Kersten Kurt Koelsch, MD, director of Medical & Scientific Affairs, Immunology and Infectious Diseases for ICON.

Kersten Kurt Koelsch, MD

Antiretroviral therapy (ART) has transformed HIV from a death sentence into a chronic condition. Yet, this success has revealed a new problem: As people with HIV live longer, they face rising rates of comorbid health concerns. These are challenges that ART, alone, cannot solve.

ART’s mechanism of action prevents progression of HIV infection to acquired immunodeficiency syndrome (AIDS) by suppressing HIV replication and viral transmission. However, it does not restore dysregulated immune function or reintroduce healthy immune cells, which are depleted over the course of infection. As a consequence, many individuals living with managed HIV infections also live with damaged immune systems and chronic inflammation, making them more vulnerable to infections, cancers, autoimmune diseases, neurocognitive disorders, and inflammation-driven disorders. Long-term use of ART itself may also increase the risk of comorbidities

While the focus of HIV therapeutic development remains on advancing ART-based medicines, developers are increasingly called to design therapies and care models that account for multimorbidity and the unique physiological needs of older adults with HIV. This article examines the shifting clinical profile of aging with HIV, the research gaps affecting this population, and the implications for drug development.

Patients Aging With HIV Face High Comorbidity Risk

Comorbidities, including many age-related conditions, are widespread among aging people with HIV. In one study, approximately 71% of patients with HIV developed at least one comorbidity after age 50, with a median of 3 comorbidities for patients older than 75.

Another study comparing people with HIV to the general population found HIV-positive individuals were twice as likely to develop cardiovascular disease.

A recent review of medical records in Malawi revealed that the dementia rate among HIV-positive individuals was 22%, compared with 10% among HIV-negative individuals.



However, among HIV-positive populations, levels of immune dysfunction are highly heterogeneous, depending on a confluence of factors that are difficult to disentangle and understand. These include the stage of an individual’s disease at which ART was initiated, and whether that person maintained an effective ART regimen over time. Other factors include whether ART-based HIV treatment fully protects the immune system from dysregulation, and whether long-term treatment with ART itself increases the risk of comorbidities.

Researchers previously theorized that starting ART soon after HIV infection would be protective against permanent immune system damage. However, growing evidence now suggests that even with immediate treatment, ART may not fully prevent long-term immune dysfunction in some populations.

 Even suppressed HIV infections can promote chronic, systemic inflammation, increasing susceptibility to age-related comorbidities such as cardiovascular disease, cancer, diabetes, and dementia.

Furthermore, some research suggests the long-term use of some formulations of ART may increase the risk of comorbidities. Specifically, protease inhibitors and antiretroviral drugs commonly used in the early 2000s negatively impact renal function. Newer formulations have been developed to address this toxicity, but older formulations continue to be used in some cases.

 This is a significant concern since, as people with HIV age, they are often prescribed multiple drugs to address comorbidities, increasing the risk of drug interactions that can damage the kidneys.

Together, these factors mean that the risk of comorbidity in people living with HIV is high, particularly as the population continues to age. However, most comorbidity care models were not designed with HIV patients in mind, leaving a great unmet need for drug developers to fill.

Many clinical trials explicitly exclude people with HIV from participation, even in well-controlled cases. This likely stems from expectations of poor outcomes in people with HIV, assumptions formed before the development of effective HIV treatments. While there may be some cases in which such criteria are scientifically justified, de facto exclusion does not reflect the current reality of HIV as a manageable chronic condition and leads to a deficiency of critical safety and efficacy information.

For example, early COVID-19 vaccine research excluded people with HIV. A meta-analysis later suggested that the vaccine was safe, but the initial dose elicited lower immunogenicity and antigenicity in HIV-positive recipients than in HIV-negative individuals, while a booster dose was comparatively more protective.

 This highlights the importance of including people with HIV in clinical trials to inform treatment decisions.

