Oral and vaginal preparations of tenofovir as pre-exposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) infection have demonstrated variable efficacy in men and women prompting ...assessment of variation in drug concentration as an explanation. Knowledge of tenofovir concentration and its active form, tenofovir diphosphate, at the putative vaginal and rectal site of action and its relationship to concentrations at multiple other anatomic locations may provide key information for both interpreting PrEP study outcomes and planning future PrEP drug development.
MTN-001 was designed to directly compare oral to vaginal steady-state tenofovir pharmacokinetics in blood, vaginal tissue, and vaginal and rectal fluid in a paired cross-over design.
We enrolled 144 HIV-uninfected women at 4 US and 3 African clinical research sites in an open label, 3-period crossover study of three different daily tenofovir regimens, each for 6 weeks (oral 300 mg tenofovir disoproxil fumarate, vaginal 1% tenofovir gel 40 mg, or both). Serum concentrations after vaginal dosing were 56-fold lower than after oral dosing (p<0.001). Vaginal tissue tenofovir diphosphate was quantifiable in ≥90% of women with vaginal dosing and only 19% of women with oral dosing. Vaginal tissue tenofovir diphosphate was ≥130-fold higher with vaginal compared to oral dosing (p<0.001). Rectal fluid tenofovir concentrations in vaginal dosing periods were higher than concentrations measured in the oral only dosing period (p<0.03).
Compared to oral dosing, vaginal dosing achieved much lower serum concentrations and much higher vaginal tissue concentrations. Even allowing for 100-fold concentration differences due to poor adherence or less frequent prescribed dosing, vaginal dosing of tenofovir should provide higher active site concentrations and theoretically greater PrEP efficacy than oral dosing; randomized topical dosing PrEP trials to the contrary indicates that factors beyond tenofovir's antiviral effect substantially influence PrEP efficacy.
ClinicalTrials.gov NCT00592124.
Postplacental intrauterine device (IUD) placement, defined as IUD placement within 10 min after delivery of the placenta, is an appealing strategy for increasing access to postpartum IUDs because it ...does not require a separate postpartum visit. These guidelines present an evidence-based assessment of postplacental IUD placement after vaginal and cesarean delivery. Postplacental IUD insertion is safe and does not have higher risks of complications than interval insertion. Most studies find that the risk of IUD expulsion is higher after postplacental insertion than after interval insertion for both vaginal and cesarean deliveries. Most studies find higher rates of expulsion after vaginal delivery than after cesarean delivery. However, expulsion rates vary widely across studies, without clear evidence about the factors that may influence expulsion. In settings where replacement of expelled IUDs is available, patient populations with low rates of return for the postpartum visit are most likely to benefit from provision of postplacental IUD placement with appropriate counseling about risks and benefits.
Vaginal rings formulated to deliver two drugs simultaneously have potential as user-controlled, long-acting methods for dual prevention of HIV and pregnancy. Two phase 1 randomized trials ...(MTN-030/IPM 041 and MTN-044/IPM 053/CCN019) respectively enrolled 24 and 25 healthy, HIV-negative participants to evaluate safety, pharmacokinetics, and vaginal bleeding associated with use of a vaginal ring containing 200mg dapivirine (DPV) and 320mg levonorgestrel (LNG) designed for 90-day use. MTN-030/IPM 041 compared the DPV/LNG ring to a DPV-only ring (200mg) over 14 days of use. MTN-044/IPM 053/CCN019 compared continuous or cyclic use of the DPV/LNG ring over 90 days of use. Safety was assessed by recording adverse events (AEs). DPV and LNG concentrations were quantified in plasma, cervicovaginal fluid, and cervical tissue. Vaginal bleeding was self-reported. There were no differences in the proportion of participants with grade greater than or equal to2 genitourinary AEs or grade greater than or equal to3 AEs with DPV/LNG ring vs. DPV ring use (p = .22), or with DPV/LNG ring continuous vs. cyclic use (p = .67). Higher plasma DPV concentrations were observed in users of DPV/LNG compared to DPV-only rings (C.sub.max p = 0.049; AUC p = 0.091). Plasma DPV and LNG concentrations were comparable with continuous and cyclic use (C.sub.max p = 0.74; AUC p = 0.25). With cyclic use, median nadir plasma DPV concentration was approximately 300 pg/mL two days after removal and median t.sub.1/2 for cervicovaginal fluid DPV concentration was 5.76 hours (n = 3). Overall bleeding experiences did not differ between continuous and cyclic users (p = 0.12). The extended duration DPV/ LNG rings were well tolerated and the observed DPV concentrations in plasma and cervicovaginal fluid when used continuously exceeded concentrations observed in previous DPV ring efficacy studies. LNG concentrations in plasma were comparable with other efficacious LNG-based contraceptives. Genital DPV concentrations had a short half-life and were thus not well sustained following ring removal.
