Comparison of self-reported female condom failure and biomarker-confirmed semen exposure.

OBJECTIVE: To investigate whether rates of self-reported Woman's Condom (WC) clinical failure and semen exposure from a functionality study are comparable to results from a contraceptive efficacy substudy. STUDY DESIGN: We structured our comparative analysis to assess whether functionality studies might credibly supplant contraceptive efficacy studies when evaluating new female condom products. Couples not at risk of pregnancy in the functionality (breakage/slippage/invagination/penile misdirection) study and women in the contraceptive efficacy study completed condom self-reports and collected precoital and postcoital vaginal samples for up to four uses of the WC. Both studies used nearly identical self-report questions and the same self-sampling procedures and laboratory for prostatic specific antigen (PSA), a well-studied semen biomarker. We compared condom failure and semen exposure proportions using generalized estimating equations methods accounting for within-couple correlation. RESULTS: Ninety-five (95) efficacy substudy participants used 334 WC and 408 functionality participants used 1572 WC. Based on self-report, 19.2% WC (64 condoms) clinically failed in the efficacy substudy compared to 12.3% WC (194 condoms) in the functionality study (p=.03). Of the 207 WC efficacy uses with evaluable postcoital PSA levels, 14.5% (30 uses) resulted in semen exposure compared to 14.2% (184 uses) of the 1293 evaluable WC functionality study uses. CONCLUSIONS: When evaluating the ability of an experimental condom to prevent semen exposure, the rate of clinical condom failure reported by participants risking pregnancy in an efficacy substudy was significantly higher than the rate reported by participants not risking pregnancy in a functionality study. The rate of semen exposure, assessed by an objective biomarker was nearly identical for the two studies. IMPLICATIONS: Our results suggest that an objective marker of semen exposure in functionality studies could provide a reasonable alternative to contraceptive efficacy studies in evaluating risk of unintended pregnancy and inferring protection from sexually transmitted infection than condom failure rates based on self-report.

Does tenofovir gel or do other microbicide products affect detection of biomarkers of semen exposure in vitro?

OBJECTIVES: There is currently no information on whether products evaluated in HIV microbicide trials affect the detection of the semen biomarkers prostate-specific antigen (PSA) or Y chromosome DNA. STUDY DESIGN: We tested (in vitro) dilutions of tenofovir (TFV), UC781 and the hydroxyethylcellulose (HEC) placebo gels using the Abacus ABAcard and the quantitative (Abbott Architect total PSA) assays for PSA and Y chromosome DNA by real-time polymerase chain reaction. RESULTS: TFV gel and the HEC placebo adversely affected PSA detection using the ABAcard but not the Abbott Architect total PSA assay. UC781 adversely affected both the ABAcard and Abbott Architect total PSA assays. While there were some quantitative changes in the magnitude of the signal, none of the products affected positivity of the Y chromosome assay. CONCLUSIONS: The presence of TFV or HEC gels did not affect quantitative PSA or Y chromosome detection in vitro. Confirmation of these findings is recommended using specimens obtained following use of these gels in vivo. IMPLICATIONS: Researchers should consider the potential for specific microbicides or any products to affect the particular assay used for semen biomarker detection. The ABAcard assay for PSA detection should not be used with TFV UC781, or HEC.

Effect of lubricants and a vaginal spermicide gel on the detection of prostate specific antigen, a biomarker of semen exposure, using a quantitative (Abbott ARCHITECT) assay.