The lack of research specifically evaluating people with HIV during clinical development is especially egregious in the study of chronic conditions and comorbidities for which this population makes up a significant demographic. And, because of the possibility for HIV-specific responses to therapies or drug-drug interactions, there is a stark need to establish treatments and care models for patients who have both HIV and comorbidities. This might mean increased screening, differences in the type of treatment or its administration.

An excellent illustration of the potential value of comorbidity research that includes people with HIV is in the use of statin therapies, which are typically used to reduce the risk of major adverse cardiovascular events (MACE), such as stroke or heart attack, by lowering low-density lipoprotein cholesterol. Although HIV-positive populations are at higher risk for MACE, one study found that statins reduced MACE in this group even more than would be expected from cholesterol lowering alone.

 These results led to exploring the interaction of statin therapy with collagen pathways to stabilize atherosclerotic plaques, a novel pathway with the potential to inform treatment and targeted therapies to protect cardiovascular health in people aging with HIV.

Less progress has been made in finding adjunctive therapies for ART that restore immune function. Such solutions would be very welcome, not only to address comorbidities for aging populations with HIV, but also to prevent them. For instance, researchers are beginning to explore therapeutic strategies to prevent chronic inflammation in HIV-positive populations. One promising avenue is GLP-1 therapies, such as semaglutide, which studies suggest may have a positive effect on inflammation markers in people with HIV. These drugs have already been proven to reduce inflammation among other populations, in part by modulation of inflammatory pathways and metabolic processes, and new evidence shows similar effects in individuals with HIV.

Including people with HIV in clinical research

Gaps in research and care for people with HIV are pronounced, but they also present an opportunity for drug developers to make a meaningful impact. Inclusion in clinical trials will aid in establishing standards of care for the health conditions faced by an aging population with HIV and contribute to the generalizability of studies.

To achieve this, clinical trials should prioritize the enrolment of patients with HIV. An important first step would be to create HIV-specific eligibility criteria relevant to the study in question. These criteria might include thresholds for CD4+ T cell count, reflecting the relative health of a patient’s immune system; a minimal or undetectable viral load, reflective of effective viral suppression; and overall clinical stability on ART, confirming that the patient has consistent access to a therapeutic regimen that will not have unexpected effects. Considering such factors would ensure that therapies are evaluated objectively for their potential response in people with HIV rather than relying on outdated assumptions, while also establishing clear guidelines for participation.

Trial designs should also account for how ART will interact with the investigational therapy and establish procedures accordingly. While concurrent treatment with ART is often recommended in non-HIV trials, it may sometimes be necessary to temporarily interrupt treatment under certain circumstances. For example, continuing ART could compromise the full intended dose of an oncology therapy or complicate toxicity management.

 In these cases, participants may switch to an alternative ART regimen while receiving investigational treatment, if one is available that minimizes negative interactions.

Continuing to improve HIV care for aging populations

As ART has transformed the outlook for people aging with HIV, it must also transform our approach to health care as this population develops comorbidities. Achieving this will require rethinking long-standing approaches to clinical trials and delivering highly interdisciplinary care that, as in the management of other chronic conditions, moves beyond siloed medicine.

Meaningful progress in HIV care will require addressing not just the virus itself, but also its impact on every aspect of health. This integrated approach is essential for developing the next generation of therapies and care models that meet the needs of aging people with HIV.

Kim J, et al. Aging with HIV: the burden of comorbidities, polypharmacy, and drug interactions in Korean people living with HIV aged ≥50 years. 

 2024;56(4):534-543. doi:10.3947/ic.2024.0132

Kawai K, et al. Viral infections and risk of cardiovascular disease: systematic review and meta-analysis. 

 2025;14(21):e042670. doi:10.1161/JAHA.125.042670

Lee H, et al. Dementia prevalence and risk factors in people with and without HIV in Malawi: a medical record review. 

 2025;21(3):e70009. doi:10.1002/alz.70009

Vlaming KE, et al. Treatment in acute HIV infection only temporarily preserves monocyte function: a comparative cohort study in adult males. 

 2025;122:105997. doi:10.1016/j.ebiom.2025.105997

Kong K, et al. AIDS patients suffer higher risk of advanced knee osteoarthritis progression due to lopinavir-induced Zmpste24 inhibition. 

