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.
Injectable PrEP
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.
Vaginal 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
PrEP Implants
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.
Immunoprophylaxis
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.
Conclusions
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.
References
1. CDC. HIV prevention pill not reaching most Americans who could benefit – especially people of color. Published April 25, 2019. Accessed August 2, 2020. https://www.cdc.gov/nchhstp/newsroom/2018/croi-2018-PrEP-press-release.html
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
4. Centers for Disease Control and Prevention, US Public Health. Preexposure prophylaxis for the prevention of HIV infection in the United States—2017 update: a clinical practice guideline. Atlanta: CDC. Published online 2018.
5. Baeten JM, Donnell D, Ndase P, et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med. 2012;367(5):399-410. doi:10.1056/NEJMoa1108524
6. Spreen W, Min S, Ford SL, et al. Pharmacokinetics, Safety, and Monotherapy Antiviral Activity of GSK1265744, an HIV Integrase Strand Transfer Inhibitor. HIV Clinical Trials. 2013;14(5):192-203. doi:10.1310/hct1405-192
7. Swindells S, Andrade-Villanueva J F. LONG-ACTING CABOTEGRAVIR + RILPIVIRINE AS MAINTENANCE THERAPY: ATLAS WEEK 48 RESULTS. In: CROI Conference. Accessed August 8, 2020. https://www.croiconference.org/abstract/long-acting-cabotegravir-rilpivirine-maintenance-therapy-atlas-week-48-results/
8. Tolley EE, Li S, Atujuna M, et al. Acceptability of rilpivirine LA (RPV LA): Long-acting injectable pre-exposure prophylaxis (PrEP) in HPTN 076. In: IXth International AIDS Society Conference on HIV Science Paris, France. ; 2017:23-26.
9. Penrose KJ, Parikh UM, Hamanishi KA, et al. Selection of Rilpivirine-Resistant HIV-1 in a Seroconverter From the SSAT 040 Trial Who Received the 300-mg Dose of Long-Acting Rilpivirine (TMC278LA). J Infect Dis. 2016;213(6):1013-1017. doi:10.1093/infdis/jiv528
10. Markowitz M, Frank I, Grant RM, et al. Safety and tolerability of long-acting cabotegravir injections in HIV-uninfected men (ECLAIR): a multicentre, double-blind, randomised, placebo-controlled, phase 2a trial. The Lancet HIV. 2017;4(8):e331-e340. doi:10.1016/S2352-3018(17)30068-1
11. Landovitz RJ. HPTN 083 FINAL RESULTS:Pre-exposure Prophylaxis containing long-acting injectable cabotegravir is safe and highly effective for cisgender men and transgender women who have sex with men. Presented at the: 23rd International AIDS Conference; July 7, 2020; Virtual.
12. Landovitz RJ, Li S, Eron JJ, et al. Tail-phase safety, tolerability, and pharmacokinetics of long-acting injectable cabotegravir in HIV-uninfected adults: a secondary analysis of the HPTN 077 trial. The Lancet HIV. 2020;7(7):e472-e481. doi:10.1016/S2352-3018(20)30106-5
13. McConville C, Major I, Devlin B, Brimer A. Development of a multi-layered vaginal tablet containing dapivirine, levonorgestrel and acyclovir for use as a multipurpose prevention technology. European Journal of Pharmaceutics and Biopharmaceutics. 2016;104:171-179. doi:10.1016/j.ejpb.2016.05.003
14. Cazorla-Luna R, Martín-Illana A, Notario-Pérez F, et al. Dapivirine Bioadhesive Vaginal Tablets Based on Natural Polymers for the Prevention of Sexual Transmission of HIV. Polymers. 2019;11(3):483. doi:10.3390/polym11030483
15. Nel A, van Niekerk N, Kapiga S, et al. Safety and efficacy of a dapivirine vaginal ring for HIV prevention in women. New England Journal of Medicine. 2016;375(22):2133-2143.
16. Brown E, Palanee-Philips T, Marzinke M, et al. Residual dapivirine ring levels indicate higher adherence to vaginal ring is associated with HIV-1 protection. In: Journal of the International Aids Society. Vol 19. JOHN WILEY & SONS LTD THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W …; 2016.
17. Nel A, Malherbe M, Mans W, Van Baelen B, Van Niekerk N, Louw C. Safety, adherence and HIV-1 seroconversion in DREAM—an open-label dapivirine vaginal ring trial. In: 9th South African AIDS Conference. ; 2019.
