Sharon L. Achilles

Prevention of infection after induced abortion

One known complication of induced abortion is upper genital tract infection, which is relatively uncommon in the current era of safe, legal abortion. Currently, rates of upper genital tract infection in the setting of legal induced abortion in the United States are generally less than 1%. Randomized controlled trials support the use of prophylactic antibiotics for surgical abortion in the first trimester. For medical abortion, treatment-dose antibiotics may lower the risk of serious infection. However, the number-needed-to-treat is high. Consequently, the balance of risk and benefits warrants further investigation. Perioperative oral doxycycline given up to 12 h before a surgical abortion appears to effectively reduce infectious risk. Antibiotics that are continued after the procedure for extended durations meet the definition for a treatment regimen rather than a prophylactic regimen. Prophylactic efficacy of antibiotics begun after abortion has not been demonstrated in controlled trials. Thus, the current evidence supports pre-procedure but not post-procedure antibiotics for the purpose of prophylaxis. No controlled studies have examined the efficacy of antibiotic prophylaxis for induced surgical abortion beyond 15 weeks of gestation. The risk of infection is not altered when an intrauterine device is inserted immediately post-procedure. The presence of Chlamydia trachomatis, Neisseria gonorrhoeae or acute cervicitis carries a significant risk of upper genital tract infection; this risk is significantly reduced with antibiotic prophylaxis. Women with bacterial vaginosis (BV) also have an elevated risk of post-procedural infection as compared with women without BV; however, additional prophylactic antibiotics for women with known BV has not been shown to reduce their risk further than with use of typical pre-procedure antibiotic prophylaxis. Accordingly, evidence to support pre-procedure screening for BV is lacking. Neither povidone-iodine nor chlorhexidine have been shown to alter the risk of infection when used as cervicovaginal preparation. However, chlorhexidine appears to be more effective than povidone iodine at reducing bacteria within the vagina. The Society of Family Planning recommends the routine use of antibiotic prophylaxis, preferably with doxycycline, before surgical abortion. Use of treatment doses of antibiotics with medical abortion may decrease the rare risk of serious infection but universal requirement for such treatment has not been established.

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.

The complexity of contraceptives: understanding their impact on genital immune cells and vaginal microbiota.

The same populations of women at risk for sexual acquisition of HIV are also at risk for pregnancy; many of these women use contraception. Combating the spread of HIV is a major global goal [1] ideally achievable with development of highly effective dual protection methods that prevent both sexual acquisition of HIV and unwanted pregnancy. Currently emerging evidence [2] suggests that some commonly used contraceptives may increase risk of sexual HIV acquisition and transmission. There are several biologically plausible mechanisms by which hormonal contraceptives could increase HIV risk including disrupting epithelial barriers (thinning of the epithelium or altering epithelial integrity) causing changes in inflammatory responses that could in turn enhance HIV replication locally [3] or altering the vaginal microbiota which itself effects local immunity and genital inflammation. The objective of this manuscript is to review the evidence linking contraceptives to genital tract changes and to identify research gaps to be addressed with future studies.

Changes in genital tract immune cell populations after initiation of intrauterine contraception.

OBJECTIVE The primary target cells for the human immunodeficiency virus (HIV) infection in the genital tract are CD4 T cells that express CCR5 on the surface. Alterations in genital tract T cells that express CCR5 could impact HIV acquisition risk. We hypothesized that, when compared with baseline, the use of a hormonal intrauterine device (IUD) would alter HIV target cells (primarily CCR5+ CD4 cells) in the female genital tract more than a nonhormonal IUD. STUDY DESIGN Thirty-four healthy HIV-negative women aged 18-40 years who were seeking an IUD for contraception were assigned randomly to receive a levonorgestrel IUD or a copper T380A IUD. A parallel group of 8 control women who did not need contraception was also enrolled. Genital tract mucosal immune cell populations that were collected by cervical cytobrush and endometrial biopsy before and 2 months after IUD placement were analyzed by flow cytometry. Mean differences in cell number and percent that expressed receptors from baseline to follow-up examination were evaluated with the use of paired Student t tests. RESULTS Neither IUD altered the number of T cells within the upper and lower genital tracts. Levonorgestrel IUD users had a decrease in T cells that expressed the HIV coreceptor CCR5 in the endometrium and cervix after 2 months of use compared with baseline. There was a decrease in activated endometrial T cells in levonorgestrel IUD users and a decrease in activated cervical T cells in copper IUD users after 2 months of IUD use, compared with baseline. CONCLUSION Women who use IUDs have reduced expression of the CCR5 HIV coreceptor on T cells in the endometrium and cervix compared with expression before IUD placement. These findings suggest that susceptibility to HIV infection would not be increased by IUD use.

