Quantitative assessment of altered rectal mucosal permeability due to rectally applied nonoxynol-9, biopsy, and simulated intercourse.

BACKGROUND: Microbicide toxicity may reduce the efficacy of topical preexposure prophylaxis for human immunodeficiency virus (HIV) transmission. Noninvasive quantitative measures of microbicide toxicity would usefully inform microbicide development. METHODS: Ten subjects received 3 one-time interventions: 5 mL of Normosol-R fluid alone (negative control), 5 mL of 2% nonoxynol-9 (N-9) gel, and 5 mL of Normosol-R with coital simulation and sigmoidoscopic biopsy (CS + BX). Each dose of N-9 and Normosol-R contained 500 µCi of (99m)technetium-diethylene triamine pentaacetic acid. Plasma and urine radioactivity was assessed over 24 hours. RESULTS: The plasma radioisotope concentration peaked 1 hour after N-9 dosing. The mean maximum radioisotope concentration after N-9 receipt was 12.0 times (95% confidence interval [CI], 6.8-21.0) and 8.4 times (95% CI, 5.2-13.5) the mean concentration after Normosol-R control receipt and CS + BX receipt, respectively; paired differences persisted for 24 hours. After N-9 dosing, the urine isotope level was 3.6 times (95% CI, 1.1-11.4) the level observed 8 hours after Normosol-R control receipt and 4.0 times (95% CI, 1.4-11.4) the level observed 4 hours after CS + BX receipt. Permeability after CS + BX receipt was greater than that after Normosol-R control receipt in 0-2-hour urine specimens only (mean permeability, 2.4; 95% CI, 1.0-5.8) but was not greater in blood. CONCLUSIONS: Plasma sampling after rectal radioisotope administration provided quantitative estimates of altered mucosal permeability after chemical and mechanical stresses. Permeability testing may provide a useful noninvasive adjunct to assess the mucosal effects of candidate microbicides. Clinical Trials Registration. NCT00389311.

Novel trichomonacidal spermicides.

Metronidazole, the U.S. Food and Drug Administration-approved drug against trichomoniasis, is nonspermicidal and thus cannot offer pregnancy protection when used vaginally. Furthermore, increasing resistance of Trichomonas vaginalis to 5-nitro-imidazoles is a cause for serious concern. On the other hand, the vaginal spermicide nonoxynol-9 (N-9) does not protect against sexually transmitted diseases and HIV in clinical situations but may in fact increase their incidence due to its nonspecific, surfactant action. We therefore designed dually active, nonsurfactant molecules that were capable of killing Trichomonas vaginalis (both metronidazole-susceptible and -resistant strains) and irreversibly inactivating 100% human sperm at doses that were noncytotoxic to human cervical epithelial (HeLa) cells and vaginal microflora (lactobacilli) in vitro. Anaerobic energy metabolism, cell motility, and defense against reactive oxygen species, which are key to survival of both sperm and Trichomonas in the host after intravaginal inoculation, depend crucially on availability of free thiols. Consequently, molecules were designed with carbodithioic acid moiety as the major pharmacophore, and chemical variations were incorporated to provide high excess of reactive thiols for interacting with accessible thiols on sperm and Trichomonas. We report here the in vitro activities, structure-activity relationships, and safety profiles of these spermicidal antitrichomonas agents, the most promising of which was more effective than N-9 (the OTC spermicide) in inactivating human sperm and more efficacious than metronidazole in killing Trichomonas vaginalis (including metronidazole-resistant strain). It also significantly reduced the available free thiols on human sperm and inhibited the cytoadherence of Trichomonas on HeLa cells. Experimentally in vitro, the new compounds appeared to be safer than N-9 for vaginal use.

Recurrent urinary tract infection.

OBJECTIVE: to provide an update of the definition, epidemiology, clinical presentation, investigation, treatment, and prevention of recurrent urinary tract infections in women. OPTIONS: continuous antibiotic prophylaxis, post-coital antibiotic prophylaxis, and acute self-treatment are all efficient alternatives to prevent recurrent urinary tract infection. Vaginal estrogen and cranberry juice can also be effective prophylaxis alternatives. EVIDENCE: a search of PubMed and The Cochrane Library for articles published in English identified the most relevant literature. Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. There were no date restrictions. VALUES: this update is the consensus of the Sub-Committee on Urogynaecology of the Society of Obstetricians and Gynaecologists of Canada. Recommendations were made according to the guidelines developed by the Canadian Task Force on Preventive Health Care (Table 1). OPTIONS: recurrent urinary tract infections need careful investigation and can be efficiently treated and prevented. Different prophylaxis options can be selected according to each patient's characteristics.

