An Algorithm for the Preclinical Development of Anti-HIV Topical Microbicides

Robert      W. Buckheit Jr.; Karen      W. Buckheit

Abstract

Throughout the world, and especially in countries comprising the developing world, women are now bearing the brunt of the HIV pandemic, with over 50% living with HIV infection primarily contracted through sexual transmission in monogamous relationships. Thus, effective chemical or physical means of preventing HIV transmission are urgently needed and in the absence of an approved and effective vaccine, microbicides have become the strategy of choice to provide women with the ability to prevent HIV transmission from their infected partners. Topical microbicides include agents specifically developed and formulated for use in either the vaginal or rectal environment to prevent the sexual transmission of infectious organisms, including pathogenic viruses, bacteria and fungi. Although a microbicide product will have many of the same properties as other anti-infective therapeutic agents and would be similarly developed through a defined preclinical program leading to human clinical trials, microbicide development bears its own challenges related to appropriate and informative preclinical investigation, formulation and delivery, and the complex biological environment in which the product must act, as well as the requirement to develop a product that is acceptable to the user. Following years of microbicide development and a series of unsuccessful human clinical trials, a preclinical microbicide development algorithm has been continuously evolving as greater understanding of the required properties of a successful microbicide are defined through laboratory and clinical experience. Herein, we discuss currently accepted practices required for the development of a successful microbicide product which will prevent cell-free and cell-associated virus transmission in the vaginal and rectal vaults.

Keywords: Efficacy, HIV-1, microbicide, pharmacokinetics, preclinical, prevention, toxicity, resistance, AIDS, vaccine