = 2.73, p < .01), and age (OR = 1.06, p < .004) predicted LTC. Conversely, felt normative HIV stigma negatively predicted LTC (OR = 0.65, p < .05). Finally, we identified regional disparities, with MSM from Takoradi being 4 times and 5 times more likely to be LTC compared to Kumasi and Accra, respectively. Our findings highlight the nuanced roles of stigmas in shaping the HIV care continuum among MSM living with HIV, while revealing potential gaps in current measures of HIV-related stigma.


Assuntos
Atenção à Saúde , Infecções por HIV/psicologia , Homossexualidade Masculina/psicologia , Estigma Social , Adulto , Continuidade da Assistência ao Paciente , Estudos Transversais , Feminino , Gana , Infecções por HIV/tratamento farmacológico , Humanos , Masculino , Comportamento Sexual , Minorias Sexuais e de Gênero
15.
EBioMedicine ; 65: 103241, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33647768

RESUMO

BACKGROUND: One strategy being pursued to clear latently infected cells that persist in people living with HIV (PLWH) on antiretroviral therapy (ART) is to activate latent HIV infection with a latency reversing agent (LRA). Surrogate markers that accurately measure virus production following an LRA are needed. METHODS: We quantified cell-associated unspliced (US), multiply spliced (MS) and supernatant (SN) HIV RNA by qPCR from total and resting CD4+ T cells isolated from seven PLWH on ART before and after treatment ex vivo with different LRAs, including histone deacetylase inhibitors (HDACi). MS and plasma HIV RNA were also quantified from PLWH on ART (n-11) who received the HDACi panobinostat. FINDINGS: In total and resting CD4+ T cells from PLWH on ART, detection of US RNA was common while detection of MS RNA was infrequent. Primers used to detect MS RNA, in contrast to US RNA, bound sites of the viral genome that are commonly mutated or deleted in PLWH on ART. Following ex vivo stimulation with LRAs, we identified a strong correlation between the fold change increase in SN and MS RNA, but not the fold change increase in SN and US RNA. In PLWH on ART who received panobinostat, MS RNA was significantly higher in samples with detectable compared to non0detectable plasma HIV RNA. INTERPRETATION: Following administration of an LRA, quantification of MS RNA is more likely to reflect an increase in virion production and is therefore a better indicator of meaningful latency reversal. FUNDING: NHMRC, NIH DARE collaboratory.


Assuntos
HIV-1/genética , Splicing de RNA , RNA Viral/sangue , Latência Viral/fisiologia , Antirretrovirais/farmacologia , Antirretrovirais/uso terapêutico , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/virologia , Proliferação de Células/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/patologia , Infecções por HIV/virologia , HIV-1/fisiologia , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Poli-Hidroxialcanoatos/farmacologia , RNA Viral/metabolismo , Acetato de Tetradecanoilforbol/farmacologia , Vorinostat/farmacologia , Vorinostat/uso terapêutico
16.
Am J Epidemiol ; 190(7): 1386-1395, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33534904

RESUMO

Ambitious World Health Organization targets for disease elimination require monitoring of epidemics using routine health data in settings of decreasing and low incidence. We evaluated 2 methods commonly applied to routine testing results to estimate incidence rates that assume a uniform probability of infection between consecutive negative and positive tests based on 1) the midpoint of this interval and 2) a randomly selected point in this interval. We compared these with an approximation of the Poisson binomial distribution, which assigns partial incidence to time periods based on the uniform probability of occurrence in these intervals. We assessed bias, variance, and convergence of estimates using simulations of Weibull-distributed failure times with systematically varied baseline incidence and varying trend. We considered results for quarterly, half-yearly, and yearly incidence estimation frequencies. We applied the methods to assess human immunodeficiency virus (HIV) incidence in HIV-negative patients from the Treatment With Antiretrovirals and Their Impact on Positive and Negative Men (TAIPAN) Study, an Australian study of HIV incidence in men who have sex with men, between 2012 and 2018. The Poisson binomial method had reduced bias and variance at low levels of incidence and for increased estimation frequency, with increased consistency of estimation. Application of methods to real-world assessment of HIV incidence found decreased variance in Poisson binomial model estimates, with observed incidence declining to levels where simulation results had indicated bias in midpoint and random-point methods.


Assuntos
Projetos de Pesquisa Epidemiológica , Infecções por HIV/epidemiologia , Vigilância da População/métodos , Minorias Sexuais e de Gênero/estatística & dados numéricos , Estatística como Assunto/métodos , Austrália/epidemiologia , Viés , Simulação por Computador , Epidemias , Humanos , Incidência , Masculino , Modelos Estatísticos , Distribuição de Poisson , Probabilidade
17.
Res Sq ; 2021 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-33594352

RESUMO

Background Public health emergencies - such as the 2020 COVID19 pandemic -accelerate the need for both evidence generation and rapid dissemination and implementation (D&I) of evidence where it is most needed. In this paper, we reflect on how D&I frameworks and methods can be pragmatic (i.e., relevant to real-world context) tools for rapid and iterative planning, implementation, evaluation, and dissemination of evidence to address public health emergencies. The Pragmatic, Rapid, and Iterative D&I (PRIDI) Cycle : The PRIDI Cycle is based on a "double-loop" learning process, reflecting the iterative and adaptive D&I, along with iterative re-consideration of goals and priorities, interventions and corresponding D&I strategies, and needs and capacities of individuals and contexts. Stakeholder engagement is essential- which itself is an evolving activity. The results of iterative evaluations should be communicated with local implementers and stakeholders through customized feedbacks. Conclusion Even when the health system priority is provision of the best care to the individuals in need, and scientists are focused on development of effective diagnostic and therapeutic technologies, planning for D&I is critical. Without a flexible and adapting process of D&I, which is responsive to emerging evidence generation cycles, and is closely connected to stakeholders and target users through engagement and feedback, the interventions to mitigate public health emergencies - such as the COVID19 pandemic - will have limited reach and impact on populations that would most benefit. The PRIDI cycle is intended to provide a pragmatic approach to support planning for D&I throughout the evidence generation process.

