THE FUTURE OF EPIDEMIC CONTROL: EVALUATING THE PHARMACOLOGICAL, CLINICAL, AND SOCIOECONOMIC LANDSCAPE OF MODERN HIV PRE-EXPOSURE PROPHYLAXIS

Kornel Pawlak; Marcin Stępiński; Julia Dobrowolska; Marta Krężołek; Mateusz Balicki; Filip Kamyszek; Paula Kaczmarczyk; Alicja Palus; Oliwia Zynek; Tomasz Arkuszyński

doi:10.31435/ijitss.2(50).2026.5716

Authors

Kornel Pawlak Medical University of Warsaw, Żwirki i Wigury 61, 02-091 Warsaw, Poland https://orcid.org/0009-0009-6435-6587
Marcin Stępiński Medical University of Warsaw, Żwirki i Wigury 61, 02-091 Warsaw, Poland https://orcid.org/0009-0004-5878-6293
Julia Dobrowolska Medical University of Warsaw, Żwirki i Wigury 61, 02-091 Warsaw, Poland https://orcid.org/0009-0008-9498-9521
Marta Krężołek Medical University of Warsaw, Żwirki i Wigury 61, 02-091 Warsaw, Poland https://orcid.org/0009-0004-3646-5640
Mateusz Balicki Corten Dental Medical Center, Dental Clinic, Etiudy Rewolucyjnej 48, 02-643 Warsaw, Poland https://orcid.org/0009-0002-5066-9645
Filip Kamyszek Corten Dental Medical Center, Dental Clinic, Etiudy Rewolucyjnej 48, 02-643 Warsaw, Poland https://orcid.org/0009-0000-2767-8215
Paula Kaczmarczyk CITODENT Dental Center, pl. Zamkowy 5, 55-200 Oława, Poland https://orcid.org/0009-0005-6099-5657
Alicja Palus PRODENTAL Private Dental Clinic - Joanna Bronowska, Zakopiańska 4A, 05-120 Legionowo, Poland https://orcid.org/0009-0002-7462-6893
Oliwia Zynek Medical University of Warsaw, Żwirki i Wigury 61, 02-091 Warsaw, Poland https://orcid.org/0009-0000-5537-565X
Tomasz Arkuszyński Wroclaw Medical University, Krakowska 26, 50-425 Wroclaw, Poland https://orcid.org/0009-0001-4894-361X

DOI:

https://doi.org/10.31435/ijitss.2(50).2026.5716

Keywords:

HIV Prevention, Pre-exposure Prophylaxis, PrEP, Cabotegravir, Lenacapavir, Pharmacoeconomics, Vaginal Microbiome, Transgender Health, Differentiated Service Delivery

Abstract

Background: Pre-exposure prophylaxis (PrEP) has fundamentally transformed the global HIV prevention paradigm. Over the past decade, the strategy has evolved from adherence-dependent daily oral regimens to ultra-long-acting injectable modalities, addressing the most critical behavioral barriers to achieving widespread epidemic control.

Objective: This comprehensive review synthesizes the current literature on the molecular evolution, clinical efficacy, pharmacokinetic variables, and implementation challenges of PrEP. It traces the trajectory from early daily oral TDF/FTC interventions to first-in-class, ultra-long-acting capsid inhibitors like lenacapavir.

Methods: An exhaustive review of recent literature- incorporating articles published in PubMed, Cochrane, and global health databases between 2019 and 2026- was conducted. This included an analysis of pivotal clinical trials (e.g., DISCOVER, HPTN 083/084, PURPOSE 1 and 2), real-world implementation data, WHO guidelines, and recent systematic reviews on pharmacoeconomics in sub-Saharan Africa.

Results: While daily oral TDF/FTC and TAF/FTC demonstrate high biological efficacy, their real-world success is heavily compromised by the "adherence-efficacy paradox." Long-acting injectable cabotegravir (CAB-LA) and lenacapavir offer superior protection by decoupling prevention from daily routines. Recent data from PURPOSE 1 demonstrate 100% efficacy of lenacapavir in cisgender women, while PURPOSE 2 showed a 96% reduction in HIV incidence among cisgender men and transgender populations. However, novel challenges have emerged, including pharmacokinetic modifiers (e.g., the vaginal microbiome's impact on local drug efficacy), the management of the "pharmacokinetic tail," and severe economic barriers.

Conclusion: The future of HIV prevention relies on a diversified, equity-driven, person-centered approach. Ensuring global access to long-acting technologies, facilitated by aggressive voluntary licensing and integrated differentiated service delivery models, remains the primary challenge in utilizing PrEP to achieve the World Health Organization’s goal of ending the HIV epidemic.

