Review Article

    
        

Sexually-transmitted diseases, including HIV/AIDS, represent one of the most serious public health concerns in the world. The World Health Organization (WHO) recently estimated that there are more than 333 million new cases of four common sexually-transmitted diseases (chlamydia, gonorrhea, syphilis, and trichomoniasis) each year.1

Barrier methods of contraception, particularly condoms, effectively prevent the transmission of most sexually-transmitted diseases (STDs). Education and interventions increased the rate of condom usage in some studies, but many couples still do not use condoms, and it is believed that there will always be a subset of people who do not use them. To help control the spread of STDs, scientists and public health officials have been trying to develop protective products that people will use more consistently.

Microbicides are substances that can be applied to the vagina or rectum during sexual activity to prevent the spread of HIV and other sexually-transmitted diseases and/or to act as a contraceptive. To encourage the use of these products, microbicides should be designed to be inexpensive, convenient, unobtrusive, and non-irritating to both partners. Ideally, microbicide preparations, which can be in the form of creams, foams or gels, should be available in contraceptive and non-contraceptive formulas. This would allow women to protect themselves from contracting sexually-transmitted diseases whether or not they wish to conceive children.

Early (Phase I) clinical trials focus on efficacy and safety of the products in humans who do not have sexually-transmitted diseases. Microbicides are also tested in animal models to determine whether a product is effective as a contraceptive or effective against disease transmission. Phase II clinical trials use large test groups that include people at risk for contracting STDs, to further study safety and efficacy. Phase III trials examine the actual disease control levels in humans. Several products are ready for testing at the Phase III stage.

Nonoxynol-9
The first compound to be tested in Phase III clinical trials as a microbicide candidate was nonoxynol-9, a popular spermicide that has been on the market for many years. This compound is frequently used with condoms and in diaphragm creams to provide additional contraceptive protection. Nonoxynol-9 is capable of inactivating some STD pathogens in the lab, but phase III trials showed that nonoxynol-9 did not provide significant protection against HIV. In fact, there is evidence that nonoxynol-9 enhances the risk of transmitting the AIDS virus.

A UNAIDS-sponsored study of the microbicidal effectiveness of a gel containing nonoxynol-9, compared to a placebo gel, was conducted in 1,000 African HIV-negative commercial sex workers. Women were counseled to use condoms consistently and correctly. Researchers found that the women who used nonoxynol-9 gel became infected with HIV at about a 50% higher rate than women who used the placebo gel.2 Women in the nonoxynol-9 group also had more vaginal lesions, which perhaps contributed to the higher rate of HIV transmission. Lesions are believed to be entry points for infectious pathogens such as HIV.

It could be argued that commercial sex workers do not represent a typical population of women, and that women who engage in sexual behavior less frequently might not experience the same risks. However, public health officials are concerned about continued widespread use of nonoxynol-9. Because this particular spermicide is used throughout the world, the results of studies on nonoxynol-9 may profoundly affect public health and the future of microbicide development. The World Health Organization gathered many leading AIDS researchers in Geneva in October 2001 and will issue a press release in January 2002 with an official policy and recommendation regarding nonoxynol-9. The uncertainty surrounding nonoxynol-9's future as a commercial spermicide could open the door to newer spermicidal products that do have microbicidal benefits.

First Generation New Microbicides
One microbicide that is ready to enter the Phase III clinical trial stage is also spermicidal. BufferGel (ReProtect, LLC, Baltimore, Maryland, USA) is a broad-spectrum microbicide that is designed to inactivate a wide range of pathogens by acidifying semen. The alkalinity of semen temporarily disrupts the natural acidity of the vagina by causing the vaginal pH to rise after sexual activity. In this more alkaline environment, sperm cells, pathogenic bacteria and pathogenic viruses remain active in the vagina after intercourse. BufferGel keeps the vaginal pH in the acidic range even after sexual activity. The acidity immobilizes sperm cells and inactivates some pathogens.3 A similar product known as Acidfast is in an earlier stage of development and testing.

Initial tests showed that BufferGel is capable of killing HIV in the lab. The product was well-received and tolerated by women in human safety trials.4,5 In rabbits, BufferGel offered significant contraceptive protection, but did not prevent pregnancy in all cases. Tests in mice demonstrated the product's effectiveness in preventing the spread of herpesvirus in addition to papillomavirus, which causes genital warts and has been linked to cervical cancer. As for bacterial pathogens, in mice BufferGel was able to reduce the transmission rate of Chlamydia trachomatis (chlamydia) but it was not effective against Neisseria gonorrheae (gonorrhea).

Another microbicide called PRO 2000 is to be examined with BufferGel in the same Phase III clinical trial. PRO 2000 is a sulfated polymer designed to block the attachment of HIV to human cells.7 PRO 2000 does not kill or inactivate viruses after sexual activity, but instead acts as an inhibitor of viral entry and essentially prevents infection. PRO2000 is likely to be more effective against viral diseases than bacterial diseases.

