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The Microbicide Trials Network 042 study (MTN-042/DELIVER) is a two-arm, randomized, open-label Phase 3b trial that is evaluating the safety, adherence, and acceptability of the monthly ring and daily oral PrEP among HIV-uninfected pregnant people in four African countries. This analysis focuses on acceptability data captured qualitatively from a subset (n = 48) of the 150 people in the first cohort of the trial who were enrolled in late-stage pregnancy at 36 to 38 weeks gestational age and followed until after delivery. Single IDIs were conducted by trained interviewers at each clinic site using a semi-structured guide. Data excerpts of key codes pertaining to acceptability, pregnancy, and maternal health were summarized, reviewed and interpreted by multinational analyst teams. Although the product use period was relatively short, the data suggested several acceptability findings that may directly translate to longer durations of product use in pregnancy. The first was the overarching maternal sentiment that being able to protect both oneself and their baby was highly valued. The second was the importance of counseling support from providers not only because participants used methods that might generate side effects, but because pregnancy itself is a period with its own set of side effects. The third was that, similar to non-pregnant participants in other trials, here study products were generally liked and described as easy to use. Concerns about ring and oral PrEP use could be addressed with provider counseling and support and should form an essential component rollout among pregnant people.

Women who acquire HIV during the pregnancy and breastfeeding periods have a higher risk of transmitting the virus to their child than women who become infected with HIV before pregnancy. We explore the context of sexual beliefs and practices that may shape both HIV risk and willingness to use HIV prevention products during pregnancy and postpartum in Malawi, South Africa, Uganda and Zimbabwe. Twenty-three single sex focus group discussions and 36 in-depth interviews took place between May and November 2018 with recently pregnant or breastfeeding women, men, mothers and mothers-in-law of pregnant or breastfeeding women, and key informants. Participants across study groups and sites (N = 232) reported various perceived benefits and harms of sex during pregnancy and postpartum. Participants discussed reasons why men might seek sex outside of the relationship. There is a critical need for alternative prevention options to protect pregnant and breastfeeding women from HIV.

IntroductionWhether intramuscular depot medroxyprogesterone acetate (DMPA-IM) and norethisterone enanthate (NET-EN) have a differential impact on the incidence of sexually transmitted infection (STI) remains unclear. In the Vaginal and Oral Interventions to Control the Epidemic (VOICE) trial, HIV-1 acquisition was higher for DMPA-IM users vs. NET-EN users. We compared DMPA-IM and NET-EN users with regard to chlamydia, gonorrhea, trichomoniasis, syphilis, and herpes simplex virus type 2 (HSV-2) infection.Materials and methodsProspective data were analyzed from VOICE, a randomized trial of HIV-1 chemoprophylaxis. Participants were evaluated annually and as indicated for chlamydia, gonorrhea, trichomoniasis, and syphilis. Stored specimens were tested for HSV-2. Proportional hazards models compared the risk of STI between DMPA-IM and NET-EN users.ResultsAmong 2,911 injectable contraception users in South Africa, 1,800 (61.8%) used DMPA-IM and 1,111 used NET-EN (38.2%). DMPA-IM and NET-EN users did not differ in baseline chlamydia: 15.1 vs. 14.3%, p= 0.54; gonorrhea: 3.4 vs. 3.7%, p= 0.70; trichomoniasis: 5.7 vs.5.0%, p= 0.40; or syphilis: 1.5 vs. 0.7%, p= 0.08; but differed for baseline HSV-2: (51.3 vs. 38.6%, p < 0.001). Four hundred forty-eight incident chlamydia, 103 gonorrhea, 150 trichomonas, 17 syphilis, and 48 HSV-2 infections were detected over 2,742, 2,742, 2,783, 2,945, and 756 person-years (py), respectively (chlamydia 16.3/100 py; gonorrhea 3.8/100 py; trichomoniasis 5.4/100 py; syphilis 0.6/100 py; HSV-2 6.4/100 py). Comparing DMPA-IM with NET-EN users, no difference was noted in the incidence of chlamydia, gonorrhea, trichomoniasis, syphilis, or HSV2 infections, including when adjusted for confounders [chlamydia (aHR 1.03, 95% CI 0.85-1.25), gonorrhea (aHR 0.88, 95% CI 0.60-1.31), trichomoniasis (aHR 1.07, 95% CI 0.74-1.54), syphilis (aHR 0.41, 95% CI 0.15-1.10), and HSV-2 (aHR 0.83, 95% CI 0.45-1.54, p= 0.56)].DiscussionAmong South African participants enrolled in VOICE, DMPA-IM and NETEN users differed in prevalence of HSV-2 at baseline but did not differ in the incidence of chlamydia, gonorrhea, trichomoniasis, syphilis, or HSV-2 infection. Differential HIV-1 acquisition, previously demonstrated in this cohort, does not appear to be explained by differential STI acquisition. However, the high incidence of multiple STIs reinforces the need to accelerate access to comprehensive sexual and reproductive health services.

