The Preexposure Prophylaxis Pipeline
The CDC reports that adherence to preexposure prophylaxis (PrEP) reduces the risk of acquiring HIV from sex by about 99% and from injection drug use by at least 74%.1 Currently, only 2 medications are approved for use as PrEP: TDF /FTC (Truvada™) and TAF/FTC (Descovy™).2 Although tenofovir disoproxil fumarate/emtricitabine is currently approved for all adults in the prevention of sexually acquired HIV, tenofovir alafenamide/emtricitabine is approved only for prevention in men who have sex with men and in transgender women.3 Most importantly, efficacy of these oral products relies on strict adherence, which poses a challenge for many at-risk populations.1,4,5 To address this disparity, several investigational products are under development that incorporate a diverse armamentarium of options, analogous to contraceptives including but not limited to on-demand PrEP, non-oral formulations, and longer-acting agents.
Cabotegravir is an investigational integrase strand transfer inhibitor with potent antiviral activity.6 In combination with rilpivirine, its efficacy in the management of HIV has been documented.7 However, despite being well tolerated and acceptable as a long-acting injectable formulation, rilpivirine for PrEP has not moved forward into phase 3 studies because of storage and transportation limitations, and a low barrier to resistance.8,9 Conversely, cabotegravir is under investigation for long-acting PrEP.10 Interim analysis from HPTN 083 showed that cabotegravir 600-mg injection given every 8 weeks was statistically superior to daily tenofovir disoproxil fumarate/emtricitabine, with a 66% relative risk reduction in HIV acquisition.11 Both agents were well tolerated, and safe though injection-related adverse events were more common with cabotegravir and resistance testing data is in progress. But, the long pharmacokinetic (PK) tail of cabotegravir might complicate the management of drug adverse events in clinical practice. Secondary analysis from the HPTN 077 trial revealed that cabotegravir may remain detectable after discontinuation for nearly 3 years in males, 4 years in females, and longer exposureswere detected in higher body-mass index individuals; irrespective of sex.12 Nonetheless, if approved, cabotegravir could address adherence issues. Yet, optimizing an implementation strategy for gluteal injection administration to suit patient needs will be critical component associated with this formulation of PrEP.
Dapivirineis an investigational nonnucleoside reverse transcriptase inhibitor (NNRTI) that has been studied in various formulations for the prevention of HIV.13–15 In two phase 3 trials (the Ring Study and ASPIRE), the monthly intravaginal ring was effective and safe with no difference in safety concerns between the dapivirine ring arm and the placebo arm.15,16 Effectiveness and tolerability of the monthly vaginal ring containing 25 mg dapivirine was further demonstrated in an extension study, DREAM, which estimated a 63% reduction in HIV-1 risk.17,18 Minimal safety concerns related to dapivirine occurred in participants (7% experienced vulvovaginitis and 2% experienced severe adverse effects). However, the study lacked a contemporaneous placebo group and findings exposed a lower risk reduction in adolescent women due to poor adherence.
Currently, the monthly ring is under regulatory review by the European Medicines Agency; a 90-day vaginal ring containing 100 mg or 200 mg of dapivirine is also under investigation. The International Partnership for Microbicides (IPM) is planning to submit applications to the South African Health Products Regulatory Authority later this year, which may make the dapivirine ring available sometime in 2021 in Africa; the IPM also plans to submit an application to the FDA later this year.19 A three-month ring with 200 mg of dapivirine and 320mg of levonorgestrel is also being investigated to simultaneously offer PrEP and contraception.20,21
Monthly Capsulated PrEP
Islatravir is a first-in-class long-acting nucleoside reverse transcriptase translocation inhibitor that is under investigation for use in prevention and treatment of HIV.22 Islatravir’s unique mechanism of action and pharmacokinetic profile provides flexibility in therapy formulations. In preclinical studies, islatravir dosed orally once weekly for PrEP protected against simian–human immunodeficiency virus infection.23 A phase 2a trial, MK-8591-016, is currently enrolling to investigate the safety and PK of 60-mg and 120-mg islatravir doses administered orally in capsule form once monthly.24
Studies have also demonstrated the safety and feasibility of islatravir triphosphateimplant.25 Modeling predicted that the levels of intracellular islatravir triphosphatewere consistent with the potential for once-yearly implantable administration. Other antiretrovirals with encouraging preclinical results for subdermal implantable PrEP include tenofovir alafenamide and cabotegravir.26,27
Multipurpose Technologies for PrEP and Microbicides
Numerous technologies are in development to address multiple health concerns like HIV prevention and contraception in a single agent and are referred to as multipurpose prevention technology (MPT) products.28,29 The Population Council is working on coformulating a dual-purpose pill composed of the active pharmaceutical ingredients (APIs) in tenofovir disoproxil fumarate/emtricitabine and the combined APIs in the oral contraceptives levonorgestrel and ethinyl estradiol.29
Many organizations are developing several other innovative MPTs including vaginal gel, vaginal ring, vaginal insert, diaphragm, microarray patch, rectal gel, rectal insert, long-acting injectable, an implant, and an intrauterine device. However, it will be several years before one is available.30–32
Also underway is investigation of PC-1005 gel, a combination of an investigational NNRTI (MIV-150) plus zinc acetate and carrageenan. This is the only product designed for vaginal and rectal use targeting HIV, human papillomavirus, and herpes simplex virus simultaneously that has undergone a phase 1 study to date.33 Other early-phase explorations of MPTs include a microarray patch using cabotegravir and norelgestromin41 and a vaginal insert containing elvitegravir and tenofovir alafenamide.34,35
An MPT that prevents HIV and sexually transmitted infections and simultaneously prevents unintended pregnancy would significantly help overcome barriers to negotiating condom use as well as adherence issues related to stigma and gender dynamics that have been seen in microbicide and PrEP trials.