Acaciaside-B-enriched fraction of Acacia auriculiformis is a prospective spermicide with no mutagenic property.

As a part of our continued venture to develop a safe and effective spermicide, we have identified a triterpene glycoside (Acaciaside-B (Ac-B))-enriched fraction (Ac-B-en) isolated from the seeds of Acacia auriculiformis and evaluated its spermicidal potential in vitro. Sperm motility was completely inhibited within 20 s at a minimum effective concentration (MEC) of 120 microg/ml. Tests for sperm viability by dual fluoroprobe staining showed the effect to be spermicidal with an EC(50) of 35.20 microg/ml. A series of investigations including tests for hypo-osmotic swelling, membrane lipid peroxidation, and electron microscopy document that the spermicidal effect of the fraction involves loss of sperm plasma membrane integrity and dissolution of the acrosomal vesicle--the two most important structural components that play diverse roles in physiological functions of sperm including fertilization. The fraction at 10 x MEC exerted no detrimental effects on in vitro growth of Lactobacillus acidophilus, which is considered the major constituent of vaginal microflora that maintains vaginal health. Ames tests performed with different strains of Salmonella typhimurium including TA 97a, 98, 100, and 102, which detect mutagens causing bp substitution or frameshifting at G-C or A-T bp, demonstrate no mutagenic potential of the fraction. Significant spermicidal potential with no possible mutagenic effect and adverse impacts on lactobacilli growth attests to the credential of Ac-B-en as a prospective future spermicide for the development of a safe and effective vaginal contraceptive formulation.

Safety studies of a recently developed microbicidal contraceptive gel (UniPron) in female baboons (Papio anubis).

To identify any toxicity on the vaginal epithelium, liver and kidney following UIniPron administration, ten healthy female olive baboons (Papio anubis) of reproductive age and of proven fertility were used. Five baboons were each treated with 15 g of UniPron intravaginally twice a week for 20-weeks and venous blood collected before and after each treatment. Venous blood was collected from five control animals as in the experimental females, but these control animals were not given any treatment. The endpoints that were evaluated included clinical chemistry profiles on kidney and liver functions and vaginal histopathology. Female baboons treated with 15 g of UniPron intravaginally showed no detectable adverse effects on clinical chemistry profiles investigated and vaginal histopathology. Repeated intravaginal exposure of female baboons to UniPron did not induce detectable vaginal irritation and there were no detectable histological changes. We conclude that administration of UniPron into baboon vagina did not cause any detectable toxicity.

Vaginosis. Vaginal microbiota. / Vaginosis. Microbiota vaginal.

The latest advances in the vaginal microbiome and molecular diagnosis of bacterial vaginosis have allowed for a better knowledge of this entity, characterising aspects of its pathogenesis and the establishment of the vaginal biolayer, the models and new theories of its aetiology, how it is transmitted, with it being considered nowadays as a probable sexually transmitted infection, the separation of other entities such as aerobic vaginosis, its molecular diagnosis and treatment with new molecules to prevent frequent relapses. This entity and the study of the vaginal microbiome have made it possible to consider these infections as a polymicrobial syndrome, putting an end to the dogma: one microorganism, one disease. In addition, a lesser-known entity such as aerobic vaginosis and the methods for its detection are updated.

A randomized crossover trial of the impact of additional spermicide on condom failure rates.

