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Breastfeeding (BF) women are an important population for biomedical HIV prevention strategies, but they are rarely included in trials. The 25-mg dapivirine vaginal ring (VR) reduced women's risk of sexually transmitted HIV infection in two phase 3 trials conducted in Africa. We conducted a phase 1, open-label study (MTN-029/IPM 039) of dapivirine VR use among lactating women in Pittsburgh, PA, and Birmingham, AL, USA. MTN-029/IPM 039 enrolled 16 healthy adult women who had already weaned their infants but were still able to express breast milk. Women were instructed to use the VR continuously for 14 days and provided milk, plasma, and cervicovaginal fluid (CVF) samples for pharmacological analysis. No infants were exposed to the drug, but infant dosage was estimated according to FDA guidance. Adverse events (AEs) were collected at all contacts. The study was completed with 100% participant retention. Median dapivirine concentrations were 676 pg/ml in breast milk, 327 pg/ml in plasma (milk/plasma ratio ∼2.0), and 36.25 ng/mg in CVF. Six participants experienced 10 total AEs, none of which required VR discontinuation. The estimated mean daily infant dosage was 74.3 ng/kg/day. In this first study of dapivirine exposure during lactation, dapivirine VR use was associated with lower concentrations of detectable dapivirine in milk and plasma than in CVF samples and a favorable safety profile. Estimated daily levels of infant dapivirine exposure were also low. Additional studies are needed to evaluate longer periods of dapivirine VR use among BF mother-infant pairs living in regions with higher incidence of sexually transmitted HIV infection. (This study has been registered at ClinicalTrials.gov under registration no. NCT02808949.)., (Copyright © 2019 American Society for Microbiology.)

MTN-017 compared the safety and acceptability of daily oral emtricitabine/tenofovir disoproxil fumarate, daily reduced-glycerin 1% tenofovir gel applied rectally, and the same gel applied before and after receptive anal intercourse. The Data Convergence Interview (DCI) and the Pharmacokinetic Data Convergence Interview (PK-DCI) were brief, collaborative interactions conducted with participants during adherence counseling sessions to improve accurate measurement of adherence to study product use. DCIs converged data from product return counts and participants' responses to daily text messages. PK-DCIs, conducted 4 weeks later, converged results of the DCI with PK from the corresponding period. CIs were easily incorporated into adherence counseling sessions, increased the accuracy of adherence data, and provided valuable context to data on product use. Participants were readily engaged in the interviews but, if they felt confronted, provided more guarded responses. As such, how these CIs are conducted is critical to engage participants, even those with poor adherence, to openly discuss challenges with product use.

Background: Safety data on pregnancy and fetal outcomes among women in HIV prevention trials are urgently needed to inform use of effective antiretroviral agents for HIV prevention. We describe an effective, efficient, and novel method to prospectively collect perinatal safety data concurrent with on-going parent clinical trials., Methods: The Microbicide Trials Network (MTN)-016 study is a multinational prospective pregnancy exposure registry designed to capture pregnancy and neonatal outcomes. Studies currently contributing data to this registry included phase I and II safety trials with planned exposures to candidate HIV prevention agents, as well as phase IIB and III efficacy trials capturing data on pregnancy and infant outcomes following inadvertent fetal exposure during study participation., Results: To date, participants from two phase I studies and two effectiveness trials have participated in MTN-016, resulting in 420 pregnant women and 381 infants enrolled. Infant retention has been high, with 329 of 381 (86%) infants completing the 12-month follow-up visit., Conclusion: In a research setting context, it is feasible to establish and implement a prospective, multinational HIV chemoprophylaxis pregnancy registry that will generate pregnancy exposure data in a robust fashion.

