Preclinical and Early Clinical Development of Tenofovir Alafenamide/Elvitegravir Topical Inserts for Effective On-Demand Vaginal and Rectal HIV Prevention.

HIV/AIDS remains a global public health issue, and products available for the prevention of HIV infections are limited, especially those for short-acting, on-demand, user-controlled applications. Topical inserts are products that can be applied vaginally or rectally and have been explored as drug delivery systems. To fill the gap in the HIV prevention product pipeline, CONRAD has developed a topical insert containing tenofovir alafenamide fumarate (TAF) and elvitegravir (EVG), two potent and synergistic antiretrovirals, as a simple, low-cost, and discreet option that can be self-administered vaginally and/or rectally, before and after coitus. In this review, we have described the development path of the TAF/EVG insert up to its current point in clinical testing, highlighting findings from acceptability, preclinical safety, pharmacokinetics, and efficacy evaluations and early clinical studies. In summary, the TAF/EVG inserts are stable, easy to manufacture, low-cost, acceptable, and show highly promising preclinical and clinical results for on-demand topical pre- or post-exposure HIV prevention.

Preferences for Long-Acting PrEP Products Among Women and Girls: A Quantitative Survey and Discrete Choice Experiment in Eswatini, Kenya, and South Africa.

While oral pre-exposure prophylaxis (PrEP) can substantially reduce HIV risk, there are important barriers to uptake and adherence. We explored preferences for long-acting injectable and implantable PrEP among women and girls in Eswatini, Kenya, and South Africa. We conducted an online quantitative survey and discrete choice experiment (DCE) among adolescent girls (15-17), young women (18-29), and adult women (30-49). Participants completed a survey about their demographics and behavior and a DCE with 5 attributes (format, insertion location, number of insertions, dual-protection, and palpability). We recruited 1236 respondents (Eswatini = 420; Kenya = 350; South Africa = 493) in May 2022. Most participants were sexually active (72%), nearly 29% of whom reported recently engaging in transactional sex. 46% had heard of oral PrEP, but of those, only 16% reported having ever used it. Product format and dual-protection were significant predictors of product choice. Relative to a 2-month injection, participants had 1.76 times the odds (95% CI 1.08-2.04) of choosing a 6-month injectable, and 1.70 the odds (95% CI 1.06-1.92) of choosing a 12-month removable implant. Compared to a single-indication product, respondents had 2.46 times the odds (95% CI 1.04-2.68) of preferring a product also protecting against pregnancy, and 2.81 the odds (95% CI 1.04-3.05) of choosing a product that also protected against STIs. Adolescent girls and women in these countries showed strong preferences for longer-acting PrEP product formats, as well as those offering dual-protection. Introduction of long-acting options could improve PrEP uptake and reduce HIV burdens in east and southern African settings.

Extended post-exposure protection against vaginal SHIV infection with tenofovir alafenamide fumarate/elvitegravir inserts in macaques.

Vaginal inserts that can be used on demand before or after sex may be a desirable HIV prevention option for women. We recently showed that inserts containing tenofovir alafenamide fumarate (TAF/20mg) and elvitegravir (EVG/16mg) were highly protective against repeated SHIV vaginal exposures when administered to macaques 4h before or after virus exposure (93% and 100%, respectively). Here, we show in the same macaque model that insert application 8h or 24h after exposure maintains high efficacy (94.4% and 77.2%, respectively). These data extend the protective window by TAF/EVG inserts and inform their clinical development for on-demand prophylaxis in women.

End-user research in support of long-acting systemic antiretroviral delivery systems: insights from qualitative research with providers and target users in South Africa.

