Those Elusive Magic Bullets
By Harrison Wein
When Dr. Sharon Hillier first turned 10 years ago to the challenge of developing a gel or cream that could prevent sexually transmitted diseases like HIV, scientists thought the path to success looked like this: they would find an agent that killed HIV in a test tube, put it in a gel or cream, and it would work just fine. But as work progressed, Hillier explained, "It became clear that that pathway was not so clear."
Hillier, who is a professor in the department of obstetrics, gynecology, and reproductive sciences at the University of Pittsburgh, said the key lies in the complicated ecosystem in what she calls the Secret Garden, a woman's vagina. "I've spent most of my academic life thinking about what grows in the garden and how to keep the garden healthy," she told the audience for a Wednesday afternoon lecture in Masur Auditorium on Jan. 10.
Hillier's search for something that could be used topically to prevent sexually transmitted infections like HIV has been complicated immensely by the complexity of the garden. "The ecosystem, the garden," she said, "differs over a woman's life. The inference from that is that what we'll need in microbicides will also differ over a woman's life." Characteristics like the pH, the types of microbes and the amount of lubrication are among the many things that need to be taken into consideration when designing a topical microbicide.
Hillier showed a slide of Lactobacillus bacteria, cousins of the bacteria that live in yogurt. "I call them the Xena warrior princesses of the vagina," she said, referring to the popular TV show featuring female super heroes, "because they're tall, they're dark, they're beautiful and they're really tough." These bacteria make peroxide and lactic acid, substances that keep the environment in the vagina unfriendly to harmful invaders. But the types of microflora in women's gardens can vary. And disruptions in the garden, like having intercourse or douching, can lead to a whole different set of microflora. Hillier said that "women with Xena" are less likely to acquire HIV or gonorrhea. So while a potential microbicide should kill HIV and other pathogens, it shouldn't kill lactobacilli.
"When we begin to talk about delivery of microbicide into the vagina," Hillier explained, "we need to understand how that microbicide will work in the vagina." To show how difficult it is to develop such a product, she talked about her experiences with nonoxynol-9 (N-9), which was the first topical microbicide they evaluated. N-9 had been shown to protect monkeys from infection by the simian equivalent of HIV, SIV, and seemed to protect monkeys against chlamydia as well. It worked against gonorrhea in the test tube, but then failed against many strains that lived in the vagina. It also caused irritation to the cervix, which could lead to infection by other pathogens.
"It all became quite clear that it was all terribly unclear," Hillier said in describing the problems they encountered in the course of their studies. "Well, you can say it became startlingly clear in a negative sort of way." In the end, they saw no clinical benefit in using N-9 against HIV, gonorrhea or chlamydia. But perhaps more important was the lesson that the microbicidal effects of a compound were highly dependent on both its formulation and how it interacted with the unique ecology of the vagina it was being put into.
There are many things to consider in searching for an effective topical microbicide. A product will have to provide sufficient lubrication because having sex without lubrication can create small tears and increase susceptibility to infection. Aside from the microbicide itself, there are also gelling agents, emulsifiers, buffering agents, preservatives and chelating agents in any given formulation. All of these things could potentially enhance or decrease the activity of the microbicide. Indeed, Hillier found that much of the "other stuff" could be microbicidal too under the right conditions. So absolutely every aspect of a formulation counts when it comes to topical microbicides.
In light of this information, Hillier detailed the breadth of approaches scientists are now using to develop topical microbicides, ranging from agents that kill microbes to compounds that prevent them from attaching to tissue, to tweaking the ecosystem in the garden to help it better protect itself. Hillier said that NIH had funded all of her work in this area and that it plays a crucial role in leading the development of microbicides. But she would still like to see increased funding for the field. She stressed, "All of us need this technology."
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