Vaginal microbicides needed for female-controlled prevention

Products to help women protect against HIV/AIDS

By the end of the century, women will outdistance men in the numbers of those living with HIV infection.1 To combat the increasing risk, women need more options for prevention. While the search continues, no "magic bullet" has emerged, notes Michael Rosenberg, MD, MPH, clinical professor of OB/GYN and epidemiology at the University of North Carolina and president of Health Decisions, a private medical research firm, both in Chapel Hill.

"Why has the search been going on now for more than 10 years, and we’re no closer to this than we were at that time?" he asks. "How well will this magic bullet will perform in relation to what we now have, nonoxynol-9 [N-9], plus some others?"

Male condoms greatly reduce disease transmission, but they must be used correctly and consistently to offer protection, and their use is ultimately outside the control of women. Female condoms represent a barrier method that women can choose to use, but because the condoms’ outer rings are visible, they may cause problems for women whose partners object to condom use.

Vaginal microbicides represent a preventive option that women can control easily. They do not require negotiation or consent from a partner. With such a "stealth" method, women gain another method to fight the war against AIDS.

Several products are in the research pipeline, and some use the spermicide nonoxynol-9 or other surfactants. Others include acid buffering gels; natural products such as lactobacillus crispatus, antimicrobial peptides, magainins, or plant extracts; inhibitors of viral entry; post-binding fusion inhibitors; and reverse transcriptase inhibitors.

N-9 and its role

Most American women are familiar with products containing the N-9 spermicide. It is available in several over-the-counter formulations, including foam, jelly, cream, film, and gel. Some believe the shortest path to introduction of a microbicide is to prove in clinical trials that N-9 spermicides are effective against HIV and sexually transmitted disease (STD) transmission.

"I think it’s felt that we could get a spermicide on the market faster than we could get a product that has an HIV or STD indication because you could do the spermicidal studies more quickly," observes Zeda Rosenberg, ScD, senior scientist for prevention research with the National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda, MD. "It is true you could get a spermicide on the market; however, you couldn’t suggest that anyone use that for STD or HIV prevention until you did the efficacy studies." (Spermicides with N-9 are now under clinical review for contraceptive effectiveness, which will end reliance on decades-old data. See Contraceptive Technology Update, January 1999, p. 5.)

What about vaginal irritation?

Concerns about N-9’s potential for vaginal irritation cloud the issue of its use in HIV/STD prevention. While N-9 is a surfactant that destroys the sperm cell membrane, frequent use has been associated with vaginal epithelial disruption.2

In the lab, N-9 is lethal to organisms that cause gonorrhea, genital herpes, trichomoniasis, syphilis, and HIV.3 However, a study published last year showed the use of a N-9 vaginal film did not reduce the rate of new HIV, gonorrhea, or chlamydia infection in a group of sex workers who used condoms and received STD treatment.4

"I don’t think we have answered the question whether N-9, in a higher dose, in a better formulation, works," remarks Zeda Rosenberg. "I think that keeping an open mind on this, the study needs to be done. Given that there are varying spermicidal capabilities of different N-9 formulations, it could very well be that the formulation is the crucial component here."

A Phase III trial sponsored by The Joint United Nations Programme on HIV/AIDS (UNAIDS) of Geneva, Switzerland, is examining the efficacy of a N-9 gel in HIV/STD transmission. Scientists with the Population Council in New York City are looking at use of N-9 in conjunction with carrageenan, a compound derived from red seaweed, in prevention of HIV and other STDs. Researchers are testing carrageenan alone and in tandem with N-9 in developing a spermicide that will protect against HIV while maintaining the same protection against pregnancy.5

What are the ideal characteristics for a new microbicide? According to Zeda Rosenberg, they include the following:

• active against a range of STD-causing pathogens;
• not irritating to mucosal surfaces;
• available in both spermicidal and non- spermicidal formulations;
• acceptable (color, taste, lubricity, portability, and "stealth factor");
• biodiffusible;
• bioadhesive;
• absence of systemic absorption;
• long-acting;
• stable at high temperatures;
• able to maintain or enhance normal vaginal ecology.

Add "inexpensive" and "available without a prescription" to the wish list as well, suggests a similar UNAIDS listing.6

Study: Odorless cream preferred

A study involving more than 600 Brazilian women examined their preferences regarding a vaginal antimicrobial contraceptive.7 Most women indicated they would prefer a cream rather than a suppository, with no taste, odor, or color, or at least a light color. Its application should precede intercourse, be done with an applicator, and last for more than eight hours. Such a method would offer protection against pregnancy, as well as against HIV and STDs.

Several challenges face researchers as they test new topical microbicides. There is insufficient knowledge on vaginal transmission of HIV and other STD pathogens, as well as limited understanding of cervico-vaginal and intercourse physiology, human sperm biology, and fertilization. There also is no well-established correlation between in vitro, animal models, and clinical testing. A lack of optimal formulations and technical issues such as amount, purity, and solubility add to the challenge.

It also is difficult to independently assess the efficacy of the microbicide in the trial without compromising current recommendations to include condoms with every act of intercourse. In the study on N-9 film, a majority of sex workers who were counseled to use condoms were able to do so with their paying clients.4 There is a move to test more populations of women in primary partnerships, rather than commercial sex workers, Zeda Rosenberg says. These women would receive intensive education on condom use in a run-in phase prior to the microbicide trial. Those who continue failing to use condoms at least half the time would be trial candidates.

Microbicides should be available in spermicidal and non-spermicidal forms so women who desire to become pregnant can safely do so without risk of HIV/STD infection. Researchers also are looking at rectal use of microbicides for use in heterosexual couples who engage in anal intercourse, as well as in men who have sex with men.

"It’s a great idea to do combination microbicides," notes Zeda Rosenberg. "We are working with forging liaisons between companies, because some companies have great formulations, and some companies have good-looking active ingredients."

Whether products protect against pregnancy and HIV, HIV alone, or against specific STDs, the time is now for their emergence, says Daniel Malamud, PhD, professor of biochemistry at the University of Pennsylvania and vice president of research and development at Biosyn, both in Philadelphia. Biosyn is working with C31G, a family of molecules with broad-spectrum capabilities.

"I think you want a broad spectrum, but if it is easier to get one that is HIV-specific, which is the real crisis now, I would certainly support that," he notes. (CTU will offer an overview of microbicide products in the research pipeline in the April issue.)

References

1. Report on the Global HIV/AIDS epidemic. UNAIDS; December 1997.

2. Roddy RE, Cordero M, Cordero C, et al. A dosing study of nonoxynol-9 and genital irritation. Int J STD AIDS 1993; 4:165-170.

3. Elias CJ, Coggins C. Female-controlled methods to prevent sexual transmission of HIV. AIDS 1996; 10 (suppl 3):S43-S51.

4. Roddy RE, Zekeng L, Ryan KA, et al. A controlled trial of nonoxynol 9 film to reduce male-to-female transmission of sexually transmitted diseases. N Engl J Med 1998; 339:504-510.

5. Carrageenan and nonoxynol-9 STI prevention investigated. Population Briefs 1998; 4:5.

6. Microbicides for HIV prevention: UNAIDS Technical Update (UNAIDS Best Practice Collection: Technical Update). Geneva: UNAIDS, April 1998.

7. Hardy E, Pádua KS, Jiménez AL, et al. Women’s preferences for vaginal antimicrobial contraceptives II. Preferred characteristics according to women’s age and socioeconomic status. Contraception 1998; 58:239-244.