Extending hormonal intrauterine system duration will allow users to have less need for procedures to provide long-term contraception.
This study aimed to evaluate the efficacy and safety of the ...levonorgestrel 52 mg intrauterine system during years 7 and 8 of use.
A total of 1751 nulliparous and multiparous participants aged 16 to 45 years enrolled in a phase 3, multicenter trial to evaluate the efficacy and safety of the use of the Liletta levonorgestrel 52 mg intrauterine system for up to 10 years. Participants aged 36 to 45 years at enrollment underwent safety evaluation only. After the first year, we evaluated participants every 6 months for intrauterine system location confirmation and urine pregnancy testing at each visit. We assessed the Pearl Indices in years 7 and 8 and the life-table analysis for cumulative pregnancy rates through 8 years of use. For the primary efficacy analyses, all participants aged 16 to 35 years at enrollment were included through year 6; years 7 and 8 included only users aged ≤39 years at the start of each use year. Safety outcomes were assessed in all participants regardless of duration of use. We assessed amenorrhea rates, defined as no bleeding or spotting in the 90 days before the end of the year.
After intrauterine system placement, we followed 1568 participants aged 16 to 35 years and 146 participants aged 36 to 45 years. The 16- to 35-year-old participants included 986 (57.5%) nulliparous and 433 (25.3%) obese users. Overall, 569 participants started year 7, 478 completed year 7 (380 aged ≤39 years at beginning of year) and 343 completed year 8 (257 aged ≤39 years at beginning of year); 77 completed 10 years of use. Eleven pregnancies occurred over 8 years, 7 (64%) of which were ectopic. Two pregnancies occurred in year 7 (Pearl Index, 0.49; 95% confidence interval, 0.06–1.78), 1 in a participant with implantation 4 days after a desired removal; no pregnancies occurred in year 8. The cumulative life-table pregnancy rate in the primary efficacy population through year 8 was 1.32 (95% confidence interval, 0.69–2.51); without the postremoval pregnancy, the rate was 1.09 (95% confidence interval, 0.56–2.13). Two perforations (0.1%) occurred, none noted after year 1. Expulsion occurred in 71 (4.1%) participants overall, with 3 in year 7 and 2 in year 8. Pelvic infection was diagnosed in 16 (0.9%) participants during intrauterine system use, 1 each in years 7 and 8. Only 44 (2.6%) participants overall discontinued because of bleeding complaints (4 total in years 7 and 8) with rates per year of 0.1% to 0.5% for years 3 to 8. Amenorrhea rates were 39% at both years 7 and 8.
The levonorgestrel 52 mg intrauterine system is highly effective over 8 years of use and has an excellent extended safety profile. This report details the longest period of efficacy and safety data for continuous use of a levonorgestrel 52 mg intrauterine system for contraception.
Given challenges with adherence to existing HIV prevention products, the development of an extended duration vaginal ring could improve adherence while reducing patient and provider burden. ...Additionally, women have other interlinked sexual health concerns such as unintended pregnancy. We evaluated acceptability of a 90-day ring to prevent HIV and hypothetical preferences for a dual (HIV and contraceptive) indication. This was a secondary analysis of a Phase 1, two-arm, multi-site, placebo-controlled randomized trial evaluating safety and pharmacokinetics of a 90-day vaginal ring containing tenofovir for HIV prevention (N = 49). We used a mixed methods approach to assess quantitative data on acceptability (n = 49) and used qualitative data from a random subset to explain the quantitative findings (N = 25). The 3-month extended duration tenofovir ring was highly acceptable. Participants perceived the ring to be easy to use, comfortable and reported liking it more over time. About half felt the ring during sex but most of those participants said it bothered them only a little. Concerns about hygiene increased over the study period but were often outweighed by the benefits of an extended duration ring. Interest in a multi-purpose ring was high (77%) and even higher among those who were sexually active and had male partners. The 3-month extended duration tenofovir ring for HIV prevention was highly acceptable among women and interest in an MPT was high.
The expected trend in serum beta-human chorionic gonadotropin (β-hCG) following treatment of an undesired heterotopic pregnancy with uterine aspiration and systemic methotrexate is not known. Thus, ...monitoring for treatment success is challenging. We describe an undesired heterotopic pregnancy treated with aspiration and two-dose methotrexate and report the observed β-hCG trend.
OBJECTIVE:To assess the 5-year contraceptive efficacy and safety of a levonorgestrel (LNG) 52-mg intrauterine system (IUS) from an ongoing 10-year phase 3 contraceptive trial.
METHODS:Study ...investigators enrolled 1,751 nulliparous and parous females aged 16–45 years and desiring contraception to receive a novel LNG 52-mg IUS at 29 centers in the United States, including reproductive health clinics, private offices, and university centers. Participants had scheduled follow-up visits four times during the first year. After year 1, study visits occurred every 6 months, with phone contact at the 3-month point between visits. We assessed the primary outcome of pregnancy rate (Pearl Index) in females aged 16–35 years at enrollment through 60 months. The safety evaluation included all females for their entire duration of participation.
