Laneta Dorflinger

SAVVY® (C31G) Gel for Prevention of HIV infection in Women: A Phase 3, Double-Blind, Randomized, Placebo-Controlled Trial in Ghana

Objective The objective of this trial was to determine the effectiveness of 1.0% C31G (SAVVY) in preventing male-to-female vaginal transmission of HIV infection among women at high risk. Methodology/Principal Findings This was a Phase 3, double-blind, randomized, placebo-controlled trial. Participants made up to 12 monthly visits for HIV testing, adverse event reporting, and study product supply. The study was conducted between March 2004 and February 2006 in Accra and Kumasi, Ghana. We enrolled 2142 HIV-negative women at high risk of HIV infection, and randomized them to SAVVY or placebo gel. Main outcome measures were the incidence of HIV-1 and HIV-2 infection as determined by detection of HIV antibodies from oral mucosal transudate specimens and adverse events. We accrued 790 person-years of follow-up in the SAVVY group and 772 person-years in the placebo group. No clinically significant differences in the overall frequency of adverse events, abnormal pelvic examination findings, or abnormal laboratory results were seen between treatment groups. However, more participants in the SAVVY group reported reproductive tract adverse events than in the placebo group (13.0% versus 9.4%). Seventeen HIV seroconversions occurred; eight in participants randomized to SAVVY and nine in participants receiving placebo. The Kaplan-Meier estimates of the cumulative probability of HIV infection through 12 months were 0.010 in the SAVVY group and 0.011 in the placebo group (p = 0.731), with a hazard ratio (SAVVY versus placebo) of 0.88 (95% confidence interval 0.33, 2.27). Because of a lower-than-expected HIV incidence, we were unable to achieve the required number of HIV infections (66) to obtain the desired study power. Conclusions/Significance SAVVY was not associated with increased adverse events overall, but was associated with higher reporting of reproductive adverse events. Our data are insufficient to conclude whether SAVVY is effective at preventing HIV infection relative to placebo. Trial Registration ClinicalTrials.gov NCT00129532

Metabolic effects of implantable steroid contraceptives for women

The metabolic impact of progestin-only contraceptives is less than that of combined oral contraceptives. Subdermal contraceptive implant systems that provide a sustained release of low levels of progestins are now becoming widely available. This review evaluates the metabolic effects of currently available products that release the progestins levonorgestrel (Norplant, Jadelle, and their Chinese equivalents); etonogestrel (Implanon); nomegestrol acetate (Uniplant); and Nestorone, formally called ST-1435 (Nestorone implant/Elcometrine). Data on liver, kidney, and renal function; carbohydrates and insulin release; hemostasis; blood pressure; and lipids are considered. The metabolic effects reported for these methods as a whole were minimal. Any changes were generally within the normal range for the populations studied and, therefore, are unlikely to be of clinical significance. However, all published studies have been conducted in healthy populations of women. To inform clinical practice, the field would be well served to have additional empiric data from well-designed, well-implemented, and well-reported trials in women who are deemed to be at elevated risk for certain diseases including cardiovascular disease and diabetes.

Standardized protocols for condom breakage and slippage trials: a proposal.

In the absence of well-controlled studies on the clinical effectiveness of condoms against pregnancy and sexually transmitted diseases, breakage and slippage data may provide the best indication of the protection offered by condom use. According to the recent literature, condom breakage rates range from 0% to 12%, with many US studies falling in the 2% to 5% range. Few studies have collected slippage data. In addition to discussing methodological issues associated with these studies, we propose a standardized protocol for future condom breakage and slippage trials and discuss how results may be used to estimate perfect-use and typical-use pregnancy rates.

Menstrual pattern changes from levonorgestrel subdermal implants and DMPA: systematic review and evidence-based comparisons

