RESUMO
BACKGROUND: Despite highly effective HIV preexposure prophylaxis (PrEP) options, no options provide on-demand, nonsystemic, behaviorally congruent PrEP that many desire. A tenofovir-medicated rectal douche before receptive anal intercourse may provide this option. METHODS: Three tenofovir rectal douches-220 mg iso-osmolar product A, 660 mg iso-osmolar product B, and 660 mg hypo-osmolar product C-were studied in 21 HIV-negative men who have sex with men. We sampled blood and colorectal tissue to assess safety, acceptability, pharmacokinetics, and pharmacodynamics. RESULTS: The douches had high acceptability without toxicity. Median plasma tenofovir peak concentrations for all products were several-fold below trough concentrations associated with oral tenofovir disoproxil fumarate (TDF). Median colon tissue mucosal mononuclear cell (MMC) tenofovir-diphosphate concentrations exceeded target concentrations from 1 hour through 3 to 7 days after dosing. For 6-7 days after a single product C dose, MMC tenofovir-diphosphate exceeded concentrations expected with steady-state oral TDF 300 mg on-demand 2-1-1 dosing. Compared to predrug baseline, HIV replication after ex vivo colon tissue HIV challenge demonstrated a concentration-response relationship with 1.9 log10 maximal effect. CONCLUSIONS: All 3 tenofovir douches achieved tissue tenofovir-diphosphate concentrations and colorectal antiviral effect exceeding oral TDF and with lower systemic tenofovir. Tenofovir douches may provide a single-dose, on-demand, behaviorally congruent PrEP option, and warrant continued development. Clinical Trials Registration . NCT02750540.
Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV , Neoplasias Colorretais , Infecções por HIV , Organofosfatos , Profilaxia Pré-Exposição , Minorias Sexuais e de Gênero , Masculino , Humanos , Tenofovir , Infecções por HIV/prevenção & controle , Infecções por HIV/tratamento farmacológico , Emtricitabina , Homossexualidade Masculina , Difosfatos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológicoRESUMO
Expression of viral capsomeres in bacterial systems and subsequent in vitro assembly into virus-like particles is a possible pathway for affordable future vaccines. However, purification is challenging as viral capsomeres show poor binding to chromatography media. In this study, the behavior of capsomeres in unfractionated bacterial lysate was compared with that for purified capsomeres, with or without added microbial DNA, to better understand reasons for poor bioprocess behavior. We show that aggregates or complexes form through the interaction between viral capsomeres and DNA, especially in bacterial lysates rich in contaminating DNA. The formation of these complexes prevents the target protein capsomeres from accessing the pores of chromatography media. We find that protein-DNA interactions can be modulated by controlling the ionic strength of the buffer and that at elevated ionic strengths the protein-DNA complexes dissociate. Capsomeres thus released show enhanced bind-elute behavior on salt-tolerant chromatography media. DNA could therefore be efficiently removed. We believe this is the first report of the use of an optimized salt concentration that dissociates capsomere-DNA complexes yet enables binding to salt-tolerant media. Post purification, assembly experiments indicate that DNA-protein interactions can play a negative role during in vitro assembly, as DNA-protein complexes could not be assembled into virus-like particles, but formed worm-like structures. This study reveals that the control over DNA-protein interaction is a critical consideration during downstream process development for viral vaccines.
Assuntos
Proteínas do Capsídeo , DNA Bacteriano/química , Escherichia coli , Vacinas de Partículas Semelhantes a Vírus , Proteínas do Capsídeo/biossíntese , Proteínas do Capsídeo/química , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/isolamento & purificação , Cromatografia Líquida , Escherichia coli/química , Escherichia coli/genética , Escherichia coli/metabolismo , Vacinas de Partículas Semelhantes a Vírus/biossíntese , Vacinas de Partículas Semelhantes a Vírus/química , Vacinas de Partículas Semelhantes a Vírus/genética , Vacinas de Partículas Semelhantes a Vírus/isolamento & purificaçãoRESUMO
Receptive anal intercourse (RAI) carries a greater per-act risk of HIV acquisition than receptive vaginal intercourse (RVI) and may influence HIV epidemics driven by heterosexual sex. This systematic review explores the association between RAI and incident HIV among women, globally. We searched Embase and Medline through September 2018 for longitudinal studies reporting crude (cRR) or adjusted (aRR) relative risks of HIV acquisition by RAI practice among women. Of 27,563 articles identified, 17 eligible studies were included. We pooled independent study estimates using random-effects models. Women reporting RAI were more likely to acquire HIV than women not reporting RAI (pooled cRR = 1.56 95% CI 1.03-2.38, N = 18, I2 = 72%; pooled aRR = 2.23, 1.01-4.92, N = 5, I2 = 70%). In subgroup analyses the association was lower for women in Africa (pooled cRR = 1.16, N = 13, I2 = 21%) than outside Africa (pooled cRR = 4.10, N = 5, I2 = 79%) and for high-risk (pooled aRR = 1.69, N = 4, I2 = 63%) than general-risk women (pooled aRR = 8.50, N = 1). Interview method slightly influenced cRR estimates (p value = 0.04). In leave-one-out sensitivity analyses pooled estimates were generally robust to removing individual study estimates. Main limitations included poor exposure definition, incomplete adjustment for confounders, particularly condom use, and use of non-confidential interview methods. More and better data are needed to explain differences in risk by world region and risk population. Women require better counselling and greater choice in prevention modalities that are effective during RVI and RAI.
