Microbicide Products Enter Human Trials

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FHI's Quarterly Health Bulletin Network

Microbicide Products Enter Human Trials

A variety of experimental products use different mechanisms to protect against HIV and other diseases.

Network: 2000, Vol. 20, No. 2

Copyright Family Health International, 1999.
Network is reprinted with permission from Family Health International.

Scientists are examining more than 50 experimental substances as possible vaginal microbicides, and about a quarter of these agents are in various stages of human testing.

Nevertheless, this group of experimental products to protect against HIV and other sexually transmitted diseases (STDs) is years away from being available for general use. Also, when they do become available, the first microbicides are likely to provide only limited protection against infections. Meanwhile, other research continues to evaluate the ability of currently available spermicides to prevent STDs.

The male latex condom provides the most effective protection against STDs, including HIV. Even when an HIV cure or preventive vaccine becomes available, using condoms consistently and reducing risky behaviors will continue to be good counseling advice to people at risk of STDs.

For couples who do not use condoms consistently and correctly, a safe and effective microbicide would offer an alternative method of protection. "Many men are unwilling to use condoms all of the time, if at all," says Lori Heise of the Center for Health and Gender Equity (CHANGE), which advocates for microbicide development. "Women need a product that they can control, and even use without their partner's consent or knowledge."

Women may be biologically more susceptible than men to many STDs, including HIV. Moreover, the number of women being infected with HIV is increasing faster than male infections. Women currently account for 43 percent of the 33 million adults living with HIV, compared with 25 percent in 1992, according to the Joint United Nations Programme on HIV/AIDS (UNAIDS).

How soon a safe and reasonably effective microbicide may be available is anyone's guess. "At this point, we just don't know which substance will turn out to be best," says Dr. Zeda Rosenberg, scientific director of FHI's HIV Prevention Trials Network, a research project involving FHI and other institutions to evaluate HIV prevention interventions, including experimental microbicides. "All of these substances are active against microorganisms in the laboratory, and some animal studies and human safety trials are promising. But we still need more information from human efficacy trials."

Experimental Microbicides in or nearing Human Trials

Agent	How It Works	Research Status
Kills or inactivates pathogens
ACIDFORM	Contraceptive. Bioadhesive gel that maintains vaginal acidity.	In safety trial, combining nonoxynol-9 (N-9) with ACIDFORM made N-9 very irritating to the vaginal lining. ACIDFORM alone soon to be tested as a contraceptive in Brazil.
BufferGel	Contraceptive. Maintains vaginal acidity. A physical barrier.	Safety and acceptability trials in India, Malawi, Thailand, Zimbabwe and the United States raised no safety or acceptability concerns.
Lactobacillus crispatus	Noncontraceptive. A vaginal suppository that promotes Lactobacillus crispatus, a bacterium that increases vaginal acidity, which protects against pathogens.	Safety trial found that insertion of capsules twice daily for three days produced sufficient bacteria in up to 88 percent of women. Safety and efficacy study soon to begin with metronidazole to treat bacterial vaginosis.
Praneem	Contraceptive. Suppository, tablet and cream formulations contain citrata oil and purified extracts from neem tree.	Expanded safety trial under way in India among 300 women with abnormal vaginal discharge due to STDs; using seven-day treatment with one tablet per day.
C31G	Contraceptive. Gel containing surfactant that damages bacterial membranes and viral envelopes.	Data from vaginal irritation study at Eastern Virginia Medical School being analyzed. Safety study soon to begin at three U.S. sites.
Inhibits entry of pathogens into vaginal or cervical cells
Cellulose sulfate (CS); Polystyrene sulfonate (PSS)	Contraceptive. High-molecular-weight polymer binds to pathogens to prevent HIV from entering human cells.	Safety trial of CS showed only minor irritation to vaginal lining. Safety trial of PSS nearing completion.
Dextrin-2-sulfate	Noncontraceptive. A sulfated polysaccharide that blocks the uptake of HIV into human cells, probably by binding to cell surfaces and possibly binding to the virus.	Shown to be safe among sexually abstinent women. Safety and acceptability trial under way in the United Kingdom among sexually active women and some male partners. Safety and acceptability trials planned in Côte d'Ivoire and Uganda.
PC-515	Noncontraceptive. Contains carrageenan, a substance derived from red seaweed, that coats the vagina and binds to viruses.	Safety studies completed in the United States, Finland, Chile, the Dominican Republic, Australia and Thailand. Trials in South Africa and Thailand to evaluate safety, acceptability and efficacy should be completed in 2001. Trials for efficacy against HIV might begin in 2001.
PRO 2000	Contraceptive. Sulfonated polymer binds to HIV, preventing the virus from entering human cells.	Trials established safety in healthy, sexually abstinent women in Europe. Safety trial being conducted in the United States and South Africa.
Prevents pathogens from replicating
Tenofovir disoproxil fumarate	Noncontraceptive. Interferes with genetic process needed for pathogens to multiply.	Small safety trial among women planned, pending review of animal studies.

