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

Abstract

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.

Introduction

According to UNAIDS (UNAIDS, 2009) around 33 million people are living with HIV. More than half are women and 2.1 million are children under 15 years of age. In 2008, there were 2.7 million new infections and 2.0 million people died of AIDS. During the same year, 4.0 million infected people in low- and middle-income countries were put on treatment. In spite of the success of this intervention, it is clear that treatment alone is insufficient to stem the tide of the epidemic. To be successful, it is now widely recognized that HIV-1 prevention programs must incorporate biomedical, behavioral, and structural strategies (Horton and Das, 2008, Stover et al., 2002).

Microbicides or topical pre-exposure prophylaxis (PrEP) are a promising biomedical prevention strategy that has recently shown proof-of-concept (Karim et al., 2010). Women who were randomized to use 1% tenofovir gel had 39–50% lower chances of getting infected when compared to those randomized to placebo gel. Adherence to the protocol, application of one dose of gel before and after sex, may have been an important factor in the seemingly lower effectiveness of the gel at 30 months of use when compared to 12 months of use.

Several microbicide candidates have been previously tested with no positive results (Feldblum et al., 2008, Halpern et al., 2008, Karim, 2010, Peterson et al., 2007, Van Damme et al., 2008, Van Damme et al., 2002). Surfactants, polyanions and acid buffers were among those which failed to protect women against HIV-1 infection in clinical trials. Lessons learned from the development and testing of these candidates have led to more stringent criteria to qualify candidates and a reduction of the development pipeline. Antiretroviral compounds are now at the forefront of microbicide/PrEP development (McGowan, 2010, Nuttall et al., 2010). Although they are very potent and specific, some having demonstrated successful viral load reduction in the clinic, they face concerns about genesis of resistance, low bioavailability when applied topically to the genital or rectal mucosa, and possible collision with their use in therapeutics (Mellors, 2010).

There is a clear need to expand the existing pipeline of microbicide candidates with more potent and specific compounds, which display new mechanisms of action and present a high genetic barrier to resistance. Preferably these compounds will not be the same as those in use as therapeutics. Equally important is to develop improved formulations for coitally associated and coitally independent modes of administration. Formulation characteristics will impact a range of microbicide properties from biological activity to acceptability and use. The qualities of an active pharmaceutical ingredient (API) and its formulation will determine the safety, efficacy and acceptability of a microbicide product, and, in conjunction with cultural and behavioral factors, will define the ultimate effectiveness and health impact of this biomedical HIV prevention approach.

Critical to the identification of a successful microbicide product is a rational selection of candidates to be tested in clinical trials through a comprehensive preclinical evaluation algorithm. This algorithm includes assays to characterize physico-chemical (P/C) properties of APIs and formulations, release rates, specific antiviral activity, toxicity, pharmacokinetics, pharmacodynamics and efficacy. Based on an enhanced understanding of mucosal HIV transmission and the challenges faced by microbicides (Hladik and Doncel, 2010), new models, assay endpoints and biomarkers have recently been reported, which provide new insights into the mechanisms underlying microbicide-tissue interaction, safety and efficacy (Cummins and Doncel, 2009, Denton et al., 2008, Lackman-Smith et al., 2008, Mesquita et al., 2009, Parikh et al., 2009, Rohan et al., 2010, Van Herrewege et al., 2006, Watson et al., 2008). Many of these novel studies are not an essential part of the investigational new drug (IND)-enabling pathway. However, they expand our understanding of the mode of action of microbicides, paving the way for improving the next generation of compounds. In this manuscript, we review the preclinical assessment of microbicide candidates, putting the emphasis on new models and biomarkers.

This paper forms part of a group of seven reviews covering presentations from the Trends in Microbicide Formulations Workshop that was held on 25–26 January, 2010 in Arlington, Virginia, USA. The other articles discuss HIV transmission (Hladik and Doncel, 2010), gel, film, and tablet formulations (Garg et al., 2010), intravaginal rings (Malcolm et al., 2010), clinical evaluation of microbicides (Morrow and Hendrix, 2010), dual protection (Friend and Doncel, 2010) and novel approaches to microbicide delivery and safety assessment (Whaley et al., 2010).