Beatrice A. Chen

MTN-001: Randomized Pharmacokinetic Cross-Over Study Comparing Tenofovir Vaginal Gel and Oral Tablets in Vaginal Tissue and Other Compartments

Background 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. Objective 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. Methods and Findings 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). Conclusions 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. Trial Registration ClinicalTrials.gov NCT00592124

Postplacental or Delayed Insertion of the Levonorgestrel Intrauterine Device After Vaginal Delivery: A Randomized Controlled Trial

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. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00476021. LEVEL OF EVIDENCE: I

Feasibility of telephone follow-up after medical abortion

BACKGROUND This study was conducted to assess the feasibility of using telephone calls combined with high-sensitivity urine pregnancy testing as a primary method of follow-up after medical abortion. METHODS We enrolled 139 women up to 63 days of gestation to receive mifepristone 200 mg orally and misoprostol 800 mcg vaginally or buccally, per their choice. Participants were contacted by phone one week after mifepristone administration and interviewed using standardized questions. If the subject or clinician thought the pregnancy was not expelled, the subject returned for an ultrasound examination. Otherwise, subjects performed high-sensitivity home urine pregnancy testing 30 days after the mifepristone and were called within 3 days of the test. Those with positive pregnancy tests returned for an ultrasound examination. Those with negative tests required no further follow-up. RESULTS Six of the 139 (4.3%, 95% CI 1.6-9.1%) subjects presented prior to Phone Call 1 for an in-person visit. All 133 (100%, 95% CI 97.8-100%) subjects eligible for their first telephone follow-up were contacted. Eight of the 133 (6.1%, 95% CI 2.6-11.5%) women were asked to return for evaluation and all did so (100%, 95% CI 63.1-100%). Eight of the 133 women eligible for the 30 day phone call presented for an interim visit prior to the call. After 30 days, 116 of the 117 (99.1%, 95% CI 97.5-100%) eligible subjects were contacted. One subject was not reached for the day 30 phone call. Twenty-seven of the 116 (23.3%, 95% CI 15.6-31.0%) subjects had a positive pregnancy test and required follow-up. Two of these subjects (7.4%, 95% CI 1.0-24.2%) did not return for in-person follow-up. Two of the 116 (1.7%, 95% CI 0.2-6.1%) subjects had inconclusive pregnancy tests and were asked to return for follow-up. One of these subjects (50%, 95% CI 1.2-98.7%) did not return. Complete follow-up was achieved in 135 of the 139 subjects (97.1%, 95% CI 94.3-99.9%). None of the 26 women evaluated for a positive or inconclusive pregnancy test had a gestational sac or continuing pregnancy. CONCLUSION Telephone follow-up combined with urine pregnancy testing after medical abortion is a feasible alternative to routine ultrasonography or serial serum hCG measurements.

Phase 1 randomized trial of the vaginal safety and acceptability of SPL7013 gel (VivaGel) in sexually active young women (MTN-004).

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, herpes simplex virus-2, and human papillomavirus in vitro and in animal models. Design:Phase 1, randomized, double-blind, placebo-controlled study on 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. Changes in vaginal flora were determined from Gram-stained vaginal smears and quantitative vaginal culture. Results:No serious adverse events or withdrawals due to adverse events were reported. Genitourinary symptoms were reported as follows: VivaGel (n = 17/22; 77.3%), VivaGel placebo (n = 14/21; 66.7%), and HEC (n = eight of 18; 44.4%; not significant, P = 0.1). The incidence of abnormal pelvic examination findings was similar across all gel arms of the study. Using pairwise comparison, women in the VivaGel arm had a significantly higher incidence of related genitourinary adverse events 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. Conclusion:VivaGel was generally well tolerated and comparable with the VivaGel placebo, although there was a higher incidence of low-grade related genital adverse events compared to the HEC placebo gel.

Phase 1 Safety, Pharmacokinetics, and Pharmacodynamics of Dapivirine and Maraviroc Vaginal Rings: a Double-Blind Randomized Trial

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.

