(Excerpts of) A Summary of Preclinical Topical Microbicide Vaginal Safety and Chlamydial Efficacy Evaluations in a Pigtailed Macaque Model

Patton, Dorothy L. PhD; Cosgrove Sweeney, Yvonne T. BA; Paul, Kathleen J. MPH

Background:
The development of topical microbicides represents a new and exciting field in the prevention of sexually transmitted diseases, and it is especially important that candidate products undergo rigorous preclinical safety and efficacy testing before advancing to clinical trials.

Methods:
We have developed a standardized protocol for preclinical vaginal safety and efficacy assessment of topical microbicide candidates in a nonhuman primate model. Over 7 years of funding under an NIH contract, we evaluated a total of 28 test compounds for vaginal safety (via colposcopy, vaginal pH, and microflora) and 9 compounds for efficacy against cervical chlamydial infection. We also outline the specific criteria used to determine which products should move into efficacy trials and which should be recommended for reformulation to the manufacturer.

Results:
Overall, we noted acceptable safety profiles for 24 of 28 candidate products. Common findings included a transient decrease in vaginal pH, petechiae, and mild erythema. Four products were associated with significant adverse colposcopic findings including blisters, epithelial abrasions, and friability; all 4 products were successfully reformulated and showed acceptable safety profiles at lower concentrations. No products showed complete protection against cervical chlamydial infection.

Conclusions:
The macaque preclinical safety and efficacy model is critical to maintaining the pace of topical microbicide development, which could ultimately offer a significant opportunity for intervention in the global HIV/AIDS epidemic.

Overall safety profiles were acceptable in 24 products. Microbiologic findings common to most products included stable populations of H2O2-producing lactobacilli and Viridans streptococci and transient decreases in anaerobic Gram-negative rods.

Microbicide Safety

The development of topical microbicides represents a new and exciting field in the prevention of sexually transmitted diseases, and it is especially important that candidate products undergo rigorous preclinical safety and efficacy testing before advancing to clinical trials.


The physico-chemical and biological properties of active pharmaceutical ingredients (APIs) and their formulations are the foundation of safe, efficacious and acceptable microbicides. Hence, the initial selection of the API and its primary formulation is crucial. Certain undesirable properties of an API can be compensated or masked by an appropriate formulation. However, there is a risk in proceeding with inadequate APIs or formulations, as they may fail later in development, costing more time and money. 

It is important to have a set of criteria that inform Go/No Go decisions prior to entering in clinical trials. This set of criteria is based on API and formulation parameters derived from a comprehensive evaluation of their in vitro P/C properties, drug release rates, specific activity, and cell and tissue toxicity, which in turn represent the base for animal studies focused on organ toxicity/safety, pharmacokinetics (PK), and pharmacodynamics (PD) and efficacy.

A solid preclinical foundation will help navigate clinical testing successfully, ultimately leading to a safe and effective microbicide. In addition to the more classical IND-enabling studies, new models, assays and biomarkers have been developed and adapted to the evaluation of genital and rectal microbicides.

Experience with previous microbicide candidates has led to the inclusion of assays evaluating the impact of genital environmental factors such as low pH, seminal plasma, CV secretions and microflora on microbicide safety and efficacy. Microbicide-induced inflammatory mediators and alteration of innate immunity have also been recently incorporated to the standard testing.

The Future of Microbicide

Topical microbicides are a broad class of agents designed to block or kill infectious microorganisms directly at the site of transmission. With the AIDS pandemic continuing its unrelenting global march (40 million current infections, 14,000 new infections per day) driven largely by sexual transmission, microbicides have moved steadily toward the front line of preventative strategies.

Indeed, many candidate anti-HIV microbicides are currently under development, with several already in clinical trials. A battery of promising protein-based HIV inhibitors can potentially be developed, but they face serious challenges of high production costs and instability during transport and storage.

In a recent issue of PNAS, Rao et al. presented an intriguing version of a “live microbicide” approach whereby a commensal bacterium is engineered to secrete a potent anti-HIV peptide. When administered orally or as a rectal suppository, the bacteria would colonize the gut mucosa and secrete the peptide in situ, thereby providing protection in advance of exposure hopefully for days, weeks, or even months. This delivery mode would be highly advantageous over others requiring repeated topical application before each act of intercourse; also, the engineered bacteria would be relatively simple and inexpensive to manufacture, transport, and store.(An anti-HIV microbicide comes alive; Laurel A. Lagenaur and Edward A. Berger)

An antiretroviral microbicide gel can cut HIV infection in women by more than 50% if used consistently.
Most of the products tested previously as microbicides were either sulphated polysaccharides — which are intended to stop the virus from entering cells — or agents that prevent infection by killing either the virus or cells that carry it.

