Phase 1 randomized pharmacokinetic and safety study of a 90-day tenofovir vaginal ring in the United States.

INTRODUCTION: Tenofovir-based oral pre-exposure prophylaxis is currently approved for HIV prevention; however, adherence in women has been low. A vaginal gel containing tenofovir (TFV) demonstrated partial protection to HIV but protection was not confirmed in additional studies. Vaginal rings offer user-controlled long-acting HIV prevention that could overcome adherence and protection challenges. TFV may also help prevent herpes simplex virus type 2 acquisition when delivered intravaginally. We evaluated the pharmacokinetics, safety, adherence and acceptability of a 90-day TFV ring. METHODS: Between January and June 2019, Microbicide Trials Network (MTN)-038 enrolled 49 HIV-negative participants into a phase 1, randomized (2:1) trial comparing a 90-day ring containing 1.4 grams (g) TFV to a placebo ring. TFV concentrations were quantified in plasma, cervicovaginal fluid (CVF), rectal fluid and cervical tissue, and TFV-diphosphate (TFV-DP) in cervical tissue. Used rings were analysed for residual TFV. Safety was assessed by adverse events (AEs); acceptability and adherence by self-report. RESULTS: Mean age was 29.5; 46 identified as cisgender-female and three gender non-conforming. There were no differences in the proportion of participants with grade ≥2 genitourinary AEs in the TFV versus placebo arms (p = 0.41); no grade ≥3 AEs were reported. Geometric mean TFV concentrations increased through day 34 in CVF/rectal fluid and day 59 in plasma, but declined across compartments by day 91. Geometric mean TFV-DP tissue concentrations exceeded the 1000 fmol/mg target through day 56, but fell to 456 fmol/mg at day 91. Among 32 rings returned at the end of the study, 13 had no or low (<0.1 g) residual TFV. Residual TFV did not differ by socio-demographics, sexual activity, Nugent Score or vaginal microbiota. Most participants reported being fully adherent to ring use: 85% and 81% in the TFV and placebo arms, respectively (p = 1.00). A majority of participants reported liking the ring (median 8 on a 10-point Likert scale) and reported a high likelihood of using the ring in the future, if effective (median 9). CONCLUSIONS: The 90-day TFV ring was well-tolerated, acceptable and exceeded target cervical tissue concentrations through day 56, but declined thereafter. Additional studies are needed to characterize the higher release from TFV rings in some participants and the optimal duration of use.

Depression Among Pregnant and Breastfeeding Persons Participating in Two Randomized Trials of the Dapivirine Vaginal Ring and Oral Pre-Exposure Prophylaxis (PrEP) in Malawi, South Africa, Uganda, and Zimbabwe.

Depression is associated with lower adherence to oral pre-exposure prophylaxis (PrEP) to prevent HIV, but data are not currently available on how depression may affect use of other HIV prevention methods including the dapivirine vaginal ring (DVR). We conducted a mixed methods study using data from the Microbicide Trials Network (MTN) 042/DELIVER (n = 558) and MTN-043/B-PROTECTED (n = 197) studies to describe the prevalence of depressive symptoms and explore how depressive symptoms may have influenced attitudes about use of the monthly DVR and once-daily oral PrEP tablet among pregnant and breastfeeding persons, respectively, in Malawi, South Africa, Uganda, and Zimbabwe. Eleven participants had high Edinburgh Postnatal Depression scores ≥ 10 in MTN-042/DELIVER (2%) and four participants (2%) in MTN-043/B-PROTECTED. In interviews with 9 participants who had high scores (6 DVR, 3 oral PrEP), those with depressive symptoms described overlapping stressors which were magnified by job loss and economic instability during the COVID-19 pandemic, and by experiences of pregnancy/postpartum. These participants experienced a lack of support from partners or family members, and conflict with partners related to trust, and infidelity. While we did not find evidence of a change in product adherence, there was a strong sense of commitment and motivation to use the study products for protection from HIV for participants themselves and their baby. Although lack of social support is usually an obstacle to adherence, in this study, the participants' lives and relationships seemed to have reinforced the need for HIV prevention and motivated women to protect themselves and their babies from HIV.

