Current Topics in Microbiology and Immunology: Microbicides for Prevention of HIV Infection

Abstract

Current Topics in Microbiology and Immunology: Microbicides for Prevention of HIV Infection teaches us that microbicide use has been recorded as early as 1850 bc (in Egypt), during the Middle Ages (Greece and Rome), and since 1918 in its more modern form for vaginal drug delivery. In addition to conveying this fascinating historical timeline, this book offers a detailed review of essentially all aspects of microbicide development, from the basic science underlying microbicide action, to strategic considerations when implementing international microbicide programs. Chapter 1, “Candidate Microbicides and Their Mechanisms of Action,” reviews the human immunodeficiency virus type 1 (HIV-1) viral replication cycle to illustrate the mechanism of action for various microbicides in development. Diagrams of the timeline of mucosal infection by HIV-1 and the steps in the viral replication cycle inhibited by each class of microbicides complement the text nicely. Chapter 2, “Microbicide Dosage Forms,” reviews methods of microbicide drug delivery, such as gels, tablets, rings, electrospun fibers, diaphragms, or films (similar to those currently used to deliver breath fresheners). Delivery methods are either coitally dependent (eg, gels) or independent (eg, rings). This chapter is dense with technical vocabulary describing microbicide product design, and the level of detail may be excessive for readers who are clinicians. The next 2 chapters, “Preclinical Safety Evaluation” and “Clinical Safety and Pharmacology Trial,” describe unique approaches to preclinical and clinical evaluation of microbicides given their local (vs systemic) sites of action. Special considerations include effects on sperm, vaginal microflora, and local inflammatory processes. Drug-specific approaches to evaluating the safety of microbicides are employed, given a surprising lack of standard criteria for evaluating these agents. The utility of using explanted cervical or rectal tissue to evaluate the anti-HIV activity of candidate drugs is discussed. The authors appropriately acknowledge the limitations of explant models, as some agents have been efficacious in explant models but ineffective in randomized human studies. Chapter 5, “Microbicides for Prevention of HIV Infection: Clinical Efficacy Trials,” informs the reader that many disappointing effectiveness studies of candidate microbicides have occurred over the past 20 years. However, in 2010, the CAPRISSA 004 trial of a pericoitally administered, intravaginal tenofovir gel represented a breakthrough in microbicide science. This study demonstrated that tenofovir gel decreased HIV-1 transmission by 39% among women in South Africa, compared with a placebo gel. Two subsequent studies with tenofovir gel tested the efficacy of daily gel use (the VOICE study) or pericoital use (FACTS 001) in African women. Both studies failed to demonstrate efficacy, though low adherence to study drug likely explains the lack of protection in these studies. Clearly, studies to understand ways to optimize microbicide acceptability and adherence are needed. At the start of chapter 6, “Rectal Microbicide Development,” an overview of the immunology and epidemiology associated with rectal transmission of HIV-1 sets the stage for why effective rectal microbicides are needed. Several phase 1 studies with rectally formulated versions of tenofovir gel have been successfully completed, and additional studies are being planned. The need for advocacy to support the development of rectal agents is highlighted, given the stigmatized or criminalized nature of anal sex in many regions of the world. The authors rightly emphasize that “from a human rights perspective, as well as a drug development perspective, there is much to be done.” “Developing Regulatory Strategy for Microbicides” (chapter 7) reviews the complex regulatory barriers to distributing microbicides worldwide. The final chapter, “Preparing for Microbicide Introduction, Rollout, and Sustained Access,” outlines strategies to disseminate new products in resource-limited settings where microbicides are most needed, notably Africa. This rollout process spans numerous disciplines, including social science research, to assess product acceptability and supply chain strategies to ensure sustained community access. The strength of this book is its comprehensive discussion of how microbicides work, how they are developed and tested, and how to distribute them internationally. A weakness is the dense jargon that fills many chapters, which could become onerous for readers without technical training in drug development. Overall, this book is well timed given several promising microbicides that are undergoing clinical studies and could be available for public use in the next several years. This text could be used as a primer for researchers entering the burgeoning field of microbicide development or for clinicians who provide these agents.