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Nonoxynol-9 research
The most thoroughly studied candidate microbicides have been based on the spermicide nonoxynol-9, also known as N-9. This is a detergent which was chosen for research on the basis of laboratory findings that it disrupted HIV and other STIs, even at very low doses, and because it was already in widespread use, including in lubricants for condoms. Animal studies confirmed that N-9 protects female monkeys against challenge with HIV-related viruses (Miller, Weber). Unfortunately, N-9 causes damage to human tissue, leading to inflammation and ulceration, which is dose related (Niruthisard).
Research into N-9 as a rectal microbicide has been minimal and where it has occured, has produced even more worrying results than in trials as a vaginal microbicide: the use of nonoxynol-9 caused the rectal lining to slough off in both mice and humans, prompting a warning about the popular use of N9-containing lubricants during anal sex. Far from protecting against HIV and other viral infections, N-9 leaves the rectum more susceptible to it (Phillips).
It was nonetheless hoped that low-dose N-9 products, used vaginally, might be able to protect against HIV without causing excess inflammation.
However, the results of the most extensive clinical trials carried out on any microbicide are clear-cut: N-9 increases HIV transmission to women who are at high risk of HIV when they use the product frequently, and appears to have no protective effect either against HIV or other STIs when used less frequently. There are better candidates available for evaluation, and the consensus is that future research should focus on those.
In the light of these findings, the use of N-9 based spermicides has also been questioned: current recommendations are set out separately here.
Clinical trials of N-9 based products
This section reviews the main clinical studies of N-9 products.
One study compared the use of a sponge containing N-9 with a placebo cream in a group of 138 female sex workers in Nairobi. This trial showed no protection for the women using N-9. There was even a suggestion that the women using the sponge were slightly more likely to acquire HIV (although the trend was not statistically significant) because they developed more genital ulcerations which facilitated the transmission of the virus (Kreiss).
Following the Nairobi study many people suggested that N-9 should not be used, even with condoms. (Although it is agreed that a condom, even with N-9 lubrication, is far better than no condom.) However, there were many problems with this trial. The dose of N-9 used was very high (1000 mg) and women often used more than one sponge. It is possible that the placebo cream protected the other women from ulcers (which were already common among all the women in the study). Also, studying a high dose of the product in sex workers, who had intercourse several times a day, did not give reliable information about the use of the product by women who had sex less frequently and might be less likely to develop dose-related reactions to such a product.
No ulcers were seen in a study of discordant couples in Zambia, who were given 100 mg N9 suppositories (10% of the dose used in the Nairobi group). In this study it seemed possible that N9 provided some protection against HIV but the observed difference did not reach statistical significance (Feldblum).
A trial in Cameroon recruited 273 sex workers who were given – and strongly advised to use – latex condoms (without spermicides) and 100 mg N9 suppositories. The women kept 'coital logs' indicating whether each occasion of intercourse was protected by condom (with or without N9), N9 alone, or was unprotected. They attended for check–ups every month for one year. One quarter of sex acts used N9 only, and nearly two thirds used condoms. The analysis of the study found that there was a two to three times higher risk of acquiring HIV with unprotected sex than when protection with either condoms or N9 was used. Women who did not use condoms but regularly used N9 were 50% less likely to acquire HIV than women who used N9 less often. The relatively small size of this trial limits the significance that can be attached to these findings (Zekeng).
A much larger trial, also in Cameroon, enrolled 1292 HIV-negative female sex workers in a double-blind placebo controlled study of an N9 film containing 70 mg of N9 compared to a placebo film. All women were encouraged to use condoms and encouraged to seek treatment for sexually transmitted infections. The rates of HIV infection were 6.7 and 6.6 per hundred women years in the N9 and placebo groups respectively, with no significant difference in rates of gonorrhoea or chlamydia either (Roddy).
A further randomised controlled trial enrolled 1251 women, excluding sex workers, at 10 community clinics and 10 pharmacies in Yaounde, Cameroon, and randomised them to receive condoms only or condoms with Conceptrol gel (N9 at 4%). In this population, the effect on HIV risk could not be assessed but it was possible to show that there was no effect on gonorrhoea or chlamydial infection (Roddy, 2002).
The most important evidence that nonoxynol-9 is ineffective - or has a negative value - as a microbicide came from a randomised, placebo-controlled trial of a low-dose nonoxynol-9 vaginal gel, COL-1492 (Van Damme).
This study enrolled 892 female sex workers in four countries: Benin, Cote d'Ivoire, South Africa and Thailand, all of whom were supplied with condoms and encouraged to use them, as well as having enhanced access to diagnosis and treatment of sexually transmitted infections. 765 women were included in the analysis of the results, of whom 376 were on N-9 and 389 on placebo. Among these women, a further distinction was made between frequent users and less frequent users, with a threshold mean value of 3.5 uses per day.
