Experiences of Accessing and Providing Contraceptive Implant Removal Services in Gaborone, Botswana: A Qualitative Study Among Implant Users and Healthcare Providers.

Introduction: This study explored implant user and healthcare provider experiences of accessing and providing contraceptive implant removal services in Gaborone, Botswana, following introduction of the implant in the public sector in 2016. We sought to understand reasons for satisfaction and dissatisfaction with services and their potential impact on wider perceptions of the implant, including influence on future uptake. Methods: Qualitative data were collected through in-depth interviews. Participants comprised ten women who had previously undergone implant removal, and ten providers whose work included provision of implant insertion and removal. Data were analyzed using thematic content analysis. Results: Seven of the ten users in this study had experienced a delay between initial request and undergoing implant removal. This interval ranged from <1 week to 3 months. Users identified the principal barriers to accessing implant removal services as lack of access to trained removal providers, inconvenient appointment times, and provider resistance to performing removal. Nine of the ten providers in this study had experienced barriers to providing implant removal, including insufficient training, lack of equipment, lack of time, and lack of a referral pathway for difficult removals. Despite experiencing barriers in accessing removal, users' perceptions of the implant remained generally positive. Providers were concerned that ongoing negative user experiences of removal services would damage wider perceptions of the implant. Conclusion: Introduction of the contraceptive implant in Botswana has been an important strategy in increasing contraceptive choice. Following an initial focus on provision of insertion services, the development of comparable, accessible removal services is critical to ensuring that the implant remains a desirable contraceptive option and is vital to upholding women's reproductive health rights. The experiences of users and providers in this study can inform the ongoing development of services for implant insertion and removal in Botswana and other lower-resource settings.

Perceptions matter: Narratives of contraceptive implant robbery in Cape Town, South Africa.

Uptake of contraceptive implants has declined in South Africa since their introduction in 2014, with side effects and inadequate health provider training cited as primary contributors underlying a poor community perception of implants. In this paper we explore a theme that emerged unexpectedly during analysis of our research in Cape Town that may be an additional factor in this decline: narratives of women being assaulted by robbers who physically remove the implants for smoking as drugs. Narratives were described consistently across interviews and focus groups with youth (aged 18-24 years) and in interviews with health providers, with six participants (two young people, four health providers) sharing personal experiences of robbery. While there was a range of perspectives on whether narratives are based on real experiences or are myths, there was strong consensus that narratives of implant robbery may be influencing women's decisions around implant use in Cape Town. This is a potent example of how perceptions of new products can affect uptake and offers important lessons for implementers to reflect on in planning for rollout of other health technologies.

Design of an Implant for Long-Acting HIV Pre-Exposure Prophylaxis: Input from South African Health Care Providers.

Implants are in the pre-clinical stage for long-acting HIV pre-exposure prophylaxis (PrEP), with an opportunity to solicit end-users' feedback early in development. Health care providers (HCPs) have been key gatekeepers for contraceptive implant uptake, and uniquely understand both technical considerations and the social context of use. Given their influential role, we gathered South African HCP perspectives on contraceptive implant implementation and features of PrEP implant prototypes that may influence future provider and patient acceptability. We conducted in-depth interviews with 30 HCPs (20 nurses and 10 doctors) in Cape Town and Soshanguve, South Africa. Interviews were conducted by a bioengineer and later transcribed, coded, and analyzed for key themes. HCPs described health system barriers such as understaffed clinics and inadequate training on contraceptive implant removal as major influences to their PrEP implant design preferences. They preferred a PrEP implant that is long lasting (>6 months) to minimize patient-clinic interactions, biodegradable to avoid need for removal, and flexible (but still palpable in case of removal). Commenting on negative experiences with contraceptive implant rollout, they recommended prioritizing both HCP and community education on the PrEP implant, with emphasis on expected side effects, and planning ahead for adequate training of HCPs before rollout. Challenges experienced with past contraceptive implant rollout may taint perspectives on future PrEP implants and must be carefully considered during product development and planning for clinical studies. Particular consideration should be given to the health system context of future distribution, including staff who would be providing and monitoring implants.

Perspectives of South African youth in the development of an implant for HIV prevention.