OBJECTIVE: Opinions remain divided concerning the potential for additional water-based lubricant to reduce condom breaks and slips. We sought to explore impact of externally applied additional lubrication on condom failure rates among regular users in stable heterosexual relationships. GOAL: To compare condom failure rates with and without additional spermicide. STUDY DESIGN: Couples randomized to use up to 70 condoms alone (control) or with additional spermicide (intervention), with midpoint crossover. Couple demographic and failure risk data collected at baseline. Follow ups at three and six months recorded condom failure events, spermicide acceptability, side-effects and adverse events. Condom failure rates were compared using an intention to treat analysis. RESULTS: Altogether 12,530 condoms were used by 145 couples completing the trial, There were 45/6,463:0.70% (95% CI 0.51%-0.93%) clinical and nonclinical failures in the additional spermicide arm, compared to 111/6,067:1.83% (95% CI 1.51%-2.20%) during the control arm. The clinical condom failure rate was 0.53% (95% CI 0.41%-0.66%), with 19 (0.31%: 95% CI 0.18%-0.43%) during the additional spermicide arm, compared to 46 (0.77%: 95% CI 0.56%-0.99%) during the control arm. Couples experienced significantly lower total (P = 0.017) and clinical (P = 0.042) condom failure rates during the additional spermicide arm. Furthermore additional spermicide significantly reduced clinical failures among the 101 couples who'd experienced a previous condom failure (P = 0.002). There were 22 urinary tract infections, equally divided between the control and additional spermicide arms, however 10 of the 12 genital irritation episodes occurred with additional spermicide (P = 0.021). CONCLUSIONS: Additional water-based external lubricant significantly reduced condom failures despite low failure rates among this stable, experienced group of condom users. Our results suggest that this may be a useful supplement to condom use, particularly among couples who experienced condom failures previously.

An overview of properties of Amphora (Acidform) contraceptive vaginal gel.

INTRODUCTION: Although only a minority of contracepting women rely solely on spermicides, they may soon be the only ongoing female method available without a prescription in the United States. Spermicides are also combined with other methods for additional pregnancy protection and/or lubrication. Nonoxynol-9 (N-9), the active ingredient in most spermicides, is cytotoxic and may increase risk of transmission of HIV and other sexually transmitted infections, especially in high-risk women. Amphora (previously called Acidform) is a noncytotoxic spermicide composed of a series of generally regarded as safe compounds, which maintains the acidity of the vagina following coitus to immobilize and kill sperm. Amphora is currently Food and Drug Administration-approved as a vaginal lubricant. Amphora is currently being tested in a multicenter Phase III contraceptive trial. AREAS COVERED: This paper describes key properties of Amphora, including its acid-buffering abilities, viscosity, stability, bioadhesiveness, and tolerability. EXPERT OPINION: Amphora is a nontoxic spermicide that maintains the pH within the vagina at levels less than 5.0 for hours, which immobilizes and kills sperm as well as many sexually transmitted pathogens. If the current clinical trial demonstrates safety, efficacy, and tolerability of Amphora as a contraceptive, it would represent a viable alternative to N-9. Its potential as a microbicide warrants further investigation.

Over-the-counter vaginal contraceptive and spermicide drug products containing nonoxynol 9; required labeling. Final rule.

The Food and Drug Administration (FDA) is issuing a final rule establishing new warning statements and other labeling information for all over-the-counter (OTC) vaginal contraceptive drug products (also known as spermicides, hereinafter referred to as vaginal contraceptives or vaginal contraceptives/spermicides) containing nonoxynol 9 (N9). These warning statements will advise consumers that vaginal contraceptives/spermicides containing N9 do not protect against infection from the human immunodeficiency virus (HIV), the virus that causes acquired immunodeficiency syndrome (AIDS), or against getting other sexually transmitted diseases (STDs). The warnings and labeling information will also advise consumers that use of vaginal contraceptives and spermicides containing N9 can irritate the vagina and rectum and may increase the risk of getting the AIDS virus (HIV) from an infected partner. This final rule is part of FDA's ongoing review of OTC drug products. FDA is issuing this final rule after considering public comments on its proposed regulation, and all relevant data and information on N9 that have come to our attention.

A phase I randomized postcoital testing and safety study of the Caya diaphragm used with 3% Nonoxynol-9 gel, ContraGel or no gel.