OBJECTIVES: Little is known about the effects of commonly used lubricants on detection of biomarkers of semen exposure. We investigated the in vitro effect of Gynol®, K-Y Jelly®, Replens®, Astroglide®, Carbopol, and Silicorel on quantitative detection of prostate specific antigen (PSA). STUDY DESIGN: A predetermined concentration of each of the gels was added to serially diluted semen samples. Additionally, serial dilutions of each of the gels were added to three different semen dilutions (high, medium, or low). The resulting samples were tested for PSA on the Abbott ARCHITECT System. RESULTS: When using the Abbott ARCHITECT system, the only products that inhibited PSA detection were Gynol® and Replens®. The inhibition caused by Gynol® was dose-dependent, but that of Replens was dose-independent. K-Y Jelly®-spiked samples had higher PSA values than controls. CONCLUSIONS: Caution is warranted when using the Abbott quantitative assay for PSA detection as a biomarker of semen exposure in settings where Gynol®, Replens® or K-Y Jelly® might also have been used. Neither Astroglide® nor Silicorel inhibited PSA detection. Additional studies evaluating other vaginal products, including microbicides, and their effects on other assays, are needed. In vivo studies will be especially important to optimize PSA detection from clinical samples. IMPLICATIONS: Researchers should consider the potential for specific lubricants or any vaginal products to affect the particular assay used for semen biomarker detection. The Abbott ARCHITECT's total PSA assay should not be used with the product Replens. Caution is warranted when using the assay in settings where Gynol or K-Y jelly may have been used.

Toward early safety alert endpoints: exploring biomarkers suggestive of microbicide failure.

Several microbicides, including nonoxynol-9 (N-9) and cellulose sulfate (CS), looked promising during early trials but failed in efficacy trials. We aimed to identify Phase I mucosal safety endpoints that might explain that failure. In a blinded, randomized, parallel trial, 60 healthy premenopausal sexually abstinent women applied Universal HEC placebo, 6% CS or 4% N-9 gel twice daily for 13½ days. Endpoints included immune biomarkers in cervicovaginal lavage (CVL) and endocervical cytobrushes, inflammatory infiltrates in vaginal biopsies, epithelial integrity by naked eye, colposcopy, and histology, CVL anti-HIV activity, vaginal microflora, pH, and adverse events. Twenty women enrolled per group. Soluble/cellular markers were similar with CS and placebo, except secretory leukocyte protease inhibitor (SLPI) levels decreased in CVL, and CD3(+) and CD45(+) cells increased in biopsies after CS use. Increases in interleukin (IL)-8, IL-1, IL-1RA, and myeloperoxidase (MPO) and decreases in SLPI were significant with N-9. CVL anti-HIV activity was significantly higher during CS use compared to N-9 or placebo. CS users tended to have a higher prevalence of intermediate Nugent score, Escherichia coli, and Enterococcus and fewer gram-negative rods. Most Nugent scores diagnostic for bacterial vaginosis were in N-9 users. All cases of histological inflammation or deep epithelial disruption occurred in N-9 users. While the surfactant N-9 showed obvious biochemical and histological signs of inflammation, more subtle changes, including depression of SLPI, tissue influx of CD45(+) and CD3(+) cells, and subclinical microflora shifts were associated with CS use and may help to explain the clinical failure of nonsurfactant microbicides.

Effect of topical vaginal products on the detection of prostate-specific antigen, a biomarker of semen exposure, using ABAcards.

BACKGROUND: Prostate-specific antigen (PSA) is a biomarker of recent semen exposure. There is currently only limited information on whether topical vaginal products affect PSA assays. We investigated this question using various dilutions of several vaginal products (lubricants and spermicides) and the Abacus ABAcard for PSA detection. STUDY DESIGN: Pooled semen controls and various dilutions of nonoxynol-9 (N9), carboxymethyl cellulose (CMC), Replens, Gynol 2, K-Y jelly, Astroglide, Surgilube, combined with pooled semen dilutions, were tested for PSA using the Abacus ABAcard. RESULTS: N9 (2% with saline) and CMC did not appear to affect the results of testing with the ABAcard, but not all semen dilutions were tested. The other products (including Replens and Gynol, which is 2% N9 with propylene glycol, K-Y, Astroglide and Surgilube) at some of the dilutions tested either affected or gave invalid results with PSA testing using the ABAcard. Both Gynol 2 and K-Y at 1:10 dilution gave false-positive results. CONCLUSIONS: Some vaginal products affect PSA results obtained by using the semiquantitative ABAcard. In vivo confirmation is necessary to further optimize PSA detection when topical vaginal products are present.

Colposcopy: still useful in microbicide safety trials?

