Robin A. Maguire

Efficacy of Carraguard for prevention of HIV infection in women in South Africa: a randomised, double-blind, placebo-controlled trial

BACKGROUND Female-initiated HIV-prevention options, such as microbicides, are urgently needed. We assessed Carraguard, a carrageenan-based compound developed by the Population Council, for its efficacy and long-term safety in prevention of HIV infection in women. METHODS We undertook a randomised, placebo-controlled, double-blind trial in three South African sites in sexually-active, HIV-negative women, aged 16 years and older. 6202 participants, who were randomly assigned by a block randomisation scheme to Carraguard (n=3103) or placebo (methylcellulose [n=3099]), were instructed to use one applicator of gel plus a condom during each vaginal sex act. Participants were followed up for up to 2 years. Visits every 3 months included testing for HIV presence and pregnancy, pelvic examinations, risk reduction counselling, and treatment for curable sexually transmitted infections and symptomatic vaginal infections. The primary outcome was time to HIV seroconversion. Analysis was in the efficacy population (a subset of the intention-to-treat population, excluding participants for whom efficacy could not be assessed). This study is registered with ClinicalTrials.gov, number NCT00213083. FINDINGS For the primary outcome (time to HIV seroconversion) we analysed 3011 women in the Carraguard group and 2994 in the placebo group. HIV incidence was 3.3 per 100 woman-years (95% CI 2.8-3.9) in the Carraguard group (134 events) and 3.8 per 100 woman-years (95% CI 3.2-4.4) in the placebo group (151 events), with no significant difference in the distribution of time to seroconversion (p=0.30). The covariate-adjusted hazard ratio was 0.87 (95% CI 0.69-1.09). Rates of self-reported gel use (96.2% Carraguard, 95.9% placebo) and condom use (64.1% in both groups) at last sex acts were similar in both groups. On the basis of applicator testing, however, gel was estimated to have been used in only 42.1% of sex acts, on average (41.1% Carraguard, 43.1% placebo). 1420 (23%) women in the intention-to-treat population had adverse events (713 Carraguard, 707 placebo), and 95 (2%) women had adverse events that were related to gel use (48 Carraguard, 47 placebo). Serious adverse events occurred in 72 (2%) women in the Carraguard group and 78 (3%) in the placebo group, only one of which was considered possibly related to gel use (placebo group). INTERPRETATION This study did not show Carraguards efficacy in prevention of vaginal transmission of HIV. No safety concerns were recorded.

Comparison of microbicides for efficacy in protecting mice against vaginal challenge with herpes simplex virus type 2, cytotoxicity, antibacterial properties, and sperm immobilization.

Background Currently, a number of different over-the-counter spermicides and potential microbicides under development are in various phases of clinical trials. It is difficult to know how the various formulations would compare with each other or how efficacious they would be because no existing microbicides are commercially available. Goal To evaluate, in a standardized manner, various parameters of potential microbicides. Study Design In an effort to make a comprehensive comparison, several potential microbicides and over-the-counter vaginal products were assayed for their efficacy in protecting mice from infection by herpes simplex virus type 2 (HSV-2), for their cytotoxicity to human vaginal epithelial cells, for their effect on the growth rate of L acidophilus, and for their spermicidal activity. Test formulations were K-Y Plus, Gynol II, Advantage S, Replens, BufferGel, No Fertil, Carrageenan, and PC-550. Additionally, several formulations were evaluated for their use as a possible placebo in microbicide clinical trials. Results The formulations tested fell into three categories of efficacy in protecting mice from HSV-2 infection. The most efficacious were Carraguard and PC-550. All the other test formulations except methyl cellulose afforded varying degrees of protection against herpes simplex virus-2 infection. It was found that formulations containing the surfactant N9 had a cytotoxic effect on human vaginal cells, inhibited the growth rate of L acidophilus, and exhibited spermicidal activity. In addition, it was found that Replens, BufferGel, No Fertil, and the Carbopol formulation might have some effect on sperm motility. Also, K-Y Jelly significantly inhibited the growth rate of L acidophilus. Conclusion Evaluating formulations under the same testing conditions can help to distinguish among potential formulations that are likely to show promise as safe and effective microbicides.

