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BACKGROUND: HIV pre-exposure prophylaxis (PrEP) is highly effective in preventing HIV acquisition. To enable routine commissioning of PrEP in England, we aimed to establish population need, duration of need, PrEP uptake, and duration of use in attendees of sexual health services (SHS) in England. METHODS: The Impact Trial was a prospective, open-label, single-arm, multicentre trial conducted at 157 SHS across England between Oct 13, 2017, and July 12, 2020. Clinicians assessed HIV-negative attendees for their risk of HIV acquisition to identify those who were eligible to participate and receive either daily or event-based oral PrEP (tenofovir disoproxil maleate with emtricitabine), as appropriate. Eligible participants were aged 16 years or older, considered HIV-negative on the day of enrolment, and willing to adhere to the trial procedures. Non-trial attendees are mutually exclusive of trial participants and included SHS attendees who were not recruited to the Impact Trial at any point. They include HIV-negative individuals aged 16 years or older who attended a participating SHS at least once after recruitment at that SHS had begun and before Feb 29, 2020. The main outcomes assessed were PrEP need, uptake, and use, and HIV and sexually transmitted infection (STI) incidence. Data are presented up to Feb 29, 2020, before the introduction of COVID-19 control measures. The study is registered with ClinicalTrials.gov, NCT03253757. FINDINGS: In this analysis, we include 21â356 of 24â268 participants enrolled before Feb 29, 2020. 20â403 participants (95·5%) were men who have sex with men (MSM). Uptake of PrEP among SHS attendees clinically assessed and coded as eligible was 21â292 (57·1%) of 37â289. 18â400 trial participants had at least one post-enrolment visit and a median of 361 days of follow-up (IQR 143-638); 14â039 (75·9%) of these had enough PrEP prescribed to provide protection for 75% of their follow-up time. Among MSM, HIV incidence was 0·13 (95% CI 0·08-0·19) per 100 person-years in trial participants (27 seroconversions) and 0·95 (95% CI 0·88-1·03) per 100 person-years in non-trial attendees (587 seroconversions; proportionate reduction of 86·8%, 95% CI 80·2-91·6). 18â607 bacterial STIs were recorded (incidence 68·1 per 100 person-years in trial participants who were MSM). 4343 (24·4%) MSM participants were diagnosed with two or more STIs, accounting for 14â800 (79·5%) of all 18â607 diagnoses. INTERPRETATION: PrEP need was higher than initially estimated by an expert stakeholder group. The high proportion of follow-up time protected by PrEP suggests that the need for protection persisted throughout trial participation for most participants. HIV incidence among MSM trial participants was low. The large unmet need for PrEP suggests that greater provision is required to maximise the potential of a national programme. The high incidence of bacterial STIs among participants, concentrated within a subgroup of PrEP users, presents an opportunity for tailored STI control measures. FUNDING: NHS England.
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Fármacos Anti-VIH , Infecciones por VIH , Profilaxis Pre-Exposición , Minorías Sexuales y de Género , Enfermedades de Transmisión Sexual , Masculino , Humanos , Femenino , Homosexualidad Masculina , Infecciones por VIH/epidemiología , Infecciones por VIH/prevención & control , Infecciones por VIH/diagnóstico , Profilaxis Pre-Exposición/métodos , Fármacos Anti-VIH/uso terapéutico , Estudios Prospectivos , Evaluación de la Tecnología Biomédica , Enfermedades de Transmisión Sexual/epidemiología , Inglaterra/epidemiologíaRESUMEN
Protein stability is fundamental to maintain pharmaceutical efficacy in the nascent field of biologics. One particular property that is essential for therapeutic effect is retention of the folded 3-dimensional conformation, i.e. once unfolding has occurred the biologic is often rendered inactive. In this work we propose a modified form of a recently published UV spectroscopic method that identifies protein unfolding. In this study we determine concentration limits to avoid protein unfolding of two model surfactants, namely polysorbate 20 and polysorbate 80, by correlating surfactant concentration with percentage 'unfolded' for three model proteins. For each scenario two distinct regions were observed, firstly surfactant concentrations at which no unfolding had occurred, followed by a second region whereby unfolding steadily increased with surfactant concentration. In general for the combinations analysed in this study, this second region began to appear around ten times below the critical micellar concentration of each surfactant, regardless of the protein or polysorbate chosen. It is therefore proposed that this adapted method could be used by researchers in the early stages of formulation development as a convenient and simple screening tool to confirm the 'onset of unfolding' concentration for protein-surfactant formulations, thus helping to optimise surfactant concentration selection in pharmaceutical formulations to maintain the benefits of surfactants yet avoid inadvertent unfolding.
