Efficacy and safety of long-acting cabotegravir compared with daily oral tenofovir disoproxil fumarate plus emtricitabine to prevent HIV infection in cisgender men and transgender women who have sex with men 1 year after study unblinding: a secondary analysis of the phase 2b and 3 HPTN 083 randomised controlled trial.

BACKGROUND: Injectable cabotegravir was superior to daily oral tenofovir disoproxil fumarate plus emtricitabine for HIV prevention in two clinical trials. Both trials had the primary aim of establishing the HIV prevention efficacy of long-acting injectable cabotegravir pre-exposure prophylaxis (PrEP) compared with tenofovir disoproxil fumarate plus emtricitabine daily oral PrEP. Long-acting PrEP was associated with diagnostic delays and integrase strand-transfer inhibitor (INSTI) resistance. This report presents findings from the first unblinded year of the HIV Prevention Trials Network (HPTN) 083 study. METHODS: The HPTN 083 randomised controlled trial enrolled HIV-uninfected cisgender men and transgender women at elevated HIV risk who have sex with men, from 43 clinical research sites in Africa, Asia, Latin America, and the USA. Inclusion criteria included: a negative HIV serological test at the screening and study entry, undetectable HIV RNA levels within 14 days of study entry, age 18 years or older, overall good health as determined by clinical and laboratory evaluations, and a creatinine clearance of 60 mL/min or higher. Participants were randomly allocated to receive long-acting injectable cabotegravir or daily oral tenofovir disoproxil fumarate plus emtricitabine PrEP. After study unblinding, participants remained on their original regimen awaiting an extension study. HIV infections were characterised retrospectively at a central laboratory. Here we report the secondary analysis of efficacy and safety for the first unblinded year. The primary outcome was incident HIV infection. Efficacy analyses were done on the modified intention-to-treat population using a Cox regression model. Adverse events were compared across treatment groups and time periods (blinded vs unblinded). This trial is registered with ClinicalTrials.gov, NCT02720094. FINDINGS: Of the 4488 participants who contributed person-time to the blinded analysis, 3290 contributed person-time to the first unblinded year analysis between May 15, 2020, and May 14, 2021. Updated HIV incidence in the blinded phase was 0·41 per 100 person-years for long-acting injectable cabotegravir PrEP and 1·29 per 100 person-years for daily oral tenofovir disoproxil fumarate plus emtricitabine PrEP (hazard ratio [HR] 0·31 [95% CI 0·17-0·58], p=0·0003). HIV incidence in the first unblinded year was 0·82 per 100 person-years for long-acting PrEP and 2·27 per 100 person-years for daily oral PrEP (HR 0·35 [0·18-0·69], p=0·002). Adherence to both study products decreased after study unblinding. Additional infections in the long-acting PrEP group included two with on-time injections; three with one or more delayed injections; two detected with long-acting PrEP reinitiation; and 11 more than 6 months after their last injection. Infection within 6 months of cabotegravir exposure was associated with diagnostic delays and INSTI resistance. Adverse events were generally consistent with previous reports; incident hypertension in the long-acting PrEP group requires further investigation. INTERPRETATION: Long-acting injectable cabotegravir PrEP retained high efficacy for HIV prevention in men and transgender women who have sex with men during the first year of open-label follow-up, with a near-identical HR for HIV risk reduction between long-acting injectable cabotegravir and daily oral tenofovir disoproxil fumarate plus emtricitabine PrEP during the first year after unblinding compared with the blinded period. Extended follow-up further defined the risk period for diagnostic delays and emergence of INSTI resistance. FUNDING: Division of AIDS at the National Institute of Allergy and Infectious Diseases, ViiV Healthcare, and Gilead Sciences.

An organophosphonate strategy for functionalizing silicon photonic biosensors.

Silicon photonic microring resonators have established their potential for label-free and low-cost biosensing applications. However, the long-term performance of this optical sensing platform requires robust surface modification and biofunctionalization. Herein, we demonstrate a conjugation strategy based on an organophosphonate surface coating and vinyl sulfone linker to biofunctionalize silicon resonators for biomolecular sensing. To validate this method, a series of glycans, including carbohydrates and glycoconjugates, were immobilized on divinyl sulfone (DVS)/organophosphonate-modified microrings and used to characterize carbohydrate-protein and norovirus particle interactions. This biofunctional platform was able to orthogonally detect multiple specific carbohydrate-protein interactions simultaneously. Additionally, the platform was capable of reproducible binding after multiple regenerations by high-salt, high-pH, or low-pH solutions and after 1 month storage in ambient conditions. This remarkable stability and durability of the organophosphonate immobilization strategy will facilitate the application of silicon microring resonators in various sensing conditions, prolong their lifetime, and minimize the cost for storage and delivery; these characteristics are requisite for developing biosensors for point-of-care and distributed diagnostics and other biomedical applications. In addition, the platform demonstrated its ability to characterize carbohydrate-mediated host-virus interactions, providing a facile method for discovering new antiviral agents to prevent infectious disease.