BACKGROUND: While oral pre-exposure prophylaxis (PrEP) has been shown to reduce the risk of HIV, challenges such as adhering to a daily-dosing regimen and persistence have emerged as barriers for at-risks populations in South Africa. This qualitative research sought to investigate perceptions of and preferences for a long-acting, biodegradable implantable PrEP product designed to address these barriers. METHODS: To identify and understand motivators, barriers, and preferences for the PrEP implant, we conducted qualitative in-depth interviews (IDIs) among health care providers (HCPs) and target end-users (young women, adolescent girls, and female sex workers) in urban and rural/peri-urban regions of Gauteng Province, South Africa. The IDIs focused on defining values, beliefs, habits, lifestyles, influencers, and information channels for potential PrEP implant end-users. RESULTS: We conducted 36 IDIs across health care providers and target end-user respondent segments. Respondents had generally positive reactions to the PrEP implant. Most end-users felt that some undesirable aspects of the implant (e.g., side effects, pain during insertion, potential scarring, and inability to remove implant) would be offset by having a highly effective, and long-lasting HIV prevention product. Although some HCPs believed the implantable PrEP would lead to increases in promiscuity and risky sexual behavior, most HCPs saw value in the PrEP implant's long duration of protection, its biodegradability, and the likelihood of higher adherence relative to oral PrEP. CONCLUSIONS: This study is a first step toward further research needed to demonstrate the demand for a biodegradable, long-acting implantable PrEP and suggests such a product would be accepted by end-users and HCPs in South Africa. This study indicates the need to develop more convenient, discreet, long-acting, and highly effective biomedical HIV prevention options for at-risk populations.

Single dose topical inserts containing tenofovir alafenamide fumarate and elvitegravir provide pre- and post-exposure protection against vaginal SHIV infection in macaques.

BACKGROUND: Vaginal products for HIV prevention that can be used on-demand before or after sex may be a preferable option for women with low frequency or unplanned sexual activity or who prefer not to use daily or long-acting pre-exposure prophylaxis (PrEP). We performed dose ranging pharmacokinetics (PK) and efficacy studies of a vaginally applied insert containing tenofovir alafenamide fumarate (TAF) and elvitegravir (EVG) in macaques under PrEP or post-exposure prophylaxis (PEP) modalities. METHODS: PK studies were performed in 3 groups of pigtailed macaques receiving inserts with different fixed-dose combinations of TAF and EVG (10/8, 20/16 and 40/24 mg). PrEP and PEP efficacy of a selected insert was investigated in a repeat exposure vaginal SHIV transmission model. Inserts were administered 4 h before (n = 6) or after (n = 6) repeated weekly SHIV exposures. Infection outcome was compared with macaques receiving placebo inserts (n = 12). FINDINGS: Dose ranging studies showed rapid and sustained high drug concentrations in vaginal fluids and tissues across insert formulations with minimal dose proportionality. TAF/EVG (20/16 mg) inserts were selected for efficacy evaluation. Five of the 6 animals receiving these inserts 4 h before and 6/6 animals receiving inserts 4 h after SHIV exposure were protected after 13 challenges (p = 0.0088 and 0.0077 compared to placebo, respectively). The calculated PrEP and PEP efficacy was 91.0% (95% CI = 32.2%-98.8%) and 100% (95% CI = undefined), respectively. INTERPRETATION: Inserts containing TAF/EVG provided high protection against vaginal SHIV infection when administered within a 4 h window before or after SHIV exposure. Our results support the clinical development of TAF/EVG inserts for on-demand PrEP and PEP in women. FUNDING: Funded by CDC intramural funds, an interagency agreement between CDC and USAID (USAID/CDC IAA AID-GH-T-15-00002), and by the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) through the U.S. Agency for International Development (USAID) under a Cooperative Agreement (AID-OAA-A-14-00010) with CONRAD/Eastern Virginia Medical School.

Pharmacokinetics and efficacy of topical inserts containing tenofovir alafenamide fumarate and elvitegravir administered rectally in macaques.

