Two public health agencies are recommending that the contraceptive spermicide nonoxynol-9 (N-9) should not be used as a means of HIV protection among high-risk women.
The Centers for Disease Control and Prevention (CDC) in the United States and the Geneva-based Joint United Nations Programme on HIV/AIDS (UNAIDS) recently recommended that women should not use N-9 spermicides to prevent HIV transmission. CDC also recommends that N-9 should not be used as a protective barrier against HIV transmission during anal intercourse.1
This means providers should discontinue counseling individuals who cannot use a condom to consider N-9 spermicides for HIV prevention. Providers should inform condom users that using an N-9 lubricated condom is better than using no condom at all, but N-9 may not offer any additional protection against HIV. Condoms without N-9 may be a better option for HIV prevention.
The recommendations reflect the implications of a recent study by UNAIDS and the U.S.-based Columbia Laboratories. In that study, preliminary data suggested that N-9 was not effective against HIV infection and may have facilitated HIV transmission. Both the CDC and UNAIDS continue to review their public health guidelines for the use of N-9 for HIV prevention and for pregnancy prevention in populations at high risk for HIV.
The UNAIDS-sponsored study, conducted among 991 prostitutes in Benin, South Africa, Thailand and Côte d'Ivoire, showed that a low-dose (52.5 mg) N-9 gel was significantly less effective in protecting women from HIV than the placebo, a vaginal moisturizer called Replens. All women were given HIV counseling, provided with condoms and encouraged to have their partners use condoms. Nevertheless, 59 of 500 women using the N9 gel acquired HIV, compared with 41 of 500 women in the placebo group. Women exposed to N-9 spermicide were also more likely to have genital lesions, thought to increase risk of HIV acquisition.2
"We know N-9 is not the answer [to HIV prevention] -- so we need to continue the search" for an effective microbicide to prevent HIV transmission, says Dr. Joseph Perriëns, head of the UNAIDS microbicide effort.
Meanwhile, individuals need to know that a male latex condom used every time they have vaginal, oral or anal sex is the most effective way to reduce the risk of sexually transmitted infections (STIs), including HIV. They should use a condom during sex if they have any of the following risk factors: they have a new sex partner, or their partner has sex with another person; they or their partner gets any STI or HIV/AIDS; or, they or their partner share drug injection needles with others.
Unanswered questions
"Given the results of the UNAIDS trial, people are appropriately cautious," says Dr. Penelope Hitchcock in the United States, chief of the Sexually Transmitted Diseases Branch of the U.S. National Institute of Allergy and Infectious Diseases (NIAID). "It is clear that N-9 can irritate the vagina and we are increasingly aware that vaginal lesions have the potential to make women vulnerable to HIV infection."
Although an earlier FHI study in Cameroon showed no difference in HIV transmission rates among women using a low-dose (72 mg) N-9 vaginal contraceptive film and women receiving a placebo film, rates of genital lesions among women who used N-9 were greater than among women using placebo.3 In another study, use of a contraceptive sponge containing 1,000 mg N-9 was associated with increased incidence of both genital ulcers and HIV infection.4
However, some experts have not abandoned hope for N-9 as a prophylactic. First, they point out, more women using N-9 in the UNAIDS trial may have acquired HIV than women using the vaginal moisturizer placebo because the moisturizer itself may have had a protective effect. Preventing the vagina from becoming dry may have reduced vaginal trauma and lesions during intercourse.
Also, the UNAIDS trial data need further, closer analysis. "Only a preliminary analysis of the UNAIDS trial data has been made public," says Dr. Hitchcock. For example, scientists have not analyzed the degree of exposure to N9 by women who became HIV-infected.
N-9 spermicides might still be shown to protect against HIV among women who use the product infrequently. The vaginal irritation or ulceration caused by N-9 is related to the N-9 concentration per dose and frequency of use, with lower concentration and less frequent use causing less or no irritation or ulceration.5
All studies of N-9 spermicide effectiveness against HIV transmission have been conducted among high-risk commercial sex workers. Conducting such trials has been considered essential "in order to get an answer in a reasonable time among a reasonable number of people," says Dr. Hitchcock. "We must do studies in high-risk populations where use of the test product possibly holds the highest benefit, as well as possibly the highest risk. The dilemma is that the results of a trial among high-risk women who use the product often may not be indicative of how well the product protects low-risk women who might use it far less often." Infrequent exposure to N-9 spermicide, for example, is less likely to lead to vaginal irritation than exposure to it several times a day.
Results from trials conducted among commercial sex workers are also difficult to interpret because of the sexual practices of these women, says Dr. Zeda Rosenberg of FHI, scientific director of the HIV Prevention Trials Network (HPTN), a research project involving FHI and other organizations to evaluate HIV prevention interventions, including experimental microbicides. "While commercial sex workers may be successful in negotiating condom and microbicide use with their clients," she says, "they tend not to use these products with their primary partners. Thus, while working, they may develop condom or microbicide-related vaginal irritation that increases their risk of HIV infection when they have unprotected sex with an infected primary partner."
