Vivek Agrahari*, M. Melissa Peet, Meredith R. Clark, Gustavo F. Doncel, CONRAD, Eastern Virginia Medical School, Macon & Joan Brock Virginia Health Sciences at Old Dominion University’, Norfolk, VA 23507, USA
Today, women have multiple options to plan pregnancy, but unfortunately the same is not true for the prevention of human immunodeficiency virus (HIV), a virus that infects more than a million people per year, disproportionately affects women in lower- and middle-income countries (LMICs), and still has no cure [1]. UNAIDS reported in 2023 that 53% of people living with HIV globally were women and girls [1]. The first contraceptive pill for women was approved by the US FDA in 1960 [2], and since then, contraceptive options have multiplied and expanded to include patches, intravaginal rings (IVR), topical vaginal products (e.g., gels, creams, films), injectables and implants, intrauterine devices, female condoms, diaphragms, tubal ligation, and emergency contraceptive pills [3]. For HIV prevention for women, the first pharmaceutical option in the form of a daily oral pill was approved in 2012; however, only recently have new methods been proven effective. Today, in theory, women have three pharmaceutical options for the prevention of HIV: daily oral Truvada® (emtricitabine [FTC]/tenofovir disoproxil fumarate [TDF]) [4, 5], a monthly dapivirine (DPV) IVR (only approved in some African countries) [6, 7], and a long-acting 2-month duration cabotegravir (CAB) injection, APRETUDE® [8, 9]. In reality, however, limiting these options are factors related to in-country regulatory approval, access, cost and availability [10, 11]. Oral pills are highly effective but only if used with high adherence to proper dosage and timing [12, 13]. Regularly taking daily oral pills to prevent HIV for a long period is burdensome, stigmatizing, and, in certain populations, difficult to properly adhere to for more than a few months. The injectable APRETUDE® became the first US FDA approved product for HIV prevention that addressed the issues of poor adherence associated with oral pills; however, it requires a typically painful 3 ml intramuscular injection every 2 months. Currently, there is significant interest in developing products that are longer acting, require less frequent and painful injections, and are more convenient to the user. Furthermore, there is also a desire for on-demand, event-driven options that reduce the number of doses that need to be taken, decreasing cost and side effects. With 1.3 million people infected with HIV in 2023, and women and girls accounting for 62% of new infections in sub-Saharan Africa [1], there is a critical need to develop more HIV prevention options, especially for women, that, in addition to being safe and effective, are acceptable, affordable, and deliverable in LMICs.
Fortunately, the pipeline of new HIV prevention methods under development (Table 1 and Figure 1) is highly promising. Herein, we provide examples of products that are under development, including those close to regulatory approval or using novel delivery technologies. Products have been placed into three categories based on the duration of protection. On-demand products are those that are administered around the time of sex; short-acting products are defined as those lasting less than a month or so; and long-acting products represent those that provide protection for more than one month. Furthermore, some of these HIV prevention products are combined with agents displaying contraceptive activity or antimicrobial activity against other sexually transmitted pathogens. These products are defined as multipurpose prevention technologies (MPTs) [14].
There are several on-demand and short-acting products currently under development with different modes of delivery. For topical application, vaginal films and fast-dissolving inserts can be applied vaginally and/or rectally. Using DPV, the same drug used in the DPV IVR and approved for use in several African countries, a monthly vaginal film is under development by the University of Pittsburgh and Magee-Womens Research Institute (MWRI) [15]. It is currently being assessed in a Phase I clinical trial for safety and acceptability in women as a placebo (no active drug) film. CONRAD’s dual-compartment (vaginal and rectal use) insert containing two antiretrovirals (ARVs), tenofovir alafenamide (TAF) and elvitegravir (EVG), is currently the most clinically advanced on-demand topical product for flexible administration before or after sex [16]. Two clinical trials have already been completed, assessing vaginal [17] or rectal applications [18], with two additional clinical trials ongoing to assess the safety and pharmacokinetics of repeated applications via the vaginal (MATRIX-001, NCT06087913) or rectal (RITE PrEP, NCT06274398) routes. Within the systemic category, a monthly oral pill based on the potent nucleoside reverse transcriptase translocation inhibitor, MK-8527, is currently in early clinical development by Merck [19]. Notably, a method available only for men, but not yet for women, is an on-demand oral regimen using Truvada® 2-1-1 dosing strategy with pills taken before and after sex [20].