PRO 2000 is one of many sulfated polymers that are under development. Researchers at St. Mary's Hospital in the United Kingdom are working with scientists at the Institute for Tropical Medicine in Belgium on a dextrin sulfate vaginal gel that is entering the Phase II clinical trial stage.8

Other products that inhibit viral entry are designed to create a physical barrier that keeps pathogens away from human cells. The Invisible Condom, developed at Universite Laval in Quebec, Canada, is a gel that hardens upon increased temperature after insertion into the vagina or rectum.9 In the lab, it has been shown to effectively block HIV and herpes simplex virus. The barrier breaks down and liquefies after several hours.

Many products have been developed over the last two decades that inhibit the replication of HIV in the lab. Some of the more promising compounds are now given to AIDS patients undergoing highly active antiretroviral therapy (HAART). Many of these drugs fall into three categories: proteinase inhibitors, nucleoside reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors. Some of the drugs found to be most effective in stopping HIV in the lab are unsuitable for human use because of toxicity or because the body simply does not absorb them well. Such compounds that are unsuitable for use as oral medications might be usable in a topical microbicide. PMPA gel (Gilead Sciences, California, USA) using the antiviral agent, tenofovir, is one antiretroviral agent that is being tested in Phase I clinical trials.10 Since many of the HAART drugs are designed specifically to stop RNA viruses like HIV, these retroviral inhibitors may prove to be less effective against DNA viruses (such as herpes simplex virus).

Other microbicides artificially boost the human immune response to STD pathogens. Monoclonal antibodies to pathogenic organisms can be produced in genetically engineered plants for use in topical microbicides.11 The Plantibodies technology would allow microbicide designers to specifically target STD-causing pathogens.

Another approach involves the insertion of lactic acid bacteria. These bacteria are part of the normal human vaginal microflora and thrive in its acidic environment. Lactic acid bacteria help to prevent yeast infections and bacterial vaginosis, in part by secreting hydrogen peroxide to help maintain the vaginal acidity. Yogurt cultures rely on lactic acid bacteria, which can use the lactose naturally present in milk as a carbon source. Some doctors recommend eating yogurt to treat yeast infections because yogurt helps to rebuild the population of lactic acid bacteria.

Researchers at the University of Pittsburgh are investigating the use of suppositories of Lactobacillus crispatus that could be inserted monthly so that vaginal lactic acid bacteria populations always remain high. Clinical trials are focusing on the suppository's ability to prevent chlamydia, gonorrhea and trichomoniasis. The resulting acidic environment and the prevention of vaginosis and lesions may also be useful in inhibiting HIV transmission.

Some scientists are focusing on combinations of the above approaches. One product ready for Phase III clinical trials is carrageenan, a product derived from seaweed that is commonly used to solidify ice cream. Carrageenan has antimicrobial properties that, combined with its ability to thicken and inhibit viral entry, offers two types of protective mechanisms in one preparation.13 After some of the first generation microbicides have gone through clinical trials, it is likely that second generation microbicides will be designed to combine two or more prevention strategies.

Ethical Issues in Clinical Testing
Before a product can be marketed for human usage, it must be proven safe and effective in clinical trials. Because the rate of HIV heterosexual transmission is relatively low in some parts of the world, clinical trials could take years to produce significant results. To produce results quickly, trials must be conducted in populations with high levels of HIV infection. For that reason, HIV clinical trials have tended to recruit commercial sex workers in sub-Saharan Africa and other developing countries. Focusing on a population that carries many untreated sexually-transmitted diseases raises some ethical concerns, specifically regarding what constitutes informed consent and whether or not women understand the implications behind possibly receiving a placebo.
Because condom use significantly reduces the rate of HIV transmission, the consistent use of condoms can complicate clinical trials. If condoms are used, the number of women in the study must be very high in order to get significant results (women testing positive for HIV). Despite that limitation, HIV and microbicide studies have always included condoms, in addition to counseling on proper condom usage. Women are strongly encouraged to use condoms; however, it is assumed that some women in each test group will fail to regularly use them. Even though sexual behavior without condoms could be beneficial to a study in that it provides HIV-positive results, nearly all AIDS researchers believe that failing to strongly encourage the use of condoms would be unethical.15 One prominent scientist, however, has publicly raised the argument that counseling subjects to use condoms prolongs trials and potentially causes tens of thousands of avoidable deaths by delaying the availability of beneficial products.

Two Phase III trials, one testing both BufferGel and PRO 2000 and the other testing a carrageenan-based gel known as Carraguard, will not use commercial sex workers. "Most HIV researchers now agree that it is pointless to continue to use sex workers," Dr. Richard Cone of Johns Hopkins University and ReProtect stated. "They are infected in too many ways and bacterial vaginosis is rampant." Vaginal infections are believed to enhance the rate of HIV transmission.

"Most people are not having sex 20 times a week," said Dr. Polly Harrison, Director of The Alliance for Microbicide Research. "Some sex workers deal with rough sex and the lack of natural lubrication and some may be very young. I would say that future trials might only include sex workers as a subpopulation."