 2025;13(1):58. doi:10.1038/s41413-025-00431-2

Livesay C, et al. Clinical considerations on the use of antiretrovirals and renal impairment. 

 2025;21(9):1059-1070. doi:10.1080/17425255.2025.2538885

Zhao T, et al. Immunogenicity and safety of COVID-19 vaccines among people living with HIV: a systematic review and meta-analysis. 

 2023;151:e176. doi:10.1017/S095026882300153X

Kolossváry M, et al. Pitavastatin, procollagen pathways, and plaque stabilization in patients with HIV: a secondary analysis of the REPRIEVE randomized clinical trial. 

 2025;10(3):254. doi:10.1001/jamacardio.2024.4115

Funderburg NT, et al. The effects of semaglutide on inflammation and immune activation in HIV-associated lipohypertrophy. 

 2025;12(4):ofaf152. doi:10.1093/ofid/ofaf152

Uldrick TS, et al. Modernizing clinical trial eligibility criteria: recommendations of the American Society of Clinical Oncology–Friends of Cancer Research HIV Working Group. 

 2017;35(33):3774-3780. doi:10.1200/JCO.2017.73.7338

Articles

As people with HIV live longer due to ART, new challenges are emerging. Aging with HIV is linked to higher risks of comorbidities, chronic inflammation, and drug interactions, while gaps in clinical trial inclusion and care models highlight the need for more integrated, patient-centered treatment strategies.

Aging with HIV: What the Next Major Challenge Is for Drug Development

DNA structure and HIV-infected, blue background

(Adobe Stock 149600914 by Giovanni Cancemi)

For decades, oral regimens of antiretroviral therapy (ART) have served as the bedrock of HIV prevention and treatment, transforming a once-fatal diagnosis into a chronic, manageable condition. The recent emergence of long-acting injectables represents a pivotal advancement in therapeutic delivery. Compared with daily oral ART regimens, generally offered in 90-day prescriptions, long-acting injectables reduce the number of required clinic visits for patients and eliminate the need for an at-home adherence regimen.

These advantages are particularly meaningful for populations in which daily pill taking is especially burdensome or logistically complex.

However, while long-acting injectables have the potential to revolutionize the logistics of HIV management, they have not overcome ART’s inherent mechanistic limitations. Like oral regimens, injectables merely suppress viral replication without eliminating latent reservoirs. Consequently, they do not offer a permanent cure or protective immunity. Because the antiviral mechanism remains contingent upon maintaining therapeutic drug levels at all times, both prevention and treatment still necessitate strict lifelong access and adherence to care. For high-risk populations in low-resource settings, this creates a persistent vulnerability: Any interruption in the clinical supply chain can trigger surges in new infections and the emergence of drug-resistant strains.

Regardless of the delivery method, viral suppression alone cannot fully restore immune function, especially if ART is initiated later in disease progression. A complex interplay of chronic inflammation, suppressed immune function, therapy-related toxicities, and social determinants of health elevates the risk of comorbidities, including cancer, cardiometabolic disease, and neurocognitive disorder, in people who age with HIV.

From Viral Suppression to Immune-Mediated Protection



To move beyond indefinite disease management, therapeutic developers must look to alternative therapeutic mechanisms that help the immune system eliminate and recover from HIV infection.

A universally effective prophylactic vaccine has long been the focus of these efforts, because such a vaccine could offer broad, population-wide protection from HIV.

However, attempts to develop such a vaccine have been thwarted by HIV’s exceptional immune-evasion tactics. Unlike other viruses for which vaccines exist, there are no cases of natural sterilizing immunity to HIV, in which the immune system eradicates an HIV infection. Instead, a successful HIV vaccine must engineer the immune system to do what it normally cannot achieve on its own.

While a vaccine remains elusive, decades of investment in vaccine development have helped researchers better understand what an effective immune response could look like and how therapeutic strategies could help achieve it.