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Mathematical models to predict skin permeation tend to be based on animal derived experimental data as well as knowing physicochemical properties of the compound under investigation, such as molecular volume, polarity and lipophilicity. This paper presents a strikingly contrasting model to predict permeability, formed entirely from simple chemical fragment (functional group) data and a recently released, freely accessible human (i.e. non-animal) skin permeation database, known as the 'Human Skin Database - HuskinDB'. Data from within the database allowed development of several fragment-based models, each including a calculable effect for all of the most commonly encountered functional groups present in compounds within the database. The developed models can be applied to predict human skin permeability (logKp) for any compound containing one or more of the functional groups analysed from the dataset with no need to know any other physicochemical properties, solely the type and number of each functional group within the chemical structure itself. This approach simplifies mathematical prediction of permeability for compounds with similar properties to those used in this study.
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Absorción Cutánea , Piel , Animales , Humanos , Piel/metabolismo , Permeabilidad , Modelos Teóricos , Bases de Datos Factuales , Modelos BiológicosRESUMEN
Modern HIV-1 treatment effectively suppresses viral amplification in people living with HIV. However, the persistence of HIV-1 DNA as proviruses integrated into the human genome remains the main barrier to achieving a cure. Next-generation sequencing (NGS) offers increased sensitivity for characterising archived drug resistance mutations (DRMs) in HIV-1 DNA for improved treatment options. In this study, we present an ultra-sensitive targeted PCR assay coupled with NGS and a robust pipeline to characterise HIV-1 DNA DRMs from buffy coat samples. Our evaluation supports the use of this assay for Pan-HIV-1 analyses with reliable detection of DRMs across the HIV-1 Pol region. We propose this assay as a new valuable tool for monitoring archived HIV-1 drug resistance in virologically suppressed individuals, especially in clinical trials investigating novel therapeutic approaches.
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Fármacos Anti-VIH , Infecciones por VIH , Seropositividad para VIH , VIH-1 , Humanos , VIH-1/genética , Infecciones por VIH/tratamiento farmacológico , Genotipo , Farmacorresistencia Viral/genética , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , Antirretrovirales/uso terapéutico , Mutación , Secuenciación de Nucleótidos de Alto RendimientoRESUMEN
Getting to Zero is a commonly cited strategic aim to reduce mortality due to both HIV and avoidable deaths among people with HIV. However, no clear definitions are attached to these aims with regard to what constitutes HIV-related or preventable mortality, and their ambition is limited. This Position Paper presents consensus recommendations to define preventable HIV-related mortality for a pragmatic approach to public health monitoring by use of national HIV surveillance data. These recommendations were informed by a comprehensive literature review and agreed by 42 international experts, including clinicians, public health professionals, researchers, commissioners, and community representatives. By applying the recommendations to 2019 national HIV surveillance data from the UK, we show that 30% of deaths among people with HIV were HIV-related or possibly HIV-related, and at least 63% of these deaths were preventable or potentially preventable. The application of these recommendations by health authorities will ensure consistent monitoring of HIV elimination targets and allow for the identification of inequalities and areas for intervention.
