HIV/AIDS Epi Update - May 2004

Nonoxynol-9 and the Risk of HIV Transmission

Introduction

At A Glance

Nonoxynol-9 should not be promoted as a means of HIV prevention.

Recent data indicate that nonoxynol-9 does not reduce the risk of HIV transmission and in some circumstancesmay increase the risk.

There is an urgent need for the development of an effective and safe anti-HIV microbicide.

The purpose of this Epi Update is to summarize recent data on the effectiveness of nonoxynol-9 (N-9) as a microbicide, with particular reference to its effect on HIV transmission. While the effectiveness of N-9 as a spermicide is well known, its usefulness as a microbicide has been questioned, and in fact recent data indicate that it may actually increase the risk of HIV transmission. This Epi Update examines the implications of these data in the context of HIV prevention efforts.

Background

Microbicides are chemical substances that kill viruses and bacteria and thus have the potential to reduce the transmission of HIV and other sexually transmitted pathogens when applied vaginally or rectally before sexual intercourse. The development of an effective microbicide is an important research objective, since it would not only improve the effectiveness of condoms in preventing disease transmission but, more importantly, it would also offer an alternative for women to protect themselves from infection without having to obtain the cooperation of their male sexual partner (to wear a male condom). Such an alternative would be especially welcome since the vast majority of global HIV transmissions occur through heterosexual activity.

An ideal microbicidal product would be effective against multiple sexually transmitted infections (STIs) including HIV, safe to use several times daily, fast acting, acceptable to users, affordable, colorless, odorless, easy to store and to use, easy to obtain, and available in a variety of preparations, including with or without a contraceptive component. None of the compounds currently in development meets these ideal standards, and experts say it is unlikely that any one product will meet them all. The immediate priority is to develop a microbicidal product that would provide protection against HIV.¹

N-9 is one of the best studied microbicides for the prevention of HIV and other STIs. N-9 was initially developed as a spermicide - a chemical that kills sperm and therefore prevents pregnancy. These chemicals are used in contraceptive spermicidal products and as complementary components in the lubricant for barrier methods of contraception, such as the male condom. Studies have demonstrated that when spermicides are used alone, they are 75% to 85% effective in preventing pregnancy.^2,3 In addition, N-9 has been identified as a compound that can kill viruses and bacteria, and so has been proposed as a candidate microbicide for HIV prevention. Laboratory studies have shown that N-9 kills or stops the growth of the HIV virus as well as the pathogens of other STIs such as genital herpes, gonorrhea, syphilis, trichomoniasis and chlamydia.⁴

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 spermicidal lubricant. Examples of products include VCF foam, Delfen foam, Advantage 24 contraceptive gel, KY Plus Jelly spermicidal lubricant, Protectaid contraceptive sponge and many brands of condoms labelled as containing spermicide. However, in Canada, there are currently no products with N-9 that are licensed or indicated for use as microbicides (Mueller T, (former) Therapeutic Products Programme, Health Canada: personal communication, September 8, 2000) ; condoms both with and without N-9 make disease prevention claims based on the efficacy of the condom as a mechanical barrier.

Evidence Regarding Nonoxynol-9 and HIV Transmission

The frequent use of N-9 can induce lesions and ulcerations to genital mucosa, thereby increasing the probability of transmission of infectious agents.⁵ Studies have also indicated that these adverse effects of N-9 are dose related, supporting the notion that it has a potentially narrow margin of safety.⁶

While laboratory studies have clearly indicated that N-9 could be an effective barrier to 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.^7-10 A meta-analysis investigation that combined data from several studies concluded that N-9 may have a protective effect against both gonorrhea and chlamydia¹¹, but a recent randomized controlled trial found that N-9 gel did not protect against urogenital gonococcal or chlamydial infection.¹² As well, a recent report from the World Health Organization (WHO) concluded that spermicides containing N-9 do not protect against gonorrhoea and chlamydia.13A recently published cohort study found no evidence of N-9 protection against HIV,¹⁴ as was also the case in two controlled trials on this subject. One trial found no significant protection but a higher incidence of genital ulcers in the N-9 group compared with the control group,¹⁵ and another trial found increased HIV infections in the N-9 group compared with the control group, though this difference was not statistically significant.16 The most significant recent data are from a study of COL-1492, a vaginal gel containing N-9, conducted between 1996 and 2000 among 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, thus increasing women=s susceptibility to HIV-1 infection. At low frequency use, nonoxynol-9 had no effect, either positive or negative, on HIV-1 infection.¹⁷

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 UNAIDS study. In this second 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.18 While it is difficult to extrapolate the findings of these two 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.

