Long acting systemic HIV pre-exposure prophylaxis: an examination of the field
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Oral pre-exposure prophylaxis for the prevention of HIV-1 transmission (HIV PrEP) has been widely successful as demonstrated by a number of clinical trials. However, studies have also demonstrated the need for patients to tightly adhere to oral dosing regimens in order to maintain protective plasma and tissue concentrations. This is especially true for women, who experience less forgiveness from dose skipping than men in clinical trials of HIV PrEP. There is increasing interest in long-acting (LA), user-independent forms of HIV PrEP that could overcome this adherence challenge. These technologies have taken multiple forms including LA injectables and implantables. Phase III efficacy trials are ongoing for a LA injectable candidate for HIV PrEP. This review will focus on the design considerations for both LA injectable and implantable platforms for HIV PrEP. Additionally, we have summarized the existing LA technologies currently in clinical and pre-clinical studies for HIV PrEP as well as other technologies that have been applied to HIV PrEP and contraceptives. Our discussion will focus on the potential application of these technologies in low resource areas, and their use in global women’s health.
KeywordsHIV prevention Pre-exposure prophylaxis Antiretroviral Chemo prophylaxis Long acting
Despite international success in the prevention and treatment of HIV-1, infection rates have stagnated throughout the twenty-first century . Over the past 10 years, oral pre-exposure prophylaxis (PrEP) has been found to successfully reduce the sexual and parenteral transmission of HIV [2, 3, 4, 5]. Currently, there is only one approved HIV PrEP product, consisting of a fixed dose combination of two nucleoside analogue reverse transcriptase inhibitors (NRTIs), tenofovir-disoproxil fumarate 200 mg (TDF) and emtricitabine 300 mg (FTC), sold under the brand name Truvada® by Gilead Sciences as a once daily oral pill. When taken daily, Truvada® is highly effective at preventing the sexual transmission of HIV by more than 75% with regular use [2, 4] and upwards of 92% with perfect adherence . This highlights the major drawback of currently available HIV PrEP: the need for daily adherence to an oral pill regimen. Furthermore, oral PrEP has lower forgiveness for prevention of vaginal transmission, which requires use of at least 85% of expected doses (6 of 7 weekly doses) to maintain protective active pharmaceutical ingredient (API) concentrations in the lower female reproductive track. Whereas protective API concentrations in rectal tissues can be maintained with as little as 28% of expected doses (2 of 7 weekly doses) [7, 8]. Notably, two clinical trials of orally dosed HIV PrEP among female study populations that had very low estimated product use (less than 40% of participants) were unable to demonstrate effectiveness [5, 9]. To overcome this adherence challenge, there has been extensive research and development invested in the optimization of long-acting (LA), user-independent HIV PrEP formulations [10, 11, 12, 13, 14, 15, 16, 17, 18]. Feedback from end-users suggests that LA dosage forms are not only acceptable but also preferred over more frequent dosing regimens [19, 20, 21]. Healthcare providers also appear to have a preference for LA approaches (Lutnick et al., 2017, unpublished data).
In this review, we summarize LA HIV PrEP delivery systems (defined by a dosing interval of at least 30 days) that are systemic (excluding transient topical and local delivery technologies). We will also address technologies that have not been directly applied to HIV PrEP, but offer promising contributions to the future delivery pipeline. Our discussion will focus on the use of these technologies in vulnerable populations, low resource settings, and their application to global women’s health.
Injectables for LA HIV PrEP
The field of LA systemic HIV PrEP has been dominated by LA injectable formulations of highly potent antiretrovirals (ARVs) [10, 16, 22, 23]. To date, a number of phase I and II clinical trials have been carried out with a range of ARVs, with a phase IIb/III efficacy trial ongoing now for LA cabotegravir (hptn.org/research/studies/176, HPTN 083).