: Introduction: End‐user perspectives are vital to the design of new biomedical HIV prevention products. Conjoint analysis can support the integration of end‐user perspectives by examining their preferences of potential pre‐exposure prophylaxis (PrEP) products. The Microbicides Trial Network (MTN) 035 protocol examined three placebo rectal dosage forms (insert, enema and suppository) that could deliver PrEP prior to receptive anal sex (RAS). Methods: Between April 2019 and July 2020, we enrolled 217 HIV‐negative, cisgender men who have sex with men (MSM; n = 172; 79.3%) and transgender people (n = 47; 20.7%) ages 18–35 into a randomized cross‐over trial across Malawi, Peru, South Africa, Thailand and the United States. Participants used each product prior to RAS over 4‐week periods. Participants completed a conjoint experiment where they selected between random profiles using seven features (dosage form, timing of use before sex, side effects, duration of protection, effectiveness, frequency of use and need for a prescription). Results: Effectiveness was the strongest determinant of choice (30.4%), followed by modality (18.0%), potential side effects (17.2%), frequency of use (10.8%), duration of protection (10.4%), timing of use before sex (7.4%) and need for a prescription (5.9%). Relative utility scores indicated that the most desirable combination of attributes was a product with 95% efficacy, used 30 minutes before sex, offering a 3‐ to 5‐day protection window, used weekly, having no side effects, in the form of an enema and available over‐the‐counter. Conclusions: Choice in next‐generation PrEP products is highly desired by MSM and transgender people, as no one‐size‐fits‐all approach satisfies all the preferences. MTN‐035 participants weighed product features differently, recognizing the need for diverse, behaviourally congruent biomedical options that fit the needs of intended end‐users., INTRODUCTION Clinical advances in the success of pre‐exposure prophylaxis (PrEP) have resulted in a greater number of PrEP modalities (e.g. daily oral, long‐acting injectable, microbicide vaginal ring) from which individuals [...]

: 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 ( 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., INTRODUCTION Over half of the 38 million people living with human immunodeficiency virus (HIV) worldwide are women [1]. In sub‐Saharan Africa, women and girls accounted for 63% of new HIV [...]

ObjectiveWe aimed to determine if the dapivirine vaginal ring and the ring device alone (flexible silicone matrix polymer) was associated with the development of cervical cytology abnormalities.DesignSecondary analysis comparing cervical cytology results between two randomized controlled microbicide trials (MTN-020/ASPIRE and MTN-003/VOICE).MethodsData from ASPIRE, a phase III, placebo-controlled trial of the dapivirine vaginal ring, were used in this analysis. Cervical cytology smears were evaluated at baseline and at the final visit with product use. We compared cytology results between women randomized to dapivirine versus placebo vaginal ring. We further assessed for the effect of the vaginal ring device on cervical cytology by comparing results with data from the oral placebo arm of VOICE, a prior HIV-1 prevention trial conducted in a similar population.ResultsCervical cytology results for 2394 women from ASPIRE (1197 per study arm) were used in this analysis; median time between baseline and final visit with product use was 22.1 months. Cytology smear findings were comparable between dapivirine and placebo vaginal ring arms: at final visit, normal: 90.6 versus 91.5%, ASC-US//LSIL: 7.8 versus 7.4%, ASC-H/HSIL/AGC/AGC-favor neoplastic: 1.7 versus 1.1%, P = 0.44. Cytology data from VOICE had findings (normal: 87.8%, ASC-US/LSIL: 9.8%, ASC-H/HSIL/AGC/AGC-favor neoplastic: 2.4%) comparable with that of both dapivirine (P = 0.93) and placebo vaginal ring arms (P = 0.24).ConclusionThese findings indicate that neither use of the dapivirine vaginal ring nor the vaginal ring device alone, over a period of 2 years, is associated with development of cervical cytology abnormalities that could lead to precancerous or cancerous lesions.