References

World Health Organization. (n.d.). HIV and AIDS. Retrieved March 11, 2025, from https://www.who.int/news-room/fact-sheets/detail/hiv-aids

Ambrosioni, J., Levi, L. I., Alagaratnam, J., Sempere, A., Mastrangelo, A., Paioni, P., Mussini, C., Marzolini, C., Nielsen, S. D., Béguelin, C., Welch, S., Koval, A., Mendao, L., Bamford, A., Calmy, A., Guaraldi, G., Oprea, C., Martínez, E., & Rockstroh, J. K. (2026). Major revision version 13.0 of the European AIDS Clinical Society guidelines 2025. HIV Medicine, 27(1), 18–32. https://doi.org/10.1111/hiv.70120

Amblard, F., Patel, D., Michailidis, E., Coats, S. J., Kasthuri, M., Biteau, N., Tber, Z., Ehteshami, M., & Schinazi, R. F. (2022). HIV nucleoside reverse transcriptase inhibitors. European Journal of Medicinal Chemistry, 240, Article 114554. https://doi.org/10.1016/j.ejmech.2022.114554

Jackson, K. J., Chitle, P., McCoy, S. I., & White, D. A. E. (2024). A systematic review of HIV pre-exposure prophylaxis (PrEP) implementation in U.S. emergency departments: Patient screening, prescribing, and linkage to care. Journal of Community Health, 49(3), 499–513. https://doi.org/10.1007/s10900-023-01320-7

Wang, W., Zhao, S., Wu, Y., Duan, W., Li, S., Li, Z., Guo, C., Wang, W., Zhang, T., Wu, H., & Huang, X. (2023). Safety and efficacy of long-acting injectable agents for HIV-1: Systematic review and meta-analysis. JMIR Public Health and Surveillance, 9, Article e46767. https://doi.org/10.2196/46767

Kristyanto, H., González-Tomé, M. I., Vlcek, V., Josephson, F., Vrijlandt, P., & Perombelon, N. (2026). Global regulatory collaboration for the assessment of lenacapavir as a long-acting pre-exposure prophylaxis against HIV infection. Frontiers in Public Health, 14, Article 1760130. https://doi.org/10.3389/fpubh.2026.1760130

Miteu, G. D. (2026). Lenacapavir and global HIV prevention: A breakthrough at risk of leaving millions behind. Annals of Medicine and Surgery, 88(3), 2462–2466. https://doi.org/10.1097/MS9.0000000000004783

Plesons, M., Forman, E., McDowell, E. C., Krakower, D., Amico, K. R., Groves, A. K., Roth, A., & Bartholomew, T. S. (2026). Staff perspectives on implementation of long-acting injectable preexposure prophylaxis at a low-barrier syringe services program in Philadelphia, PA. Journal of the International Association of Providers of AIDS Care, 25, Article 23259582261420655. https://doi.org/10.1177/23259582261420655

Baker, D., Collins, L. F., Cantos, V. D., Hollenberg, E., Kaplan, A., Cowan, T., Garcia, J., & Lora, M. (2026). Early implementation of long-acting injectable cabotegravir for HIV prevention in a safety net hospital-based primary care center in U.S. South. Journal of General Internal Medicine, 41(1), 43–52. https://doi.org/10.1007/s11606-025-09350-8

Habtie, T. E., Feleke, S. F., Chanie, G. M., Munie, M. A., Derso, Y. A., & Adisu, M. A. (2026). Global perspectives on pre-exposure prophylaxis: A systematic review and meta-analysis of health care providers’ awareness, willingness, and barriers. AIDS Patient Care and STDs. Advance online publication. https://doi.org/10.1177/10872914261424544

Ebrahim, S., Gloeck, N., Adam, Z., Tatz, G., Nel, J., Sinxadi, P. Z., Dawood, H., Kredo, T., & Cohen, K. (2026). Lenacapavir as pre-exposure prophylaxis for HIV prevention. Cochrane Database of Systematic Reviews, 2026(4), Article CD016347. https://doi.org/10.1002/14651858.CD016347

Mursal, M., Fatima, G., & Gushchina, Y. S. (2026). Pharmacoeconomic perspectives on HIV: Integrating data for long-term treatment and prevention. Frontiers in Medicine, 12, Article 1716965. https://doi.org/10.3389/fmed.2025.1716965

Mishriky, F., & Chan, P. A. (2026). The current and future impact of WHO guidance on global HIV pre-exposure prophylaxis programs: A narrative review. Infection and Drug Resistance, 19, Article 547635. https://doi.org/10.2147/IDR.S547635