RESULTS:The 1,751 enrollees included 1,600 females aged 16–35 years and 151 aged 36–45 years. Successful IUS placement occurred in 1,714 (97.9%) participants. At the time of the data evaluation, 495 participants finished 5 years and 176 had entered the seventh year of IUS use. Nine pregnancies occurred, six of which were ectopic. The Pearl Indices for years 1 and 5 were 0.15 (95% CI 0.02–0.55) and 0.20 (95% CI 0.01–1.13) pregnancies per 100 women-years, respectively. The cumulative life-table pregnancy rate was 0.92% (0.46–1.82%) through 5 years. Participants aged 16–35 years at enrollment were significantly more likely to report new or worsening acne, dyspareunia, pelvic pain, and dysmenorrhea; participants aged 36–45 years at enrollment were more likely to report new or worsening weight increase. Discontinuation for adverse events occurred in 322 (18.8%) participants, most commonly related to expulsion (n=65 3.8%). Only 39 (2.2%) IUS users discontinued as a result of bleeding symptoms. Pelvic infection was diagnosed in 14 (0.8%) participants.
CONCLUSION:This LNG 52-mg IUS is highly effective and safe over 5 years of use in U.S. females.
CLINICAL TRIAL REGISTRATION:Clinicaltrials.gov, NCT00995150.
FUNDING SOURCE:Medicines360.
INTRODUCTION:Pain during intrauterine device (IUD) insertion is a barrier to uptake. We compared insertion-related pain and short-term satisfaction between two copper (Cu) IUDs.
METHODS:We conducted ...a multicenter, single-blind randomized trial comparing two CuIUDs. Participants were randomized (4:1 ratio) to a smaller (Mona Lisa NT Cu380-Mini 24 mm x 30 mm) or standard (Paragard TCu380A 32 mm x 36 mm) CuIUD. Participants recorded maximum pain levels on a 10 cm visual analog scale at nine timepoints (pre- and immediately post-IUD insertion, daily for 7 days). At day 7, participants reported overall satisfaction (5-point scale) and whether they would recommend the product to others. For each timepoint, we computed mean pain level and mean change in pain from baseline, and stratified by parity. We used T-tests and chi-square tests to compare results between products.
RESULTS:We enrolled 1,105 women, 84% nulliparous (n=924). Mean pain levels immediately post-insertion were 4.9 cm (SD 2.3) for both the smaller (n=886) and standard (n=219) products. Subsequent pain levels decreased equally across both products, from 2.5 cm (day 2) to 0.7 cm (day 7). Mean pain after baseline adjustment was similar between products. Nulliparous women using either IUD reported higher pain levels at all timepoints than parous women (P<.05). Among nulliparous women, 54% were highly satisfied with the smaller versus 45% with standard IUD (P<.05); over 92% using each product would recommend it. Parous women reported similar satisfaction by product.
CONCLUSION:Reported pain was similar between IUDs. Satisfaction among nulliparous women was higher at 7 days with a smaller CuIUD. Longer-term data may elucidate possible differences between products.
BACKGROUND:Variable adherence limits effectiveness of daily oral and intravaginal tenofovir-containing pre-exposure prophylaxis. Monthly vaginal antiretroviral rings are one approach to improve ...adherence and drug delivery.
METHODS:MTN-013/IPM 026, a multisite, double-blind, randomized, placebo-controlled trial in 48 HIV-negative US women, evaluated vaginal rings containing dapivirine (DPV) (25 mg) and maraviroc (MVC) (100 mg), DPV only, MVC only, and placebo used continuously for 28 days. Safety was assessed by adverse events. Drug concentrations were quantified in plasma, cervicovaginal fluid (CVF), and cervical tissue. Cervical biopsy explants were challenged with HIV ex vivo to evaluate pharmacodynamics.
RESULTS:There was no difference in related genitourinary adverse events between treatment arms compared with placebo. DPV and MVC concentrations rose higher initially before falling more rapidly with the combination ring compared with relatively stable concentrations with the single-drug rings. DPV concentrations in CVF were 1 and 5 log10 greater than cervical tissue and plasma for both rings. MVC was consistently detected only in CVF. DPV and MVC CVF and DPV tissue concentrations dropped rapidly after ring removal. Cervical tissue showed a significant inverse linear relationship between HIV replication and DPV levels.
CONCLUSIONS:In this first study of a combination microbicide vaginal ring, all 4 rings were safe and well tolerated. Tissue DPV concentrations were 1000 times greater than plasma concentrations and single drug rings had more stable pharmacokinetics. DPV, but not MVC, demonstrated concentration-dependent inhibition of HIV-1 infection in cervical tissue. Because MVC concentrations were consistently detectable only in CVF and not in plasma, improved drug release of MVC rings is needed.
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