Efficacy, Safety, and Tolerability of Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate Fixed-Dose Combination Tablets in Adolescents Living With HIV: Results Through Week 96 from IMPAACT 2014.

BACKGROUND: IMPAACT 2014 study is a phase I/II, multicenter, open-label, nonrandomized study of doravirine (DOR) co-formulated with lamivudine (3TC) and tenofovir disoproxil fumarate (TDF) as fixed-dose combination (DOR FDC) in adolescents with HIV-1. We report the efficacy, safety, and tolerability of DOR FDC through 96 weeks. METHODS: Participants were adolescents aged 12 to <18 years who weighed at least 45 kg and who were either antiretroviral (ARV)-naïve or virologically suppressed without documented resistance mutations to DOR/3TC/TDF. The efficacy endpoint was the proportion of participants with HIV-1 RNA <40 copies/mL assessed at weeks 48 and 96 using the observed failure approach. Safety and tolerability outcomes were incidence of adverse events (AEs) and treatment discontinuations. RESULTS: A total of 45 adolescents, median age 15 (range, 12-17) years, 58% females, were enrolled and 2 (4.4%) participants were ARV naïve. Of the 45 participants, 42 (93.3%) completed the study and 41 (91.1%) completed the study treatment. At week 48, 41/42 (97.6%; 95% confidence interval [CI], 87.4-99.9) and week 96, 37/40 (92.5%; 95% CI, 79.6-98.4) participants had achieved or maintained HIV-1 RNA <40 copies/mL. There were no treatment-related discontinuations due to AEs and no drug-related AEs ≥grade 3 or deaths. CONCLUSIONS: We found once-daily dosing of DOR FDC to be safe and well tolerated for maintaining viral suppression through 96 weeks in adolescents living with HIV-1.

Acceptability and Use of the Dapivirine Vaginal Ring and Daily Oral Pre-exposure Prophylaxis (PrEP) During Breastfeeding in South Africa, Malawi, Zimbabwe, and Uganda.

This study examines qualitative acceptability of the dapivirine vaginal ring (DVR) and oral daily pre-exposure prophylaxis (PrEP) among breastfeeding persons participating in Microbicide Trials Network 043/B-PROTECTED, a phase 3B safety and drug detectability study of DVR and oral PrEP in breastfeeding. A subsample of 52 participants were purposively sampled to participate in an in-depth interview (IDI). Breastfeeding participants found both study products to be acceptable, and easy to use. A common motivation for product use was to protect the baby from HIV, although participants' understanding of how the study drug would work to protect their babies was often unclear. While most participants did not report experiencing side effects, fears about side effects were common as both initial worries about how the study products would affect their health and the health of their baby, and increased anxiety that health issues experienced by them, or their baby were from the products.

Pharmacokinetics, Tolerability, and Safety of Doravirine and Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate Fixed-Dose Combination Tablets in Adolescents Living With HIV: Week 24 Results From IMPAACT 2014.