Avoiding commercial sex workers further increases the number of women needed to obtain timely and significant results. Designers of a Phase III trial to simultaneously study BufferGel and PRO 2000 initially estimated that 11,000 women must be recruited in order to obtain significant conclusions. A similar study involving Carraguard gel will need 6,600 women.

Political Issues
Funding for microbicidal research and development is relatively low in comparison to funding for other types of AIDS research. In 2000, Contraceptive Research and Development (CONRAD) established the Global Microbicide Project (GMP) with a $35 million grant from the Bill and Melinda Gates Foundation. The GMP and the National Institutes of Health (NIH) currently fund the bulk of microbicides research in the USA. Britain's Medical Research Council is among the funding leaders in Europe.

A bill that would increase government funding for microbicides research is under consideration in both houses of the United States Congress. The Microbicide Development Act of 2001 (H.R. 2405), sponsored by Rep. Connie Morella (R-Md.) along with Rep. Greg Ganske (R-Iowa) would establish the Centers for Microbicide Research and Development at the National Institutes of Health and would expand funding for research through both the new center at NIH and through the Centers for Disease Control and Prevention. Sen. John Corzine (D-N.J.) and Sen. Olympia Snowe (R-Me.) sponsored a similar bill in the Senate.

The bill specifically defines microbicides as products that protect women from HIV and other sexually-transmitted diseases. Spermicidal and contraceptive properties are not mentioned. If passed, the resulting law would fund research on microbicidal products whether or not those products have contraceptive properties. Contraception is believed to be more controversial than public health in the United States government; therefore, pending legislation focuses exclusively on the microbicidal aspects of the research.

Research into developing products to help women to protect themselves is not very controversial, at least with vaginal products. Rectal microbicides research may prove to be more difficult to fund, because some people associate anal intercourse with homosexual behavior.

Cervical Barriers
Since microbicides must be inserted into the vagina, an application method must be designed for each product. A microbicidal preparation can be prepared to use with a diaphragm or sponge that protects the cervix. Essentially, the applicator and microbicide would be one and the same, and would remain inside the vagina during sexual activity. The diaphragm or sponge would provide contraceptive properties, and the microbicidal coating on both sides of the barrier would help protect the woman from contracting a sexually-transmitted disease.

The presence of a diaphragm might be beneficial in other ways. Because the barrier prevents semen from entering the cervix, it would allow the microbicide and the semen to mix inside the vagina for a long time period, ensuring that the microbicide inactivates all pathogens. Additionally, the cervix is an entry point for STD pathogens. Closing that entry point might significantly inhibit the ability of the pathogen to infect a woman.17

Some researchers are now re-investigating whether cervical barriers by themselves protect against sexually-transmitted diseases. Because diaphragms are frequently used with nonoxynol-9, it is possible that the detrimental effects of nonoxynol-9 have masked the beneficial effects of the diaphragm blocking the cervical entry point.

Because diaphragms are not the most popular contraceptive in any geographical region, some argue that a diaphragm-based microbicide might not be used 100% of the time, much like condoms. Proponents of barrier-based microbicides point out that diaphragms are not popular because other contraceptives are more effective.18 If a diaphragm that offers effective STD protection were made available, it could become a more popular choice for women, but that conclusion is still the subject of much debate within the scientific and sociological communities.

Projections
In the United States, the history of contraceptive products is closely tied to disease prevention.19 The passage of the Comstock law in 1873 branded contraception as obscene and severely restricted public access to condoms. The popularity of condoms among American soldiers in Europe who wished to avoid contracting STDs during World War I created public pressure that led to a 1918 court ruling that allowed the sale of birth control for the cure or prevention of disease. Although condoms became readily available, many state laws still outlawed contraception. A woman could obtain a legal prescription for a diaphragm only if her doctor was willing to prescribe it for the prevention of disease. The 1965 Supreme Court decision in the case of Griswold v. Connecticut overturned 17 state laws by mandating that married couples must have access to legal forms of contraception. A 1972 decision gave unmarried individuals the same freedom.

For many years, contraceptives were sold in the U.S. as "disease control agents". Ironically, projections indicate that people who wish to use new microbicides may have to shop in the contraceptives section. The first microbicidal products on the market will likely be sold as contraceptive formulations. While clinical trials to establish microbicidal claims can be time-consuming, separate trials on the contraceptive properties of spermicidal microbicides can be completed quickly. If nonoxynol-9 were to be removed from the market, the resulting void might be filled by new spermicidal microbicides. While their microbicidal properties may not yet be proven, widespread usage of such products as contraceptives may help control diseases.

Epidemiological modeling studies performed at The London School of Hygiene & Tropical Medicine have predicted that microbicidal availability will have a positive public health effect. The model shows that even low efficacy products that are used with high frequency are as effective as high efficacy products that are not used consistently (such as condoms). Microbicides as an alternative to or in addition to condoms are likely to significantly inhibit disease transmission.

According to most estimates, the first generation of microbicidal products could be available to the public by the end of the current decade. In 10 years (2012), first generation products may be widely available and second generation microbicides, both contraceptive and non-contraceptive, may be emerging on the marketplace.