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MicrobicidesBy Susan Forrest Scary STD Statistics
Sexually transmitted diseases (STDs) including HIV, chlamydial infection and gonorrhea are the most common infectious diseases reported to the Centers for Disease Control and Prevention (CDC). More than 15 million people in the Unites States contract a STD each year. Current data suggests that one in four people will contract a STD in her lifetime. Currently, 900,000 Americans are believed to be HIV-positive, and more than 5 million new HIV infections occurred worldwide during 1999. According to the Joint United Nations Programme on AIDS (UNAIDS), 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. UNAIDS estimates that 33.6 million people are either infected with HIV or have AIDS. According to government estimates, by 2010 at least half of all Americans infected with HIV will be women. This rapid feminization of HIV clearly speaks to the consequences of relying on condoms as virtually our only HIV prevention tool.
Studies have also demonstrated that co-infection with HIV and another STD results in making an HIV-positive women more infectious. In addition to that, STDs can increase the number of HIV target cells in cervical secretions, thereby increasing HIV susceptibility in women . For these reasons, it is critical that all women, regardless of HIV status, take measures to protect ourselves from STDs.
A word about protection
In studies done on the subject, consistent condom use is rarely reported by more than 50% of those surveyed. Most surveys of heterosexual primary partnerships show that condom use happens 20% of the time or less. The only studied populations that have reported using condoms regularly for more than half of their acts of intercourse are serodiscordant couples and commercial sex workers.
With access to antibiotics, people, especially in developed nations such as ours, often think of STDs as nothing more than minor embarrassments that require antibiotics to rid themselves of. In many cases this is true, albeit far less true for those of us who are HIV-positive. Contagious germs (also called "microbes") are what cause STDs. Herpes and HIV are two examples of STDs that can't be cleared from the body (cured) unlike many 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." States Anna Forbes in an article for HIVInSite (http://hivinsite.ucsf.edu)
In obvious scenarios such as domestic violence or rape, we are not in a position to negotiate 'safer sex' or condom use. Social factors surrounding women's inability to negotiate safer sex have been discussed ad nauseum, often pitting us as innocent victims of men's prowess and innate ability and desire to dominate. I believe that is each woman's responsibility to learn how to protect herself, and to decide whether or not to do so. I also understand, however, that this is not always possible in the face of enormous pressures from virtually all cultures for women to negate their decisions or to be physically unable to carry out those decisions. There are also many cultures in which childbearing is directly linked to a person's self worth, and the prospect of childlessness often outweighs the risk of HIV infection in women's minds. It is unfortunately true that social norms generally reflect woman's secondary status in societies, so these factors cannot be ignored.
The Pill revolutionized our ability to avoid unplanned pregnancy. Microbicides have the potential to provide us with an equal amount of control with regard to protection from STDs, and when desired, from pregnancy as well. Microbicides can be used with condoms or without them. Truly, microbicides leave the matter of protection firmly in the grasp of our own hands. Microbicides act as a secret tool to aid women in their quest to obtain and/or maintain sexual health despite all of the afore-mentioned variables.
In Africa, the region with the greatest need, there are many gender-based constraints (cultural and political) upon women who want to control their reproductive and sexual health. An example of this was presented by Flavia Ndikuno, a Ugandan member of the International Community of Women Living with HIV/AIDS when she stated that women who used microbicides would be considered 'non-obedient' by their mates. 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.
One of the main benefits of microbicides is that they will be able to be used without a male (insertive) partner's knowledge or consent. Another benefit is that microbicide usage would not require women to admit that they consider themselves at risk. What might be the biggest selling point, though, is that, microbicides have an advantage over condoms in that they allow for skin-to-skin contact. Some, albeit not much, consideration has been given to the role of microbicides during anal sex, however most research along these lines seems to insinuate that this is an issue of primary interest to gay men. While we need to advocate for vaginal microbicides, we also need to advocate for studies involving STD protection during anal sex. Obviously, studies of microbicides for anal use will benefit women as well as men.
What are microbicides?