Supporting the Production of Broadly Effective Antibodies



One promising mechanism for the prevention and treatment of HIV is assisting the production of antibodies that are broadly effective against genetically diverse strains of HIV. Antibodies against HIV can target only one protein, which encapsulates the virus. But the exposed regions of this protein mutate very rapidly. Consequently, the virus can change to escape most antibodies produced by the immune system. 

Meanwhile, conserved regions of this protein generally evade immune detection because they are cloaked in a thick layer of host-derived sugars, known as the glycan shield. Natural safeguards against autoimmunity frequently eliminate the B-cell lineages that could eventually mature to produce broadly neutralizing antibodies (bnAbs).

 Occasionally, functional bnAbs do develop in people with HIV, but only after years of chronic infection. These edge cases offer a potential path to prevention or even cure, if therapeutic developers can determine how to reliably guide the adaptive immune system to rapidly mature these rare lineages of bnAb-producing B cells.

One such approach, which has demonstrated early proof of concept, involves stepwise vaccination. First, mRNA delivery platforms deliver "germline-targeting" immunogens, which activate specific, rare precursor B cells. After the first shot initiates the desired immune response, a booster guides the immune system toward bnAb production.

 Alternative methods of introducing bnAbs include direct infusion of long-acting bnAb therapy and gene-editing approaches to induce bnAb production.

Following infection, HIV establishes latent reservoirs of infected cells that are immunologically invisible. This raises the bar even higher for a prophylactic vaccine that prevents HIV acquisition, because such a vaccine must completely prevent HIV from infecting cells. However, therapeutic vaccines, in combination with therapies that “flush out” these reservoirs, offer a possible pathway towards treatment-free remission or cure.

Latency-reversing agents (LRAs) currently in development are designed to “shock” latent viruses into transcriptional activity, making infected cells susceptible to immune system targeting. One class of LRAs is chromatin remodelers. Chromatin structure helps suppress HIV gene expression in latently infected cells, and therapeutically altering chromatin-remodelling complexes can promote reactivation.

Following the initial shock, HIV can then be treated with traditional ART and emerging immune-mediated mechanisms, including therapeutic vaccines and direct infusion of bnAbs.Multiple clinical trials incorporating different combinations of vaccines, ART, LRAs, and bNAbs are in the pipeline, but as of this writing, the trials remain ongoing.

Newborns at risk of acquiring HIV at childbirth or during breastfeeding may be especially good candidates for ART alternatives that offer sustained immune protection or remission, because the at-risk population is well defined and the value of avoiding life-long ART dependence is clear. Additionally, unique qualities of the pediatric immune system may make children better able to mount a durable HIV response.



Research in non-human primates suggests that inducing bnAb production may be most feasible in newborns, whose immune systems have unique qualities that may make them more tolerant of these B-cell lineages.

 Additionally, in rare cases, ART, in combination with the pediatric immune system, is able to achieve long-term remission.

Therefore, many of the ongoing trials focused on inducing immunity against HIV are focused on children. One ongoing AbVax trial with an estimated study completion in 2028 is investigating three different ARMs of combination treatment, including vaccines and bNAB infusion interspersed with treatment interruption.

Genetically Engineering Infection Resistance

An alternative to immune-mediated therapy is to achieve cellular resistance to infection. Documented cures using this method have involved stem cell transplants carrying a homozygous CCR5Δ32 genetic mutation. The genetic deletion renders cells resistant to some strains of HIV. When combined with immune reconstitution, a cell transplant carrying this mutation can result in the clearance of infected cells and the establishment of an HIV-resistant immune system. But the approach is limited to individuals with concurrent blood cancers and carries significant procedural risks.

More scalable alternatives in the future would likely involve gene editing. CRISPR/Cas9 and other platforms are being explored to disrupt HIV co-receptors, such as CCR5 and CXCR4, or to excise integrated proviral DNA directly from host genomes.

 to autologous CD4+ T cells or hematopoietic stem cells, which are then reinfused into the patient. Multiplex editing strategies that target multiple viral and host loci simultaneously are under investigation to reduce the risk of viral escape.

Despite promising preclinical data, significant challenges remain in achieving efficient delivery, minimizing off-target effects, and ensuring long-term engraftment and immune function.