INTRODUCTION: Implants are a new dosage form in development for HIV pre-exposure prophylaxis (PrEP) with potential for high adherence given that they are provider-administered and are intended for long-acting protection. Integrating end-user preference into early stage product development may further overcome challenges with future product uptake and adherence. Hence, we sought to optimize the design of a PrEP implant in early-stage development by gathering opinions about implant attributes from potential end-users in South Africa. METHODS: We conducted 14 focus group discussions (FGDs) with young women and men aged 18 to 24 in Cape Town and Soshanguve, South Africa, inviting participants into discussion as co-designers. FGDs were homogenous by gender and previous implant experience. During FGDs, we showed prototype devices and followed a semi-structured guide with questions on history of contraceptive implant use, preferences for physical characteristics of an implant, implant biodegradability, insertion process, participant-driven ideas for implant design, and social adoption considerations. FGDs were facilitated in English, isiXhosa, Tswana, isiZulu, or Tsonga, audio-recorded, transcribed into English, and qualitatively coded and analysed. RESULTS: In this qualitative sample of 105 youth (68 women and 37 men), 58 participants were from Soshanguve and 47 from Cape Town, and 23% had previously used contraceptive implants. Participants expressed preferences for several implant design features; specifically, longer duration (≥6 months) was more important to most participants than the size or number of devices implanted. A majority preferred a flexible versus stiff implant to minimize palpability, thereby increasing discreetness and comfort. Nearly all participants favoured a biodegradable implant to avoid removal and thus reduce clinic visits. Concerns about the implant centred on its possible side effects and the "plastic" look of the prototype displayed for demonstration. CONCLUSIONS: This study offers preliminary insights into an implant for HIV prevention that provides long-lasting protection may be well received among young South Africans. Additionally, flexibility, discreetness, and biodegradability may increase acceptability of the implant. Such end-user feedback is being incorporated into current implant designs in the hope of creating an effective long-acting PrEP product that is likely to achieve high uptake and adherence in target populations.

Nanoparticle-releasing nanofiber composites for enhanced in vivo vaginal retention.

Current approaches for topical vaginal administration of nanoparticles result in poor retention and extensive leakage. To overcome these challenges, we developed a nanoparticle-releasing nanofiber delivery platform and evaluated its ability to improve nanoparticle retention in a murine model. We individually tailored two components of this drug delivery system for optimal interaction with mucus, designing (1) mucoadhesive fibers for better retention in the vaginal tract, and (2) PEGylated nanoparticles that diffuse quickly through mucus. We hypothesized that this novel dual-functioning (mucoadhesive/mucus-penetrating) composite material would provide enhanced retention of nanoparticles in the vaginal mucosa. Equivalent doses of fluorescent nanoparticles were vaginally administered to mice in either water (aqueous suspension) or fiber composites, and fluorescent content was quantified in cervicovaginal mucus and vaginal tissue at time points from 24 h to 7d. We also fabricated composite fibers containing etravirine-loaded nanoparticles and evaluated the pharmacokinetics over 7d. We found that our composite materials provided approximately 30-fold greater retention of nanoparticles in the reproductive tract at 24 h compared to aqueous suspensions. Compared to nanoparticles in aqueous suspension, the nanoparticles in fiber composites exhibited sustained and higher etravirine concentrations after 24 h and up to 7d, demonstrating the capabilities of this new delivery platform to sustain nanoparticle release out to 3d and drug retention out to one week after a single administration. This is the first report of nanoparticle-releasing fibers for vaginal drug delivery, as well as the first study of a single delivery system that combines two components uniquely engineered for complementary interactions with mucus.

Manufacturing scale-up of electrospun poly(vinyl alcohol) fibers containing tenofovir for vaginal drug delivery.