For these reasons, testing the effectiveness of N-9 as a microbicide against HIV among women who use the product infrequently but are still at high risk of infection "would be useful," says Dr. Rosenberg.
Status of N-9 trials
Due to safety concerns, FHI and the other organizations involved in HPTN have discontinued testing N-9 as an agent for HIV prevention. A proposed HPTN study of a high-dose (100 mg) N-9 gel among some 4,500 HIV-negative women in Malawi and Zimbabwe will not proceed as planned.
An N-9 study in Cameroon by the Care and Health Program, a nongovernmental agency, and FHI evaluated the effectiveness of high-dose (100 mg) N-9 gel against male-to-female transmission of gonorrhea and chlamydia among 1,000 high-risk women. (The use of N-9 spermicide among volunteers in the study was nearly completed when the UNAIDS trial results were released.) There is no evidence that N-9 used relatively infrequently, as it was in this study, increases risk of HIV infection.
Meanwhile, FHI is conducting a randomized, controlled U.S. study to evaluate further the contraceptive efficacy and consistency of use of N-9 spermicide products in various doses and formulations. This trial involves women who are at low risk for HIV, unlike the high-risk study population in the UNAIDS study. Also, participants in the efficacy study are monogamous. "Nevertheless, we feel that it is appropriate to inform women in our trial about the UNAIDS trial results," says Dr. Elizabeth Raymond of FHI, an obstetrician-gynecologist who is the study's principal investigator. "For women who are currently enrolled, we have issued a fact sheet informing them of the results and stressing the need to take precautions in situations of high risk for STI/HIV infection. For future participants, we have modified the existing informed consent form to include more information about spermicides and HIV."
Concerns raised by the UNAIDS study have fueled a sense of urgency to test experimental microbicidal candidates. Several products currently in advanced safety testing in women could proceed more quickly to combined safety and efficacy evaluation.
All microbicidal agents under scrutiny for advanced efficacy testing are unlikely to cause the vaginal irritation associated with N-9. Some of them are noncontraceptive. "This is very important," says Dr. Hitchcock, "since women throughout the world need a way to get pregnant without running the risk of becoming infected with HIV."
-- Kim Best
References
Gayle HD. Notice to readers: CDC statement on study results of product containing nonoxynol-9. MMWR 2000;49(31):717-18.
Van Damme L, Laga M. Vaginal microbicides, an update. The XIII World Conference on HIV/AIDS, Durban, South Africa, July 9-14, 2000.
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(8):504-10.
Kreiss J, Ngugi E, Holmes KK, et al. Efficacy of nonoxynol-9 contraceptive sponge use in preventing heterosexual acquisition of HIV in Nairobi prostitutes. JAMA 1992;268(4):477-82.
Roddy RE, Cordero M, Cordero C, et al. A dosing study of nonoxynol-9 and genital irritation. Int J STD AIDS 1993;4(3):165-70; Martin HL, Stevens CE, Richardson BA, et al. Safety of a nonoxynol-9 vaginal gel in Kenyan prostitutes: a randomized clinical trial. Sex Trans Dis 1997;24(5):279-83; Martin HL Jr, Richardson BA, Stevens CE, et al. Evaluation of a low dose nonoxynol-9 gel for the prevention of sexually transmitted diseases, Abstract No. 33610. Int Conf AIDS 1998;12:29.
In some cultures, heterosexual anal intercourse has been practiced for many reasons, including pleasure, curiosity, preventing pregnancy, preserving virginity or avoiding contact with menstrual blood.1
Survey data from both developed and developing countries show that between 10 percent and 50 percent of sexually active adolescents and adults in the general population have engaged in heterosexual anal intercourse.2Most of these individuals do not use condoms to protect themselves from disease. Having unprotected, receptive anal sex presents more risk of sexual HIV transmission for women than does unprotected vaginal intercourse.3It is also associated with anorectal sexually transmitted infections (STIs), hepatitis B infection and human papilloma virus (HPV)-related anal lesions and cancer in women.4
"Not only is the prevalence of this culturally taboo practice probably underestimated in self-reports from survey data, but its health risks appear to be severely underestimated by a substantial proportion of sexually active women and men in North and Latin America as well as parts of South Asia, Africa, and other regions," says Dr. Daniel Halperin, assistant professor at the Center for AIDS Prevention (CAPS) and Medical Anthropology at the University of California, who has researched the subject.
"The idea that only vaginal HIV transmission causes heterosexual AIDS is perpetuated by the fact that HIV/STI prevention programs targeted at the general population do not specifically address anal sex. This typically stigmatized and hidden sexual practice should be given greater emphasis in AIDS/STI prevention, women's care, and other health promotion programs."
Condoms are typically used less frequently for anal sex than for vaginal intercourse, he says. In studies conducted in the developing world, approximately 70 percent to 90 percent of people engaging in heterosexual anal intercourse report never or inconsistently using condoms during the practice. The same pattern of lower condom use for anal sex has been documented in U.S. studies.5
Lack of protection
Low levels of condom use for heterosexual anal sex are explained in part by concerns that male condoms are more likely to break or slip during anal sex than during vaginal sex.
