HIV Microbicides Require Safety, Efficacy, Good Marketing

Daniel M. Keller, PhD

October 29, 2013

BRUSSELS, Belgium — Designing a successful topical microbicide against HIV must balance efficacy and toxicity. Microbicides are intended to cut down the risk for transmission of HIV, and they may give a measure of control to people whose partners do not use condoms.

If a product is unpleasant or irritating, people will not use it, and even worse, it could damage sensitive epithelial barriers. "When talking about the vagina and rectum, there is always the possibility of increasing infectivity," said Janneke van de Wijgert, MSc, PhD, of the Institute of Infection and Global Health, at the University of Liverpool, in Liverpool, United Kingdom.

Dr. van de Wijgert explained that the vaginal epithelium consists of multiple layers, whereas the cervical epithelium is a single layer, as are parts of the rectal epithelium. Innate mucosal immunity in each of these areas provides some protection, as do the microbiota. The thinner layers of tissue are more susceptible to invasion and are more vulnerable when less mucus is present (eg, at points in the menstrual cycle and in the rectum). The risk for HIV transmission is greater when the viral load in the infected person is higher. And semen itself can have an effect on the epithelium.

Speaking to a large audience here at a symposium organized by the Combined Highly Active Anti-Retroviral Microbicides (CHAARM) organization on the first day of the 14th European AIDS Conference, Dr. van de Wijgert said the risk of acquiring infection is higher when epithelium is damaged, inflammation is present, the microbiota become unbalanced, or there is other sexually transmitted infection.

She described the results of the Microbicide Safety Biomarkers Study of 430 women having vaginal sex conducted by CHAARM in Rwanda, Kenya, and South Africa to assess normal ranges of vaginal biomarkers in the absence of microbicides. The study also included 202 female sex workers in Rwanda.

In the 2 African populations the researchers identified 5-6 clusters of vaginal microbiome clusters dominated by Lactobacillus crispatus andL iners, as well as 3-4 clusters with intermediate to high loads of mixtures of anaerobes (eg, Gardnerella vaginalis, Atopobium vaginae, Prevotella, Clostridium, Dialister, Megasphaera, Sneathia, Mobiluncus species). In contrast to Europe and the US, these samples contained less L crispatus, more L iners, little L jensenii and L gasseri, and more mixed anaerobes.

New technologies have allowed more precise identification of bacterial species. "We're finding more mixed anaerobe clusters in African women," Dr. van de Wijgert said. Whereas L crispatus appears to be protective, the mixed anaerobe microbiota do not.

In clusters with dominant L crispatus (n = 11), the prevalence of HIV was < 10%, and no bacterial sexually transmitted infections were found. But in clusters of L iners (n = 69) or moderate (n = 35) or high levels (n = 32) of mixed anaerobes, HIV prevalence ranged from about 33% to 57%, and bacterial STI prevalence was about 38% to 60%.

Female sex workers less often had L crispatus and more mixed anaerobes and Escherichia coli. Lactobacilli lowered vaginal pH, hormone use promoted and stabilized lactobacilli, and antibiotic use reduced them.

Higher levels of specific vaginal cytokines were found in association with different bacterial species. Female sex workers, women infected with HIV, and those practicing vaginal sex were more likely to have detectable levels. Inflammatory cytokines were associated with sexual activity.

The researchers found that about 50% of the sex workers and the HIV-positive women used condoms consistently, but other women used them inconsistently or not at all. One behavior of concern is vaginal washing after intercourse, reported by 20% to 60% of women. Washing can remove microbicide and reduce its effectiveness.

Implications for Microbicide Research

The findings led the researchers to conclude that any microbicide should not unbalance the vaginal microbiota, and that microbiome should be a key measure in safety trials. So should epithelial integrity and cytokines as vaginal or rectal products should not cause epithelial disruption or inflammation. Ideally, products may even be designed to stabilize the vaginal and rectal microenvironments, possibly by adding hormones to vaginal products to stabilize lactobacilli while at the same time preventing pregnancy. The behavior of vaginal washing will need to be addressed when promoting microbicides.

Any alteration of the local environment, such as disruptions in the microbiome, vaginosis or vaginitis, and urinary tract or sexually transmitted infections, can throw the system off balance. Similarly, treatment of any 1 can affect the others, so Dr. van de Wijgert advised a holistic approach.

Will People Use Microbicides?

Developing safe and effective microbicides is hard enough, but could you get people to use them? Harriet Langanke, from the German Sexuality and Health Foundation, in Cologne, addressed the question of what people say they want from microbicides and how they could be marketed.

Before becoming an HIV/AIDS activist and journalist with interests in sexual health and women's health issues more than 20 years ago, she worked in marketing and is using that expertise to figure out how to get people to use microbicides.

More than 60 acceptability studies have been conducted around the world in developed and developing countries and involving men and women from a variety of demographic groups using microbicidal gels, films, foaming tablets, and devices. Studies are now being done with microbicidal vaginal rings, which seem to be acceptable in terms of comfort but which still cause users concern about safety.

Gathering anecdotal information from women in Europe and Central Asia, people at risk for or living with HIV, and sex workers, Langanke has found that they want microbicides to be effective, easy to use, easily available, affordable, and safe without unwanted side effects. They said that an effective microbicide should protect against HIV, other sexually transmitted infections, and possibly pregnancy. The effectiveness should extend to both vaginal and anal intercourse and to receptive and insertive sex.

She learned that people want products to be readily available, such as at pharmacies, and should be easily "at hand," as sexual encounters may be spontaneous and not always planned. Packaging could go either of 2 ways — discreet or "sexy." The products should not be overly sensitive to temperature and should have long expiration dates. Some people want more lubrication, some less, and the smell and taste should be pleasant. Women said it would be good if a microbicide could improve their vaginal flora, and that might be accomplished by adding hormones to a product. Finally, some said they would like a product to make them "more sexy."

Usability would depend on the individual and the situation of the sexual encounter. A product would have to ensure that a woman feel safe inserting the device or substance into herself.

Getting public acceptance of any kind of microbicide will require market research focusing on potential users and enlisting the trend-setters in each community along with advocates and others who can multiply the effect.

There was no commercial funding for the studies. The DNA microarray testing of the vaginal microbiome was done by TNO Quality of Life in Zeist, The Netherlands, at reduced cost to the investigators. Dr. van de Wijgert and Ms. Langanke have disclosed no other relevant financial relationships.

European AIDS Clinical Society. 14th European AIDS Conference: No abstracts. Presented October 16, 2013.


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