OBJECTIVES: The Caya® Diaphragm is a newly approved single-size, nonlatex diaphragm. Contragel® is a personal lubricant containing lactic acid approved in Europe and other countries for use with vaginal barrier devices. This study assessed the effectiveness in preventing sperm from penetrating midcycle cervical mucus of Caya with Contragel, Caya with 3% nonoxynol-9 (N-9) and Caya alone. STUDY DESIGN: Phase I multicenter, single-blind, randomized, crossover, nonsignificant risk study at two sites: Eastern Virginia Medical School, Norfolk, VA, USA, and Profamilia, Santo Domingo, Dominican Republic. Healthy, sexually active women 18-45years old, not at risk for pregnancy due to tubal occlusion, were eligible. Each participant was seen in nine visits, completing a baseline cycle (without product use) followed by three test cycles (sequence determined by randomization), each consisting of a cervical mucus check visit and a postcoital test visit. To proceed to test cycles, the baseline postcoital test had to show adequate cervical mucus and >5 progressively motile sperm per high power field (PMS/HPF). RESULTS: All women had an average of <5 PMS/HPF during the test cycle of each study arm, the primary endpoint. Caya with ContraGel and Caya with N-9 reduced the average number of PMS/HPF from 22.5 to 0. Caya alone reduced the average number of PMS/HPF from 22.5 to 0.4. There were two possibly product-related mild adverse events. CONCLUSION: This study supports that Caya with ContraGel is safe and functions as well as Caya with N-9 in preventing PMS from reaching midcycle cervical mucus. IMPLICATIONS: A single-size diaphragm used with a personal lubricant gel containing lactic acid appears to be safe and to function as well as the same diaphragm used with N-9 in preventing PMS from reaching midcycle cervical mucus.

Effects of long-term use of nonoxynol-9 on vaginal flora.

OBJECTIVE: Products containing nonoxynol-9 have been used as spermicidal contraceptives for many years, but limited data have been published describing the long-term effects of nonoxynol-9 use on the vaginal microbial ecosystem. This longitudinal study was conducted to examine the effects of nonoxynol-9 on the vaginal ecology. METHODS: Vaginal swabs were obtained from 235 women enrolled in a randomized clinical trial before initiation of use of 1 of 5 different formulations of nonoxynol-9 for contraception, and up to 3 more samples were gathered over 7 months of use. The swab samples were evaluated in a single laboratory. The prevalence of several constituents of the normal vaginal flora was evaluated. The associations between nonoxynol-9 dosage, formulation, average product use per week, and number of sex acts per week were calculated. RESULTS: The changes in prevalence of vaginal microbes after nonoxynol-9 use were minimal for each of the different nonoxynol-9 formulations. However, when both nonoxynol-9 concentration and number of product uses are taken into account, nonoxynol-9 did have dose-dependant effects on the increased prevalence of anaerobic gram-negative rods (odds ratio [OR] 2.4, 95% confidence interval [CI] 1.1-5.3), H2O2-negative lactobacilli (OR 2.0, 95% CI 1.0-4.1), and bacterial vaginosis (OR 2.3, 95% CI 1.1-4.7). CONCLUSION: This study demonstrated that most nonoxynol-9 users experienced minimal disruptions in their vaginal ecology. There were no differences between the different formulations evaluated with respect to changes in vaginal microflora. However, independent of the nonoxynol-9 formulation, there was a dose-dependent effect with increased exposure to nonoxynol-9 on the risk of bacterial vaginosis and its associated flora. LEVEL OF EVIDENCE: II-2.

A polyherbal vaginal pessary with spermicidal and antimicrobial action: evaluation of its safety.

A polyherbal vaginal pessary (Praneem) has been formulated that has antimicrobial properties against genital pathogens in addition to spermicidal action. Thus, it has dual potential as a barrier method for contraception and for providing protection against some sexually transmitted infections. The present study reports the findings of a multicentre trial that was conducted to evaluate the safety of this product. Trials were carried out in 23 women in three centres in India: the Postgraduate Institute of Medical Education and Research, Chandigarh; Safdarjang Hospital, New Delhi; and Kamla Nehru Memorial Hospital, Allahabad. Thorough clinical and pelvic examinations were carried out as well as cervical cytology, blood biochemistry and haematology before and after use of the polyherbal pessary intravaginally once daily for 7 consecutive days. No toxicity was observed on clinical examination or by laboratory investigations. Daily intravaginal use of this pessary for 7 days had no adverse effects on cervical cytology or on metabolic and organ functions.

Vaginal safety after use of a bioadhesive, acid-buffering, microbicidal contraceptive gel (ACIDFORM) and a 2% nonoxynol-9 product.