BackgroundGenital infection with herpes simplex virus type 2 (HSV-2) is common and increases risk of human immunodeficiency virus (HIV) transmission and acquisition. Pericoital use of tenofovir (TFV) gel provided protection from HSV-2 acquisition in the CAPRISA 004 study.MethodsWe measured estimate of effect of vaginal TFV 1% gel in preventing HSV-2 acquisition among women in VOICE, randomized, double-blinded, placebo-controlled trial assessing daily use of oral and vaginal TFV for HIV-1 preexposure prophylaxis. The TFV level in plasma at the first quarterly visit was used as a measure of gel use.ResultsOf 566 participants at risk for HSV-2 acquisition, 532 (94%) had first-quarter plasma TFV and end-of-study HSV-2 serologic data available. Over a follow-up period of 501 person-years, 92 incident cases of HSV-2 acquisition occurred: 77 were in women with no TFV detected in plasma, and 15 occurred in women with TFV detected in plasma (incidence, 20.6 cases/100 person-years [95% confidence interval [CI], 16.2-25.7] vs 11.9 cases/100 person-years [95% CI, 6.6-19.6], respectively). TFV detection in plasma was associated with a trend toward a reduced risk of HSV-2 seroconversion, with an unadjusted hazard ratio (HR) of 0.59 (95% CI, .34-1.02; P = .060) and a HR adjusted for site, age, having ≥2 male sex partners in the past 3 months, use of hormonal contraception, having anal sex in the past 3 months, and HIV status of 0.60 (95% CI, .33-1.08; P = .086).ConclusionsDetection of TFV in plasma among TFV gel users was associated with a trend toward a reduced risk of HSV-2 acquisition, after controlling for sexual behavior and HIV-1 acquisition.

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.).

End-user feedback early in product development is important for optimizing multipurpose prevention technologies for HIV and pregnancy prevention. We evaluated the acceptability of the 90-day dapivirine levonorgestrel ring (DPV-LNG ring) used for 14 days compared to a dapivirine-only ring (DVR-200mg) in MTN-030/IPM 041 (n = 23), and when used for 90 days cyclically or continuously in MTN-044/IPM 053/CCN019 (n = 25). We enrolled healthy, non-pregnant, HIV-negative women aged 18–45 in Pittsburgh, PA and Birmingham, AL (MTN-030 only). Self-reports of vaginal bleeding and adherence (ring removals, expulsions) were collected via daily short message service. Acceptability data were recorded in face-to-face interviews at study exit. We assessed differences in acceptability by product characteristics and adherence; and associations between baseline characteristics/demographics, number of bleeding days, adherence, and overall acceptability. Most (21/23) women in the 14-day MTN-030 study and about half (13/25) in the 90-day MTN-044 study liked their assigned rings. In MTN-030 there were no significant associations between any variables and overall acceptability of either ring. In MTN-044, women who disliked the DPV-LNG ring had a significantly higher incidence of unanticipated vaginal bleeding, and reporting that vaginal bleeding changes were unacceptable than those who liked it. Although we found no overall association between adherence and acceptability, significantly more women who disliked (versus liked) the DPV-LNG ring reported expulsions during toileting. The DPV-LNG ring could meet the needs of women seeking simultaneous protection from HIV and unintended pregnancy. Addressing issues related to vaginal bleeding and expulsions early in product development will likely enhance acceptability of the DPV-LNG ring. Trial registration: Clinical Trial Registration: MTN-030/IPM 041: ClinicalTrials.gov NCT02855346; MTN-044/IPM 053/CCN019: ClinicalTrials.gov NCT03467347. [ABSTRACT FROM AUTHOR]

