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.

A phase I study to assess safety, pharmacokinetics, and pharmacodynamics of a vaginal insert containing tenofovir alafenamide and elvitegravir.

Background: New multi-purpose prevention technology (MPT) products are needed to prevent human immunodeficiency virus (HIV) and herpes simplex virus type 2 (HSV2). In this study, we evaluated a fast-dissolve insert that may be used vaginally or rectally for prevention of infection. Objective: To describe the safety, acceptability, multi-compartment pharmacokinetics (PK), and in vitro modeled pharmacodynamics (PD) after a single vaginal dose of an insert containing tenofovir alafenamide (TAF) and elvitegravir (EVG) in healthy women. Methods: This was a Phase I, open-label, study. Women (n=16) applied one TAF (20mg)/EVG (16mg) vaginal insert and were randomized (1:1) to sample collection time groups for up to 7 days post dosing. Safety was assessed by treatment-emergent adverse events (TEAEs). EVG, TAF and tenofovir (TFV) concentrations were measured in plasma, vaginal fluid and tissue, and TFV-diphosphate (TFV-DP) concentration in vaginal tissue. PD was modeled in vitro by quantifying the change in inhibitory activity of vaginal fluid and vaginal tissue against HIV and HSV2 from baseline to after treatment. Acceptability data was collected by a quantitative survey at baseline and post treatment. Results: The TAF/EVG insert was safe, with all TEAEs graded as mild, and acceptable to participants. Systemic plasma exposure was low, consistent with topical delivery, while high mucosal levels were detected, with median TFV vaginal fluid concentrations exceeding 200,000 ng/mL and 1,000 ng/mL for up to 24 hours and 7 days post dosing, respectively. All participants had vaginal tissue EVG concentrations of > 1 ng/mg at 4 and 24 hours post dosing. The majority had tissue TFV-DP concentrations exceeding 1000 fmol/mg by 24 - 72 hours post dosing. Vaginal fluid inhibition of HIV-1 and HSV-2 in vitro significantly increased from baseline and was similarly high at 4 and 24 hours post dosing. Consistent with high tissue TFV-DP concentrations, p24 HIV antigen production from ectocervical tissues infected ex vivo with HIV-1 significantly decreased from baseline at 4 hours post dosing. HSV-2 production from tissue also decreased post treatment. Conclusions: A single dose of TAF/EVG inserts met PK benchmarks, with PK data supporting an extended window of high mucosal protection. PD modeling supports mucosal protection against both HIV-1 and HSV-2. The inserts were safe and highly acceptable. Clinical trial registration: ClinicalTrials.gov, identifier NCT03762772.

Preferred product attributes of a multipurpose vaginal ring: Findings from a phase 1 trial.

Introduction: Most women face multiple and co-occurring risks from unwanted pregnancy, human immunodeficiency virus (HIV) and other sexually transmitted infections (STIs) at some point during their lifetime. While a range of contraceptive methods exist and options for HIV prevention are increasing, to date, only male and female condoms provide multipurpose protection from both pregnancy and disease. Methods: From September 2017 to December 2018, 60 women from the United States and the Dominican Republic, randomized 1:1 to continuous or interrupted use and 4:1 to active vs. placebo ring, participated in a Phase I trial to assess the safety and tolerability of a three-month multipurpose intravaginal ring (IVR) containing the antiviral tenofovir and the contraceptive levonorgestrel. This study examines survey responses from all participants and qualitative data from a subset of 17 women to assess acceptability of and preferences for IVR characteristics. Results: Overall, women liked the concept of a multipurpose IVR and found it easy to insert and remove. Initial concerns about the size or thickness of the ring generally disappeared with use experience. Women weighed trade-offs between the ease of continuous use for a longer duration against concerns about hygiene and discoloration of the ring when left in place during menses. Whether randomized to continuous or interrupted use, most women found ring attributes (size, thickness, flexibility) very acceptable. They provided recommendations via survey and qualitative interviews for ring modifications that would further increase acceptability. Insights into women's use experiences also suggest the need for clear counseling messages and introduction strategies that can facilitate women's choice and use of prevention methods. Discussion: Study findings suggest that a multipurpose IVR would make a valuable contribution to women's sexual and reproductive health options, and that both continuous and interrupted use strategies may be preferred.