BACKGROUND: We studied the pharmacokinetics (PK) and safety of 100-mg doravirine and doravirine/lamivudine/tenofovir disoproxil fumarate fixed-dose combination (100/300/300 mg DOR FDC) treatment in adolescents with HIV-1. METHODS: Adolescents ages 12 to younger than 18 years were enrolled in 2 sequential cohorts. Cohort 1 evaluated intensive PK and short-term safety of 100-mg single-dose doravirine in adolescents ≥35 kg. Cohort 2 participants either initiated treatment with DOR FDC (antiretroviral (ARV)-naïve) or switched to DOR FDC from a previous ARV regimen (virologically suppressed). The first 10 Cohort 2 participants had intensive PK evaluations, and safety, sparse PK, and HIV RNA were assessed through week 24. RESULTS: Fifty-five adolescents, median age 15.0 years and baseline weight 51.5 kg, were enrolled. Nine participants completed Cohort 1 PK assessments (8 of the 9 participants weighed ≥45 kg) and 45 initiated study drug in Cohort 2. The doravirine geometric mean (GM) AUC 0-∞ was 34.8 µM∙hour, and the GM C 24 was 514 nM after a single dose, with a predicted steady-state GM C 24,ss,pred of 690 nM. Cohort 2 enrolled adolescents weighing ≥45 kg. Plasma concentrations of doravirine, tenofovir, and lamivudine achieved by Cohort 2 participants were similar to those reported in adults. No drug-related serious or grade 3 or 4 adverse events occurred. Forty-two of 45 participants (93.3%; 95% CI: [81.7, 98.6]) achieved or maintained HIV-1 RNA <40 copies/mL. CONCLUSIONS: Doravirine and DOR FDC achieved target PK in adolescents with HIV-1. DOR FDC was well-tolerated and maintained excellent virologic efficacy through 24 weeks, offering a favorable option for adolescents.

Integrating Gender-Based Violence Screening and Support into the Research Clinic Setting: Experiences from an HIV Prevention Open-Label Extension Trial in Sub-Saharan Africa.

HIV and gender-based violence (GBV) are syndemic in sub-Saharan Africa and provision of support for participants who disclose GBV constitutes part of comprehensive care. Consequently, a process was undertaken to develop, implement, and evaluate standard operating procedures (SOPs) in MTN-025/HOPE, a study of the dapivirine vaginal ring for HIV prevention. The SOP was developed using needs assessment surveys in addition to World Health Organization (WHO) guidelines and other literature. Sites tailored and implemented the SOP through HOPE implementation. At study end, staff reported increased training 32/35 (91.43%); improved confidence (18/26; 69.23%); and improved vicarious trauma prevention onsite (17/28; 60.71%). Leadership reported increased staff competence in GBV response. Obstacles included limited referral organizations and time for follow-up, continued training needs, and cultural norms. Development and implementation of an SOP is a feasible strategy to build a GBV response to improve health systems and support sustained effective use of HIV prevention products.

Acceptability of PC-1005 Gel Administered Rectally to HIV-1 Seronegative Adults at Three Different Volume Levels (MTN-037).

Multipurpose prevention technologies (MPT) have been increasingly researched for their dual-purpose preventative properties against HIV and other STIs. The acceptability of PC-1005, a topical MPT candidate, was explored among men and women participating in the MTN-037 Phase I trial at two U.S. sites (Pittsburgh, PA, and Birmingham, AL). We triangulated quantitative and qualitative assessments of the acceptability of three volumes (4 mL, 16 mL, 32 mL) of PC-1005 administered rectally (N = 12; 6 males, 6 females). Participants rated overall gel acceptability on a scale of 1-10, with a median of 7.17 (SD = 2.04) and had positive feelings about all three dose volumes, citing them to be very comfortable or comfortable (dose 1 = 91.7%; dose 2 = 91.7%; dose 3 = 83.3%). High acceptability of and comfort with all three dose volumes shows promise for PC-1005 as an MPT to prevent HIV and STIs, warranting future clinical development.

Women's experience receiving drug feedback and adherence counseling in MTN-025/HOPE - an HIV Prevention open-label trial of the Dapivirine Vaginal Ring.

In the Phase IIIB MTN-025/HOPE open label extension trial, participants were offered the dapivirine vaginal ring as HIV prophylaxis, and those who accepted the ring received semi real-time individual adherence feedback, based on residual drug level (RDL) from returned rings, during Motivational Interviewing-based counseling. Counseling messages, based on the best knowledge at the time, framed RDL results in terms of ring use and HIV protection, from no use /no protection (0 RDL) to high use /high protection (3 RDL). At six HOPE sites, in-depth-Interviews (IDIs) about RDL were conducted with 64 participants who had received at least one RDL result. We found mixed interpretations of what the RDL meant and strong emotional reactions with a focus on the external validation of the level itself. Counseling was critical to help participants process their reactions to the RDL and make decisions accordingly (i.e., persistence, adherence improvement, and/or switching to another HIV prevention method). Providing drug adherence feedback was complex to implement yet proved useful as a component of a multi-pronged adherence support strategy.