BACKGROUND: Topical on-demand forms for HIV pre-exposure prophylaxis (PrEP) may be a desirable alternative for people that prefer not to use daily PrEP. CONRAD has developed inserts containing tenofovir alafenamide (TAF) and elvitegravir (EVG) for on-demand vaginal or rectal pericoital use. We assessed the pharmacokinetics (PK) and pre-exposure efficacy of rectally applied TAF/EVG inserts in macaques. METHODS: PK was assessed in 12 pigtailed macaques. Tenofovir (TFV) and EVG levels were assayed in rectal biopsies and secretions, and tenofovir-diphosphate (TFV-DP) levels in biopsies and peripheral blood mononuclear cells (PBMC). Drug biodistribution was evaluated in 10 animals at necropsy 4 h post-dosing. For efficacy assessments, one or two TAF/EVG inserts were administered to macaques (n = 6) 4 h before repeated rectal SHIV162p3 challenges. FINDINGS: One TAF/EVG insert resulted in rapid and high EVG and TFV-DP in rectal tissue 4 h after application. Adding a second insert led to a 10-fold increase in EVG and TFV-DP in rectal tissue. Efficacy of one and two TAF/EVG inserts were 72.6% (CI 24.5%-92.6%) and 93.1% (CI 73.3%-99.2%), respectively. INTERPRETATION: Although high TFV-DP and EVG levels were observed with one rectal TAF/EVG insert, it only conferred partial protection from rectal SHIV challenges. Adding a second insert led to an increase in TFV and EVG in rectal tissues resulting in higher (>90%) efficacy. These results highlight the high efficacy of TAF/EVG inserts as topical on-demand rectal PrEP, as well as the need for appropriate drug coverage in the deep rectum and colon to achieve high protection. FUNDING: The work related to animal studies was funded by CDC intramural funds and an interagency agreement between CDC and USAID (USAID/CDC IAA AID-GH-T-15-00002). The work related to the insert formulation was funded by U.S. PEPFAR through USAID under a Cooperative Agreement (AID-OAA-A-14-00010) with CONRAD/Eastern Virginia Medical School. The findings and conclusions of this manuscript are those of the authors and do not necessarily represent the official views of the Centers for Disease Control and Prevention (CDC), USAID, President's Emergency Plan for AIDS Relief (PEPFAR), Eastern Virginia Medical School (EVMS), or the US government.

Randomized, placebo controlled phase I trial of the safety, pharmacokinetics, pharmacodynamics and acceptability of a 90 day tenofovir plus levonorgestrel vaginal ring used continuously or cyclically in women: The CONRAD 138 study.

Multipurpose prevention technologies (MPTs), which prevent sexually transmitted infection(s) and unintended pregnancy, are highly desirable to women. In this randomized, placebo-controlled, phase I study, women used a placebo or tenofovir (TFV) and levonorgestrel (LNG) intravaginal ring (IVR), either continuously or cyclically (three, 28-day cycles with a 3 day interruption in between each cycle), for 90 days. Sixty-eight women were screened; 47 were randomized to 4 arms: TFV/LNG or placebo IVRs used continuously or cyclically (4:4:1:1). Safety was assessed by adverse events and changes from baseline in mucosal histology and immune mediators. TFV concentrations were evaluated in multiple compartments. LNG concentration was determined in serum. Modeled TFV pharmacodynamic antiviral activity was evaluated in vaginal and rectal fluids and cervicovaginal tissue ex vivo. LNG pharmacodynamics was assessed with cervical mucus quality and anovulation. All IVRs were safe with no serious adverse events nor significant changes in genital tract histology, immune cell density or secreted soluble proteins from baseline. Median vaginal fluid TFV concentrations were >500 ng/mg throughout 90d. TFV-diphosphate tissue concentrations exceeded 1,000 fmol/mg within 72hrs of IVR insertion. Mean serum LNG concentrations exceeded 200 pg/mL within 2h of TFV/LNG use, decreasing quickly after IVR removal. Vaginal fluid of women using TFV-containing IVRs had significantly greater inhibitory activity (87-98% versus 10% at baseline; p<0.01) against HIV replication in vitro. There was a >10-fold reduction in HIV p24 antigen production from ectocervical tissues after TFV/LNG exposure. TFV/LNG IVR users had significantly higher rates of anovulation, lower Insler scores and poorer/abnormal cervical mucus sperm penetration. Most TFV/LNG IVR users reported no change in menstrual cycles or fewer days of and/or lighter bleeding. All IVRs were safe. Active rings delivered high TFV concentrations locally. LNG caused changes in cervical mucus, sperm penetration, and ovulation compatible with contraceptive efficacy. Trial registration: ClinicalTrials.gov #NCT03279120.

Long-acting HIV pre-exposure prophylaxis (PrEP) approaches: recent advances, emerging technologies, and development challenges.

