HIV/AIDS Epi Notes

Nonoxynol - 9 (N-9) and HIV Transmission

Overview

This Epi note presents current data on the spermicide nonoxynol-9 (N-9) and its effects on human immunodeficiency virus (HIV) transmission/acquisition.

N-9 was initially developed as a spermicide, a chemical that kills sperm and therefore prevents pregnancy. N-9 is commonly used in contraceptives as a spermicidal product and as a complementary component in lubricants for barrier methods of contraception, such as the diaphragm and the male condom.

A number of products containing N-9 are licensed for use as contraceptives in Canada. These products are available without a prescription and come in a variety of forms, including creams, films, foams, gels, and condoms with N-9 lubrication. Examples of such products are VCF foam, Delfen foam, Protectaid and Today contraceptive sponges. In addition, Trojan and Lifestyles brands of condoms are available with N-9 in Canada. However, at present there are no products in Canada with N-9 that are licensed or indicated for use as microbicides. Microbicides are compounds that can be applied inside the vagina or rectum to protect against STIs, including HIV. They can be formulated as gels, creams, films, or suppositories. Condoms, both with and without N-9, are claimed to prevent disease on the basis of the efficacy of the condom as a mechanical barrier.

N-9 is one of the best studied potential microbicides for the prevention of HIV and other STIs. N-9 was identified as a compound that can kill viruses and bacteria, and was earlier proposed as a candidate microbicide for HIV prevention. Research has since clearly shown that N-9 is not to be used as a microbicide.

Safety of N-9

• N-9 has long been considered a safe and effective contraceptive method.
• Recent data indicate that N-9 may damage both vaginal and rectal cells, which could facilitate transmission/acquisition of HIV under certain conditions.
• Frequent use of vaginal doses of N-9 causes damage to cells in the vagina, but it is unclear whether small doses and infrequent vaginal use of N-9 can cause such damage.
• When used rectally, even low doses or infrequent use of N-9 causes cell damage and likely increases susceptibility to HIV infection.

N-9 and HIV Transmission

The frequent use of N-9 can induce lesions and ulcerations in genital and rectal mucosa, thereby increasing the probability of transmitting/ acquiring infectious agents.

While laboratory studies have clearly indicated that N-9 can kill HIV, clinical trials in humans have produced mixed results. Several observational studies have indicated that N-9 may reduce the risk of HIV transmission, but the study design did not permit definitive conclusions.^1-3 A cohort study found no evidence of N-9 protection against HIV,⁴ a result similar to the findings of two controlled trials on this subject. One trial found no significant protection but, rather, a higher incidence of genital ulcers in the N-9 group, as compared with the control group,⁵ and another trial found increased HIV infections in the N-9 group compared with the control group, though this difference was not statistically significant.⁶

The most significant data come from a study conducted with COL-1492, a vaginal gel containing N-9, between 1996 and 2000 among female sex trade workers in four countries: Benin, Cote D'Ivoire, South Africa, and Thailand. The results showed that this gel had an adverse effect on vaginal integrity when used frequently, thereby increasing women's susceptibility to HIV-1 infection. At low frequency use, N-9 had no effect on HIV-1 infection.⁷

The association between N-9 and genital lesions was also seen in a study of monogamous, low-risk women who had a much lower frequency of sexual intercourse than the sex workers in the other studies. In this study, women applied a vaginal N-9 gel or a placebo gel twice daily. The N-9 group had significantly more vaginal itching, burning and mucosal lesions.8 In a safety evaluation of N- 9 gel (COL-1492 containing 52.5 mg of N-9 per dose) in women at low risk of infection, once daily use for 14 days was not associated with a significant level of lesions with epithelial disruption.⁹

While it is difficult to extrapolate the findings of these studies to the general population in terms of sexual frequency, dosage, and mode of N-9 use (including the occasional use of an N-9 lubricated condom), the theoretical benefits of N-9 use in such situations would have to be weighed against the demonstrated potential for harmful side effects.

Studies in humans and in mice suggest that using products containing N-9 in the rectum may actually increase an individual's risk of HIV transmission/acquisition rather than offer extra protection.¹⁰ A study that compared the effect of two over-the-counter lubricants that contained N-9 with two gels that did not contain it showed that the products containing N-9 caused extensive damage to the rectum. ¹¹ This damage to the rectal epithelium may enhance the probability of HIV transmission/ acquisition.¹²

A meta-analysis that combined data from several studies concluded that N-9 may have a protective effect against both gonorrhea and chlamydia,¹³ but a recent randomized controlled trial found that N-9 gel did not protect against urogenital gonococcal or chlamydial infection.¹⁴ As well, a report from the World Health Organization concluded that spermicides containing N-9 do not protect against gonorrhoea and chlamydia.¹⁵

Conclusion

The recent evidence is convincing that frequent use of N-9 does not reduce the risk of infection by HIV and may, in fact, increase the risk by causing disruptions and lesions in the ano-genital mucosal lining. In the case of rectal use, even the single use of a low dose of N-9 may increase the risk of HIV infection by causing disruptions and lesions in the rectal mucosal lining. N-9 should not be used rectally.