Will Next-Generation Therapies Have a Real-World Impact?

In whatever form it takes, an HIV-1 vaccine will likely be the most complex vaccine ever designed, involving advanced modalities and multi-step vaccination. It may also require a combination with other therapies. This may limit the feasibility of population-wide vaccination for HIV control. Instead, a vaccine is more likely to provide an alternative to ART-based prevention and treatment for specific high-risk populations in need of other options.

But what would be the point of an HIV vaccine that doesn’t deliver population-wide protection from HIV? This question highlights a central tension between developing biologically advanced therapies that address ART’s mechanistic limitations and investing in approaches that are feasible relative to existing standards of care.

First-generation therapies that achieve protective immunity or a cure may be ingenious but inaccessible, requiring further adaptation to become cost-effective, scalable, and deployable in low-resource settings. The recent success of long-acting injectables for prophylaxis and for treatment further raises the bar for therapeutic developers, who should carefully identify populations most underserved by ART-based interventions and determine whether a novel therapeutic approach could better attain improved outcomes for these populations.

Even as therapeutic developers reckon with the real-world value of ART alternatives, it’s important to recognize what has been achieved by research that was initially unclear in value. More than 40 years ago, HIV was a near-certain death sentence. Now, it is a manageable and preventable chronic condition. Incremental but profound victories paved the way to this success. Some of these victories failed to produce an HIV vaccine but provided insight into the human immune system that advanced other fields of medicine. Today, therapeutic developers have made progress towards a future where HIV is curable, but the finish line remains an incalculable distance away. Continuing to make meaningful advances in HIV therapeutic development will require ongoing interrogation of novel alternatives to ART-based therapies that push the boundaries of what is possible.

Łupina K, Nowak K, Lorek D, et al. Pharmacological advances in HIV treatment: from ART to long-acting injectable therapies. 

. 2025;170(9):195. doi:10.1007/s00705-025-06381-8

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. 

. 2024;12(4):915. doi:10.3390/biomedicines12040915

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? 

. 2022;22(1):745. doi:10.1186/s12879-022-07739-y

Prakoeswa FRS, Maharani F, Bestari RS, et al. Aging and HIV: recent findings in contributing factors. 

. 2025;2025(1):8814760. doi:10.1155/arat/8814760

Boomgarden AC, Upadhyay C. Progress and Challenges in HIV-1 Vaccine Research: A Comprehensive Overview. Vaccines. 2025;13(2):148. doi:10.3390/vaccines13020148

Shim I, Rogowski L, Venketaraman V. Progress and Recent Developments in HIV Vaccine Research. Vaccines (Basel). 2025;13(7):690. Published 2025 Jun 26. doi:10.3390/vaccines13070690

Liao, Y., Wen, Z., Shi, M., Zou, H., & Sun, C. (2025). Biomedical Interventions for HIV Prevention and Control: Beyond Vaccination. Viruses, 17(6), 756. 

Willis JR, Prabhakaran M, Muthui M, et al. Vaccination with mRNA-encoded nanoparticles drives early maturation of HIV bnAb precursors in humans. 

Borrajo A. Breaking Barriers to an HIV-1 Cure: Innovations in Gene Editing, Immune Modulation, and Reservoir Eradication. 

. 2025;15(2):276. doi:10.3390/life15020276

Nel C, Frater J. Enhancing broadly neutralising antibody suppression of HIV by immune modulation and vaccination. 

. 2024;15:1478703. doi:10.3389/fimmu.2024.1478703

Persaud D, Coletti A, Nelson BS, et al. ART-free HIV-1 remission in children with in-utero HIV-1 after very early ART (IMPAACT P1115): a multicentre, open-label, phase 1/2 proof-of-concept study. 