BACKGROUND: Colposcopy is used to evaluate vaginal microbicides, but its link to risk of HIV is unknown. This reanalysis of 9 safety studies determined the impact of omitting colposcopy on the number of findings detected and assessed whether colposcopy was useful in identifying nonoxynol-9 (N-9) as an unsafe product in one study. METHODS: Product-related findings seen with naked eye and colposcopy or by colposcopy alone were evaluated. Using data from one study, the ratio of findings in N-9 users to those in hydroxyethylcellulose (HEC) users was compared for findings seen by naked eye and colposcopy versus findings detected only by colposcopy. RESULTS: Of the 403 finding observations in the 9 studies, 173 (43%) would have been missed without colposcopy. Data from the N-9/HEC study showed that without colposcopy, there would have been 7 times as many observations in the N-9 group as in the HEC group (63 vs. 9). With colposcopy, the N-9/HEC ratio was 13:9 or 1.4. Considering epithelial integrity, finding type, and size showed similar patterns, except that among the smallest findings (<5 mm), the N-9/HEC ratio was 1.2 by naked eye and nearly the same at 1.4 by colposcopy. CONCLUSION: Colposcopy was not helpful in identifying an unsafe product: the conclusions reached using naked eye examination alone were more alarming regarding the safety of N-9 than reached by including colposcopy. Recommendations include: (1) naked eye examinations should be continued in microbicide studies; (2) colposcopy may be considered for early studies, such as first-in-human studies, but has no place in large studies; and (3) colposcopy should be replaced as soon as possible with a more objective validated biomarker of HIV risk.

Baseline variation and associations between subject characteristics and five cytokine biomarkers of vaginal safety among healthy non-pregnant women in microbicide trials.

Interleukins (IL)-8, IL-1α, IL-1ß, and IL-1 receptor antagonist (IL-1RA) have emerged as indicators of vaginal inflammation and HIV-1 transmission risk. We provide values and factors of normal variation of these immune mediators in premenopausal women to allow their wider clinical application as biomarkers of vaginal health. Cross-sectional analyzes (Kruskal-Wallis and Wilcoxon exact tests) of cytokine concentrations in relation to sociodemographic variables and Nugent score were performed on baseline (prior to product) cervicovaginal lavage from two Phase I randomized microbicide trials. All women in the analysis had regular menstrual cycles, 72 h abstinence, normal blood and Pap tests, and absence of genitourinary infections, study-relevant allergies, antibiotics use and history of substance abuse. Cytokine norms were defined as the values among those with Nugent score <4. Among women with normal Nugent score (n=92), IL-8 and IL-1ß were lowest in those using abstinence as compared to hormonal contraceptives or male/female sterilization as their primary method for birth control. No difference was found by age, prior pregnancy, or education, and also by race after controlling for contraceptive method. Women with abnormal (>7) and borderline (4-6) Nugent scores had elevated IL-1α and/or IL-1ß although their IL-1RA-to-IL(α+ß) ratio remained within the normal range due to higher IL-1RA. Women with borderline Nugent scores had IL-8 levels above the normal range. IL-8 and the IL-1RA-to-IL-1 ratio can be used as independent biomarkers of vaginal immune balance. More studies must determine the role of sexual activity, contraceptive method, and borderline Nugent scores, which normally are not exclusion criteria for enrollment in microbicide trials but may affect product tolerability and HIV-1 risk due to the aberrant cytokine levels.

Comparative crossover study of the PATH Woman's Condom and the FC Female Condom.

