Why Microbicide Development Must Progress Quickly
Unprotected sex with an HIV-positive man is by far the leading cause of HIV infection among women, and the result is that more women than men are now getting infected with HIV annually.
According to government estimates, by 2010 at least half of all Americans infected with HIV will be women. Currently, UNAIDS estimates that 33.6 million people are either infected with HIV or have AIDS.
"This rapid feminization of HIV clearly speaks to the consequences of relying on condoms as virtually our only HIV prevention tool," says Anna Forbes, U.S. field organizer for the Alliance for Microbicide Development.
Studies have also demonstrated that co-infection with HIV and other STDs make an HIV-positive person more capable of transmitting HIV and other STDs. Additionally, sores, lesions and inflammations caused by STDs compromise certain physical barriers to disease.
For these reasons, taking measures to prevent STD transmission is critical for all women, regardless of HIV status.
A Word About Protection
According to studies, heterosexuals consistently use condoms 20 percent of the time or less. Serodiscordant couples and commercial sex workers are the only studied populations that report using condoms during sex at least half of the time. Many people, especially in developed nations, think of STDs as minor embarrassments that can be treated with antibiotics. In many cases this is true, albeit far less true for those who are HIV positive.
Contagious germs (also called microbes) cause STDs (also called pathogens). Among human papilloma virus (HPV), herpes and HIV, for example, the microbe can't be cleared from the body (cured) as it can with other STDs.
"If regular condom use is low among women of wealthy nations -- where a higher proportion of women and men would presumably have the economic and social agency to refuse unprotected sex -- it is hardly surprising that millions of woman globally simply do not or cannot insist that their partners wear condoms," said Anna Forbes.
It is each woman's responsibility to decide whether to protect herself and to learn how to do so. In scenarios involving domestic violence or rape, however, women are not in a position to negotiate "safer sex" or condom use.
In many cultures, childbearing is directly linked to a person's self worth, and the prospect of childlessness may outweigh the risk of HIV infection. Social factors such as domestic violence, rape and attitudes about parenthood cannot be ignored. Unfortunately, because social norms generally reflect woman's secondary status, women don't always make choices that are in their best interest.
Just as the Pill revolutionized women's ability to avoid unplanned pregnancy, microbicides have the potential to provide women with an equal amount of control with regard to protection from STDs. Microbicides can be used with or without condoms, so they could be formulated with or without spermicide to allow for or to prevent pregnancy.
Microbicides leave protection firmly in the grasp of women, and act as a secret aid in women's quest to obtain and maintain sexual health.
Not Under Some Women's Control
In Africa, the region with the greatest need, women are constrained from controlling their reproductive and sexual health. This was illustrated by Flavia Ndikuno, a Ugandan member of the International Community of Women Living with HIV/AIDS when she stated that male partners consider women who use protection to be "non-obedient." In African societies, where men are often polygamous, the "non-obedient" wife can be deprived of her children. In negotiating safer sex, the threat of the loss of one's children is definitely a trump card.
"In some parts of the world, women can be at risk of violence or abandonment if they try to negotiate safer sex," says Dr. Mathilde Krim, Founding Co-Chair and Chairman of the Board of the American Foundation for AIDS Research (amfAR). "This fact makes it imperative that we develop more methods to prevent infection, especially methods that put women in control. Microbicides would do just that." Microbicides can be used without a male partner's knowledge or consent.
Microbicide usage would not require women to admit to their partner(s) that they consider themselves at risk. The biggest selling point over condoms, however, is that microbicides allow for skin-to-skin contact.
While some consideration should be given to the role of microbicides during anal sex, most research insinuates that this is an issue of primary interest to gay men. Since this is not the case, while we need to advocate for vaginal microbicides, we also need to push for studies involving HIV protection during anal sex.
What Are Microbicides?
Simply stated, a microbicide is any agent that kills or deactivates disease-causing microbes. According to the International Association of Physicians in AIDS CARE (IAPAC), the definition of microbicides also includes "therapeutic interventions that can block or prevent infection, as well as amplification of the body's natural defenses to prevent infection through sexual acts." Researchers are currently studying substances that may:
Kill or otherwise immobilize STD pathogens
Block infection by creating a barrier between the pathogen and the vagina (and possibly the rectum)
Prevent the infection from taking hold after it has entered the body by fortifying innate immune defenses
Scientists are working on products that would combine these agents, making them stronger and more likely to prevent disease transmission. Sixty-four compounds are in some phase of development, and 20 additional compounds are ready for human safety trials.