INTRODUCTION: Poor or inconsistent adherence to daily oral pre-exposure prophylaxis (PrEP) has emerged as a key barrier to effective HIV prevention. The advent of potent long-acting (LA) antiretrovirals (ARVs) in conjunction with advances in controlled release technologies has enabled LA ARV drug delivery systems (DDS) capable of providing extended dosing intervals and overcome the challenge of suboptimal drug adherence with daily oral dosing. AREAS COVERED: This review discusses the current state of the LA PrEP field, recent advances, and emerging technologies, including ARV prodrug modifications and new DDS. Technological challenges, knowledge gaps, preclinical testing considerations, and future directions important in the context of clinical translation and implementation of LA HIV PrEP are discussed. EXPERT OPINION: The HIV prevention field is evolving faster than ever and the bar for developing next-generation LA HIV prevention options continues to rise. The requirements for viable LA PrEP products to be implemented in resource-limited settings are challenging, necessitating proactive consideration and product modifications during the design and testing of promising new candidates. If successfully translated, next-generation LA PrEP that are safe, affordable, highly effective, and accepted by both end-users and key stakeholders will offer significant potential to curb the HIV pandemic.

Development and Preclinical Investigation of Physically Cross-Linked and pH-Sensitive Polymeric Gels as Potential Vaginal Contraceptives.

This study explored the development of cross-linked gels to potentially provide a physical barrier to vaginal sperm transport for contraception. Two types of gels were formulated, a physically cross-linked iota-carrageenan (Ci) phenylboronic acid functionalized hydroxylpropylmethyacrylate copolymer (PBA)-based (Ci-PBA) gel, designed to block vaginal sperm transport. The second gel was pH-shifting cross-linked Ci-polyvinyl alcohol-boric acid (Ci-PVA-BA) gel, designed to modulate its properties in forming a viscoelastic, weakly cross-linked transient network (due to Ci gelling properties) on vaginal application (at acidic pH of ~3.5-4.5) to a more elastic, densely cross-linked (due to borate-diol cross-linking) gel network at basic pH of 7-8 of seminal fluid, thereby acting as a physical barrier to motile sperm. The gels were characterized for dynamic rheology, physicochemical properties, and impact on sperm functionality (motility, viability, penetration). The rheology data confirmed that the Ci-PBA gel was formed by ionic interactions whereas Ci-PVA-BA gel was chemically cross-linked and became more elastic at basic pH. Based on the screening data, lead gels were selected for in vitro sperm functionality testing. The in vitro results confirmed that the Ci-PBA and Ci-PVA-BA gels created a barrier at the sperm-gel interface, providing sperm blocking properties. For preclinical proof-of-concept, the Ci-PBA gels were applied vaginally and tested for contraceptive efficacy in rabbits, demonstrating only partial efficacy (40-60%). Overall, the in vitro and in vivo results support the development and further optimization of cross-linked gels using commercially available materials as vaginal contraceptives.

HIV Pre-exposure Prophylaxis Implant Stated Preferences and Priorities: Results of a Discrete Choice Experiment Among Women and Adolescent Girls in Gauteng Province, South Africa.

For adolescent girls (AG) and young women (YW), adherence barriers may limit the effectiveness of daily oral HIV pre-exposure prophylaxis (PrEP). Due to its low-burden and long-lasting product attributes, PrEP implants could remove some of the critical adherence barriers of oral PrEP products for individuals at risk of HIV. To explore stated preferences for a long-acting PrEP implant, we conducted a quantitative survey and discrete choice experiment with AG (ages 15-17), YW (18-34), and female sex workers (FSW; ≥ 18) in Gauteng Province, South Africa. We completed 600 quantitative surveys across the three subgroups of women. Respondents stated preference for an implant that provided longer HIV protection (24 months versus 6 months) and required a single insertion. They stated that they preferred a biodegradable implant that could be removed within 1 month of insertion. Respondents had no preference for a particular insertion location. Overall, 78% of respondents said they would be likely (33%) or very likely (45%) to use a PrEP implant were one available, with the majority (82%) stating preference for a product that would provide dual protection against HIV and unintended pregnancies. To reduce their risk of HIV, AG, YW, and FSW in our survey reported a strong willingness to use long-acting, highly-effective, dissolvable PrEP implants.