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Infecciones por VIH , Humanos , Consenso , Salud Pública , Personal de SaludRESUMEN
A freely accessible database has recently been released that provides measurements available in the literature on human skin permeation data, known as the 'Human Skin Database - HuskinDB'. Although this database is extremely useful for sourcing permeation data to help with toxicity and efficacy determination, it cannot be beneficial when wishing to consider unlisted, or novel compounds. This study undertakes analysis of the data from within HuskinDB to create a model that predicts permeation for any compound (within the range of properties used to create the model). Using permeability coefficient (Kp) data from within this resource, several models were established for Kp values for compounds of interest by varying the experimental parameters chosen and using standard physicochemical data. Multiple regression analysis facilitated creation of one particularly successful model to predict Kp through human skin based only on three chemical properties. The model transforms the dataset from simply a resource of information to a more beneficial model that can be used to replace permeation testing for a wide range of compounds.
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Absorción Cutánea , Piel , Bases de Datos Factuales , Humanos , Permeabilidad , Piel/metabolismoRESUMEN
Surfactants are used in a vast array of products including pharmaceuticals, cosmetics and household formulations. From an industrial perspective, non-ionic surfactants are ideal for inclusion within such products as they are non-toxic, simple to formulate and economic to use. This study considers five non-ionic surfactants (Tween 20, Tween 80, Crodasol, Croduret and Etocas 35) to determine the critical micellar concentration (CMC) for each using isothermal titration calorimetry, thus avoiding issues regarding poor accuracy found with other techniques. Furthermore, this methodology has not previously been applied to this group of surfactants. For the most commonly used non-ionics (Tween 20 and Tween 80) a further study was undertaken to consider the influence of surfactant purity on the CMC determined, using standard grade (Tween 20 and 80), high purity (Tween 20 HP and Tween 80 HP) and Super Refined (SR PS20 and SR PS80). Results permitted calculation of the CMC for the surfactants whereupon the values were determined to range from 1.0 mM for Tween 20 HP to 2.9 mM for Tween 80 HP. Such information regarding the CMC event is useful from a formulation perspective as it can ensure that the most optimum concentration of surfactant is included within a formulation to maximize its efficacy.
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Polisorbatos , Tensoactivos , Calorimetría/métodos , Excipientes , Micelas , Polisorbatos/química , Tensoactivos/químicaRESUMEN
BACKGROUND: Modeling of the London hepatitis C virus (HCV) epidemic in men who have sex with men (MSM) and are living with human immunodeficiency virus (HIV) suggested that early access to direct-acting antiviral (DAA) treatment may reduce incidence. With high rates of linkage to care, microelimination of HCV within MSM living with HIV may be realistic ahead of 2030 World Health Organization targets. We examined trends in HCV incidence in the pre- and post-DAA eras for MSM living with HIV in London and Brighton, United Kingdom. METHODS: A retrospective cohort study was conducted at 5 HIV clinics in London and Brighton between 2013 and 2018. Each site reported all acute HCV episodes during the study period. Treatment timing data were collected. Incidence rates and reinfection proportion were calculated. RESULTS: A total of.378 acute HCV infections were identified, comprising 292 first infections and 86 reinfections. Incidence rates of acute HCV in MSM living with HIV peaked at 14.57/1000 person-years of follow-up (PYFU; 95% confidence interval [CI], 10.95-18.20) in 2015. Rates fell to 4.63/1000 PYFU (95% CI, 2.60 to 6.67) by 2018. Time from diagnosis to starting treatment declined from 29.8 (2013) to 3.7 months (2018). CONCLUSIONS: We observed a 78% reduction in the incidence of first HCV episode and a 68% reduction in overall HCV incidence since the epidemic peak in 2015, which coincides with wider access to DAAs in England. Further interventions to reduce transmission, including earlier access to treatment and for reinfection, are likely needed for microelimination to be achieved in this population.
