Metabolic Fingerprints Predict Early Arterial Damage in HIV

Could a simple blood test be used to spot people at risk of developing heart disease by leaving a unique metabolic fingerprint? Research into potential early artery damage in HIV positive people as they age is intensifying in the face of rising risk. While much of this work is still in its infancy and little translated in to real world practice, consideration needs to be given to test accuracy as well as the pathways, cost and indeed affordability and equity of access.

Why It Matters

People living with HIV have an elevated risk of developing cardiovascular disease. This risk appears to be independent of the level of HIV control and immunorecovery. Several of the established risk factors for cardiovascular disease such as smoking, hypertension, diabetes, hypercholesterolemia are more prevalent in HIV-positive individuals compared to the general population. Yet additional HIV-related factors contribute to arterial aging, stiffening and atherosclerosis. Many individuals living with HIV develop heart disease at an early age, experiencing their first myocardial infarction or stroke by the age of 50. Carotid disease can be present even before the patient shows signs or symptoms of disease. The degree of arterial disease may even exceed the disease risk of several established cardiovascular risk factors.

The clinical problem presented by focal lesions visible on radiographs between 6 and 18 months before the onset of clinical symptoms is vastly overshadowed by the problem of the changes which have occurred to the artery over the previous years of injury and damage. These changes do not occur in a short period of time. They occur by print over years and even decades. It is these early biological changes that the clinician can potentially identify by metabolic fingerprints and intervene in a period of prevention when such intervention is most effective. It is far easier to prevent the damage to the arterial wall than it is to reverse the established damage.

A blood-based metabolic signature may complement currently available clinical risk calculators that, possibly, underestimate the risk of CVD in HIV infection. Current CVD risk calculators were derived in general population cohorts and may not capture all of the HIV-specific factors that confer risk of CVD including chronic inflammation, immune activation and dysregulation and the direct and indirect effects of ART on metabolism. A validated biomarker panel for CVD could help address these gaps in knowledge and enable identification of individuals at greater risk of CVD earlier in HIV disease for intensified lifestyle and aggressive management of BP and lipids as well as consideration of alternative therapies to reduce vascular disease risk in the long term.

The potential benefit of earlier risk assessment for dental caries is that care and prevention strategies could become more proactive. However, clinicians and patients need to know what to do with a biomarker test result indicating “high risk” of dental caries. In other words, they need to know the risk of caries indicated by the test result and what steps they should take to prevent caries. Systems of care need to establish the boundaries between a biomarker test result and actions, and define how biomarker test results will be used in risk management decisions and what additional steps clinicians and patients will take as a result of the test results. The biomarker result could be seen as adding a new dimension to the existing risk management process or as a trigger to more intense caries prevention.

The discussions at the meeting also highlighted important issues at the systems level, such as who will pay for these biomarkers and how will they be integrated into clinical and prevention settings that may be under-resourced or even understaffed. Depending on the site, these tests might only be available in well-funded centers such as university-based academic medical centers, potentially widening the gap between what is needed for optimal cardiovascular prevention and what is available for HIV prevention for clinics that serve both populations. Payers will also play a significant role in determining which patients have access to these tests, potentially limiting use to patients who already have good access to care, undermining efforts to improve equity in HIV health services. A tool for prevention that is most effective when integrated into routine clinical care could thus only benefit patients who already have good access to the health care system.

Why Metabolism Matters in HIV Vascular Risk

We believe a metabolic fingerprint is important because HIV and some of its treatments have a number of effects on the lipids, glucose metabolism, fat distribution and levels of inflammation. Many of these changes are known to affect the risk of arterial disease over time. Importantly, even when viral load is suppressed, there are low levels of ongoing inflammation. We believe that the effects of HIV and its treatment on inflammation, cholesterol metabolism and vascular function can be detected by metabolomics-derived signals earlier than conventional clinical biochemistry tests. A metabolic fingerprint provides a roadmap of the trajectory of metabolic changes in HIV infection, and allows monitoring of changes in cholesterol, glucose etc. over time.

While many health care providers are familiar with the term silent hypertension, what may be a surprise to some is that silent arterial damage is an under-recognized and widespread health threat. By the age of forty-five, approximately one out of three middle-aged men and half of middle-aged women have developed high blood pressure that has beenundiagnosed until serious damage has occurred to their arteries. The health

Silent arterial injury is a blind spot in HIV care, because patients look and feel well, vitals are normal, and imaging is not typically performed unless there is clear risk for future events. Ultrasound, CT, and other imaging studies can identify plaque; however, widespread imaging is not currently realistic due to cost considerations. Thus, a blood-based screening test could be a more practical approach if accurate and cost-effective. The hope is that such a screening approach could enable early prevention interventions even with limited resources, but these would need to be reliable and effective.

Who It Affects

Screening for arterial stress could potentially bring benefits to the clinical management of people with HIV (PLHIV). As HIV patients age into the decades in which CVD becomes more common, whilst at the same time being on older ART and carrying chronic exposure to metabolic risk factors for which they may receive untreated levels of care, early detection of vascular injury by a simple blood test may allow for intense focus on CVD risk before symptoms or imaging have developed.