Recommendations

Taken together, 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 genital mucosal lining. There are currently few data available to address the question of whether these results also apply to situations in which the dosage and/or frequency of N-9 use is lower. The WHO has stated that N-9 clearly does not prevent HIV infection and may even favour infection if used frequently.13 It has recommended that N-9 should not be used to prevent STIs (including HIV) or for contraception in females who have frequent intercourse or have a high risk of HIV infection, and that N-9 not be used rectally.¹⁹

The United States Food and Drug Administration has proposed new warning labels for over-the-counter contraceptives that contain this spermicide.20 The warning will state that these contraceptives do not protect against infection from HIV or other STIs. The proposed label warnings would also tell consumers that the use of the contraceptives can increase vaginal irritation, which may raise the risk of contracting HIV and other STIs. A number of condom manufacturers, including SSL International, Johnson & Johnson and Mayer, have voluntarily decided to stop producing condoms with N-9.21

Health Canada has never recommended N-9 on its own as an effective means of HIV prevention. Current assessment of the data indicates the following:

• N-9 should not be promoted as an effective means of HIV prevention. In particular, individuals who cannot use a condom for HIV prevention should not be counseled to use N-9 as an alternative.
• For the prevention of STIs, including HIV, 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.
• If N-9 is used as an aid to contraception, its benefit should be carefully considered in light of the increased risk of genital lesions and the resulting potential for an increased risk of HIV transmission.

Similar recommendations have been released from the Centers for Disease Control and Prevention in the USA.^22,23

Future Directions

These disappointing 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. Other classes of compounds that show promise include topical non-nucleoside reverse transcriptase inhibitors (such as efavirenz), inhibitors of viral attachment (such as cellulose sulphate) and natural products (such as buffer gels). Recently, an experimental gel has been developed that appears to be a safe, effective contraceptive, according to animal studies. The compound known as mandelic acid condensation

polymer, or SAMMA, blocked HIV and two strains of herpes simplex virus in laboratory testing.²⁴ In addition, there have been promising developments from a study of sulfated K5 Escherichia coli polysaccharide derivatives. These derivatives appeared to prevent infection as well as suppress HIV-1 viral replication, suggesting that their action may be specific to initial phases of viral attachment and cellular entry.²⁵

There is an urgent need to develop a microbicide that can substantially reduce the transmission of sexually transmitted infections, including HIV, and that can be used by women. For individuals who are unable to access condoms or negotiate condom use, particularly women, the identification of safe and effective alternatives in HIV prevention is a public health priority.

References

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   Measuring true contraceptive efficacy. A randomized approach -condom vs. spermicide vs. no method. Contraception 1998;58(6):375-8.
4. U.S. National Library of Medicine. Spermicides (vaginal). MEDLINE plus Health Information. Micromedex Inc. Revised July 28, 1993.
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   Protective effect of a thermoreversible gel against the toxicity of nonoxynol-9. Sex Transm Dis 1999;26:N.3 177-83.
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   The protective effect of condoms and nonoxynol-9 against HIV infection. National Conference Women and HIV, May 4-7, 1997 (Abstract no. P1.68).
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   Nonoxynol-9 in preventing heterosexual transmission of HIV- using multivariate methods in re-analysing previous and planning future studies. 12th International AIDS Conference, June 28-July 3, 1998, Geneva, Switzerland (Abstract no. 33142).
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   The protective effect of condoms and Nonoxynol-9 against HIV infection. Am J Pub Health 1998;88(4):590-6.
10. Comment. Am J Public Health 1999; 89(1):198-10.
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13. World Health Organization (WHO).
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    Effectiveness of COL-1492, a non-oxynol-9 vaginal gel, on HIV-1 transmission in female sex workers: a randomised controlled trial. Lancet 2002;360(9338):971-7. Erratum in Lancet 2002;360(9348):1892.
18. Hoffman T, Taha TE, Martinson F et al.
    Adverse health event occurring during an N-9 Gel pilot study: Malawi. 13th International AIDS Conference, July 9-14, 2000, Durban, South Africa (Abstract no. TuPpC1171).
19. World Health Organization (WHO).
    Declaration on dual protection: male and female condoms and spermicides. AIDS Summary, No. 9 (Sept. 2003):3.
20. Centers for Disease Control and Prevention.
    FDA proposes new warning for over-the-counter contraceptive drugs containing nonoxynol 9. Associated Press (01.16.03). Prevention news@cdcnpin.org. CDC HIV/STD/TB Prevention News Update 01/17/03.
21. The body: an AIDS and HIV information resource. HIV/AIDS Newsroom, January 21, 2004. (accessed Jan. 30, 2004).
22. Centers for Disease Control and Prevention. Dear Colleague Letter, August 4, 2000.
23. Centers for Disease Control and Prevention. CDC statement on study results of product containing nonoxynol-9. MMWR 2000;49(31):717.
24. Reuters Health. Vaginal contraceptive/ HIV fighter seems promising (12.05.02).
25. Vicenzi E, Gatti A, Ghezzi S et al.
    Broad spectrum inhibition of HIV-1 infection by sulfated K5 Escherichia coli polysaccharide derivatives. AIDS 2003;17(2):177-81.

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