18. Baeten JM, Palanee-Phillips T, Mgodi N, et al. High adherence and sustained impact on HIV-1 incidence: Final results of an open-label extension trial of the dapivirine vaginal ring. In: JOURNAL OF THE INTERNATIONAL AIDS SOCIETY. Vol 22. JOHN WILEY & SONS LTD THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W …; 2019:29-29.
19. International Partnership for Microbicides (IPM). Final Results of Open-label Study of IPM’s Dapivirine Vaginal Ring Show Increased Use and Suggest Lower Infection Rates Compared to Earlier Phase III Study. Published June 12, 2019. Accessed August 9, 2020. https://www.ipmglobal.org/content/final-results-open-label-study-ipm%E2%80%99s-dapivirine-vaginal-ring-show-increased-use-and-suggest
20. Dallal Bashi YH, McCoy CF, Murphy DJ, et al. Towards a dapivirine and levonorgestrel multipurpose vaginal ring: Investigations into the reaction between levonorgestrel and addition-cure silicone elastomers. International Journal of Pharmaceutics. 2019;569:118574. doi:10.1016/j.ijpharm.2019.118574
21. MTN-030/IPM 041. Microbicide Trials Network (MTN). Accessed August 13, 2020. https://mtnstopshiv.org/research/studies/mtn-044
22. Molina J, Yazdanpanah, Afani Saud A. Tolerability, Safety, and Efficacy of Islatravir (MK-8591) at Doses of 0.25 to 2.25 mg QD, in Combination With Doravirine and Lamivudine Through 24 Weeks in Treatment-Naïve AdultsWith HIV-1 Infection. In: ; 2019. Accessed August 8, 2020. https://www.natap.org/2019/IAS/IAS_15.htm
23. Markowitz M, Gettie A, St. Bernard L, et al. Once-weekly oral dosing of MK-8591 protects male rhesus macaques from intrarectal challenge with SHIV109CP3. The Journal of Infectious Diseases. 2020;221(9):1398-1406.
24. Safety and Pharmacokinetics of Oral Islatravir (MK-8591) Once Monthly in Participants at Low Risk of Human Immunodeficiency Virus 1 (HIV-1) Infection (MK-8591-016) - Full Text View - ClinicalTrials.gov. Accessed August 8, 2020. https://clinicaltrials.gov/ct2/show/NCT04003103
25. Barrett SE, Teller RS, Forster SP, et al. Extended-Duration MK-8591-Eluting Implant as a Candidate for HIV Treatment and Prevention. Antimicrob Agents Chemother. 2018;62(10):e01058-18, /aac/62/10/e01058-18.atom. doi:10.1128/AAC.01058-18
26. Gunawardana M, Remedios-Chan M, Miller CS, et al. Pharmacokinetics of long-acting tenofovir alafenamide (GS-7340) subdermal implant for HIV prophylaxis. Antimicrob Agents Chemother. 2015;59(7):3913-3919. doi:10.1128/AAC.00656-15
27. Pons-Faudoa FP, Sizovs A, Di Trani N, et al. 2-Hydroxypropyl-β-cyclodextrin-enhanced pharmacokinetics of cabotegravir from a nanofluidic implant for HIV pre-exposure prophylaxis. Journal of Controlled Release. 2019;306:89-96.
28. The Dual Prevention Pill. PrEPWatch. Accessed August 9, 2020. https://www.prepwatch.org/nextgen-prep/dual-prevention-pill/
29. Friedland B. FROM THE PIPELINE | Fast track to an MPT: Development of a dual-purpose pill containing oral PrEP and an oral contraceptive. IMPT for Reproductive Health. Published July 22, 2019. Accessed August 9, 2020. https://www.theimpt.org/blog-impt/item/from-the-pipeline-fast-track-to-an-mpt-development-of-a-dual-purpose-pill-containing-oral-prep-and-an-oral-contraceptive
30. AIDS Vaccine Advisory Council (AVAC)). HIV Prevention Trials. AVAC Global Advocacy for HIV Prevention. Accessed August 9, 2020. https://www.avac.org/trial-search
31. Rein-Weston A, Tekko I, Vora L, et al. LB8. Microarray Patch Delivery of Long-Acting HIV PrEP and Contraception. In: Open Forum Infectious Diseases. Vol 6. ; 2019.
32. Mc Crudden MT, Larrañeta E, Clark A, et al. Design, formulation, and evaluation of novel dissolving microarray patches containing Rilpivirine for Intravaginal delivery. Advanced healthcare materials. 2019;8(9):1801510.