BACKGROUND Many women want a lengthy duration of contraception but are wary of the menstrual changes from depot medroxyprogesterone acetate (DMPA). A subdermal levonorgestrel (LNG) implant may be a reasonable alternative. However, information on menstrual changes from these methods has not been summarized and compared in an easy-to-understand form. STUDY DESIGN We systematically reviewed the published literature on these contraceptives to find research that used menstrual diaries and standard World Health Organization definitions. We attempted to find information on amenorrhea, number of bleeding or spotting episodes, number of bleeding or spotting days and normal patterns, as reported in four consecutive 90-day reference periods. RESULTS We found 16 published articles meeting our criteria and involving diaries of up to 1600 DMPA users and 2300 LNG implant users. We were able to compare the two methods on only three outcomes. For DMPA use, the weighted prevalence of amenorrhea at successive 90-day periods was 12%, 25%, 37% and 46%. The comparable estimates for the LNG implant were 11%, 13%, 9% and 13%. Levonorgestrel implant users experienced a higher average number of bleeding or spotting days compared to DMPA users, but this average was similar to what is expected naturally. At 12 months, normal menstrual patterns were experienced by 23% of LNG implant users compared to 11% of DMPA users. CONCLUSIONS Like most hormonal contraception, LNG implants usually produce menstrual changes; however, the changes do not appear to deviate from normal patterns as much as the changes from DMPA. Understanding these differences and other method attributes might help women make an informed choice about which contraceptive to use.

Contraceptive effectiveness of a polyurethane condom and a latex condom: A randomized controlled trial

OBJECTIVE To compare the contraceptive effectivenesses of a polyurethane condom and a standard latex condom. Secondary outcomes of interest were safety, functionality, discontinuation, and acceptability. METHODS We randomized 901 couples to use either the polyurethane condom or a standard latex condom as their only form of contraception. We tested for pregnancy at enrollment and at every scheduled follow-up visit (weeks 4, 10, 16, 22, and 30). RESULTS The 6-month typical-use pregnancy probabilities were 9.0% (95% confidence interval [CI] 5.9, 12.2) for the polyurethane group and 5.4% (95% CI 2.9, 7.8) for the latex group; the hazard ratio was 1.7 (95% CI 1.1, 2.7), and we failed to reject the null hypothesis of our test of noninferiority. Females in the polyurethane group reported fewer genital irritations (hazard ratio 0.6; 95% CI 0.5, 0.8; P < .01), whereas males in both groups reported the same number of genital irritations (hazard ratio 1.0; 95% CI 0.7, 1.5; P = .94). Total clinical failures (breakage and slippage) were 8.4% for the polyurethane condom and 3.2% for the latex condom (difference 5.3%, 90% CI 2.8, 7.7). The risk of discontinuation did not differ between groups. Participants judged both condoms favorably in terms of the four primary acceptability outcomes (willingness to purchase, willingness to recommend, confidence in method, and general comfort). CONCLUSION The polyurethane condom was not shown to be as effective as the latex comparator condom for pregnancy prevention. However, the risk of pregnancy in the polyurethane group falls in the range of other barrier methods. For people with latex sensitivity or who find latex condoms unacceptable, this polyurethane condom represents one of several synthetic male condom alternatives currently available on the US market.

Sino-implant (II)--a levonorgestrel-releasing two-rod implant: systematic review of the randomized controlled trials.

BACKGROUND Sino-implant (II) is a subdermal contraceptive implant manufactured in China. This two-rod levonorgestrel-releasing implant has the same amount of active ingredient (150 mg levonorgestrel) and mechanism of action as the widely available contraceptive implant Jadelle. We examined randomized controlled trials of Sino-implant (II) for effectiveness and side effects. STUDY DESIGN We searched electronic databases for studies of Sino-implant (II) and then restricted our review to randomized controlled trials. The primary outcome of this review was pregnancy. RESULTS Four randomized trials with a total of 15,943 women assigned to Sino-implant (II) had first-year probabilities of pregnancy ranging from 0.0% to 0.1%. Cumulative probabilities of pregnancy during the 4 years of the products approved duration of use were 0.9% and 1.06% in the two trials that presented date for 4-year use. Five-year cumulative probabilities of pregnancy ranged from 0.7% to 2.1%. In one trial, the cumulative probability of pregnancy more than doubled during the fifth year (from 0.9% to 2.1%), which may be why the implant is approved for 4 years of use in China. Five-year cumulative probabilities of discontinuation due to menstrual problems ranged from 12.5% to 15.5% for Sino-implant (II). CONCLUSIONS Sino-implant (II) is one of the most effective contraceptives available today. These available clinical data, combined with independent laboratory testing, and the knowledge that 7 million women have used this method since 1994, support the safety and effectiveness of Sino-implant (II). The lower cost of Sino-implant (II) compared with other subdermal implants could improve access to implants in resource-constrained settings.