Assuntos
Canal Anal/virologia , Infecções por HIV/epidemiologia , Infecções por HIV/transmissão , Heterossexualidade/estatística & dados numéricos , Sexo Seguro/estatística & dados numéricos , Comportamento Sexual/estatística & dados numéricos , Adulto , Epidemias , Feminino , Infecções por HIV/diagnóstico , Humanos , Incidência , Masculino , Fatores de Risco , Comportamento Sexual/psicologiaRESUMO
HIV is more efficiently acquired during receptive anal intercourse (AI) compared to vaginal intercourse (VI) and may contribute substantially to female sex workers' (FSW) high HIV burden. We aim to determine how common and frequent AI is among FSW globally. We searched PubMed, Embase and PsycINFO for studies reporting the proportion of FSW practising AI (prevalence) and/or the number of AI acts (frequency) worldwide from 01/1980 to 10/2018. We assessed the influence of participant and study characteristics on AI prevalence (e.g. continent, study year and interview method) through sub-group analysis. Of 15,830 identified studies, 131 were included. Nearly all (N = 128) reported AI prevalence and few frequency (N = 13), over various recall periods. Most studies used face-to-face interviews (N = 111). Pooled prevalences varied little by recall period (lifetime: 15.7% 95%CI 12.2-19.3%, N = 30, I2 = 99%; past month: 16.2% 95%CI 10.8-21.6%, N = 18, I2 = 99%). The pooled proportion of FSW reporting < 100% condom use tended to be non-significantly higher during AI compared to during VI (e.g. any unprotected VI: 19.1% 95%CI 1.7-36.4, N = 5 and any unprotected AI: 46.4% 95%CI 9.1-83.6, N = 5 in the past week). Across all study participants, between 2.4 and 15.9% (N = 6) of all intercourse acts (AI and VI) were anal. Neither AI prevalence nor frequency varied substantially by any participant or study characteristics. Although varied, AI among FSW is generally common, inconsistently protected with condoms and practiced sufficiently frequently to contribute substantially to HIV acquisition in this risk group. Interventions to address barriers to condom use are needed.
Assuntos
Canal Anal , Preservativos/estatística & dados numéricos , Infecções por HIV/transmissão , Profissionais do Sexo/estatística & dados numéricos , Comportamento Sexual/estatística & dados numéricos , Coito , Feminino , Infecções por HIV/epidemiologia , Humanos , Prevalência , Fatores de Risco , Sexo Seguro , VaginaRESUMO
"Vaults" are ubiquitously expressed endogenous ribonucleoprotein nanoparticles with potential utility for targeted drug delivery. Here, we show that recombinant human vault nanoparticles are readily engulfed by certain key human peripheral blood mononuclear cells (PBMC), predominately dendritic cells, monocytes/macrophages, and activated T cells. As these cell types are the primary targets for human immunodeficiency virus type 1 (HIV-1) infection, we examined the utility of recombinant human vaults for targeted delivery of antiretroviral drugs. We chemically modified three different antiretroviral drugs, zidovudine, tenofovir, and elvitegravir, for direct conjugation to vaults. Tested in infection assays, drug-conjugated vaults inhibited HIV-1 infection of PBMC with equivalent activity to free drugs, indicating vault delivery and drug release in the cytoplasm of HIV-1-susceptible cells. The ability to deliver functional drugs via vault nanoparticle conjugates suggests their potential utility for targeted drug delivery against HIV-1.
Assuntos
Antirretrovirais/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Infecções por HIV/tratamento farmacológico , Nanopartículas/uso terapêutico , Antirretrovirais/química , Células Cultivadas , Citoplasma/metabolismo , Liberação Controlada de Fármacos , Infecções por HIV/prevenção & controle , HIV-1 , Humanos , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/virologia , Nanopartículas/química , Nanopartículas/metabolismo , RibonucleoproteínasRESUMO
A 48-year-old woman was infected with a vpr-defective human immunodeficiency virus (HIV)-1 molecular clone. Seroconversion was markedly delayed, and without treatment she had durably suppressed viremia and normal T-cell levels. Neutralizing antibody and CD8+ T-cell immune responses against HIV-1 were unremarkable. Viral sequences confirmed the source but evolved defective nef, suggesting an unknown mechanistic link to vpr. There were subtle qualitative defects in T and B cells. To our knowledge, this is the only case of human infection with a characterized defective HIV-1 molecular clone, which furthermore recapitulated live-attenuated vaccination in macaque models of HIV-1 vaccine research.