Self-Administered Lidocaine Gel for Intrauterine Device Insertion in Nulliparous Women: A Randomized Controlled Trial.

OBJECTIVE: To evaluate self-administration of vaginal lidocaine gel to decrease pain with intrauterine device (IUD) insertion in nulliparous women. METHODS: In this randomized, double-blind, placebo-controlled trial, women self-administered 2% lidocaine or placebo vaginal gel 5 minutes before IUD insertion. The primary outcome was change in pain from baseline to IUD insertion on a 100-mm visual analog scale. We also assessed pain after speculum insertion, tenaculum placement, uterine sounding, and 5 minutes after IUD insertion. Secondary outcomes included patient acceptability, ease of IUD insertion, and need for pain medication for up to 7 days. RESULTS: From July 2012 to May 2013, 59 women were randomized; 30 received lidocaine gel and 29 placebo. Baseline demographics, including age, race, and body mass index, were similar. There was no difference in median change in pain during IUD insertion in women receiving lidocaine (61 mm [interquartile range 53–71]) compared with placebo (69 mm [interquartile range 63–80], P=.06). Women receiving lidocaine experienced less pain with tenaculum placement (32 mm [interquartile range 18–54]) compared with placebo (56 mm [interquartile range 26–75], P=.02). Most (76%) women were satisfied with their IUD insertion experience and 86% would probably or definitely recommend an IUD to a friend. Thirty-four percent of women required pain medication for at least 3 days after IUD insertion. CONCLUSION: For nulliparous women, self-administered vaginal lidocaine gel does not reduce pain with IUD insertion, but does decrease pain with tenaculum placement. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT01534520.

Transvaginal administration of intraamniotic digoxin prior to dilation and evacuation

BACKGROUND Transabdominal injection of digoxin into the amniotic fluid or fetus to induce fetal demise before dilation and evacuation (D&E) abortion has become common practice since the passage of the Partial-Birth Abortion Ban Act in 2007. STUDY DESIGN We performed a prospective study to assess the feasibility of transvaginal administration of intraamniotic digoxin the day before D&E. All women between 18 0/7 and 23 5/7 weeks of gestation seeking termination from December 2009 to May 2011 were approached for study participation. Women who declined participation were asked to identify their primary rationale. For women declining study participation, transection of the umbilical cord during D&E was performed to meet the requirements of the ban. RESULTS Over 18 months, 134 women met study entry criteria and 108 (81%) declined to participate. Of the 26 women who enrolled, 1.0 mg undiluted digoxin was successfully administered transvaginally in 24 (92%, 95% confidence interval 75%-99%). The most common reasons for declining participation were discomfort with preoperatively inducing fetal demise (37%) and desire to avoid a medically unnecessary medication (36%). CONCLUSIONS Transvaginal administration of digoxin is a feasible alternative to transabdominal administration to induce preoperative fetal demise. The majority of women decline digoxin administration when an alternative is available.

Levonorgestrel in contraceptives and multipurpose prevention technologies: does this progestin increase HIV risk or interact with antiretrovirals?

Mounting observational evidence suggests that use of certain types of hormonal contraception, specifically the progestin-only injectable depot medroxyprogesterone acetate (DMPA), may be associated with an increased risk of HIV acquisition in women [1]. This relationship has been examined in several observational studies and is currently being assessed in a randomized trial, the evidence for contraceptive options and HIV outcomes (ECHO) study (NCT02550067). As evidence continues to evolve, it is also necessary to critically examine knowledge gaps for other contraceptive progestins. Levonorgestrel is used in many existing contraceptives and is being evaluated for use in multipurpose prevention technologies (MPTs). MPTs are designed to simultaneously prevent two or more of the following: unintended pregnancy, HIV, and other sexually transmitted infections. Potential drug–drug interactions and side-effect profiles must also be considered in developing products, including some MPTs, which would contain levonorgestrel and antiretrovirals. Vaginal rings containing dapivirine or tenofovir (NCT02235662) for HIV

Synthetic osmotic dilators with adjunctive misoprostol for same-day dilation and evacuation: a randomized controlled trial ☆ ☆☆ ★ ★★