Mechanisms of action

Most potential topical vaginal microbicides under investigation involve at least one of three mechanisms: killing or disabling the disease pathogens; inhibiting entry into vaginal or cervical cells; or preventing replication of the pathogen once it enters the body.

Some substances that kill or disable bacteria or viruses do so by damaging bacterial membranes and viral envelopes, as do currently available spermicides. Experimental agents that act in this way include sodium dodecyl sulfate.

Other experimental microbicide agents kill or disable bacteria or viruses by maintaining the natural acidity of the vagina, a condition that is hostile to many pathogens. These include substances called ACIDFORM and BufferGel. In addition, a vaginal suppository promotes Lactobacillus crispatus in the vagina, a beneficial bacterium that increases acidity.

Substances that block passage into vaginal or cervical cells include those that cover the cells of a woman's body to block viral attachment and those that bind with the pathogens to stop them from penetrating the lining of the vagina and cervix. Cellulose sulfate, dextrin-2-sulfate, PRO 2000, and PC-515 are among promising substances under study. The New York-based Population Council is developing PC-515, which contains carrageenan derived from red seaweed, a common substance used in cosmetics, toothpaste and food. Carrageenan binds to viruses, including HIV, human papilloma virus (HPV) and herpes simplex virus (HSV).

Monoclonal antibodies are another category of substances that bind to pathogens. Monoclonal antibody products have been approved for the treatment of breast cancer, Crohn's disease and various auto-immune conditions. They can be obtained from genetically engineered plants, such as corn.

"This monoclonal approach is like selectively removing weeds from a garden," says Dr. Kevin Whaley of Johns Hopkins University in the United States, who is collaborating on a U.S. $3.8 million effort to develop a microbicide using monoclonal antibodies. "The idea is for the monoclonal antibodies to attack particular disease-causing pathogens like herpes simplex virus or HIV at the vaginal mucosal surface before infection occurs, without otherwise disrupting the vaginal environment. These agents are potentially potent and specific in terms of what they attack. That means that several pathogen-specific antibodies would have to be combined to produce a substance with broad effectiveness. It also means that formulations could be prepared with sperm antibodies for women who desire contraception, or without them for women who wish to conceive."

Substances that may prevent the replication of HIV or other pathogens once the virus has entered vaginal cells of the body include tenofovir disoproxil fumarate, which works by interfering with the genetic process needed for cells to multiply. Pending review of animal toxicology studies, a small trial among women to examine safety issues is planned.