Assuntos
Vacinas contra a AIDS/imunologia , Produtos do Gene vpr/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Vacinas Atenuadas/imunologia , Linfócitos B/imunologia , Linfócitos T CD8-Positivos/imunologia , Clonagem Molecular , Feminino , Humanos , Pessoa de Meia-Idade , Vacinação/métodosRESUMO
BACKGROUND: Intravaginal rings (IVRs) for HIV pre-exposure prophylaxis (PrEP) theoretically overcome some adherence concerns associated with frequent dosing that can occur with oral or vaginal film/gel regimens. An innovative pod-IVR, composed of an elastomer scaffold that can hold up to 10 polymer-coated drug cores (or "pods"), is distinct from other IVR designs as drug release from each pod can be controlled independently. A pod-IVR has been developed for the delivery of tenofovir (TFV) disoproxil fumarate (TDF) in combination with emtricitabine (FTC), as daily oral TDF-FTC is the only Food and Drug Administration (FDA)-approved regimen for HIV PrEP. A triple combination IVR building on this platform and delivering TDF-FTC along with the antiretroviral (ARV) agent maraviroc (MVC) also is under development. METHODOLOGY AND FINDINGS: This pilot Phase I trial conducted between June 23, 2015, and July 15, 2016, evaluated the safety, pharmacokinetics (PKs), and acceptability of pod-IVRs delivering 3 different ARV regimens: 1) TDF only, 2) TDF-FTC, and 3) TDF-FTC-MVC over 7 d. The crossover, open-label portion of the trial (N = 6) consisted of 7 d of continuous TDF pod-IVR use, a wash-out phase, and 7 d of continuous TDF-FTC pod-IVR use. After a 3-mo pause to evaluate safety and PK of the TDF and TDF-FTC pod-IVRs, TDF-FTC-MVC pod-IVRs (N = 6) were evaluated over 7 d of continuous use. Safety was assessed by adverse events (AEs), colposcopy, and culture-independent analysis of the vaginal microbiome (VMB). Drug and drug metabolite concentrations in plasma, cervicovaginal fluids (CVFs), cervicovaginal lavages (CVLs), and vaginal tissue (VT) biopsies were determined via liquid chromatographic-tandem mass spectrometry (LC-MS/MS). Perceptibility and acceptability were assessed by surveys and interviews. Median participant age was as follows: TDF/TDF-FTC group, 26 y (range 24-35 y), 2 White, 2 Hispanic, and 2 African American; TDF-FTC-MVC group, 24.5 y (range 21-41 y), 3 White, 1 Hispanic, and 2 African American. Reported acceptability was high for all 3 products, and pod-IVR use was confirmed by residual drug levels in used IVRs. There were no serious adverse events (SAEs) during the study. There were 26 AEs reported during TDF/TDF-FTC IVR use (itching, discharge, discomfort), with no differences between TDF alone or in combination with FTC observed. In the TDF-FTC-MVC IVR group, there were 12 AEs (itching, discharge, discomfort) during IVR use regardless of attribution to study product. No epithelial disruption/thinning was seen by colposcopy, and no systematic VMB shifts were observed. Median (IQR) tenofovir diphosphate (TFV-DP) tissue concentrations of 303 (277-938) fmol/10(6) cells (TDF), 289 (110-603) fmol/10(6) cells (TDF-FTC), and 302 (177.1-823.8) fmol/10(6) cells (TDF-FTC-MVC) were sustained for 7 d, exceeding theoretical target concentrations for vaginal HIV prevention. The study's main limitations include the small sample size, short duration (7 d versus 28 d), and the lack of FTC triphosphate measurements in VT biopsies. CONCLUSIONS: An innovative pod-IVR delivery device with 3 different formulations delivering different regimens of ARV drugs vaginally appeared to be safe and acceptable and provided drug concentrations in CVFs and tissues exceeding concentrations achieved by highly protective oral dosing, suggesting that efficacy for vaginal HIV PrEP is achievable. These results show that an alternate, more adherence-independent, longer-acting prevention device based on the only FDA-approved PrEP combination regimen can be advanced to safety and efficacy testing. TRIAL REGISTRATION: ClinicalTrials.gov NCT02431273.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Infecções por HIV/prevenção & controle , HIV-1 , Profilaxia Pré-Exposição/métodos , Administração Intravaginal , Adulto , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/farmacocinética , Dispositivos Anticoncepcionais Femininos , Estudos Cross-Over , Composição de Medicamentos , Sistemas de Liberação de Medicamentos , Emtricitabina/administração & dosagem , Emtricitabina/efeitos adversos , Emtricitabina/farmacocinética , Feminino , Humanos , Maraviroc/administração & dosagem , Maraviroc/efeitos adversos , Maraviroc/farmacocinética , Satisfação do Paciente , Tenofovir/administração & dosagem , Tenofovir/efeitos adversos , Tenofovir/farmacocinética , Adulto JovemRESUMO