Patterns of Adherence to a Dapivirine Vaginal Ring for HIV-1 Prevention Among South African Women in a Phase III Randomized Controlled Trial.

BACKGROUND: Persistent use of HIV prevention methods can be a challenge, particularly for some younger women. The long-acting, discreet, woman-centric dapivirine vaginal ring offers promise as a prevention method with less user burden, which could support continued use. We assessed dapivirine vaginal ring use to understand adherence patterns and identify characteristics influencing patterns. SETTING: Participants enrolled in South Africa in the MTN-020/ASPIRE randomized placebo-controlled trial. METHODS: We used group-based trajectory modeling to identify clusters of participants with similar longitudinal patterns of adherence in the last year of participation and potential predictors of group membership. Women with at least 1 year of follow-up were included (n = 626). RESULTS: Five adherence patterns were identified: (1) consistently high, 34%, (2) consistently moderate, 34%, (3) consistently low, 16%, (4) decreasing, 9%, and (5) increasing, 7%. Women younger than 22 years [adjusted odds ratio (AOR) 1.8, 95% confidence interval (CI): 1.0 to 3.0], using an intrauterine device (AOR 3.3, 95% CI: 1.4 to 7.8) or oral contraceptives (AOR 3.9, 95% CI: 1.7 to 8.9), experiencing menses (AOR 1.8, 95% CI: 1.1 to 3.0), and who reported inconsistent condom use (AOR 1.8, 95% CI: 1.0 to 3.3) were more likely to be classified as consistently low compared to consistently high (referent). CONCLUSIONS: Most South African women successfully persisted with a moderate or high level of use. Encouraging ring replacement with completion of menses may help to decrease concerns about hygiene and improve persistence. Associations between contraception and persistent low adherence suggest efforts may be needed to ensure contraceptive method choice does not interfere with ring use.

Acceptability of an extended duration vaginal ring for HIV prevention and interest in a multi-purpose ring.

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.

Users' Preferred Characteristics of Vaginal Rings for HIV Prevention: A Qualitative Analysis of Two Phase I Trials.

Vaginal rings address a critical need for an independently initiated, long-acting HIV prevention method, but their design must be acceptable to promote uptake and adherence. Human-centered design (HCD) may help address design preference questions. In two Phase I studies of vaginal rings for HIV prevention conducted in the United States, we used qualitative interviews to assess participants' perceptions and opinions of the physical characteristics of the ring they used and of a ring's physical characteristics after comparing four ring designs presented via a visual tool. Users were found to prefer ring designs that appear easy to use, are physically comfortable, that function well, and are aesthetically pleasing. The parameters for these features varied widely. Product developers and marketers should consider marketing messages in which the target users feel this product is made to meet their needs and desires. Product developers are encouraged to design using HCD early in ring development (Clinical Trial Registration number: NCT03234400 and NCT03670355).

Impact and experience of participant engagement activities in supporting dapivirine ring use among participants enrolled in the phase III MTN-020/ASPIRE study.