LA injectables span a wide range of formulations and processing strategies [24, 25]. In this review, we will primarily focus on wet nanomilling approaches that have been applied to the development of LA ARV depot injectables. Nanomilling describes the process of applying physical agitation and stresses to reduce the size of poorly soluble solid drug crystals as a means to improve their pharmacokinetic (PK) properties, aqueous solubility, and bioavailability [26, 27, 28, 29]. Nanomilling—generating particles on the order of 200 nm in diameter —uses coated metal ball bearings (often zirconium) to mechanically grind drug suspensions that include a stabilizing polymer or surfactant coating [30, 31]. The coating enables colloidal stability of the particles and prevents agglomeration of the nanosuspension by blocking hydrophobic collapse. This is accomplished either via steric hindrance or ionic repulsion. Common stabilizers include polyethylene glycol, cyclodextrin, and other polymers or surfactants [24, 25]. Nanomilling dramatically increases the surface area of a drug suspension. Increased surface area has a positive impact on dissolution by increasing the solvent-accessible drug . This increases the possible peak plasma concentration (Cmax), compared to more traditional injectable solutions [33, 34]. Because absorbance and dissolution time is delayed in the case of an intra-muscular (IM) nanosuspension injection, there is also an improved safety profile and a decrease in injection site reactions [35, 36]. It is important to note, however, that because the distribution of nanosuspensions is dissolution-limited, concentration-dependent kinetics of low solubility agents can be accompanied by long, sub-therapeutic PK tails [10, 25].
Injectable LA PrEP technologies in development
Number and volume of injections
2b (combination with LA CAB)
200-nm particle formulated with poloxamer 338 as a stabilizer
2 × 2 mL IM injections
200-nm particle with stabilizing surfactants and tonicity agents
2 × 2 mL IM injections
CAB is related to the INSTI dolutegravir but has been modified to increase serum protein binding, while reducing solubility and clearance, affording CAB an extended in vivo half-life compared to dolutegravir . CAB exhibits sub-nanomolar potency against various lab strains of HIV-1 (IC50 0.22 to 0.34 nM) and binds tightly to serum albumin leading to a target IC90 (PA-IC90) of 166 ng/mL . This high potency combined with low aqueous solubility (0.015 mg/mL) and low clearance (0.32 mL/min/kg) has identified CAB as a target for LA PrEP applications [16, 46]. This extended half-life has made it possible to formulate a once per 8-week intramuscular (IM) injection of 800 mg in 4 mL of CAB delivered bilaterally in the gluteus with two 2-mL injections . Bilateral dosing was shown to increase dissolution rate and Cmax after dosing . LA CAB is observed to persist for an extended period of time in serum, with a half-life of 25–54 days after an IM depot injection . Repeat dosing studies have also shown that CAB accumulates in plasma during monthly dosing, suggesting that bi-monthly dosing regimen would be the most effective at maintaining non-toxic serum concentrations . CAB is currently being explored as a monotherapy for HIV prevention, and in combination with RPV for chronic HIV treatment [22, 43].
RPV is a potent API, with an unbound IC50 of 0.26 nM in culture, leading to a serum PA-IC90 of 12 ng/mL [38, 39]. It is known to be potent against a range of HIV-1 isolates and has been found to be generally tolerable to patients during repeat dosing [47, 48]. The nanosuspension was formulated with a Poloxamer 338 (Pluronics F108) stabilizing surfactant and ground using 500-μm zirconium beads in a continuous wet milling process to a particle size on the order of 200 nm, then formulated in water along with tonicity agents at a concentration of 600 mg/mL [39, 49, 50]. LA RPV has been dosed either at 600 mg as a single IM injection, or at 1200 mg in two bilateral injections in the gluteus . Phase Ia human studies of LA RPV have found that RPV poorly distributes to vaginal and cervical tissues as measured by poor correlation between blood plasma concentrations and tissue drug concentrations . Additionally, RPV only modesty distributes to rectal tissue at high IM dosages (1200 mg) . Measurements of viral inhibition using homogenized vaginal and cervical tissue explants show little to no efficacy 40 days after a single 600- or 1200-mg dose, with mild suppression in rectal tissue . However, dose proportionality studies using beagle dog models of PK distribution suggest that RPV accumulates in lymphoid tissues, potentially due to macrophage engulfment . These findings suggest that RPV may be limited in its utility as a PrEP agent because of its limited presence in virus-exposed tissues. However, LA RPV is potentially promising as a LA treatment option because of its accumulation in lymphatic tissues which are thought to be viral reservoirs.
In the case of an adverse reaction to an LA injectable API, removal, or dialysis, the API from whole blood is not possible, necessitating a 14-day lead in oral dose to asses individual safety for LA CAB and RPV [17, 22, 40]. Additionally, both LA formulations take on the order of a week to achieve therapeutic plasma concentrations. Therefore, oral lead in dosing might be required to cover this sub-therapeutic window. Clinical research with LA CAB has also required a lead out oral Truvada® regimen to cover the sub-therapeutic PK tail of CAB for up to a year after the end of the LA regimen to reduce the risk of break through resistance in volunteers . These additional oral dosing requirements increase the complexity of the dosing regimen and could interfere with appropriate compliance. Most study participants (70%–100%) experienced some form of injection site discomfort or pain. Severe discomfort, which may disincentivize users, was rare .