BACKGROUND & AIMS: Persistent activation of the inflammatory response contributes to the development of inflammatory bowel diseases, which increase the risk of colorectal cancer. We aimed to identify microRNAs that regulate inflammation during the development of ulcerative colitis (UC) and progression to colitis-associated colon cancer (CAC). METHODS: We performed a quantitative polymerase chain reaction analysis to measure microRNAs in 401 colon specimens from patients with UC, Crohn's disease, irritable bowel syndrome, sporadic colorectal cancer, or CAC, as well as subjects without these disorders (controls); levels were correlated with clinical features and disease activity of patients. Colitis was induced in mice by administration of dextran sodium sulfate (DSS), and carcinogenesis was induced by addition of azoxymethane; some mice also were given an inhibitor of microRNA214 (miR214). RESULTS: A high-throughput functional screen of the human microRNAome found that miR214 regulated the activity of nuclear factor-κB. Higher levels of miR214 were detected in colon tissues from patients with active UC or CAC than from patients with other disorders or controls and correlated with disease progression. Bioinformatic and genome-wide profile analyses showed that miR214 activates an inflammatory response and is amplified through a feedback loop circuit mediated by phosphatase and tensin homolog (PTEN) and PDZ and LIM domain 2 (PDLIM2). Interleukin-6 induced signal transducer and activator of transcription 3 (STAT3)-mediated transcription of miR214. A miR214 chemical inhibitor blocked this circuit and reduced the severity of DSS-induced colitis in mice, as well as the number and size of tumors that formed in mice given azoxymethane and DSS. In fresh colonic biopsy specimens from patients with active UC, the miR214 inhibitor reduced inflammation by increasing levels of PDLIM2 and PTEN. CONCLUSIONS: Interleukin-6 up-regulates STAT3-mediated transcription of miR214 in colon tissues, which reduces levels of PDLIM2 and PTEN, increases phosphorylation of AKT, and activates nuclear factor-κB. The activity of this circuit correlates with disease activity in patients with UC and progression to colorectal cancer.
Assuntos
Biomarcadores Tumorais/metabolismo , Colite Ulcerativa/prevenção & controle , Colo/metabolismo , Neoplasias do Colo/prevenção & controle , MicroRNAs/metabolismo , Terapêutica com RNAi , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Azoximetano , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Linhagem Celular , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/genética , Colite Ulcerativa/metabolismo , Colite Ulcerativa/patologia , Colo/patologia , Neoplasias do Colo/induzido quimicamente , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Sulfato de Dextrana , Modelos Animais de Doenças , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Mediadores da Inflamação/metabolismo , Interleucina-6/metabolismo , Proteínas com Domínio LIM/metabolismo , Camundongos , MicroRNAs/genética , NF-kappa B/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interferência de RNA , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Transcrição Gênica , Transfecção , Células Tumorais CultivadasRESUMO
An applicator designed for rectal delivery of microbicides was tested for acceptability by 95 young men who have sex with men, who self-administered 4 mL of placebo gel prior to receptive anal intercourse over 90 days. Subsequently, 24 of the participants self-administered rectally 4 mL of tenofovir or placebo gel over 7 days using a vaginal applicator, and compared both applicators on a Likert scale of 1-10, with 10 the highest rating. Participants reported high likelihood to use either applicator in the future (mean scores 9.3 and 8.8 respectively, p = ns). Those who tested both liked the vaginal applicator significantly more than the rectal applicator (7.8 vs. 5.2, p = 0.003). Improvements in portability, conspicuousness, aesthetics, tip comfort, product assembly and packaging were suggested for both. This rectal-specific applicator was not superior to a vaginal applicator. While likelihood of future use is reportedly high, factors that decrease acceptability may erode product use over time in clinical trials. Further attention is needed to develop user-friendly, quick-acting rectal microbicide delivery systems.