Other research involves better ways to deliver microbicides into the vagina. One such experimental product is called the "invisible condom," a liquid gel that hardens at body temperature to form a temporary barrier throughout the vagina. Potent microbicides, such as sodium dodecyl sulfate, can be added into the gel, exposing pathogens to the microbicide while reducing the exposure of vaginal cells to toxic microbicidal agents. The gel may even prolong microbicidal activity.¹ In the first human trial being planned for this year, "we will investigate its safety and acceptability when used alone and when used with nonoxynol-9," says Dr. Michel Bergeron, chairman of the Infectious Diseases Research Center at Laval University in Quebec City, Canada, where the research is being conducted.

Degree of protection

Most researchers do not expect the first vaginal microbicides to provide complete protection against STDs, including HIV. But "a microbicide that was even 30 percent to 40 percent effective would be significant from a public health perspective that is, in its potential to slow down the AIDS epidemic," says Dr. Penelope Hitchcock of the U.S. National Institute of Allergy and Infectious Diseases (NIAID), which is sponsoring microbicide research. But women who use such a product should understand that they should not rely on it alone for effective protection from STDs.

"Studies are needed to understand how to introduce a microbicide in a way that would not undermine the fundamental recommendation to use a condom at every act of intercourse," says Dr. Hitchcock.

FHI believes good prevention counseling would continue to be essential, says Dr. Willard Cates, president of FHI and an STD expert. "We would still have to counsel people to use condoms and to reduce risky sexual behaviors, to minimize risk of STD acquisition," he says. "But, if we had a vaginal microbicide that was 30 percent or 40 percent effective, we would recommend it, just as we would vaccinate everybody if we had a vaccine that was 30 percent or 40 percent effective."

A well-accepted, woman-initiated vaginal microbicide that is used more consistently than a condom may be more successful than condoms in preventing new STD infections. For example, researchers calculate that a 30 percent efficacious method used 60 percent of the time would prevent more infections than a 90 percent efficacious method used only 20 percent of the time.²

Among other expectations and hopes researchers share for a topical vaginal microbicide are the following:

Microbicides should be effective against pathogens other than HIV. "An HIV vaccine and microbicide are very high priorities for researchers, but not to the exclusion of vaccines and microbicides for other STDs," says Dr. Hitchcock. "Important and concerted efforts are going forward to develop microbicides against other STDs, whose presence increase a woman's risk of acquiring HIV. These other STDs also pose a significant health burden, whether or not HIV infection is endemic."
Noncontraceptive formulations of microbicides should be developed. While many microbicidal substances under scrutiny work by disrupting cells, including sperm cells, some 15 new substances have no documented spermicidal activity. If successful, these products would appeal to the many women who need STD protection, but wish to conceive.
A product that can protect against HIV infection when used postcoitally, just as emergency contraceptive pills are used to prevent pregnancy after unprotected sexual intercourse, would be very desirable. Whether a microbicide could provide such protection depends upon how fast infection occurs. For women unable to control when they will have sex, other protective strategies are under study, including time-released microbicides or microbicides that continue to be active over a number of hours.
Products should be effective for rectal use. Researchers are focusing on how topical microbicides work in the vagina, but the rectum and vagina greatly differ in many ways. The safety and effectiveness of a topical microbicide for rectal use would have to be demonstrated independently from that for vaginal use.

Topical application of microbicides to vaginal and rectal mucosal surfaces is the only method of application currently being considered. "We are looking for something that will have a local effect; that will not be absorbed throughout the body," says Dr. Hitchcock. "Scientific experience indicates that topical application of these substances will be successful. We have delivered drugs into the vagina before, and we have been able to kill or inactivate pathogens on the vaginal mucosal surface with the topical delivery of drugs."

