BackgroundOral 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.ObjectiveMTN-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.Methods and FindingsWe 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).ConclusionsCompared 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.Trial RegistrationClinicalTrials.gov NCT00592124

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 multi-site, double-blind, randomized, placebo-controlled trial in 48 HIV-negative U.S. women, evaluated vaginal rings containing dapivirine (25 mg) and maraviroc (100 mg), dapivirine-only, maraviroc-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 to placebo. Dapivirine and maraviroc concentrations rose higher initially before falling more rapidly with the combination ring compared to relatively stable concentrations with the single drug rings. Dapivirine concentrations in CVF were 1 and 5 log10 greater than cervical tissue and plasma for both rings. Maraviroc was consistently detected only in CVF. Dapivirine and maraviroc CVF and dapivirine tissue concentrations dropped rapidly after ring removal. Cervical tissue showed a significant inverse linear relationship between HIV replication and dapivirine levels. Conclusions In this first study of a combination microbicide vaginal ring, all four rings were safe and well tolerated. Tissue dapivirine concentrations were 1,000 times greater than plasma concentrations and single drug rings had more stable pharmacokinetics. Dapivirine, but not maraviroc, demonstrated concentration-dependent inhibition of HIV-1 infection in cervical tissue. Since maraviroc concentrations were consistently detectable only in CVF and not in plasma, improved drug release of maraviroc rings is needed.

OBJECTIVE To estimate whether 6-month use of the levonorgestrel-releasing intrauterine device (IUD) would be higher when insertion occurred within 10 minutes of placental delivery compared with 6–8 weeks postpartum. METHODS We enrolled pregnant women planning vaginal deliveries and desiring a postpartum levonorgestrel-releasing IUD. Patients were randomly assigned when admitted in labor to postplacental or delayed IUD insertion. The women followed up in person at 6–8 weeks and 6 months and were contacted by telephone at 3 months. Women were ineligible for a study IUD postenrollment for intrapartum events including infection, hemorrhage, and cesarean delivery; these women were contacted by phone at 3 and 6 months. Expelled IUDs were replaced per patient preference. RESULTS Successful IUD placement occurred in 50 of 51 participants (98.0%) and 46 of 51 participants (90.2%) in the postplacental and delayed groups, respectively (P=.2). Expulsion within 6 months occurred in 12 of 50 (24.0%; 95% confidence interval [CI], 13.1–38.2) and two of 46 (4.4%; 95% CI 0.5–14.8) participants, respectively (P=.008). Intrauterine device use at 6 months was 43 of 51 (84.3%; 95% CI 71.4–93.0) and 39 of 51 (76.5%; 95% CI 62.5–87.2), respectively (P=.32). For ineligible patients, only 11 of 41 (26.8%) women were using IUDs at 6 months and two (4.9%) had become pregnant. CONCLUSION Intrauterine device use 6 months after delivery is similar in women who have postpartum or scheduled delayed IUD placement through a study after replacement of expelled IUDs. Expulsions are significantly higher with postplacental compared with delayed IUD placement. Women asked to follow up with their own health care providers for delayed insertion are significantly less likely to receive an IUD. CLINICALTRIALREGISTRATION ClinicalTrials.gov, www.clinicaltrials.gov, NCT00476021. LEVEL OF EVIDENCE I

Objectives The study was designed to assess the safety, adherence, acceptability, and effect on vaginal microflora of 3% SPL7013 Gel (VivaGel®), a novel dendrimer topical microbicide that inhibits HIV, HSV-2 and HPV in vitro and in animal models. Design Phase 1, randomized, double-blind, placebo-controlled study in sexually active women. Methods Sixty-one sexually active women aged 18–24 years were recruited from three sites in the United States. Participants were randomized 1:1:1 to receive VivaGel, VivaGel placebo, or a hydroxyethylcellulose (HEC) placebo twice daily for 14 consecutive days. Safety endpoints included genitourinary and/or other adverse events (AE). Changes in vaginal flora were determined from Gram-stained vaginal smears and quantitative vaginal culture. Results No serious AEs or withdrawals due to AEs were reported. Genitourinary symptoms were reported as follows: VivaGel (n=17/22; 77.3%), VivaGel placebo (n=14/21; 66.7%) and HEC (n=8/18; 44.4%) (NS, p=0.1). The incidence of abnormal pelvic exam findings was similar across all gel arms of the study. Using pair-wise comparison, women in the VivaGel arm had a significantly higher incidence of related genitourinary AEs compared with women in the HEC gel arm (0.297 versus 0.111 per 100 person years, respectively; p=0.003). Exposure to VivaGel and VivaGel placebo resulted in minor shifts in the vaginal microflora but there was no overall impact on incidence of bacterial vaginosis as assessed by Nugent score. Conclusions VivaGel was generally well tolerated and comparable with the VivaGel placebo, although there was a higher incidence of low grade related genital AEs compared to the HEC placebo gel.

Early pregnancy failure is a common pregnancy complication. This paper reviews the terminology, diagnosis, and treatment of early pregnancy failure. Although surgical curettage has been the standard of care for more than 50 years, additional treatment options exist which appear to be satisfactory to patients. Manual vacuum curettage in the office is an effective alternative to electric vacuum curettage in an operating room. Nonsurgical treatments, including expectant and medical management, are reasonable alternatives depending on the clinical situation and the patient's desires. Clinicians need to understand how these options compare to provide appropriate counseling to patients.

We compared adherence to and acceptability of daily topical and oral formulations of tenofovir (TFV) used as pre-exposure prophylaxis (PrEP) for HIV prevention among women in South Africa, Uganda and the United States. 144 sexually active, HIV-uninfected women participated in a cross-over study of three regimens: oral tablet, vaginal gel, or both. We tested for differences in adherence and evaluated product acceptability. Self-reported adherence for all regimens was high (94%), but serum TFV concentrations indicated only 64% of participants used tablets consistently. Most women in the U.S. (72%) favored tablets over gel; while preferences varied at the African sites (42% preferred gel and 40% tablets). Findings indicate a role for oral and vaginal PrEP formulations and highlight the importance of integrating pharmacokinetics-based adherence assessment in future trials. Biomedical HIV prevention interventions should consider geographic and cultural experience with product formulations, partner involvement, and sexual health benefits that ultimately influence use.

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.

A phase 3 study of a levonorgestrel 52-mg intrauterine system in U.S. females shows high 5-year contraceptive efficacy and low hormonal adverse effect rates.