33. ClinicalTrials.gov. Evaluating the Safety and Pharmacokinetics of PC-1005 Administered Rectally to HIV-1 Seronegative Adults - Full Text View - ClinicalTrials.gov. Accessed August 9, 2020. https://clinicaltrials.gov/ct2/show/NCT03408899
34. MPT Microarray Patch (MAP). The Initiative for Multipurpose Prevention Technologies (IMPT). Accessed August 11, 2020. http://mpts101.org/mpt-database/product-page/37-mpts/140-mpt-map
35. CONRAD. Safety, PK, and PD Study of a Vaginal Insert Containing TAF and EVG - Full Text View - ClinicalTrials.gov. Accessed August 11, 2020. https://clinicaltrials.gov/ct2/show/NCT03762772
36. Delany-Moretlwe S, Lombard C, Baron D, et al. Tenofovir 1% vaginal gel for prevention of HIV-1 infection in women in South Africa (FACTS-001): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Infect Dis. 2018;18(11):1241-1250. doi:10.1016/S1473-3099(18)30428-6
37. Stephenson KE, Wagh K, Korber B, Barouch DH. Vaccines and Broadly Neutralizing Antibodies for HIV-1 Prevention. Annu Rev Immunol. 2020;38(1):673-703. doi:10.1146/annurev-immunol-080219-023629
38. National Institute of Allergy and Infectious Diseases (NIAID). Evaluating the Safety and Efficacy of the VRC01 Antibody in Reducing Acquisition of HIV-1 Infection Among Men and Transgender Persons Who Have Sex With Men - Full Text View - ClinicalTrials.gov. Accessed August 10, 2020. https://clinicaltrials.gov/ct2/show/NCT02716675
39. Stieh DJ. ASCENT: Phase 2a, randomized, double-blind, placebo controlled study evaluating safety and immunogenicity of two HIV-1 prophylactic vaccine regimens comprising Ad26.Mos4.HIV and either clade C gp140 or bivalent gp140. In: Hot off the Press: What’s New in HIV Prevention. Janssen Vaccines & Prevention B.V, Netherlands; 2020. Accessed August 10, 2020. http://programme.ias2019.org/Abstract/Abstract/4979
40. Janssen Vaccines & Prevention B.V. A Study of Heterologous Vaccine Regimen of Adenovirus Serotype 26 Mosaic4 Human Immunodeficiency Virus(Ad26.Mos4.HIV), Adjuvanted Clade C gp140 and Mosaic gp140 to Prevent HIV-1 Infection Among Cis-gender Men and Transgender Individuals Who Have Sex With Cis-gender Men and/or Transgender Individuals - Full Text View - ClinicalTrials.gov. Accessed August 10, 2020. https://clinicaltrials.gov/ct2/show/NCT03964415
41. Janssen Vaccines & Prevention B.V. A Study to Assess the Efficacy of a Heterologous Prime/Boost Vaccine Regimen of Ad26.Mos4.HIV and Aluminum Phosphate-Adjuvanted Clade C gp140 in Preventing Human Immunodeficiency Virus (HIV) -1 Infection in Women in Sub-Saharan Africa - Full Text View - ClinicalTrials.gov. Accessed August 10, 2020. https://clinicaltrials.gov/ct2/show/NCT03060629
42. Tyo KM, Vuong HR, Malik DA, et al. Multipurpose tenofovir disoproxil fumarate electrospun fibers for the prevention of HIV-1 and HSV-2 infections in vitro. Int J Pharm. 2017;531(1):118-133. doi:10.1016/j.ijpharm.2017.08.061
43. Ball C, Woodrow KA. Electrospun solid dispersions of Maraviroc for rapid intravaginal preexposure prophylaxis of HIV. Antimicrob Agents Chemother. 2014;58(8):4855-4865. doi:10.1128/AAC.02564-14
44. Xiao P, Gumber S, Marzinke MA, et al. Hypo-osmolar Formulation of Tenofovir (TFV) Enema Promotes Uptake and Metabolism of TFV in Tissues, Leading to Prevention of SHIV/SIV Infection. Antimicrob Agents Chemother. 2018;62(1). doi:10.1128/AAC.01644-17
45. Cunha-Reis C, Machado A, Barreiros L, et al. Nanoparticles-in-film for the combined vaginal delivery of anti-HIV microbicide drugs. J Control Release. 2016;243:43-53. doi:10.1016/j.jconrel.2016.09.020
46. Bunge KE, Dezzutti CS, Hendrix CW, et al. FAME-04: A Phase 1 trial to assess the safety, acceptability, pharmacokinetics and pharmacodynamics of film and gel formulations of tenofovir. J Int AIDS Soc. 2018;21(8):e25156. doi:10.1002/jia2.25156
