A Microbicide Candidate Works with the Vagina’s Natural Defenses to Combat HIV
by Chael Needle
LifeGuide [Treatment Horizons]
At the International AIDS Conference in Toronto last August, microbicides continued to garner increased attention. Former President Bill Clinton, UNAIDS’ executive director Peter Piot, Stephen Lewis, and Bill and Melinda Gates were among the bold-face names at the conference to highlight microbicides. And grass-roots activists, like members of the Women’s Leadership Network for Microbicides, and researchers, including Dr. Gita Ramjee, who gave a plenary presentation on microbicides, advocated for microbicide development.
Support from those in the HIV/AIDS research community has been a long time in coming. Part of the reason why microbicides were not front and center, says Dr. Donald P. Waller, PhD, one of the discoverers and subsequent principal investigators of Amphora, a vaginal microbicide candidate, is that many in the scientific community were holding out hope for a vaccine. “In the early days, everyone thought that a [preventative] vaccine would be forthcoming in a very short period of time. It took a long time for the scientific community to recognize that [HIV] is not a normal virus, and that the typical mechanisms to put together a vaccine were not going to work. And so it’s been many years now and we still don’t have an effective vaccine,” notes Waller, a professor of pharmacology and toxicology at the University of Illinois at Chicago who has served as codirector of the Topical Prevention of Conception and Disease (TOPCAD) as well as a consultant for Instead, Inc., developer of Amphora. Some in the scientific community, like Waller, had the foresight to think outside of the vaccine box, and zeroed in on microbicides as a viable way to prevent the spread of HIV, and one that might not involve the kind of puzzle that is vaccine science.
Even if microbicides proved to be less than 100 percent effective, Waller says, there is still an opportunity to create a huge impact in decreasing new cases of HIV. Yet, he says, the field of vaginal topicals has been “extremely ignored for many, many years”—funding and outside enthusiasm from granting agencies and foundations has been sparse. But this has turned around—the concept has increasingly gathered support and the approach is seen as having potential. Waller notes that major pharmaceuticals have shied away from vaginal and rectal microbicides, as they tend to do with any areas of development in which they do not already have a marketed product. And a perceived lack of profit potential keeps Big Pharma away from the microbicide pipeline or, at best, in a wait-and-see holding pattern, says Waller.
But sense, not profit, has seemed to appeal first to microbicide developers. Knowing that women are the fastest-growing group of HIV seroconverters and very often face situations where males do not cooperate in protecting women’s health, developers are motivated to deliver to women a tool to prevent against HIV infection during vaginal intercourse, notes Waller. The rate of mother-to-child HIV transmission would be reduced as well. While microbicides might achieve the highest level of efficacy with the use of male condoms (and Amphora has been shown to be compatible with both latex and polyurethane), Waller thinks that ultimately “the whole microbicide concept empowers women to have some control, [creating a situation] where they can actually protect themselves and therefore have control over whether they might be engaging in risky practices and whether or not the practices they’re engaging in have some reduced risks.”
Addressing the immediate need for easily accessible and inexpensive self-protection has been one of the guiding forces of the makers of Amphora (generic name: Acidform), which has already been approved by the FDA as a personal lubricant. Amphora is the only microbicide candidate approved for human use, albeit for a nonmicrobicidal indication. Instead, Inc., a San Diego-based women’s health company, and former Health and Human Services Secretary Tommy Thompson joined forces to form a new company, Instead Sciences, Inc., last August in order to complete the final stage of clinical trials, product development, and market launch of Amphora in the coming years.
The microbicide candidate hopes to prove its efficacy both as a contraceptive and as a protective against STDs, including HIV. One of Amphora’s working concepts is to maintain as long as possible the natural defenses that already exist in the vagina—the acidity within the vaginal vault that acts as a protective mechanism.