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.

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.

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.

Acceptability of a Long-Acting, Multipurpose Vaginal Ring: Findings from a Phase I Trial in the U.S. and Dominican Republic.

Background: Women worldwide face risks from pregnancy, HIV, and other sexually transmitted infections (STIs). To date, highly effective contraceptive methods provide no HIV/STI protection, and HIV prevention products, excluding condoms, provide no pregnancy protection. Intravaginal rings (IVRs) delivering antiretrovirals and contraceptives are a promising multipurpose prevention technology (MPT). Methods: Embedded within a Phase I randomized, placebo-controlled trial, we examined acceptability of continuous versus interrupted use of a 90-day MPT IVR among 47 low-risk women in Norfolk, Virginia and the Dominican Republic. A baseline survey assessed menstruation attitudes, risk perceptions and trial-related motivations. Follow-up surveys (M1/M3) examined user experiences with and preferences for IVR attributes; 18 women also participated in two in-depth interviews. Results: Most women rated the IVR's flexibility and smoothness (86%) and ease of insertion/removal (76%) as very acceptable. Fewer women similarly rated the IVR size (57%) and changes in color from menstruation (52%). Most participants experienced no changes or less bleeding. Those reporting more/heavier bleeding (20% M1, 15% M3) disliked the change. Overall, women preferred a 3-month (75%) to a 1-month IVR (7.5%) or a bimonthly injectable (10%). In qualitative interviews, women were willing to continuously use an IVR for 6-12 months, providing it did not "degrade" inside the body. Reasons for trial participation and prevention preferences, menstrual attitudes, and perceived IVR benefits and doubts varied by site. Conclusions: Findings provide strong evidence of demand for an MPT IVR that protects from pregnancy and HIV/STIs, lasts longer than 1 month, minimally disrupts menstrual bleeding, and is in women's control. numberClinicalTrials.gov: #NCT03279120.

Adaptation and validation of simple tools to screen and monitor for oral PrEP adherence.

INTRODUCTION: Oral, vaginal and other pre-exposure prophylaxis (PrEP) products for HIV prevention are in various stages of development. Low adherence poses a serious challenge to successful evaluation in trials. In a previous study, we developed tools to screen for general adherence and specifically monitor intravaginal ring adherence within the context of HIV prevention clinical trials. This study aimed to further validate the screening tool and to adapt and provide initial psychometric validation for an oral pill monitoring tool. MATERIALS AND METHODS: We administered a cross-sectional survey between June and October 2018 at a trial site located near Cape Town, South Africa, and another in Thika, Kenya, with 193 women who had experience using daily oral pills. We fit confirmatory factor analysis models on the screening tool items to assess our previously-hypothesized subscale structure. We conducted an exploratory factor analysis of oral PrEP monitoring items to determine the underlying subscale structure. We then assessed the construct validity of each tool by comparing subscales against each other within the current sample and against our original sample, from a study conducted in four sites in South Africa, including Cape Town. RESULTS: The screening tool structure showed moderate evidence of construct validity. As a whole, the tool performed in a similar way to the original sample. The monitoring tool items, which were revised to assess perceptions about and experiences using daily oral PrEP, factored into five subscales that showed moderate to good reliability. Four of the five subscales had a similar structure overall to the vaginal ring monitoring tool from which they were adapted. CONCLUSIONS: Accurate measurement of HIV-prevention product adherence is of critical importance to the assessment of product efficacy and safety in clinical trials, and the support of safe and effective product use in non-trial settings. In this study, we provide further validation for these measures, demonstrating the screening tool's utility in additional populations and adapting the monitoring tool's utility for different HIV-prevention products.

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.

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.

HIV+ men need reproductive counseling too: Assessing childbearing goals and provider communication among HIV+ male patients in Rio de Janeiro, Brazil.