Clinicians from all disciplines (infectious disease, primary care, cardiology, lipid) will be involved in the metabolic care of the HIV-positive patient. HIV care teams are already managing complex therapeutic regimens, managing a variety of common and uncommon opportunistic infections and comorbidities. The primary care physician will interpret the lipid and other biomarkers and make appropriate clinical decisions such as starting statin therapy or increasing antihypertensive therapy, referring the patient to a cardiologist, counselling the patient on smoking cessation and healthy nutritional behaviors.

Biomarkers don’t just get interpreted by clinicians. Their impact is felt by the budgets and work flows of health systems and payers as well as by the policies and the assays offered by laboratory networks. Should screening for these biomarkers become part of routine preventive care for all people living with HIV or should it be reserved for select high-risk individuals to prevent disease progression? These are the kinds of decisions that insurers and national health programs will face. Similarly, biomarkers will influence the considerations of policymakers and those responsible for developing clinical guidelines to integrate this testing into existing standards of HIV care while also trying to make the testing as accessible as possible.

What Changes

• Earlier identification of vascular risk: A validated metabolic fingerprint could permit screening for arterial damage before it is visible on imaging, enabling preventive interventions sooner.
• New clinical pathways: Care teams will need protocols for interpreting biomarker results and deciding on treatments — balancing conventional risk-factor management (cholesterol, blood pressure, smoking cessation) with consideration of anti-inflammatory strategies and ART adjustments.
• Laboratory and reimbursement shifts: Health systems must invest in standardized testing platforms and negotiate coverage policies; without payer support, access could be limited and inequities magnified.
• Research and regulatory priorities: The field will require prospective validation, clinical trials of targeted therapies, and clear regulatory paths so that tests and treatments move from promising science to approved clinical tools.

Practical implications for care

Metabolic fingerprints may not serve as a diagnostic tool for clinicians but can be useful as prognostic markers. A positive test result will require a full cardiovascular risk assessment and shared decision making with the patient. Clinicians could potentially counsel patients on their level of risk to meet their metabolic targets more intensely; intensify BP and glucose control; and/or consider maximization of current lipid therapy with statins. In select cases, there may be a need to alter the patient’s antiretroviral medication (with input of the patient’s HIV specialist and other health care team members) if related metabolic effects are implicated.

For patients, a blood test that could indicate future risk of heart disease could be helpful or even distressing. Health-care professionals have a particular role and responsibility to ensure that patients are informed and understand their test results, the steps they can take to reduce their risk of developing heart disease and the evidence base for the test. Patients and professionals must then work together to decide on the best treatment and prevention options for that individual, taking into account the patient’s priorities, overall health needs, and the practical challenges of living with a long-term condition.

System-level trade-offs and challenges

Screening by metabolic fingerprint will come at a cost however, in the form of false positives leading to further testing and treatment and their attendant costs and side effects. Alternatively, there is the risk of false negatives, potentially blinding both patients and healthcare providers to the presence of HIV infection. Therefore, prior to implementation, assurance that the test(s) are accurate would be necessary, followed by confirmation of the assay’s reproducibility in other laboratories. In addition, for each assay, the rationale for choosing cutoffs would need to be established and tested in different populations (by age, sex, race and duration of HIV infection).

An additional cost consideration would pertain to the cascade of further visits and tests that could be necessary for patients found to have abnormal biomarker levels. Moreover, many of the current targets for cardiovascular disease management are based on medication whose cost could increase as a result of the use of new biomarker panels. An economic evaluation of the longer-term benefits of such tests, in terms of fewer heart attacks and hospitalisations, in addition to the initial cost of the test itself, would be needed. Payers might be reluctant to provide universal reimbursement without such evidence, leaving the test to be paid for by the well-insured.

Equity and access

Introducing screening for pre-ART HIV may potentially introduce new health disparities. A screening strategy for pre-ART HIV must, therefore, be designed with an equity focus. Decisions about tests and counseling will need to take into account the settings in which HIV care is provided (e.g. community clinics) and ways to address stigma. Access to screening must not be restricted by restrictive payer policies. Training and support of frontline providers in low resource settings will be essential.

What comes next

Metabolic fingerprints of HIV infection are far from being ready for clinical application. Firstly, the identified blood markers of arterial damage and cardiovascular risk prediction need to be validated in other HIV patient cohorts. Secondly, interventional clinical trials have to be performed to study the effect of potential interventions suggested by the different markers of HIV-associated metabolic disturbances (e.g. anti-inflammatory treatments, lipid-lowering medication and optimisation of antiretroviral therapy) on the risk of myocardial infarctions and strokes.

Clearance/endorsement by regulatory bodies/guideline committees will be primarily supported by accumulating evidence, but at the same time, separate efforts will be needed to standardize the laboratory testing methods and quality control materials, as well as to incorporate test results into the EHR for decision support and population health management. Additional efforts will be required to interface with payers and conduct health economic studies to demonstrate value and support reimbursement and widespread adoption.

Bottom line

Metabolic fingerprints of arterial damage could be used to monitor for early damage in individuals with HIV and focus treatment and intervention on those most at risk of disease rather than treating advanced damage in late stages of HIV disease. Further validation and standardization of the technique and a reduction in cost are required followed by consideration of equitable access. Ultimately, decisions by clinicians about the pathway of care for individuals with HIV, by health systems about where to invest and by policymakers about how to regulate the application of this technology will determine whether or not this molecular read-out translates into tangible benefit to individuals with HIV.

References:

https://pmc.ncbi.nlm.nih.gov/articles/PMC13002097/