Assuntos
Anti-Infecciosos Locais/administração & dosagem , Sistemas de Liberação de Medicamentos/instrumentação , Infecções por HIV/prevenção & controle , Homossexualidade Masculina , Aceitação pelo Paciente de Cuidados de Saúde/psicologia , Administração Intravaginal , Administração Retal , Boston , Sistemas de Liberação de Medicamentos/métodos , Géis , Humanos , Entrevistas como Assunto , Masculino , Pennsylvania , Porto Rico , Pesquisa Qualitativa , Fatores SocioeconômicosRESUMO
BACKGROUND: Therapeutic gene transfer is currently being evaluated as a potential therapy for inflammatory bowel disease. This study investigates the safety and therapeutic benefit of a locally administered lentiviral vector encoding murine interleukin-10 in altering the onset and relapse of dextran sodium sulfate induced murine colitis. METHODS: Lentiviral vectors encoding the reporter genes firefly-luciferase and murine interleukin-10 were administered by intrarectal instillation, either once or twice following an ethanol enema to facilitate mucosal uptake, on Days 3 and 20 in Balb/c mice with acute and relapsing colitis induced with dextran sulfate sodium (DSS). DSS colitis was characterized using clinical disease activity, macroscopic, and microscopic scores. Bioluminescence optical imaging analysis was employed to examine mucosal lentiviral vector uptake and transgene expression. Levels of tumor necrosis factor-α and interleukin-6 in homogenates of rectal tissue were measured by ELISA. Biodistribution of the lentiviral vector to other organs was evaluated by real time quantitative PCR. RESULTS: Mucosal delivery of lentiviral vector resulted in significant transduction of colorectal mucosa, as shown by bioluminescence imaging analysis. Lentiviral vector-mediated local expression of interleukin-10 resulted in significantly increased levels of this cytokine, as well as reduced levels of tumor necrosis factor-α and interleukin-6, and significantly reduced the clinical disease activity, macroscopic, and microscopic scores of DSS colitis. Systemic biodistribution of locally instilled lentiviral vector to other organs was not detected. CONCLUSIONS: Topically-delivered lentiviral vectors encoding interleukin-10 safely penetrated local mucosal tissue and had therapeutic benefit in this DSS model of murine colitis.
Assuntos
Colite/terapia , Terapia Genética/métodos , Vetores Genéticos , Interleucina-10/genética , Lentivirus , Administração através da Mucosa , Administração Retal , Animais , Colite/induzido quimicamente , Colite/prevenção & controle , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Técnicas de Transferência de Genes , Camundongos , Camundongos Endogâmicos BALB C , RecidivaRESUMO
We assessed the acceptability of three of over-the-counter products representative of potential rectal microbicide (RM) delivery systems. From 2009 to 2010, 117 HIV-uninfected males (79 %) and females (21 %) who engage in receptive anal intercourse participated in a 6-week randomized crossover acceptability trial. Participants received each of three products (enema, lubricant-filled applicator, suppository) every 2 weeks in a randomized sequence. CASI and T-ACASI scales assessed product acceptability via Likert responses. Factor analysis was used to identify underlying factors measured by each scale. Random effects models were fit to examine age and gender effects on product acceptability. Three underlying factors were identified: Satisfaction with Product Use, Sexual Pleasure, and Ease of Product Use. For acceptability, the applicator ranked highest; however, differences between product acceptability scores were greatest among females and younger participants. These findings indicate that RM delivery systems impact their acceptability and should be considered early in RM development to enhance potential use.
Assuntos
Anti-Infecciosos Locais/administração & dosagem , Anti-Infecciosos Locais/efeitos adversos , Sistemas de Liberação de Medicamentos/métodos , Infecções por HIV/prevenção & controle , Aceitação pelo Paciente de Cuidados de Saúde/psicologia , Reto/efeitos dos fármacos , Administração Retal , Adulto , Estudos Cross-Over , Sistemas de Liberação de Medicamentos/instrumentação , Enema/estatística & dados numéricos , Feminino , Humanos , Lubrificantes/administração & dosagem , Lubrificantes/efeitos adversos , Masculino , Pessoa de Meia-Idade , Reto/química , Comportamento Sexual , Supositórios/administração & dosagem , Supositórios/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND: Use of lubricant products is extremely common during receptive anal intercourse (RAI) yet has not been assessed as a risk for acquisition of sexually transmitted infections (STIs). METHODS: Between 2006 and 2008, a rectal health and behavior study was conducted in Baltimore and Los Angeles as part of the University of California, Los Angeles Microbicide Development Program (NIAID IPCP# #0606414). Participants completed questionnaires, and rectal swabs were tested for Neisseria gonorrhoeae and Chlamydia trachomatis with the Aptima Combo 2 assay, and blood was tested for syphilis (for RPR and TPHA with titer) and HIV. Of those reporting lubricant use and RAI, STI results were available for 380 participants. Univariate and multivariate regressions assessed associations of lubricant use in the past month during RAI with prevalent STIs. RESULTS: Consistent lubricant use during RAI in the past month was reported by 36% (137/380) of participants. Consistent past month lubricant users had a higher prevalence of STI than inconsistent users (9.5% vs. 2.9%; P = 0.006). In a multivariable logistic regression model, testing positive for STI was associated with consistent use of lubricant during RAI in the past month (adjusted odds ratio: 2.98 95% confidence interval: 1.09, 8.15) after controlling for age, gender, study location, HIV status, and numbers of RAI partners in the past month. CONCLUSIONS: Findings suggest some lubricant products may increase vulnerability to STIs. Because of wide use of lubricants and their potential as carrier vehicles for microbicides, further research is essential to clarify if lubricant use poses a public health risk.