Out of all of the products currently being researched, only Nonoxynol-9 (N-9) has been approved. Nonoxynol-9 is marketed as a spermicide (an agent that neutralizes sperm thereby preventing pregnancy) under the trade name Advantage S. Oddly, it appears to be the least effective product of all, and has been seen as actually creating an environment that AIDS HIV transmission.
As newly infected HIV-positive women outnumber newly infected men worldwide, the need for female-controlled protection is becoming more obvious, and dire. "After 10 years of being nice about this, I think it's time we start acting up," said Lori Heise of the Global Campaign for Women-Controlled Prevention Alternatives at a meeting on microbicides at the 13th International AIDS Conference. "With the current state of the art, it is likely that we will have a microbicide before we will have a vaccine (against HIV)," said UNAIDS Director Peter Piot at the Microbicides 2000 conference last March. Health advocates have long sought unobtrusive means by which women could control their own health. "Microbicides are the theoretical Holy Grail of this quest for female-controlled protection," said Bob Rohr of IAPAC.
In the future, some microbicides may be developed in other formulations such as a mouth rinse for protection during oral sex, a vaginal wash that can be used by HIV-positive women prior to childbirth as a low-cost way of reducing risk of perinatal transmission, and applications for post-coital use to reduce risk of infection after forced sex or condom failure.
As better microbicides are developed, they will be designed to be "bi-directional." Use of a vaginal microbicide will protect a woman's partner by inactivating HIV in vaginal secretions; as well as protect a woman from HIV in her partner's semen.
What Is the "Perfect Microbicide"?
When one considers the daunting task of developing effective and safe microbicides, a number of issues come into play. STDs are not all transmitted by the same pathogen. There are many microbes that the product will have to have the capability of defending the body against.
Researchers says that the ideal microbicide will have to withstand varying temperatures and also function within varied pH ranges (ranges of alkaline and acidic levels in the vagina). In addition, it could not kill the natural beneficial lactobacilli that reside in the vagina and regulate vaginal health. Lastly, it would have to be strategically marketed.
Women are going to have to want to put this product into their vaginas. "The ideal would be a microbicide that is safe and effective against HIV and other sexually transmitted infections," said Awa Coll-Seck, M.D., director of policy, strategy and research at UNAIDS. "That allows women to become pregnant if she want to, and is active as soon as it is applied and for a long time afterwards." The vagina maintains its health by using bacteria, the immune system and pH levels to monitor and protect itself against pathogens.
The epithelium is membranous cellular tissue that covers a free surface or lines a tube or cavity of an animal body and serves especially to enclose and protect the other parts of the body, to produce secretions and excretions and to function in assimilation.
"Vaginal and cervical mucosa and epithelium are major barriers to infection," said Preston Marx, M.D., of the Aaron Diamond AIDS Research Center. "They reduce risk of infection about a thousand-fold compared with direct injection exposure to a pathogen."
"Vaginal flora actually alters the vaginal inflammatory response," said Sharon Hiller, M.D., a researcher at the University of Pittsburgh. "Not only are the organisms interacting with the pathogen, they are interacting with the host in altering the immune function. When we talk about putting products in the vagina, we should maintain the pH and the flora because that preserves both the pH and the epithelium."
Cytokines are a class of immunoregulatory substances that are secreted by cells of the immune system. One of these is CCR5, a chemokine which is also a co-receptor of HIV. When the vagina is unbalanced, the body sends cytokines to the area to restore the natural balance and to rid the body of microbes. Because CCR5 actually works with HIV, the presence of a STD can pave the way for HIV transmission because of the influx of CCR5 to the area.
"Cytokine expression increases with bacterial vaginosis, human papilloma virus (HPV) and chlamydial infection [by] offering more targets on the cell surface by which to enter," said Kenneth Mayer, M.D., of Brown University.
Bacterial vaginosis eliminates the lactobacillus bacteria in the vagina. As these bacteria are largely responsible for the acidic environment, this leaves a woman susceptible to infection because HIV is rendered unstable in a highly acidic environment.
In development now are some products that may fit the bill.
Antibiotic peptides are small protein molecules that form part of the body's first line of defense against infection. These peptides line every surface of the body -- eyes, skin, lungs, tongue and intestinal tract -- and kill bacteria within minutes of contact. If applied in concentrated quantities at the site of potential infection, these peptides may kill pathogens before they infect the body.
