Investing in Anti-HIV: How Anti-HIV Therapeutic Developers Can Reshape the Future of HIV Control

Therapeutic advancements in combination antiretroviral therapies (ART) have played a central role in curtailing the HIV epidemic and redefining the outcomes of infection. As prescribed, when uninfected individuals take antiretroviral agents as preexposure prophylaxis (PrEP), it is highly effective at preventing HIV infection.

Therapeutically, when ART is taken as prescribed, it suppresses viral replication in people with HIV to levels that avert disease progression and transmission, allowing them to live long and productive lives. Together, ART therapies for prevention and treatment have transformed HIV from a highly lethal disease to a chronic condition, and enabled public health initiatives to reverse the course of HIV epidemics across the globe.¹

However, ART is not a panacea for HIV control. While mechanistically effective, there are exceptionally high access- and adherence-based barriers to ART-based prevention and treatment, particularly when ART is formulated as a daily oral regimen.² Moreover, ART does not cure HIV infection or fully restore immune function in advanced disease, and it carries a lifelong risk of medication resistance.³

Prioritizing Therapeutics Intended to Enhance Access and Adherence

The real-world utility of existing therapies can be improved by addressing systematic barriers to access and adherence.1 National and international public health initiatives could theoretically eliminate HIV transmission and mortality if they succeeded at:

• Eliminating HIV stigma and discrimination
• Implementing regionally adapted public health programs to reduce infection and transmission risk
• Implementing disease surveillance programs to identify at-risk individuals and link them to appropriate HIV care
• Ensuring uninterrupted, life-long access to affordable, high-quality health care

In practice, while multipronged global health efforts are essential to combating HIV, systemic impediments are not going to disappear. Instead, they will remain the primary hurdle to the real-world efficacy and utility of HIV interventions.⁴ This means that the most impactful pharmacologic interventions will come from therapeutic developers who:

1. Understand the many converging challenges faced by people at risk of HIV and AIDS
2. Develop interventions that are highly effective in the actual contexts in which they are prescribed.

In other words, therapeutic developers can reshape the future of HIV control by creating effective interventions, despite persistent real-world challenges.

Long-Acting Injectables Are Poised to Make HIV Epidemic Control Easier

Recent breakthroughs in long-acting injectable forms of ART are poised to enhance efforts at HIV control by addressing persistent deterrents to access and adherence.⁵ Compared to ART prescribed as a daily oral pill, long-acting injectables can make ART-based interventions more sustainable by reducing side effects, lowering the risk of resistance, increasing the ease and convenience of adherence, and decreasing the visibility of treatment.² These advantages are particularly meaningful in high-risk populations in which stigma and logistical obstacles are significant.

The PURPOSE 1 trial (the first of 4), which was sponsored by Gilead Sciences and conducted with regional research partners, investigated the efficacy of long-acting injectable PrEP in 5,338 cisgender women living in South Africa and Uganda. A twice-yearly injection of lenacapavir resulted in zero HIV infections among participants, compared with 16 infections among women taking daily oral PrEP.⁶

By eliminating the daily pill burden and reducing social and structural hurdles such as stigma, mobility constraints, and limited health care access, PURPOSE 1 illustrates how thoughtfully designed therapeutic options can improve adherence and real-world outcomes.

Investing in Alternative Pathways Towards HIV Immunity and Cure

Although long-acting injectables are superior to oral-based ART, they still share the inherent limitations of ART-based therapies, remaining suppressive rather than curative, and dependent on ongoing access, adherence, and monitoring. In settings with global treatment disparities, the long-term success of these interventions is jeopardized, and treatment resistance will continue to emerge.³

Moreover, some research suggests lifelong use of antiretroviral therapies may come with side effects, including persistent inflammation and comorbidity risk, such as cardiovascular and neurocognitive disorders.^7,8 Additional comorbidity risks associated with living with HIV can be attributed to the therapy’s incomplete immune restoration, especially in those who receive therapeutic intervention later in their disease course.⁸

These realities underscore the need for continued research investment into preventative modalities that interrupt transmission at the population level and curative strategies that eliminate viral reservoirs.^9,10 While the exact blueprints for an efficacious vaccine or straightforward cure remain elusive, areas of growing interest include mRNA-based vaccines that train the immune system to detect diverse HIV strains, and combination therapies designed to expose and eliminate latent reservoirs of HIV-infected cells.^9,10

Developing Anti-HIV Interventions for Real-World Impact

Whichever therapeutic approach developers of anti-HIV interventions pursue, its value will be judged by whether it can simplify and improve HIV control efforts in the regions and populations at highest risk.⁴ Establishing this value during initial clinical development is critical but challenging.