Theory-inspired development of organic electro-optic materials.

Correlated time-dependent density functional theory (TDDFT) quantum mechanical and pseudo-atomistic Monte Carlo (PAMC) statistical mechanical methods have been used to assist in the understanding of and to guide the improvement of organic electro-optic (OEO) materials, prepared by electric field poling of pi-electron chromophore-containing materials near their glass transition temperature. Theoretical treatment of the effects of dielectric permittivity and optical frequency on molecular (chromophore) first hyperpolarizabilities has been carried out as well as the analysis of the influence of spatially anisotropic intermolecular electrostatic interactions on the poling-induced noncentrosymmetric order of chromophores. Three classes of OEO materials have been considered in correlated theoretical and experimental investigations: (1) traditional chromophore/polymer composite materials, (2) chromophores covalently incorporated into polymers, dendrimers, and dendronized polymers, and (3) recently discovered materials consisting of chromophores incorporated into chromophore-containing host materials. This latter class of materials is referred to as binary chromophore organic glasses (BCOGs). These BCOGs exhibit exceptional electro-optic activity because of a combination of high chromophore number density, the effect of high dielectric permittivity on molecular first hyperpolarizability, and improved acentric order arising from the intermolecular electrostatic interactions among the two types of chromophores. The electrical conductivity of materials can also influence achievable electro-optic activity, and thin metal oxide buffer layers, introduced to limit charge injection, can significantly improve poling efficiency. Chromophore order can also be influenced, in some cases, by novel processing techniques, such as laser-assisted electric field poling. Thermal and photostability are important parameters for practical application of materials and have been improved dramatically in recent times. Diels-Alder and fluorovinyl ether cycloaddition reactions have been used to elevate final material glass transition temperatures to above 200 degrees C. Photostability is dominated by the photoactivation of singlet oxygen and subsequent attack on electro-optic chromophores. Photostability can be improved by more than 4 orders of magnitude by chromophore modification and material packaging.

Determination of HIV status and identification of incident HIV infections in a large, community-randomized trial: HPTN 071 (PopART).

INTRODUCTION: The HPTN 071 (PopART) trial evaluated the impact of an HIV combination prevention package that included "universal testing and treatment" on HIV incidence in 21 communities in Zambia and South Africa during 2013-2018. The primary study endpoint was based on the results of laboratory-based HIV testing for> 48,000 participants who were followed for up to three years. This report evaluated the performance of HIV assays and algorithms used to determine HIV status and identify incident HIV infections in HPTN 071, and assessed the impact of errors on HIV incidence estimates. METHODS: HIV status was determined using a streamlined, algorithmic approach. A single HIV screening test was performed at centralized laboratories in Zambia and South Africa (all participants, all visits). Additional testing was performed at the HPTN Laboratory Center using antigen/antibody screening tests, a discriminatory test and an HIV RNA test. This testing was performed to investigate cases with discordant test results and confirm incident HIV infections. RESULTS: HIV testing identified 978 seroconverter cases. This included 28 cases where the participant had acute HIV infection at the first HIV-positive visit. Investigations of cases with discordant test results identified cases where there was a participant or sample error (mixups). Seroreverter cases (errors where status changed from HIV infected to HIV uninfected, 0.4% of all cases) were excluded from the primary endpoint analysis. Statistical analysis demonstrated that exclusion of those cases improved the accuracy of HIV incidence estimates. CONCLUSIONS: This report demonstrates that the streamlined, algorithmic approach effectively identified HIV infections in this large cluster-randomized trial. Longitudinal HIV testing (all participants, all visits) and quality control testing provided useful data on the frequency of errors and provided more accurate data for HIV incidence estimates.

Rational enhancement of second-order nonlinearity: bis-(4-methoxyphenyl)hetero-aryl-amino donor-based chromophores: design, synthesis, and electrooptic activity.