Benefits for adolescent women, men

If a microbicide is found to be safe and effective in older women, safety and efficacy for adolescent women would still need to be established. An adolescent woman's cervix differs anatomically from that of an older woman and might be more easily irritated by a vaginal product. In addition, an adolescent may not produce enough vaginal fluid to dissolve a microbicidal product properly. Because adolescents often are unable to appreciate their vulnerability and the risks and consequences of their actions, they may not feel the need to use a microbicidal product consistently. Also, an adolescent woman who is not yet familiar with other vaginal products — such as tampons or douches — may feel less comfortable using a vaginal microbicide than an older woman experienced in using such products. Finally, adolescents' acceptance of a vaginal microbicide could depend upon whether it were an easily available, nonprescription product.³

Similarly, how topical vaginal microbicides might affect men's health is not known. "However, men might be protected or benefit from microbicides in four ways," says Dr. Hitchcock of NIAID. While microbicides are being developed to protect a woman from being infected by a man, they may also protect a man from being infected by a woman who uses them. "If a microbicide inactivated pathogens in male ejaculate, it would be expected to inactivate them in female cervical secretions. Because the volume of cervical secretions to which men are exposed is less than that of the ejaculate to which women are exposed and, because female-to-male transmission of STDs is usually less common than male-to-female transmission, the benefit of microbicide use might actually be more marked in men than in women."

A second benefit, Dr. Hitchcock says, is that some experimental microbicides have the potential to protect against HPV better than condoms. In addition, if microbicides protect women against infection, the prevalence of STDs among women will decline, thus reducing the risk that men will encounter an infected woman and be infected themselves.

"Finally, if microbicides protect women against infection, STD-related infertility or adverse effects on pregnancy may be avoided," adds Dr. Hitchcock. "Becoming fathers of healthy children can be a major benefit for men."

Vaginal microbicidal products are less likely to be toxic in men than in women. This is because the penis would be exposed to the product for less time. Also, the skin of the penile shaft is tougher, sturdier and less vulnerable than the vaginal lining. However, the foreskin may be different. Uncircumcised men might be more likely than circumcised men to experience discomfort with microbicides. This is because the topical substance could accumulate under the foreskin and, if not washed off, irritate the penile tissue. Several studies of the effects of microbicides on rabbit penile tissue are under way.

Acceptability

Because consistency of use affects how well a barrier method works, it is essential that microbicide researchers consider the preferences and concerns of women and their partners.

Whether use of a microbicide allows women to conceive will be a pivotal factor in some cultures. "Many women in developing countries, where infant mortality rates continue to be high and where the value of family planning is not well understood, will prefer a product that — while protecting them from infection — allows them to conceive," says Muriel Harris of the University of South Carolina in Columbia, SC, USA, and former president of the Society for Women and AIDS in Africa, based in Sierra Leone. "In Africa, for example, there is a great desire for children, who are considered to be a form of social wealth. Women feel a strong need to fulfill their roles as childbearers."

In terms of physical characteristics, most people can be expected to prefer a product that does not have an unpleasant odor or flavor and that does not stain. Beyond that, preferences greatly vary. The key, researchers agree, is that several formulations will be necessary to meet everyone's needs and desires. Individuals' race, ethnicity, cultural customs, age, and the attitudes of male partners are just a few factors potentially affecting acceptability.

In some cultural settings, for example, women may be unwilling to touch their own genitalia to insert a product. Or, they and their partners may dislike a product that significantly increases vaginal lubrication.

In a survey of vaginal product preferences of 635 Brazilian women, half of whom were adolescents, more than 40 percent of all respondents said they would tolerate a messy product if it protected against both pregnancies and STDs. However, a messy product was acceptable to only a third of the adolescents, "a group among which protection against pregnancy and particularly against STDs/AIDS is very important," researchers noted.⁴

In many parts of Africa, "dry" sex is preferred, with vaginal dryness and tightness associated with virginity, purity and cleanliness. In a study conducted by the Population Council involving focus group discussions with 19 male taxi drivers and 16 male farm workers in Zimbabwe, taxi drivers particularly objected to "wet" sex. "When you manufacture this product, make sure it does not promote wet sex," commented one taxi driver, "because the women who use it might be thrown out of their homes." Many of the men in this study also worried about the safety of the vaginal microbicides and whether they would prevent pregnancy or cause infertility.⁵

Male taxi drivers and farmers in Mexico, the United States and Zimbabwe who participated in focus group discussions voiced concerns about the potential impact on sexual pleasure and future fertility, as well as possible side effects they might experience, due to their partner's use of a microbicide.⁶

Clearly, it will be a challenge to develop products that both women and men throughout the world will want to use. "But we do believe researchers need to be responsive to the communities that will use these products," says Dr. Hitchcock of NIAID. "Otherwise, we will have delivered an ineffective tool."