In addition to small molecule therapeutics, there has been increasing interest in the use of broadly neutralizing anti-HIV antibodies (e.g., VRC01) as a prophylactic [51, 52, 53, 54, 55]. Antibodies have the advantage of being both highly potent and naturally long lasting with serum half-lives on the order of a month. In studies using non-human primates, a single infusion of VRC01 was protective against high dose rectal challenge for up to 2 weeks [51, 52]. In vitro studies of tissue explants have suggested that various antibodies might be effective at preventing mucosal transmission of HIV . Current ongoing studies such as the AMP trials (HPTN 085 and HVTN 704) will provide more information on the clinical effectiveness of antibody-based prophylaxis (clinicaltrials.gov #NCT02716675). There are also ongoing antibody engineering studies focused on extending the half-lives of broadly neutralizing antibodies. By modifying the Ig constant region, researchers increased binding affinity to FcRn receptors by an order of magnitude and were able to extend the serum half-lives of IgGs by 4-fold out to 3 months without a detectable decrease in antigen-binding potency [57, 58]. This extended half-life in combination with efforts to formulate high concentration (100 mg/mL) antibody reagents makes antibody-based PrEP injections a potentially feasible approach .
Implantable delivery technologies for LA HIV PrEP
The range of implantable drug delivery technologies, targeting a variety of indications, is vast and has been reviewed extensively elsewhere [60, 61, 62, 63, 64, 65, 66]. Compared to LA injectables, LA ARV releasing implants have four main advantages: the capacity to (1) enable release profiles that can exceed 12 months in duration [67, 68, 69]; (2) enable extended zero-order release, and “flat” serum-drug concentration profiles with limited sub-therapeutic tailing; (3) be fully removed and “reverse” treatment; and (4) deliver highly soluble ARV agents [64, 70, 71]. Similar to LA injectables, LA implantable systems benefit from highly potent APIs, as well as APIs that accumulate in tissues of interest. This allows for low API mass payloads to effectively cover the intended device life span, which is critical for devices with constrained geometries . Additionally, it is important to consider the solubility, formulation, and shelf stability of APIs for implantable systems [72, 73]. Implantable drug depots, like the etonogestrel Nexplanon® rod, that utilize outpatient implantation procedures necessitate local anesthetic as well as wound closing measures [74, 75]. Feedback from regulatory agencies has suggested that devices should maintain protective release profiles for more than 6 months per procedure . In the context of implantable devices for LA PrEP and broadly in the field of controlled release implants, it is necessary to consider the implications of the foreign body response and fibrotic encapsulation, which has recently been reviewed extensively and will not be addressed in depth here [76, 77, 78].
Implantable LA PrEP technologies in development
In vivo release rate (mg/day)
Device lifetime (days)
Silicone and PVA
40 mm × 1.9 mm
2:1 TAF:PEG 300
40 mm × 2.5 mm
While there are numerous polymer systems for rate-limiting membranes and matrix-type devices , a smaller subset has been used in the context of HIV PrEP. It is necessary to consider the polymer along with the API, as their interaction will ultimately govern the diffusion through and partitioning of drug into the membrane . Hydrophilic drugs tend to pass quickly through hydrophobic layers without partitioning into the polymer matrix in order to reduce energetically unfavorable interactions, whereas interactions between the API and the membrane will slow release . Of the more conventional membrane materials, there are polyesters such as polycaprolactone (PCL) , polyurethanes (PURs) , polyvinyl alcohol (PVA) [95, 96], poly(ethylene-co-vinyl acetate) (EVAc) , and silicone [98, 99]. Specifically, researchers have looked at PVA and PCL in the context of HIV PrEP.
PVA is a non-degradable hydrophilic polymer that can be formed into membranes by heat annealing the polymer into a solid form that possess increased crystallinity and remains intact under aqueous conditions [95, 100, 101]. PCL is a relatively hydrophobic “soft” polyester that is bioresorbable via hydrolysis [81, 102, 103]. The degradation properties of PCL are tunable depending on the starting molecular weight of polymers used, on a scale of months to years, from implantation to total dissolution [102, 104]. PCL has notably been used in the development of implantable contraceptive technologies [87, 105].