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Infecciones por VIH , Hepatitis C Crónica , Hepatitis C , Minorías Sexuales y de Género , Antivirales/uso terapéutico , Inglaterra , VIH , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Hepacivirus , Hepatitis C/tratamiento farmacológico , Hepatitis C/epidemiología , Hepatitis C/prevención & control , Hepatitis C Crónica/tratamiento farmacológico , Homosexualidad Masculina , Humanos , Incidencia , Londres/epidemiología , Masculino , Estudios Retrospectivos , Reino Unido/epidemiologíaRESUMEN
Despite the advantages of transdermal drug delivery (TDD), which makes it a fast-growing area of research in pharmaceutics, numerous challenges affect their development, which limits exploring the full potential of this alternate drug delivery route. In trying to address one of these problems, it is strongly believed that the need for a sustainable skin alternative is paramount. Efforts made in an attempt to provide a sustainable alternative to employing skin in pharmaceutical analysis, by better utilising a polymer membrane, namely poly(dimethylsiloxane), also known as PDMS are discussed. Several combined properties of this polymer, which includes its relative stability in comparison with human skin, make it a good candidate for the replacement of skin. Modifications undertaken to this polymer membrane (to create an enhanced skin mimic for permeation analysis) are discussed and reviewed in this paper, including the improved ability to predict permeability for both hydrophobic and hydrophilic drugs. Optimisations related to studying TDD including limitations encountered are also documented and reviewed. It is hoped that such developments in this field will ultimately lead to researchers replacing skin with optimised polymer-based alternatives to predict transdermal drug delivery.
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Preparaciones Farmacéuticas , Absorción Cutánea , Administración Cutánea , Dimetilpolisiloxanos , Sistemas de Liberación de Medicamentos , Humanos , Permeabilidad , Preparaciones Farmacéuticas/metabolismo , Piel/metabolismoAsunto(s)
COVID-19 , Infecciones por VIH , Estudios de Cohortes , Humanos , Atención Primaria de Salud , SARS-CoV-2 , Reino UnidoRESUMEN
Non-ionic surfactants such as polysorbates, known as Tween™ 20 and Tween™ 80, are routinely used within the healthcare and pharmaceutical industry to enhance solubility. This work focuses on analysing the two aforementioned polysorbates, each considered at three purity levels with four model compounds, across the critical micellar concentration (CMC) range for each surfactant. Such data is of interest to investigate the influence of micelle formation upon compound-polysorbate interaction. Two analytical techniques were utilised, namely spectroscopic solubility determination and micellar liquid chromatography (MLC). In all cases it was apparent that the maximum solubility for all four compounds increased substantially at concentrations greater than the CMC and that, in most cases, a different retention profile was observed using MLC once the CMC had been exceeded. This paper is the first to have used such techniques to investigate the behaviour of these polysorbates over a series of concentrations and three levels of polysorbate purity. The findings indicate that the solubilisation potential of polysorbates differs once the CMC has been surpassed and is dependent upon the level of purity selected, i.e. compound-surfactant interactions are partially a consequence of the presence of micelles rather than monomer as well as polysorbate purity. Thus, formulators should include such polysorbates at optimised concentrations and purity if they wish to maximise their solubilisation potential.
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Micelas , Polisorbatos/química , Acetaminofén/análisis , Benzamidas/análisis , Cromatografía Liquida , Hidrocortisona/análisis , Solubilidad , Tensoactivos/químicaRESUMEN
This work evaluates permeation of 12 model pharmaceutical compounds through a chemically modified form of poly(dimethylsiloxane), whereby the polymer surface had undergone silanization. Standard polymer membrane has been widely used as a simplified skin model to investigate transdermal permeation yet does not fully mimic human skin. The surface chemistry of modified polymer was investigated such as the ability to bind to drugs, hydrophobicity and pore size using optical microscopy, the Brunauer-Emmett-Teller technique and Fourier-transform infrared spectroscopy, followed by permeation analysis with UV spectroscopy. For 11 of the 12 compounds, an appreciable increase in the extent of permeation was observed after 6 h when using the silanized polymer compared with the standard poly(dimethylsiloxane). Furthermore, a correlation was found between the degree of permeation increase and hydrophobicity (logP) of the drug (R2 = 0.90). These findings indicate that permeation can be controlled by modifying the membrane surface, although the hydrophobicity of the permeant also plays a vital role in the extent of permeation observed. This concept study presents a potential alternative membrane for pharmaceutical transdermal analysis, providing many benefits over existing options.