Electrospun fibers containing antiretroviral drugs have recently been investigated as a new dosage form for topical microbicides against HIV-1. However, little work has been done to evaluate the scalability of the fiber platform for pharmaceutical production of medical fabrics. Scalability and cost-effectiveness are essential criteria in developing fibers as a practical platform for use as a microbicide and for translation to clinical use. To address this critical gap in the development of fiber-based vaginal dosage forms, we assessed the scale-up potential of drug-eluting fibers delivering tenofovir (TFV), a nucleotide reverse transcriptase inhibitor and lead compound for topical HIV-1 chemoprophylaxis. Here we describe the process of free-surface electrospinning to scale up production of TFV fibers, and evaluate key attributes of the finished products such as fiber morphology, drug crystallinity, and drug loading and release kinetics. Poly(vinyl alcohol) (PVA) containing up to 60 wt% TFV was successfully electrospun into fibers using a nozzle-free production-scale electrospinning instrument. Actual TFV loading in fibers increased with increasing weight percent TFV in solution, and encapsulation efficiency was improved by maintaining TFV solubility and preventing drug sedimentation during batch processing. These results define important solution and processing parameters for scale-up production of TFV drug-eluting fibers by wire electrospinning, which may have significant implications for pharmaceutical manufacturing of fiber-based medical fabrics for clinical use.

Delivery of multipurpose prevention drug combinations from electrospun nanofibers using composite microarchitectures.

BACKGROUND: Electrospun drug-eluting fabrics have enormous potential for the delivery of physicochemically diverse drugs in combination by controlling the underlying material chemistry and fabric microarchitecture. However, the rationale for formulating drugs at high drug loading in the same or separate fibers is unknown but has important implications for product development and clinical applications. METHODS: Using a production-scale free-surface electrospinning instrument, we produced electrospun nanofibers with different microscale geometries for the co-delivery of tenofovir (TFV) and levonorgestrel (LNG) - two lead drug candidates for multipurpose prevention of HIV acquisition and unintended pregnancy. We investigated the in vitro drug release of TFV and LNG combinations from composites that deliver the two drugs from the same fiber (combined fibers) or from separate fibers in a stacked or interwoven architecture. For stacked composites, we also examined the role that fabric thickness has on drug-release kinetics. We also measured the cytotoxicity and antiviral activity of the drugs delivered alone and in combination. RESULTS: Herein, we report on the solution and processing parameters for the free-surface electrospinning of medical fabrics with controlled microarchitecture and high drug loading (up to 20 wt%). We observed that in vitro release of the highly water-soluble TFV, but not the water-insoluble LNG, was affected by composite microarchitecture, fabric thickness, and drug content. Finally, we showed that the drug-loaded nanofibers are noncytotoxic and that the antiviral activity of TFV is preserved through the electrospinning process and when combined with LNG. CONCLUSION: Electrospun fabrics with high drug loading create multicomponent systems that benefit from the independent control of the nanofibrous microarchitecture. Our findings are significant because they will inform the design and production of composite electrospun fabrics for the co-delivery of physicochemically diverse drugs that may be useful for multipurpose prevention.

Electrospun fibers for vaginal anti-HIV drug delivery.

Diversity of microbicide delivery systems is essential for future success in the prevention and treatment of HIV in order to account for the varied populations of women all over the world that may benefit from use of these products. Recently, a novel dosage form for intravaginal drug delivery has been developed using drug-eluting fibers fabricated by electrospinning. There is a strong rationale to support the idea that drug-eluting fibers can be designed to realize multiple design constraints in a single product for topical HIV prevention: fibers are able to deliver a wide range of agents, incorporate multiple agents via composites, and facilitate controlled release over relevant time frames for pericoital and sustained (coitally-independent) use. It is also technologically feasible to scale-up production of fiber-based microbicides. Electrospun fibers may allow for prioritization of physical attributes that affect user perceptions without compromising biological efficacy. Challenges with using fibers as a microbicide include issues related to vehicle deployment, spreading and retention in the vaginal vault. In addition, studies will need to address the interaction of the fibers with the mucosal environment, including unknown safety and toxicity. Sustained release fiber microbicides capable of delivering multiple antiretroviral drugs while simultaneously exhibiting tunable degradation or dissolution of the fibers is also a challenge. However, electrospun fibers are a promising new platform for vaginal delivery of anti-HIV agents and future research will inform their place in the field. This article is based on a presentation at the "Product Development Workshop 2013: HIV and Multipurpose Prevention Technologies", held in Arlington, Virginia on February 20-21, 2013. It forms part of a special supplement to Antiviral Research.