BackgroundIn sub-Saharan Africa, there are limited data on the incidence of sexually transmitted infections (STIs) among women, largely because routine screening for asymptomatic infection is not performed. We conducted a secondary analysis to measure STI incidence rates and determine risk factors for new STI acquisition among women enrolled in the VOICE trial.MethodsWe analyzed data from 4843 women screened for chlamydia, gonorrhoea, syphilis, and trichomonas infection at baseline, annually, at interim visits when clinically indicated and at their study termination visit. Risk reduction counseling and condoms were provided throughout the trial.ResultsTwenty percent of evaluable participants had one or more curable STIs at baseline. Over 5660 person-years at risk (PYAR) of observation, incidence rates were 13.8% (95% confidence interval [CI], 12.7-14.8) PYAR for chlamydia, 3.5% (95% CI, 3.0-4.1) PYAR gonorrhea, 0.1% (95% CI, 0.6-1.1) PYAR syphilis, and 6.6% (95% CI, 5.8-7.2) PYAR trichomoniasis. South African sites had the highest incidence of chlamydia. The Uganda site had the highest incidence of gonorrhoea and syphilis, and Zimbabwe the lowest incidence overall. The majority of these cases were diagnosed at a routine scheduled testing visit. In multivariate analysis, positive baseline STI, younger than 25 years, being unmarried, and some alcohol consumption were associated with acquiring a new STI.ConclusionsWe observed high rates of STIs during follow up among women in the VOICE study. Women living in human immunodeficiency virus endemic countries should be screened for common STIs.

Introduction: Vaginalrings are a promising approach to provide a woman-centred, long-acting HIV prevention strategy. Prior trials of a 25 mg dapivirine (DPV) ring have shown a favourable safety profile and approximately 30% risk reduction of HIV-1 infection. Extended duration rings replaced every three months may encourage user adherence, improve health service efficiency and reduce cost overall. We evaluated safety, pharmacokinetics, adherence and acceptability of two three-month rings with different DPV dosages, compared with the monthly DPV ring. Methods: From December 2017 to October 2018, MTN-036/IPM-047 enrolled 49 HIV-negative participant in Birmingham, Alabama and San Francisco, California into a phase 1, randomized trial comparing two extended duration (three-month) rings (100 or 200 mg DPV) to a monthly 25 mg DPV ring, each used over 13 weeks, with follow-up completed in January 2019. Safety was assessed by recording adverse events (AEs). DPV concentrations were quantified in plasma, cervicovaginalfluid (CVF) and cervicaltissue, at nominaltimepoints. Geometric mean ratios (GMRs) relative to the comparator ring were estimated from a regression model. Results: There were no differences in the proportion of participants with grade [greater than or equal to]2 genitourinary AEs or grade [greater than or equal to]3AEs in the extended duration versus monthly ring arms (p = 1.0). Plasma and CVF DPV concentrations were higher in the extended duration rings compared to the monthly ring. Plasma GMRs were 1.31 to 1.85 and 1.41 to 1.86 and CVF GMRs were 1.45 to 2.87 and 1.74 to 2.60 for the 100 and 200 mg ring respectively. Cervicaltissue concentrations were consistently higher in the 200 mg ring (GMRs 2.36 to 3.97). The majority of participants (82%) were fully adherent (ring inserted at alltimes, with no product discontinuations/outages) with no differences between the monthly versus three-month rings. Most participants found the ring acceptable (median = 8 on 10-point Likert scale), with a greater proportion of participants reporting high acceptability (9 or 10) in the 25 mg arm (73%) compared with the 100 mg (25%) and 200 mg (44%) arms (p = 0.01 and p = 0.15 respectively). Conclusions: The extended duration DPV rings were well-tolerated and achieved higher DPV concentrations compared with the monthly DPV ring. These findings support further evaluation of three-month DPV rings for HIV prevention. Keywords: dapivirine; vaginalring; pharmacokinetics; safety; microbicide; pre-exposure prophylaxis, 1 INTRODUCTION Over half of the 38 million people living with the human immunodeficiency virus (HIV) globally are women [1]. In sub-Saharan Africa, women and girls account for 59% of [...]