Two new highly hyperpolarizable chromophores, based on N,N- bis-(4-methoxyphenyl) aryl-amino donors and phenyl-trifluoromethyl-tricyanofuran (CF3-Ph-TCF) acceptor linked together via pi-conjugation through 2,5-divinylenethienyl moieties as the bridge, have been designed and synthesized successfully for the first time. The aryl moieties on the donor side of the chromophore molecules were varied as to be thiophene and 1-n-hexylpyrrole. The linear and nonlinear optical (NLO) properties of all compounds were evaluated in addition to recording relevant thermal and electrochemical data. The properties of the two new molecules were comparatively studied. These results are critically analyzed along with two other compounds, reported earlier from our laboratories and our collaborator's, that contain (i) aliphatic chain-bearing aniline and (ii) dianisylaniline as donors, keeping the bridge (2,5-divinylenethienyl-), and the acceptor (CF3-Ph-TCF), constant. Trends in theoretically (density functional theory, DFT) predicted, zero-frequency gas-phase hyperpolarizability [beta(0;0,0)] values are shown to be consistent with the trends in beta HRS(-2omega;omega,omega), as measured by Hyper-Rayleigh Scattering (HRS), when corrected to zero-frequency using the two-level model (TLM) approximation. Similarly, trends in poling efficiency data (r33/E(p)) and wavelength dispersion measured by reflection ellipsometry (using a Teng-Man apparatus) and attenuated total reflection (ATR) are found to fit the TLM and DFT predictions. A 3-fold enhancement in bulk nonlinearity (r33) is realized as the donor subunits are changed from alkylaniline to dianisylaminopyrrole donors. The results of these studies provide insight into the complicated effects on molecular hyperpolarizability of substituting heteroaromatic subunits into the donor group structures. These studies also demonstrate that, when frequency dependence and electric-field-induced ordering behavior are correctly accounted for, ab initio DFT generated beta(0;0,0) is effective as a predictor of changes in r33 behavior based on chromophore structure modification. Thus DFT can provide valuable insight into the electronic structure origin of complex optical phenomena in organic media.

Direct electron beam writing of electro-optic polymer microring resonators.

Electro-optic polymer waveguides in electron beam sensitive polymethyl methacrylate (PMMA) polymer matrix doped with organic nonlinear chromophores could be directly patterned by electron beam exposure with high resolution and smoothness. The polymer in the exposed regions was removed with standard electron beam resist developer and without damaging the chromophore containing polymer waveguides. Feature sizes on the order of 100 nm could be clearly resolved. High quality microring resonators made of YL124/PMMA electro-optic polymer were successfully fabricated with this technique. The measured resonance extinction ratios were more than 16 dB and quality factors were in the range of 10(3) approximately 10(4).

Polarization selective electro-optic polymer waveguide devices by direct electron beam writing.

A novel technique for the fabrication of polarization selective electro-optic polymer waveguide devices with direct electron beam writing was described. Birefringence induced by the electric field poling in the electro-optic polymer film was erased in the electron beam exposed regions. The formed waveguides had stronger confinement for the light polarized along the poling direction. High fabrication resolution on the 100 nm scale or smaller could be achieved. Fabrication of polymer polarizer and polarization selective microring resonators with this technique was reported. The highest polarization extinction ratio was measured to be 21.4 dB.

Improved Pulsed Laser Operation with Engineered Nanomaterials.

The power efficiency of a diode-pumped solid state laser was improved by encasing the Nd:YAG lasing medium with gold nanorod-doped epoxy. Gold nanorods were synthesized with a specific aspect ratio tuned to absorb at the Nd:YAG lasing wavelength of 1064 nm. The surfactant-stabilized nanorods in aqueous solution were then treated with a sequential, two-step functionalization in order to improve nanorod solubility in organic solvents. This process required treating the gold nanorods with a thiol-containing polyethylene glycol (PEG) polymer followed by replacing the PEG-SH polymer with a multidentate thiol containing block copolymer synthesized using RAFT synthesis. With a multidentate polymer, the nanorods were soluble in traditional epoxies that could be used to coat the outside of Nd:YAG rods. By absorbing excess lateral 1064 nm emission, the gold nanorod coating attenuates amplified spontaneous emission (ASE), a parasitic, incoherent process that limits power produced by Q-switch laser designs. Laser power increased by nearly 2-fold with addition of the 1064 nm absorbing gold nanorod coating. Gold nanorod epoxy coatings stand out as attractive materials for attenuating ASE by avoiding the fabrication difficulties of samarium oxide ceramics and the photostability limitations of organic dyes.

Nano-engineering lattice dimensionality for a soft matter organic functional material.

A high performing electro-optic (EO) chromophore with covalently attached coumarin-based pendant groups exhibits intermolecular correlation of coumarin units through molecular dynamics (MD) simulations. Unique, orthogonal molecular orientations of the chromophore and coumarin units are also evident when investigated optically. Such molecular orientation translates to reduced lattice dimensionality of the bulk C1 soft matter material system, leading to increased acentric order and EO activity. Results are corroborated by nanorheological experimental methods.