Assuntos
Chlamydia trachomatis/isolamento & purificação , Lubrificantes/efeitos adversos , Neisseria gonorrhoeae/isolamento & purificação , Comportamento Sexual/estatística & dados numéricos , Infecções Sexualmente Transmissíveis/epidemiologia , Treponema pallidum/isolamento & purificação , Adolescente , Adulto , Baltimore/epidemiologia , Infecções por Chlamydia/epidemiologia , Feminino , Gonorreia/epidemiologia , Infecções por HIV/epidemiologia , Humanos , Los Angeles/epidemiologia , Masculino , Pessoa de Meia-Idade , Prevalência , Saúde Pública , Medição de Risco , Inquéritos e Questionários , Sífilis/epidemiologia , Adulto JovemRESUMO
Mobile phone social networking applications such as GRINDR are potential tools for recruitment of men who have sex with men (MSM) for HIV prevention research. Demographics and sexual risk behaviors of men recruited through GRINDR and through traditional media were compared. GRINDR participants were younger (mean age 31 vs. 42, p < 0.0001), more White identified (44 vs. 30 %, p < 0.01), and had more sex partners in the previous 14 days (1.88 vs. 1.10, p < 0.05) than other recruits. Email responses were less successful for enrollment than phone calls (5 vs. 50 %). This approach resulted in successful recruitment of younger and more educated, White identified MSM.
Assuntos
Anti-Infecciosos/administração & dosagem , Infecções por HIV/prevenção & controle , Internet , Rede Social , Administração Retal , Humanos , Masculino , Seleção de Pacientes , PesquisaRESUMO
The SARS-CoV-2 infection kinetics in a real-world, clinical setting represent a knowledge gap in understanding the underlying COVID-19 pathogenesis. There are scant reports on the dynamics describing the two principal components of the viral life cycle, namely the rapid proliferation and slower clearance phases. Here, we present results from an ongoing workplace clinical surveillance study where two vaccinated participants became infected with SARS-CoV-2 Omicron variant (BA.1. lineage). The subjects were followed longitudinally at high temporal resolution allowing the kinetics of both viral phases to be characterized. The viral doubling times in the proliferation phase (3.3-3.5 h) and maximum measured viral loads were similar to those observed for unvaccinated individuals infected with an earlier SARS-CoV-2 strain. However, the clearance phase was much shorter in the current study and unexpectedly displayed a multimodal profile. Longitudinal whole genome SARS-CoV-2 sequencing identified a stable mutation that arose in one of the participants over the 2-week period of positivity. Our small study provides a rare insight into the clinical SARS-CoV-2 dynamics holding significance to public health measures and the biology underlying COVID-19.
RESUMO
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection kinetics in a real-world, clinical setting represent a knowledge gap in understanding the underlying coronavirus disease 2019 (COVID-19) pathogenesis. There are scant reports of the dynamics describing the two principal components of the viral life cycle, namely, the rapid proliferation and slower clearance phases. Here, we present results from an ongoing workplace clinical surveillance study during which two vaccinated participants became infected with SARS-CoV-2 Omicron variant (BA.1. lineage). The subjects were followed longitudinally with high temporal resolution, allowing the kinetics of both viral phases to be characterized. The viral doubling times in the proliferation phase (3.3 to 3.5 h) and maximum measured viral loads were similar to those observed for unvaccinated individuals infected with an earlier SARS-CoV-2 strain. However, the clearance phase was much shorter in the current study and unexpectedly displayed a multimodal profile. Longitudinal whole-genome SARS-CoV-2 sequencing identified a stable mutation that arose in one of the participants over the 2-week period of positivity. Our small study provides rare insight into the clinical SARS-CoV-2 dynamics, with significance for public health measures and the biology underlying COVID-19. IMPORTANCE We are conducting an ongoing SARS-CoV-2 workplace clinical study based on frequent, longitudinal disease surveillance of staff and household members. Here, we investigated the viral dynamics in two recently vaccinated participants who became infected with the same Omicron variant of SARS-CoV-2. Because the subjects were enrolled in our study, we were able to track the entire viral life cycle with high temporal resolution, with samples collected every 12 h. Surprisingly, the short viral proliferation phase and maximum viral loads in nasal swab samples were similar to our previous observations with unvaccinated participants and an earlier viral strain. However, the decay phase, indicative of viral clearance, was much shorter here. Our results provide a rare, real-world glimpse of the clinical SARS-CoV-2 replication kinetics, potentially impacting immediate therapies and awareness of earlier and greater transmission potential.