Ngwoke, I., Adedire, A. M., Danladi, N. P., Eze, C. C., Dada, O. K., & Okesanya, O. J. (2026). Barriers and facilitators of oral PrEP uptake against HIV among selected priority populations: A global perspective. Current HIV/AIDS Reports, 23(1), Article 14. https://doi.org/10.1007/s11904-026-00783-2

Jogiraju, V., Pawar, P., Yager, J., Ling, J., Shen, G., Chiu, A., Hughes, E., Palaparthy, R., Carter, C., & Singh, R. (2025). Pharmacokinetics and safety of once-yearly lenacapavir: A phase 1, open-label study. The Lancet, 405(10485), 1147–1154. https://doi.org/10.1016/S0140-6736(25)00405-2

Brizzi, M., Pérez, S. E., Michienzi, S. M., & Badowski, M. E. (2023). Long-acting injectable antiretroviral therapy: Will it change the future of HIV treatment? Therapeutic Advances in Infectious Disease, 10, Article 20499361221149773. https://doi.org/10.1177/20499361221149773

Nachega, J. B., Scarsi, K. K., Gandhi, M., Scott, R. K., Mofenson, L. M., Archary, M., Nachman, S., Decloedt, E., Geng, E. H., Wilson, L., Rawat, A., & Mellors, J. W. (2023). Long-acting antiretrovirals and HIV treatment adherence. The Lancet HIV, 10(5), e332–e342. https://doi.org/10.1016/S2352-3018(23)00051-6

Lanzafame, M., Mori, G., & Vento, S. (2025). Advances in HIV treatment: Long-acting antiretrovirals and the path toward a cure. Biomedicines, 13(2), Article 493. https://doi.org/10.3390/biomedicines13020493

Iannone, V., Rossotti, R., Bana, N. B., Cavazza, G., D’Amico, F., Lombardi, F., Salvo, P. F., Baldin, G., Di Giambenedetto, S., Bernacchia, D., Pagani, G., Borghetti, A., & Rusconi, S. (2025). Unconventional use of injectable long-acting cabotegravir and rilpivirine against HIV-1 in PWH in clinical need: 52 weeks real-world data. BMC Infectious Diseases, 25(1), Article 105. https://doi.org/10.1186/s12879-025-10499-0

Dvory-Sobol, H., Shaik, N., Callebaut, C., & Rhee, M. S. (2022). Lenacapavir: A first-in-class HIV-1 capsid inhibitor. Current Opinion in HIV and AIDS, 17(1), 15–21. https://doi.org/10.1097/COH.0000000000000713

Subramanian, R., Tang, J., Zheng, J., Lu, B., Wang, K., Yant, S. R., Stepan, G. J., Mulato, A., Yu, H., Schroeder, S., Shaik, N., Singh, R., Wolckenhauer, S., Chester, A., Tse, W. C., Chiu, A., Rhee, M., Cihlar, T., Rowe, W., & Smith, B. J. (2023). Lenacapavir: A novel, potent, and selective first-in-class inhibitor of HIV-1 capsid function exhibits optimal pharmacokinetic properties for a long-acting injectable antiretroviral agent. Molecular Pharmaceutics, 20(12), 6213–6225. https://doi.org/10.1021/acs.molpharmaceut.3c00626

Kelley, C. F., Acevedo-Quiñones, M., Agwu, A. L., Avihingsanon, A., Benson, P., Blumenthal, J., Brinson, C., Brites, C., Cahn, P., Cantos, V. D., Clark, J., Clement, M., Creticos, C., Crofoot, G., Diaz, R. S., Doblecki-Lewis, S., Gallardo-Cartagena, J. A., Gaur, A., Grinsztejn, B., . . . Ogbuagu, O. (2025). Twice-yearly lenacapavir for HIV prevention in men and gender-diverse persons. The New England Journal of Medicine, 392(13), 1261–1276. https://doi.org/10.1056/NEJMoa2411858

Parikh, U. M., Koss, C. A., & Mellors, J. W. (2022). Long-acting injectable cabotegravir for HIV prevention: What do we know and need to know about the risks and consequences of cabotegravir resistance? Current HIV/AIDS Reports, 19(5), 384–393. https://doi.org/10.1007/s11904-022-00616-y

Ariyo, O. E., & Jones, C. E. (2022). Use of long-acting injectable antiretroviral agents for human immunodeficiency virus: A review. Journal of Clinical Virology, 146, Article 105032. https://doi.org/10.1016/j.jcv.2021.105032