The MTN-008 trial was the first multi-dose study conducted to evaluate the safety of a microbicide gel (2:1 randomized to tenofovir 1% or hydroxycellulose (HEC) placebo gel) during pregnancy. The study aim was to evaluate safety, tolerability and pharmacokinetics of the study products. Procedures included daily gel administration, with Day 0 and Day 6 in clinic, and Days 1-5 at home. Because pregnancy may pose unique challenges to consistent gel use and acceptability, evaluation of adherence and acceptability was a secondary objective of the trial. The study enrolled healthy, HIV-negative, pregnant women aged 18-40 in Pittsburgh, PA and Birmingham, AL, USA in 2 consecutive groups: cohort 1 was 37-39 weeks gestation, cohort 2 was 34-36 weeks. Ninety-one women completed the study (45 and 46 in each cohort, respectively) and were evaluable per protocol. Adherence was evaluated using self-reports: participants completed a web-based computer-assisted self-interview (CASI) at Days 0 and 6 about gel attitudes and behaviors. At Day 6 trained research staff conducted a short interviewer-administered questionnaire with both structured and open-ended questions. Frequencies of quantitative data were tabulated in SAS and descriptive statistics are presented; open-ended textual data were summarized by a behavioral scientist experienced in qualitative analysis. Participants reported generally neutral perceptions of gel characteristics. A small number of women (7-8%) reported pain (6/90), other physical discomfort (7/90), or mental discomfort (7/90) associated with the process of applicator insertion. About 5% reported the same for the gel itself. Two-thirds (61/90) thought the gel was runny, many complained of bothersome gel leakage and several cited this reason for not inserting a full dose. The majority were not worried the gel would cause problems for their pregnancy or babies. Ninety-seven percent (83/86) said they would use the gel in the future if they were pregnant, and 90% (81/90) when nonpregnant. Self-reported adherence was high with 88% (79/90) reporting daily gel use on both the computerized and interviewer-administered questionnaires. The majority (67/90) reported no difficulty with daily use. However, drug was undetectable (<0.31 ng/mL) among 45% (27/60; 95% CI 32-58%) of the women on active product prior to observed dosing at Day 6. The most common reason for reported nonuse (N = 6) was forgetting. Study gel was generally acceptable, but many complained of a runny consistency (61/90) and leakage (83/90). No frequent or strong concerns about the effects of the study gel on the pregnancy/fetus were reported. Self-reported adherence to study gel self-administered at home for 5 days was high, however plasma drug levels suggest actual use may have been considerably lower. Findings from this study can provide insights relevant to use of other antiretroviral-based, vaginally-inserted HIV prevention methods during pregnancy.

Oral pre-exposure prophylaxis (PrEP) can prevent HIV transmission. Yet, some may prefer not to take systemic daily medication. MTN-017 was a 3-period, phase 2 safety and acceptability study of microbicide gel applied rectally either daily or before and after receptive anal intercourse (RAI), compared to daily oral tablet. At baseline, cisgender men and transgender women who reported RAI (N = 187) rated the daily oral regimen higher in overall liking, ease of use, and likelihood of future use than the gel regimens. After trying all three, 28% liked daily oral the least. Gel did not affect sexual enjoyment (88%) or improved it (7-8%). Most partners had no reaction to gel use. Ease of gel use improved significantly between the first and the last few times of daily use. A rectal gel used before and after RAI may constitute an attractive alternative to daily tablet. Experience with product use may increase acceptability.

VOICE-a phase 2B, placebo-controlled, randomized trial testing daily use of an antiretroviral tablet (tenofovir or Truvada) or daily use of tenofovir gel in 5029 women from South Africa, Uganda, and Zimbabwe-found none of the drug regimens effective in reducing HIV-1 acquisition in the intent-to-treat analysis. More than half of women assigned to active products in a case cohort sample had no drug detected in any plasma specimens tested during the trial. Yet, in response to questions asked of participants during the trial, ≥90 % of doses were reportedly taken. To explore factors associated with low adherence, a behavioral termination visit questionnaire was developed after early closure of the oral tenofovir and vaginal gel arms. We hypothesized that participants would be more forthcoming about nonuse after they exited the trial than during monthly/quarterly follow-up visits. Comparison of adherence reporting at routine follow-up visits with reporting at trial termination, however, indicates that disclosure of product nonadherence did not increase at the termination visit as anticipated. In resource-limited settings where women value the ancillary benefits provided by trial participation and are concerned that disclosure of nonuse may jeopardize trial participation, objective measures of adherence may yield more meaningful data regarding the inability or reluctance to use than measures of product use derived from self-report.