Effectiveness of the Yuzpe regimen of emergency contraception by cycle day of intercourse: implications for mechanism of action

OBJECTIVE The purpose of this study was to provide evidence about the mechanism of action of the Yuzpe method of emergency contraception by examining effectiveness by cycle day of intercourse relative to ovulation. METHODS Through a literature search, we identified eight studies that present the number of women treated and outcome of treatment by cycle day of unprotected intercourse relative to expected day of ovulation. Using five sets of external estimates of conception probabilities by cycle day of intercourse among women not using contraception, we assessed and compared the effectiveness of the Yuzpe regimen by whether intercourse occurred on or before the second day before ovulation or afterward, and whether intercourse occurred on or before the first day before ovulation or afterward. RESULTS In 36 of the 45 pairs of estimates of effectiveness, based on eight separate studies and the eight studies combined and five different sets of conception probabilities by cycle day, effectiveness was higher-and in most cases substantially higher-when intercourse occurred on or before the second day before ovulation (day -2) than when it occurred later. When data were stratified by whether intercourse occurred on or before the day before ovulation (day -1), effectiveness was greater when intercourse occurred early in 43 of 45 pairs. CONCLUSIONS These results suggest that one hypothesized mechanism of action of the Yuzpe method, inhibiting implantation of a fertilized egg, is unlikely to be the primary mechanism of action.

Pharmacokinetics of subcutaneous depot medroxyprogesterone acetate injected in the upper arm

BACKGROUND The abdomen and thigh are recommended injection sites in the label for Depo-SubQ Provera 104™. We evaluated the pharmacokinetic profile of medroxyprogesterone acetate (MPA) following injection of Depo-SubQ Provera 104 in the upper arm, a preferred injection site in developing countries. STUDY DESIGN Twenty-six women in Norfolk, VA, received a single injection of Depo-SubQ Provera 104 in the upper arm in this prospective noncomparative study. We measured MPA serum concentrations prior to injection (day 1) and 11 times postinjection (days 2, 4, 8, 14, 30, 44, 60, 74, 91, 104 and 120). RESULTS Serum MPA levels peaked at 0.953 ng/mL 2-14 days (interquartile range; median=8) after dosing. Mean AUC0-91 was 45.1 ng·day/mL. Mean MPA levels at days 91, 104 and 120 were 0.427, 0.367 and 0.327 ng/mL, respectively. A total of 15 individual measurements of MPA were below 0.2 ng/mL. All women but one had MPA levels above 0.1 ng/mL on day 91. CONCLUSIONS Injection of Depo-SubQ Provera 104™ in the upper arm provided sufficient MPA levels for contraceptive protection for 3 months (13 weeks). The uptake and metabolism of MPA when injected in the upper arm may be different from the abdomen and thigh.

New developments in contraception for US women.

Despite the variety of contraceptive options today unintended pregnancy continues to be a major public health issue in the United States. Roughly half of all unintended pregnancies in the US occur among women who report using contraception during the month they become pregnant. Some unintended pregnancies among contraception users are due to inherent failure rates of specific methods but most of these unintended pregnancies result from inconsistent or incorrect use of methods that require some regular action by the user. User-dependent methods have high typical use failure rates when compared with long-acting reversible contraceptives (LARCs) such as IUDs and implants. However the use of LARCs remains relatively low in the US particularly when compared with other developed countries. As new contraceptive methods may soon enter the US market providers should be aware of these new options because they will play a critical role in ensuring that women are appropriately counseled to understand the advantages and disadvantages of each. This report is a brief summary of some of these new contraceptives including new hormone-releasing intrauterine systems contraceptives patches (i.e. Twirla®) the Population Council vaginal ring updated female condoms and diaphragm the return of the monthly injectable and different pill formulations. Copyright

Global Introduction of a Low-Cost Contraceptive Implant

Hormone-releasing subdermal implants are a safe, highly effective, and reversible form of contraception that provides continuous pregnancy protection for 3–5 years depending on the type of implant. Implants are among the most effective forms of contraception available; efficacy is comparable to other long-acting and permanent methods including the intrauterine device (IUD) and sterilization, with annual pregnancy rates less than 1 % for women using these methods (Mansour et al. 2010). However, unlike the IUD or female sterilization which requires a gynecological procedure, implants are inserted under the skin of a woman’s upper arm. Because no regular action is required by the user and no routine resupply or clinical follow-up is needed, implants are widely seen as an ideal method for women with limited access to health services, particularly women in developing countries (Frost and Reich 2008). However, despite the advantages of this method, worldwide use of implants is low: whereas 56 % of married women between the ages of 15 and 49 around the globe use a modern method of contraception, less than 1 % use implants (United Nations 2011).