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

Abstract

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.

Keywords: Adherence; HIV prevention; antiretroviral; drug delivery system; implants; injectable; long-acting; microbicide; nanoformulations; prodrug.

Figure 1.

Schematic representation of prodrug technologies for generating long-acting (LA) antiretrovirals (ARVs). (a) ProTide prodrug concept; (b) Fatty acid ester prodrug conjugates; (c) Drugamer-based prodrug approach for TAF (Reproduced with permission from [76]).

Figure 2.

Long-acting (LA) subdermal/subcutaneous implants in clinical development. (a) Merck EFdA implant (Reproduced with permission from [35]); (b) RTI thin film TAF implant (Reproduced with permission from [85] under the terms and conditions of the Creative Commons Attribution (CC BY) license http://creativecommons.org/licenses/by/4.0/); (c) Oak Crest TAF subdermal implant (Reproduced with permission from [95]) (Three-dimensional model (A) and cross-sectional drawings (B and C) of TAF implant. The TAF core (black) inside the silicone scaffold with PVA membrane coating is shown (not to scale). Cross sections were sliced through the y-z (B) and x-y planes (C). (d) HMRI nanofluidic refillable CAB implant (Reproduced with permission from [98]) ((A) Rendered image of cross-section of polyether ether ketone (PEEK) (left) and titanium (right) drug reservoirs. (B) Assembled PEEK βCAB (left) and titanium CAB (middle) drug reservoirs and 13 nm nanofluidic membrane (right). (C) SEM image of nanochannel membrane cross-section displaying drug release through perpendicular microchannels and horizontal nanochannels r, reservoir, e, epoxy, m, nanochannel membrane, s, implant shell); (e) HMRI nanofluidic refillable TAF/FTC implant (Reproduced with permission from [93]) ((G) Cross-sectional rendering of nanochannel delivery implant depicting drug refill needles through the loading ports with resealable silicone plugs. (H) Nanochannel membranes of two different sizes, square (TAF) and rectangle (FTC); top and bottom view of nanochannel delivery implant in medical-grade titanium for TAF (with silicone plug) and FTC (before affixing silicone plug); (f) Northwestern CAB PU reservoir implant (Reproduced with permission from [99]); (g) CONRAD subdermal biodegradable CAB pellet implant system (Reproduced with permission from [100] under the terms and conditions of the Creative Commons Attribution (CC BY) license http://creativecommons.org/licenses/by/4.0/).

Figure 3.

(a) Design and mechanism of release of an ISFIs (Reproduced with permission from [9]); (b) The design of the gastric resident dosage forms consisting of an elastomeric core (grey) and six rigid arms loaded with a drug polymer matrix (multi-colored) (Reproduced with permission from [122]); (c) Schematics of intradermal administration of TAF using dissolving and implantable microarray patch (MAP) (Reproduced with permission from [131]). All the figures are reproduced under the terms and conditions of the Creative Commons Attribution (CC BY) license http://creativecommons.org/licenses/by/4.0/).

Figure 4.

Technical challenges, design considerations, and knowledge gaps in the development of long-acting (LA) HIV products.