The N-9 product was made by Columbia Laboratories as Advantage S and the placebo, which was provided in identical packaging, was a vaginal lubricant called Replens. The women were asked to keep a diary of their activities (although this was replaced by interviews after some women were seen to complete their diaries in the clinic). All women were provided with condoms (free of N-9), which they were advised to urge their partners to use.
The findings were that among less frequent users, HIV rates were not significantly different between N-9 and placebo groups. However, among more frequent users, HIV rates among N-9 users were twice the rate among placebo users. There was no effect of N-9 on rates of gonorrhoea or chlamydia infection.
The Phase III study was double blinded, so neither the researchers nor the participants knew whether they were receiving Advantage S or placebo.
The researchers had anticipated that those receiving the placebo would have higher rates of infection than those who received Advantage S. Several safety studies carried out using this formulation before the start of the phase III trial failed to show any side-effects usually associated with N-9 such as genital sores and irritation.
The use of placebos as an alternative to active treatment (rather than to disguise which of two active treatments is being given) has become increasingly controversial in HIV clinical trials and is inappropriate as soon as a standard of treatment is established. Some commentators have extended this concern to argue that placebos should not be used in prevention trials either. However, until we have a microbicide of proven effectiveness, placebos must continue to be used. The COL-1492 researchers have drawn attention, however, to the challenge this represents in explaining to trial volunteers precisely what placebo use means. (Ramjee).
Similarly, concerns that the promotion of condoms might prevent a valid finding of difference have not been borne out by these results. While condom use varied between the trial sites, it was clearly higher in the trial. This may help explain the finding that HIV infection rates among women receiving N9 were lower than in women who did not take part in the trial. But surely, this is what we should all want to see in every trial?
The most reasonable conclusion would seem to be, that N9 will not be the answer to the need for a microbicide but the trials show that other more promising candidates can and should be evaluated with the utmost urgency.
Lessons for the next wave of clinical trials
In conducting any large-scale clinical trial, some of what can be learned will apply equally to trials of other products. Some of these findings may be important in selecting other candidate products to take forwards in development and in thinking about educational strategies to promote their ultimate use.
Female sex workers who took part in the COL 1492 study of N-9 were invited to take part in focus group discussions and interviews; 94 agreed to do so. They were asked about disclosure to partners (steady male partners and clients). Most of the women did not choose to disclose. Sometimes male partners found out either because the substance leaked or because they saw the woman applying it or asked her about it. Reactions from male partners varied depending on the nature of their relationship, from hostility to active support. (Morar).
A 14-day randomised double-blind placebo-controlled trial recruited 180 women in Malawi and Zimbabwe, randomised to receive one of two gels - a placebo or one containing N-9 (Conceptrol). All were advised to use condoms (it is not clear how many actually did so). Interviewer-administered questionnaires and focus-group discussions involving women and their male partners were used to explore the acceptability of the gels. Both men and women preferred the gel to condoms; women said they would be more likely to use the gel consistently over long periods if it enhanced the experience of sex for herself and/or her sexual partner and if it dried out quickly (Brown).
References
Kreiss J et al. Efficacy of nonoxynol-9 contraceptive sponge use in preventing heterosexual acquisition of HIV in Nairobi prostitutes. Journal of the American Medical Association 268: 477-482, 1992.
Miller C et al. The effect of contraceptives containing nonoxynol-9 on the genital transmission of simian immunodeficiency virus in rhesus macaques. Fertility and Sterility 57: 1126-1128, 1992.
Morar NS et al. Disclosure of microbicide use to male partners: Impact on microbicide acceptability among sex workers in South Africa. XIV International AIDS Conference, Barcelona, abstract ThPeD7682, 2002.
Niruthisard S et al. The effects of frequent nonoxynol-9 use on the vaginal and cervical mucosa. Sexually Transmitted Diseases 18: 176-179, 1991.
Phillips D et al. Nonoxynol-9 causes rapid exfoliation of sheets of rectal epithelium. Contraception 62: 149-154, 2000.
Ramjee G et al. Challenges in the conduct of vaginal microbicide effectiveness trials in the developing world. AIDS 14: 2553-2557, 2000.
Roddy R et al. A controlled trial of nonoxynol-9 film to reduce male-to-female transmission of sexually transmitted diseases. New England Journal of Medicine 339: 504-510, 1998.
Roddy R et al. Effect of nonoxynol-9 gel on urogenital gonorrhea and chlamydial infection: a randomized controlled trial. Journal of the American Medical Association 287: 1117-1122, 2002.
Van Damme L et al. Effectiveness of COL-1492, a nonoxynol-9 vaginal gel, on HIV-1 transmission in female sex workers: a randomised controlled trial. Lancet 360:971-977, 2002.
Weber J et al. 'Chemical condoms' for the prevention of HIV infection: evaluation of novel agents against SHIV 89.6 PD in vitro and in vivo. AIDS 15: 1563-1568, 2001.
Zekeng L et al. Barrier contraceptive use and HIV infection among high-risk women in Cameroon. AIDS 7: 725-31, 1993.