Contemporary management of early pregnancy failure.

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 patients desires. Clinicians need to understand how these options compare to provide appropriate counseling to patients.

Postplacental or delayed levonorgestrel intrauterine device insertion and breast-feeding duration.

BACKGROUND The objective of this study was to assess the effect of timing of postpartum levonorgestrel-releasing intrauterine device (IUD) insertion on breast-feeding continuation. STUDY DESIGN Women interested in using a levonorgestrel IUD postpartum were randomized to immediate postplacental insertion (postplacental group) or insertion 6-8 weeks after vaginal delivery (delayed group). Duration and exclusivity of breast-feeding were assessed at 6-8 weeks, 3 months, and 6 months postpartum. Only women who received an IUD were included in this analysis. RESULTS Breast-feeding was initiated by 32 (64%) of 50 of women receiving a postplacental IUD and 27 (58.7%) of 46 of women receiving a delayed IUD (p=.59). More women in the delayed group compared with the postplacental group continued to breast-feed at 6-8 weeks (16/46 vs. 15/50, p=.62), 3 months (13/46 vs. 7/50, p=.13), and 6 months postpartum (11/46 vs. 3/50, p=.02). The results did not differ when only women who initiated breast-feeding or only primiparous women with no prior breast-feeding experience were analyzed. CONCLUSIONS Immediate postplacental insertion of the levonorgestrel IUD is associated with shorter duration of breast-feeding and less exclusive breast-feeding. Further studies on the effects of early initiation of progestin-only methods on womens lactation experience are needed.

Duration of use of a levonorgestrel IUS amongst nulliparous and adolescent women

BACKGROUND Intrauterine devices are cost-effective if used for 2 or more years. Early discontinuation may lead to reduced cost-effectiveness of this method and unintended pregnancy if other contraceptives are not used. This study sought to examine rates and reasons for discontinuation of IUS use in adolescents versus older women and nulliparous versus parous women, as these groups may be more likely to discontinue use. STUDY DESIGN Retrospective cohort study of women receiving a levonorgestrel IUS between June 2005 and April 2008 was conducted. Medical records were reviewed for all visits following placement of the IUS; rates and reasons for IUS discontinuation were calculated and categorized. Data were examined under two scenarios: (1) assuming that all women not seen for follow-up continued IUS use and (2) only including women with follow-up visits. Cox regression was used to control for age, parity, race and marital status in comparing rates of IUS discontinuation and expulsion in nulliparous versus parous women and adolescents versus older women. RESULTS Of the 828 women included in this analysis, 104 (12.6%) were nulliparous, and 131 (15.8%) were ≤20 years of age. Nulliparous women were not more likely than parous women to have expelled their IUS [hazard ratio (95% confidence interval), 1.40 (0.57, 3.43)]. Adolescent women were more likely to experience expulsion than older women, although this did not reach statistical significance [hazard ratio, 1.49 (0.76, 2.92)]. When we looked at reasons for IUS removal, we found that nulliparous women were not more likely than parous women to have their IUS removed because of dissatisfaction with the contraceptive method (6.7% vs. 11.5%, p=.15) or desire to become pregnant (1.9% vs. 2.6%, p=.50). Similarly, adolescents were not more likely than older women to have their IUS removed because of dissatisfaction with the contraceptive method (10.7% vs. 10.9%, p=.94) or desire to become pregnant (3.1% vs. 2.4%, p=.43). CONCLUSIONS Adolescents and nulliparous women are not more likely to prematurely discontinue use of their IUS than adult or parous women.