BufferGel is an acidic polymer developed to maintain the vaginal environment at a pH below 5. At pH 4.2, the healthy vagina is too acidic for HIV to survive. Semen decreases the acidity of the vagina, which makes a more welcome environment for HIV to survive. BufferGel, currently in development by ReProtect, LLC. is both a spermicide and microbicide. In addition to blocking sperm, in early animal studies it also blocked sexual transmission of herpes (HSV-2) and to a lesser extent, chlamydia. It also prevented papilloma virus infection.
Carrageenan is a seaweed (red algae) derivative that turns into a gel when mixed with water. It's stable on the shelf and at boiling temperatures, and is not degraded by bacteria. It is also so safe that the FDA approved its use in food in 1972. This product would work by coating the vagina, preventing HIV from entering the vaginal epithelium. So far in study, the protective effect was seen across a wide range of pH levels and seems to last up to 18 hours.
Cyanovirin-N comes from blue-green alga found in Hawaii. In other words, it's pond scum. By binding to the cell, Cyanovirin-N appears to change the shape of HIV surface proteins, therefore prohibiting cell fusion. It is water soluble, stable in solution on the shelf for at least six months. It does no harm to lactobacilli, nor does it bind to sperm. All of this means that it provides excellent and non-toxic protection against microbes while still allowing for conception if desired. It can be produced for mere pennies per gram.
Detergents and surfactants work by disrupting the outer membranes of cells and envelopes (outer shells) of viruses. N-9 is in this class.
Lactobacillus crispatus (LB) suppositories work by re-colonizing the vagina with hydrogen-peroxide producing Lactobacillus. LB helps keep the vagina free from infection by producing hydrogen peroxide, which is a highly acidic substance. When the ecology of the vagina is disrupted (through infection, douching or poor hygiene) the LB bacteria die, leading to a condition known as bacterial vaginosis.
Monoclonal antibodies have been studied in animal models. They have high potency and low toxicity and seem to work as microbicidal agents.
Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are highly targeted with high potency against a broad spectrum of quasispecies of HIV-1, act directly on the target without first needing to be metabolized, and are not toxic to cells because they are so "pathogen-specific." They are so focused on cells that exhibit HIV markers that they will ignore other cells, therefore, not devastating or severely altering the ecology of the area.
"Plantibodies" represent an innovative approach to microbicide development using genetically engineered plants to produce human antibodies active against a range of STIs/STDs. This technology raises the possibility of delivering anti-HIV antibodies directly to the vagina, allowing them to combat pathogens before actual infection occurs.
Pro-2000 Gel contains a synthetic polymer that binds to HIV, disrupting the binding of the virus to target cells.
Secretory leukocyte protease inhibitor (SLPI) is naturally produced by the body, and is found in mucosal tissue and saliva. Some people reason that the presence of SLPI in the mouth explains the lower-than-expected incidence of HIV transmission through oral sex. SLPI works by interacting with the targeted cells (CD4 and CCR5 cells) as opposed to the virus itself. It binds to the cells, blocking access to infection. SLPI coats the target cells so that the virus can't gain entry, thus preventing the cell from becoming infected.
Nonoxynol-9: The Loser of the Lot
Nonoxynol-9 is approved for sale in the U.S. as a spermicide. Studies have shown that extensive use can result in increased inflammation of the vagina, which could facilitate transmission of HIV.
In studies of N-9 used in the rectum, David Phillips of the Population Council compared lubricants containing Nonoxynol-9 with lubricants containing PC515. After 15 minutes, the Nonoxynol-9 lubricants had stripped sheets of epithelial cells from the rectum and exposed underlying tissue; the other product did not. Because of this, Phillips warns against using Nonoxynol-9 containing lubricants during anal sex.
What's the Hold-up?
Why aren't microbicides on the market? Although a vaccine for HIV may come to fruition someday, there isn't time to wait. Microbicides cost less than condoms (and certainly less than the cost of treating a person after she is infected with HIV), are for the most part non-toxic, can be used without another person's consent and are effective.
The answer comes down to money, as it always does when big pharmaceutical companies are invited to become involved. Although a few pharmaceutical companies sponsored the Microbicides 2000 conference, very few pharmaceutical reps actually showed up.
Family Health International epidemiologist Willard Cates reported that relatively good progress has been made in getting candidate products ready for Phase I/II safety trials but not in getting them into efficacy trials (Phase III). Noting that an estimated 15 to 20 candidates were likely to be ready to enter Phase III trials in the next few years, Cates observed that, under current conditions, the money to do those trials simply isn't available.
The research pipeline, Cates said, is "impacted": clogged by the growing number of promising product leads that are stalled because their developers cannot afford to move them on to the next phase of research.