BACKGROUND: Only one female condom [FC1 Female Condom (FC1)] is currently marketed, but it is poorly utilized, perhaps due to difficulty with insertion, discomfort and suboptimal functional performance during intercourse. The Program for Appropriate Technology in Health (PATH) Woman's Condom (WC) was developed in an effort to overcome these obstacles. STUDY DESIGN: This was a randomized crossover study to evaluate the functional performance, safety and acceptability of the FC1 and WC. Seventy-five couples were assigned to one of two condom use sequences (WC/FC1 or FC1/WC) at three centers. Four condoms of the first type were used by couples in four acts of intercourse at home over a 2-4-week period. After a follow-up visit, these procedures were repeated with the second assigned condom type. In a substudy of participants (n=25), a colposcopy was performed prior and subsequent to the first condom use of each of the two condom types. Condom performance was evaluated by calculating measures of function from questionnaires completed by the couple after each condom use. Safety was evaluated by reported urogenital symptoms with a given condom during or immediately following condom use and colposcopic signs of genital irritation in the substudy. Acceptability of each given condom type was measured by questionnaire. RESULTS: Total condom failure (slippage, breakage, etc., divided by the number of female condoms opened) was 31% for the WC and 42% for the FC1. Total clinical failure (slippage, breakage, etc., divided by the number of female condoms used) was 17% for the WC and 24% for the FC1. The proportion of condom failures was 10.9 percentage points less, and the proportion of clinical failure 6.7 percentage points less, when couples used the WC compared to the FC1 [90% CI: -18.5 to -3.3 and -12.6 to -0.8, respectively). Fewer women reported symptoms of urogenital irritation when using the WC vs. the FC1 either overall or when analyzing each use of the condom [woman as unit: -20 percentage points (90% CI: -30.5 to -9.3); condom use as unit: -12.3 percentage points (90% CI: -18.0 to -6.7)]. A similar result was seen for signs of urogenital irritation [woman as unit: -20 percentage points (90% CI: -42.7 to 4.8)]. Among participants with a preference, WC was preferred over the FC1 by twice as many males and by 2.6 times as many females. CONCLUSIONS: While both female condoms were safe and acceptable in short-term use, the PATH Woman's Condom leads to less failure, was associated with fewer adverse events, and was more acceptable than the FC1 Female Condom.

Six-day randomized safety trial of intravaginal lime juice.

OBJECTIVES: Nigerian women reportedly apply lime juice intravaginally to protect themselves against HIV. In vitro data suggest that lime juice is virucidal, but only at cytotoxic concentrations. This is the first controlled, randomized safety trial of lime juice applied to the human vagina. METHODS: Forty-seven women were randomized to apply water or lime juice (25%, 50%, or undiluted) intravaginally twice daily for two 6-day intervals, separated by a 3-week washout period. Product application also was randomized: during 1 interval, product was applied using a saturated tampon and in the other by douche. Vaginal pH, symptoms, signs of irritation observed via naked eye examination and colposcopy, microflora, and markers of inflammation in cervicovaginal lavages were evaluated after 1 hour and on days 3 and 7. RESULTS: The largest reduction in pH was about one-half a pH unit, seen 1 hour after douching with 100% lime juice. We observed a dose-dependent pattern of symptoms and clinical and laboratory findings that were consistent with a compromised vaginal barrier function. CONCLUSIONS: The brief reduction in pH after vaginal lime juice application is unlikely to be virucidal in the presence of semen. Lime juice is unlikely to protect against HIV and may actually be harmful.

A randomized six-day safety study of an antiretroviral microbicide candidate UC781, a non-nucleoside reverse transcriptase inhibitor.

GOAL: This study evaluated the effect of a single dose and 5 additional consecutive daily doses of UC781 gel at concentrations of 0.1%, 0.25%, 1.0%, and 0% on urogenital irritation. STUDY DESIGN: Forty-eight healthy sexually abstinent women were randomly assigned to 1 of 4 groups. METHODS: Urogenital irritation was assessed by pelvic examination, colposcopy, and reports of genital symptoms at baseline and after 1 and 6 doses. Vaginal health was assessed by wet mount and systemic safety by laboratory evaluation after 1 and 6 doses, and UC781 levels were assessed at baseline and after 6 doses. RESULTS: Some evidence of urogenital irritation was common in all treatment groups and was most often transient and mild. Colposcopic findings were infrequent in the placebo group (8%) and more common in the 3 treatment groups (24%-42%). Edema, which may indicate underlying inflammation, was observed in the vaginal fornix of 2 women exposed to UC781. There was no apparent increase in vaginal infection or clinically significant changes in laboratory values. Two of 12 participants randomized to 1% UC781 gel had detectable plasma levels that were less than the lower level of quantification. CONCLUSIONS: UC781 was well tolerated in this initial dose ranging safety study when used once daily for 6 days in sexually abstinent women. Five safety/pharmacokinetic studies of UC781 are currently underway in women and men, all utilizing UC781 concentrations less than 1%, with twice-daily dosing in some studies, and all involving careful monitoring of exposed epithelium.