Estimates of condom breakage and slippage rates associated with anal use are difficult to interpret. But, unless lubricant is used, anal sex has been associated with a much higher risk of condom slippage than has vaginal sex.6 Meanwhile, studies consistently show that individuals with less condom experience report more condom breakage and slippage,7 and heterosexual women generally have far less experience using condoms during anal intercourse than vaginal intercourse.
Given these condom-related concerns, researchers are increasingly interested in whether topical rectal microbicides might protect against HIV transmission during anal intercourse. Vaginal use of nonoxynol-9 (N-9) spermicidal products has been shown to be ineffective against HIV transmission and may even facilitate it, so anal use of these products is likely to be risky and is not recommended.8 Researchers from the New York-based Population Council have also observed in a small study that rectal use of commercially available lubricants containing moderate to low dosages of N-9 causes sloughing of extensive areas of the rectal surface, a situation expected to increase risk for HIV/STI infection.9
"The results of our study were alarming," says Population Council senior scientist Dr. David Phillips, "although more research must be done to confirm them. We continue to look at N-9 because it remains available and people are still using it rectally. However, I would not recommend the rectal use of N-9." Meanwhile, he cautions, other lubricants marketed for use during anal intercourse are unregulated, untested and may irritate rectal tissue, at least as much as N-9 does.
-- Kim Best
References
Halperin DT. Heterosexual anal intercourse: prevalence, cultural factors, and HIV infection and other health risks, part I. AIDS Patient Care STDs 1999;13(12):717-30; Voeller B. AIDS and heterosexual anal intercourse. Arch Sex Behav 1991;20(3):233-76.
Laumann EO, Gagnon JH, Michael RT, et al. The Social Organization of Sexuality: Sexual Practices in the United States. (Chicago: University of Chicago Press, 1994)98-99,107-9; Hein K, Dell R, Futterman D, et al. Comparison of HIV+ and HIV- adolescents: risk factors and psychosocial determinants. Pediatrics 1995;95(1):96-104; Kotloff K, Tacket C, Wasserman S, et al. A voluntary serosurvey and behavioral risk assessment for human immunodeficiency virus infection among college students. Sex Trans Dis 1991;18(4):223-27; Reinisch J, Hill C, Sanders S, et al. High-risk sexual behavior at a midwestern university: a confirmatory survey. Fam Plann Perspect 1995;27(2):79-82; MacDonald NE, Wells GA, Fisher WA, et al. High-risk STD/HIV behavior among college students. JAMA 1990;263(23):3155-59; Melbye M, Biggar R. Interactions between persons at risk for AIDS and the general population in Denmark. Am J Epidemiol 1992;135(6):593-602; Cunningham I, Díaz-Esteve C, González-Santiago M, et al. University students and AIDS: some findings from three surveys -- 1989, 1990, 1992. Boletín de Estudios Puertorriqueños. 1994;5:44-59; Leal de Santa Inez A. Hábitos e Atitudes Sexuais dos Brasileiros. (São Paulo: Editora Cultrix, 1983)41.
Halperin D. Neglected risk factors for heterosexual HIV infection: anal intercourse, male circumcision, and dry sex. The XIII International AIDS Conference, Durban, South Africa, July 9-14, 2000; European Study Group on Heterosexual Transmission of HIV. Comparison of female to male and male to female transmission of HIV in 563 stable couples. BMJ 1992;304(6830):809-13; Padian N, Shiboski S, Glass S, et al. Heterosexual transmission of HIV in northern California: results from a ten-year study. Am J Epidemiol 1997;146(4):350-57.
Moscicki AB, Hills NK, Shiboski S, et al. Risk factors for abnormal anal cytology in young heterosexual women. Cancer Epidemiol Biomarkers Prev 1999;8(2):173-78; Rosenblum L, Darrow W, Witte J, et al. Sexual practices in the transmission of hepatitis B virus and prevalence of hepatitis delta virus infection in female prostitutes in the United States. JAMA 1992;267(18):2477-81; McMillan A, Young H, Moyes A. Rectal gonorrhea in homosexual men: source of infection. Int J STD AIDS 2000;11(5):284-87; Voeller.
Baldwin JI, Baldwin JD. Heterosexual anal intercourse: an understudied, high-risk sexual behavior. Arch Sex Behavior 2000;29(4):357-73; Hein; Halperin DT.
Smith A, Jolley D, Hocking J, et al. Does additional lubrication affect condom slippage and breakage? Int J STD AIDS 1998;9(6):330-35.
Silverman BG, Gross TP. Use and effectiveness of condoms during anal intercourse: a review. Sex Trans Dis 1997;24(1):11-17.
Gayle HD. Notice to readers: CDC statement on study results of product containing nonoxynol-9. MMWR 2000;49(31):717-18.
Phillips DM, Taylor CL, Zacharopoulos V, et al. N-9 causes exfoliation of sheets of rectal epithelium. Microbicides 2000 Conference. Alexandria, VA, March 13-16, 2000.
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