Fast Facts:
- Microbicides are substances designed to prevent or reduce the sexual transmission of HIV or other sexually transmitted infections (STIs) when applied topically on the inside of the vagina or rectum.
- 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. Microbicides are seen as a method women can control themselves.
- 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 being developed for rectal use by either men or women.
- Different microbicide products are being tested in clinical trials, although none is yet approved or available for widespread use.
Overview:
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, was developed as a spermicide, but there was reason to believe it might also be effective against HIV. 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.
Microbicides are classified according to their primary mechanism of action:
- Surfactants 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 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. Example: BufferGel, ACIDFORM.
- Fusion or entry inhibitors 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 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.
The Clinical Development Process:
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. Different gels work in different ways. At this point in time, researchers do not yet know the ones that will work. 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.
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, say, 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.
Current and Planned Late-Stage Clinical Trials of Candidate Microbicides:
- MDP 301 – Phase III trial of PRO 2000 in 9,395 women. Enrollment has been completed and results are expected late 2009. Being conducted by the Microbicides Development Programme.
- CAPRISA 004 – Phase IIb trial of tenofovir gel evaluating a dosing strategy timed around sexual intercourse. Study will enroll 980 women and is expected to be completed in 2010. Being conducted by the Centre for the AIDS Programme of Research in South Africa (CAPRISA).
- VOICE (MTN-003) – Phase IIb trial of tenofovir gel as well as oral tenofovir and Truvada. Enrollment of nearly 5,000 women began August 2009. Being conducted by the MTN.
- IPM-009 – Phase III trial of dapivirine (TMC-120) being planned by the International Partnership for Microbicides.
Earlier Trials:
- HPTN 035 – This Phase IIb trial of PRO 2000 and BufferGel involved more than 3,000 women in Africa and the United States and demonstrated for the first time the promise of a vaginal microbicide for preventing HIV in women. Results, reported February 2009, found PRO 2000 was 30 percent effective. While encouraging, the level was not statistically significant, and additional clinical evidence is needed to determine more definitively its effectiveness. Conducted by the Microbicide Trials Network (MTN).
- Carraguard – A Phase III trial of Carraguard, a microbicide candidate developed from carrageenan, a derivative of seaweed, showed the product was safe and acceptable to women, but did not reduce their risk of acquiring HIV. Study was conducted by the Population Council and enrolled 6,202 women between 2004-2007. Results were announced 2008.
- Cellulose Sulfate – In 2007, two Phase III trials were closed early after an interim review by the Data Safety and Monitoring Board (DSMB) for the CONRAD study suggested increased risk of HIV infection among women using the gel. As a precaution, the Family Health International (FHI) study was also closed, although its DSMB review found no evidence of increased risk.
- Savvy (C-31G) – Two Phase III trials of Savvy closed, the first in 2005 and the second in 2006, after interim reviews indicated little convincing evidence that Savvy protects against HIV. Both studies were conducted by FHI.
What About Rectal Microbicides?
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 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. As such, studies evaluating rectal safety of vaginal microbicides are gaining in importance with two trials being planned. 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. Early phase clinical studies of a rectal-specific formulation are in development.
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15-July-09
The Microbicide Trials Network (MTN) is an HIV/AIDS clinical trials network established in 2006 by the National Institute of Allergy and Infectious Diseases with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health, all components of the U.S. National Institutes of Health. Based at Magee-Womens Research Institute and the University of Pittsburgh, the MTN brings together international investigators and community and industry partners who are devoted to reducing the sexual transmission of HIV through the development and evaluation of products applied topically to mucosal surfaces or administered orally. More information about the MTN is available at http://www.mtnstopshiv.org .