Immediate versus delayed insertion of the levonorgestrel-releasing intrauterine device following dilation and evacuation: a randomized controlled trial

BACKGROUND The study was conducted to compare 6-month usage of the levonorgestrel-releasing intrauterine device (LNG-IUD) when placed immediately or 3 to 6 weeks after dilation and evacuation (D&E) procedure. STUDY DESIGN We enrolled women undergoing D&E at 15 to 23 weeks of gestation. After completion of the D&E, subjects without contraindications to immediate IUD insertion were randomized to immediate or delayed (3 to 6 weeks later) LNG-IUD insertion. Subjects in the immediate group had the LNG-IUD placed using ultrasound guidance. All subjects returned at 3 to 6 weeks and 8 to 10 weeks after D&E and were contacted by phone at 6 months. RESULTS Of the 93 subjects enrolled, 88 were randomized. All 44 subjects (100%) randomized to immediate insertion had successful IUD placement, while only 20 (45.5%) of the 44 subjects randomized to delayed insertion returned for IUD placement, all of which were successful [difference 54.5%, 95% confidence interval (CI) 39.8%-69.3%]. Seventeen (38.6%) participants in each group were lost to follow-up. Of subjects contacted at the 6-month follow-up phone call, 23 of 27 women (85.2%) and 17 of 27 women (62.9%) were utilizing the LNG-IUD in the immediate and delayed groups, respectively (difference 22.2%, 95% CI -0.4% to 44.8%). Intrauterine device expulsion occurred in three subjects (6.8%) and one subject (5.0%) in whom the IUD was placed in the immediate and delayed groups, respectively (p=1.0). No significant adverse events occurred. CONCLUSION Significantly more participants had the LNG-IUD placed in the immediate insertion group compared with the delayed insertion group. Given the low risk of complications, immediate post-D&E insertion of the LNG-IUD should be offered, especially for populations that may have difficulty returning for follow-up.

Long-acting rilpivirine as potential pre-exposure prophylaxis for HIV-1 prevention (the MWRI-01 study): an open-label, phase 1, compartmental, pharmacokinetic and pharmacodynamic assessment

BACKGROUND Long-acting injectable antiretroviral agents are being developed for HIV-1 prevention. The MWRI-01 study was done to characterise the safety, acceptability, and pharmacokinetic and pharmacodynamic profile of long-acting rilpivirine. METHODS We did a phase 1 open-label study at the University of Pittsburgh. We enrolled healthy individuals (aged 18-45 years) who were seronegative for HIV-1. Participants were assigned alternately one intramuscular dose of either 1200 mg or 600 mg long-acting rilpivirine, beginning with the 1200 mg dose. We obtained plasma specimens, genital and rectal fluids, and tissue samples (rectal, cervical, and vaginal) before and after exposure to long-acting rilpivirine for assessment of pharmacokinetics and ex-vivo biopsy challenge with HIV-1. Our primary objective was to characterise product safety, and the analysis included all enrolled participants. This trial is registered with ClinicalTrials.gov, number NCT01656018. FINDINGS 36 participants were enrolled into the study, of whom 24 were women and 12 men. 12 women and six men received each dose. 204 adverse events were reported among the 36 participants, of which 200 (98%) were grade 1-2. The most common adverse event was injection site reaction. All grade 3 and 4 adverse events were deemed not related to rilpivirine. Geometric mean (90% CI) concentrations in plasma of rilpivirine at day 28 post dose were 53 ng/mL (38-67) in women and 43 ng/mL (23-63) in men for the 1200 mg dose and 28 ng/mL (19-37) in women and 17 ng/mL (9-24) in men for the 600 mg dose. The tissue-to-plasma ratio for rilpivirine in rectal tissue was about two-fold higher than in vaginal and cervical tissue (1·10-1·53 vs 0·61-0·72 and 0·50-0·71, respectively). Exposure to long-acting rilpivirine suppressed viral replication significantly in rectal tissue (p<0·0001), and this suppression persisted for up to 4 months. By contrast, no viral suppression was seen in cervical or vaginal tissue. INTERPRETATION Ongoing research will characterise longer term safety and acceptability of multiple injections and help ascertain whether long-acting rilpivirine should advance to assessment of efficacy in preventing HIV-1 infection. FUNDING Bill & Melinda Gates Foundation.