The term microbicide is, simply stated, any agent that kills or deactivates disease-causing microbes, commonly referred to as "pathogens. The International Association of Physicians in AIDS CARE (IAPAC) adds to this definition: "ƒIt also includes therapeutic interventions that can block or prevent infection, as well a amplification of the body's natural defenses to prevent infection through sexual acts."
Current studies are exploring three different approaches to microbicide development. Among these are substances that will:
á Kill or otherwise immobilize STD pathogens (virucides)
á Block infection by creating a barrier between the pathogen and the vagina (and possibly the rectum);
and /or
á Prevent the infection from taking hold after it has entered the body by fortifying innate immune defenses
Combinations of these agents are likely to have synergistic effects when mixed in a topical product. In other words, scientists are working on products that would combine these agents, making them stronger and more likely to prevent disease transmission.
Are microbicides pipe dreams? Actually, not at all. There are currently 64 compounds in some phase of development, and 20 that are ready for human safety trials .Out of all of the products currently being researched, one has been approved. Nonoxynol-9 (N-9) is marketed as a spermicide 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 now outnumber newly infected men worldwide, the need for female-controlled protection is becoming more and 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)" stated UNAIDS director Peter Piot at the Microbicides 2000 conference which was held in Alexandria, VA March 13-16, 2000. 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" says Bob Rohr .
In the future, some microbicides may also 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. And, as better microbicides are developed, they will be designed to be "bi-directional"; in other words, use of a vaginal microbicide will inactivate HIV present in the vaginal secretions, thus protecting her partner, as well as protecting 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, there are a number of issues that will have to come into play. First, 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 tell us that, ideally, the microbicide will have to withstand varying temperatures and would also need to function within various acidic and alkaline (pH) levels. 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 marketed in a way that is "user-friendly". In other words, 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. That allows women to become pregnant if the want to, and is active as soon as it is applied and for a long time afterwards" says Awa Coll-Seck, MD and director of policy, strategy and research at UNAIDS.
The Vagina - not just another pretty face
The vagina maintains its health by using bacteria, the immune system and pH levels to monitor and protect itself against pathogens."Vaginal and cervical mucosa and epithelium are major barriers to infection. They reduce risk of infection about a thousand-fold compared with direct injection exposure to a pathogen." states Preston Marx, MD, of the Aaron Diamond AIDS Research Center.
When the vagina is unbalanced (due to an STD, for example), the body sends cytokines to the area to restore the natural balance and to rid the body of microbes. CCR5 is one of the cytokines that the immune system sends. CCR5 is also a co-receptor of HIV. 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. Kenneth Mayer, MD and researcher at Brown University states that "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". Bacterial vaginosis (BV) 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 more stable in a less acidic environment.
In the Pipeline
Antibiotic Peptides are 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 off pathogens before they infect the body.
BufferGel is an acidic polymer developed to maintain the vaginal environment at a pH below 5. The healthy vagina is normally about pH 4.2, which is too acidic an environment for HIV to survive in. When semen, which is very alkaline, is introduced, it decreases the acidity of the vagina, which makes a much more welcome environment for HIV to survive in. BufferGel neutralizes sperm and many STDs in vitro and has the additional benefit of promoting lactobacilli. This is both a spermicide and a microbicide currently in development by ReProtect, LLC. In early animal studies, in addition to blocking sperm, it also blocked sexual transmission of herpes (HSV-2) and to a lesser extent, chlamydia. It also prevented papillomavirus infection.
Carrageenan is a seaweed (red algae) derivative that turns into a gel when mixed with water that David Phillips, Ph.D. at the Population Council in New York, is studying carrageenan. It's stable on the shelf and at boiling temperatures, and is not degraded by bacteria. It also "It is 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. Michael Boyd, Ph.D. and colleagues at the National Cancer Institute are studying this substance. Cyanovirin-N changes the shape of HIV surface proteins, by binding to them, therefore prohibiting cell fusion. Boyd calls it "the most widely neutralizing, the most potent neutralizing substance known." It is water soluble, stable in solution on the shelf for at least six months ("probably indefinitely" states Boyd). 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 a detergent.