Because existing HIV therapies are already highly effective when taken as prescribed, traditional trial settings often fail to reveal the added value of emerging approaches. Instead of relying on idealized trial conditions, developers should prioritize trials that reflect the lived realities of the populations they aim to serve.¹¹

To establish pharmacologic performance in real-world contexts, developers first need to understand which populations are disproportionately affected by HIV and where those populations are located.¹¹ With this context, they can aim to implement trials in environments that mirror the social, logistical, and structural challenges faced by target populations, with independent assessments across diverse demographic groups.

Building on this framework, the 5 PURPOSE trials for lencapavir provided a valuable model for approaching clinical development and commercialization pipelines in ways that anticipate how interventions will perform post-approval.¹² Collectively, these trials form the most comprehensive and diverse effort in investigational HIV PrEP ever conducted.

Covering a wide range of regions and high-risk populations, the 5 trials allow each phase 3 study to more accurately capture how long-acting injectables perform under real-world conditions, including factors that influence uptake, availability, and social acceptance.¹³

Partnering for real-world impact

Achieving meaningful diversity in trial populations and designing trials that account for population-specific constraints requires authentic partnerships with affected communities.¹¹ Their input should inform study design, recruitment strategies, and cultural alignment, ensuring that evidence generated is rigorous and broadly applicable. Postapproval and commercialization, these same partnerships will be critical to integrating emerging therapies into existing public health systems and HIV control efforts.

Developers who embed community collaboration into their research, development, and commercialization frameworks will be better positioned to demonstrate and realize the full therapeutic potential of new anti-HIV interventions.

References

1. Joint United Nations Programme on HIV/AIDS. AIDS, Crisis and the Power to Transform: UNAIDS Global AIDS Update 2025. Geneva: UNAIDS; 2025. Accessed August 7, 2025. Licence: CC BY NC SA 3.0 IGO.
2. Łupina K, Nowak K, Lorek D, et al. Pharmacological advances in HIV treatment: from ART to long-acting injectable therapies. Arch Virol. 2025;170(9):195. doi:10.1007/s00705-025-06381-8
3. Apetroaei MM, Velescu B Ștefan, Nedea MI (Ilie), et al. The phenomenon of antiretroviral drug resistance in the context of human immunodeficiency virus treatment: dynamic and ever-evolving subject matter. Biomedicines. 2024;12(4):915. doi:10.3390/biomedicines12040915
4. Daoud O, Gladstein JE, Brixner D, O’Brochta S, Naik S. Health disparities in HIV care and strategies for improving equitable access to care. Am J Manag Care. 2025;31(1 Suppl):S3 S12. doi:10.37765/ajmc.2025.89687
5. Murdock NA, Alajaji NE, Schaefer R, et al. Long-acting HIV treatments: study design, logistics, and access. Open Forum Infect Dis. 2024;11(7):ofae337. doi:10.1093/ofid/ofae337
6. Xu S, Zhan P. Twice yearly lenacapavir demonstrated exceptional efficacy for HIV prevention. The Innovation. 2024;5(5). doi:10.1016/j.xinn.2024.100683
7. Maggi P, De Socio GV, Menzaghi B, et al. Growing old with antiretroviral therapy or elderly people in antiretroviral therapy: two different profiles of comorbidity? BMC Infect Dis. 2022;22(1):745. doi:10.1186/s12879-022-07739-y
8. Prakoeswa FRS, Maharani F, Bestari RS, et al. Aging and HIV: recent findings in contributing factors. AIDS Res Treat. 2025;2025(1):8814760. doi:10.1155/arat/8814760
9. Borrajo A. Breaking barriers to an HIV 1 cure: innovations in gene editing, immune modulation, and reservoir eradication. Life. 2025;15(2):276. doi:10.3390/life15020276
10. Clees J, Basic M, Cruz P, Ramirez S, Andrews AM. In pursuit of an HIV cure: from stem cell transplants to gene therapies. Front Genome Ed. 2025;7. doi:10.3389/fgeed.2025.1634193
11. Schwartz SR, Rao A, Rucinski KB, et al. HIV related implementation research for key populations: designing for individuals, evaluating across populations, and integrating context. J Acquir Immune Defic Syndr. 2019;82(Suppl 3):S206 S216. doi:10.1097/QAI.0000000000002191
12. Phelan M. The road to lenacapavir, a breakthrough HIV treatment. Science. 2025;388(6750):989 991. doi:10.1126/science.adz2598
13. PURPOSE Studies. PURPOSE Studies. Accessed October 14, 2025. https://www.purposestudies.com/