Assuntos
COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/genética , COVID-19/prevenção & controle , Cinética , VacinaçãoRESUMO
Background: A comprehensive understanding of the SARS-CoV-2 infection dynamics and the ensuing host immune responses is needed to explain the pathogenesis as it relates to viral transmission. Knowledge gaps exist surrounding SARS-CoV-2 in vivo kinetics, particularly in the earliest stages after exposure. Methods: An ongoing, workplace clinical surveillance study was used to intensely sample a small cohort longitudinally. Nine study participants who developed COVID-19 between November, 2020 and March, 2021 were monitored at high temporal resolution for three months in terms of viral loads as well as associated inflammatory biomarker and antibody responses. CD8 + T cells targeting SARS-CoV-2 in blood samples from study participants were evaluated. Results: Here we show that the resulting datasets, supported by Bayesian modeling, allowed the underlying kinetic processes to be described, yielding a number of unexpected findings. Early viral replication is rapid (median doubling time, 3.1 h), providing a narrow window between exposure and viral shedding, while the clearance phase is slow and heterogeneous. Host immune responses different widely across participants. Conclusions: Results from our small study give a rare insight into the life-cycle of COVID-19 infection and hold a number of important biological, clinical, and public health implications.
RESUMO
The Combination HIV Antiretroviral Rectal Microbicide-3 (CHARM-03) study was a randomized, open-label, crossover Phase 1 safety and pharmacokinetic (PK) study of oral maraviroc (MVC) and MVC 1% gel. At a single site, healthy HIV-uninfected men and women were enrolled and randomized to an open label crossover sequence of eight consecutive daily exposures to MVC 300 mg dosed orally, MCV 1% gel dosed rectally, and MVC 1% gel dosed vaginally. Male participants received oral and rectal dosing and female participants received oral, rectal, and vaginal dosing. Assessments were undertaken at baseline and following each 8-day period and included collection of plasma, rectal/cervical tissue (CT), and rectal/endocervical/vaginal fluids. Eleven men and nine women were enrolled. Two participants withdrew from the study before receiving study product. There were 25 adverse events, of which 24 were Grade 1 (G1) and one was G2 (unrelated). After eight doses, MVC was quantifiable in all samples following oral, rectal, or vaginal product administration. The highest drug concentrations in plasma, rectal tissue (RT), and CT were associated with oral, rectal, and vaginal drug delivery, respectively. There were significant reductions in tissue drug concentrations when rectal and cervical biopsies were incubated in media before tissue processing for PK (p < .0001). Only oral MVC was associated with limited protection in the rectal explant HIV challenge model (p < .05). There were no immunological changes in RT, and all products were acceptable to participants. In conclusion, all products were found to be safe and acceptable and did not induce local inflammation. The lack of ex vivo efficacy demonstrated in study samples may be due to rapid disassociation of MVC from the explant tissue. ClinicalTrials.gov Identifier: NCT02346084.
Assuntos
Fármacos Anti-HIV , Anti-Infecciosos , Infecções por HIV , Fármacos Anti-HIV/farmacologia , Anti-Infecciosos/uso terapêutico , Antirretrovirais/uso terapêutico , Cicloexanos/efeitos adversos , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/prevenção & controle , Humanos , Masculino , Maraviroc/efeitos adversosRESUMO
BACKGROUND: The objective of this study is to identify the critical formulation parameters controlling distribution and function for the rectal administration of microbicides in humans. Four placebo formulations were designed with a wide range of hydrophilic characteristics (aqueous to lipid) and rheological properties (Newtonian, shear thinning, thermal sensitive and thixotropic). Aqueous formulations using typical polymers to control viscosity were iso-osmotic and buffered to pH 7. Lipid formulations were developed from lipid solvent/lipid gelling agent binary mixtures. Testing included pharmaceutical function and stability as well as in vitro and in vivo toxicity. RESULTS: The aqueous fluid placebo, based on poloxamer, was fluid at room temperature, thickened and became shear thinning at 37°C. The aqueous gel placebo used carbopol as the gelling agent, was shear thinning at room temperature and showed a typical decrease in viscosity with an increase in temperature. The lipid fluid placebo, myristyl myristate in isopropyl myristate, was relatively thin and temperature independent. The lipid gel placebo, glyceryl stearate and PEG-75 stearate in caprylic/capric triglycerides, was also shear thinning at both room temperature and 37°C but with significant time dependency or thixotropy. All formulations showed no rectal irritation in rabbits and were non-toxic using an ex vivo rectal explant model. CONCLUSIONS: Four placebo formulations ranging from fluid to gel in aqueous and lipid formats with a range of rheological properties were developed, tested, scaled-up, manufactured under cGMP conditions and enrolled in a formal stability program. Clinical testing of these formulations as placebos will serve as the basis for further microbicide formulation development with drug-containing products.