BACKGROUND: ACIDFORM is a microbicidal and contraceptive candidate with strong buffering capacity. METHODS: This was a Phase I blinded, randomized and crossover clinical study on two products, ACIDFORM and a commercial nonoxynol-9 (N-9) product (2%), evaluating their vaginal safety in 20 couples aged between 19 and 45 years. The women had regular menses, underwent previous tubal ligation, were not breast-feeding, had no vaginal sign and symptom and were in a stable partnership; both partners had no previous STI. Colposcopy, vaginal microbiology, inflammation markers and subject complaints were studied after coitus. Women were randomly assigned sequentially to receive ACIDFORM 0-30 min (0-30 min before intercourse), ACIDFORM 8-10 h (8-10 h before intercourse) or N-9 0-30 min after a control cycle. RESULTS: Mild/moderate vulvar irritation was observed in five postcoital test colposcopies, burning and pruritus were reported in six treated cycles and non-irritation-related symptoms were found in five cycles with different treatments. No difference in vaginal pH, Nugent scores, H2O2-producing lactobacillus or leukocytes and interleukin 6 in the cervicovaginal lavage was found between the treatment and control cycles. CONCLUSIONS: ACIDFORM appears to be safe for clinical use once a day. There is a potential spermicidal-microbicidal role for ACIDFORM as a vaginal flora helper or as a vehicle for products, except N-9.

Nonoxynol-9 vaginal pessary: a preliminary Indian experience.

BACKGROUND: Barrier methods of contraception do not have systemic effects and allow the user complete control over their use. For women, the ease of use of a contraceptive is often more important than its efficacy. Hence, barrier methods could be offered as a useful alternative method of contraception. Nonoxynol-9 (a spermicide) is a locally acting, non-hormonal method free from systemic side-efforts. It is a woman-controlled, reversible method which is to be used before intercourse. There are little data available on its efficacy, side-effects and acceptability among Indian women. METHODS: The vaginal pessary nonoxynol-9 was offered as a contraceptive option to 3200 women attending the Family Planning clinics at 31 Human Reproduction Research Centres (HRRCs) of the Indian Council of Medical Research. The other contraceptives offered included an intrauterine device, oral pills, condoms, Norplant, tubal sterilization and vasectomy using the cafeteria approach. Those who accepted nonoxynol-9 were followed up to assess the rates of continuation, failure and side-effects. RESULTS: The nonoxynol-9 pessary was accepted by 541 women who were followed up for 3470 woman-months of use. The reasons given for acceptance were that it was user-controlled and/or they did not wish to use other methods because of the side-effects or contraindications of these methods. The overall continuation rates were 41.2% and 33% at 9 and 12 months of use, respectively. Most women (31.3%) discontinued its use due to personal reasons such as husband dissatisfaction, desire for further pregnancy, irregular use of pessary and difficulty in insertion. Twenty-nine women became pregnant during the study period (15 due to method failure and 14 due to user failure) giving a use-effectiveness of 8.8% at 12 months. The method failure rate was 4.3% at 12 months of use. The failure rates were lower compared with the reported failure rates of barrier contraceptives (1%-30% at 1 year of use) and the side-effects were minimal. CONCLUSION: Nonoxynol-9 had low acceptability (16.9%) and overall continuation rates--41.2% and 33% at 9 and 12 months of use. It could be offered to women looking for a short term, user-controlled contraceptive.

Phase I safety study of Praneem polyherbal vaginal tablet use among HIV-uninfected women in Pune, India.

Praneem polyherbal formulations containing purified extracts of Azadirachta indica (neem tree) have shown activity against HIV and sexually transmitted disease pathogens in studies in vitro. The product also has contraceptive properties. This has prompted its development as a possible microbicide. We evaluated the safety of Praneem polyherbal tablet use among HIV-uninfected women. Twenty eligible women were enrolled in a Phase I open-label study requiring 14 days of consecutive intravaginal use of Praneem polyherbal tablets. Nine (45%) participants experienced 17 episodes of genital irritation. Transient genital itching was reported by eight (40%) participants, burning micturation by two (10%) and lower abdominal pain, genital burning and intermenstrual spotting by one (5%) each. On colposcopy, petechial haemorrhage was observed in two participants, one on day 7 and the other on day 14, and both were resolved without any treatment. There were no serious adverse events. Praneem polyherbal tablets were found to be safe for once daily intravaginal use for 14 consecutive days in sexually active HIV-uninfected women and a Phase II study may be taken up as a priority.