Tuberculosis is a major cause of morbidity and mortality in women of childbearing age (15-44 years). Despite increased tuberculosis risk during pregnancy, optimal clinical treatment remains unclear: safety, tolerability, and pharmacokinetic data for many tuberculosis drugs are lacking, and trials of promising new tuberculosis drugs exclude pregnant women. To advance inclusion of pregnant and postpartum women in tuberculosis drug trials, the US National Institutes of Health convened an international expert panel. Discussions generated consensus statements (>75% agreement among panelists) identifying high-priority research areas during pregnancy, including: (1) preventing progression of latent tuberculosis infection, especially in women coinfected with human immunodeficiency virus; (2) evaluating new agents/regimens for treatment of multidrug-resistant tuberculosis; and (3) evaluating safety, tolerability and pharmacokinetics of tuberculosis drugs already in use during pregnancy and postpartum. Incorporating pregnant women into clinical trials would extend evidence-based tuberculosis prevention and treatment standards to this special population., (© The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Objectives: In VOICE, a phase IIB trial of daily oral and vaginal tenofovir for HIV prevention, at least 50% of women receiving active products had undetectable tenofovir in all plasma samples tested. MTN-003D, an ancillary study using in-depth interviews (IDIs) and focus group discussions (FGDs), together with retrospective disclosure of plasma tenofovir pharmacokinetic results, explored adherence challenges during VOICE., Methods: We systematically recruited participants with pharmacokinetic data (median six plasma samples), categorized as low (0%, N = 79), inconsistent (1-74%, N = 28) or high (≥75%; N = 20) on the basis of frequency of tenofovir detection. Following disclosure of pharmacokinetic results, reactions were captured and adherence challenges systematically elicited; IDIs and FGDs were audio-recorded, transcribed, coded and thematically analysed., Results: We interviewed 127 participants from South Africa, Uganda and Zimbabwe. The most common reactions to pharmacokinetic results included surprise (41%; low pharmacokinetic), acceptance (39%; inconsistent pharmacokinetic) and happiness (65%; high pharmacokinetic). On the basis of participants' explanations, we developed a typology of adherence patterns: noninitiation, discontinuation, misimplementation (resulting from visit-driven use, variable taking, modified dosing or regimen) and adherence. Fear of product side effects/harm was a frequent concern, fuelled by stories shared among participants. Although women with high pharmacokinetic levels reported similar concerns, several described strategies to overcome challenges. Women at all pharmacokinetic levels suggested real-time drug monitoring and feedback to improve adherence and reporting., Conclusion: Retrospective provision of pharmacokinetic results seemingly promoted candid discussions around nonadherence and study participation. The effect of real-time drug monitoring and feedback on adherence and accuracy of reporting should be evaluated in trials.

Background: Several observational studies have reported that HIV-1 acquisition seems to be higher in women who use depot medroxyprogesterone acetate (DMPA) than in those who do not use hormonal contraception. We aimed to assess whether two injectable progestin-only contraceptives, DMPA and norethisterone enanthate (NET-EN), confer different risks of HIV-1 acquisition., Methods: We included data from South African women who used injectable contraception while participating in theVOICE study, a multisite, randomised, placebo-controlled trial that investigated the safety and efficacy of three formulations of tenofovir for prevention of HIV-1 infection in women between Sept 9, 2009, and Aug 13, 2012. Women were assessed monthly for contraceptive use and incident infection. We estimated the difference in incident HIV-1infection between DMPA and NET-EN users by Cox proportional hazards regression analyses in this prospective cohort. The VOICE trial is registered with ClinicalTrials.gov, NCT00705679., Findings: 3141 South African women using injectable contraception were included in the present analysis: 1788 (56·9%)solely used DMPA, 1097 (34·9%) solely used NET-EN, and 256 (8·2%) used both injectable types at different times during follow-up. During 2733·7 person-years of follow-up, 207 incident HIV-1 infections occurred (incidence7·57 per 100 person-years, 95% CI 6·61–8·68). Risk of HIV-1 acquisition was higher among DMPA users (incidence 8·62 per 100 person-years, 95% CI 7·35–10·11) than among NET-EN users (5·67 per 100 person-years, 4·35–7·38;hazard ratio 1·53, 95% CI 1·12–2·08; p=0·007). This association persisted when adjusted for potential confoundingvariables (adjusted hazard ratio [aHR] 1·41, 95% CI 1·06–1·89; p=0·02). Among women seropositive for herpes simplex virus type 2 (HSV-2) at enrolment, the aHR was 2·02 (95% CI 1·26–3·24) compared with 1·09 (0·78–1·52)for HSV-2-seronegative women (pinteraction=0·07)., Interpretation: Although moderate associations in observational analyses should be interpreted with caution, thesefi ndings suggest that NET-EN might be an alternative injectable drug with a lower HIV risk than DMPA in high HIV-1 incidence settings where NET-EN is available., Funding: National Institutes of Health, Mary Meyer Scholars Fund, and the Ruth Freeman Memorial Fund.

