Elsevier

The Lancet

Volume 360, Issue 9338, 28 September 2002, Pages 971-977
The Lancet

Articles
Effectiveness of COL-1492, a nonoxynol-9 vaginal gel, on HIV-1 transmission in female sex workers: a randomised controlled trial

https://doi.org/10.1016/S0140-6736(02)11079-8Get rights and content

Summary

Background

Nonoxynol-9 (rINN, nonoxinol-9) is an over-the-counter spermicide that has in-vitro anti-HIV-1 activity. Results of studies of its effectiveness in prevention of HIV-1 infection in women have been inconclusive. We aimed to assess effectiveness of this vaginal gel.

Methods

We did a randomised, placebo-controlled, triple-blinded, phase 2/3 trial with COL-1492, a nonoxynol-9 vaginal gel, in 892 female sex workers in four countries: Benin, Côte d'lvoire, South Africa, and Thailand. 449 women were randomly allocated nonoxynol-9 and 443 placebo. Primary endpoint was incident HIV-1 infection. Secondary endpoints included Neisseria gonorrhoeas and Chlamydia trachomatis infections. Analysis was by intention to treat.

Findings

765 women were included in the primary analysis. HIV-1 frequency in nonoxynol-9 users was 59 (16%) of 376 compared with 104 (27%) of 389 in placebo users (402·5 vs 435·0 woman-years; hazard ratio adjusted for centre 1·5; 95% Cl 1·0–2·2; p=0·047). 239 (32%) women reported use of a mean of more than 3·5 applicators per working day, and in these women, risk of HIV-1 infection in nonoxynol-9 users was almost twice that in placebo users (hazard ratio 1·8; 95% Cl 1·0–3·2). 516 (68%) women used the gel less frequently than 3·5 times a day, and in these, risk did not differ between the two treatments. No significant effect of nonoxynol-9 on N gonorrhoeas (1·2; 0·9–1·6) or C trachomatis (1·2; 0·8–1·6) infections was reported.

Interpretation

This study did not show a protective effect of COL-1492 on HIV-1 transmission in high-risk women. Multiple use of nonoxynol-9 could cause toxic effects enhancing HIV-1 infection. This drug can no longer be deemed a potential HIV-1-prevention method. Assessment of other microbicides should continue.

Introduction

Although the male condom, when used consistently and correctly, provides high levels of protection against HIV-1 and other sexually transmitted infections, negotiating its use is not always feasible for many women. Therefore, there is need for a female-controlled method for prevention of HIV-1. Research on microbicides is part of this global effort.

The product that has been tested most is the spermicide nonoxynol-9 (recommended international name nonoxinol-9), which shows in-vitro activity against HIV-1 and other sexually transmitted infections1, 2, 3, 4, 5 and can prevent simian immunodeficiency virus infection in macaques.6 Results of several studies in women showed that nonoxynol-9 had a protective effect against Neisseria gonorrhoeae and Chlamydia trachomatis infection.7, 8, 9, 10

At the time we planned our study, data for HIV-1 prevention were conflicting. Although results of an observational study in female sex workers in Cameroon showed a protective effect in more consistent spermicide users than less consistent users (relative risk 0·1; 95% Cl 0·1–0·6),11 results of a randomised placebo-controlled trial did not show a significant protective effect (1·6; 0·8–2·8).12 The high number of toxic effects seen in this study was thought to be attributable to the high dose of nonoxynol-9—ie, 1000 mg, with about 50% of this dose bioavailable.

Because nonoxynol-9 is readily available, low in price, and has been on the US market as an over-the-counter product since the 1960s, we thought controversy surrounding the drug as a potential HIV-1-prevention method needed to be resolved. We decided to study a new gel formulation with a low nonoxynol-9 dose (52·5 mg), COL-1492, which covers the cervix and the vaginal walls and gives immediate availability of the drug. Because of the known dose-dependent effect of this drug,13 the absence of any local toxic effects of the gel was documented first in women in developed countries, then by a study of the phase 3 target population.14, 15 Results of both trials showed no difference between nonoxynol-9 and placebo with respect to frequency of lesions.

Our aim was to compare the effectiveness of nonoxynol-9 with placebo gel in prevention of HIV-1 infection in HIV-1-negative female sex workers.

Section snippets

Participants

Between September, 1996, and June, 2000, we did a randomised, placebo-controlled, triple-blind trial, in which we screened healthy, HIV-l-negative female sex workers in South Africa (Durban and Johannesburg), Thailand (Bangkok and Hat Yai), Benin (Cotonou), and Côte d'lvoire (Abidjan) for inclusion in our study. Women were recruited from clinics for sexually transmitted infection in Bangkok, Hat Yai, and Johannesburg; from clinics for female sex workers in Cotonou and Abidjan; and in Durban

Results

2146 women were screened and 1005 were enrolled. A total of 892 women (excluding 113 from Johannesburg) were randomly allocated (figure), of whom 127 had no HIV-1 test after enrolment. These women were excluded from the primary analysis, which thus included 765 women. 563 women completed the study, including 57 women with a follow-up visit within 6 weeks before the end of study enrolment. 37 women withdrew during the study (figure).

The overall retention rate of participants in the study was 71%

Discussion

Our results show that nonoxynol-9 increased risk of HIV-1 infection compared with placebo. Risk was especially high in women who used the study drug gel more than 3·5 times per day and who also had a high incidence of lesions with epithelial disruption. This finding suggests that nonoxynol-9 has 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

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