Johnson, J. E., Brotherton, A. L., Rossi, M. R., Sanchez, M. C., & Beckwith, C. G. (2025). Long-acting injectable antiretroviral therapy for treatment of human immunodeficiency virus: A review. Current HIV/AIDS Reports, 22(1), Article 31. https://doi.org/10.1007/s11904-025-00741-4

Sun, Y., & Wang, L. (2024). Development of anti-HIV therapeutics: From conventional drug discovery to cutting-edge technology. Pharmaceuticals, 17(7), Article 887. https://doi.org/10.3390/ph17070887

Singh, A. K., & Das, K. (2022). Insights into HIV-1 reverse transcriptase (RT) inhibition and drug resistance from thirty years of structural studies. Viruses, 14(5), Article 1027. https://doi.org/10.3390/v14051027

Yoshida, Y., Honma, M., Kimura, Y., & Abe, H. (2021). Structure, synthesis and inhibition mechanism of nucleoside analogues as HIV-1 reverse transcriptase inhibitors (NRTIs). ChemMedChem, 16(5), 743–766. https://doi.org/10.1002/cmdc.202000695

Popović-Djordjević, J., Quispe, C., Giordo, R., Kostić, A., Katanić Stanković, J. S., Tsouh Fokou, P. V., Carbone, K., Martorell, M., Kumar, M., Pintus, G., Sharifi-Rad, J., Docea, A. O., & Calina, D. (2022). Natural products and synthetic analogues against HIV: A perspective to develop new potential anti-HIV drugs. European Journal of Medicinal Chemistry, 233, Article 114217. https://doi.org/10.1016/j.ejmech.2022.114217

Bekker, L. G., Das, M., Abdool Karim, Q., Ahmed, K., Batting, J., Brumskine, W., Gill, K., Harkoo, I., Jaggernath, M., Kigozi, G., Kiwanuka, N., Kotze, P., Lebina, L., Louw, C. E., Malahleha, L., Manentsa, M., Mansoor, L. E., Moodley, D., Naicker, V., . . . Matovu Kiweewa, F. (2024). Twice-yearly lenacapavir or daily F/TAF for HIV prevention in cisgender women. The New England Journal of Medicine, 391(13), 1179–1192. https://doi.org/10.1056/NEJMoa2407001

GBD 2019 HIV Collaborators. (2021). Global, regional, and national sex-specific burden and control of the HIV epidemic, 1990–2019, for 204 countries and territories: The Global Burden of Diseases Study 2019. The Lancet HIV, 8(10), e633–e651. https://doi.org/10.1016/S2352-3018(21)00152-1

Klatt, N. R., Cheu, R., Birse, K., et al. (2017). Vaginal bacteria modify HIV tenofovir microbicide efficacy in African women. Science, 356(6341), 938–945.

Thurman, A. R., Ravel, J., Gajer, P., Marzinke, M. A., Ouattara, L. A., Jacot, T., Peet, M. M., Clark, M. R., & Doncel, G. F. (2022). Vaginal microbiota and mucosal pharmacokinetics of tenofovir in healthy women using a 90-day tenofovir/levonorgestrel vaginal ring. Frontiers in Cellular and Infection Microbiology, 12, Article 799501. https://doi.org/10.3389/fcimb.2022.799501

Marzinke, M. A., Hanscom, B., Wang, Z., Safren, S. A., Psaros, C., Donnell, D., Richardson, P. A., Sullivan, P., Eshleman, S. H., Jennings, A., Feliciano, K. G., Jalil, E., Coutinho, C., Cardozo, N., Maia, B., Khan, T., Singh, Y., Middelkoop, K., Franks, J., . . . Grinsztejn, B. (2023). Efficacy, safety, tolerability, and pharmacokinetics of long-acting injectable cabotegravir for HIV pre-exposure prophylaxis in transgender women: A secondary analysis of the HPTN 083 trial. The Lancet HIV, 10(11), e703–e712. https://doi.org/10.1016/S2352-3018(23)00200-X

Mugari, C., Lukwa, A. T., Nembaware, V., et al. (2025). Cost-effectiveness of HIV prevention interventions in sub-Saharan Africa (2019–2025): A systematic review. Expert Review of Pharmacoeconomics & Outcomes Research. Advance online publication.

Bansi-Matharu, L., Phillips, A. N., et al. (2023). Cost-effectiveness of long-acting cabotegravir for HIV pre-exposure prophylaxis in South Africa: A mathematical modelling study. The Lancet Global Health, 11(9), e1394–e1404.