Subdermal implants for HIV prevention with increased dapivirine release rates

Abstract

Dapivirine (DPV) is an antiretroviral drug used for prevention of sexually acquired HIV infection in the form of a monthly matrix-type silicone elastomer vaginal ring. As part of efforts to develop longer acting antiretroviral products for HIV pre-exposure prophylaxis (PrEP), we previously reported reservoir-type DPV-releasing silicone elastomer subdermal implants. These early prototypes were constrained by relatively low DPV daily release rates (7–14 µg/day), which are likely too low to prevent sexual transmission of HIV.

Here, we report in vitro formulation development of next-generation implant formulations as part of efforts to increase DPV release rates. Three strategies were evaluated—(i) reservoir-type implants fabricated from medical-grade silicone tubing comprising a core containing DPV solubilised in a liquid polyethoxylated castor oil (Kolliphor® EL), (ii) dip-coated reservoir rods, comprising a matrix-type silicone core and a relatively thin (∼0.33–0.66 mm) drug-free, silicone elastomer, rate-controlling membrane applied by dip coating, and (iii) simple matrix-type silicone elastomer rods. Replacing the conventional silicone elastomer core of the implants with Kolliphor® EL increased DPV solubility and enhanced steady-state flux ∼1.5-fold. Dip-coated implants provided mean daily release rates of 19–41 µg/day. Matrix-type implants lacking a rate-controlling membrane delivered up to 185 µg/day.

While these release rates represent a substantial improvement over first-generation devices, it remains uncertain whether they would produce systemic concentrations sufficient for HIV prevention, given dapivirine’s relatively low potency and the absence of a local delivery advantage with subdermal administration. Nonetheless, the findings are useful in demonstrating the feasibility of designing silicone-based implants, illustrating how core composition, membrane geometry, and release conditions influence DPV release from silicone subdermal implants, and providing a basis for future in vivo pharmacokinetic and preclinical evaluation.

Introduction

Despite the decline in global incidence of new HIV infections in the past decade, some worrying trends are emerging. The 2024 estimate of 1.3 million new HIV infections worldwide reflects a 40% reduction since 2010 and deaths from AIDS‑related illnesses continue to decline, mostly due to increased access to antiretroviral treatments. However, there is considerable regional variation. New infections fell substantially between 2010 and 2024 in sub-Saharan Africa, but infections increased 94% in the Middle East & North Africa, 13% in Latin America, and 7% in Eastern Europe & Central Asia (UNAIDS, 2025). Further, 105,922 HIV diagnoses were reported in 49 European countries in 2024, a slight drop compared to 2023 (WHO, 2025). However, 11 out of 49 countries still reported a year-on-year increase in HIV diagnoses. Despite substantial reductions in both new HIV infections and AIDS‑related deaths since 2010 (40% fewer new infections and 55% fewer deaths), the most recent data show that we have a long way to go if we are to achieve the goals set by Sustainable Development Goal (SDG) target 3.3 on ending AIDS as a public health threat by 2030 (i.e., reducing new HIV infections by 90% from 2010, a continued 5% decline per year after 2030, and reducing AIDS-related deaths by 90% from 2010). Based on the current trajectory and in the absence of renewed efforts to accelerate prevention, testing, and treatment—especially among high-risk and underserved populations—the 2030 goals will not be met.

Despite this somewhat gloomy backdrop, there have been major advances in HIV pre-exposure prophylaxis (PrEP) in recent years. Daily oral regimens comprising tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) have been supplemented by tenofovir alafenamide/emtricitabine (TAF/FTC), offering comparable efficacy with improved renal and bone safety profiles. Long-acting injectable products have also been developed (Delany-Moretlwe et al., 2022, Flexner, 2018, Landovitz et al., 2018, Margolis et al., 2017, Spreen et al., 2013, Spreen et al., 2014, Weld and Flexner, 2020, Delany-Moretlwe et al., 2023). Approved in 2021, long-acting injectable cabotegravir administered bi-monthly shows superior efficacy to daily oral TDF/FTC in high-risk populations (Landovitz et al., 2023, Landovitz et al., 2021). In June 2025, the FDA approved a lenacapavir six-monthly injectable which greatly reduces the burden of frequent dosing and improves adherence compared with daily oral or bi-monthly injection. The one-month dapivirine vaginal ring—approved in 2020 and currently being rolled out across Africa and Asia—further expands prevention options for women in high-incidence settings (Baeten et al., 2016, Devlin et al., 2013, Nel et al., 2016). The success of these newer HIV PrEP products highlights the advantages of longer-acting drug therapies, including reduced dosing frequency, improved adherence, more discreet use, consistent drug levels (leading to potential reduction in HIV resistance), improved convenience and satisfaction for users, and potential for co-formulating with injectable contraceptive progestins (Haeck et al., 2023).