RESUMEN: Las niñas adolescentes (NA) y mujeres jóvenes (MJ), pueden enfrentar barreras de adherencia que limitan la eficacia de la profilaxis oral previa a la exposición al VIH (PrEP). Ya que el implante de PrEP es un producto que requiere de poca intervención de la usuaria y es de larga duración, podría eliminar algunas de las barreras de adherencia más importantes en el uso de los productos orales de PrEP para aquellas personas en riesgo de infección de VIH. Para explorar las preferencias declaradas en cuanto al implante de PrEP de acción prolongada, llevamos a cabo una encuesta cuantitativa y un experimento de elección discreta (DCE) con NA (de 15 a 17 años), MJ (de 18 a 34 años) y mujeres trabajadoras del sexo (MTS; ≥ 18 años) en la provincia de Gauteng, Sudáfrica. Administramos 600 encuestas cuantitativas en los tres subgrupos de mujeres. Los resultados indican la preferencia por un implante que proporciona una protección contra el VIH más prolongada (24 meses a comparación con 6 meses) y que requiere de una única inserción. Las participantes afirmaron que prefieren un implante biodegradable que puede retirarse un mes después de su inserción. Las participantes no tenían preferencia por un sitio específico de inserción. En general, el 78% de las participantes indicaron que probablemente (33%) o muy probablemente (45%) utilizarían un implante de PrEP si estuviera disponible, y la mayoría (82%) manifestó su preferencia por un producto que proporcionaba una doble protección contra el VIH y el embarazo no deseado. Para reducir el riesgo de contraer el VIH, las NA, MJ y MTS participantes se mostraron muy dispuestas a utilizar implantes de PrEP de larga duración, altamente eficaces y disolubles.

Vaginal Microbiota and Mucosal Pharmacokinetics of Tenofovir in Healthy Women Using a 90-Day Tenofovir/Levonorgestrel Vaginal Ring.

Background: A relationship between the vaginal microbiota and tenofovir (TFV) concentrations and activity after topical administration has been previously reported. Objective: CONRAD A15-138 was a randomized, placebo-controlled Phase I study aimed at characterizing the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of TFV and levonorgestrel (LNG) administered through a vaginal ring (IVR) for 90 days. Herein, we describe changes from baseline in the vaginal microbiota with IVR use and the impact of the vaginal microbiota on mucosal TFV PK. Methods: The study screened 68 participants and randomized 47 (37 TFV/LNG, 10 placebo), assessing the vaginal microbiota by sequencing the V3-V4 regions of 16S rRNA genes prior to IVR insertion and monthly for 3 months. Concentrations of TFV in vaginal fluid (VF), and TFV and TFV-diphosphate (TFV-DP) in vaginal tissue, and modeled PD against HIV-1 in vitro were measured before and after treatment. Results: There were no clinically significant changes in relative abundance of vaginal bacterial phylotypes from pre-insertion baseline at any month among active and placebo IVR users. There were no significant changes in community state type (CST) with IVR use. Participants with diverse, anaerobic CST IVA/B microbiota had higher in vivo release of TFV from the IVR compared to women with Lactobacillus-dominated (LbD) microbiota, who had expected in vivo TFV release rates. Median VF TFV concentrations were significantly higher among women with CST IVA/B microbiota in months 1 (3,135 ng/mg VF) and 2 (3,800 ng/mg). Women with LbD microbiota had significantly higher median VF TFV concentration (1,423 ng/mg) and median TFV (103 ng/mg) and TFV-DP (5,877 fmol/mg) tissue concentrations versus women with CST IVA/B microbiota at month 3. All women demonstrated a significant increase from pre-insertion baseline of in vitro HIV-1 inhibition by VF (p values <0.05). PD differences in tissue according to CST, however, were not statistically significant. Conclusion: TFV/LNG IVR use did not change the vaginal microbiota nor increase the incidence of CST IVA/B. Vaginal microbiota, and in particular CST IVA/B, possibly through increased vaginal pH, impacted in vivo TFV release and cervicovaginal (CV) PK, but both PK and PD data suggest CV protection against HIV-1. Clinical Trial Registration: ClinicalTrials.gov (#NCT03279120).

Drug-releasing vaginal rings for HIV/STI and pregnancy prevention: a review of recent advances and clinical applications.