We assessed reported communication with HIV providers about reproductive plans among HIV+ men in Rio de Janeiro, Brazil, and factors associated with having had such communication. A total of N=311 HIV+ men (18-50 years) receiving HIV care at one of six public primary care clinics in Rio de Janeiro between 2008-2009 were surveyed. We used descriptive statistics, and multivariate logistic regression to identify factors associated with communication about childbearing with an HIV provider. HIV+ male patients (mean age=42.7 years, 57% mixed race; 23% bisexual, 51% married/committed partner, 61% with at least one biological child, 77% on ART) reported accepting attitudes of HIV and childbearing (51%), the desire (39%), and/or intention (19%) to have a future child, and reported communication with the HIV provider (14%) or their primary partner (28%) about having children. There were no significant differences between the responses of HIV+ heterosexual and bisexual men on the above outcomes. Men who discussed childbearing with their HIV provider were more likely to have accepting attitudes about HIV and childbearing [AOR 2.8, 95%CI (1.2-6.4), p=0.014], and intend to have a child [AOR 2.6, 95% CI (1.2-5.6), p=0.018], but less likely to have discussed this topic with their partner [AOR 0.32 (0.15-0.68), p=0.003]. Among men reporting communication, 40% (17/42) reported advice against having a child. An unmet need for collaborative, nonjudgmental, and provider-initiated communication about childbearing goals exists for HIV+ men in clinical care.

Where does treatment optimism fit in? Examining factors associated with consistent condom use among people receiving antiretroviral treatment in Rio de Janeiro, Brazil.

In the era of highly active antiretrovirals, people living with HIV (PLWH) have resumed sexual activity in the context of longer and healthier lives, and thus the chances of transmitting the HIV virus, as well as the potential to be re-infected also increase. HIV treatment optimism has been found to be associated with sexual risk behaviors among PLWH in different settings. A cross sectional survey was conducted to examine the relationship between treatment optimism, safer sex burnout and consistent condom use as well as variables associated with treatment optimism in a sample of PLWH on antiretrovirals (ARVs) in Rio de Janeiro, Brazil (n = 604). Seventy-two percent of participants always used a condom in the last 6 months. Homosexual, bisexual, transexual persons were less likely to use condoms consistently than heterosexuals (AOR .58 CI .42-.78). Those who were treatment optimistic (AOR .46 CI .25-.88) were more likely not use a condom consistently in the past 6 months, as were participants who reported safer sex burnout (AOR .58 CI .36-.90). Sexual orientation, safer sex burnout, and lower education levels were significantly associated with higher treatment optimism in multivariate analysis. Study findings highlight the need to address psychosocial factors such as treatment optimism and safer sex burnout associated with lower consistent condom use among PLWH in Rio de Janeiro, Brazil.

Individual and contextual factors of influence on adherence to antiretrovirals among people attending public clinics in Rio de Janeiro, Brazil.

BACKGROUND: There are inconsistencies in the determinants of adherence to antiretrovirals (ARVs) across settings as well as a lack of studies that take into consideration factors beyond the individual level. This makes it necessary to examine factors holistically in multiple settings and populations while taking into consideration the particularities of each context, in order to understand the patterns of ARV adherence. This research explored ARV adherence and individual, relational and environmental-structural factors. METHODS: A cross-sectional survey was conducted from August 2008 through July 2009 among participants currently on ARVs recruited from 6 public health clinics, selected to maximize diversity in terms of caseload and location, representing the range of clinics within Rio de Janeiro city, Brazil. Multivariate logistic regression analysis was used to assess the association between our multilevel factors with ARV adherence among participants with complete cases (n = 632). RESULTS: Eighty-four percent of respondents reported adherence to all of their ARV doses in the last 4 days. Of the socio-demographic variables, those who had one child were positively associated with adherence (AOR 2.29 CI [1.33-3.94]). On the relational level, those with high social support (AOR 2.85 CI [1.50-5.41]) were positively associated with adherence to ARVs. On the environmental-structural level, we found gender was significant with women negatively associated with adherence to ARVs (AOR 0.58 CI [0.38-0.88]) while those with a high asset index (AOR 2.47 CI [1.79-3.40]) were positively associated with adherence to ARVs. CONCLUSIONS: This research highlights the importance of examining the multiple levels of influence on ARV adherence. Intervention research in lower and middle-income settings should address and evaluate the impact of attending to both gender and economic inequalities to improve ARV adherence, as well as relational areas such as the provision of social support.