It is also important to consider other polymers and LA device systems for applications in HIV PrEP. PURs have tunable hydrophilicity and degradation properties and have been applied extensively in the area of membrane-based implantable drug delivery devices [94, 109, 110]. Notably, PURs have been used in the development of reservoir devices for the long-term delivery of the peptide steroid agonist histrelin in the treatment of advanced prostate cancer (Vantas) and central precocious puberty (Supprelin LA) [67, 111, 112, 113]. Non-degradable polymers such as ethylene-vinyl acetate (EVAcs) have been applied extensively in the most modern iteration of implantable contraceptive devices including the Nexplanon® system. EVAc has many desirable qualities as a controlled release medium but can be difficult to source at a medical grade [69, 97, 114].
There is also interest in long-term, refillable silicon nanochannel devices [85, 115, 116]. These devices are constructed from rationally designed silicone nanoslits, with a width corresponding to the hydrodynamic diameter of the intended deliverable, which can be tuned to enable single file diffusion through the slits. By altering the channel lengths and channel density, it is possible to tune the release of APIs from these devices . These devices have seen extensive studies in animal models and have been shown to rapidly establish zero-order release regimes that persist for upwards of 70 days with multiple APIs . Investigators are also exploring methods to make the devices refillable, potentially enabling life-long PrEP administration from a single implant.
Intarcia Therapeutics, in conjunction with the Bill and Melinda Gates Foundation, is developing an osmotic pump-based implant for long-term HIV PrEP delivery. Recently, their DUROS® device has completed a phase III clinical trial for the delivery of exenatide for the treatment of type 2 diabetes as a 9-month subcutaneous implant . The DUROS® device can achieve zero-order release of a range of APIs and can be designed to last for 6–12 months .
CONRAD, in collaboration with Dr. Patrick Kiser (Northwestern University), is developing a combination contraceptive-PrEP intrauterine system (IUS) for sustained (1+ year) use. A first-generation product in preclinical stages of development combines the INSTI elvitegravir (EVG) with copper as a non-hormonal contraceptive. The design of the device builds on that of existing T-shaped contraceptive IUS (e.g., Mirena, Paraguard). To date, this EVG-eluting IUS has demonstrated preclinical proof of concept that an ARV administered via the intrauterine route can be distributed throughout the female reproductive tract in animal models at levels expected to be prophylactic (Clark et al. 2016 , poster P07.40, HIV R4P, Chicago, IL). Simian immune deficiency virus (SIV) challenge studies in the pig tailed macaque are planned to initiate in early 2017.
Acceptability, end-users, and cost considerations
HIV prevention products require users’ active engagement in preventive health behaviors. Hence, product acceptability is necessary for correct and consistent use of prevention technologies. The Scientific Agenda Working Group of the Initiative for Multipurpose Prevention Technologies conducted a pipeline evaluation exercise, which led to the recommendation of developing a suite of product types to accommodate the diverse needs and preference of women, including sustained release topical devices such as vaginal rings, systemic long-acting injectable products, and on-demand formulations .
Overall, attitudes toward hypothetical LA injectable PrEP products are favorable in diverse populations and across geographical locations, including among men who have sex with men (MSM), injection drug users, sex workers, serodiscordant couples, young and adult women ([21, 121, 122] Quaife et al., 2016, HIV R4P, Chicago, IL). In two exploratory studies, when presented with a variety of possible PrEP formulations, a majority of African women participating in prevention trials expressed interest in methods such as injectables, implants, and rings (, van der Straten AIDS conference poster 2016 abstract 1742). The main positive attributes of these methods included being long-acting, discreet, and easy-to-use. A study conducted by Ipsos Healthcare assessing the potential for MPTs in Uganda, South Africa, and Nigeria also found that injectables and implants had high resonance with women . In end-user feedback surveys, both men and women have shown a willingness to undergo mild to moderate discomfort to achieve LA prevention of unintended pregnancy or HIV given long dosing intervals [19, 123].