Unlabelled: There is a paucity of normative bone mineral density (BMD) data in healthy African women. Baseline total hip and lumbar spine BMD was measured in premenopausal women. BMD distribution was comparable to that of a reference population and was impacted by several factors including contraception and duration of lactation., Introduction: Normative data on bone mineral density (BMD) and the cumulative impact of lactation, contraceptive use, and other factors on BMD in healthy African women have not been well studied., Objectives: The objective of this study was to determine the factors associated with BMD in healthy premenopausal women in Uganda and Zimbabwe., Methods: Baseline total hip (TH) and lumbar spine (LS) BMD was measured by dual x-ray absorptiometry in 518 healthy, premenopausal black women enrolling in VOICE, an HIV-1 chemoprevention trial, at sites in Uganda and Zimbabwe. Contraceptive and lactation histories, physical activity assessment, calcium intake, and serum vitamin D levels were assessed. Independent factors associated with BMD were identified using an analysis of covariance model., Results: The study enrolled 331 women from Zimbabwe and 187 women from Uganda. Median age was 29 years (IQR 25, 32) and median body mass index (BMI) was 24.8 kg/m(2) (IQR 22.2, 28.6). In univariate analyses, lower TH BMD values were associated with residence in Uganda (p < 0.001), lower BMI (p < 0.001), and any use of and duration of depot-medroxyprogresterone acetate. Use of oral contraceptives, progestin-only implants, and higher physical activity levels were protective against reduced BMD. Similarly, lower LS BMD values were associated with these same factors but also higher parity and history of breastfeeding. In a multivariable analysis, lower TH and LS BMD values were associated with enrollment in Uganda, lower BMI, and lower physical activity level; contraceptive use was associated with lower spine BMD, and breastfeeding contributed to lower total hip BMD., Conclusions: Among healthy premenopausal women, TH and LS BMD was higher in Zimbabwe than Uganda. Additional factors independently associated with BMD included BMI, physical activity level, contraceptive use, and lactation.

The Wisebag™, a lunchbag-style container with an electronic events-monitoring system, was designed as a real-time indirect objective measure of microbicide gel use. Due to cost, alternative functionalities (i.e. use of offline and dummy versions) were explored. We conducted a three-arm, double-blinded pilot study among 50 HIV-negative women in Durban, South Africa to assess participant adherence and Wisebag acceptability and performance. Participants were randomized 2:2:1 to Wisebag with online (events transmitted via cellular signal in real-time), offline (events stored in device memory) or inactive "dummy" devices. Participants were instructed to open the Wisebag daily for 2 weeks, retrieve a study sticker and affix it on a diary card. All participants completed the study. At exit, 94 % did not know which device they had received, nor could they differentiate the Wisebag types when presented with the three options. Five offline devices failed (no data recorded). Per Wisebag events, 26 % of women were perfectly adherent compared to 48 % by self-report and 46 % per diary card. Of reported non-adherence, 92 % did not open the Wisebag (travelling or forgot) and 22 % opened Wisebag >1×/day (curiosity). Participants liked and were comfortable carrying Wisebag. Successful blinding will allow inclusion of offline and/or dummy Wisebags in future study designs. Perfect adherence by opening events was significantly lower than by self-report, highlighting the importance of objective measures of adherence in clinical trials. Additional studies to validate Wisebag data with actual products, with and without SMS and online functionality, in different populations and settings, and in comparison to biomarkers are warranted.

Because the acquisition of sexually transmitted infections (STIs) is based on individual sexual behaviors, the most successful STI prevention initiatives have been behavioral interventions seeking to change individual risk behaviors. This article explores systematic and community-based prevention initiatives and the steps in development and validation of behavioral interventions to reduce STIs. Key interventions and the trials in which they were proven effective are discussed in detail. It is hoped that a greater understanding of the development and validation of behavioral interventions for STI prevention will encourage physicians to accept these interventions as additional tools to prevent disease and suffering.

Mexican and African American women with sexually transmitted diseases (STDs) underwent targeted physical exams and questioning regarding sexual or physical abuse, current genitourinary symptomatology, and pelvic inflammatory disease (PID) risk behaviors to determine the relationship of sexual or physical abuse to the pathology of genitourinary symptoms affecting diagnoses of STDs and risk for PID. Bivariate comparisons found abused women reported more PID risk behaviors including earlier coitus, more sex partners, higher STD recurrence, and delayed health-seeking behavior. Multivariate comparisons found abused women were more likely to report pathologic genitourinary symptomatology than nonabused women. Clinicians made more presumptive diagnoses of PID for abused than for nonabused women upon physical examination. These findings indicate abused women are at high risk for PID. Its considerable impact on genitourinary symptomatology and risk for PID make assessment for abuse essential in clinical management of women with STDs and diagnosis of PID.