A phase I study to assess safety, pharmacokinetics, and pharmacodynamics of a vaginal insert containing tenofovir alafenamide and elvitegravir.

Background: New multi-purpose prevention technology (MPT) products are needed to prevent human immunodeficiency virus (HIV) and herpes simplex virus type 2 (HSV2). In this study, we evaluated a fast-dissolve insert that may be used vaginally or rectally for prevention of infection.

Objective: To describe the safety, acceptability, multi-compartment pharmacokinetics (PK), and modeled pharmacodynamics (PD) after a single vaginal dose of an insert containing tenofovir alafenamide (TAF) and elvitegravir (EVG) in healthy women.

Single-Administration Long-Acting Microarray Patch with Ultrahigh Loading Capacity and Multiple Releases of Thermally Stable Antibodies.

Current antibody (Ab) therapies require development of stable formulations and an optimal delivery system. Here, we present a new strategy to create a single-administration long-lasting Ab-delivery microarray (MA) patch, which can carry high doses of thermally stabilized Abs. The MA fabricated by an additive three-dimensional manufacturing technology can be fully embedded into the skin via a single application to deliver doses of Abs at multiple programmable time points, thus sustaining Ab concentrations in systemic circulation.

Synthesis and Evaluation of Anti-HIV Activity of Mono- and Di-Substituted Phosphonamidate Conjugates of Tenofovir.

The activity of nucleoside and nucleotide analogs as antiviral agents requires phosphorylation by endogenous enzymes. Phosphate-substituted analogs have low bioavailability due to the presence of ionizable negatively-charged groups. To circumvent these limitations, several prodrug approaches have been proposed.

Vaginal Microbiota and Mucosal Pharmacokinetics of Tenofovir in Healthy Women Using a 90-Day Tenofovir/Levonorgestrel Vaginal Ring.

Background: A relationship between the vaginal microbiota and tenofovir (TFV) concentrations and activity after topical administration has been previously reported.

Objective: CONRAD A15-138 was a randomized, placebo-controlled Phase I study aimed at characterizing the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of TFV and levonorgestrel (LNG) administered through a vaginal ring (IVR) for 90 days. Herein, we describe changes from baseline in the vaginal microbiota with IVR use and the impact of the vaginal microbiota on mucosal TFV PK.

Ex Vivo HIV Infection Model of Cervico-Vaginal and Rectal Tissue.

Globally, the most frequent route of HIV transmission is through sexual intercourse. In women, sexual transmission of HIV involves cervical, vaginal, endometrial, and rectal mucosal exposure to the virus. Here we describe technical protocols for ex vivo cervical, vaginal, and rectal tissue infection models and cultures that can be used to assess tissue susceptibility to infection under different conditions as well as the potential antiviral efficacy of a treatment for HIV prevention or cure.

Genital Mucosal Drug Concentrations and anti-HIV Activity in Tenofovir-Based PrEP Products: Intravaginal Ring vs. Oral Administration.

Objective: To describe and compare systemic and local pharmacokinetics (PK) and cervicovaginal (CV) pharmacodynamics (PD) of oral tenofovir disoproxil fumarate (TDF) in combination with emtricitabine (FTC) with tenofovir (TFV) intravaginal ring (IVR).

Design: Phase I, randomized, parallel-group study. Women (n = 22) used TDF/FTC oral tablets daily or TFV IVR continuously and were assessed at baseline and 14 days.

Seminal exosomes and HIV-1 transmission.

Exosomes are endosomal-derived membrane-confined nanovesicles secreted by many (if not all) cell types and isolated from every human bodily fluid examined up to now including plasma, semen, vaginal secretions and breast milk. Exosomes are thought to represent a new player in cell-to-cell communication pathways and immune regulation, and be involved in many physiological and pathological processes. Susceptibility to HIV-1 infection can be impacted by exosomes, while HIV-1 pathogenesis can alter exosomal function and composition.

A MIV-150/zinc acetate gel inhibits SHIV-RT infection in macaque vaginal explants.

To extend our observations that single or repeated application of a gel containing the NNRTI MIV-150 (M) and zinc acetate dihydrate (ZA) in carrageenan (CG) (MZC) inhibits vaginal transmission of simian/human immunodeficiency virus (SHIV)-RT in macaques, we evaluated safety and anti-SHIV-RT activity of MZC and related gel formulations ex vivo in macaque mucosal explants. In addition, safety was further evaluated in human ectocervical explants. The gels did not induce mucosal toxicity.

MIV-150-containing intravaginal rings protect macaque vaginal explants against SHIV-RT infection.

Recent studies demonstrated that intravaginal rings (IVRs) containing 100 mg of the nonnucleoside reverse transcriptase inhibitor (NNRTI) MIV-150 significantly protect macaques against a chimeric simian-human immunodeficiency virus that expresses the HIV-1 HxB2 reverse transcriptase (SHIV-RT) when present before and after vaginal challenge. The objectives of this study were to (i) evaluate the pharmacodynamics (PD) of MIV-150 in vaginal fluids (VF) and in ectocervical and vaginal tissues following 100-mg MIV-150 IVR exposure and to (ii) gain more insight whether pharmacokinetics (PK) of MIV-150 can predict PD. MIV-150 in VF collected at 1 day and 14 days post-MIV-150 IVR insertion inhibited ex vivo SHIV-RT infection in vaginal biopsy specimens from untreated animals (not carrying IVRs) in a dose-dependent manner.

Novel human reovirus isolated from children with acute necrotizing encephalopathy.

For many encephalitis cases, the cause remains unidentified. After 2 children (from the same family) received a diagnosis of acute necrotizing encephalopathy at Centre Hospitalier Universitaire (Tours, France), we attempted to identify the etiologic agent. Because clinical samples from the 2 patients were negative for all pathogens tested, urine and throat swab specimens were added to epithelial cells, and virus isolates detected were characterized by molecular analysis and electron microscopy.