Microbicides are substances designed to prevent or reduce the sexual transmission of HIV when applied topically inside the vagina or rectum. Theoretically, microbicides could be produced in many forms, including gels, 
creams, suppositories, films, or as a sponge or ring that releases the active ingredient over time. Some microbicides are also being developed for rectal use by either men or women.
Testing of many products will likely be required before finding even one microbicide that is safe and effective against HIV and that’s also easy to use and acceptable to both sexual partners.
If proven effective, microbicides could have particular impact among women in developing countries, where HIV most often is spread through unprotected heterosexual intercourse despite educational efforts that promote abstinence, monogamy and condoms, approaches that are not often practical anyway. Condoms may not be readily available at the time of sexual intercourse, or if they are, women can’t always convince their partners on their use. Abstinence is not desirable for women wanting children, and for many women, being faithful to one partner is far from foolproof. Indeed, in countries such as India, a married woman is among those at highest risk for HIV. Microbicides are seen as an HIV prevention method that women can control themselves.
The idea for a microbicide-like product was first proposed more than 15 years ago by reproductive health specialists and advocates who recognized the need for female-controlled HIV prevention methods. One of the first products considered, nonoxynol-9, had been developed as a spermicide, and there was reason to believe it would be effective against HIV as well. As trials proved it neither safe nor effective against HIV, the field focused its efforts on developing products intended to prevent HIV, and other STIs, by either enhancing vaginal defenses or creating a barrier between target cells. Researchers are now beginning to evaluate products with specific action against HIV that are based on the same antiretroviral drug platform used successfully for HIV treatment regimens. Unlike their predecessors, these newer generation products do not have to be applied at the time of sex. Researchers are exploring their daily use as a gel and other formulations, such as a ring, that in theory could be inserted once a month, for example. Products that employ multiple active ingredients or mechanisms of action are also being explored.
Microbicides are classified according to their primary mechanism of action, which include:
- Surfactants that disrupt microbial cell membranes, thereby inactivating or killing the virus. Examples: Nonoxynol-9, Savvy. (Surfactants are no longer being considered for testing.)
- Vaginal defense enhancers that seek to make the vagina an environment hostile to STIs and HIV by maintaining or boosting the naturally protective acidity of the vagina or by increasing the colonization of protective microorganisms. (Examples: BufferGel, ACIDFORM)
- Fusion or entry inhibitors that block cellular receptors so that HIV is unable to attach to and infect target cells. (Examples: PRO 2000, Carraguard, cellulose sulfate, VivaGel)
- Replication inhibitors or ARV-based microbicides that prevent HIV from replicating once inside a cell. Some of these employ the same mechanism of action as the ARV drugs used in the treatment of HIV. (Examples: tenofovir gel, UC-781, MV-150, dapivirine)
Finding a microbicide that is effective against HIV will not be enough. A microbicide must also be safe, easy to use and acceptable to both sexual partners. The safest and most effective product will do no good if people don’t use it. Toward this end, a critical step in the development of microbicides is the design of products that do not have to be used at the time of intercourse. Replication inhibitors, or ARV-based microbicides, may have this advantage, as may ring delivery systems that women would insert on a monthly or periodic basis.
To date, the majority of microbicide research has focused on vaginal microbicides used for the prevention of HIV in women. Yet, receptive anal intercourse is 
common among men who have sex with men and there is increasing evidence that heterosexual women in both the developed and developing world also practice receptive anal intercourse. The risk of HIV associated with unprotected anal sex is 20 times greater than with unprotected vaginal sex, according to some estimates. Current studies are evaluating rectal safety of vaginal microbicides. But because products formulated for the vagina may have limited effectiveness in the rectum, research is also focusing attention on the need for candidate microbicides formulated specifically for rectal use.
Drug development is an arduous journey that can take more than 15 years before a single agent is approved for use. Thousands of potential compounds may be considered during the drug discovery stage but only the most promising candidates will be subjected to rigorous laboratory and animal study, and fewer still will make it as far as a clinical trial. Clinical trials are carried out in a prescribed progression under the oversight of regulatory and research authorities and in accordance with stringent ethical and scientific guidelines. Phase I trials are designed to evaluate safety in a small number of individuals who are exposed to study products for short periods, perhaps one to two weeks. If results of a Phase I study suggest the product is safe, investigation will progress to a Phase II trial, in which researchers continue to track safety over more extended periods of time. Phase IIb and III trials are performed to determine effectiveness and are conducted in large numbers of participants, usually at multiple centers. They may be designed to compare one product’s effectiveness with another’s and/or with an inactive agent, or placebo. Data from a Phase III trial are often used by regulatory agencies to determine if a particular product should be approved for widespread use.
Different gels work in different ways. At this point in time, researchers do not yet know the ones that will work the best. More than 10 candidate microbicides are in various stages of clinical study and more than 50 are in preclinical development. Researchers predict it will be some years before any one of these is available as an approved product. For the latest information on microbicide development see the Alliance for Microbicide Development’s monthly pipeline update at http://www.microbicide.org/cs/pipeline.
