Topical Control of HIV Transmission Possible

Image: Courtesy of Karl Malcolm SAFETY RING: This X-ray image depicts the position of the silicone intravaginal ring in vivo. When researchers learned that the spermicide nonoxynol-9 (N9) killed HIV in vitro, they were hoping that they had a cheap, ready-made, effective topical microbicide that women could use to block sexual transmission of HIV. But clinical trials showed that N9 increased vulnerability to HIV infection because it damaged mucosal cells, making the mucous membrane more permeable to the virus.1 This disappointment, however, did not discourage researchers from investigating topical microbicides, which are designed to prevent transmission of bacterial or viral infections; in this case, HIV or other sexually transmitted diseases. Moreover, such products would not be expensive, would be sold over the counter, and women would control their use: The less detectable the microbicide, the better the odds that women will use it. So, researchers turned to other substances and unique methods to develop microbicides. Judging by the size of the pipeline, many scientists have invested a lot of effort. At least 50 topical microbicide candidates are in various stages of investigation, including several first-generation products nearly ready for Phase III clinical trials. These new topical microbicides include carrageenan compounds, the so-called plantibodies, monoclonal antibodies, and modified Lactobacillus bacteria, which is the normal flora found in the adult vaginal tract. Some candidates are in preclinical research, while others are in early clinical trials. Finding potential candidates is not the problem; the difficulty, many note, is ushering these products--most likely targeted for less-developed countries--through large Phase III clinical trials, formulation, production, marketing, and delivery. Topical microbicides allow women to be in control. There is "profound gender inequity. ...Women have no way to protect themselves if their husbands [or] partners refuse to use condoms," remarks George Brown, associate director of health equity at the Rockefeller Foundation in New York. To assist microbicide development, the foundation brought together key players from research, the pharmaceutical industry, international organizations, advocacy groups, and donors in 2000 "to find ways to accelerate the development of safe, effective, and accessible microbicides."2 Last April, the foundation established the International Partnership on Microbicides, in Arlington, Va., with the goal of developing "a product for which there's little profit potential in the developing world," says virologist Zeda Rosenberg, IPM's interim executive director. SAME GOAL, DIFFERENT APPROACHES Functionally, products in development are divided into several groups. There are acid buffers that enhance vaginal defenses by maintaining vaginal pH below 5,3 such as BufferGel™, an aqueous gel that's in Phase II/III clinical trials against HIV in Africa and in Phase II/III contraceptive trials in the United States. Surfactants, such as the now largely discredited N9, attack and destroy the outer surfaces of bacteria and viruses. Entry inhibitors, such as the Population Council's carrageenan-based Carragard™, coat the virus and the vaginal mucosa, thus preventing the virus' entry through the mucous membrane. There are also replication inhibitors, like phosphonyl-methoxypropyl-adenine (PMPA), a reverse transcriptase inhibitor similar in function to other antiretroviral drugs. And newer molecules and methods, including engineered antibodies and bacteria, are under investigation. Selecting molecules for likely microbicides is scientifically driven. Robin Shattock, department of infectious diseases, St. George's Hospital Medical School, London, says "In vivo, people predict that there are two possible mechanisms of HIV infection. One would be localized infection of the cervical mucosa. The other is that these dendritic cells rapidly pick up virus and take them to local lymph nodes." The goal is to protect against both routes of entry. Carrageenan protects because it "is a very large molecule, very negatively charged," says Robin Maguire, program manager for microbicides at the Population Council's center for biomedical research. These large, sulfated polysaccharides block viral adhesion by coating the virus while also covering the vaginal mucosa to form a physical barrier. The Population Council has completed Phase II safety and efficacy studies of Carragard and is preparing for large Phase III studies, Maguire says. New molecules are in earlier phases of study. Shattock is part of an international project, coordinated by John Moore at Cornell University, to evaluate which microbicides are suitable as specific entry inhibitors. The group includes researchers who study primates, and AIDS vaccine researchers. The teams are looking at several other types of molecules, including sulfated polyanions, reverse transcriptase inhibitors, and inhibitors for specific coreceptors. The first molecule the group tried, as proof of principle, was the B12 monoclonal antibody. "In our tissue-based systems ... the monoclonal is very potent at inhibiting infection, and ... it inhibits infection of human cervical tissue. It blocks both infection of the SHIV [simian/human immunodeficiency virus] virus that they use in the macaque model, but also against the HIV virus, as well," notes Shattock. Image: Courtesy of Starpharma Ltd. EXPERIMENTAL DESIGN: An artist's conception of the proposed mechanism by which the dendrimer SPL 7013 (blue) binds to the gp120 binding sites (yellow) on the HIV molecule, preventing its approach to a healthy cell membrane (magenta). PLANT POWER Plantibodies are unique antibody formulations, manufactured in plants genetically engineered to include human antibody genes. EPIcyte Pharmaceuticals, San Diego, Calif., is beginning its plantibody research process for a molecule that targets HIV by first growing maize containing the antibodies gene against human herpes simplex virus-1 (HSV-1) and HSV-2, which can be sexually transmitted. Kevin Whaley, EPIcyte's director of antibody discovery, explains that the antibodies work by blocking adhesion of the pathogen, agglutinating it, and then trapping the virus in the vaginal mucus. Whaley sees plantibodies as a highly economical means of producing large volumes of product. EPIcyte is in the early stages of making four antibodies against the gp120 and gp41 envelope glycoproteins on HIV. Laurel Lagenauer of Osel in San Diego, Calif., is working on a CRADA (cooperative research and development agreement) with the National Institutes of Health to create a unique microbicide that uses a woman's normal flora as the delivery system. They are genetically modifying Lactobacillus, part of the normal vaginal flora, by adding a CD4+ ligand that will attach to the HIV gp120 glycoprotein. The goal is to "recolonize women with the normal bacteria that's modified," says Lagenauer. The advantage of recolonization over topical gels is that "it wouldn't have to be applied every time everyone has intercourse," she says. The Lactobacillus will be engineered to have multivalent binding sites, so binding between the Lactobacillus CD4+ ligand and HIV, says Lagenauer, will be "almost irreversible." The CD4+ ligand was selected because HIV avoids mutating at that binding site, says Lagenauer. "It's not going to mutate to move away." The vagina would need enough modified Lactobacillus for sufficient HIV binding. But the advantage of introducing live bacteria--possibly as a lyophilized pellet--is that they will grow and the colonies will increase once introduced into the vagina. Starpharma Limited in Victoria, Australia, is using an artificial macromolecule called a dendrimer in preclinical studies of a candidate microbicide. Its NIH- funded, in vitro model shows that this large experimental dendrimer, SPL7013, binds to the gp120 glycoprotein in the HIV envelope. Tom McCarthy, Starpharma's development manager, says that this big molecule protected mice and guinea pigs from HSV-2 infection. The company hopes to receive approval from the Food & Drug Administration (FDA) for early clinical trials in 2003. A LORD OF THE RINGS Polymer chemist Karl Malcolm, lecturer in pharmaceutics, Queen's University of Belfast, Northern Ireland, says that generally, the only method of delivery is a gel-based formulation. "They're very messy; they're very difficult to apply to the vagina." Moreover, sex workers in third-world countries may have to apply the gel 10 to 12 times per day, he says. His group's solution is an intravaginal ring made of silicone. The rings, which are in preclinical testing with potent antiviral compounds, can hold material either within their silicone matrix, from which it slowly diffuses, or within a reservoir--a central drug-loaded core covered with a permeable silicone layer. Malcolm's group currently is studying dissolution characteristics of several non-nucleoside reverse transcriptase inhibitors, including PMPA and nevirapine. Malcolm, who jokingly refers to himself as "lord of the rings," says that the ring could be combined with contraceptive steroids, giving it a multiple purpose. Another advantage of the ring: the woman can insert and remove it without medical intervention. Similar rings have received FDA approval for hormone replacement therapy. Men who have sex with men also would benefit from microbicides, but achieving this protection will be more difficult. The vagina, notes Shattock, is "closed off at one end by the cervix. If you're talking about rectal sex, you just don't know how much of an area you need to protect. You may need a much larger volume of a product or [be] thinking about a product in much different ways." EPIcyte's Whaley is doing the latter. "You could have access to the rectum via the oral route. Antibodies that people do ingest by mouth actually do end up in feces." IPM's Rosenberg sees the first-generation products poised for Phase III clinical trials by mid-2003 to 2004. "When we say we would like to see a product on the market by the end of this decade, I think this is exactly right." Myrna Watanabe is a freelance writer in Patterson, NY. References 1. World Health Organization, "WHO/CONRAD technical consultation on nonoxynol-9, summary report," June 25, 2002, available online at www.who.int/reproductive-health/rtis/index.htm. 2. The Rockefeller Foundation, "Mobilization for microbicides: The decisive decade," The Rockefeller Foundation Microbicide Initiative, 2000, available online at www.rockfound.org. 3. "Prevention technology: An overview of microbicide development," available online at www.aidsmap.com/web/pb1/eng/F163CA49-DB88-4451-A0D6-8C3FBF4504CB.htm.

Topical Control of HIV Transmission Possible

Nov 10, 2002

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Image: Courtesy of Karl Malcolm
SAFETY RING: This X-ray image depicts the position of the silicone intravaginal ring in vivo.