BACKGROUND: Low adherence to investigational products can negatively impact study outcomes, limiting the ability to demonstrate efficacy. To continue advancing potential new HIV prevention technologies, efforts are needed to improve adherence among study participants. In MTN-020/ASPIRE, a phase III randomized, double-blind, placebo-controlled study of the dapivirine vaginal ring carried out across 15 sites in sub-Saharan Africa, a multifaceted approach to adherence support was implemented, including a strong focus on participant engagement activities (PEAs). In this manuscript, we describe PEAs and participant attendance, and analyze the potential impact of PEAs on ring use. METHODS: All sites implemented PEAs and submitted activity and attendance reports to the study management team throughout the study. Participant demographics were collected via case report forms. Residual dapivirine remaining in the last ring returned by each participant was used to estimate drug released from the ring, which was then adjusted for time participants had the ring to calculate probable use categorized into three levels (low/intermittent/high). Product use was connected to PEA attendance using participant identification numbers. We used multivariate Poisson regression with robust standard errors to explore differences in ring use between PEA attendance groups and reviewed qualitative reports for illustrative quotes highlighting participant experiences with PEAs. RESULTS: 2312 of 2629 study participants attended at least one of 389 PEAs conducted across sites. Participant country and partner knowledge of study participation were most strongly associated with PEA attendance (p < 0.005) with age, education, and income status also associated with event attendance (p < 0.05). When controlling for these variables, participants who attended at least one event were more likely to return a last ring showing at least some use (RR = 1.40) than those who never attended an event. There was a stronger correlation between a last returned ring showing use and participant attendance at multiple events (RR = 1.52). CONCLUSIONS: Our analysis supports the growing body of work illustrating the importance of meaningfully engaging research participants to achieve study success and aligns with other analyses of adherence support efforts during ASPIRE. While causation between PEA attendance and product use cannot be established, residual drug levels in returned rings strongly correlated with participant attendance at PEAs, and the benefits of incorporating PEAs should be considered when designing future studies of investigational products.

Impact of Women's Home Environment on Use of the Dapivirine Vaginal Ring for HIV Prevention in Sub-Saharan Africa.

The monthly dapivirine vaginal ring has proven efficacious in reducing HIV incidence in two Phase 3 clinical trials. When considering the potential future availability of the ring to the public, key questions remain about the feasibility of integrating the ring as an HIV prevention intervention into women's lives. We conducted qualitative mapping interviews (n = 66) among women enrolled in MTN-025/HOPE, an open-label trial conducted in Malawi, South Africa, Uganda and Zimbabwe, to examine how home environments influenced use of the dapivirine vaginal ring. Most women had secure places to store their rings including wardrobes, suitcases, and bags. The primary concerns for ring storage were potential tampering from children or rodents. Household overcrowding limited the privacy some women had which made removal and insertion of vaginal rings challenging. Despite these challenges, ring storage, insertion, and removal was feasible across social and living contexts.

Safety, uptake, and use of a dapivirine vaginal ring for HIV-1 prevention in African women (HOPE): an open-label, extension study.

BACKGROUND: Two phase 3 clinical trials showed that use of a monthly vaginal ring containing 25 mg dapivirine was well tolerated and reduced HIV-1 incidence in women by approximately 30% compared with placebo. We aimed to evaluate use and safety of the dapivirine vaginal ring (DVR) in open-label settings with high background rates of HIV-1 infection, an important step for future implementation. METHODS: We did a phase 3B open-label extension trial of the DVR (MTN-025/HIV Open-label Prevention Extension [HOPE]). Women who were HIV-1-negative and had participated in the MTN-020/ASPIRE phase 3 trial were offered 12 months of access to the DVR at 14 clinical research centres in Malawi, South Africa, Uganda, and Zimbabwe. At each visit (monthly for 3 months, then once every 3 months), women chose whether or not to accept the offer of the ring. Used, returned rings were tested for residual amounts of dapivirine as a surrogate marker for adherence. HIV-1 serological testing was done at each visit. Dapivirine amounts in returned rings and HIV-1 incidence were compared with data from the ASPIRE trial, and safety was assessed. This study is registered with ClinicalTrials.gov, NCT02858037. FINDINGS: Between July 16, 2016, and Oct 10, 2018, of 1756 women assessed for eligibility, 1456 were enrolled and participated in the study. Median age was 31 years (IQR 27-37). At baseline, 1342 (92·2%) women chose to take the DVR; ring acceptance was more than 79% at each visit up until 12 months and 936 (73·2%) of 1279 chose to take the ring at all visits. 12 530 (89·3%) of 14 034 returned rings had residual dapivirine amounts consistent with some use during the previous month (>0·9 mg released) and the mean dapivirine amount released was greater than in the ASPIRE trial (by 0·21 mg; p<0·0001). HIV-1 incidence was 2·7 per 100 person-years (95% CI 1·9-3·8, 35 infections), compared with an expected incidence of 4·4 per 100 person-years (3·2-5·8) among a population matched on age, site, and presence of a sexually transmitted infection from the placebo group of ASPIRE. No serious adverse events or grade 3 or higher adverse events observed were assessed as related to the DVR. INTERPRETATION: High uptake and persistent use in this open-label extension study support the DVR as an HIV-1 prevention option for women. With an increasing number of HIV-1 prophylaxis choices on the horizon, these results suggest that the DVR will be an acceptable and practical option for women in Africa. FUNDING: The Microbicide Trials Network and the National Institute of Allergy and Infectious Diseases, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health, all components of the US National Institutes of Health.

