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Where Are the Microbicides? A Never-Ending Wait

Winter 2007/2008

Where Are the Microbicides? A Never-Ending WaitThe UNAIDS has placed a new face on the HIV pandemic. Its data show that, in some parts of the underdeveloped world, women between the ages of 15 and 24 years are now three times more likely to be HIV-positive than young men. The outlook for women becomes graver when statistics gathered by the Joint United Nations Programme on HIV/AIDS are considered: although approximately 40 million people worldwide are living with HIV and AIDS, more than half of new HIV infections worldwide are occurring in women. As Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health (NIH), pointed out, "[T]he majority of women living with HIV/AIDS worldwide became infected through heterosexual intercourse, usually in settings where they could not say no or negotiate condom use. These issues compel us to develop HIV prevention tools that women can use in situations when negotiating with sexual partners is difficult or impossible."1 These facts highlight the need for a female-controlled method of preventing HIV and other sexually transmitted diseases (STDs) that would empower women with regard to their sexual and reproductive health.

For many years, women have been offered a preventive method that meets this need, although in a small way. Female condoms have been available since the mid-1990s, but they have never gained much popularity as an HIV-prevention method for several reasons. They are difficult to use, usually require the cooperation of the male partner, and are much more expensive than male condoms. Costliness is perhaps the most limiting factor for poor women, both in the United States and in the developing world. The unfortunate outcome of this circumstance is that women are left with few other options to protect themselves from HIV infection or reinfection from their sexual partners. This point becomes especially salient when the other dangers posed to women who are unable to initiate condom use with a sexual partner are considered. Cultural norms worldwide support male sexual hegemony and gender inequality, and the threat of intimate-partner violence is very real.

Despite this reality, progress in the development of female-controlled prevention methods has been slow, if not completely stalled. Microbicides, which first received attention in the early 1990s, function as a barrier method when applied inside the vagina or rectum to protect against HIV and other sexually transmitted diseases (STDs). They can be formulated as gels, creams, films, or suppositories and may or may not have spermicidal activity (i.e., a contraceptive effect).2 Ideally, microbicides would be female-controlled, inserted by the woman before sex to control her risk for HIV or pregnancy, and would be affordable and simple to use. Nevertheless, not a single microbicide has been approved for use as an HIV preventative since the beginning of the pandemic.

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Currently, there are 36 organizations involved in microbicide research, and clinical trials of 12 products in the U.S. and of 15 in other countries are ongoing. Most microbicides under development, including the five being tested in phase III clinical trials, act in one or more of the following ways3: (See Figure 1.)

Where Are the Microbicides? A Never-Ending Wait
Click on image to enlarge.

  • Vaginal defense enhancers boost the body's natural defenses against infection by increasing lactobacilli or by rapidly acidifying the ejaculate, reinforcing the natural mild acidity of the vagina that inactivates both sperm and STDs. BufferGel® and ACIDFORM™ are vaginal defense enhancers.
  • Surfactants damage the surface membranes of disease pathogens, thereby disabling them and preventing them from causing infection. Savvy® vaginal gel (C31G) and octoxynol-0 are surfactants.
  • Entry and fusion inhibitors bind to disease pathogens or to healthy cells before pathogens have a chance to invade and attach to them. Carraguard®, PRO 2000®, and cellulose sulfate are entry and fusion inhibitors.
  • Replication inhibitors prevent viruses from replicating in cells that they have entered. Replication inhibitors are still being tested in preclinical studies or in phase I or phase II clinical trials. None has yet reached phase III. Tenofovir (Viread®) and dapivirine (TMC120 gel) are replication inhibitors.

Because of the urgent need for a female-controlled product, the Population Council has focused on creating a vaginal, noncontraceptive microbicide. Unfortunately, the news has not been encouraging. Clinical trials of cellulose sulfate (Ushercell) had to be cancelled in 2007 because interim results suggested an increase in HIV acquisition rates among women randomized to receive the active product rather than placebo.4

Carraguard, a microbicide that protects against HIV by providing a physical barrier that keeps HIV and other pathogens from reaching target genital and rectal cells, was close to being marketed. However, in breaking news, the Population Council has just announced that its phase III study of Carraguard failed to reduce the risk of HIV infection among women who received it in a large, placebo-controlled study. The good news is that the Population Council is continuing to advance the study of microbicides. They are now in the earliest stages of clinically testing two newer microbicidal formulations, PC 815 and Carraguard/LNG.

