Journals Excerpts of Microbicide & HPV

About HPV
Human papillomavirus (HPV) is a virus from the papillomavirus family that is capable of infecting humans. Like all papillomaviruses, HPVs establish productive infections only in keratinocytes of the skin or mucous membranes.

While the majority of the known types of HPV cause no symptoms in most people, some types can cause warts (verrucae), while others can – in a minority of cases – lead to cancers of the cervix, vulva, vagina, penis, oropharynx and anus. Recently, HPV has been linked with an increased risk of cardiovascular disease.In addition, HPV 16 and 18 infections are strongly associated with an increased odds ratio of developing orophanyngeal cancer.

More than 30 to 40 types of HPV are typically transmitted through sexual contact and infect the anogenital region. Some sexually transmitted HPV types may cause genital warts. Persistent infection with "high-risk" HPV types — different from the ones that cause skin warts — may progress to precancerous lesions and invasive cancer. HPV infection is a cause of nearly all cases of cervical cancer. However, most infections with these types do not cause disease.

Microbicide & HPV
HIV-1, herpes simplex virus type 2 (HSV-2), and human papillomavirus (HPV), among other sexually transmitted infections, represent a major burden for global health. Initial insights into the mucosal transmission of these viral pathogens have raised optimism with regard to the rapid generation of protective vaccines. Nevertheless, setbacks for HIV-1 and HSV-2 vaccines have seriously challenged the initial enthusiasm.

Recently, two new vaccines that efficiently prevented HPV infection have renewed the hope that vaccinal prevention of viral mucosal sexually transmitted infections is possible. HIV-1 and HSV-2 differ from HPV, and each virus needs to be tackled with a distinct approach. However, vaccines are not the only possible answer. Topically applied agents (microbicides) are an attractive alternative in the prevention of HIV-1 and HSV-2 mucosal transmission. Progress in understanding the mechanisms of genital transmission of HIV-1 and HSV-2 is required for successful vaccine or microbicide candidates to emerge from current approaches.
(Vaccines and microbicides preventing HIV-1, HSV-2, and HPV mucosal transmission; Nikolic DS, Piguet V.)

Microbicide & Herpes (2)

Genital herpes is one of the most prevalent sexually transmitted infections worldwide and is the most common cause of genital ulcers. Despite increased public awareness and the initiation of efforts to prevent transmission, the prevalence of herpes simplex virus (HSV) type 2 continues to increase.

What makes HSV so difficult to control is that most sexual and perinatal transmission occurs during unrecognized or asymptomatic shedding. The impact of genital herpes as a public health threat is amplified because of its epidemiological synergy with HIV/AIDS. Thus, there is an urgent need for novel prophylactic methods, such as topical microbicides designed for genital application, to prevent both HSV and HIV transmission.

In summary, genital herpes is a critical global health priority because of its devastating impact on young adults and infants and its association with the HIV/AIDS epidemic. Topical microbicides that block transmission at the mucosal surface may provide a realistic method of intervention for worldwide distribution. Currently, there are several candidate drugs being advanced to clinical trials that block both HSV and HIV infection by inhibiting binding and entry in vitro.

Whether blockade of entry will be sufficient to prevent sexual transmission or whether a combination strategy targeting multiple steps in the viral life cycle will be required is not yet known. Importantly, before embarking on large-scale clinical trials, more extensive evaluation of candidate microbicides, including assessment of the impact on innate defences, is warranted. Assessment of the safety and mucosal response to microbicides should be accrued from several different models including cell and organ cultures, animal models and, most importantly, pilot clinical studies.

((Excerpt of)Topical microbicides for the prevention of genital herpes infection: Marla J. Keller, Ana Tuyama, Maria Josefina Carlucci and Betsy C. Herold)

A topical microbicide that silences two genes can safely protect against genital herpes infection for as long as one week, according to a joint study by researchers at the Albert Einstein College of Medicine of Yeshiva University and Harvard Medical School.

(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.

Looking for a Few Good Microbicides Candidates

Until recently, microbicide discovery was a by-product of the search for anti-HIV drugs. Early in the search for microbicides, for example, attention focused on detergents because of their ability to disrupt HIV’s coat. Most such easily testable candidates, however, failed as microbicides. Now that scientists know more about HIV’s life cycle,
they are beginning to identify multiple points at which the virus could be stopped.

Ideally, a microbicide should be:
• Colorless and odorless
• Inexpensive to manufacture and purchase
• Safe to use more than once a day and for long periods of time
• Effective against multiple STDs, including HIV/AIDS
• Fast-acting, long-lasting, and non-irritating
• Undetectable to either partner
• Available in contraceptive and non-contraceptive forms
• Available without a prescription

In theory, creating an effective topical microbicide should be easy. Simply identify chemicals that kill disease-causing organisms, blend the chemicals with an inert gel or foam, and place it in the vagina. Experience, however, has shown that the simple approach may not work.

The Research Pipeline 
Like a new drug or vaccine, topical microbicide development will follow a pathway—the research pipeline—from basic research to commercial production. The key points along the pipeline are basic research, product formulation and preclinical testing, and clinical testing.

Microbicide actions

Microbicides can act in various ways. Microbicides can be nonspecific, moderately specific or highly (exclusively) specific to HIV. The nonspecific and moderately specific agents are often active against a variety of sexually transmitted microorganisms (e.g., chlamydia and herpesvirus) and may have a contraceptive effect. The HIV-specific agents interact directly with one or several steps of the infection or replication cycle of HIV.

Nonspecific microbicides
The nonspecific microbicides consist of buffering agents and of detergents or surfactants that include nonionic, anionic or cationic compounds. The detergents destroy the viral envelope by solubilizing membrane proteins. However, this nonspecific mechanism of action may also disrupt the cell membranes of the vaginal and cervical epithelium and cause erosions and lesions, leading to an increased risk of HIV infection.

Moderately specific microbicides
Moderately specific microbicides mainly comprise  macromolecular linear anionic polymers. Linear polyanions are active against HIV, HSV and in some cases demonstrate inhibitory activity against human papillomavirus (HPV), Neisseria gonorrhoeae and Chlamydia trachomatis. They block viral entry into cells through electrostatic interactions with the viral envelope proteins and, in some cases, host cell receptors. The lack of potency of linear polyanions for HIV and the ability of semen to further abrogate anti-HIV activity, may in part explain the lack of in vivo efficacy of these microbicides. In addition, adherence to product use and transmission via anal receptive sex, which would not be prevented by a vaginally applied microbicide, are other considerations.

Highly specific anti-HIV agents
HIV-specific microbicides should preferentially block the viral infection cycle before the viral genome gets
incorporated in the target cells as proviral DNA.

Targeting viral entry seems the most promising method, preventing virus particles from entering its susceptible cells and, as shown or expected for most entry inhibitors, also preventing transmission of the virus from virus-infected cells to uninfected cells or transmission of dendritic cell-captured virus to lymphoid cells, or both.

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.

(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). 

(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.