First Impressions Matter: How Initial Worries Influence Adherence to the Dapivirine Vaginal Ring.

BACKGROUND: In MTN-020/ASPIRE, a dapivirine vaginal ring effectiveness trial in sub-Saharan Africa, we assessed whether worries about ring use changed over time and were associated with adherence. METHODS: Participants (N = 2585) were surveyed at baseline and follow-up about worries regarding daily ring use. First, they answered a question about general worries and then responded to 15 items covering specific worries. From a nested qualitative component (N = 214), we extracted themes related to ring worries and adherence. Seven months into the trial, aggregate adherence data were shared with study sites as part of an intervention that included counseling and social support. Nonadherence was defined as dapivirine plasma levels of ≤95 pg/mL. Mixed-effect logistic regression models were used to assess changes in ring worries and nonadherence from baseline to month 3 and later. RESULTS: Worry about wearing the ring decreased from 29% at baseline to 4% at month 3 (P < 0.001), while having a specific worry decreased from 47% to 16% (P < 0.001). Among those enrolled before intervention, 29% with baseline worries were nonadherent at month 3 (95% confidence interval: 19% to 39%) compared to 14% without worries (95% confidence interval: 9% to 19%; P = 0.005); the difference persisted through month 6. There was no difference in nonadherence by baseline worry for those enrolled after intervention (P = 0.40). In the qualitative subset, initial ring anxieties reportedly subsided with self-experimentation and practice and the beneficial influence of the intervention. CONCLUSIONS: Although worries may be an initial deterrent to correct ring use, intervening early by leveraging social influences from peers and clinicians should facilitate successful adoption and correct ring use.

Pharmacokinetics of Dapivirine Transfer into Blood Plasma, Breast Milk, and Cervicovaginal Fluid of Lactating Women Using the Dapivirine Vaginal Ring.

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.).

Pregnancy and Infant Outcomes Among Women Using the Dapivirine Vaginal Ring in Early Pregnancy.

BACKGROUND: Monthly use of the dapivirine vaginal ring has been shown to be safe and effective for HIV-1 prevention in nonpregnant reproductive-aged women. The impact of dapivirine on pregnancy outcomes and infant is not known. We compared pregnancy incidence and outcomes by study arm among HIV-1-uninfected women who became pregnant while participating in MTN-020/ASPIRE. METHODS: ASPIRE was a randomized, double-blind, placebo-controlled phase III safety and effectiveness study of the dapivirine ring for HIV-1 prevention. Sexually active women aged 18-45 years from Malawi, South Africa, Uganda, and Zimbabwe were enrolled. Urine pregnancy tests were performed monthly, and, if positive, study product was withheld during pregnancy and breastfeeding. Pregnancy-related outcomes included the following: pregnancy incidence, pregnancy outcomes (live birth, preterm birth, pregnancy loss, and congenital anomalies), and infant growth. RESULTS: Of 2629 women enrolled in ASPIRE, 169 became pregnant during follow-up, resulting in 179 incident pregnancies and 181 pregnancy outcomes. No difference in pregnancy incidence by study arm was observed (hazard ratio = 0.93; 95% confidence interval: 0.68 to 1.26). The distribution of pregnancy outcomes was similar by study arm, and no difference was noted in the frequency or pattern of congenital anomalies or infant growth parameters by study arm. CONCLUSIONS: Dapivirine use in the periconception period does not seem to be associated with adverse effects on pregnancy or infant outcomes. Our findings provide support for additional safety studies of the dapivirine ring throughout pregnancy.