RESUMO
Defining tissue and plasma-specific prophylactic drug concentrations is central to pre-exposure prophylaxis product development for sexual transmission of HIV-1. Pharmacokinetic (PK) data from study RMP-02/MTN-006 comparing single dose oral tenofovir disoproxil fumarate with single and multiple dose rectal tenofovir (TFV) gel administration in HIV-1 seronegative adults was used to construct a multicompartment plasma-rectal tissue population PK model for TFV and tenofovir-diphosphate (TFVdp) in plasma and rectal tissue. PK data were collected in five matrices: TFV (plasma, rectal tissue homogenate), TFVdp (peripheral blood mononuclear cells, rectal mononuclear cells (MMCs), rectal tissue homogenate). A viral growth compartment and a delayed effect compartment for p24 antigen expression measured from an ex vivo explant assay described HIV-1 infection and replication. Using a linear PK/pharmacodynamic model, MMC TFVdp levels over 9,000 fmol/million cells in the explant assay provided apparent viral replication suppression down to 1%. Parameters were estimated using NONMEM version 7.4.
Assuntos
Fármacos Anti-HIV/farmacocinética , Infecções por HIV/prevenção & controle , Leucócitos Mononucleares/efeitos dos fármacos , Tenofovir/farmacocinética , Replicação Viral/efeitos dos fármacos , Administração Oral , Administração Retal , Adulto , Idoso , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/farmacologia , Disponibilidade Biológica , Desenvolvimento de Medicamentos/métodos , Feminino , Géis/farmacologia , Géis/uso terapêutico , Proteína do Núcleo p24 do HIV/efeitos dos fármacos , Proteína do Núcleo p24 do HIV/metabolismo , Soronegatividade para HIV/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , Profilaxia Pré-Exposição/métodos , Reto/citologia , Reto/efeitos dos fármacos , Tenofovir/administração & dosagem , Tenofovir/farmacologiaRESUMO
Public health practices and high vaccination rates currently represent the primary interventions for managing the spread of coronavirus disease 2019 (COVID-19). We initiated a clinical study based on frequent, longitudinal workplace disease surveillance to control severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission among employees and their household members. We hypothesized that the study would reduce the economic burden and loss of productivity of both individuals and small businesses resulting from standard isolation methods, while providing new insights into virus-host dynamics. Study participants (27 employees and 27 household members) consented to provide frequent nasal or oral swab samples that were analyzed by reverse transcription-quantitative PCR (RT-qPCR) for SARS-CoV-2 RNA. Two study participants were found to be infected by SARS-CoV-2 during the study. One subject, a household member, was SARS-CoV-2 RNA positive for at least 71 days and had quantifiable serum virus-specific antibody concentrations for over 1 year. One unrelated employee became positive for SARS-CoV-2 RNA over the course of the study but remained asymptomatic, with low associated viral RNA copy numbers, no detectable serum IgM and IgG concentrations, and IgA concentrations that decayed rapidly (half-life: 1.3 days). A COVID-19 infection model was used to predict that without surveillance intervention, up to 7 employees (95% confidence interval [CI] = 3 to 10) would have become infected, with at most 1 of them requiring hospitalization. Our scalable and transferable surveillance plan met its primary objectives and represents a powerful example of an innovative public health initiative dovetailed with scientific discovery. IMPORTANCE The rapid spread of SARS-CoV-2 and the associated COVID-19 has precipitated a global pandemic heavily challenging our social behavior, economy, and health care infrastructure. In the absence of widespread, worldwide access to safe and effective vaccines and therapeutics, public health measures represent a key intervention for curbing the devastating impacts from the pandemic. We are conducting an ongoing clinical study based on frequent, longitudinal workplace disease surveillance to control SARS-CoV-2 transmission among employees and their household members. Our study was successful in surveying the viral and immune response dynamics in two participants with unusual infections: one remained positive for SARS-CoV-2 for 71 days, while the other was asymptomatic, with low associated viral RNA copy numbers. A COVID-19 infection model was used to predict that without surveillance intervention, up to 7 employees would have become infected, with at most 1 of them requiring hospitalization, underscoring the importance of our program.