OBJECTIVE This study aims to evaluate buccal misoprostol as an adjunct to synthetic osmotic dilators for same-day dilation and evacuation (D&E). STUDY DESIGN A randomized, double-blinded, placebo-controlled trial of women 16 0/7 to 20 6/7 weeks gestation desiring D&E was used. Participants received synthetic osmotic cervical dilators (Dilapan-S®) at least 4 h prior to D&E and were randomized to 400mcg buccal misoprostol or placebo 3 h preoperatively, stratified by gestational age. The primary outcome was operative time with 36 participants needed to detect a 4-min difference (two-sided α=0.05, 80% power). Secondary outcomes included total procedure time, patient and provider acceptability, baseline cervical dilation and complications. RESULTS Twenty-nine women were enrolled (misoprostol n=14, placebo n=15) and mean operative time was similar between the groups (11.1 vs. 13.5 min, respectively, p=.17). Complications were nonsignificantly more common for participants ≥19 weeks compared to <19 weeks (22% vs. 9%, p=.62) and those who received placebo compared to misoprostol (27% vs. 7%, p=.33). Two serious adverse events in the placebo group prompted early study closure for safety and futility. Placebo participants had longer overall procedure times (24 vs. 18 min, p=.03) and less cramping preoperatively (p<.01) but similar results for other secondary outcomes compared to those receiving misoprostol. Women strongly preferred same-day cervical preparation (98%). CONCLUSIONS Adjunctive buccal misoprostol may not decrease operative times but may decrease complications when combined with synthetic osmotic dilators for cervical preparation for same-day D&E procedures. IMPLICATIONS Although the trial was halted early and underpowered to make conclusions about the primary outcome, complication frequency and type warrant caution for use of synthetic osmotic dilators alone for cervical preparation for same-day D&E at ≥19 weeks gestation.

Outcomes of medical abortion through 63 days in women with twin gestations

BACKGROUND Twin gestation is not considered a contraindication to medical abortion with mifepristone and misoprostol. However, data comparing the efficacy of medical abortion for singleton gestations as compared with multiple gestations are limited. We examined medical abortion outcomes for twin gestations through 63 days. STUDY DESIGN We performed a secondary analysis of treatment efficacy and side effects using pooled data from two randomized medical abortion trials. All subjects received mifepristone 200 mg orally and misoprostol 800 mcg vaginally. Outcomes in women with singleton and twin gestations were compared. RESULTS Of 2208 subjects, 24 (1.1%) women had twins. Treatment success was not statistically different for twin and singleton gestations (91% vs. 97%, p=.19). Perceived bleeding and pain were not significantly different between groups. CONCLUSIONS Treatment success of medical abortion for twins is not significantly different than for singletons, although small differences cannot be excluded due to the limited number of twins.

Efavirenz decreases etonogestrel exposure: a pharmacokinetic evaluation of implantable contraception with antiretroviral therapy

Objectives: The primary objective of this study was to characterize the pharmacokinetics of etonogestrel (ENG) released from a contraceptive implant in Ugandan women living with HIV who were receiving efavirenz (EFV) or nevirapine (NVP)-based antiretroviral therapy (ART), compared with ART-naive women over 24 weeks. Design: Nonrandomized, parallel-group study with three arms: ART-naive, NVP, or EFV-based ART (N = 20/group). Methods: Sparse pharmacokinetic sampling of ENG, NVP, or EFV were performed at screening, entry, and then 1, 4, 12, and 24-week postimplant insertion. The primary endpoint was ENG concentrations at week 24, compared between the ART-naive group and each ART group, using geometric mean ratio (GMR) with 90% confidence intervals. Results: Sixty participants competed the 24-week study and data from 58 participants are included; one participant each was excluded from the NVP group and EFV group because of a sample processing error and ART nonadherence, respectively. At week 24, geometric mean ENG was 362, 341, and 66 pg/ml in the ART-naive, NVP, and EFV groups, respectively [GMR: NVP : ART-naive 0.94 (0.90–1.01); EFV : ART-naive 0.18 (0.17–0.20)]. NVP and EFV concentrations were lower at week 24 compared to preimplant [NVP: geometric mean 5.7 versus 6.8 mg/l, respectively, GMR 0.84 (0.83–0.85); EFV: geometric mean 3.6 versus 4.9 mg/l, respectively, GMR 0.73 (0.69–0.80)]. Conclusion: After 24 weeks of combined use, ENG exposure was 82% lower in women using EFV-based ART compared with ART-naive women. In contrast, NVP did not significantly impact ENG exposure. These results raise concerns about reduced effectiveness of implantable contraception for women taking EFV-based ART.