Implementation of a prospective pregnancy registry for antiretroviral based HIV prevention trials.

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.

Use of a Vaginal Ring Containing Dapivirine for HIV-1 Prevention in Women.

BACKGROUND: Antiretroviral medications that are used as prophylaxis can prevent acquisition of human immunodeficiency virus type 1 (HIV-1) infection. However, in clinical trials among African women, the incidence of HIV-1 infection was not reduced, probably because of low adherence. Longer-acting methods of drug delivery, such as vaginal rings, may simplify use of antiretroviral medications and provide HIV-1 protection. METHODS: We conducted a phase 3, randomized, double-blind, placebo-controlled trial of a monthly vaginal ring containing dapivirine, a non-nucleoside HIV-1 reverse-transcriptase inhibitor, involving women between the ages of 18 and 45 years in Malawi, South Africa, Uganda, and Zimbabwe. RESULTS: Among the 2629 women who were enrolled, 168 HIV-1 infections occurred: 71 in the dapivirine group and 97 in the placebo group (incidence, 3.3 and 4.5 per 100 person-years, respectively). The incidence of HIV-1 infection in the dapivirine group was lower by 27% (95% confidence interval [CI], 1 to 46; P=0.046) than that in the placebo group. In an analysis that excluded data from two sites that had reduced rates of retention and adherence, the incidence of HIV-1 infection in the dapivirine group was lower by 37% (95% CI, 12 to 56; P=0.007) than that in the placebo group. In a post hoc analysis, higher rates of HIV-1 protection were observed among women over the age of 21 years (56%; 95% CI, 31 to 71; P<0.001) but not among those 21 years of age or younger (-27%; 95% CI, -133 to 31; P=0.45), a difference that was correlated with reduced adherence. The rates of adverse medical events and antiretroviral resistance among women who acquired HIV-1 infection were similar in the two groups. CONCLUSIONS: A monthly vaginal ring containing dapivirine reduced the risk of HIV-1 infection among African women, with increased efficacy in subgroups with evidence of increased adherence. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01617096 .).

Breastfeeding support in child care: an international comparison of findings from Australia and the United States.

INTRODUCTION: Many women in industrialized countries return to work while their children are infants. This is often associated with decreased breastfeeding duration or exclusivity. In order to better understand the breastfeeding support activities in childcare settings, studies were undertaken in settings with very different levels of infant mortality, breastfeeding, and breastfeeding support: Adelaide, Australia, and Wake County, North Carolina. The researchers collaborated to explore, contrast, and compare their baseline data. METHODS: Available data on breastfeeding rates and infant mortality rates were explored for the two settings. In addition, the two childcare datasets were explored for common questions, and descriptive and χ(2) analyses were carried out. RESULTS: Similarities were found between the response from childcare settings providers in Australia and the United States. Rates of having at least one breastfeeding infant (70.6% vs. 66.3%), a place to breastfeed (90.7% vs. 95%), and a refrigerator for storage (100% vs. 100%) were similar for Adelaide and Wake County, respectively. Qualitative data from Adelaide also mirrored Wake County data in that providers in neither setting were actively promoting breastfeeding. However, the Adelaide data reflected significantly higher rates of encouragement (95.3% vs. 21.7%), written policy (77.8% vs. 20.8%), resource/materials distribution (76.6% vs. 1% and 93.8% vs. 17%), and training (44.4% vs. 13.9%). CONCLUSIONS: Childcare practices may reflect the environment of support, or lack thereof, for breastfeeding in the society as a whole. The similarities and differences seen in these settings may reflect both official guidance as well as the breastfeeding environment. There is much work to be done in the United States to come up to the same level of support for breastfeeding in child care and in other programs as is seen in Australia.