According to the Global Campaign for STI/HIV Prevention Alternatives for Women, roughly $75 million per year would be required to make the "five years to market" scenario a reality. Lori Heise, co-director of the Center for Health and Gender Equity and cofounder of the global campaign, explained that with increased commitments from governmental funders, private philanthropists, and the pharmaceutical industry totaling $300 to $500 million over the next five years, microbicide research would be able to proceed efficiently.
The perception on the part of major pharmaceutical companies that microbicides are going to be targeted primarily at Third World women ensures that they are not seen as being potential money-makers, and therefore are not of interest. There also seems to be the perception that microbicides will be marketed as over-the-counter, which does not provide the profit incentive that prescription drugs do.
Since the Microbicide conference, a push toward developing microbicides has emerged, however. "We've been ramping up the microbicide program a lot more rapidly than our overall AIDS program," said Dr. Neal Nathanson, director of the Office of AIDS Research at the National Institutes of Health. "The situation is so desperate that I think the burden of proof is really on someone who claims we shouldn't pursue every possible avenue of research."
The National Women's Health Coalition wants a 2001 NIH microbicide budget of $50 million. This year, the NIH will spend $30 million on basic microbicide research and NAIAD director Anthony Fauci has committed another $27 million next year. Under the name Alliance for Microbicide Development, a consortium of American women's health groups hopes to raise $10 million for private research as well.
In July 2000, the HIV Prevention Trials Network (HPTN) was formed by the NIH in cooperation with the National Institute of Child Health and Human Development, the National Institute of Mental Health and the National Institute on Drug Abuse. HPTN will develop and test promising non-vaccine strategies to prevent the spread of HIV. Funding for the first year totals slightly over $30 million.
"Today we see a level of seriousness and credibility that microbicide development didn't have before," said UNAIDS director Dr. Peter Piot said at Microbicides 2000. This enthusiasm is admirable and necessary to further the research and development of microbicides, but research commitment will not be enough to bring these drugs to market. A large pharmaceutical company must agree to manufacture the product and in order to bring the drug into the global marketplace, cultural, political and financial barriers must be overcome. And, of course, women must be willing to use vaginal gels, foams, creams and films. "We determine that 12.6 million women in the U.S. would use microbicides," the Guttmacher Institute's Heather Boonstra told the opening meeting at Microbicides 2000.
"I genuinely believe that microbicides are the key to ending the epidemic," said River Huston, writer and (potential) consumer. "Every 10 seconds another woman on the planet gets HIV -- needlessly. An effective, cheap, and above-all, woman-controlled method of prevention would work wonders. I suppose I got a little giddy at a panel on microbicides. I offered to donate my vagina to science on the spot."
Safety and efficacy trials add morals and politics to the already encumbered process of drug approval. Because of the ethical need to protect research subjects against becoming infected, researchers face the dilemma of encouraging study participants to use condoms along with microbicides and at the same time attempting to determine quickly and efficiently as possible what effect the microbicide has. If condoms are being used in addition to the product, the efficacy of the product alone will be difficult to establish.
In a survey of the 30 largest pharmaceutical firms in the world, 88 percent said that they had no interest in getting involved in microbicide product development. Those who expressed some interest in the product insisted that "someone else," such as government laboratories, must first conduct all necessary safety and efficacy trials.
Despite the fact of the humanitarian face the development and distribution of a microbicide would provide to the pharmaceutical company that rose to the challenge, the profit motive still stand firm. This makes major Pharma in part responsible for an incalculable number of HIV infections. Despite lip service (in a few instances) to the contrary, there is no plan to assist the poor worldwide in protection from HIV disease. They can talk about distributing condoms and providing anti-retrovirals post-infection, but when it comes down to it, to provide those in a suitable number and amount to make a difference, would cost so much more than an effective microbicide that it is obvious that there is currently no intention on the part of major pharma to halt the spread of HIV into so-called Third-World countries.
Push for Progress
To activists, all of this means that we must push a national and international dialogue that keeps women's health in the forefront of HIV/STD prevention research.
We must put pressure on our government, the governments of all industrialized nations, UNAIDS and on pharmaceutical companies in the private sector. It is not a lack of research that is keeping these drugs from the marketplace. It is a lack of financial commitment.
As people who have political clout (compared to other nations), who have access to the ears of our elected officials, and who will benefit by the development of a microbicide, it is our responsibility to do all that we can to ensure that development of these products does not get stalled.
Susan Forrest is a housing counselor in AIDS Project Los Angeles' Residential Services Department. She can be reached by calling (213) 201-1572 or by e-mail at sforrest@APLA.org .