Numerous microbicide products have been or will be investigated, including vaginal dosage forms (gel, film, tablet, ring, and insert) and rectal dosage forms (gel, douche, enema, suppository, and insert).36 Tenofovir 1% vaginal gel is furthest along in development, with a completed phase 3 study (FACTS 001). However, results revealed that the gel didn’t protect from HIV and adherence was a crucial factor in the unfavorable trial results.
Darunavir, maraviroc, raltegravir, and rilpivirine are also being investigated preclinically for utilization in HIV prevention as various microbicide topical products. Even though microbicides would fill an important HIV prevention need, it is imperative that any such product is safe and effective.
Immunologic approaches have been studied, include active immunization with vaccines and passive immunization with broadly neutralizing antibodies (bNAbs).37 VRC01 is the first of the bNAbs to be found safe and to advance to efficacy trials for HIV-1 prevention, with final results expected by 2021.38 Additionally, five sizeable clinical efficacy trials are underway to evaluate vaccination strategies for PrEP.39–41 Even with high manufacturing costs, bNAbs are expected to have favorable safety and PK profiles, potentially allowing for longer intervals between administrations. However, these immuno-prophylaxis products require intravenous administration, which may not be widely acceptable for patients.
Other Preclinical Formulations
A number of other delivery methods are in preclinical trials. Products using microneedles, fibers, enemas, mucoadhesive intravaginal tablets, thin-film polymer devices, foams, sponges, diaphragms, and nanotechnology are being investigated for PrEP.42–46 Early-phase studies of PK and tolerability are encouraging, but few additional data are available.
HIV prevention does not happen in isolation and there is not an ideal PrEP formulation as one size does not fit all. However, the investigational products described above address some challenges in HIV prevention by employing a mix of delivery systems that account for different transmission circumstances, discreet on-demand methods, and offer a consistent use routine that's available at every high-risk encounter or lack of adherence situation. On the contrary, these investigation therapies will not address the need for improved provider and public health education to ultimately employ positive attitudes related to HIV prevention strategies. Nonetheless, cost and overall feasibility will be additional considerations upon implementing these technologies.
Mikayla S. Johnson is in the postgraduate year 2 HIV clinical pharmacy resident at the University of Illinois at Chicago, College of Pharmacy in Chicago, Illinois.
Renata O. Smith is a clinical assistant professor at University of Illinois at Chicago College of Pharmacy and clinical pharmacy specialist in HIV/HCV/Gender affirming care at UI Health. She is the director of the PGY2 residency in HIV.
Melissa E. Badowski is a clinical associate professor at the University of Illinois at Chicago, College of Pharmacy. She provides clinical pharmacy services through telehealth to patients living with HIV in the Illinois Department of Corrections.
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2. FDA approves second drug to prevent HIV infection as part of ongoing efforts to end the HIV epidemic. FDA. Published October 3, 2019. Accessed August 8, 2020. https://www.fda.gov/news-events/press-announcements/fda-approves-second-drug-prevent-hiv-infection-part-ongoing-efforts-end-hiv-epidemic
3. Mayer KH, Molina J-M, Thompson MA, et al. Emtricitabine and tenofovir alafenamide vs emtricitabine and tenofovir disoproxil fumarate for HIV pre-exposure prophylaxis (DISCOVER): primary results from a randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial. The Lancet. 2020;396(10246):239-254. doi:10.1016/S0140-6736(20)31065-5
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