Background On-demand topical products could be an important tool for human immunodeficiency virus (HIV) prevention. We evaluated the safety, pharmacokinetics, and ex vivo pharmacodynamics of a tenofovir alafenamide/elvitegravir (TAF/EVG, 20 mg/16 mg) insert administered rectally. Methods MTN-039 was a phase 1, open-label, single-arm, 2-dose study. Blood, rectal fluid, and rectal tissue were collected over 72 hours following rectal administration of 1 and 2 TAF/EVG inserts for each participant. Results TAF/EVG inserts were safe and well tolerated. EVG and tenofovir (TFV) were detected in blood plasma at low concentrations: median peak concentrations after 2 inserts were EVG 2.4 ng/mL and TFV 4.4 ng/mL. Rectal tissue EVG peaked at 2 hours (median, 2 inserts = 9 ng/mg) but declined to below limit of quantification in the majority of samples at 24 hours, whereas tenofovir diphosphate (TFV-DP) remained high >2000 fmol/million cells for 72 hours with 2 inserts. Compared to baseline, median cumulative log10 HIV p24 antigen of ex vivo rectal tissue HIV infection was reduced at each time point for both 1 and 2 inserts (P <.065 and P <.039, respectively). Discussion Rectal administration of TAF/EVG inserts achieved high rectal tissue concentrations of EVG and TFV-DP with low systemic drug exposure and demonstrable ex vivo inhibition of HIV infection for 72 hours. Clinical Trials Registration. NCT04047420. [ABSTRACT FROM AUTHOR]

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.

BackgroundLimited data exist on effect of tenofovir disoproxil fumarate (TDF) when used for preexposure prophylaxis (PrEP) on bone mineral density (BMD) in HIV-negative women. We evaluated the effect of daily oral TDF and emtricitabine/TDF compared with placebo on BMD among women enrolled in an HIV-1 PrEP trial.MethodsHIV-uninfected women in Uganda and Zimbabwe had BMD measurements of lumbar spine (LS) and total hip (TH) by dual-energy x-ray absorptiometry at baseline and every 24 weeks for 48 weeks of active treatment and for 48 weeks after discontinuation of study medication. Plasma tenofovir levels were assessed every 12 weeks for the first 48 weeks.ResultsOf 518 women enrolled, 432 had dual-energy x-ray absorptiometry results at baseline and week 48. In the primary analysis, no significant differences in percent BMD change in hip or spine between arms observed, likely because of low product adherence. Among the subset with tenofovir detection in 75%-100% of plasma samples, the mean percent BMD change from baseline to week 48 in the LS was 1.4% lower for TDF or emtricitabine/TDF recipients than for placebo (P = 0.002) and TH BMD was 0.9% lower (P = 0.018). BMD changes from end of active treatment to 48 weeks were significantly greater in the active arm participants compared with placebo participants with a net difference of approximately +0.9% at the LS (P = 0.007) and +0.7% (P = 0.003) at the TH.ConclusionsTDF-containing oral PrEP resulted in small but significant reversible decreases in hip and spine BMD among young African women.