(The Excerpt of) Potential Impact of Vaginal Microbicides on HIV Risk Among Women with Primary Heterosexual Partners

James M. McMahon, PhD, Associate Professor, Kathleen M. Morrow, PhD, Associate Professor, Margaret Weeks, PhD, Professor, Dianne Morrison-Beedy, PhD, RN, FNAP, WHAP, Professor and Dean, and Amanda Coyle, APRN, Senior Associate

Over the past 2 decades women have increasingly shouldered the burden of the global HIV pandemic (Joint United Nations Programme on HIV/AIDS [UNAIDS], 2004), with the majority of infected women acquiring HIV through sexual contact with a primary male partner (O’Leary, 2000). These trends are the result of multiple factors. Women may be biologically more susceptible to heterosexual transmission of HIV than men, especially via receptive anal intercourse (Boily et al., 2009; Mastro & Kitayaporn, 1998; Padian, Shiboski, & Jewell, 1991). 

In addition, gender-based social inequalities limit women’s options with regard to protective sexual behavior (Higgins, Hoffman, & Dworkin, 2010; Quinn & Overbaugh, 2005; Remien, Halkitis, O’Leary, Wolitski, & Gomez, 2005). Latex condoms, currently the only effective form of barrier protection against HIV, are under the control of men, who often are unwilling to use them, especially in the context of primary relationships (Conley & Collins, 2005).

Vaginal microbicides represent a female-initiated form of barrier and/or chemical protection that can potentially empower women with a means of self-protection. Vaginal microbicides are self-administered chemical compounds, most commonly in the form of a gel, that women can apply intravaginally prior to sexual intercourse to prevent or reduce HIV transmission. Modeling studies indicate that even a partially effective microbicide could have a major impact on the global HIV pandemic (Watts, 2002). 

While it is anticipated that the first generation of vaginalmicrobicides will be less effective at preventing HIV than latex condoms, the enormous potential of this new technology lies in its enhanced acceptability and usability by women. As our experience with the female condom has demonstrated, the importance of the acceptability of any new HIV prevention technology cannot be overstated (Kaler, 2004). It is therefore critically important that the public health sector in the United States prepare for the introduction of commercially available vaginal microbicides (Van de Wijgert & Coggins, 2002). While many American women have expressed a keen interest in vaginal microbicides (Darroch & Frost, 1999), the issues surrounding their acceptability and preference in relation to condom use are complex and have not received adequate attention. One complexity involves the potential reduction of condom use that might result from the introduction and adoption of microbicides.

How microbicide works & its efficacy

How Will They Work?

"Microbicide" is simply a common term put on anything created to prevent contamination by HIV and other sexually transmitted pathogens when applied in the vagina or rectum. Since HIV and STI (sexually transmitted infection) pathogens can attack your body in various ways, an effective microbicide should stop this attack at several stages in the infection process.

Each uses at least one of these five basic mechanisms of steps:
# Eliminating or inactivating pathogens.
Some microbicides work by breaking down the top or envelope of the virus or pathogen.

# Developing physical barriers.
Microbicides could give you a physical barrier between pathogens and vulnerable cells in the epithelium (cell wall) of the vagina or rectum.

# Building up your body's normal defenses.
The body has many naturally sourced immunity process that a microbicide may be able to supplement or boost.
Lactobacillus, for example, is a naturally occurring, "good" bacteria that can help protect the vagina by keeping its acidic environment.
This natural level of acidity allows an inhospitable environment for most pathogens, including HIV.
Therefore, a microbicide that supports the lactobacilli in performing this purpose is one potential procedure of action being explored.

# Inhibiting viral entry.
Some microbicides bind to viruses and bacteria in order to prevent them from binding to and infecting healthy cells.

# Suppressing viral replication.
Some microbicides are being developed from the antiretroviral medicines that HIV-positive people use to reduce the quantity of virus in their bodies.
Designed as gels or creams, these medicines may be able to restrain replication of HIV that enters the vagina or rectum during intercourse.
In that case, they could significantly lower the chances that the microbicide user will become infected or re-infected (if already HIV-positive).
Microbicides may also be combined with physical barriers for higher performance.