Vaginal distribution of Replens and K-Y Jelly using three imaging techniques.

BACKGROUND: Determination of vaginal distribution is important to the development of potential vaginal microbicidal or spermicidal products. STUDY DESIGN: This was a descriptive study of three imaging techniques with a randomized crossover assignment of two gels and activity status within each technique. METHOD: Each of three sites utilized one technique. Three nulligravid women and three parous women were to be enrolled at each site. We studied the effects of time, ambulation, parity and body mass index on vaginal spreading of two commonly used gels, K-Y Jelly and Replens. Imaging by magnetic resonance imaging and gamma scintigraphy was performed at 5, 20, 35 and 50 min after insertion of 3.5 mL of gel. Imaging with a fiberoptic probe was performed at 5 and 20 min after insertion. RESULTS: Initial application of the gel resulted in approximately two thirds of maximum coverage possible, both in linear extent along the vaginal axis and in surface area covered. Over the next 45 min, spreading increased to about three quarters of the maximum possible. Ambulation generally increased linear spreading and the proportions of women with gel at the introitus and os. Effects of parity and body mass index (BMI) were similar on most measures of gel spreading, with nulligravid women tending toward greater spread than parous women and women of high BMI usually showing somewhat greater spread than women of normal weight. Differences between the two gels were not seen when all conditions of application were considered together. CONCLUSION: In vivo imaging of gel distribution demonstrated that ambulation, parity and BMI affect vaginal gel spreading. The three imaging techniques have advantages and disadvantages and provide complementary information for microbicide development.

Biomarkers of semen in the vagina: applications in clinical trials of contraception and prevention of sexually transmitted pathogens including HIV.

Biomarkers of vaginal exposure to semen, long used in forensic medicine, are now becoming important in the development of vaginal microbicides to prevent HIV/STIs and the development of contraceptives. Semen biomarkers could help evaluate the safety of a new physical or chemical barrier, give preliminary indication of the effectiveness of physical barriers such as diaphragms or condoms, and provide information on unprotected intercourse among participants in a clinical trial who have been advised to use condoms. Candidate biomarkers of semen exposure fall into two broad categories: (1) biomarkers of seminal plasma, among which prostate-specific antigen (PSA) is the best characterized; and (2) biomarkers of spermatozoa and other cells present in semen. This paper, authored by a working group of investigators performing research in the field of semen biomarkers, summarizes the characteristics of an ideal semen biomarker, reviews preclinical and clinical data on existing and potential biomarkers, and outlines the steps that should be carried out to develop an improved biomarker of semen exposure.

Fourteen-day safety and acceptability study of the universal placebo gel.

OBJECTIVE: This study evaluated the effect of the so-called universal placebo compared to the polystyrene sulfonate (PSS) placebo on genital irritation. DESIGN: A single-center, Phase I, randomized, closed-label study was performed to evaluate the genital irritation of microbicide placebo gels. Thirty healthy, sexually abstinent women were randomly assigned to apply 3.5 mL of either the universal placebo or the PSS placebo gel intravaginally twice daily for 14 days. METHODS: Genital irritation was assessed by signs as seen on pelvic examination and colposcopy and reports of symptoms. Vaginal health was assessed by wet mounts, Gram stains for Nugent score and polymorphonuclear leukocytes, and semiquantitative vaginal cultures. Acceptability was assessed as reported on the follow-up questionnaire. RESULTS: The universal placebo was less irritating than the PSS placebo with a lower proportion of women experiencing signs and/or symptoms of genital irritation throughout follow-up (36% compared to 80%, p=.0253). The universal placebo was associated with few and mild genital symptoms, few and minor colposcopic findings and good vaginal health with no clinically significant changes in genital flora. Most participants found the feel of the universal placebo gel neutral or pleasant, and all participants found it odorless. CONCLUSIONS: The universal placebo appeared safe and acceptable when used twice daily for 14 days. The strategy of creating a de novo inert universal placebo is a successful approach. The universal placebo is appropriate for use as a placebo gel in HIV prevention trials with microbicide candidates.