INTRODUCTION: Adolescent girls and young women (AGYW), as well as pre- and post-menopausal women globally would benefit from expanded choice to address their sexual and reproductive health (SRH) needs related to Human Immunodeficiency Virus (HIV), sexually transmitted infections (STIs) and pregnancy prevention. Lack of adequate preventative vaccines for HIV/STIs reinforces public health prioritization for options women may use to mitigate risk for infectious disease and unplanned pregnancy. Drug releasing intravaginal rings (IVRs) represent one such technology that has garnered attention based on the modality's success as a pre-exposure prophylaxis (PrEP) delivery option in HIV risk reduction. AREAS COVERED: This article provides a synopsis of three IVR technologies in active clinical development for prevention of HIV, STI, and unintended pregnancy demonstrating advancements in terms of compatibility with a wide range of drug types with a focus on dapivirine-based silicone rings (International Partnership for Microbicides (IPM), tenofovir-based polyurethane rings (Conrad), and pod-based rings (Oak Crest Institute of Science)). EXPERT OPINION: The goals of IVR research are to reduce burdens of HIV/STIs and unplanned pregnancies. Through the evolution of IVR technologies, the potential exists to trigger integration of health-care services through formulation of products with multiple indications.

Preferences and Acceptability of Vaginal Delivery Forms for HIV Prevention Among Women, Male Partners and Key Informants in South Africa and Zimbabwe: Qualitative Findings.

The attributes of an HIV microbicide may affect its acceptability, uptake and use. Quatro, a clinical study with a qualitative component, was conducted to elicit input from end-users and key informants (KIs) on four different placebo vaginal microbicide delivery forms; fast dissolving insert, ring, film and gel. In-depth interviews and focus group discussions were conducted with young women, their male partners and KIs, to explore acceptability and preferences of the four placebo products, with the intention of improving product attributes, adherence, and consequently, long term effectiveness. None of the four microbicide delivery forms stood well above others as the most preferred. Product attributes; long-action, ease of use, invisibility, female initiated and non-interference during sex were favourable in both countries. Despite preference for the long-action, on-demand products were the most liked by women. Qualitative data from the Quatro study provided rich feedback on specific attributes important to the acceptability of four HIV prevention product platforms currently in development, enabling more informed and guided product development efforts moving forward.

Vitamin D Status Impacts Genital Mucosal Immunity and Markers of HIV-1 Susceptibility in Women.

While vitamin D insufficiency is known to impact a multitude of health outcomes, including HIV-1, little is known about the role of vitamin D-mediated immune regulation in the female reproductive tract (FRT). We performed a pilot clinical study of 20 women with circulating 25(OH)D levels <62.5 nmol/L. Participants were randomized into either weekly or daily high-dose oral vitamin D supplementation groups. In addition to serum vitamin D levels, genital mucosal endpoints, including soluble mediators, immune cell populations, gene expression, and ex vivo HIV-1 infection, were assessed. While systemic vitamin D levels showed a significant increase following supplementation, these changes translated into modest effects on the cervicovaginal factors studied. Paradoxically, post-supplementation vitamin D levels were decreased in cervicovaginal fluids. Given the strong correlation between vitamin D status and HIV-1 infection and the widespread nature of vitamin D deficiency, further understanding of the role of vitamin D immunoregulation in the female reproductive tract is important.

Pharmacokinetics of a weekly transdermal delivery system of tenofovir alafenamide in hairless rats.

Tenofovir alafenamide (TAF) is a potent prodrug of tenofovir (TFV) for HIV prophylaxis, and HIV and HBV treatment. Compared to oral daily doses, transdermal administration of TAF may be more advantageous for long-term adherence by offering sustained drug delivery and reduced dosing frequency. Here, we described the plasma pharmacokinetics (PK) of an optimized once-weekly suspension transdermal delivery system (TDS) for TAF (96 mg/25 cm2 of TDS) in female hairless rats. Over the study period, the TAF TDS delivered an overall low level of TAF (median: 1.43 [0.02-3.28] ng/mL) and a sustained level of the stable metabolite and parent drug, TFV. Relative to the projected exposure corresponding to six-day oral daily doses, a comparable TAF exposure but a substantially lower TFV exposure was resulted from the TAF TDS, suggesting a lower risk of TFV-associated adverse effects. TAF, TFV, and phosphorylated TFVs (TFV-monophosphate and diphosphate) were found distributed in vaginal tissue, the portal of entry for HIV during male-to-female sexual transmission. Skin adhesion and tolerance were acceptable given the animal model used. PK evaluation of the TAF TDS in hairless rats demonstrates the proof of concept that transdermal delivery can be an alternative route for a sustained, once-weekly systemic delivery of TAF.

