02/11/2018
Implants for Delivery of Antiretroviral Drugs for HIV Pre-Exposure Prophylaxis
Strategies to reduce new HIV infections span multifaceted efforts, including safe-s*x counseling, voluntarcumcision, treatment as prevention, and pre- (PrEP) and postexposure prophylaxis. PrEP entails the use of antiretroviral (ARV) drugs prophylactically by HIV-negative individuals at risk of infection to thwart acquisition of the virus.
In 2012, the US Food and Drug Administration (FDA) approved Truvada, a daily oral pill for PrEP comprising 2 reverse transcriptase inhibitors, tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC). This landmark approval was followed by approval from several other countries in North America and South America, Europe, and Africa. Support for oral PrEP emerged through pivotal randomized controlled trials investigating Truvada in men who have s*x with men (MSM),1-3 serodiscordant heteros*xual couples in Kenya and Uganda,4 heteros*xual men and women in Botswana,5 and users of injection drugs in Thailand.6 The 2015 guidelines from the World Health Organization recommend oral PrEP for all populations at significant risk of HIV infection.7
ONE APPROACH DOESN’T FIT ALL
Clinical findings for oral PrEP in healthy participants demonstrated efficacy but also illuminated the importance of user adherence for protection. For example, the first randomized controlled trial for PrEP (iPrEx, daily oral TDF and FTC in MSM) showed a 44% reduction in HIV acquisition but protection as high as 92% in the subset of individuals with detectable levels of tenofovir in the plasma.8 Importantly, oral PrEP is particularly unforgiving for women, with over 5 doses per week required to confer protection from vaginal exposure. As the FEM-PrEP9 and the VOICE10 clinical trials underscored, inconsistent use (or low adherence)11,12 of daily oral and vaginal ARV-based prevention products among the participating women resulted in no protection against HIV. Research about product preference in hypothetical settings or with actual products has shown that no single product is appealing across different groups of women and that a diversification of drug delivery forms is needed to optimize prevention coverage.13-15 Because PrEP is an elective tactic for HIV prevention, the ability of an individual to select a product that suits his or her lifestyle from an array of options may enhance the likelihood of adherence.
Efforts to develop alternative PrEP delivery systems have leveraged existing technologies, particularly with the plethora of products available for contraception. Strategies for PrEP include approved oral pills and topical delivery forms, such as vaginal rings, that are currently in the regulatory approval process.16 Long-acting injectables, comprising the nanosuspension formulation of cabotegravir that requires dosing every 2 months, are in phase 3 clinical trials for HIV-uninfected women, MSM, and transgender women.17,18 Implants for HIV PrEP are in preclinical and early clinical studies, with a first-in-human trial planned to evaluate a subdermal implant containing tenofovir alafenamide (TAF) in South African women.19
THE PREP IMPLANT: GENERAL FEATURES
Long-acting implants for PrEP are currently under development and mimic many aspects of contraceptive implants currently on the market (eg, Nexplanon and Jadelle). The PrEP implants are designed for placement under the skin, where the device resides and releases the ARV drug at a controlled rate over time. A subdermal implant can assist individuals seeking discretion when stigmatized for accessing oral PrEP or when unable to negotiate safe s*x—a challenge of particular salience to young women and girls in high-incidence regions.20 Similar to long-acting injectable nanosuspensions, the long-acting delivery of ARV drugs from an implant supports user independence by eliminating the need for adherence to regimens of daily pills or on-demand products. However, unlike long-acting injectables, implants are retrievable throughout the duration of drug delivery, a critical feature in cases of adverse reaction or desire for discontinuation. Additionally, implants offer an improved, sustained pharmacokinetic profile compared with pills. Subdermal delivery of an HIV PrEP implant will likely use a trocar approach similar to that of contraceptive implants, which may require local capacity building and training for providers to support product implementation.
Ref: JUN 20, 2018 | LEAH M. JOHNSON, PHD, AND ARIANE VAN DER STRATEN, PHD, MPH