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. "Provided as multi-antibody cocktails, they have the potential to give very broad-spectrum protection against pathogens" states Dr. Thomas Moench, medical director of Re Protect.
Nonnucleoside reverse transcriptase inhibitors (NNRTIs) "may be ideal topical microbicides" states Michael Parniak, PhD. NNRITs 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". What that means is that 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.
One positive thing to note about using previously developed drugs is that what may not work internally may work very well topically. CSIS, for example, was an NNRTI developed and later dropped by Merck because of poor bioavailability. In vitro it appears that poor bioavailability may be an asset when it comes to developing topical products because a topical agent should not be absorbed.
"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) pronounced SLIPee, 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-one-might-expect incidence of HIV-transmission through oral sex. SLPI works by interacting with the targeted HIV receptor cells (CD4 and CCR5) as opposed to the virus itself. It binds to the cells, blocking access to infection. In a nutshell, SLPI coats the target cells so that the virus can't gain entry, thus preventing the cell from becoming infected.
A Little About nonoxynol-9 - the loser of the lot
N-9 is approved for sale in the Unites States 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 discovered that lubricants containing N-9 were compared with lubricants containing PC515. After 15 minutes, the N-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 N-9 containing lubricants during anal sex.
What's the hold-up?
N-9 aside, microbicides seem like an obtainable solution to an otherwise unanswerable problem. Although a vaccine for HIV may come to fruition someday, there isn't time to wait. Microbicides cost relatively little (less than condoms or the cost of treating a person after she is infected with HIV, certainly), are for the most part non-toxic, can be used without another person's consent and are effective. Why aren't these products on the market?
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 15-20 candidates were likely to be ready to enter Phase III trials in the next few years, Cates observed that the money to do those trials simply isn't available under current conditions. The research pipeline, he 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.
How much would it take to make the goal of "five years to market" a reality? Roughly $75 million per year, according to the Global Campaign for STI/HIV Prevention Alternatives for Women, an international coalition of microbicide advocates. Lori Heise, co-director of the Center for Health and Gender Equity (CHANGE) and cofounder of the global campaign, explained that -- with increased commitments from governmental funders, private philanthropists, and the pharmaceutical industry totaling $300 - $500 million over the next five years -- microbicide research would be able to proceed efficiently.
The perception on the part of major pharma 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 (OTC), which does not provide the profit incentive (therefore the interest) that prescription drugs do.
Since the Microbicide conference, there has been a push toward developing microbicides, however. "We've been ramping up the microbicide program a lot more rapidly than our overall AIDS program" states Dr. Neal Nathanson, director of the NIH's Office of AIDS Research. "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. A consortium of American women's health groups, under the blanket name of Alliance for Microbicide Development hopes to raise $10 million for private research as well.
In July 2000, formation of the HIV Prevention Trials Network (HPTN) was announced. The 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 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" 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 US 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: 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. Says River Huston, writer and (potential) consumer. "I suppose I got a little giddy at a panel on microbicides -- I offered to donate my vagina to science on the spot."
When it comes to safety and efficacy trials, the situation becomes more complex, adding morals and politics to the already encumbered process of drug approval. There is an ethical need to protect research subjects against protection (can anyone say Tuskeegee?), so 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.
British consultant Alan Stone surveyed the 30 largest pharmaceutical firms in the world, and 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 proves that despite lip service (in a few instances) to the contrary; there is no plan to assist the needy worldwide in protection from HIV disease. Big pharma can talk about distributing condoms and providing anti-retrovirals post-infection until the cow jumps over the moon, 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.
What does all of this mean to you and to me? It means that we must behave as activists, pushing 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 (starting with pressuring them to pay their UN dues), 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, and as women who (a) have political clout (compared to other nations), (b) have access to the ears of our elected officials, and (c) will benefit by the development of a microbicide, it is our responsibility to do all that we can to ensure that these products do not get stalled in development.
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