Efficacy is Not Everything: Eliciting Women's Preferences for a Vaginal HIV Prevention Product Using a Discrete-Choice Experiment.

As new female-initiated HIV prevention products enter development, it is crucial to incorporate women's preferences to ensure products will be desired, accepted, and used. A discrete-choice experiment was designed to assess the relative importance of six attributes to stated choice of a vaginally delivered HIV prevention product. Sexually active women in South Africa and Zimbabwe aged 18-30 were recruited from two samples: product-experienced women from a randomized trial of four vaginal placebo forms and product-naïve community members. In a tablet-administered survey, 395 women chose between two hypothetical products over eight choice sets. Efficacy was the most important, but there were identifiable preferences among other attributes. Women preferred a product that also prevented pregnancy and caused some wetness (p < 0.001). They disliked a daily-use product (p = 0.002) and insertion by finger (p = 0.002). Although efficacy drove preference, wetness, pregnancy prevention, and dosing regimen were influential to stated choice of a product, and women were willing to trade some level of efficacy to have other more desired attributes.

Topical Inserts: A Versatile Delivery Form for HIV Prevention.

The development of topical inserts for the prevention of sexually transmitted infections (STIs), particularly human immunodeficiency virus (HIV), represents a promising alternative to oral and parenteral pre-exposure prophylaxis (PrEP) dosage forms. They may be used for vaginal and/or rectal administration of a variety of agents with antiviral activity. Topical inserts deliver drugs to the portal of viral entry, i.e., the genital or rectal mucosa, with low systemic exposure, and therefore are safer and have fewer side effects than systemic PrEP agents. They may dissolve fast, releasing the active drugs within minutes of insertion, or slowly for long-acting drug delivery. Furthermore, they are user-friendly being easy to administer, discreet and highly portable. They are also economical and easy to manufacture at scale and to distribute, with excellent stability and shelf-life. Altogether, topical inserts represent a particularly promising form of drug delivery for HIV and STI prevention. Highlighted within this review are end-user acceptability research dedicated to understanding preferred attributes for this form of drug delivery, advantages and disadvantages of the formulation platform options, considerations for their development, clinical assessment of select placebo prototypes, future directions, and the potential impact of this dosage form on the HIV prevention landscape.

Development and clinical assessment of new objective adherence markers for four microbicide delivery systems used in HIV prevention studies.

BACKGROUND: Adherence is critical for successful topical, vaginally delivered anti-retroviral (ARV)-based HIV pre-exposure prophylaxis (PrEP). Quantitating systemic or tissue ARV levels through LC-MS/MS is currently viewed as the most reliable measure of adherence. However, for placebo-controlled trials, this is a high cost analysis that measures adherence only in the drug treatment group. A desirable marker of adherence is one that is measured in both placebo and drug treatment groups using a simple on-site clinical laboratory test, which allows necessary interventions for supporting participant adherence. Our objective was to develop adherence markers for four vaginal placebo products currently used as microbicide delivery systems: gel, film, insert, and intravaginal ring. Excipient and spectroscopy-based approaches were used for preclinical development of the placebo markers and subsequently validated by the CONRAD 135 study. The study collected vaginal swabs collected each day for 1 week post vaginal application of gel, film, or insert in the clinic with or without sex. Intravaginal rings were collected after 1 day, 7, and 30 days of use. RESULTS: Placebo gel, film, and insert in vaginal swabs were successfully detected by specific excipient colorimetric or probe-based assays for hydroxyethylcellulose, glycerin, and sorbitol respectively, as well as spectroscopy-based prediction models. The range of detection for gel, film, and insert in swabs collected up to 16 h post vaginal application was 70-100% of the total swabs per time point, with some markers showing potential for longer duration. Decreasing residual glycerin levels and increasing bioanalyte penetration of vaginally used intravaginal rings showed significant changes between 1 and 30 days of use. CONCLUSIONS: We demonstrated clinical proof-of-concept that adherence markers for placebo product can be measured using simple, lower cost approaches. Measuring adherence in both placebo and drug arms of a HIV PrEP study would better inform future trial designs.