The evaluation of the local tolerance of vaginal formulations containing dapivirine using the Slug Mucosal Irritation test and the rabbit vaginal irritation test.

The purpose of this study was to evaluate the local tolerance of vaginal gels (three gels containing dapivirine, the placebo gel, and Conceptrol) with the Slug Mucosal Irritation test and to compare the results with those of the rabbit vaginal irritation test. The irritation potential on the slug mucosa was assessed by the mucus production caused by a repeated treatment for 5 successive days. Additionally, membrane damage was estimated by the protein and enzyme release. By means of a classification prediction model the formulations were classified into four irritation classes. The effect of a 10-day intravaginal application of the gels on the rabbit vaginal and cervical mucosa was evaluated by means of macroscopic and microscopic examination. The placebo and dapivirine gels induced no irritation of the slug mucosa (low mucus production and protein release, no enzyme release) and no vaginal or cervical irritation in rabbits. Conceptrol caused severe irritation of the slug mucosa (increased mucus production, protein release, and enzyme release) and irritation of the rabbit vagina and cervix. The results obtained with the Slug Mucosal Irritation test were comparable to those of the rabbit vaginal irritation test.

Use of spermicide-coated condoms and other risk factors for urinary tract infection caused by Staphylococcus saprophyticus.

BACKGROUND: Staphylococcus saprophyticus is the second most common cause of urinary tract infection (UTI) in young women. Relatively little is known about risk factors for this infection including exposure to vaginal spermicides, which increases the risk of UTI caused by Escherichia coli. PATIENTS AND METHODS: We conducted a case-control study in a large health maintenance organization Case patients were sexually active young women with acute UTIs caused by S saprophyticus identified from computerized laboratory files during 1990 to 1993. Population-based control patients were randomly selected from the organization's enrollment files. Exposures such as sexual activity and contraceptive practice were determined by interview. RESULTS: Of 1299 eligible women, 66% (96 case patients and 629 control patients) were interviewed. Case patients were more often unmarried and were more sexually active. Ninety-nine percent of case patients and 57% of control patients reported previous UTIs. Exposure to any type of condom during the previous year was reported by 53% of case patients and 31% of control patients. Exposure to spermicide-coated condoms during the previous month was associated with a higher risk of UTI (odds ratio [OR], 3.8; 95% confidence interval, 1.4-10.3). The OR for exposure during the previous year ranged from 2.2 (95% confidence interval, 1.0-4.8) for less than once weekly to 6.05 (95% confidence interval, 2.2-16.6) for more than twice weekly. In multivariate analyses, younger age (OR, 0.97 per year), intercourse frequency (OR, 1.2 per weekly episode), prior UTI (OR, 3.3), and frequency of exposure to spermicide-coated condoms (OR, 8.4 for more than once weekly and 10.9 for more than twice weekly) were independent predictors of UTI. Among women exposed to spermicide-coated condoms, 74% of UTIs caused by S saprophyticus were attributable to this exposure. CONCLUSIONS: Spermicide-coated condoms were associated with an increase risk of UTI caused by S saprophyticus. Because sexual activity and spermicide exposure are important risk factors for UTI caused by both S saprophyticus and E coli, it is likely that they share a similar pathogenesis.

Contraceptive efficacy, safety, fit, and acceptability of a single-size diaphragm developed with end-user input.

OBJECTIVE: To estimate contraceptive efficacy, safety, acceptability, and fit of a single-size diaphragm used with contraceptive gel. METHODS: We conducted a multicenter trial in which 450 couples used the single-size diaphragm, 300 randomized to acid-buffering gel and 150 to nonoxynol-9, for at least 190 days and six menstrual cycles. Visits were at enrollment and after menstrual cycles 1, 3, and 6. Study outcomes included pregnancy probability, safety, acceptability, and fit. Pregnancy and safety were compared with an historical control group who used a standard diaphragm with these gels. RESULTS: Most (439/450 [98%]) women could be fitted with the single-size diaphragm. A total of 421 of 450 (94%) provided follow-up. The 35 study pregnancies yielded 6-month Kaplan-Meier cumulative typical use pregnancy probabilities per 100 women with 95% confidence intervals (CIs) of 10.4 (6.9-14.0) for all users and 9.6 (5.5-13.6) and 12.5 (5.4-19.5) with acid-buffering gel and nonoxynol-9, respectively. Historical control analysis yielded a propensity score-adjusted estimate of this pregnancy probability for the single-size diaphragm of 11.3 compared with 10.7 per 100 women for the standard diaphragm ([rounded] difference 0.7, 95% CI -3.6 to 4.9). Approximately half (51%) reported at least one urogenital event but compared favorably to the standard diaphragm in historical control analysis. Most (282/342 [82%]) liked the diaphragm. Results suggest that if provided by a clinician, 94% (95% CI 92-96%) could insert, correctly position, and remove the diaphragm. CONCLUSION: The single-size diaphragm was safe, as effective as a standard diaphragm, and acceptable when used with contraceptive gel. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00578877.