Lea's Shield: colposcopic and microbiological testing during 8 weeks of use.

OBJECTIVES: The aims of this study were to assess the effects of Lea's Shield(R) plus nonoxynol-9 spermicide on signs and symptoms of female genital irritation and cervical and vaginal microflora during 8 weeks of use with intercourse and to analyze problems associated with the use of the device. METHODS: In this open-label, single-arm study, participants were evaluated by pelvic examination, colposcopy and vaginal and cervical cultures. RESULTS: About 13% of women (4/30) reported symptoms of irritation, and minor product-related colposcopic findings were seen in about one third (11/30). Although average colony counts for enterococcus, Escherichia coli and anaerobic gram-negative rods increased during product use, no clinical diagnoses of infection were made. Most users reported at least one problem using Lea's Shield. CONCLUSION: Lea's Shield, when used for 8 weeks during intercourse, is associated with evidence of genital irritation in a minority of users and with changes in vaginal microflora that do not appear to correlate with clinical infections.

Male tolerance study of 1% C31G.

BACKGROUND: C31G is being studied as a vaginal contraceptive and microbicide. This study was conducted to ensure that male partners of the women in future trials of C31G will not be subjected to an undue risk of penile irritation. METHODS: This was a randomized, double-blinded, single-center Phase I study in circumcised and uncircumcised men to assess penile irritation, safety and acceptability of seven consecutive daily doses of 1.0% C31G compared with a marketed spermicide, Extra Strength Gynol II(R) (3% nonoxynol-9) (ES Gynol II). Each participant was instructed to apply the study product to his penis at bedtime, to wash it off 6-10 h later, and to record any symptoms on a diary card. At the follow-up visit, a genital examination was performed and participants were again asked about adverse events and to complete an acceptability questionnaire. RESULTS: Of the 36 men enrolled, 12.5% of C31G users and 16.7% of Extra Strength Gynol II users reported product-related adverse events (AEs). All product-related AEs were considered mild by the investigator, except for one in the ES Gynol II group. Both products were acceptable. CONCLUSION: The manner in which the products were used in this study is not the route by which men will be exposed to such products in actual use, and results should be considered in this light. Based on the observations in this study, C31G appears to be at least as safe and acceptable for male penile exposure as the marketed product ES Gynol II.

A phase I comparative postcoital testing study of three concentrations of C31G.

BACKGROUND: C31G is a broad-spectrum antibacterial agent that shows contraceptive properties in vitro. This postcoital testing study evaluated the ability of three C31G concentrations, 0.5%, 1.0% and 1.7%, administered as a 3.5-mL dose of a vaginal gel to prevent sperm from entering mid-cycle cervical mucus. Irritation of the genitalia and acceptability were also assessed. METHOD: At baseline, a mid-cycle cervical mucus test and a postcoital test were performed within 24 h of each other without use of any study products to establish normal mid-cycle cervical mucus and sperm penetration. Subjects then completed up to three test cycles using one of the three concentrations of study product during intercourse. RESULTS: Twenty-two of the 61 women enrolled completed a baseline cycle and at least one test cycle. An average of 14.6 progressively motile sperm per high power field was seen at baseline. This was reduced to 0.3 after use of 0.5% C31G, 0.5 after use of 1.0% C31G, and 0.4 after use of 1.7% C31G. There was no significant difference between test products (p >/= 1.000) but each test product was significantly different from baseline (p < 0.002). Very little genital irritation was observed. There were more reports of leakage and messiness with increasing C31G concentration. CONCLUSION: This study suggests that all three concentrations of C31G are likely to give reasonable results in a contraceptive effectiveness trial. Based on the results of this and other trials, the 1.0% concentration has been selected for further development, including Phase III trials of contraceptive effectiveness.

A randomized Phase I vaginal safety study of three concentrations of C31G vs. Extra Strength Gynol II.