18.
EBioMedicine ; 65: 103252, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33640794

RESUMO

BACKGROUND: A research priority in finding a cure for HIV is to establish methods to accurately locate and quantify where and how HIV persists in people living with HIV (PLWH) receiving suppressive antiretroviral therapy (ART). Infusing copper-64 (64Cu) radiolabelled broadly neutralising antibodies targeting HIV envelope (Env) with CT scan and positron emission tomography (PET) identified HIV Env in tissues in SIV infected non-human primates . We aimed to determine if a similar approach was effective in people living with HIV (PLWH). METHODS: Unmodified 3BNC117 was compared with 3BNC117 bound to the chelator MeCOSar and 64Cu (64Cu-3BNC117) in vitro to assess binding and neutralization. In a clinical trial 64Cu-3BNC117 was infused into HIV uninfected (Group 1), HIV infected and viremic (viral load, VL >1000 c/mL; Group 2) and HIV infected aviremic (VL <20 c/mL; Group 3) participants using two dosing strategies: high protein (3mg/kg unlabeled 3BNC117 combined with <5mg 64Cu-3BNC117) and trace (<5mg 64Cu-3BNC117 only). All participants were screened for 3BNC117 sensitivity from virus obtained from viral outgrowth. Magnetic resonance imaging (MRI)/PET and pharmacokinetic assessments (ELISA for serum 3BNC117 concentrations and gamma counting for 64Cu) were performed 1, 24- and 48-hours post dosing. The trial (clincialtrials.gov NCT03063788) primary endpoint was comparison of PET standard uptake values (SUVs) in regions of interest (e.g lymph node groups and gastrointestinal tract). FINDINGS: Comparison of unmodified and modified 3BNC117 in vitro demonstrated no difference in HIV binding or neutralisation. 17 individuals were enrolled of which 12 were dosed including Group 1 (n=4, 2 high protein, 2 trace dose), Group 2 (n=6, 2 high protein, 4 trace) and Group 3 (n=2, trace only). HIV+ participants had a mean CD4 of 574 cells/microL and mean age 43 years. There were no drug related adverse effects and no differences in tissue uptake in regions of interest (e.g lymph node gut, pharynx) between the 3 groups. In the high protein dosing group, serum concentrations of 3BNC117 and gamma counts were highly correlated demonstrating that 64Cu-3BNC117 remained intact in vivo. INTERPRETATION: In PLWH on or off ART, the intervention of infusing 64Cu-3BNC117 and MRI/PET imaging over 48 hours, was unable to detect HIV-1 env expression in vivo. Future studies should investigate alternative radiolabels such as zirconium which have a longer half-life in vivo. FUNDING: Funded by the Alfred Foundation, The Australian Centre for HIV and Hepatitis Virology Research with additional support from the Division of AIDS, National Institute of Allergy and Infectious Disease, US National Institutes of Health (USAI126611). JHM and SRL are supported by the Australian National Health and Medical Research Council.


Assuntos
Anticorpos Monoclonais/química , Anticorpos Anti-HIV/química , Infecções por HIV/diagnóstico por imagem , HIV-1/imunologia , Compostos Radiofarmacêuticos/administração & dosagem , Adulto , Antirretrovirais/uso terapêutico , Anticorpos Monoclonais/imunologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/virologia , Estudos de Casos e Controles , Radioisótopos de Cobre/química , Feminino , Anticorpos Anti-HIV/imunologia , Proteína gp120 do Envelope de HIV/imunologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/isolamento & purificação , HIV-1/metabolismo , Meia-Vida , Humanos , Marcação por Isótopo , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/imunologia , Compostos Radiofarmacêuticos/farmacocinética , Tomografia Computadorizada por Raios X
19.
AIDS Res Hum Retroviruses ; 37(4): 322-328, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33586997

RESUMO

As of January 12, 2021, Australia has reported 28,634 COVID-19 cases. Most (20,411) cases are from the state of Victoria. In response to rising infections and community transmission in July 2020, on August 2nd, several restrictions were imposed for the following 111 days, including an 8pm curfew, a travel restriction to 5 km from home, and closure of nonessential services. It is unknown how this affected people living with HIV (PLHIV), who already experience disproportionate levels of mental health issues, comorbidity, and stigma. An online survey was designed with HIV community-based organizations to investigate the impact of the pandemic on Victorian PLHIV. Participants were recruited voluntarily both through social media and Infectious Diseases clinics at participating hospitals. There were 153 respondents. Most were male (77%), aged between 30 and 60 years (77%), and Australian-born (63%). Forty-three percent, 31%, and 25% reported negative impacts upon personal relationships, employment, and income, respectively. HIV care continued with 95% and 98% being able to access their HIV provider and antiretroviral therapy (ART), respectively. Telehealth was used by 92% and was largely well received. PLHIV reported worry about physical health (68%), mental health (66%), finances (50%),z and accommodation (25%). Fifty percent of participants reported weight gain and 27% increased alcohol intake. This study demonstrated the widespread negative effects of the COVID-19 pandemic on PLHIV in Victoria, although provision of HIV care and ART continued uninterrupted. This highlighted the importance of mental health support and social welfare programs during times of health care and societal strain.


Assuntos
COVID-19/epidemiologia , Infecções por HIV/complicações , Pandemias , Adulto , COVID-19/complicações , COVID-19/virologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/isolamento & purificação , Vitória/epidemiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...