Randomized, placebo controlled phase I trial of safety, pharmacokinetics, pharmacodynamics and acceptability of tenofovir and tenofovir plus levonorgestrel vaginal rings in women.

To prevent the global health burdens of human immunodeficiency virus [HIV] and unintended/mistimed pregnancies, we developed an intravaginal ring [IVR] that delivers tenofovir [TFV] at ~10mg/day alone or with levonorgestrel [LNG] at ~20µg/day for 90 days. We present safety, pharmacokinetics, pharmacodynamics, acceptability and drug release data in healthy women. CONRAD A13-128 was a randomized, placebo controlled phase I study. We screened 86 women; 51 were randomized to TFV, TFV/LNG or placebo IVR [2:2:1] and 50 completed all visits, using the IVR for approximately 15 days. We assessed safety by adverse events, colposcopy, vaginal microbiota, epithelial integrity, mucosal histology and immune cell numbers and phenotype, cervicovaginal [CV] cytokines and antimicrobial proteins and changes in systemic laboratory measurements, and LNG and TFV pharmacokinetics in multiple compartments. TFV pharmacodynamic activity was measured by evaluating CV fluid [CVF] and tissue for antiviral activity using in vitro models. LNG pharmacodynamic assessments were timed based on peak urinary luteinizing hormone levels. All IVRs were safe with no significant colposcopic, mucosal, immune and microbiota changes and were acceptable. Among TFV containing IVR users, median and mean CV aspirate TFV concentrations remained above 100,000 ng/mL 4 hours post IVR insertion and mean TFV-diphosphate [DP] concentrations in vaginal tissue remained above 1,000 fmol/mg even 3 days post IVR removal. CVF of women using TFV-containing IVRs completely inhibited [94-100%] HIV infection in vitro. TFV/LNG IVR users had mean serum LNG concentrations exceeding 300 pg/mL within 1 hour, remaining high throughout IVR use. All LNG IVR users had a cervical mucus Insler score <10 and the majority [95%] were anovulatory or had abnormal cervical mucus sperm penetration. Estimated in vivo TFV and LNG release rates were within expected ranges. All IVRs were safe with the active ones delivering sustained high concentrations of TFV locally. LNG caused changes in cervical mucus, sperm penetration, and ovulation compatible with contraceptive efficacy. The TFV and TFV/LNG rings are ready for expanded 90 day clinical testing. Trial registration ClinicalTrials.gov #NCT02235662.

Rapid measures of user's adherence to vaginal drug products using attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) and multivariate discriminant techniques.

BACKGROUND: The topical HIV prevention (microbicides) field is in acute need of a method to rapidly and objectively measure adherence to product use in clinical trials. Infrared (IR) spectroscopy has been used in many pharmaceutical and forensic applications but has yet to be applied to adherence monitoring. In this study, we report on efforts to test the feasibility of using IR spectroscopy as a means to measure residual active or placebo vaginal product, semen exposure and vaginal insertion from a single swab. METHODS: A portable IR spectrometer equipped with diamond attenuated total reflectance (ATR) was used to capture spectra of unused vs. vaginally-used swabs, vaginal swabs containing semen, and vaginal swabs to which either tenofovir-containing or matching placebo products (vaginal gel or insert) were added. Spectral data obtained from swabs placed directly on the spectrometer were divided into calibration and testing sets for developing and validating discriminant models set up to provide yes/no predictions of: vaginal vs. non-vaginal use, presence vs. no presence of each test product, and presence vs. no presence of semen. Further validation of models was performed using vaginal swabs collected from a clinical study evaluating vaginally administered placebo insert formulations. RESULTS: For each discriminant model developed to predict vaginal vs. non-vaginal use, presence vs. no presence of each test product, and presence vs. no presence of semen, classified validation samples not included in the model development were correctly identified into their respective classes with minimal prediction error. Clinically obtained vaginal swabs collected 15-60 minutes after placebo insert use were also correctly identified, further validating the models. CONCLUSION: Our findings demonstrate the proof of concept that IR spectroscopy can be a method for rapid detection and characterization of microbicide products and biological fluids present in vaginal swabs. This novel method has potential to support real-time, on-site adherence monitoring in clinical or field settings.