BACKGROUND: C31G is an antimicrobial and spermicidal agent that contains two surface-active compounds, cetyl betaine and myristamine oxide. It is being developed as a vaginal microbicide and contraceptive. METHOD: Three C31G concentrations (0.5%, 1.0% and 1.7%) were tested and compared with Extra Strength Gynol II(R), a marketed spermicide containing 3% nonoxynol-9 (N-9), in a randomized, double-blinded, Phase I, dose-escalation study to assess genital irritation (by subject report, visual examination at pelvic examination and colposcopy), plasma and vaginal lavage levels of C31G, product leakage, systemic safety and acceptability. Women were randomized to use 3.5 mL of one of the three C31G products or the N-9 gel at night for 7 days then twice daily for another 7 days. Pelvic and colposcopic evaluations were performed after 7 and 14 days of product use. RESULTS: The percent of women experiencing irritation in the 0.5% and 1.0% C31G groups in the study were similar to each other and were lower than the percent experiencing irritation in the 1.7% and N-9 groups, which were also similar to each other. Differences were statistically significant between 1.0% C31G vs. N-9 at 7 days and between 0.5% C31G and 1.0% C31G vs. N-9 at 14 days. There was no significant difference between groups in leakage or acceptability. No C31G was detected in the plasma of any volunteer. CONCLUSIONS: These results suggest that 0.5% and 1.0% C31G are less irritating to the female genital tract than 1.7% C31G or Extra Strength Gynol II.

A comparison of techniques to assess cervicovaginal irritation and evaluation of the variability between two observers.

BACKGROUND: Colposcopy is used to evaluate effects of new vaginal products on cervicovaginal epithelium as part of the US Food and Drug Administration-mandated product approval process, yet few aspects of its use have been investigated. OBJECTIVES: To determine the effect of the colposcopic examination itself on the number and type of findings seen, to compare colposcopy with the AviScope hand-held device and the naked eye and to compare the findings reported by two examiners during a single visit. STUDY DESIGN: Fourteen healthy women volunteered for five paired examinations in random order: (1) naked eye inspection plus colposcopy done twice by a single examiner; (2) naked eye inspection plus AviScope examination, then naked eye inspection plus colposcopy by a single examiner; (3) Examination 2 repeated with the order of device reversed; (4) naked eye inspection plus colposcopy done by two examiners; (5) Examination 4 repeated with the order of examiner reversed. The colposcopic examinations were done per published standards but were limited to the areas visible without manipulation of the speculum. RESULTS: Length of colposcopic examination averaged 7 min. The number of colposcopic findings found when the examination was done twice by the same clinician was not statistically different (p = 0.12), suggesting that the examination itself did not induce findings. More findings were seen using magnification than naked eye. A similar number of findings were seen by AviScope compared to the colposcope (p = 0.99), but clinically significant findings were "undercalled" or "overcalled" by the AviScope. A weighted kappa score of the "worst" colposcopic finding was 0.32 (SE 0.10, p = 0.00), indicating moderate agreement between examiners. CONCLUSIONS: The colposcopic examination is not burdensome nor does it induce findings. If naked eye observation were used alone in practice, these data suggest that half the colposcopically detected findings would be missed. Using the naked eye observation for screening would minimally reduce the number of magnified observations carried out. For detecting epithelial changes, the colposcope seems to be the most sensitive technique, followed by the AviScope.

Single and multiple exposure tolerance study of polystyrene sulfonate gel: a phase I safety and colposcopy study.

OBJECTIVES: To evaluate symptoms and signs of genital irritation, vaginal leakage and acceptability of polystyrene sulfonate (PSS), which is being studied as a vaginal contraceptive and microbicide. METHODS: Forty-nine women applied 2.5 mL of either 5% PSS, 10% PSS, PSS vehicle, or Conceptrol (a marketed spermicidal product containing 4% nonoxynol-9) for 6 consecutive days. RESULTS: All women completed the study except one in the Conceptrol group who experienced vaginal symptoms after her first use and was discontinued. After both the first use and after all uses, irritation was seen among more women in the Conceptrol group than in the PSS groups, reaching statistical significance with regard to any evidence of irritation, signs of irritation and product-related irritation. There were no adverse events that were serious, unexpected and related to product use in any group. The 5% concentration of PSS may be preferable in terms of leakage and acceptability. CONCLUSION: The results suggest that PSS has a safety profile comparable to that of the marketed nonoxynol-9 product, Conceptrol, and appears to be associated with less genital irritation.