It is unclear whether N-9 products, when used vaginally in small doses and infrequently, increase the risk of HIV transmission and acquisition.

Products containing N-9 should not be promoted as a primary means of contraception in women with the potential for frequent usage.

Products containing N-9 should not be promoted as an effective means for the prevention of HIV or STIs.

For the prevention of STIs, including HIV, it is best to use a condom without N-9. However, a condom lubricated with N-9 is better than no condom at all. The protection provided by the mechanical barrier of the condom would appear to outweigh the potential risk of the N-9, at least for low frequency of use and dosage.

The data on the ineffectiveness of N-9 as a microbicide serve to further reinforce the importance and urgency of research on the development of other possible compounds as microbicides.

Acknowledgements

The Centre for Infectious Disease Prevention and Control acknowledges the contribution of the Canadian AIDS Society and the Marketed Pharmaceuticals and Medical Devices Bureau, Health Canada, in development of this Epi note.

Need more Information?

More information on N-9 and the risk of HIV transmission can be found in the Epi Update
Nonoxynol-9 and the Risk of HIV Transmission, May 2005, available at
http://www.phac-aspc.gc.ca/.

For information on this document or related products, please contact

Surveillance and Risk Assessment Division
Centre for Infectious Disease Prevention and Control
Public Health Agency of Canada
Tunney's Pasture
Postal Locator 0602B
Ottawa, ON K1A 0K9

Tel: (613) 954-5169
Fax: (613) 957-2842

References

1. Wittkowski KM, Dietz K. The protective effect of condoms and nonoxynol-9 against HIV infection. National Conference on Women and HIV, May 4-7, 1997 (Abstract no. P1.68).
2. Wittkowski KM, Susser E, Dietz K. Nonoxynol- 9 in preventing heterosexual transmission of HIV - using multivariate methods in reanalysing previous and planning future studies. 12th International AIDS Conference, Geneva, Switzerland, June 28-July 3, 1998 (Abstract no. 33142).
3. Wittkowski KM, Susser E, Dietz K. The protective effect of condoms and nonoxynol-9 against HIV infection. Am J Public Health 1998;88(4):590-96 and Comment: Am J Public Health 1999;89(1):108-10.
4. Hira SK, Feldblum PJ, Kamanga J et al. Condom and nonoxynol-9 use and the incidence of HIV infection in serodiscordant couples in Zambia. Int J STD AIDS 1997;8(4):243-50.
5. 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.
6. Kreiss J, Ngugi E, Holmes K et al. Efficacy of nonoxynol 9 contraceptive sponge use in preventing heterosexual acquisition of HIV in Nairobi prostitutes. JAMA 1992;268(4): 477- 82.
7. Van Damme L, Ramjee G, Alary M et al. Effectiveness of COL-1492, a nonoxynol-9 vaginal gel, on HIV-1 transmission in female sex workers: a randomised controlled trial. Lancet 2002;360(9338):971-77. Erratum: Lancet 2002;360(9348):1892.
8. Hoffman T, Taha TE, Padian NS et al. Nonoxynol-9 100 mg gel: multi-site safety study from sub-Saharan Africa. AIDS 2004;18(16):2191-95.
9. Van Damme L, Niruthisard S, Atisook R et al. Safety evaluation of nonoxynol-9 gel in women at low risk of HIV infection. AIDS 1998;12:433-37.
10. Phillips DM, Zacharopoulos VR. Nonoxynol-9 enhances rectal infection by herpes simplex virus in mice. Contraception 1998;57:341-48.
11. Phillips DM, Taylor CL, Zacharopoulos VR et al. Nonoxynol-9 causes rapid exfoliation of sheets of rectal epithelium. Contraception 2000;62:149-54.
12. Phillips DM, Sudol KM, Taylor CL et al. Lubricants containing N-9 may enhance rectal transmission of HIV and other STIs. Contraception 2004;70:107-110.
13. Cook RL, Rosenberg MJ. Do spermicides containing N-9 prevent sexually transmitted infections? A meta-analysis. Sex Transm Dis 1998;25(3):144-50.
14. Roddy RE, Zekeng L, Ryan KA et al. Effect of nonoxynol-9 gel on urogenital gonorrhea and chlamydial infection: a randomized controlled trial. JAMA 2002;287:1117-122.
15. WHO/CONRAD Technical Consultation on Nonoxynol-9. Geneva: World Health Organization, October 2001.