The vagina “is a very, very hostile environment for various things to grow—substances like sperm, in fact, don’t like acidity [because they are alkaline],” reminds Waller, adding that early clinical and preclinical testing has shown that HIV and other STD-causing organisms, like gonococci, herpes, chlamydia, HPV, and HIV, cannot live in acidic environments. The Amphora gel works to help maintain a woman’s natural pH level, between 3.8 and 4.2. “Unfortunately, during things like intercourse and when a woman has a vaginal infection, oftentimes the pH of her vagina is no longer acidic. Semen itself has a very good capacity to neutralize [acidity] and of course that’s a mechanism to allow the sperm to survive and go on and fertilize an egg,” reminds Waller.
Amphora also utilizes bioadhesiveness. “One of the problems with something that’s administered vaginally is to get it distributed and to get it to remain in the vaginal vault. Many products, if placed in the vaginal vault, don’t adhere to the wall. They will fairly quickly be removed. The vaginal vault is actually a collapsed tube with significant pressure, and it will squeeze out most things, like fluids that are put in there. If you think of something like water and you pour it out, it comes out pretty easy and does not stick to the walls of the glass.” The bioadhesive character of Amphora allows the gel to be distributed throughout the entire vaginal wall area and to adhere to the vagina and cervix. In doing so, it creates a protective coating that acts as a physical barrier to organisms—another line of defense along with its acid-buffering property.
Amphora’s potential efficacy to protect against pregnancy goes hand in hand with its potential to protect against STDs. The same hostile environment that Amphora’s mechanism strives to create will kill sperm as well as HIV. “What’s going to be hostile for sperm should also be hostile for HIV and other STDs. If it works good as a spermicide it should work also well for HIV prevention,” theorizes Waller. “There’s no guarantees. There’s lots of things that could happen that might potentially allow either pregnancy or HIV infection to occur. But we think it could work very well.”
Working well, says Waller, might also depend on working with something added to Amphora, agents “which might be more effective and more specific against HIV.” Notes Waller: “I think that even if Amphora itself is not completely effective it might deal a severe blow to HIV, or any other STD, or sperm and then in combination with something that might sweep up and take care of all the ones that might survive...I think it can be leveraged and used even more than just a stand-alone product.”
While Amphora has yet to undergo large-scale clinical testing, its developers are working to put together the infrastructure around the world for study sites, and identifying study candidates. Instead Sciences will first focus on finalizing a six-month contraceptive study showing Amphora’s spermicidal properties, as well as establishing it to be at least as effective as nonoxynol-9, the only topical contraceptive currently approved by the FDA. As Amphora’s development as a contraceptive moves forward, more research will investigate the gel’s microbicidal properties. The research includes a 2007 trial in Madagascar by the U.S. Centers for Disease Control and Prevention, the United States Agency for International Development, Contraceptive Research and Development (CONRAD), and the University of North Carolina at Chapel Hill that will evaluate Amphora’s effectiveness in preventing gonorrhea and chlamydia infections, while also monitoring pregnancy and HIV data.
While proving the efficacy of Amphora as a contraceptive is reasonably simple, says Waller, proving its effectiveness against HIV is challenged by ethical issues and clinical trial design problems. “HIV prevention studies require that all the males who participate in the study have condoms available, and they’re encouraged and counseled to use condoms. So the transmission rate is extremely low. And when you have a very low transmission rate, you have to have larger and larger numbers of participants in the clinical trial to show that it works. With a contraceptive end-point you could find out whether it’s working with a couple of hundred subjects. On the other hand, HIV clinical trials [for prevention]...require four, five, six thousand people in a study. The study cost and requirements go way, way up and become almost impossible....HIV of course could be deadly but pregnancies are also something you want to avoid and it’s difficult to find subjects for these studies in many cases. Another issue, as far as HIV goes, concerns the tendency to recruit among ‘high-risk’ populations and it’s very difficult to find four or five thousand trial participants [who would be good candidates].”
Chael Needle wrote about patients’ knowledge about resistance in the September issue.
October 2006
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