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

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 75.¹

Another study comparing people with HIV to the general population found HIV-positive individuals were twice as likely to develop cardiovascular disease.² 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.³

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.⁴ 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.^5,6 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.

Unmet research needs for people with HIV

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.⁷ 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.⁸ 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.⁹

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.¹⁰ 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.

References

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