Only a very small number of currently marketed pharmaceutical products can maintain drug release at therapeutic levels over one year or longer. These include subdermal contraceptive implants Jadelle®, Nexplanon®, and Levoplant® (Bahamondes et al., 2025); the Supprelin LA® implant releasing histrelin acetate for 12 months for treatment of central precocious puberty in children (Silverman et al., 2015); steroid-releasing ocular implants Retisert® and Iluvien® (Abdulla et al., 2022); levonorgestrel-releasing intrauterine systems (IUS) such as Mirena® and Skyla® (Grandi et al., 2018); and the Annovera® contraceptive vaginal ring (Micks and Jensen, 2020). It is notable that the active drug in all but one of these devices is a highly potent steroid molecule with daily release rates typically lower than 100 μg/day. A one-year or longer antiretroviral delivery device would represent a major advance for HIV prevention or treatment, and indeed several experimental devices have been reported in the scientific literature (Pons-Faudoa et al., 2023, Weld and Flexner, 2020). The challenge with most antiretroviral drugs is that their potency is often some 1000-fold lower compared with that of the steroid molecules released from marketed ultra-long-acting drug delivery devices. Doses for oral antiretrovirals are typically in the 25–800 mg/day range, compared to the 20–500 µg/day doses required for estrogens/progestins for oral contraception. For example, initial levonorgestrel release for the Mirena® IUS is 20 µg/day and after 5 years release decreases to 10 µg/day (Grandi et al., 2018). Consequently, relatively large antiretroviral loadings are needed to meet daily dosing requirements and these cannot easily be achieved given constraints around the sizes of long-acting implant devices. Ultra-long-acting local administration of an antiretroviral drug—such as dapivirine or a more potent antiretroviral—at the site of sexual acquisition of HIV using a relatively large vaginal ring device (typically 2–8 g) is at least plausible and likely feasible. However, the challenges escalate very significantly when administering the same antiretroviral drug remotely and systemically via a subdermal implant device (typically 100–600 mg).

Although the field of ultra‑long‑acting (≥12 months) antiretroviral-releasing subdermal implants for HIV PrEP has advanced rapidly and represents the “next frontier” (Torres and Hoagland, 2025), none have reached regulatory approval and they lag long‑acting injectables in clinical development. The primary motivation for implantable PrEP is to overcome adherence limitations associated with daily oral therapies and periodic injections. Several studies have reported implants releasing tenofovir and its derivatives (Gengiah et al., 2025, Gunawardana et al., 2015, Gunawardana et al., 2023, Gunawardana et al., 2022, Gengiah et al., 2022). Karunakaran et al. described a reservoir-type subcutaneous implant offering release of cabotegravir over several months (Karunakaran et al., 2021); the 47 × 3.6 mm implants, comprising four compressed cabotegravir pellets sealed in hydrophilic poly(ether-urethane) tubing of thickness 200 μm, released ∼300 μg/day cabotegravir in rhesus macaques. Subdermal implant devices have also been reported for release of islatravir (a nucleoside reverse transcriptase translocation inhibitor; NRTTI), including a phase I safety/pharmacokinetic study of a Nexplanon®-like device and a preclinical study in macaques testing a refillable nanofluidic implant (Matthews et al., 2023, Matthews et al., 2021, Pons-Faudoa et al., 2023).

As part of efforts to develop ultra-long-acting products for HIV PrEP, we recently reported reservoir-type DPV-releasing silicone elastomer subdermal implants (Wang et al., 2026). While these first-generation implants provided proof-of-concept that DPV (or an alternative antiretroviral drug) could be released in a controlled manner over at least one year, they were constrained by their very low daily DPV release rates (7–14 µg/day) which fell significantly below quantities estimated to prevent sexual transmission of HIV. Here, three further subdermal implant formulation strategies have been evaluated as part of efforts to increase DPV release rates—(i) reservoir-type implants fabricated from medical-grade silicone tubing and containing DPV solubilised in a liquid Kolliphor® EL core, (ii) matrix-type silicone rods having a thin drug-free silicone elastomer membrane applied by dip coating, and (iii) simple matrix-type silicone rods. The aim was to determine how core composition, membrane thickness, and release conditions affect in vitro DPV release, and to provide a basis for future formulation development and preclinical evaluation.

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Materials

Micronized DPV was supplied by the International Partnership for Microbicides (now Population Council, New York; synthesized by S.A. Ajinomoto OmniChem N.V., Wetteren, Belgium). Custom medical-grade addition-cure silicone elastomers (DDU-4320) were supplied by NuSil Silicone Technology Inc. (Carpinteria, CA, USA). Translucent platinum-cured silicone elastomer tubing (1.6 mm luminal diameter, 3.2 mm external diameter; 60 Shore Hardness A) was purchased from Silex Limited (Hampshire, UK). Polyvinyl chloride (PVC) tubing (3.0 mm luminal diameter, 6.0 mm external diameter) was purchased from RS Components (Corby, UK). Kolliphor® EL (polyethoxylated castor oil) was obtained from BASF (Ludwigshafen, Germany). Tween® 80, HPLC-grade acetone, acetonitrile, and phosphoric acid (85% w/w in water) were purchased from Sigma Aldrich (Gillingham, UK). Analytical-grade potassium dihydrogen orthophosphate was purchased from VWR (Dublin, Ireland). HPLC-grade water was obtained using a Millipore Direct-Q 3 UV Ultrapure Water System (Watford, UK).

Siqi Wang, Rand Z. Murtadha, R. Karl Malcolm, Subdermal implants for HIV prevention with increased dapivirine release rates, International Journal of Pharmaceutics, Volume 701, 2026, 127118, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2026.127118.