— Kim Best

References

Gagné N, Cormier H, Omar R, et al. Protective effect of a thermoreversible gel against the toxicity of nonoxynol-9. Sex Transm Dis 1999;26(3):177-83; Désormeaux A, Omar RF, Bergeron MG. Topical microbicides for the prevention of sexually transmitted diseases and HIV. Can J Infect Dis 1999;10(Suppl C):41C-48C.
Watts CH, Thompson WA, Heise LL. The impact of microbicides for HIV prevention: results of a mathematical modeling exercise. The 12th World AIDS Conference. Geneva, July 1998.
Rosenthal SL, Cohen SS, Stanberry LR. Topical microbicides: current status and research considerations. Sex Transm Dis 1998;25(7):368-77.
Hardy E, de Pádua KS, Osis MJD, et al. Women's preferences for vaginal antimicrobial contraceptives IV, attributes of a formulation that would protect from STD/AIDS. Contraception 1998;58(4):251-55.
Van de Wijgert JH, Khumalo-Sakutukwa GN, Coggins C, et al. Men's attitudes toward vaginal microbicides and microbicide trials in Zimbabwe. Int Fam Plann Perspect 1999;25(1):15-20.
Blanchard K, Coggins C. Men's attitudes toward a potential vaginal microbicide in Mexico, the United States, and Zimbabwe. The 12th World AIDS Conference. Geneva, July 1998.

Spermicides as Microbicides?

Commercially available spermicides have already undergone extensive safety testing, and most have been widely used. Thus, if their active ingredients were found to protect against sexually transmitted diseases (STDs), they might be promoted as vaginal microbicides much sooner than new products are likely to be available.

The active ingredients in commercially available spermicides now being tested for microbicidal activity include nonoxynol-9 (N-9), benzalkonium chloride and octoxynol9. N-9 spermicides are the only substances in advanced trials to determine antimicrobial efficacy in humans.

Developed as a contraceptive spermicide more than 40 years ago, N-9 has been available in the form of gels, foams, creams, impregnated sponges, suppositories, films and foaming tablets. It is potentially effective as a microbicide because it disrupts the outer membranes of bacteria and viruses. However, frequent N-9 use can irritate the vaginal lining, possibly allowing pathogens a way to enter the woman's bloodstream.

Some small studies suggest a modest protective effect from N-9 against gonorrhea and chlamydia. But a large, randomized, controlled FHI study in Cameroon using a low-dose (70 mg) N-9 film recommended for use with condoms indicated that N-9 did not give any additional protection against HIV, gonorrhea or chlamydia beyond that provided by condom use alone.¹

Research currently is examining other N-9 doses, frequencies of use and delivery formulations (such as gel, foam, cream or suppository) to evaluate whether they can protect against microorganisms without causing vaginal irritation:

A low-dose (52.5 mg) N-9 gel, commercially available in the United States as Advantage-S, is being evaluated for its effectiveness in preventing transmission of HIV, gonorrhea and chlamydia in 1,000 to 1,500 women at high risk of HIV infection in Benin, South Africa, Thailand and Côte d'Ivoire. This trial, sponsored by the Joint United Nations Programme on HIV/AIDS (UNAIDS), is being coordinated by the Institute of Tropical Medicine, Antwerp, Belgium, with results expected this year.
The effectiveness of a high-dose (100 mg) N-9 gel, commercially available in the United States as Conceptrol, against male-to-female transmission of gonorrhea and chlamydia among 1,000 high-risk, Cameroonian women is being examined in a study funded by the U.S. Agency for International Development (USAID) and conducted by FHI and the Care and Health Program, a nongovernmental agency in Cameroon. The effect of the gel on HIV acquisition also will be studied, with results expected this year.
Conceptrol's effectiveness in preventing male-to-female HIV transmission also will be evaluated in a study funded by the U.S. National Institute of Allergy and Infectious Diseases (NIAID) to be conducted among some 4,500 HIV-negative women in Malawi and Zimbabwe. The gel's effectiveness in preventing transmission of syphilis, chlamydia, gonorrhea and trichomoniasis also will be evaluated. Study results are expected in two to three years.
N-9 formulated into a suppository at various high-dose concentrations (greater than those commercially available) is being developed by the Program for the Topical Prevention of Conception and Disease, Advanced Care Products, and the Contraceptive Research and Development Program. N-9 delivered in this way would be expected to coat the vagina and provide longer protection as a contraceptive and, perhaps, as a microbicide. One safety trial has been completed.

Benzalkonium chloride and octoxynol-9 — both surfactants that disrupt cell membranes — are two of three active ingredients in another spermicidal substance under study, known as GEDA Plus. A safety trial among 280 healthy women found it caused little vaginal irritation.

N-9, benzalkonium chloride and sodium cholate — the three surfactants found in the F-5 gel contained in the Protectaid contraceptive sponge approved for use in Canada and Europe — are to be combined in a reformulated gel for testing as an STD microbicide. This mix of substances has been found in the laboratory to be very potent against STD pathogens. Yet, when delivered in the Protectaid sponge, the mix does not irritate the vaginal lining because only small amounts of each substance are present.

Finally, gramicidin — an active component of contraceptive gels and foams used in the former Soviet Union by millions of women over the last 40 years — shows promise as a topical microbicide. A broad-spectrum antibiotic, it inhibits STD infection. A study of gramicidin's safety and efficacy in treating symptoms of herpes infection is planned in the United States and Brazil.

— Kim Best

Reference

Roddy RE, Zekeng L, Ryan KA, et al. A controlled trial of nonoxynol 9 film to reduce male-to-female transmission of sexually transmitted diseases. N Engl J Med 1998;339(8):504-10.

Microbicide Research Faces Challenges

Microbicide researchers face formidable challenges, the first of which is how to design studies to determine effectiveness in humans.

The ideal way to evaluate microbicide effectiveness is to test a product in a large group of women at high risk of infection from sexually transmitted diseases (STDs). For the safety and well-being of participants, however, it is essential to give all study participants condoms and counsel them to use them. Meaningful data about the effectiveness of microbicides are available only when a condom fails or is not used.

Further complicating the interpretation of research results are questions of how consistently condoms and microbicides are used in these studies. There also are questions about the base formulations (or delivery systems) for the active ingredients in potential products. These vehicles keep active ingredients stable and facilitate their distribution in the vagina, but may have either protective or toxic effects.

Also, in a placebo-controlled trial, a placebo product that resembles the experimental microbicide is given to some participants. But the placebo itself may affect infection rates. For example, lubrication in the placebo may prevent vaginal abrasions, which could result in fewer infections.

Yet another research obstacle is the cost of doing clinical studies. Large pharmaceutical companies have expressed little interest in microbicide research and development. Concerns about regulatory complexities, difficulties in securing patent protection, and product-liability suits discourage companies.

The U.S.-based Alliance for Microbicide Development, an advocacy group comprised of some 85 members involved in research, believes a successful vaginal microbicide could be produced in about five years, but only with substantial increases in both private and government support. The Alliance is requesting that the U.S. government first double, then triple, the approximately U.S. $25 million a year now budgeted for microbicide research and development, says Alliance director Dr. Polly Harrison.

— Kim Best

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