The effectiveness of barrier methods of contraception in preventing the spread of HIV.

Because barrier methods provide protection against bacterial sexually transmitted diseases, these methods are valuable public health adjuncts irrespective of their effect on HIV. Male latex condoms offer substantial protection against HIV infection. Women at risk of sexual acquisition of HIV infection need one or more prophylactic methods that they can control. While the available spermicide products may serve this purpose, current data do not allow firm casual inferences. Large and well designed epidemiologic studies are required to examine the association between female use of barrier methods and HIV infection. These are difficult and costly to perform, however, and to date have yielded conflicting results. Finally, prospective studies in high-incidence cohorts are necessary, and the relationships between spermicide use, local irritation, the vaginal flora and HIV incidence rates must be clarified.

PIP: The effectiveness of barrier methods of contraception in preventing sexually transmitted diseases (STDs) such as human immunodeficiency virus (HIV) has been assessed in vitro studies and epidemiologic research. Both types of studies have indicated that consistent use of high-quality latex condoms confers substantial protection against HIV transmission. Less certain is the capability of nonoxynol-9 to inactivate HIV. Of concern are several studies indicating that 1-8% of female nonoxynol-9 users experience signs and symptoms of tissue irritation, which can facilitate HIV transmission. These findings may reflect overenrollment of women with a high incidence of STDs and above-average (more than one per day) spermicide doses. Meetings sponsored by the World Health Organization and the US Public Health Service during 1993-94 reached consensus on five ethical and methodological principles to govern studies investigating whether currently available nonoxynol-9 spermicides reduce the incidence of HIV infections: 1) a randomly allocated controlled trial in which all participants are given male condoms; 2) allocation of half the women to an active spermicidal product and the other half to a placebo product; 3) counseling participants to use both a condom and the vaginal product at every coital act; 4) sufficient study size to measure HIV rate ratios within frequency strata; and 5) inclusion of colposcopic examinations and regular appraisal of participant safety by a data and safety monitoring board. Studies of less irritating yet effective spermicidal compounds, the determinants of consistent use of barrier methods, and the impact of social marketing are also recommended.

Nonoxynol-9 100 mg gel: multi-site safety study from sub-Saharan Africa.

OBJECTIVES: To evaluate the safety of 100 mg nonoxynol-9 (N-9) gel, a vaginal microbicide, on the genital mucosa of women from Malawi and Zimbabwe in preparation for a phase III efficacy study. METHODS: HIV-uninfected women (180) were enrolled and randomized to either N-9 or placebo gel and instructed to insert gel into the vagina twice daily for 14 days. Follow up examinations were conducted at 7 and 14 days. RESULTS: The number of adverse events in the N-9 gel group was higher than in the placebo group (40% versus 13%; P < 0.01). Reported number of any genital symptoms was significantly higher in the N-9 group (38% N-9, 13% placebo; P = 0.01). The number of total epithelial disruptions was higher in the N-9 group (20% versus 3%; P < 0.01); however, the number of genital ulcers and abrasions in the N-9 group was low (2% and 3%, respectively) and not different from that in the placebo group (1% and 2%, respectively). CONCLUSIONS: N-9 gel 100 mg caused a significant increase in the rate of genital symptoms and epithelial disruptions compared with placebo. The clinical significance of these epithelial disruptions is unknown. Although these findings alone were not sufficient to cancel the planned phase III study, when considered together with the negative results from the COL-1492 effectiveness trial of 52.5 mg N-9 gel, the decision was made to cancel the planned phase III trial of 100 mg N-9 gel.