Long-acting products are another area targeted for development. Injectables represent a large portion of products under this category and come in different forms such as nanosuspensions, in-situ forming implant (ISFI), and shear-thinning hydrogel depots that become semisolid or solid when injected into the body from where they release the drug, typically a potent ARV, enabling HIV protection for 2 months or longer. In addition to the approved 2-month APRETUDE® (cabotegravir, CAB), the most clinically advanced products are the 6-month subcutaneous (SC) injection of lenacapavir (LEN, from Gilead Sciences) and the 4-month CAB intramuscular (IM) nanosuspension from ViiV Healthcare. The US FDA has already approved injectable LEN for the treatment of HIV-1 infection [21] and recently released findings from the PURPOSE 1 and 2 Phase III clinical trials have provided compelling data demonstrating its effectiveness in preventing HIV when used twice yearly [22, 23]. An additional formulation of CAB (400 mg/ml concentration) is also being clinically investigated as a longer-acting HIV prevention option. Phase I trial results presented by ViiV Healthcare showed that the formulation was well tolerated and achieved drug levels comparable to the approved 2-month CAB formulation (APRETUDE®), but lasted longer, potentially supporting a 4-month duration [24]. In collaboration with DelSiTech, CONRAD is developing a biodegradable hydrogel injectable capable of long-term release of CAB and/or levonorgestrel (LNG) for the prevention of HIV and/or contraception as a MPT [25]. The University of North Carolina (UNC) is also investigating dolutegravir or CAB as an injectable option for longer durations of protection using a technology that, when delivered subcutaneously, forms a biodegradable and removable ISFI (depot) under the skin [26].
Subdermal biodegradable and non-biodegradable implants are also being developed as longer-acting HIV prevention options [27]. When placed under the skin, these implants release drugs at a controlled rate for several months. Non-biodegradable implants need to be removed after their intended therapeutic duration, while biodegradable implants dissolve into non-toxic byproducts in the body, so they do not need to be removed. Some notable examples in this category are Houston Methodist Research Institute’s transcutaneous refillable nanochannel-based non-biodegradable implant containing different ARVs [28, 29] and CONRAD’s bioresorbable multi-pellet implant system for CAB [27].
Microarray patches (MAPs) made of microneedles are drug delivery platforms that can be painlessly (self-)applied onto the surface of the skin [30]. These patches contain tiny microneedles that pierce the skin to deliver drugs systemically into the blood. These specialized needles can be designed to dissolve immediately for quick drug release or to slowly release drugs over weeks or months by adding a polymer shell that coats the needles to slow down or delay drug release [30]. Examples from researchers at Queen’s University are MAPs loaded with CAB or TAF for long-term (weeks) HIV prevention [31, 32]. CONRAD, in collaboration with the University of Connecticut, has also explored MAPs for controlled release of ARVs such as TAF and co-delivery of multiple antibodies (Abs) for expanded protection against HIV infection [33]. CONRAD’s ongoing work is now focused on broadly neutralizing antibodies (bnAbs) to protect infants from HIV transmission through breastfeeding. As an alternative to ARVs, passive immunization with long-lasting bnAbs is under investigations for long-term protection against HIV [34, 35]. These bnAbs have shown promising safety, tolerability, and efficacy in early clinical trials. Technical advances have also enabled scientists to make them more potent and longer lasting [35]. Combining more than one bnAb also has the potential to increase effectiveness. Clinical trials (NCT06517693; NCT05184452; NCT05184452) are ongoing in healthy adults and infants to test a combination of bnAbs that could provide protection from HIV acquisition for months.
MPTs are also being investigated to lower the risk of HIV and other sexually transmitted infections or provide contraception to women using just one product [14]. These combination products are expected to improve product adherence by reducing stigma, the number of clinic visits needed, and overall manufacturing and delivery costs, providing additional incentives to continue getting refills and remain adherent. There are several MPTs that are in different stages of development, including IVRs, topical inserts, oral pills, implants, and injectables (Table 1). The Dual Prevention Pill (DPP) under development by Viatris, now close to approval, combines two approved oral products to prevent HIV (FTC/TDF) and pregnancy (ethinyl estradiol and LNG) [36]. Oak Crest is developing a novel IVR delivering a non-ARV molecule and a non-hormonal contraceptive [37]. The Population Council and MWRI are developing combinations of DPV and LNG delivered by an IVR [38] and film [39], respectively. CONRAD is developing a 3-month injectable that combines CAB and LNG to prevent both HIV and pregnancy [25]. UNC is also using their injectable ISFI technology to combine ARVs and contraceptives to provide long-acting dual protection [40].
With a pipeline that spans so many novel delivery technologies for HIV prevention, as well as dual protection for more than just HIV, the field is advancing options that may one day enable women to choose one of a variety of different products that better suits their lifestyle and preferences, as they currently do for contraception. As seen with contraceptives [41], uptake and population coverage are greater when more methods are available to choose from. Predictably, some will prefer long-acting and less user-dependent products, while others will choose short-acting or on-demand options. A perfect product that fits all women’s preferences and changing life conditions is likely unachievable, so we must continue on the path to developing different options that reach more users and increase product uptake, adherence, and persistence. HIV continues to be a major public health issue globally. Developing new, safer, and more effective products that are acceptable, affordable, and deliverable, and that women want to use, will ensure a substantial reduction on the number of new HIV infections and a significant step forward in the control of the global epidemic.
Figure 1: Schematics of HIV prevention-only and MPT drug delivery products under preclinical and clinical development
Table 1: Examples of HIV prevention-only and MPT drug delivery products under preclinical and clinical development
Disclaimer: The views expressed in this article are solely those of the authors and do not reflect the views or opinions of their organizations, funders, or collaborators.
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