Nonoxynol-9 causes rapid exfoliation of sheets of rectal epithelium

Nonoxynol-9 (N-9) containing spermicides and other N-9 containing products are commonly used as lubricants during rectal intercourse. We have previously demonstrated that rectal application of N-9 products in mice can cause exfoliation of epithelial cells, increasing the probability of infection by HSV-2. To determine if N-9-containing products would have a similar effect on the rectal epithelium in humans, the application of K-Y Plus and ForPlay, both over-the-counter (OTC) N-9 products, were compared to the application of two formulations, carrageenan and methyl cellulose, that do not contain N-9. The effects of each formulation were evaluated in 4 human participants. Light and electron microscope examination of rectal lavage specimens collected 15 min post application of N-9 products revealed the presence of sheets of epithelium. Each sheet contained hundreds of epithelial cells that included columnar and goblet cells, varieties of cells typical of rectal epithelial morphology. Sheets of epithelium were not observed in rectal lavage specimens collected 8 to 12 hr post N-9 product use or in either of the timed lavages involving non-N-9 containing formulations. In addition, no sheets of epithelial cells were observed in the baseline lavage specimens. We conclude that the rectal use of N-9-containing products causes a rapid exfoliation of extensive areas of the rectal epithelium. Exfoliation of the epithelium is no longer observed at 8 hr. It is reasonable to assume that the loss of the protective epithelium would render a person more at risk for infection by HIV and other sexually transmitted pathogens. We, therefore, caution against the use of N-9-containing products during rectal intercourse.

Carrageenan-based nonoxynol-9 spermicides for prevention of sexually transmitted infections.

Background and Objectives: Carrageenan‐based nonoxynol‐9 (N‐9)‐containing formulations were developed in response to the concern that over the counter (OTC) spermicides may not protect people from HIV infection and other sexually transmitted pathogens. Goal of this Study: The goal of this study was to compare the efficacy of carrageenan‐based formulations to OTC spermicides in protecting mice from infection by herpes simplex virus 2 (HSV‐2). Study Design: Mice were challenged with vaginal inoculation of HSV‐2 after pretreatment with test formulations. Results: Carrageenan‐based formulations were significantly more effective than currently marketed spermicides containing the same amount of N‐9. Efficacy was demonstrated over a wide pH range. The carrageenan‐based formulations could be autoclaved without losing antiviral activity and remained active in the vagina for several hours. Conclusions: We conclude that carrageenan‐based N‐9 formulations are likely to provide a more significant degree of protection against HSV‐2 and other enveloped viruses than current OTC spermicides while providing comparable spermicidal activity.

Assay for establishing whether microbicide applicators have been exposed to the vagina.

Objectives: To develop an accurate, rapid, and inexpensive method for verifying vaginal applicator use. Goal: To develop a method for assessing compliance in microbicide clinical trials. Study Design: Single use Microlax applicators containing a placebo formulation either were or were not exposed to the vagina. Three assays were developed to determine whether the applicators had been used vaginally. Results: Blinded examiners were able to discern 63% of the time whether or not applicator tips had been exposed to the vagina. Optical density (to measure lactobacilli), increased in media exposed to used applicators but not in media exposed to unused applicators. When tips of applicators were stained with trypan blue, used applicators could be distinguished easily from unused applicators. Conclusion: Staining of applicator is accurate, simple, rapid, and inexpensive. This method could be be used in clinical settings in the developing world. Dying applicator tips could prove useful in excluding non-compliant subjects, analyzing data, or developing social intervention strategies to improve compliance.

Effect of sexual intercourse on the absorption of levonorgestrel after vaginal administration of 0.75 mg in Carraguard® gel : a randomized, cross-over, pharmacokinetic study

BACKGROUND The Population Council studied a pre-coital contraceptive microbicide vaginal product containing levonorgestrel (LNG) as active component and Carraguard gel as a vehicle (Carra/LNG gel) for couples who engage in occasional unplanned intercourse. The objective of this study was to evaluate the effect of sexual intercourse after vaginal application of Carra/LNG gel on serum levels of LNG in women and to assess LNG absorption by the male partner. STUDY DESIGN This was a randomized, cross-over, pharmacokinetic study including an abstinence arm and an arm in which couples engaged in sexual intercourse between 2 and 4 h after gel application. In each study arm, each woman received a single application of Carra/LNG gel (0.75 mg in 4 mL gel) followed by serial blood samples taken at 0, 1, 2, 4, 8, 24 and 48 h after gel application for LNG measurements. In the intercourse arm, LNG was measured in blood samples taken from the male partner before intercourse and at 4, 8 and 24 h after gel application in the female partner. RESULTS Time concentration curves for serum LNG levels showed a mean C(max) of 7.8+/-5.5 and 8.3+/-5.7 nmol/L, a mean T(max) of 6.2+/-5.9 and 7.5+/-5.7, and comparable area under the curve for the intercourse and abstinence arm, respectively. Pharmacokinetic parameters presented large variability between subjects, but excellent reproducibility within each subject. LNG was undetectable in 10 out of 12 male partners. CONCLUSION Sexual intercourse does not appear to interfere with vaginal absorption of LNG after application of a Carra/LNG gel. A vaginal pre-coital contraceptive gel is feasible.