. 2025;12(11):e743-e752. doi:10.1016/S2352-3018(25)00189-4

Ardeshir, A., O’Hagan, D., Mehta, I. et al. Determinants of successful AAV-vectored delivery of HIV-1 bNAbs in early life. Nature 645, 1020–1028 (2025). doi:10.1038/s41586-025-09330-2

University of Oxford. Combination Vaccination and Broadly Neutralising Antibody Therapy in HIV (AbVax). 

https://clinicaltrials.gov/study/NCT07054931

Clees J, Basic M, Cruz P, Ramirez S, Andrews AM. In Pursuit of an HIV Cure: from Stem Cell Transplants to Gene Therapies. 

ICON plc. Investing in Anti-HIV: How HIV Therapeutic Developers Can Reshape the Future of HIV Control. 2025. Accessed November 12, 2025. 

https://www.iconplc.com/insights/therapeutics/infectious-diseases/hiv

Long-acting injectables have transformed HIV management, but viral suppression alone is not enough. Researchers are advancing mRNA vaccines, broadly neutralizing antibodies, latency-reversing agents, pediatric immune strategies, and gene editing to eliminate reservoirs and achieve remission. Here’s how next-generation HIV therapeutics aim to move beyond lifelong ART.

Beyond Viral Suppression: Next-Generation HIV Therapeutics Target Reservoirs, Broadly Neutralizing Antibodies, and Gene Editing

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.

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.

 Moreover, ART does not cure HIV infection or fully restore immune function in advanced disease, and it carries a lifelong risk of medication resistance.

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.

 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.

 This means that the most impactful pharmacologic interventions will come from therapeutic developers who:

Understand the many converging challenges faced by people at risk of HIV and AIDS

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, 

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.

 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.

 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.

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.



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.

 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.

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.

 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.

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.

 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.

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.

 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.

 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.

Achieving meaningful diversity in trial populations and designing trials that account for population-specific constraints requires authentic partnerships with affected communities.

 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.

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.

 2025;170(9):195. doi:10.1007/s00705-025-06381-8

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. 

 2024;12(4):915. doi:10.3390/biomedicines12040915

Daoud O, Gladstein JE, Brixner D, O’Brochta S, Naik S. Health disparities in HIV care and strategies for improving equitable access to care. 

 2025;31(1 Suppl):S3 S12. doi:10.37765/ajmc.2025.89687

Murdock NA, Alajaji NE, Schaefer R, et al. Long-acting HIV treatments: study design, logistics, and access. 

 2024;11(7):ofae337. doi:10.1093/ofid/ofae337

Xu S, Zhan P. Twice yearly lenacapavir demonstrated exceptional efficacy for HIV prevention. 

 2024;5(5). doi:10.1016/j.xinn.2024.100683

 2022;22(1):745. doi:10.1186/s12879-022-07739-y

 2025;2025(1):8814760. doi:10.1155/arat/8814760

Borrajo A. Breaking barriers to an HIV 1 cure: innovations in gene editing, immune modulation, and reservoir eradication. 

 2025;15(2):276. doi:10.3390/life15020276

Clees J, Basic M, Cruz P, Ramirez S, Andrews AM. In pursuit of an HIV cure: from stem cell transplants to gene therapies. 

Schwartz SR, Rao A, Rucinski KB, et al. HIV related implementation research for key populations: designing for individuals, evaluating across populations, and integrating context. 

 2019;82(Suppl 3):S206 S216. doi:10.1097/QAI.0000000000002191

Phelan M. The road to lenacapavir, a breakthrough HIV treatment. 

 2025;388(6750):989 991. doi:10.1126/science.adz2598

PURPOSE Studies. PURPOSE Studies. Accessed October 14, 2025. 

Despite decades of progress transforming HIV from a fatal diagnosis into a manageable chronic condition, today’s antiretroviral therapies still face a stubborn barrier: They work brilliantly in theory but fall short when access, adherence, and real-world challenges get in the way. As long-acting injectables emerge and curative research accelerates, developers are being pushed to design interventions that perform not just in controlled trials, but in the complex realities of the communities most affected by HIV.

Kersten Kurt Koelsch, MD

Articles

Aging with HIV: What the Next Major Challenge Is for Drug Development

Beyond Viral Suppression: Next-Generation HIV Therapeutics Target Reservoirs, Broadly Neutralizing Antibodies, and Gene Editing

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