Microbicides are substances designed to address the biological factors that make women more vulnerable to infection that when applied topically to the vagina could prevent sexual transmission of HIV. Unlike condoms, microbicides represent a method that women could control themselves. Theoretically, they could be produced in many forms, including gels, creams, suppositories, films, or as a sponge or ring that release the active ingredient over time. Some microbicides are also being developed for rectal use.

Several microbicide products are being tested in clinical trials, although none is yet approved or available for widespread use. If proven effective, microbicides could be an inexpensive and readily available approach for many women, especially those in developing countries where HIV most often is spread through unprotected heterosexual intercourse despite educational efforts that promote abstinence, monogamy and condoms. Even a partially effective microbicide could have a profound impact on the dynamics of HIV transmission.

In reality, not everyone may be able to negotiate condom use, condoms may not be readily available at the time of sexual intercourse, or couples simply may choose not to use them. And for women in many countries, being faithful to one partner is far from being foolproof. Indeed, in countries like India, a married woman is among those at highest risk of HIV acquisition.

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. Unfortunately, it proved neither safe nor effective for HIV prevention. Still, it was recognized that new microbicide products needed to be developed and the field focused its efforts on developing what would be first-generation microbicides. These worked to enhance vaginal defenses or prevent the fusion of the virus with the target cell. With a greater understanding of how HIV is transmitted and the specific viral and cell targets involved, researchers are now looking to develop microbicides with greater specificity against HIV. 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:

• 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
• Surfactant or detergent microbicides that disrupt microbial cell membranes, thereby inactivating or killing the virus
• Fusion or entry inhibitors that block cellular receptors so that HIV is unable to attach to and infect target cells
• Replication inhibitors that prevent HIV from replicating once inside a cell. Some of these employ the same mechanism of action as oral anti-retroviral (ARV) therapy used for the treatment of HIV

Beyond being effective, microbicides for HIV prevention must be safe. As well, they must be easy to use, and both women and their partners must find them acceptable. Toward this end, a critical step in the development of microbicides will be 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 do ring delivery systems that women would insert on a monthly or periodic basis.

More research is beginning to focus on the development of rectal microbicides. An ongoing trial and others being planned involve products formulated for the vagina, which may have limited effectiveness in the rectum. As such, there is increasing interest in evaluating candidate microbicides that have been formulated specifically for rectal use.

Like any pharmaceutical product, candidate microbicides must first undergo rigorous testing in the laboratory before they may be considered for testing in humans in carefully designed clinical trials. 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 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.

There are currently 10 candidate microbicides in various stages of clinical study and more than 30 in preclinical development. [insert link to Alliance website]. Researchers predict it may be five to 10 years before any one of these is available as an approved product.