During the past year, tenofovir has received greater attention as a possible microbicide for men who have sex with men. Although a trial in monkeys is still ongoing, the rate of protection achieved thus far was significant.5 Because of its demonstrated effectiveness as a microbicide, the Centers for Disease Control and Prevention has launched several trials to test the drug as an HIV-prevention tool. When tested in HIV-negative women, the non-nucleoside reverse transcriptase inhibitor (NNRTI) dapivirine has also demonstrated clinical safety and tolerability as a potential vaginal microbicide. And when used in combination, tenofovir, dapivirine, and another investigational product (L-860,167) have shown in-vitro anti-HIV activity, suggesting that they may be candidates for a combination microbicide.6

There has also been significant research on spermicides. Many women are familiar with nonoxynol- 9, which is an over-the-counter spermicide that has been used to prevent HIV infection. The results of a study published in 2001, however, indicate that nonoxynol-97:

  • Increases the risk of HIV infection when used by women at high risk for such infection but can be used by women at low risk
  • Does not offer any protection from STDs
  • Causes genital lesions in women
  • Should not be used rectally
  • Does not offer any more protection than a condom not lubricated with the spermicide.

Despite these findings, the authors of the study recommended that nonoxynol-9 be used whenever possible.

Even in the 21st century, HIV infection among women is often driven by social, cultural, and economic gender inequalities that decrease women's ability to negotiate the use of prevention methods. Having an affordable female-controlled prevention method would increase a woman's ability to exercise control of both her risk for HIV and for pregnancy. In the latter case, such a prevention method could also help reduce mother-to-child transmission of HIV. Yet an effective female-controlled microbicide is still not visible on the horizon. Like most interventions, advocacy seems to help move the process along. Community-based women's groups are mobilizing throughout the world in support of microbicides, but the numbers of people involved overall are inadequate to make the needed impact. In the United States, the number of women involved is particularly few, even though the case for the development of a microbicide has been made as the face of the HIV pandemic has changed.

Many researchers believe that female-controlled contraception would lower the number of women exposed to HIV through sexual relations and have not been daunted by the negative results obtained with cellulose sulfate and with nonoxynol-9. For them, these results do not signal failure for the microbicide field or for the broader biomedical HIV-prevention research effort as a whole. As Fauci asserted, "[T]he NIH intends to test microbicides that include antiretroviral drugs to increase the protective effects even if vaginal inflammation [caused by spermicides] occurs ... Women have difficulty getting access to health care and ... are diagnosed at later stages of HIV/AIDS than men. Therefore, we need to expand and support educational and employment opportunities for women and girls to address the harmful effects of inequality."1

The problems inherent to interpersonal relationships will not be resolved with the development of an effective microbicide. Nevertheless, having this preventive tool will allow each individual in a relationship to share in the responsibility of protecting himself or herself against HIV and other STDs. Whether microbicides are developed specifically for women or for men, a reduction in the spread of HIV and other STDs is the ultimate goal no matter one's sexuality. As individuals take more control over their sexual health, the dynamic of their interpersonal relationships are likely to be changed as well. The real promise of microbicides, then, is the empowerment of individuals to make the choices needed to maintain their health and well-being.

So, where are the microbicides? We are still waiting.

Deneen Robinson is an independent consultant with many years of experience in HIV-related issues. Her company is the Savant Consulting Group.


References

  1. Kaiser Daily HIV/AIDS Report. NIAID Director Fauci Discusses Effect of HIV/AIDS on Women. Accessible at: www.kaisernetwork.org/daily_reports/rep_index.cfm?hint=1&DR_ID=43522.
  2. World Health Organization. Microbicides. Accessible at: www.who.int/hiv/topics/microbicides/microbicides/en/.
  3. The Info Project. Five Microbicides in Development. Accessible at: www.infoforhealth.org/inforeports/microbicides/microbs1.shtml.
  4. Buchbinder S. Emerging Strategies to Curb HIV Transmission. Accessible at: http://www.medscape.com/viewarticle/554189.
  5. Cairns G, Carter M. Tenofovir microbicide stops rectal infection in monkeys better than PrEP. Accessible at: www.aidsmap.com/en/news/CA55C631-3741-4634-9BDD-56500A0A4C0D.asp.
  6. Thaczuk D, Carter M. Dapivirine safe and tolerable as potential vaginal microbicide; displays potential in combination with other agents. Accessible at: www.aidsmap.com/en/news/8E207FCB-F436-4EAF-8811-68EA1C288805.asp.
  7. Richardson BA, Lavreys L, Martin HL Jr, et al. Sex Transm Dis. 2001 ;28 :394-400.


  
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This article was provided by The Center for AIDS. It is a part of the publication Research Initiative/Treatment Action!. Visit CFA's website to find out more about their activities and publications.
 
See Also
Winter 2007/2008 Issue of Research Initiative/ Treatment Action!
More Information on HIV Prevention Research
More on Microbicides

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