Beyond hypothetical preference, researchers have examined users’ sensory perceptions and actual experiences to inform product development and improve usability and desirability of new technologies delivering ARVs [124, 125]. In South Africa and Kenya, over 60% of women who ranked three placebo delivery forms (oral tablets, vaginal rings, or IM injections), most preferred the injections, both before and after using all three placebo products. A majority of participants also selected the injections for a continued use period (van der Straten CROI meting poster 2017 abstract 936). Furthermore, men participating in the Phase II ÉCLAIR study of LA cabotegravir as PrEP found it to be an appealing alternative to oral PrEP (Kerrigan et al. AIDS 2016 poster, Durban South Africa) with 87% of participants willing to recommend the LA injection and 79% reporting a willingness to continue with study medication (Murray et al. Abstract 471 CROI 2017, Seattle WA; Bekker et al. Abstract 421LB CROI 2017, Seattle WA).
Despite these reported preferences and positive attitudes, LA PrEP formulations will not solve all end-user challenges. In the contraception literature, high rate of non-persistence are reported after initial injectable contraception use [126, 127]. Despite the growing popularity of contraceptive implants, due to high effectiveness and longer duration, insertion and removal procedures require a clinic setting and specially trained staff [128, 129]. Cost is thus an important consideration, particularly in the context of HIV PrEP. When applying a cost-effectiveness model of preventing AIDS in South Africa, monthly costs of LA-PrEP and laboratory visits were cost saving when compared to no PrEP, but more costly than oral . The implementation of LA PrEP may require more frequent access to a clinic, rather than a pharmacy, which may be unattractive to some potential end-users. Multiple groups have estimated that in sub-Saharan Africa, the annual cost for a single annual regimen of Truvada® is on the order of $100 USD, and on the order of $400–$600 USD when the cost of clinical visits are included [131, 132, 133]. This comes out to a cost of about $0.27 USD per day to cover the cost of pharmaceuticals. For LA PrEP systems to be competitive and usable in this space, they must have a similar cost of goods profile. It is conceivable that LA PrEP formulations will have a greater material cost than oral PrEP, but will reduce costs long term due to reduced dosing frequency and improved patient adherence to treatment leading to a reduction in seroconversions, as well as a reduction in API related toxicity [72, 134, 135]. Studies have looked specifically at the costs associated with implementing LA PrEP on a country-wide basis in South Africa. Researchers found, through a comprehensive modeling approach, that oral PrEP and LA PrEP are both cost saving in the long term compared to no PrEP. When estimating the efficacy of LA PrEP at 75%, researchers showed comparable per-person lifetime costs to oral PrEP ($5300 and $5270 in 2014 USD, respectively) . The authors and others note that when expanding this analysis to women over the age of 25, and when incorporating vertical transmission to infants, the cost per prevented infection increasingly favors LA PrEP over oral PrEP [130, 136].
Summary and future prospects
LA HIV PrEP should ultimately simplify HIV prevention methods, and thereby increase user adherence (specifically, quality of execution and persistence) [137, 138]. There is substantial precedent in the contraceptive space for the movement toward LA HIV prevention strategies, including 2–3-month LA injectables like Depo-Provera and Net-En, and 3–5-year LA implantables such as the Nexplanon® rod or the Jadelle 2-rod system. These products have dramatically expanded access to contraceptives for women globally by improving ease of use and coverage . Current products in clinical trials for LA HIV PrEP (e.g., LA CAB) promise a reduced dose burden, from daily oral pills to bi-monthly injections, which would dramatically reduce potential user treatment error . However, the need for lead in and lead out dosing concurrent with current injectable formulations might make them cumbersome in practice. Implantable products, currently in preclinical trials, could further reduce this dosing interval to once every 6 months or longer. There are important regulatory challenges associated with developing a LA injectable or prophylactic implant that, while not covered in depth here, must also be considered carefully in the future development of these systems [140, 141].
There are still substantial challenges to be overcome for LA HIV PrEP, including demonstrating efficacy in human trials. However, in order to increase the prevention options available to vulnerable populations, embracing LA systematic HIV PrEP technologies is necessary, and a clinical breakthrough is likely in the near future.
The authors would like to acknowledge Zach Demkovich for his help with literature reviews, and reviews of the draft manuscript. We would also like to acknowledge Meredith Clark, Gustavo Doncel, and Marc Baum for the use of figures and information. This research is made possible by the generous support of the American people through the US President’s Emergency Plan for AIDS Relief. The contents are the responsibility of the authors and do not necessarily reflect the views of USAID, PEPFAR, or the US Government. The TFPD program is also sponsored by the Bill and Melinda Gates Foundation. WL is funded by the NSF GRFP.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
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