Marianne M. Callahan

SILCS diaphragm: postcoital testing of a new single-size contraceptive device

BACKGROUNDnThis study was conducted to compare the effectiveness of a new, single-size silicone contraceptive diaphragm used with either spermicide [2% nonoxynol-9 (N-9)] or lubricant in preventing sperm from penetrating midcycle cervical mucus.nnnSTUDY DESIGNnA crossover postcoital test (PCT) in healthy, sexually active women not at risk for pregnancy due to tubal occlusion was conducted. Couples had a baseline PCT without a device to verify normal fertility parameters. Qualified couples underwent up to two test cycles using the SILCS diaphragm with a metal spring. A subgroup of couples underwent a third test cycle with the SILCS polymer spring diaphragm used with N-9 gel.nnnRESULTSnFifteen couples completed a baseline cycle and were randomized to order of study gel. Of these, 14 couples completed a baseline cycle and at least one test cycle, 12 couples completed a baseline cycle and two test cycles and 8 couples completed a third test cycle with the polymer spring prototype. Sperm was detected in the vaginal pool in all completed test cycles. The SILCS metal spring diaphragms used with N-9 gel reduced the average number of progressively motile sperm per high power field in the cervical mucus from a baseline of 12.5 to 0, while use of this device with lubricant reduced the number to 0.5. The SILCS polymer spring diaphragm used with N-9 performed the same as the metal spring used with N-9.nnnCONCLUSIONnThe SILCS diaphragm used with N-9 gel performed well. It is likely that the SILCS diaphragm will give acceptable results in a contraceptive effectiveness study but that adjunctive use of a chemical barrier such as N-9 gel will be necessary for it to be most effective.

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

BACKGROUNDnOnly 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) Womans Condom (WC) was developed in an effort to overcome these obstacles.nnnSTUDY DESIGNnThis 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.nnnRESULTSnTotal 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.nnnCONCLUSIONSnWhile both female condoms were safe and acceptable in short-term use, the PATH Womans Condom leads to less failure, was associated with fewer adverse events, and was more acceptable than the FC1 Female Condom.

A comparative study of the safety and efficacy of femcap®, a new vaginal barrier contraceptive, and the ortho all-flex® diaphragm

The FemCap is a new silicone rubber barrier contraceptive shaped like a sailors hat, with a dome that covers the cervix, a rim that fits into the fornices, and a brim that conforms to the vaginal walls around the cervix. It was designed to result in fewer dislodgments and less pressure on the urethra than the cervical cap and diaphragm, respectively, and to require less clinician time for fitting. This was a phase II/III, multicenter, randomized, open-label, parallel group study of 841 women at risk for pregnancy. A subset of 42 women at one site underwent colposcopy. Women were randomized to use the FemCap or Ortho All-Flex contraceptive diaphragm, both with 2% nonoxynol-9 spermicide, for 28 weeks. The objectives were to compare the two devices with regard to their safety and acceptability and to determine whether the probability of pregnancy among FemCap users was no worse than that of the diaphragm (meaning not more than 6 percentage points higher). The 6-month Kaplan-Meier cumulative unadjusted typical use pregnancy probabilities were 13.5% among FemCap users and 7.9% among diaphragm users. The adjusted risk of pregnancy among FemCap users was 1.96 times that among diaphragm users, with an upper 95% confidence limit of 3.01. Clinical equivalence (noninferiority) of the FemCap compared with the diaphragm, as defined in this study, would mean that the true risk of pregnancy among FemCap users was no more than 1.73 times the pregnancy risk of diaphragm users. Because the observed upper 95% confidence limit (and even the point estimate) exceeded 1.73, the probability of pregnancy among FemCap users, compared with that among diaphragm users, did not meet the definition of clinical equivalence used in this study. The FemCap was believed to be safe and was associated with significantly fewer urinary tract infections. More women reported problems with the FemCap with regard to insertion, dislodgement, and especially removal, although their general assessments were positive. The two devices were comparable with regard to safety and acceptability, but a 6-point difference in the true 6-month pregnancy probabilities of the two devices could not be ruled out. Further studies are needed to determine whether design modifications can simplify insertion and removal.