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Dimetilpolisiloxanos , Preparaciones Farmacéuticas , Administración Cutánea , Humanos , Preparaciones Farmacéuticas/metabolismo , Piel/metabolismo , Absorción CutáneaRESUMEN
The extent of human intestinal absorption (HIA) for a drug is considered to be an important pharmacokinetic parameter which must be determined for orally administered drugs. Traditional experimental methods relied upon animal testing and are renowned for being time consuming and expensive as well as being ethically unfavourable. As a result, the development of alternative methods to evaluate a drug's pharmacokinetics is crucial. Micellar liquid chromatography is considered to be one of these methods that can replace the use of animals in the prediction of HIA. In this study, the combination of an aminopropyl column with the biosurfactant sodium deoxycholate bile salt was used in the experimental determination of micelle-water partition coefficients (log Pmw ) for a group of compounds. Multiple linear regression was then used for the prediction of HIA using the experimentally determined log Pmw along with other molecular descriptors, leading to the construction of a model equation of R2 = 85% and a prediction power represented by R2 Pred. = 72%. The use of micellar liquid chromatography with an aminopropyl column in combination with sodium deoxycholate was found to be a good method for the prediction of human intestinal absorption, providing data for a far wider range of compounds compared with previous studies.
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Cromatografía Liquida/métodos , Absorción Intestinal/fisiología , Modelos Biológicos , Ácido Desoxicólico/análisis , Ácido Desoxicólico/química , Ácido Desoxicólico/metabolismo , Humanos , Modelos Lineales , Micelas , Reproducibilidad de los ResultadosRESUMEN
The permeation of ten model drugs through silicone membrane was analysed to investigate the effect of the presence of a biosurfactant obtained from corn steep liquor. The ten selected pharmaceutical compounds were chosen to include a diverse range of physicochemical properties, such as variable hydrophobicities, pKa's, molecular masses and degrees of ionisation. When compared with compound permeation alone, the additional inclusion of biosurfactant in the donor phase altered the rate and extent of permeation. It significantly enhanced permeation for five of the compounds, whereas it decreased permeation for four of the compounds and remained approximately the same for the tenth compound. These effects were observed at both biosurfactant concentrations considered, namely 0.005 mg/mL, i.e. below the critical micellar concentration (CMC) and 0.500 mg/mL, i.e. above the CMC of the biosurfactant. Upon analysing permeation change with respect to physicochemical properties of the compounds, it was determined that compounds with a relative molecular mass below 200 resulted in an increase in permeation with biosurfactant present, and those above 200 resulted in a decrease in permeation with biosurfactant present. This effect was therefore attributed to the formation of a drug-biosurfactant interaction that enhanced permeation of smaller compounds, yet retarded permeation for those with a higher molecular mass. These in vitro findings can be considered an indication of potential novel formulation options that incorporate biosurfactant to create transdermal products that have bespoke permeation profiles.