Measuring order in contact-poled organic electrooptic materials with variable-angle polarization-referenced absorption spectroscopy (VAPRAS).

Organic nonlinear electrooptical (ONLO) chromophores must be acentrically ordered for the ONLO material to have electrooptic (EO) activity. The magnitude of the order is characterized by the acentric order parameter, , where ß is the major Euler angle between the main axis of the chromophore and the poling field which imposes the acentric order. The acentric order parameter, which is difficult to measure directly, is related to the centrosymmetric order parameter, defined as = ½(3-1), through the underlying statistical distribution. We have developed a method to determine centrosymmetric order of the ONLO chromophores when the order is low (i.e., < 0.1). We have extended the method (begun by Graf et al. J. Appl. Phys. 1994, 75, 3335.) based on the absorption of light to determine the centrosymmetric order parameter induced by a poling field on a thin film sample of ONLO material. We find that the order parameters, analyzed by two different methods, are similar and also consistent with theoretical estimates from modeling of the system using coarse-grained Monte Carlo statistical mechanical methods.

Reduced dimensionality in organic electro-optic materials: theory and defined order.

Identification of electronic intermolecular electrostatic interactions that can significantly enhance poling-induced order is important to the advancement of the field of organic electro-optics. Here, we demonstrate an example of such improvement achieved through exploitation of the interaction of coumarin pendant groups in chromophore-containing macromolecules. Acentric order enhancement is explained in terms of lattice-symmetry effects, where constraint of orientational degrees of freedom alters the relationship between centrosymmetric and acentric order. We demonstrate both experimentally and theoretically that lattice dimensionality can be defined using the relationship between centrosymmetric order and acentric order. Experimentally: Acentric order is determined by attenuated total reflection measurement of electro-optic activity coupled with hyper-Rayleigh scattering measurement of molecular first hyperpolarizability, and centrosymmetric order is determined by the variable angle polarization referenced absorption spectroscopy method. Theoretically: Order is determined from statistical mechanical models that predict the properties of soft condensed matter.

Modeling the optical behavior of complex organic media: from molecules to materials.

For the past three decades, a full understanding of the electro-optic (EO) effect in amorphous organic media has remained elusive. Calculating a bulk material property from fundamental molecular properties, intermolecular electrostatic forces, and field-induced net acentric dipolar order has proven to be very challenging. Moreover, there has been a gap between ab initio quantum-mechanical (QM) predictions of molecular properties and their experimental verification at the level of bulk materials and devices. This report unifies QM-based estimates of molecular properties with the statistical mechanical interpretation of the order in solid phases of electric-field-poled, amorphous, organic dipolar chromophore-containing materials. By combining interdependent statistical and quantum mechanical methods, bulk material EO properties are predicted. Dipolar order in bulk, amorphous phases of EO materials can be understood in terms of simple coarse-grained force field models when the dielectric properties of the media are taken into account. Parameters used in the statistical mechanical modeling are not adjusted from the QM-based values, yet the agreement with the experimentally determined electro-optic coefficient is excellent.

Theory-guided design and synthesis of multichromophore dendrimers: an analysis of the electro-optic effect.

Extensive experimental and theoretical study suggests that interchromophore electrostatic interactions are among the most severe impediments to the induction and stability of large electro-optic coefficients in electric-field-poled organic materials. In this report, multichromophore-containing dendritic materials have been investigated as a means to minimize unwanted attenuation of nonlinear optical (electro-optic) activity at high chromophore loading. The dendritic molecular architectures employed were designed to provide optimized molecular scaffolding for electric-field-induced molecular reorientation. Design parameters were based upon past experimental results in conjunction with statistical and quantum mechanical modeling. The electro-optic behavior of these materials was evaluated through experimental and theoretical analysis. Experimental data collected from the dendrimer structures depict a reasonably linear relationship between chromophore number density (N) and electro-optic activity (r(33)) demonstrating a deviation from the dipolar frustration that typically limits r(33) in conventional chromophore/polymer composite materials. The observed linear dependence holds at higher chromophore densities than those that have been found to be practical in systems of organic NLO chromophores dispersed in polymer hosts. Theoretical analysis of these results using Monte Carlo modeling reproduces the experimentally observed trends confirming linear dependence of electro-optic activity on N in the dendrimer materials. These results provide new insight into the ordering behavior of EO dendrimers and demonstrate that the frequently observed asymptotic dependence of electro-optic activity on chromophore number density may be overcome through rational design.