Comparative evaluation of three TactylonTM condoms and a latex condom during vaginal intercourse: breakage and slippage

This study compared breakage and slippage rates of three male condom styles made of Tactylon(TM), a synthetic elastomer, to those of a marketed latex condom during vaginal intercourse. Safety and acceptability outcomes were also assessed. This two-center, prospective, crossover study enrolled 443 couples. Each couple was randomly assigned to use three condoms of each type in one of 24 use sequences. Couples completed questionnaires after using each condom, all of one condom type, and all four condom types. The percentage and standard error (SE, in parentheses) of latex condoms with clinical breakage was 0.86% (0.295). Percentages for Tactylon condoms were not equivalent to the latex study condom, ranging from 3.50% to 4.17%. The percentage and SE of latex condoms with complete slippage was 1.11% (0.328). Percentages for Tactylon condoms were equivalent to those for latex, ranging from 0.70% to 1.31%. The Low-Modulus Tactylon condom was the most preferred. Fewer medical events were reported with the Tactylon condoms than with the latex condom. It was concluded that Tactylon condoms were equivalent to the latex condom in terms of slippage but not breakage. However, safety and acceptability seemed to be better for Tactylon condoms. This may improve consistency of use and may attract new users.

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-1β, 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-1β 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-1β although their IL-1RA-to-IL(α+β) 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.

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.

Results of a safety and feasibility study of the diaphragm used with ACIDFORM Gel or K-Y Jelly

BACKGROUNDnNew strategies are needed for preventing HIV infection in women. One potential approach is female-initiated use of an effective topical microbicidal gel in combination with a cervical barrier such as the diaphragm.nnnSTUDY DESIGNnRandomized, placebo-controlled safety and feasibility trial of diaphragm with vaginal gel during 6 months of use among 120 HIV-negative sexually active women in Johannesburg, South Africa.nnnRESULTSnPelvic event rates were 338.3 and 247.1 per 100 women-years in the ACIDFORM gel (plus diaphragm) and K-Y(R) Jelly (plus diaphragm) groups, respectively, with a rate ratio of 1.37 (95% CI: 0.89-2.11). Most women found diaphragm with gel use acceptable.nnnCONCLUSIONnThere was a trend towards more safety events in the ACIDFORM plus diaphragm group, although no primary comparisons achieved statistical significance. Adding an effective microbicidal gel to a mechanical barrier may still prove to be an important and acceptable combination method to help prevent pregnancy and HIV/sexually transmitted infection transmission.

Safety evaluation of 1% tenofovir gel in healthy men.

This study was conducted to determine the safety of tenofovir (TFV) gel, a potential microbicide, following seven consecutive daily penile applications. Eighteen circumcised and 18 uncircumcised healthy men were randomly assigned to TFV gel versus K-Y® Jelly in a 2:1 ratio within circumcision group. TFV gel or K-Y Jelly was applied onto the penis at bedtime and washed off 6–10 hours later. Safety was assessed by reported symptoms, findings and laboratory tests. Three of 24 (13%) men in the TFV group reported mild genital symptoms compared with two of 11 (18%) men in the K-Y group. Few mild genital findings were observed and no significant systemic toxicities were reported or observed. TFV gel applied to the penis for seven days was well tolerated locally and systemically and it is unlikely that male partners exposed to small amounts of TFV gel will experience significant genital or systemic toxicity.

Reddy female condom: functional performance of a 90-mm shaft length in two clinical studies

BACKGROUNDnWe report on the functional performance, safety and acceptability of the 90-mm Reddy female condom in two clinical trials, one in Los Angeles, CA, and one in Pune, Maharashtra, India.nnnSTUDY DESIGNnBoth studies used a Phase I, crossover design involving 25 couples. Each couple used three condoms of each of two shaft lengths: in Los Angeles, shaft lengths of 150 and 90 mm were used; in Pune, shaft lengths of 120 and 90 mm were used. This paper focuses on the 90-mm condom since it is commercially available. The primary endpoint of each study was invagination, defined as the outer frame of the condom being pushed into the vagina during intercourse. Secondary functionality endpoints included nonclinical breakage, clinical breakage, penile misdirection and complete slippage.nnnRESULTSnInvagination occurred in 26.9% of uses in Los Angeles vs. 6.8% of uses in Pune. Penile misdirection and complete slippage were reported only in Pune during 4.0% and 9.5% of uses, respectively. There were two clinical breaks in Pune and none in Los Angeles. Total clinical failure was 26.9% in Los Angeles and 23.0% in Pune.nnnCONCLUSIONSnTwo clinical studies of the 90-mm Reddy female condom suggest that its functional performance is inferior to other female condoms.