Introduction: Women in sub-Saharan Africa spend a substantial portion of their reproductive lives pregnant and/or breastfeeding (P/BF), yet they have limited options to prevent HIV during these maternal stages. In preparation for phase 3b prevention trials in P/BF women, we explored attitudes about using a vaginal ring or oral pills for pre-exposure prophylaxis (PrEP), perceptions of HIV risk during P/BF and key influences on future PrEP use. Methods: In 2018, we conducted 16 single-sex focus group discussions (FGDs) with community- and clinic-recruited HIV-uninfected women, currently or recently P/BF, aged 18 to 40, and men with (currently or recently) P/BF partners, aged 18+. Participants completed a behavioural questionnaire, viewed an educational video and handled prototype placebo products. FGDs were conducted in local languages and transcribed, coded and analysed, using a socio-ecological framework, for key influences on willingness to use products, HIV risk perceptions and opinions on product attributes. Results: Of the 128 participants (65 women, 63 men) 75% lived with their partner and 84% had a child. Women reported the most important influencers when P/BF were partners, and all stated that health decisions when P/BF are typically made jointly (e.g. medication use; ante/postnatal and baby care). There was consensus that P/BF women are at high risk for HIV, primarily because of their partner's infidelities, and new prevention options were welcomed. Participants valued multiple options and stated that woman's personal preference would be key to product choice. Anticipated concerns about products included risk of miscarriage, impact on infant development, complications during delivery and adequate production or taste of breastmilk. Specific perceived disadvantages emerged for the ring (e.g. vaginal discomfort, difficulty inserting/removing) and for pills (e.g. nausea/vomiting) that may be exacerbated during pregnancy. Health care providers' (HCPs) knowledge and approval of product use during P/BF was needed to mitigate anticipated fears. Conclusions: Participants perceived pregnancy and breastfeeding as high HIV risk periods and valued new prevention options. HIV protection of the mother-child dyad, safety of the baby, and ultimately, health of the family were paramount. Endorsement by HCPs and support from partners were key to future product acceptance. Participants recommended involving partners and HCPs in sensitization efforts for future trials. Keywords: vaginal dapivirine ring; Truvada pills; HIV; safety; stigma; socio-ecological framework; acceptability, 1 | INTRODUCTION High fertility rates in sub-Saharan Africa translate to women spending substantial time in their reproductive years (12% to 29%) either pregnant or breastfeeding [1,2]. Pregnant and/or breastfeeding [...]

Background: Vaginal rings formulated to deliver two drugs simultaneously have potential as user-controlled, long-acting methods for dual prevention of HIV and pregnancy. Methods: Two phase 1 randomized trials (MTN-030/IPM 041 and MTN-044/IPM 053/CCN019) respectively enrolled 24 and 25 healthy, HIV-negative participants to evaluate safety, pharmacokinetics, and vaginal bleeding associated with use of a vaginal ring containing 200mg dapivirine (DPV) and 320mg levonorgestrel (LNG) designed for 90-day use. MTN-030/IPM 041 compared the DPV/LNG ring to a DPV-only ring (200mg) over 14 days of use. MTN-044/IPM 053/CCN019 compared continuous or cyclic use of the DPV/LNG ring over 90 days of use. Safety was assessed by recording adverse events (AEs). DPV and LNG concentrations were quantified in plasma, cervicovaginal fluid, and cervical tissue. Vaginal bleeding was self-reported. Results: There were no differences in the proportion of participants with grade ≥2 genitourinary AEs or grade ≥3 AEs with DPV/LNG ring vs. DPV ring use (p =.22), or with DPV/LNG ring continuous vs. cyclic use (p =.67). Higher plasma DPV concentrations were observed in users of DPV/LNG compared to DPV-only rings (Cmax p = 0.049; AUC p = 0.091). Plasma DPV and LNG concentrations were comparable with continuous and cyclic use (Cmax p = 0.74; AUC p = 0.25). With cyclic use, median nadir plasma DPV concentration was approximately 300 pg/mL two days after removal and median t1/2 for cervicovaginal fluid DPV concentration was 5.76 hours (n = 3). Overall bleeding experiences did not differ between continuous and cyclic users (p = 0.12). Conclusions: The extended duration DPV/ LNG rings were well tolerated and the observed DPV concentrations in plasma and cervicovaginal fluid when used continuously exceeded concentrations observed in previous DPV ring efficacy studies. LNG concentrations in plasma were comparable with other efficacious LNG-based contraceptives. Genital DPV concentrations had a short half-life and were thus not well sustained following ring removal. [ABSTRACT FROM AUTHOR]