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Membranas Artificiales , Preparaciones Farmacéuticas/química , Siliconas/química , Tensoactivos/química , Ácido Benzoico , Permeabilidad , Procaína , Triazoles/químicaRESUMEN
The unique character of bile salts to self-assemble into hydrogels in the presence of halide salts was exploited in this work to facilitate the prediction of human intestinal absorption (%HIA) for a set of 25 compounds. This was achieved by firstly incorporating each compound separately within the process of gel formation to create a series of gel-drug membranes. Scanning electron microscopy analysis of the freeze-dried samples of the blank bile salt hydrogels and drug-loaded bile salt hydrogels indicated a unique microstructure made of a network of intertwined fibrils. Drug-loaded sodium deoxycholate hydrogels were then utilized as the donor phase to study permeability using flow-through and static diffusion cells. The resulting values of the release-permeability coefficient (Kp) were then analyzed, along with other molecular descriptors, for the %HIA using multiple linear regression. Overall, when comparing predicted values (using the systems presented in this study) with known literature values, it can be seen that both methods (i.e., using static and flow-through cells) had good predictability with R2PRED values of 79.8% and 79.7%, respectively. This study therefore proposes a novel, accurate, and precise way to predict HIA for compounds of pharmaceutical interest using a simple in vitro permeation system. It is important to develop alternatives to the current methods used in prediction of HIA, which are expensive and time-consuming or include the use of animals. Therefore, the proposed method in this study being economic and time-saving provides superiority over these current methods and suggests the possibility of its use as an alternate to such methods for prediction of HIA.
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Ácidos y Sales Biliares/química , Hidrogeles/química , Absorción Intestinal , Membranas Artificiales , Modelos Biológicos , Preparaciones Farmacéuticas/química , Ácido Desoxicólico/química , Humanos , PermeabilidadRESUMEN
Isothermal titration calorimetry was used to investigate thermodynamic and kinetic binding interactions between 4 clinically relevant drugs: doxorubicin (Dox), irinotecan (Iri), mitoxantrone (Mitox), and topotecan (Topo) and a range of commercially available embolization microspheres. Five drug-eluting beads were chosen to consider the effect of bead size (ranging from 70-150 µm to 500-700 µm) and bead type (sulfonate-modified polyvinylalcohol hydrogel, known commercially as DC BeadM1™, and a sulfonate-modified polyethylene glycol hydrogel bead, known commercially as LifePearl™). The molar ratio of drug to SO3- was found to be 0.9:1, 0.8:1, 0.4:1, and 0.9:1 for Dox, Iri, Mitox, and Topo, respectively. These findings indicate the steric effects of drug shape, charge, and size on binding ability. Four distinct bead sizes all produced drug:bead binding ratios of >0.9:1 doxorubicin:SO3-, thus indicating that bead size does not affect binding stoichiometry. Interestingly, bead size did affect the rate of binding as bead size was found to be indirectly proportional to binding rate. Finally, it was found for the sulfonate-modified polyethylene glycol hydrogel beads that doxorubicin binding was faster (at certain ratios of drug to bead) than that for the sulfonate-modified polyvinylalcohol hydrogel yet was maximal at a drug to bead ratio of only 0.7:1.
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Preparaciones Farmacéuticas/química , Polímeros/química , Calorimetría/métodos , Sistemas de Liberación de Medicamentos/métodos , Hidrogeles/química , Microesferas , Tamaño de la Partícula , Polietilenglicoles/química , Alcohol Polivinílico/químicaRESUMEN
Micellar liquid chromatography is a popular method used in the determination of a compound's lipophilicity. This study describes the use of the obtained micelle-water partition coefficient (log Pmw ) by such a method in the prediction of human intestinal absorption (HIA). As a result of the close resemblance of the novel composition of the micellar mobile phase to that of physiological intestinal fluid, prediction was deemed to be highly successful. The unique micellar mobile phase consisted of a mixed micellar mixture of lecithin and six bile salts, i.e. a composition matching that found in the human intestinal environment, prepared in ratios resembling those in the intestine. This is considered to be the first method to use a physiological mixture of biosurfactants in the prediction of HIA. As a result, a mathematical model with high predictive ability (R2 PRED = 81%) was obtained using multiple linear regression. The micelle-water partition coefficient (log Pmw ) obtained from micellar liquid chromatography was found to be a successful tool for prediction where the final optimum model included log Pmw and polar surface area as key descriptors with high statistical significance for the prediction of HIA. This can be attributed to the nature of the mobile phase used in this study which contains the lecithin-bile salt complex, thus forming a bilayer system and therefore mimicking absorption across the intestinal membrane.