Vitamin D Status Impacts Genital Mucosal Immunity and Markers of HIV-1 Susceptibility in Women.

While vitamin D insufficiency is known to impact a multitude of health outcomes, including HIV-1, little is known about the role of vitamin D-mediated immune regulation in the female reproductive tract (FRT). We performed a pilot clinical study of 20 women with circulating 25(OH)D levels <62.5 nmol/L. Participants were randomized into either weekly or daily high-dose oral vitamin D supplementation groups. In addition to serum vitamin D levels, genital mucosal endpoints, including soluble mediators, immune cell populations, gene expression, and ex vivo HIV-1 infection, were assessed. While systemic vitamin D levels showed a significant increase following supplementation, these changes translated into modest effects on the cervicovaginal factors studied. Paradoxically, post-supplementation vitamin D levels were decreased in cervicovaginal fluids. Given the strong correlation between vitamin D status and HIV-1 infection and the widespread nature of vitamin D deficiency, further understanding of the role of vitamin D immunoregulation in the female reproductive tract is important.

Multipurpose prevention technologies: products in development.

Multipurpose prevention technologies (MPTs) are broadly defined as products capable of simultaneously addressing multiple sexual and reproductive health needs including unintended pregnancy, STIs including HIV-1, and other reproductive tract infections. MPTs have been discussed for a few decades but little product development has occurred. With the recent proof-of-concept that a topically applied antiretroviral (ARV) can effectively reduce sexual transmission of HIV-1 (tenofovir 1% gel) the impetus to develop MPTs is gaining momentum. Products currently in development are broadly categorized as either long-acting or on-demand. Long-acting MPTs include intravaginal rings (IVRs) and long-acting injectable products. Several IVR MPTs are under development including one designed to release tenofovir to prevent transmission of HIV-1 and levonorgestrel (LNG) to prevent unintended pregnancy over a 90-day period. Another MPT IVR under development is designed to release the ARV dapivirine and LNG for 2 months. Long-acting injectable pre-exposure prophylaxis (PrEP) formulations of rilpivirine (TMC278) and GSK1265744 have entered clinical evaluation and could form the basis of long-acting injectable products for HIV-1 prevention and prevention of unintended pregnancy. On-demand products include TFV 1% gel (HIV-1/HSV-2 prevention), a zinc/carrageenan zinc gel (HIV-1/HSV-2 prevention), and the SILCS diaphragm administered with TFV 1% gel. Significant technical, funding, and regulatory hurdles must be overcome to develop most MPTs; however, the significant reproductive health benefits to many women around the world should provide motivation to overcome these hurdles. This article is based on a presentation at the "Product Development Workshop 2013: HIV and Multipurpose Prevention Technologies", held in Arlington, Virginia on February 21-22, 2013. It forms part of a special supplement to Antiviral Research.

Preclinical evaluation of anti-HIV microbicide products: New models and biomarkers.

A safe and effective microbicide product designed to prevent sexual transmission of HIV-1 rests on a solid foundation provided by the proper selection and preclinical characterization of both its active pharmaceutical ingredient (API) and formulation. The evaluation of API and formulation physicochemical properties, drug release, specific antiviral activity, cell and tissue toxicity, organ toxicity, pharmacokinetics, and pharmacodynamics and efficacy provides information to understand the product, make go/no go decisions in the critical path of product development and complete a regulatory dossier to file an investigational new drug (IND) with the US Food and Drug Administration. Incorporation of new models, assays and biomarkers has expanded our ability to understand the mechanisms of action underlying microbicide toxicity and efficacy, enabling a more rational selection of drug and formulation candidates. This review presents an overview of the models and endpoints used to comprehensively evaluate an anti-HIV microbicide in preclinical development. This article forms part of a special supplement on presentations covering HIV transmission and microbicides, based on the symposium "Trends in Microbicide Formulations", held on 25 and 26 January 2010, Arlington, VA.